EA042342B1 - AMINOPYRROLOTRIAZINES AS KINASE INHIBITORS - Google Patents

Description

Field of invention

The present invention relates to novel compounds that inhibit receptor-interacting protein kinases, as well as methods for their preparation and use. More specifically, the present invention relates to aminopyrrolotriazines as receptor-interacting protein kinase 1 (RIPK1) inhibitors.

State of the art invention

Apoptosis and necrosis are two different mechanisms of cell death. Apoptosis is a highly regulated process involving caspases, a family of cysteine proteases, and is characterized by cell size reduction, chromatin condensation, and DNA degradation. In contrast, necrosis is associated with swelling of cells and organelles and an increase in plasma membrane permeability, followed by release of intracellular contents and secondary inflammation (Kroemer et al. (2009) Cell Death Differ 16:3-11). Necrosis is considered a passive, unregulated form of cell death; however, recent data indicate that some degree of necrosis may be induced by regulated signal transduction pathways, such as those mediated by receptor-interacting protein kinases (RIPKs), especially under conditions where caspases are inhibited or cannot be effectively activated (Golstein P & Kroemer G ( 2007) Trends Biochem Sci 32:37-43; Festjens et al (2006) Biochim Biophys Acta 1757:1371-1387). Stimulation of death receptors (DRs) of the Fas family and TNFR is known to mediate apoptosis in most cell types via an external caspase activation pathway. In addition, in some cells deficient in caspase-8 or treated with the pancaspase inhibitor Z-VAD, stimulation of death receptors (DR) induces receptor-interacting protein kinase 1 (RIPK1) dependent programmed necrotic cell death instead of apoptosis (Holler et al. (2000) Nat Immunol 1:489-495 Degterev et al (2008) Nat Chem Biol 4:313321). This new mechanism of cell death is called programmed necrosis or necroptosis (Degterev et al. (2005) Nat Chem Biol 1:112-119).

Necroptosis can be caused by a number of mechanisms, including TNF receptor activation, Toll-like receptor binding, genotoxic stress, and viral infection. Following from various influences, the signaling pathway that leads to necroptosis depends on the kinase activity of RIPK1 and RIPK3 (He et al. (2009) Cell 137:1100-1111; Cho et al., (2009) Cell 137:1112-1123; Zhang et al (2009) Science 325:332-336). Dysregulation of the necroptosis signaling pathway has been associated with inflammatory diseases such as macrophage necrosis in the development of atherosclerosis, virus-induced inflammation, systemic inflammatory response syndrome and ethanol-induced liver injury, neurodegeneration such as retinal detachment, ischemia, amyotrophic lateral sclerosis (ALS), non-alcoholic steatohepatitis (NASH) and Gaucher disease (Trichonas et al. (2010) Proc. Natl. Acad. Sci. 107, 21695-21700; Lin et al. (2013) Cell Rep. 3, 200-210; Cho et al. ( 2009) Cell, 137, 1112-1123; Duprez et al. (2011) Immunity 35, 908-918; Roychowdhury et al., Hepatology 57, 1773-1783; Vandenabeele et al. (2010) Nature 10, 700-714; Vandenabeele et al (2010) Sci Signalling 3, 1-8, Zhang et al (2010) Cellular & Mol Immunology 7, 243-249, Moriwaki et al (2013) Genes Dev 27, 1640-1649; Ito et al (2016) Science 353, 603-608 Vitner et al (2014) Nature Med 20, 204-208); Afonso, et al. (2015) Clinical Science 129, 721-739.

PCT application publications WO2016/064957 and WO2016/064958 describe aminopyrrolotriazines that are active as PI3K inhibitors. PI3K inhibitors should not be expected to be RIPK1 inhibitors.

A highly potent, selective, small molecule inhibitor of RIPK1 activity could block the RIPK1-dependent pro-inflammatory signaling pathway and thus provide therapeutic benefit in inflammatory diseases characterized by elevated and/or deregulated RIPK1 kinase activity.

Description of the invention

The present invention relates to novel aminopyrrolotriazines, including their stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts or solvates, which are useful as inhibitors of RIPK1.

The present invention also relates to methods and intermediates for the preparation of the compounds of the present invention.

The present invention also relates to pharmaceutical compositions containing a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or its stereoisomers, tautomers, isotopes, prodrugs, pharmaceutically acceptable salts, salts or solvates.

The compounds of the invention may be used to treat and/or prevent conditions associated with aberrant RIPK1 activity.

The compounds of the present invention may be used in therapy.

- 1 042342

The compounds of the present invention may be used in the manufacture of a medicament for the treatment and/or prevention of a condition associated with aberrant RIPK1 activity.

The compounds of the present invention may be directed to a method of treating diseases mediated at least in part by RIPK1, including inflammatory diseases, ischemia, neurodegeneration, NASH, and Gaucher's disease, which comprises administering to a patient in need of such treatment a compound of the present invention, as described above.

The compounds of the invention may be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one or two, other agent(s).

These and other features of the invention will be set forth in greater detail as the disclosure proceeds.

Detailed description of embodiments of the invention

In one aspect, the present invention relates, inter alia, to compounds of Formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs thereof,

where A is N or CR;

R is hydrogen, halogen, C _1-3 alkyl;

R ¹ is hydrogen, C _1-3 alkoxy-C _1-3 alkyl or C _2-3 hydroxyalkyl, C(O)-C _1-3 alkyl, C(O)C _1-3 haloalkyl;

R ² is hydrogen, halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 deutero-C _1-3 alkoxy, halo-C _1-3 alkoxy, amino, C _{1 -3} alkylamino, or C _1-3 dialkylamino;

R ³ R ⁴

R ⁵ 1) is hydrogen, halogen, C _1-3 alkyl;

is hydrogen, halogen, cyano, tetrazolyl, C _1-3 alkyl tetrazolyl;

represents:

hydrogen, halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, halo-C _1-3 alkoxy, C _1-3 hydroxyalkyl,

C _1-3 alkoxy-C _1-3 alkyl, amino-C _1-3 alkyl, C _1-3 alkylamino-C _1-3 alkyl, C _1-3 dialkylamino-C _1-3 alkyl, (C _1-3 alkyl -CONH)-C _1-3 alkyl, or (C _1-3 alkyl-SO ₂ NH)C _1-3 alkyl, -(CH ₂ ) _n -NH-OCH ₃ , C _3-6 cycloalkyl, methylphenyl-SO ₂ -O-; or _R ¹ °a

^R10b .

' or

2) or

^R11a

3)

4) ^R ' where L is methylene, -C(R ^5a ) ₂ -, amino, C _1-3 alkylamino, SO2 or O; or

O*v'

^R5c

O. UK

NH

5) or

6) -(CH ₂ ) _r -phenyl, -(CH ₂ ) _r - 4- to 10-membered heterocycle or -(CH ₂ ) _r - 4- to 10-membered heteroaryl, where these heterocycle and heteroaryl contain 1 , 2, 3 or 4 heteroatoms selected from N, O and S, and where any phenyl, heterocycle or heteroaryl may be substituted with 0-3 halogen, =O, C _1-3 alkyl or amino; or

R ^5a is independently hydrogen, halogen, C _1-3 haloalkyl;

R ^5c is independently selected from hydrogen, C _1-3 alkyl, C _1-3 cyanoalkyl-, C _1-3 hydroxyalkyl, C _1-3 (C _1-3 alkyl-CO) alkyl;

R ⁶ is hydrogen;

R ⁷ is:

-L ⁿ ~ ^r ”

1) ^{n 0} ; or

- 2 042342

2) or

3)

4)

5)

6)

’ or or ’ or ’ or uh

7)

B is absent or is CO, C(O)O, C(O)NR ^12a , SO ₂ or CR ^12a R ^12b ;

Z is CH ₂ or CF2;

R ^8a and R ^8b are each independently selected from hydrogen, halogen, C _1-3 alkyl and C _1-3 haloalkyl;

R ^8c is hydrogen or CH2-O-CH3 or CH ₂ -O-CH ₂ -phenyl;

^R9 is:

1) phenyl, naphthalenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolinyl, benzisoxazolyl, or benzthiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy, C _1-3 halo-C _1-3 alkoxy, and C _1-3 alkyl-SO ₂ ; or

2) thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, C _1-3 alkyl, C _1-3 phenylalkyl; or

3) dihydro-1H-indenyl, tetrahydro-5H-benzo[7]annulene, tetrahydronaphthalene, and 6,7-dihydro-5Hcyclopenta[b]pyridine, any of which are substituted with 1-3 groups selected from halo, C _1-3 alkylα;

or

4) C _1-6 alkyl, C _2-3 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl or C _1-3 halocycloalkyl, each optionally substituted with 1-3 groups selected from halo, NH2, -NHC(O)OC _1-6 alkylα, -N(CH ₃ )C(O)OC _1-6 alkyl, -C(O)-C _1-3 alkyl, hydroxyl, C _1-6 alkoxy, and C _1-6 haloalkyl, halo-C _1-3 alkoxy, phenyl, thiazolyl, pyridinyl, where phenyl, pyridinyl and thiazolyl are optionally substituted with 1-2 halogen, nitro, or C _1-6 haloalkyl; or

5) C _0-2 (C _3-7 cycloalkyl) alkyl, cyclohexenyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, pyridinonyl, or tetrahydrothiophenyl dioxide, each of which is optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl and C _1-3 haloalkyl, C _1-3 alkoxy, hydroxyl, C _1-3 haloalkyl, C _3-6 cycloalkyl, C(O)OC _1-6 αalkyl and amino;

6) tetrahydropyranyl optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl and phenyl;

7) C _1-4 alkylamino, C _1-4 dialkylamino;

R ^10a and R ^10b are independently selected from hydrogen, halogen, hydroxy, amino;

R ^11a and R ^11b are independently selected from hydrogen and C _1-6 alkyl;

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R ^12a and R ^12b are independently selected from hydrogen, deuterium, methyl;

R ¹⁵ is C ₁ . ₆ alkyl, C ₁ . ₃ haloalkyl, hydroxy-C ₁ . ₆ haloalkyl, C ₁ . ₃ (C ₃ . ₆ cycloalkyl)alkyl, phenyl-C ₁ . ₃ αkyl, phenyl-C ₁ . ₃ haloalkyl-, where phenyl is optionally substituted with 1-3 groups selected from halo, C ₁ . ₃ haloalkylα, halo-C ₁ . ₃ alkoxy;

R ^15a is hydrogen, halogen, or C ₁ . ₃ alkyl;

R ¹⁶ is hydrogen;

R ¹⁷ is:

1) _C1 . ₆ (phenyl)alkyl, where alkyl is optionally substituted with 1-3 groups selected from hydroxy, ═O, C ₁ . ₃ αlkoxy, and halo-C ₁ . ₃ alkyl, or halo-C ₁ . ₃ alkoxy, and wherein the phenyl is optionally substituted with 1-3 groups selected from halo, C ₁ . ₃ haloalkyl, halo-C ₁ . ₃ alkoxy and phenoxy;

2) C ₀ - ₆ (cyclopropyl)alkyl, where the alkyl is optionally substituted with 1-3 groups selected from hydroxy;

3) _C1 . ₃ (phenoxy)alkyl, C ₁ . ₃ ((phenyl)(C ₁ . ₃ αkyl)amino)alkyl, where phenoxy or phenyl is optionally substituted with 1-3 groups selected from C ₁ . ₃ alkyl;

4) _C1 . ₃ (pyrazinyl)alkyl, where the pyrazinyl is optionally substituted with 1-2 groups selected from halogen;

5) _C3 . ₇ cycloalkyl, where cycloalkyl is substituted with 0-3 OH, (-OCH ₂ C(CH ₃ ) ₂ CH ₂ O-), phenyl, which is substituted with 0-3 F, Cl, Br;

6) _C1 . ₃ (C ₁ . ₄ αlkoxy)alkyl;

R ¹⁹ is -CH ₂ -phenyl or -C(O)-NR ^19a R ^19b ;

R ^19a is hydrogen or C ₁ . ₃ alkyl;

R ^19b is hydrogen, C ₁ . ₆ αkyl, C ₃ . ₆ cycloalkyl-C ₀ . ₃ alkyl-, phenyl-C ₀ - ₃ alkyl-, each independently substituted with 0-3 halo, halo-C ₁ . ₃ α alkoxy;

R ²⁰ is H, -CH ₂ -phenyl, -CH(OH)-phenyl, -C(CH ₃ )(OH)-phenyl, where each of the phenyls is independently substituted with 0-1 F;

R ^20a is independently methyl or OH;

R ²¹ is phenyl, CO-C ₃ . ₆ cycloalkyl, any of which are substituted with 0-4 F;

R ²² is C ₀ . ₁ phenylalkyl, where phenyl is optionally substituted with 1-3 groups selected from halo, C ₁ . ₃ αkyl, C ₁ . ₃ haloalkylα, C ₁ . ₃ alkoxy;

and either R ¹ or R ¹⁸ are a represents a single or double bond; and b is a single or double bond;

with the proviso that when a is a single bond then b is a double bond and R ¹⁸ is absent, and when a is a double bond then b is a single bond and R ¹ is absent;

n is 0, 1, or 2;

m is 1 or 2; and r is 1.

In another aspect of the invention, a compound of formula I is provided, wherein A is N; R ¹ is hydrogen; R ² is C1.3αlkoxy; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is halo-C1. ₃ alkoxy; R ⁶ is hydrogen; a is a single bond, b is a double bond, and R ¹⁸ is absent, and R ^{7 is} pre

constitutes

In another aspect of the invention, a compound of formula I is provided, wherein A is N; R ¹ is hydrogen; R ² is C1.3αlkoxy; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is C1. ₃ haloalkoxy; R ⁶ is hydrogen; a is a single bond, b is a double bond, and R ¹⁸ is absent. In a different

aspect of the invention provides a compound of formula I, where R ⁷ represents

In another aspect of the invention, a compound of formula I is provided wherein R ⁷ is

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable

- 4 042342 salts, solvates or prodrugs, where R ⁵ represents 1) H or CF3; or or *

2)

^R10a

^R10b .

' or

^R11a

3)

R ^11b

R ^10a ' where L represents CH ₂ , -O-, CF2 or -CH(CF ₃ )-; or

4)

5)

^R10b . ' or

-(CH ₂ ) _r -phenyl, -(CH ₂ ) _g -pyrrolidinyl, -(CH ₂ ) _r -piperidinyl, -(CH ₂ ) _r -azetidinyl, azaspiroheptanyl, -(CH ₂ ) _r- benzimidazolyl, -(CH ₂ ) _r -azabiclooctane, -(CH ₂ ) _r -azaspirooctane,

-(CH2)r-(CH2)r-tetrazolyl, -( _CH2 ) _r -tetrahydroquinolinyl, -( _CH2 ) _r -pyrazolyl, -( _CH2 ) _r -imidazolyl, or -( _CH2 ) _r -triazolyl, any of which may be substituted with 0-3 halogen, C _1-3 alkyl or amino.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where

R ¹ is H;

R ² is H, F, CH ₃ or OCH ₃ ;

R ³ is H or F; And

R ⁴ is H.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where R ⁷ represents

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where

R ^8a is halogen;

R ^8b is hydrogen;

In absent, CO, C(O)O, C(O)NR ^12a , SO ₂ or CR ^12a R ^12b .

^R9 is:

1) phenyl, naphthalenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl quinolinyl, benzisoxazolyl, or benzthiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, cyano, C _1-3 alkyl, C _1-3 deuteroalkyl, C _{1 -3} haloalkyl, C _{1-3 phenylalkyl} , C _1-3 (phenyl)hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuteroalkoxy, C _1-3 haloalkoxy, and C _1-3 alkyl-SO ₂ ; or

2) thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, cyano, C _1-3 alkyl, C _1-3 deuteroalkyl, C _1-3 haloalkyl, C _{1-3 phenylalkyl} , C _1-3 (phenyl)hydroxyalkyl, C _1-3 alkoxy, C _1-3 deuteroalkoxy, C _1-3 haloalkoxy, and C _1-3 alkyl-SO ₂ -cyclopropyl; or

3) C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 deuteroalkyl, C _1-6 haloalkyl, C _1-6 alkoxyalkyl, C _3-6 cycloalkyl or C _1-6 halocycloalkyl, each optionally substituted with 1-3 groups selected from halo, NH2, -NC(O)OC _1-6 alkyl, -C(O)-C _1-6 alkyl, hydroxyl, C _1-6 alkoxy, and C _{1 -6} haloalkyl, C _1-6 haloalkoxy, phenyl, thiazolyl, pyridinyl, where phenyl, pyridinyl and thiazolyl are optionally substituted with 0-2 halogen, nitro, or C _1-6 haloalkyl; or

4) C _0-2 (C _3-7 cycloalkyl) alkyl, cyclohexenyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, pyridinonyl, or tetrahydrothiophenyl dioxide, each of which is optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl and C _1-3 haloalkyl, C _1-3 alkoxy, hydroxyl-C _1-3 haloalkyl, C _3-6 cycloalkyl, C(O)OC _1-6 alkyl, and amino;

5) tetrahydropyranyl optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl, C _1-3 haloalkyl; C _1-2 (C _1-3 alkoxy)alkyl, C _1-4 alkoxy, and phenyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where: B is CO, C(O)O, or SO2; and R ⁹ represents co

- 5 042342 fight

1) phenyl or pyridyl, each of which is optionally substituted with 1-3 halo; or

2) _C2 . ₆ alkyl, C ₂ . ₆ deuteroalkyl, C ₂ . ₆ haloalkyl, C ₂ . ₆ alkoxyalkyl, C ₃ . ₆ cycloalkyl or C ₁ . ₆ halocycloalkyl, each of which is optionally substituted with 1-3 groups selected from halogen, hydroxyl, and C ₁ . ₆ haloalkyl; or

3) _C1 . ₂ (C ₃ . ₆ cycloalkyl)alkyl which is optionally substituted with 1-4 groups selected from halo, hydroxy, C _1-3 alkylα and C ₁ . ₃ haloalkyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs wherein A is N.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs wherein A is CR and R is H or halo.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where R ¹ represents H;

R ² is H, F, CH3 or OCH3;

R ³ is H or F; And

R ⁴ is H.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where

1)

R ⁵ is H, CF3,

2)

3)

4)

where L represents CH2, -O-, CF2 or -CH(CF ₃ )-;

And

where L represents CH ₂ , -O-, CF ₂ or -CH(CF ₃ )-.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where R ⁵ is:

1) hydrogen, halogen, cyano, C ₁ . ₃ alkyl, C ₁ . ₃ deuteroalkyl, C ₁ . ₃ haloalkyl, C ₁ . ₃ haloalkoxy, C ₁ . ₃ hydroxyalkyl, C ₁ . ₃ alkoxyalkyl, aminoalkyl, C ₁ . ₃ alkylaminoalkyl, C1-3 dialkylaminoalkyl, amino, C ₁ . ₃ alkylamino, C ₁ . ₃ dialkylamino, (C ₁ . ₃ alkyl-CONH)-C ₁ . ₃ alkyl, (C ₁ . ₃ alkoxy-CONH)-C ₁ . ₃ alkyl, or (C ₁ . ₃ alkyl-SO ₂ NH)-C ₁ . ₃ alkyl, -(CH2) _n -NH-OCH ₃ , C ₃ . ₆ cycloalkyl, methylphenyl-SO ₂ -O-; or

2)

3)

where L is methylene, -C(R ^5a ) ₂ -, amino, C ₁ . ₃ alkylamino, SO2, or O;

or O * N o5c 4) ’ or

- 6 042342

5)

6) -(CH ₂ ) _g -phenyl, -(CH ₂ ) _r - 4- to 10-membered heterocycle or 4- to 10-membered heteroaryl, where the heterocycle and heteroaryl contain 1, 2, 3 or 4 heteroatoms, selected from N, O and S, and where any phenyl, heterocycle or heteroaryl may be substituted with 0-3 halogen, C _1-3 alkyl or amino.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs wherein R ^10a and R ^10b are independently selected from hydrogen, halogen, cyano, hydroxy, amino, C _1-3 alkylamino, C _1-3 dialkylamino, acetylamino, (amino)carbonyl, (C _{b 3} alkylamino)carbonyl, and (C _1-3 dialkylamino)carbonyl; and R ^11a and R ^11b are independently selected from hydrogen and alkyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where R ⁵ represents -(CH ₂ ) _r -phenyl, -(CH ₂ ) _g -pyrrolidinyl, (CH ₂ ) _r -piperidinyl, -(CH ₂ ) _r -azetidinyl, -(CH ₂ ) _r -azaspiroheptanyl, -(CH ₂ ) _r -benzimidazolyl, -(CH ₂ ) _r azabicyclooctane, -(CH ₂ ) _r -azaspirooctane, -(CH ₂ ) _r -tetrazolyl, -(CH ₂ ) _r -tetrahydroquinolinyl, -(CH ₂ ) _r pyrazolyl, -(CH ₂ ) _r -imidazolyl, or -(CH ₂ ) _r -triazolyl, any of which may be substituted with 0-3 halogen, C _1-3 alkyl or amino.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where

R ⁷ is

where R ¹⁵ is hydroxy-C _1-6 haloalkyl, phenyl-C _1-3 alkyl, or phenyl-C _1-3 haloalkyl-, where phenyl is optionally substituted with 1-3 groups selected from halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy and C _1-3 haloalkoxy; And

R ^15a is hydrogen, halogen or C _1-3 alkyl.

In another embodiment, a compound of formula (I), (II) is provided, or a compound as

described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where R ⁷ represents where R ¹⁵ represents hydroxy-C _{1 -6} haloalkyl, phenyl-C _1-3 alkyl, or phenyl-C _1-3 haloalkyl-, where phenyl is optionally substituted with 1-3 groups selected from halogen, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} alkoxy and C _1-3 haloalkoxy; And

R ^15a is hydrogen or C _1-3 alkyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts is provided. , solvates or prodrugs, where R ⁷ is

where R ¹⁵ is hydroxy-C _1-6 haloalkyl, phenyl-C _1-3 alkyl, or phenyl-C _1-3 haloalkyl-, where phenyl is optionally substituted with 1-3 groups selected from halo, C _1-3 alkyl, C _1-3 haloalkyl,

C _1-3 alkoxy and C _1-3 haloalkoxy; And

R ^15a is hydrogen or C _1-3 alkyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable

salts, solvates or prodrugs, where R ⁷ is

B is absent or is CO, C(O)O, C(O)NR ^12a , SO ₂ or CR ^12a R ^12b .

In another embodiment, a compound of formula (I), (II) is provided, or a compound as

- 7 042342 described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable ^R VR ⁹ * L / ^N ~ ^B salts, solvates or prodrugs, where R ⁷ represents ⁿ ' or alternatively os-

the existence of R ⁷ is a

' or in another embodiment, R ⁷ is represented In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where

R ^8a is H; R ^8b is F;

B is CO, C(O)O, or SO2, and

R ⁹ is phenyl or pyridyl optionally substituted with 1-3 halo;

or R ⁹ is C ₂ . ₆ alkyl, C ₂ . ₆ deuteroalkyl, C ₂ . ₆ haloalkyl, C ₂ . ₆ alkoxyalkyl, C ₃ . ₆ cycloalkyl or C1. ₆ halocycloalkyl optionally substituted with 1-3 groups selected from halo, hydroxyl and haloalkyl;

or R ⁹ is C ₁ . ₂ (C _{3 .6} cycloalkyl)alkyl optionally substituted with 1-4 groups selected from halo, hydroxy, C1. ₃ alkyl and C1. ₃ haloalkyl.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where either a is a single bond and b is a double bond, or a is a double bond and b is a single bond, ^HO /o—.

and R ¹ or R ¹⁸ is C1. ₃ hydroxyalkyl, C ₁ . ₃ (C ₁ . ₃ alkoxy) alkyl, ^o >

_HOV ° ^H

or ( _C1.3 alkoxy)alkyl.

' or where R ²³ represents C1. ₃ alkyl, C1. ₃ hydroxyalkyl or

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where the compound is selected from examples 1 to 541.

In another embodiment, a compound of formula (I), (II) or a compound as described in the first, second or third aspect or other embodiments described herein, or its stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs, where the compound is selected from examples 542 to 1848.

In another embodiment, a compound of formula (I) or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof is provided, wherein the compound is selected from the examples.

The present invention also relates to pharmaceutical compositions useful in the treatment of diseases associated with the modulation of kinase activity, including the modulation of receptor-interacting protein kinases such as RIPK1, containing compounds of formula (I) or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or diluents.

The invention also relates to methods for treating diseases associated with modulation of kinase activity, including modulation of receptor-interacting protein kinases such as RIPK1, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

The present invention also relates to processes and intermediates for the preparation of the compounds of the present invention, or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also relates to a method for the treatment of proliferative diseases, allergic diseases, autoimmune diseases and inflammatory diseases, comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or its stereoisomers, tautomers, pharmaceutically acceptable salts, solvates or prodrugs.

The present invention also relates to a method of treating a disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the disease is inflammatory bowel disease, Crohn's disease or ulcerative colitis, psoriasis, systemic lupus erythematosus (SLE) , rheumatoid arthritis, multiple sclerosis (MS), ischemia-reperfusion syndrome, non-alcoholic steatohepatitis (NASH), or transplant rejection.

The present invention also relates to a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the condition is selected from acute myelocytic leukemia, chronic myelocytic leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, ocular neovascularization and infantile hemangiomas, B-cell lymphoma, pancreatic cancer, pancreatic ductal adenocarcinoma, psoriatic arthritis, multiple vasculitis, idiopathic thrombocytopenic purpura (ITP), myasthenia gravis, allergic rhinitis, type I diabetes mellitus, membranous nephritis, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and heat agglutination diseases, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), sarcoidosis, Sjögren's syndrome, peripheral neuropathies, pemphigus ordinary and bronchial asthma.

The present invention also relates to a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the condition is selected from macrophage necrosis in the development of atherosclerosis, virus-induced inflammation, systemic inflammatory response syndrome, and ethanol-induced liver injury. , neurodegeneration such as retinal detachment, retinal degeneration, wet and dry age-related macular degeneration (AMD), ischemia, amyotrophic lateral sclerosis (ALS), and Gaucher disease.

The present invention also relates to a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the condition is selected from inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, rheumatoid arthritis (RA), non-alcoholic steatohepatitis (NASH) and heart failure. The present invention also relates to a method of treating a condition comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), wherein the condition is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, psoriasis, ischemia-reperfusion syndrome, cardiac insufficiency and non-alcoholic steatohepatitis (NASH). The present invention also relates to a method of treating rheumatoid arthritis comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I).

The present invention also relates to a method of treating a disease comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with other therapeutic agents.

The present invention also relates to the compounds of the present invention or their stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates or prodrugs for use in therapy.

In another embodiment, the compounds of formula (I) are selected from the illustrative examples or combinations of illustrative examples, or other embodiments provided herein.

In another embodiment, the IC ₅₀ value of the compounds of formula (I) in the RIPK1 assays described below is >200 nM.

In another embodiment, the IC ₅₀ value of the compounds of formula (I) in the RIPK1 assays described below is <200 nM.

In another embodiment, the IC ₅₀ value of the compounds of formula (I) in the RIPK1 assays described below is < 20 nM.

In another embodiment, the compounds of the present invention selectively inhibit RIPK1 over PI3K. In one embodiment, the selectivity is greater than 10x. In another embodiment, the selectivity is greater than 100x.

The present invention also contemplates the use of the compounds of the present invention, or stereoisomers, tautomers, isotopes, salts, pharmaceutically acceptable salts, solvates, or prodrugs thereof, for the manufacture of a medicament for the treatment of cancer, an allergic disease, an autoimmune disease, or an inflammatory disease.

- 9 042342

The present invention may be embodied in other specific forms without departing from its spirit or essential features. The present invention covers all combinations of preferred aspects and/or embodiments of the present invention mentioned herein. It should be understood that any and all embodiments of the present invention may be used in conjunction with any other embodiment or embodiments to describe additional embodiments. It should also be understood that each individual element of the embodiments is its own independent embodiment. In addition, any element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe a further embodiment.

The following are definitions of terms used in the present specification and the appended claims. The initial definition provided for a group or term in this specification applies to such group or term throughout the specification and claims alone or as part of another group, unless otherwise indicated. If any variable (eg, R ³ ) occurs more than once in any structural constituent or formula of a compound, its definition in each instance is independent of its definition in every other instance. Thus, for example, if a group is shown to be substituted with 0-2 R ³ , then said group may optionally be substituted with up to two R ³ groups, and R ³ in each case is independently selected from the definition of R ³ . Also, combinations of substituents and/or variables are allowed only if such combinations lead to the formation of stable compounds.

If a bond to a substituent is shown to cross a bond connecting two atoms in the ring, then that substituent may be bonded to any atom in the ring. When a substituent is indicated without designating the atom through which such substituent is bonded to the remainder of a compound of a given formula, then such substituent may be bonded through any atom in such substituent. Combinations of substituents and/or variables are allowed only if such combinations result in stable compounds.

In cases where nitrogen atoms (eg, amines) are present in the compounds of the present invention, they can be converted to N-oxides by treatment with an oxidizing agent (eg, MCPBA and/or hydrogen peroxide) to obtain other compounds of the present invention. Thus, all nitrogen atoms shown and claimed are considered to encompass both the shown nitrogen and its N-oxide (N^O) derivative.

Conventional convention used in the art is used in the structural formulas presented to depict a bond that is the point of attachment of a moiety or substituent to the core or backbone structure. In some substructures, * (asterisk) is used to indicate the point of attachment to the rest of the molecule.

A bar - that is not between two letters or symbols is used to indicate the attachment point of a substituent. For example, -CONH ₂ is attached via a carbon atom.

The term optionally substituted with respect to a particular moiety of a compound of formula (I) (eg, an optionally substituted heteroaryl group) refers to a moiety containing 0, 1, 2 or more substituents. For example, the term optionally substituted alkyl encompasses both alkyl and substituted alkyl as defined below. One of ordinary skill in the art will appreciate, with respect to any group containing one or more substituents, that such groups are not intended to include any substitution or groups of substitutions that are sterically unfeasible, artificially unfeasible, and/or inherently unstable.

As used herein, the term alkyl or alkylene is intended to include both branched and straight chain saturated aliphatic hydrocarbon groups with a specific number of carbon atoms. For example, _C1 . ₁₀ αalkyl (or alkylene) is provided to include C1, C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ and C ₁₀ alkyl groups. In addition, for example, C ₁ -C ₆ -alkyl means alkyl containing from 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of their hydrogen atoms are replaced by another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (for example, n-propyl and isopropyl), butyl (for example, n-butyl, isobutyl, t-butyl), pentyl (for example, n-pentyl, isopentyl, neopentyl) and the like.

When the term alkyl is used together with another group, such as arylalkyl, this compound means more specifically at least one of the substituents which will contain a substituted alkyl. For example, arylalkyl refers to a substituted alkyl group as defined above, wherein at least one of the substituents is aryl, such as benzyl. Thus, the term aryl(C ₀ . ₄ )alkyl includes a substituted lower alkyl containing at least one aryl substituent, and also includes an aryl directly attached to another group, i. aryl(C ₀ )alkyl. The term heteroarylalkyl refers to a substituted alkyl group as defined above, wherein at least one of the substituents is heteroaryl.

- 10 042342

The term alkenyl or alkenylene is intended to include hydrocarbon chains, either straight or branched, and containing one or more carbon-carbon double bonds, which may occur at any stable point along the chain. For example, C ₂ _ ₆ alkenyl (or alkenylene) is intended to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkenyl groups. Examples of alkenyl include, without limitation, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2 -methyl-2-propenyl, 4-methyl-3-pentenyl and the like.

The term alkynyl or alkynylene is intended to include hydrocarbon chains, either straight or branched, and containing one or more carbon-carbon triple bonds, which may occur at any stable point along the chain. For example, C ₂ balkynyl (or alkynylene) is provided to include C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like.

When referring to a substituted alkenyl, alkynyl, alkylene, alkenylene or alkynylene group, these groups are substituted with one to three substituents as defined above for substituted alkyl groups.

The term alkoxy refers to an oxygen atom substituted with alkyl or substituted alkyl as defined herein. For example, the term alkoxy includes the -O-C1 group. ₆ alkyl such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, 3-methylpentoxy and the like similar. Lower alkoxy refers to alkoxy groups containing from one to four carbon atoms.

It should be understood that the choice of all groups, including, for example, alkoxy, thioalkyl and aminoalkyl, will be made by a person skilled in the art to provide stable compounds.

As used herein, the term substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with a choice from the designated group, provided that the normal valence of the designated atom is not exceeded. If the substituent is oxo or keto (i.e. =O), then 2 hydrogens per atom are replaced. Keto substituents are not present on aromatic moieties. Unless otherwise indicated, substituents are named based on the basic structure. For example, it is understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of that substituent to the base structure is the alkyl moiety. As used herein, ring double bonds are double bonds that are formed between two adjacent ring atoms (eg, C=C, C=N, or N=N).

Combinations of substituents and/or variables are only permitted if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or structure is meant to mean a compound that is stable enough to be maintained to an acceptable degree of purity after isolation from a reaction mixture and subsequent incorporation into an effective therapeutic agent. It is preferred that the compounds listed herein do not contain an N-halogen, S(O) ₂ H or S(O)H group.

The term carbocyclyl or carbocyclic refers to a saturated or unsaturated or partially unsaturated monocyclic or bicyclic ring in which all atoms of all rings are carbon atoms. Thus, the term includes cycloalkyl and aryl rings. Monocyclic carbocycles contain 3 to 6 ring atoms, more often 5 or 6 ring atoms. Bicyclic carbocycles contain 7 to 12 ring atoms, e.g. arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [ 4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As shown above, bridged rings are also included in the definition of a carbocycle (eg [2.2.2]bicyclooctane). Carbocycles may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term carbocycle is used, it is meant to include aryl. A bridged ring occurs when one or more carbon atoms link two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It should be noted that the bridge always transforms a monocyclic ring into a bicyclic ring. When a ring is bridged, the substituents specified for that ring may also be present on the bridge.

The term aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups containing from 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl groups, each of which may be substituted. A preferred aryl group is an optionally substituted phenyl.

The term cycloalkyl refers to cyclized alkyl groups including mono-,

- 11 042342 bi- or polycyclic ring systems. C ₃ . ₇ cycloalkyl provides for the inclusion of C ₃ , C4, C ₅ , C ₆ and C7 cycloalkyl groups. An example of cycloalkyl groups includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like, which may optionally be substituted on any available ring(s) atoms.

The terms heterocycloalkyl, heterocyclo, heterocyclic, or heterocyclyl may be used interchangeably and refer to substituted and unsubstituted non-aromatic 3-7 membered monocyclic groups, 7-11 membered bicyclic groups, and 10-15 membered tricyclic groups in which at least one of the rings contains at least one heteroatom (O, S, or N), wherein said heteroatom-containing ring preferably contains 1, 2, or 3 heteroatoms selected from O, S, or N. Each heteroatom-containing ring of such a group may contain one or two oxygen atoms or sulfur and/or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and further provided that the ring contains at least one carbon atom. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. The fused rings terminating the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The heterocyclo group may be attached at any available nitrogen or carbon atom. The term heterocycle includes heteroaryl groups. When valency permits, if said additional ring is cycloalkyl or heterocyclo, it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, imidazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, tetrahydrofuranyl, piperidyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidyl, 2oxopyrrodinyl, 2-oxoazepinyl, 1-azepinyl, pyridonyl, 4-piperidonyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane and tetrahydro-1,1-dioxothienyl and the like. Exemplary bicyclic heterocyclo groups include quinuclidinyl.

The term heteroaryl refers to substituted and unsubstituted aromatic 5- or 6-membered monocyclic groups, 9- or 10-membered bicyclic groups, and 11-14-membered tricyclic groups that contain at least one heteroatom (O, S, or N) , in at least one of the rings, where the specified heteroatom-containing ring preferably contains 1, 2 or 3 heteroatoms selected from O, S or N. Each heteroaryl group ring containing a heteroatom may contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less, and that each ring contains at least one carbon atom. The fused rings terminating the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. Heteroaryl groups that are bicyclic or tricyclic must include at least one fully aromatic ring, and the other fused ring or rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom on any ring. When valency permits, if said additional ring is cycloalkyl or heterocyclo, it is additionally optionally substituted with ═O (oxo).

Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, furanyl, thienyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like.

Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnoridlinyl, quinoxalinyl, pyrropyridazolyl, dihydroisoindolyl, tetrahydroquinolinyl and the like.

Exemplary tricyclic heteroaryl groups include carbazolyl, benzdolyl, phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

Unless otherwise noted, when referring to a specifically named aryl (e.g. phenyl), cycloalkyl (e.g. cyclohexyl), heterocyclo (e.g. pyrrolidinyl, piperidinyl and morpholinyl) or heteroaryl (e.g. tetrazolyl, imidazolyl, pyrazolyl, triazolyl, thiazolyl and furyl ), the reference is intended to include rings containing 0 to 3, preferably 0 to 2, substituents appropriately selected from those listed above for aryl, cycloalkyl, heterocyclo and/or heteroaryl groups.

The term halo or halogen refers to chlorine, bromine, fluorine and iodine.

The term haloalkyl means a substituted alkyl containing one or more halogen substituents. For example, haloalkyl includes mono-, bi-, and trifluoromethyl.

The term haloalkoxy denotes an alkoxy group containing one or more halogen substituents. For example, haloalkoxy includes OCF ₃ .

The term heteroatoms should include oxygen, sulfur and nitrogen.

Where the term "unsaturated" as used herein refers to a ring or group, that ring or group may be fully unsaturated or partially unsaturated.

One skilled in the art will appreciate that when the CO2 value is used in the present specification, it is intended to refer to the group to

Throughout the description, the groups and their substituents can be selected by one of ordinary skill in the art to provide stable moieties and compounds and compounds useful as pharmaceutically acceptable compounds and/or intermediates useful in the preparation of pharmaceutically acceptable compounds. The compounds of formula (I) may exist in free form (in the absence of ionization) or may form salts, which are also within the scope of the present invention. Unless otherwise indicated, reference to compounds of the present invention is intended to include reference to their free form and salts. The term salt(s) means acidic and/or basic salts formed with inorganic and/or organic acids and bases. In addition, the term salt(s) may include zwitterions (internal salts), for example, when the compound of formula (I) contains both a basic moiety, such as an amine, or a pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid . Pharmaceutically acceptable (ie, non-toxic, physiologically acceptable) salts are preferred, such as, for example, acceptable metal and amine salts in which the cation does not significantly contribute to the toxicity or biological activity of the salt. However, other salts may be used, for example in isolation or purification steps that may be used in the preparation process, and thus are contemplated within the scope of the present invention. Salts of compounds of formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization. Specific examples may be provided in the specific salt form, however, it should be understood that the compounds may exist in free form as well as alternative salt forms.

Exemplary acid addition salts include acetates (which are formed with acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates. , cyclopentane propionates, digluconates, dodecyl sulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides (formed with hydrochloric acid), hydrobromides (formed with hydrogen bromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates (formed with maleic acid ), methanesulfonates (formed with methanesulfonic acid), 2naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates (which are formed with sulfuric acid), sulfonates (which mentioned in this description), and rtrates, thiocyanates, toluenesulfonates such as tosylates, undecanoates and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; barium, zinc and aluminum salts; salts with organic bases (e.g. organic amines) such as trialkylamines such as triethylamine, procaine, dibenzylamine, Nbenzyl-p-phenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, dehydroabiethylamine, Nethylpiperidine, benzylamine, dicyclohexylamine or similar pharmaceuticals acceptable amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quaternized with agents such as lower alkyl halides (eg methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (eg dimethyl, diethyl, dibutyl diamyl sulfates), long chain halides (eg decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides) and others.

In one embodiment, the salts include the monohydrochloride, hydrogen sulfate, methanesulfonate, phosphate, or nitrate salts.

As used herein, the expression pharmaceutically acceptable refers to those compounds, substances, compositions and/or dosage forms that are medically suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problems or complications, in accordance with a reasonable benefit/risk ratio.

As used herein, the term pharmaceutically acceptable salts refers to derivatives of the disclosed compounds, where the parent compound has been modified by making it

- 13 042342 acid or basic salts. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amines; and alkali or organic salts of acidic groups such as carboxylic acids. Pharmaceutically acceptable salts include typical non-toxic salts or quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such exemplary non-toxic salts include salts derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic and isethionic and the like.

The pharmaceutically acceptable salts of the present invention may be synthesized from a parent compound that contains a basic or acid moiety by conventional chemical methods. Typically, such salts can be obtained by reacting the free acidic or basic forms of these compounds with a stoichiometric amount of the corresponding base or acid in water or in an organic solvent, or in a mixture of the two; in general, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred. Lists of suitable salts are provided in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Easton, PA, 1990, the disclosure of which is incorporated herein by reference.

All stereoisomers of the compounds of the present invention are contemplated, either in admixture or in pure or substantially pure form. Stereoisomers may include compounds that are optical isomers as a result of the inclusion of one or more chiral atoms, as well as compounds that are optical isomers due to limited rotation around one or more bonds (atropisomers). The definition of the compounds of the present invention covers all possible stereoisomers and mixtures thereof. It particularly embraces racemic forms and isolated optical isomers having said activity. The racemic forms can be isolated by physical means, such as, for example, fractional crystallization, separation or crystallization of diastereomeric derivatives, or separation by chiral column chromatography. Individual optical isomers can be obtained from racemates by conventional means, such as, for example, salt formation with an optically active acid followed by crystallization.

The present invention provides for the inclusion of all isotopes of the atoms that make up the compounds of the present invention. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include ¹³ C and ¹⁴ C. Isotopically labeled compounds of the invention can generally be prepared by conventional methods known to those skilled in the art, or by methods similar to those described herein using an appropriate isotopically labeled reagent. instead of the non-isotopically labeled reagent used in other cases.

Also provided are prodrugs and solvates of the compounds of the present invention. The term prodrug means a compound which, after administration to a subject, undergoes chemical transformation by metabolic or chemical processes to give a compound of formula (I) and/or a salt and/or solvate thereof. Any compound that will be converted in vivo to produce a bioactive agent (ie, a compound of formula (I)) is a prodrug within the scope and spirit of the present invention. For example, compounds containing a carboxy group can form physiologically hydrolysable esters that serve as prodrugs when hydrolyzed in the body to form compounds of formula (I) per se. Such prodrugs are preferably administered orally, since hydrolysis in many cases occurs mainly under the influence of digestive enzymes. Parenteral administration may be used if the ester itself is active, or in cases where hydrolysis occurs in the blood. Examples of physiologically hydrolysable esters of compounds of formula (I) include C ₁₆ alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl, methoxymethyl, C ₁ . ₆ alkanoyloxy-C ₁ . ₆ αkyl, eg acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl, C ₁ .6alkoxycarbonyloxy-C ₁ . ₆ alkyl, e.g. methoxycarbonyloxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well-known physiologically hydrolyzable esters used, for example, in the field penicillins and cephalosporins. Such esters may be prepared by conventional methods known in the art.

Various forms of prodrugs are well known in the art. For examples of derivatives of such prodrugs, see:

a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985), and Methods in Enzymology, Vol.

- 14 042342

112, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985);

b) A Textbook of Drug Design and Development, edited by Krosgaard-Larsen, and H. Bundgaard,

Chapter 5, Design and Application of Prodrugs, edited by H. Bundgaard, pp. 113-191 (1991); And

c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, pp. 1-38 (1992), each of which is incorporated herein by reference.

The compounds of formula (I) and their salts may exist in their tautomeric form in which the hydrogen atoms are transferred to other parts of the molecules and the chemical bonds between the atoms of the molecules are rearranged accordingly. It should be understood that all tautomeric forms, if they may exist, are included in the present invention. The compounds of the present invention may have one or more asymmetric centers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms of the compounds of the present invention are included in the present invention. Many geometric isomers of olefins, C=N double bonds and the like may also be present in the compounds, and all such stable isomers are contemplated in the present invention. The cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separate isomeric forms. The compounds of the invention may be isolated in optically active or racemic forms. It is well known in the art how to obtain optically active forms, for example by reduction of racemic forms or by synthesis from optically active starting materials. All chiral (enantiomeric and diastereomeric) and racemic forms are contemplated, as well as all geometric isomeric forms of the structure, unless a specific stereochemical or isomeric form is specifically indicated. All geometric isomers, tautomers, atropisomers, hydrates, solvates, polymorphs and isotopically labeled forms of the compounds mentioned herein and mixtures thereof are contemplated within the scope of the present invention. Solvation methods are generally known in the art.

Utility

Compounds of the invention modulate kinase activity, including modulation of RIPK1 activity. Accordingly, the compounds of formula (I) are useful in the treatment of conditions associated with the modulation of kinase activity, and in particular the selective inhibition of RIPK1 activity. In another embodiment, the compounds of formula (I) have an advantageous selectivity for RIPK1 activity, preferably a greater selectivity of at least 20-fold to more than 1000-fold.

As used herein, the terms treatment or therapy encompasses the treatment of a disease state in a mammal, in particular a human, and includes: (a) preventing or delaying the onset of a disease state in a mammal, in particular if said mammal is predisposed to the disease state, but not yet found to have one; (b) inhibition of the disease state, ie. cessation of its development; and/or (c) achieving total or partial amelioration of the symptoms or disease state and/or alleviation, amelioration of symptoms, reduction or treatment of the disease or disorder and/or its symptoms.

In terms of their activity as selective RIPK1 inhibitors, the compounds of formula (I) are useful in the treatment of RIPK1 related conditions including, but not limited to, inflammatory diseases such as Crohn's disease and ulcerative colitis, inflammatory bowel disease, bronchial asthma, graft-versus-host disease, chronic obstructive pulmonary disease and non-alcoholic steatohepatitis (NASH); autoimmune diseases such as Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis; destructive bone diseases such as bone resorption disease, osteoarthritis, osteoporosis, multiple myeloma-associated bone disease; proliferative diseases such as acute myeloid leukemia, chronic myelogenous leukemia; angiogenic disorders including ischemia-reperfusion syndrome, heart failure, solid tumors, ocular neovascularization and infantile hemangiomas; infectious diseases such as sepsis, septic shock and shigellosis; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, ALS, cerebral ischemia or neurodegenerative disease caused by traumatic injury, cancer and viral diseases such as metastatic melanoma, Kaposi's sarcoma, multiple myeloma and HIV infection and CMV retinitis, AIDS, respectively. More specifically, specific conditions or diseases that can be treated with the compounds of the present invention include, without limitation, pancreatitis (acute or chronic), bronchial asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, non-alcoholic steatohepatitis (NASH ), glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, ALS, multiple sclerosis bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, general rubella-mediated arthritis, acute synovitis, β-cell disease of the pancreas; diseases characterized by massive infiltration of neutrophils; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption disease, allograft rejection, fever and myalgia due to infection, cachexia due to infection, keloid formation, scar tissue formation , ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock and shigellosis; Alzheimer's disease, Parkinson's disease, cerebral ischemia or trauma-induced neurodegenerative disease; angiogenic disorders including solid tumors, ocular neovascularization and infantile hemangiomas; viral diseases including acute infectious hepatitis (including hepatitis A, hepatitis B and hepatitis C), HIV infection and CMV retinitis, AIDS, ARC or malignancy, and herpes; stroke, myocardial ischemia, ischemia in stroke-induced acute heart failure, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, conditions associated with prostaglandin endoperoxide synthase-2 and pemphigus vulgaris. Preferred treatments are those in which the condition is selected from inflammatory bowel disease, Crohn's disease and ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, non-alcoholic steatohepatitis (NASH), and pemphigus vulgaris. Alternatively, preferred treatments are those in which the condition is selected from ischemia-reperfusion injury, including cerebral ischemia-reperfusion injury arising from stroke and cardiac ischemia-reperfusion injury arising from myocardial infarction.

When the terms RIPK1 related condition or RIPK1 related disease or disorder are used herein, each is intended to encompass all of the above conditions as recited in all detail, as well as any other condition that is affected by RIPK1 kinase activity. The present invention thus provides methods for treating such conditions comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. A therapeutically effective amount is intended to encompass the amount of a compound of the present invention that is effective, when administered alone or in combination, to inhibit RIPK1.

Methods for treating RIPK1 kinase related conditions may include administering compounds of formula (I) alone or in combination with each other and/or with other suitable therapeutic agents useful in the treatment of such conditions. Accordingly, a therapeutically effective amount is also intended to include an amount of a combination of the claimed compounds that is effective in inhibiting RIPK1 and/or treating RIPK1 related diseases.

Examples of such other therapeutic agents include corticosteroids, rolipram, calfostin, cytokine suppressing anti-inflammatory drugs (CSAID), interleukin 10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear translocation inhibitors such as deoxyspergualine (DSG); non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, celecoxib and rofecoxib; steroids such as prednisone or dexamethasone; anti-inflammatory antibodies such as vedolizumab and ustekinumab, anti-inflammatory kinase inhibitors such as TYK2 inhibitors, antivirals such as abacavir; antiproliferatives such as methotrexate, leflunomide, FK506 (tacrolimus, Prograf); anticoagulant drugs such as clopidogrel, ticagrelor, prasugrel, enoxaparin, eptifibatide, tirofiban; antifibrotic drugs such as an FGF21 agonist; cytotoxic drugs such as azatiprine and cyclophosphamide; TNF-α inhibitors such as tenidap, anti-TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof, and PD-1 immunotherapy.

The above other therapeutic agents, when used in combination with the compounds of the present invention, may be used, for example, in the amounts indicated in the Physicians' Desk Reference (PDR) or otherwise determined by one of ordinary skill in the art. In the methods of the present invention, such other therapeutic agent(s) may be administered before, simultaneously with, or after administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating RIPK1 kinase related conditions, including IL-1, IL-6, IL-8, IFNy and TNF-α mediated conditions as described above.

Compositions of the present invention may contain other therapeutic agents described above and may be formulated, for example, using conventional solid or liquid

- 16 042342 carriers or diluents, as well as pharmaceutical additives of a type that corresponds to the type of administration desired (for example, excipients, binders, preservatives, stabilizers, flavorings, etc.) in accordance with methods that are well known in the field of pharmaceutical drugs.

Accordingly, the present invention further provides compositions comprising one or more compounds of formula (I) and a pharmaceutically acceptable carrier.

The term pharmaceutically acceptable carrier refers to media generally accepted in the art for the delivery of biologically active agents to animals, in particular mammals. Pharmaceutically acceptable carriers are formulated according to a number of factors that are within the purview of those skilled in the art. These include, without limitation, the type and nature of the active agent being formulated; the subject to whom the agent-containing composition is to be administered; the intended route of administration of the composition and the intended therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers may include a number of different ingredients and additives in addition to the active agent, such additional ingredients included in the composition for a variety of reasons, for example, to stabilize the active agent, binders, etc., are well known to those skilled in the art. Descriptions of suitable pharmaceutically acceptable carriers and factors involved in their selection can be found in various available sources such as, for example, Remington's Pharmaceutical Sciences, 17th Ed., 1985, which is incorporated herein by reference in its entirety.

The compounds of formula (I) may be administered by any route suitable for the condition being treated, which may depend on the need for treatment of particular sites or the amount of drug administered. Topical administration is generally preferred for skin-related diseases, and systemic treatment is preferred for malignant or pre-carcinogenic conditions, although other modes of delivery are contemplated. For example, the compounds can be delivered orally, for example, in the form of tablets, capsules, granules, powders or liquid dosage forms, including syrups; topically, for example, in the form of solutions, suspensions, gels or ointments; sublingual; buccal; parenterally, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (eg, as sterile injectable aqueous or non-aqueous solutions or suspensions); intranasally, for example, by inhalation sprays; topically, for example, in the form of a cream or ointment; rectally, for example in the form of suppositories; or through liposome entrapment. Dosage unit formulations containing non-toxic, pharmaceutically acceptable carriers or diluents may be administered. The compounds may be administered in a form suitable for immediate release or sustained release. Immediate release or sustained release can be achieved with suitable pharmaceutical compositions or, in particular in the case of sustained release, with devices such as subcutaneous implants or osmotic pumps.

Illustrative compositions for topical administration include a topical carrier such as PLASTIBASE® (mineral oil gelled with polyethylene).

Exemplary compositions for oral administration include suspensions which may contain, for example, microcrystalline cellulose for bulking, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents as are known in the art. technology; and immediate-release tablets, which may contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose, and/or other excipients, binders, fillers, disintegrants, diluents and lubricating agents that are known in the present field. technology. The compounds of the present invention may also be administered orally by sublingual and/or buccal administration, for example with molded, compressed or freeze-dried tablets. Exemplary compositions may include instant diluents such as mannitol, lactose, sucrose, and/or cyclodextrins. In addition, high molecular weight excipients such as celluloses (AVICEL®) or polyethylene glycols (PEGs) may be included in such formulations; mucosal adhesion adjuvants such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (SCMC) and/or maleic anhydride copolymer (eg GANTREZ®); and release control agents such as polyacrylic copolymer (eg CARBOPOL 934®). Lubricants, glidants, fragrances, colorants and stabilizers may also be added for ease of manufacture and use.

Exemplary compositions for nasal aerosol or inhalation administration include solutions which may contain, for example, benzyl alcohol or other suitable

- 17 042342 preservatives, absorption promoters to enhance absorption and/or bioavailability, and/or other solubilizing or dispersing agents, which are known in the present technical field.

Exemplary compositions for parenteral administration include injectable solutions or suspensions which may contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, isotonic sodium chloride solution, or others. suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides and fatty acids, including oleic acid.

Exemplary compositions for rectal administration include suppositories which may contain, for example, suitable non-irritating excipients such as cocoa butter, synthetic esters of glycerol or polyethylene glycols which are solid at ordinary temperatures but melt and/or dissolve in the rectal drug-release cavities.

A therapeutically effective amount of a compound of the present invention can be determined by one of ordinary skill in the art and includes exemplary mammalian doses of about 0.05 to 1000 mg/kg; 1-1000 mg/kg; 1-50 mg/kg; 5-250 mg/kg; 250-1000 mg/kg body weight of the active compound per day, which can be administered as a single dose or as separate divided doses, for example 1 to 4 times a day. It should be understood that the specific dose and frequency of administration for any particular subject may vary and will depend on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, species, age, body weight, general health, sex, and diet. subject, regimen and time of administration, rate of excretion, combination of drugs, and severity of the particular condition. Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and pets such as dogs, cats, horses, and the like. Thus, when the term patient is used herein, the term is intended to include all subjects, most preferably mammalian species, that are dependent on levels of the RIPK1 enzyme.

Simultaneous multiparameter analysis of MLKL phosphorylation.

HT29-L23 human colorectal adenocarcinoma cells were maintained in RPMI 1640 medium containing 10% heat-inactivated FBS, 1% pennicillin-streptomycin, and 10 mM HEPES. Cells were seeded at 2,000 cells/well in 384w microplates (Greiner #781090-3B) treated with tissue culture and incubated at 37°C (5% CO ₂ /95% O ₂ ) for two days. On the day of analysis, cells were treated with test compounds at a final concentration of 6.25 to 0.106 μM for 30 min at 37°C (5% CO ₂ /95% O ₂ ). Necroptosis was induced using a mixture of human TNFa (35 ng/ml) (Peprotech #300-01A), SMAC mimetic (from US 2015/0322111 A1) (700 nM) and ZVAD (140 nM) (BD Pharmingen #51-6936). After six hours of incubation at 37°C (5% CO ₂ /95% O ₂ ), the cells were fixed with 4% formaldehyde (ACROS 11969-0010) for 15 minutes at room temperature, and then permeabilized with phosphate buffered saline (PBS) containing 0.2% Triton-X-100, for 10 min. Phosphorylation of MLKL was detected using an anti-MLKL antibody (phospho S358) (Abcam #ab187091) (1:1000 dilution in blocking buffer [PBS supplemented with 0.1% BSA]) with overnight incubation at 4°C. After washing three times in PBS, goat anti-rabbit antibodies labeled with Alexa-488 (1:1000 dilution) (Life Technologies, A11008) and Hoechst 33342 (Life Technologies, H3570) (1:2000 dilution) were added in blocking buffer for 1 h at room temperature. After three more wash cycles in PBS, the microplates were capped and cell imaging was performed using a Cellomics ArrayScan VTI high performance imager equipped with an X1 camera. Fluorescent images were acquired using a 10x objective and filter sets 386-23 BGRFRN_BGRFRN and 485-20 BGRFRN_BGRFRN for nuclear phosphorylation and MLKL, respectively. Image sets were analyzed using Compartmental Analysis Bioapplication (Cellomics) software. The level of MLKL phosphorylation was quantified as MEAN_CircRingAvgIntenRatio. The maximum inhibitory response was determined by activity induced by Nec-1 (CAS #: 852391-15-2, 6.25 μM). The IC ₅₀ value was defined as the concentration of the compound that causes 50% of the maximum inhibition. Data were fitted using a 4-parameter logistic equation to calculate IC ₅₀ and Ymax values.

Analysis of RIPK1 binding by HTRF.

A solution was prepared containing 0.2 nM anti-GST-Tb (Cisbio, 61GSTTLB), 90.6 nM probe, and 1 nM HisGST-TVMV-hRIPK1 (1-324) in FRET buffer (20 mM HEPES, 10 mM MgCl ₂ , 0.015% Brij -35, 4 mM DTT, 0.05 mg/ml BSA). Using Formulatrix Tempest, the detection antibody/enzyme/probe solution (2 ml) was dispensed into the wells of a 1536-well plate (Black Low Binding Polystyrene 1536 Plate (Coining, 3724)) containing 10 nl of test compounds at the appropriate concentration in DMSO. The plate was incubated at room temperature for 1 h. FRET was measured using

- 18 042342 EnVision plate reader (excitation: 340 nM, emission: 520 nM/495 nM). The overall signal (0% inhibition) was calculated from wells containing only 10 nl DMSO. The quenching signal (100% inhibition) was calculated from wells containing 10 nl of 15 nM staurosporine and internal controls.

Cloning and baculovirus expression of the RIPK1 construct.

The coding region of human RIPK1 (1-324), flanked by an NdeI restriction site at the 5' end of the sense strand and a TGA stop codon and an XhoI restriction site at the 3' end of the sense strand, was codon-optimized and the gene was synthesized at GenScript USA Inc. . (Piscataway, NJ) and subcloned into a modified pFastBac1 vector (Invitrogen, Carlsbad, CA) N-tagged with His-GST-TVMV, generating His-GST-TVMV-hRIPK1(1-324)-pFB. The correct assembly of the synthesized fragment was confirmed by sequencing.

The construct baculovirus was generated using a Bac-to-Bac baculovirus expression system (Invitrogen) according to the manufacturer's protocol. Briefly, recombinant bacmid was isolated from transformed competent cells of E. coli strain DH10Bac (Invitrogen) and used to transfect Spodoptera frugiperda (Sf9) insect cells (Invitrogen). Baculovirus was harvested 72 hours after transfection, and viral material was prepared by infecting fresh cells with Sf9 at a ratio of 1/1000 (v/v) for 66 hours.

For large scale protein production, Sf9 cells (Expression System, Davis, CA) grown in ESF921 insect medium (Expression System) at 2x106 cells/ml were infected with viral material at a ratio of 1/100 (v/v) for 66 hours. Yields were either 10 L in a 22 L working volume cell culture bag (GE Healthcare Bioscience, Pittsburgh, PA) or 20 L in a 50 L working volume cell culture bag using a WAVE-Bioreactor System 20 /50 (GE Healthcare Bioscience). Infected cells were harvested by centrifugation at 2000 rpm for 20 min at 4°C in a SORVALL® RC12BP centrifuge. The cell pellet was stored at -70° C. prior to protein purification.

Purification of His-GST-TVMV-hRIPK1 (1-324)

Cellular biomass containing RIPK1 was resuspended in a solution of 50 mM Tris, pH 7.5, 150 mM NaCl, 10 mM imidazole, 5% glycerol, 5 mM MgSO ₄ , 1 mM TCEP, 25 U/mL benzonase, and total protease inhibitor tablets (1 /50 ml, Roche Diagnostics, Indianapolis, IN). Cells were lysed by nitrogen cavitation using a pressure vessel without agitation at 525 psi (Parr Instrument Company, Moline, IL). The suspension was purified from impurities by centrifugation at 136,000xg for 40 min at 4°C. The lysate was decanted from the pellet and passed through a 5 ml NiNTA Superflow cartridge (Qiagen, Valencia, CA) using an AKTA Pure chromatography system (GE Healthcare). The column was eluted with a linear gradient (10 column volumes) of 50 mM Tris, pH 7.5, 150 mM NaCl, 500 mM imidazole, 5% glycerol, 1 mM TCEP. Peak fractions were pooled and immediately loaded onto a 5 ml GSTrap 4B column (GE Healthcare). The column was washed with 50 mM Tris, pH 7.0, 150 mM NaCl, 5% glycerol, 1 mM DTT and eluted with a linear gradient (10 column volumes) of 50 mM Tris, pH 8.0, 150 mM NaCl, 20 mM reduced glutathione, 5% glycerol, 1 mM DTT. Fractions identified by SDS-PAGE as containing RIPK1 were pooled and concentrated using 30 kDa MWCO centrifuge concentrators (Amicon Ultra-15, Millipore, Billerica, MA) and loaded onto a HiLoad 26/600 Superdex 200 column (GE Healthcare) equilibrated 25 mM Tris, pH 7.5, 150 mM NaCl, 2 mM TCEP, 5% glycerol. The RIPK1 protein was eluted as a dimer from the SEC column.

The yield was ˜8 mg/L with >95% purity as determined by SDSPAGE gel analysis using Coomassie staining. LC-MS analysis of the protein showed that the protein had lost the N-terminal methionine, had one phosphorylated site, and was partially acetylated. The protein was aliquoted and stored at -80°C.

Using these assays, IC ₅₀ values were determined for the following compounds. See table. A.

- 19 042342

Table A

Example HTRF Binding Assay (ICso, µM) Cellular analysis of HCS for pMLKL (1C ₅₀ , µM) 1 8.5 77 2 5.8 31 3 1.7 5.0 4 32 412 5 147 16 6 10 thirty 7 14 62 8 2.7 eleven 9 2.1 21 10 4.1 4.9 eleven 18 153 23 79 60 24 56 247 25 41 71 26 5.8 8.2 27 22 99 28 2.3 3.1 29 46 106 thirty 19 13 31-1 7.4 13 31-2 2.222 32 5.3 82 33 1.7 34 34 5.7 28 35 321 104 36 8.6 98 37 214 42 39 1.945 327 38 7.0 8.4 40 42 82 41-1 AND 10 41-2 121 288 42 0.25 8.7 43 6.0 eleven 44-1 4.7 9.3 44-2 74 44-3 401 296 44-4 517 835 45-1 24 eleven 45-2 13 22 46 26 109 47 51 160 48 52 8.6 49 1.3 0.46 50 2.2 3.6 51 4.2 3.7 52 7.1 42 53 4.4

Example HTRF Binding Assay (ICso, µM) Cellular analysis of HCS for pMLKL (1C ₅₀ , μM) 12 50 401 13 14 thirty 14 453 2.621 15 32 257 16 735 1.577 17 8.9 9.8 18 12 24 19 16 47 20 112 49 21 25 15 22 59 167 54 285 263 55 142 479 56 42 76 57 8.8 14 58 2.5 4.1 59 50 231 60 7.6 41 61 7.2 thirty 62 2.3 37 63 123 64 65 2.2 3.5 66 42 183 67 8.5 5.2 68 29 348 69 8.2 74 70 32 209 71 4.8 65 72 12 74 73 1.4 33 74 1.5 thirty 75 24 81 76 3.4 4.1 77 4.5 26 78 7.0 113 79 17 139 80 17 261 81 7.7 38 82 9.5 45 83 57 279 84 70 85 363 86 15 33 87 134 245 88 31 117 89 67 87 90 4.2 13

- 20 042342

91 2.9 9.0 92 5.9 27 93 16 22 94 4.3 12 95 39 64 96 24 82 97 34 96 98 98 182 99 25 218 100 18 61 101 15 41 102 7.8 123 103 12 50 104 12 45 105 20 72 106 7.5 12 107 23 50 108 19 53 109 6.3 9.7 BY 3.0 1.2 111 24 112 112 111 343 113 19 85 114 14 50 115 17 29 116 20 43 117 7.1 79 118 15,000 402 119 9.7 42 120 52 303 121 12 130 122 12 eleven 123 18 5.1 124 89 388 125 3.3 5.0 126 10 16 127 13 23

128 68 313 129 9.3 22 130 38 78 131 31 73 132 33 75 133 7.0 16 134 12 15 135 13 17 136 4.621 435 137 19 453 138 23 82 139 17 35 140 5.1 eleven 141 123 208 142 24 70 143 56 311 144 26 162 145 53 153 146 108 419 147 42 201 148 174 24 149 32 26 150 82 397 151 18 9.0 152 58 100 153 3.0 14 154 57 66 155 217 367 156 27 100 157 39 156 158 42 253 159 31 65 160 2.0 12 161 31 43 162 37 351 163 57 170 164 8.522 97

- 21 042342

165 5.5 1.1 166 3.1 0.85 167 7.2 9.3 168 4.3 2.8 169 2.3 1.7 170 17 16 171 2.4 3.0 172 21 thirty 173 17 5.7 174 18 6.6 175 95 29 176 51 66 177 6.2 1.0 178 330 179 48 180 16 21 181 6.0 5.7 182 151 160 183 66 85 184 9.0 1.8 185 36 55 186 120 228 187 274 307 188 29 25 189 14 32 190 26 37 191 95 152 192 125 282 193 23 66 194 28 85 195 59 349 196 33 5.5 197 26 64 198 27 14 199 16 54 200 71 316 201 5.5 16

202 51 135 203 3.1 14 204 281 218 205 8.9 22 206 1.1 21 207 53 144 208 4.0 4.2 209 132 181 210 22 90 211 5.6 6.2 212 111 479 213 4.6 2.3 214 3.0 26 215 2.6 3.4 216 216 51 217 5.9 4.6 218 3.8 3.8 219 174 209 220 120 89 221 12 13 222 6.7 6.3 223 200 412 224 12 8.9 225 6.9 21 226 51 259 227 9.2 3.8 228 137 174 229 24 18 230 3.8 15 231 eleven 7.3 232 18 6.2 233 10 thirty 234 17 15 235 20 25 236 384 210 237 10 39 238 8.5 10

- 22 042342

239 23 68 240 90 271 241 38 33 242 3.3 32 243 7.6 45 244 54 258 245 17 160 246 5.0 81 247 3.6 24 248 5.8 26 249 54 201 250 6.5 72 251 42 223 252 25 38 253 14 22 254 12 38 255 43 93 256 20 64 257 13 32 258 174 194 259 14 20 260 24 191 261 34 315 262 45 232 263 19 102 264 26 104 265 47 161 266 46 220 267 51 185 268 136 122 269 6.4 28 270 4.4 1.1 271 8.7 26 272 3.7 8.3 273 101 148 274 13 26 275 12 27

276 7.2 6.9 277 8.0 25 278 15,000 249 279 22 80 280 210 351 281 312 284 282 267 429 283 89 142 284 68 109 285 3.5 22 286 3.3 29 287 17 20 288 91 276 289 45 70 290 149 162 291 31 29 292 81 133 293 127 53 294 54 46 295 20 65 296 26 63 297 27 115 298 thirty 187 299 85 195 300 48 126 301 12 34 302 40 12 303 33 28 304 9.3 thirty 305 9.5 18 306 4.6 9.4 307 19 21 308 eleven 43 309 75 63 310 90 294 311 3.3 2.3 312 19 17

- 23 042342

313 74 65 314 13 29 315 19 316 42 45 317 26 328 318 31 124 319 23 23 320 96 123 321 26 120 322 94 83 323 97 86 324 119 178 325 34 106 326 85 112 327 39 120 328 33 157 329 57 194 330 7.1 9.9 331 eleven 27 332 140 361 333 46 39 334 32 23 335 7.1 9.0 336 37 129 337 1.2 12 338 2.4 eleven 339 79 90 340 54 217 341 3.3 eleven 342 5.6 24 343 2.2 6.5 344 8.8 191 345 18 50 346 351 239 347 eleven 26 348 eleven 6.4 349 5.1 7.2

350 12 14 351 23 22 352 23 13 353 52 58 354 221 265 355 43 7.8 356 16 19 357 19 16 358 eleven 19 359 19 15 360 7.4 25 361 189 362 31 363 76 88 364 8.2 10 365 31 121 366 12 18 367 6.9 8.7 368 39 56 369 eleven 17 370 27 130 371 6.0 9.2 372 42 117 373 44 50 374 16 13 375 20 13 376 4.3 9.1 377 6.3 5.5 378 154 251 379 eleven eleven 380 eleven 23 381 7.2 26 382 29 29 383 5.2 7.2 384 22 51 385 60 291 386 2.8 1.9

- 24 042342

387 8.0 15 388 8.0 7.2 389 7.2 9.9 390 4.5 eleven 391 105 215 392 390 277 393 255 264 394 28 76 395 20 12 396 93 145 397 8.7 398 10 9.4 399 2.9 25 400 46 48 401 15 27 402 8.5 4.8 403 33 25 404 25 63 405 7.3 8.5 406 14 10 407 24 15 408 17 12 409 13 9.2 410 7.3 6.3 411 5.5 3.8 412 7.2 413 4.5 48 414 2.0 eleven 415 26 18 416 20 32 417 7.1 7.9 418 4.7 4.2 419 42 19 420 63 140 421 15,000 37 422 144 148 423 39 47

424 353 24 425 15,000 51 426 7.0 7.4 427 173 405 428 22 8.4 429 20 4.0 430 26 22 431 89 74 432 2.3 3.0 433 10 3.7 434 9.1 24 435 14 6.0 436 21 8.5 437 9.5 12 438 2.5 2.1 439 5.8 eleven 440 3.0 2.7 441 9.1 25 442 7.7 17 443 2.5 21 444 12 28 445 2.7 0.83 446 100 171 447 35 126 448 5.6 6.7 449 5.3 2.8 450 22 45 451 3.1 4.3 452 37 101 453 12 23 454 2.9 4.0 455 12 27 456 20 20 457 6.1 3.8 458 16 5.8 459 13 2.6 460 7.4 12

- 25 042342

461 14 15 462 8.7 9.1 463 12 4.6 464 14 33 465 101 388 466 48 116 467 14 31 468 9.5 37 469 15 79 470 18 51 471 9.0 143 472 79 74 473 58 88 474 19 98 475 42 47 476 206 72 477 16 72 478 60 78 479 9.3 8.5 480 22 323 481 2.9 106 482 40 205 483 38 44 484 5.1 9.7 485 4.8 2.9 486 70 22 487 4.3 1.3 488 3.7 12 489 3.0 0.76 490 6.0 thirty 491 4.4 5.2 492 5.8 6.7 493 42 106 494 8.3 139 495 18 313 496 6.7 13 497 9.4 286

498 eleven 3.8 499 4.3 eleven 500 19 36 501 18 129 502 5.7 58 503 38 206 504 8.7 46 505 2.8 12 506 14 94 507 7.9 33 508 13 By 509 167 315 510 34 99 511 13 41 512 18 97 513 40 184 514 17 170 515 53 196 516 36 80 517 19 eleven 518 59 22 519 49 57 520 71 77 521 53 44 522 103 131 523 91 20 524 168 118 525 240 140 526 130 108 527 138 79 528 108 430 529 65 47 530 29 43 531 264 313 532 115 126 533 258 334 534 24 23

- 26 042342

535 46 28 536 27 36 537 27 21 538 32 37 539 44 55 540 69 96 541 190 404 542 4.0 58 543 25 6.250 544 124 5.666 545 thirty 330 546 19 107 547 44 95 548 thirty 91 549 13 18 550 24 0.85 551 60 532 552 82 369 553 145 943 554 7.1 BY 555 144 1.535 556 771 5.379 557 140 1.975 558 1.186 6.250 559 263 4.453 560 14 219 561 21 271 562 8.4 1.0 563 33 564 56 39 565 35 2.9 566 21 31 567 19 15 568 6.9 5.2 569 3.2 3.4 570 6.2 1.2 571 12 14

572 2.8 573 17 574 22 575 13 576 51 31 577 2.7 578 6.7 579 24 580 41 581 20 582 5.4 583 4.2 584 10 585 49 586 16 3.6 587 22 588 157 589 eleven 590 108 591 309 237 592 92 86 593 36 39 594 65 245 595 94 202 596 94 253 597 7.1 9.7 598 10 28 599 eleven 29 600 20 72 601 eleven 17 602 87 178 603 54 95 604 eleven 29 605 7.7 8.8 606 7.6 22 607 3.4 8.4 608 13 17

- 27 042342

609 28 79 610 13 13 611 9.6 35 612 5.4 3.1 613 5.8 2.7 614 16 2.6 615 5.8 2.8 616 5.2 2.5 617 5.3 2.4 618 3.8 2.3 619 9.1 3.1 620 6.0 1.8 621 10 1.6 622 12 1.2 623 33 10 624 26 10 625 6.0 1.8 626 eleven 2.8 627 7.1 3.6 628 5.7 3.9 629 13 5.5 630 eleven 16 631 15 6.6 632 305 2.2 633 12 3.8 634 7.5 2.8 635 9.4 7.3 636 8.8 13 637 12 2.6 638 6.8 6.6 639 BY 68 640 47 47 641 5.8 7.4 642 4.3 3.1 643 15 32 644 7.5 6.8 645 7.4 24

646 6.0 4.2 647 32 25 648 38 21 649 16 35 650 7.3 4.5 651 12 12 652 7.8 8.6 653 9.4 22 654 14 6.7 655 eleven 6.8 656 8.6 3.0 657 10 13 658 8.2 8.2 659 10 18 660 13 9.4 661 18 26 662 3.8 1.4 663 6.1 2.0 664 14 10 665 15 25 666 5.1 2.9 667 3.9 2.6 668 7.9 7.9 669 1.8 3.0 670 4.2 2.9 671 5.9 3.9 672 7.4 15 673 6.3 7.9 674 6.9 4.9 675 15 3.9 676 10 2.5 677 7.5 2.1 678 3.8 2.9 679 3.2 2.7 680 28 36 681 6.2 19 682 10 18

- 28 042342

683 28 34 684 21 44 685 5.3 29 686 4.9 2.7 687 22 37 688 7.7 29 689 50 184 690 282 5.0 691 10 16 692 4.7 15 693 12 eleven 694 12 26 695 13 86 696 13 23 697 9.4 32 698 eleven 26 699 51 112 700 82 105 701 9.5 9.0 702 9.3 5.1 703 7.9 9.0 704 15 12 705 thirty 18 706 7.9 25 707 119 36 708 4.3 9.3 709 12 4.4 710 10 14 711 17 12 712 12 31 713 13 13 714 4.6 3.7 715 14 124 716 6.9 8.7 717 54 29 718 eleven 7.3 719 122

720 10 721 129 722 26 9.0 723 252 724 213 725 68 726 234 727 69 728 59 729 80 730 384 731 253 732 24 733 39 734 13 26 735 64 105 736 27 46 737 26 27 738 24 99 739 39 223 740 25 20 741 8.8 6.1 742 24 26 743 22 8.8 744 15 34 745 4.9 746 8.1 747 26 748 3.5 749 9.6 2.5 750 2.5 751 24 752 1.2 753 25 754 16 755 9.6 756 3.9

- 29 042342

757 234 758 3.4 759 17 2.7 760 42 761 6.7 5.9 762 2.0 763 51 43 764 29 67 765 78 195 766 17 76 767 9.0 25 768 49 82 769 157 295 770 43 335 771 189 128 772 46 113 773 75 230 774 eleven 22 775 88 74 776 113 143 777 12 12 778 10 26 779 10 48 780 21 19 781 5.3 26 782 15 23 783 6.9 8.7 784 3.7 2.6 785 17 6.2 786 16 16 787 7.9 12 788 17 8.3 789 62 29 790 4.9 5.1 791 10 4.0 792 9.9 6.2 793 7.8 4.4

794 2.7 2.7 795 9.5 3.7 796 8.1 3.5 797 3.1 2.2 798 13 4.7 799 6.1 4.8 800 7.1 3.0 801 6.9 1.8 802 8.6 14 803 2.9 3.4 804 2.0 4.9 805 2.4 806 4.0 2.9 807 eleven 13 808 6.1 25 809 5 5 15 810 5.2 3.9 811 3.8 23 812 eleven 27 813 16 42 814 3.8 4.3 815 7.2 eleven 816 eleven 28 817 8.2 22 818 eleven 8.7 819 9.8 14 820 4.5 16 821 9.5 1.8 822 7.9 eleven 823 3.3 8.6 824 4.3 4.2 825 eleven 8.3 826 4.6 2.4 827 2.3 9.9 828 8.4 13 829 13 7.2 830 4.9 3.8

- 30 042342

831 2.5 2.5 832 7.6 12 833 6.2 8.8 834 7.2 10 835 6.1 4.1 836 8.3 5.2 837 22 38 838 7.8 17 839 29 19 840 49 77 841 28 25 842 9.6 23 843 324 357 844 15 24 845 17 36 846 33 57 847 28 16 848 34 272 849 17 14 850 60 248 851 eleven 15 852 14 eleven 853 26 43 854 15 22 855 10 41 856 4.0 857 6.3 858 7.2 859 17 3.5 860 10 3.5 861 4.9 6.1 862 48 103 863 eleven 8.3 864 118 131 865 84 146 866 104 347 867 7.6 2.3

868 14 9.2 869 6.6 5.6 870 8.3 8.1 871 13 6.2 872 9.1 7.6 873 3.4 8.6 874 12 25 875 12 3.2 876 14 3.4 877 eleven 3.9 878 13 8.9 879 24 4.6 880 7.4 881 5.6 882 7.0 5.0 883 5.2 884 6.6 885 8.7 5.0 886 3.7 2.6 887 16 1.6 888 5.8 2.2 889 18 12 890 43 92 891 32 9.3 892 956 28 893 15,000 17 894 75 115 895 12 12 896 65 64 897 242 482 898 42 19 899 28 48 900 18 23 901 7.124 141 902 23 18 903 29 58 904 20 15

- 31 042342

905 15 15 906 7.4 20 907 47 36 908 25 27 909 10 5.6 910 6.4 3.5 911 12 3.5 912 6.7 2.3 913 4.1 2.8 914 17 9.5 915 7.8 1.8 916 10 15 917 4.0 2.6 918 5.5 4.6 919 5.0 3.2 920 0.73 2.3 921 13 16 922 9.6 4.2 923 3.2 5.3 924 5.6 5.0 925 5.7 5.1 926 13 3.0 927 4.6 4.3 928 25 24 929 69 50 930 2.9 3.2 931 5.5 2.7 932 468 7.0 933 9.9 eleven 934 4.7 8.1 935 2.7 2.0 936 7.0 7.5 937 23 4.5 938 8.0 15 939 2.1 3.4 940 9.7 3.0 941 3.9 2.5

942 20 5.0 943 48 326 944 2.5 22 945 9.4 65 946 eleven 65 947 6.6 71 948 147 22 949 25 63 950 10 69 951 2.3 15 952 3.2 24 953 20 182 954 2.7 20 955 6.8 22 956 24 185 957 6.1 13 958 46 78 959 3.6 26 960 23 194 961 6.5 25 962 23 130 963 3.2 34 964 4.4 8.2 965 10 966 5.6 967 16 968 9.8 4.1 969 8.2 970 9.3 971 2.9 972 6.9 973 9.1 974 7.4 975 8.1 976 3.1 977 10 978 5.8

- 32 042342

979 19 980 33 981 24 982 8.0 983 3.8 2.2 984 8.0 4.4 985 15 6.7 986 4.0 1.6 987 4.9 2.9 988 29 18 989 2.7 1.6 990 6.6 2.3 991 3.2 1.4 992 6.6 2.0 993 2.9 1.4 994 3.9 1.3 995 3.8 2.4 996 5.8 1.0 997 6.4 1.4 998 2.7 1.2 999 115 3.2 1000 8.4 5.4 1001 12 65 1002 3.4 5.2 1003 4.3 3.8 1004 6.2 17 1005 7.1 2.9 1006 2.4 7.2 1007 7.3 9.0 1008 2.4 5.7 1009 10 24 1010 5.6 9.6 1011 5.1 15 1012 15,000 7.1 1013 4.1 9.9 1014 3.6 3.7 1015 6.5 22

1016 2.7 5.2 1017 1.5 6.9 1018 8.0 9.3 1019 7.2 8.1 1020 3.7 7.6 1021 3.0 12 1022 3.4 4.6 1023 15 1024 0.75 1025 2.9 1026 0.52 1027 168 1028 254 1029 1.3 1030 367 1031 162 1032 85 1033 97 1034 1.1 1035 3.2 1036 119 1037 3.5 1038 6.2 1039 0.78 1040 58 1041 1.5 1042 2.9 1043 2.3 1044 1.1 1.4 1045 3.3 4.2 1046 12 223 1047 10 91 1048 385 389 1049 153 100 1050 14 70 1051 14 35 1052 39 263

- 33 042342

1053 32 231 1054 35 83 1055 15 53 1056 49 295 1057 37 109 1058 17 244 1059 16 248 1060 14 80 1061 13 7.1 1062 14 98 1063 49 414 1064 35 103 1065 23 96 1066 12 16 1067 83 76 1068 39 106 1069 90 375 1070 23 22 1071 42 131 1072 41 79 1073 47 215 1074 43 291 1075 37 108 1076 37 222 1077 42 227 1078 40 thirty 1079 3.4 40 1080 1.6 7.1 1081 5.1 7.2 1082 eleven thirty 1083 3.7 17 1084 3.7 21 1085 13 50 1086 6.1 42 1087 2.8 10 1088 7.5 9.8 1089 2.9 44

1090 9.0 41 1091 4.6 17 1092 1.7 35 1093 3.8 36 1094 5.6 21 1095 6.3 13 1096 3.2 25 1097 155 310 1098 39 26 1099 9.2 21 1100 138 247 1101 23 7.1 1102 12 19 1103 35 22 1104 12 57 1105 32 114 1106 25 4.3 1107 13 4.7 1108 51 49 1109 16 19 1110 40 18 1111 22 33 1112 23 21 1113 18 29 1114 7.6 6.4 1115 16 25 1116 38 49 1117 3.0 7.3 1118 3.7 3.4 1119 eleven 35 1120 43 1.5 1121 62 39 1122 4.8 8.6 1123 eleven 31 1124 3.6 5.5 1125 eleven eleven 1126 7.3 1.8

- 34 042342

1127 5.9 14 1128 7.4 10 1129 13 37 ISO 7.9 15 1131 84 3.3 1132 9.5 12 1133 7.7 9.5 1134 7.3 6.8 1135 46 32 1136 19 15 1137 75 20 1138 7.2 0.55 1139 35 1.2 1140 5.7 1.1 1141 6.0 0.75 1142 6.3 0.58 1143 5.8 0.53 1144 8.8 0.34 1145 8.5 1.9 1146 4.4 0.47 1147 6.3 1.1 1148 5.2 1.0 1149 4.0 2.6 1150 4.2 1.3 1151 4.0 2.8 1152 5.7 1.0 1153 7.4 2.8 1154 2.6 1.0 1155 17 eleven 1156 34 3.0 1157 4.8 1.7 1158 6.0 2.3 1159 4.1 0.85 1160 7.3 10 1161 5.3 2.6 1162 6.6 3.2 1163 2.5 2.7

1164 2.5 6.0 1165 2.5 0.65 1166 3.0 8.6 1167 2.2 1.2 1168 3.3 0.37 1169 3.9 1.8 1170 3.0 0.74 1171 2.4 1.3 1172 2.7 5.5 1173 2.3 0.95 1174 3.6 1.3 1175 2.8 1.3 1176 3.7 1.4 1177 4.7 0.79 1178 2.2 1.8 1179 3.9 2.4 1180 2.3 1.1 1181 2.4 1.3 1182 214 139 1183 341 209 1184 50 23 1185 121 189 1186 32 36 1187 127 13 1188 76 86 1189 92 27 1190 77 12 1191 123 22 1192 183 98 1193 209 29 1194 267 166 1195 77 41 1196 360 336 1197 150 23 1198 81 67 1199 97 164 1200 54 20

- 35 042342

1201 62 15 1202 15,000 40 1203 3.0 25 1204 7.8 34 1205 eleven 46 1206 7.6 40 1207 2.8 24 1208 15 216 1209 72 241 1210 220 264 1211 575 116 1212 56 74 1213 107 20 1214 230 181 1215 87 76 1216 5.5 48 1217 6.3 67 1218 32 98 1219 117 270 1220 8.8 2.3 1221 5.6 3.9 1222 5.3 4.7 1223 13 41 1224 2.1 9.1 1225 8.8 1226 2.8 8.5 1227 2.9 1228 7.5 40 1229 3.8 1.3 1230 6.6 10 1231 35 18 1232 eleven 3.3 1233 7.2 2.4 1234 23 12 1235 34 7.7 1236 14 3.2 1237 4.8 0.90

1238 6.2 13 1239 2.2 1.1 1240 4.2 1.3 1241 5.7 0.61 1242 2.2 0.44 1243 3.3 0.37 1244 6.1 2.9 1245 3.5 0.75 1246 6.0 0.72 1247 8.4 0.58 1248 6.1 3.1 1249 15 2.5 1250 6.6 1.5 1251 3.5 0.90 1252 2.0 0.73 1253 13 1.5 1254 5.0 1.5 1255 3.4 4.7 1256 3.0 2.1 1257 19 56 1258 4.4 0.53 1259 4.3 1.6 1260 5.4 0.55 1261 eleven 2.8 1262 7.3 1.1 1263 5.7 2.8 1264 9.4 3.9 1265 eleven 0.72 1266 7.6 0.87 1267 2.5 1.1 1268 4.4 1.5 1269 2.1 3.0 1270 3.3 0.79 1271 1.9 1.2 1272 3.6 0.38 1273 3.2 0.86 1274 2.3 0.42

- 36 042342

1275 2.4 0.98 1276 4.1 0.64 1277 2.6 1.1 1278 4.8 1.9 1279 2.7 0.27 1280 2.7 0.32 1281 2.6 0.43 1282 2.9 5.0 1283 2.0 2.4 1284 2.0 1.7 1285 2.2 0.60 1286 4.5 2.5 1287 2.7 0.75 1288 5.0 5.2 1289 5.646 0.49 1290 7.5 25 1291 2.9 2.8 1292 1.9 0.58 1293 16 3.8 1294 7.0 24 1295 2.7 0.61 1296 2.3 0.69 1297 5.7 9.1 1298 1.7 1.4 1299 4.0 0.58 1300 89 328 1301 175 298 1302 67 356 1303 91 291 1304 51 383 1305 866 480 1306 1.9 2.8 1307 3.3 0.89 1308 9.3 1.4 1309 4.4 0.62 1310 5.9 1.5 1311 2.4 0.81

1312 2.0 1.9 1313 2.1 1.3 1314 4.8 eleven 1315 17 52 1316 15 6.8 1317 12 7.5 1318 3.6 1319 8.4 1320 44 1.8 1321 2.3 1322 12 23 1323 8.8 4.9 1324 5.8 8.1 1325 9.2 2.9 1326 5.0 4.3 1327 3.2 1.2 1328 82 71 1329 1.6 3.7 1330 5.0 3.3 1331 19 21 1332 5.3 0.81 1333 19 15 1334 332 8.7 1335 18 4.4 1336 thirty 15 1337 8.0 2.8 1338 5.0 4.7 1339 39 1340 3.3 1341 4.1 1342 thirty 1343 106 0.87 1344 5.8 8.3 1345 31 1346 55 35 1347 51 213 1348 10 29

- 37 042342

1349 21 41 1350 136 220 1351 4.4 29 1352 14 73 1353 19 288 1354 20 20 1355 19 28 1356 16 42 1357 42 39 1358 331 323 1359 167 342 1360 7.7 105 1361 43 thirty 1362 260 1363 26 1364 45 1365 253 1366 84 1367 64 1368 26 1369 47 1370 122 1371 255 1372 192 1373 20 1374 328 1375 39 1376 37 1377 375 1378 17 1379 134 1380 50 242 1381 87 71 1382 14 26 1383 187 364 1384 47 45 1385 9.7 16

1386 thirty 50 1387 4.0 1388 4.9 1389 85 1390 13 1391 372 1392 3.3 1393 18 1394 300 1395 10 1396 33 1397 28 1398 28 1399 3.1 1400 4.1 1401 78 1402 17 1403 92 1404 93 1405 38 1406 136 153 1407 38 94 1408 thirty 1409 224 1410 271 1411 167 1412 433 1413 95 1414 85 1415 78 40 1416 53 209 1417 4.9 1418 132 1419 46 99 1420 2.3 2.2 1421 109 274 1422 17 16

- 38 042342

1423 3.5 25 1424 4.2 2.5 1425 2.1 1.5 1426 7.8 eleven 1427 thirty 18 1428 3.7 2.9 1429 16 28 1430 1.2 4.2 1431 2.4 5.5 1432 32 291 1433 4.1 eleven 1434 4.4 4.5 1435 5.6 7.6 1436 9.2 8.4 1437 3.0 1438 136 1439 1.9 1440 3.9 1441 7.5 1442 16 1443 2.9 1444 4.8 1445 7.6 1446 1.9 1447 7.5 1448 1.5 1449 131 1450 73 164 1451 99 1452 85 1453 318 1454 10 6.8 1455 61 64 1456 97 1457 7.3 1458 8.2 1459 2.9

1460 9.5 42 1461 4.1 32 1462 3.1 3.2 1463 2.9 2.0 1464 2.8 4.7 1465 4.7 16 1466 4.5 3.3 1467 44 16 1468 125 278 1469 44 212 1470 76 287 1471 18 94 1472 1.3 3.2 1473 3.8 12 1474 13 14 1475 21 191 1476 26 77 1477 3.3 22 1478 23 221 1479 14 31 1480 2.0 12 1481 36 369 1482 2.7 17 1483 8.6 5.2 1484 0.63 1.9 1485 1.5 6.6 1486 2.2 4.2 1487 3.8 31 1488 4.2 15 1489 1.3 22 1490 1.2 12 1491 5.8 64 1492 3.2 7.6 1493 1.9 eleven 1494 5.9 143 1495 15 238 1496 12 85

- 39 042342

1497 2.7 9.4 1498 223 1499 1.4 0.77 1500 3.8 1.4 1501 2.7 2.6 1502 2.9 0.53 1503 4.4 2.9 1504 10 1505 eleven 2.4 1506 9.3 4.3 1507 8.9 0.37 1508 15,000 8.0 1509 7.0 2.1 1510 8.6 1.6 1511 66 6.0 1512 96 5.1 1513 21 2.9 1514 6.3 4.8 1515 9.7 1.5 1516 5.8 0.62 1517 5.5 1.1 1518 4.6 1.6 1519 9.8 3.7 1520 7.8 3.3 1521 12 3.2 1522 14 3.8 1523 61 59 1524 9.2 4.3 1525 10 2.6 1526 1.667 6.8 1527 87 10 1528 96 78 1529 66 3.8 1530 15,000 44 1531 128 39 1532 50 2.1 1533 27 1.9

1534 47 1.9 1535 6.0 1.5 1536 66 7.9 1537 50 129 1538 64 71 1539 15,000 446 1540 19 eleven 1541 3.2 0.83 1542 4.1 2.5 1543 3.2 1544 2.3 1545 5.5 21 1546 eleven 17 1547 29 34 1548 3.0 0.60 1549 5.8 1.2 1550 4.8 2.9 1551 3.2 1.2 1552 6.6 9.7 1553 6.6 1.8 1554 9.2 1.4 1555 8.5 1.5 1556 28 3.5 1557 7.9 18 1558 4.3 8.8 1559 16 64 1560 2.9 0.93 1561 7.4 0.67 1562 3.8 0.55 1563 9.5 1.5 1564 3.3 1.0 1565 4.2 4.1 1566 15 8.9 1567 2.3 2.1 1568 10 46 1569 9.7 14 1570 6.7 2.0

- 40 042342

1571 1.4 1572 0.41 1573 2.7 1574 16 0.61 1575 4.7 0.55 1576 10 0.56 1577 4.6 0.45 1578 2.8 1.0 1579 38 233 1580 25 117 1581 3.0 0.95 1582 3.7 2.3 1583 2.6 1.3 1584 15 1.9 1585 5.4 1.6 1586 2.7 0.60 1587 8.3 1.4 1588 2.4 1.1 1589 1.0 0.29 1590 8.2 0.82 1591 1.1 1592 4.3 6.1 1593 5.9 10 1594 3.3 6.1 1595 5.3 13 1596 2.2 2.2 1597 6.3 8.6 1598 9.5 1.2 1599 4.2 5.1 1600 eleven 1.6 1601 26 4.3 1602 5.1 9.5 1603 5.9 9.9 1604 eleven 5.7 1605 6.0 8.4 1606 2.4 2.0 1607 2.9 1.2

1608 2.8 0.59 1609 5.6 1.5 1610 0.51 1611 4.7 5.1 1612 1.5 8.4 1613 eleven 4.6 1614 12 eleven 1615 7.4 5.5 1616 1.6 0.24 1617 4.0 1.1 1618 4.2 0.68 1619 3.8 1.3 1620 13 0.96 1621 1.1 0.67 1622 3.0 1.1 1623 2.7 2.3 1624 21 1.4 1625 2.4 1.1 1626 3.9 0.91 1627 8.6 1628 61 1629 9.2 1630 24 1631 8.3 1632 4.1 1633 3.8 2.4 1634 5.3 3.3 1635 51 8.1 1636 2.9 2.8 1637 5.1 1.2 1638 7.3 1.7 1639 7.3 1.4 1640 10 3.8 1641 0.43 1642 19 0.81 1643 1.4 1644 0.92

- 41 042342

1645 2.5 1646 0.34 1647 9.0 0.86 1648 0.67 1649 1.8 1650 23 1.7 1651 0.68 1652 0.77 1653 1.1 1654 0.44 1655 3.1 1.3 1656 8.3 1.0 1657 12 1.1 1658 7.4 1.2 1659 1.6 0.48 1660 2.2 0.79 1661 36 31 1662 43 9.5 1663 3.3 6.3 1664 28 76 1665 92 33 1666 eleven 13 1667 20 73 1668 2.9 9.7 1669 427 231 1670 6.6 14 1671 4.9 8.0 1672 55 1673 36 1674 51 1675 134 1676 56 1677 10 1678 119 281 1679 56 156 1680 159 1681 40 121

1682 59 200 1683 188 1684 235 1685 64 478 1686 26 15 1687 35 154 1688 20 86 1689 5.1 10 1690 28 70 1691 8.6 13 1692 12 59 1693 8.7 4.0 1694 46 94 1695 13 9.0 1696 12 9.3 1697 66 191 1698 12 26 1699 158 487 1700 17 456 1701 15 377 1702 67 294 1703 309 1704 20 272 1705 35 150 1706 4.8 7.5 1707 10 12 1708 34 63 1709 27 14 1710 6.6 49 1711 16 1712 28 75 1713 121 143 1714 15 7.8 1715 14 38 1716 6.4 14 1717 3.4 0.65 1718 3.8 0.28

- 42 042342

1719 4.7 1.1 1720 19 217 1721 37 42 1722 201 295 1723 3.1 1724 0.61 1725 17 20 1726 8.4 1.4 1727 4.7 4.3 1728 93 25 1729 75 25 1730 13 20 1731 60 28 1732 52 82 1733 234 1734 284 1735 251 1736 222 1737 36 1738 63 1739 62 46 1740 33 1741 26 101 1742 29 28 1743 9.8 36 1744 8.6 eleven 1745 eleven 4.2 1746 105 74 1747 126 274 1748 106 39 1749 207 204 1750 450 194 1751 53 48 1752 13 2.7 1753 9.6 4.1 1754 7.9 27 1755 177 197

1756 7 3.2 1757 26 25 1758 9.0 18 1759 4.4 4.0 1760 2.9 8.7 1761 8.5 3.8 1762 3.3 3.6 1763 14 3.7 1764 8.6 7.4 1765 eleven 10 1766 228 375 1767 47 1768 16 34 1769 9.6 7.6 1770 376 352 1771 139 146 1772 20 26 1773 9.5 0.85 1774 8.7 2.7 1775 21 9.9 1776 2.2 0.74 1777 3.5 0.55 1778 4.7 12 1779 392 485 1780 20 39 1781 18 22 1782 283 239 1783 126 169 1784 31 49 1785 2.7 2.3 1786 7.2 9.6 1787 3.7 2.9 1788 102 131 1789 118 67 1790 112 95 1791 19 31 1792 4.9 0.37

- 43 042342

1793 1.8 2.9 1794 3.2 1.0 1795 7.3 10 1796 243 1797 8.4 1798 36 15 1799 9.9 4.6 1800 17 3.0 1801 27 7.9 1802 1.9 0.45 1803 6.4 0.86 1804 15,000 420 1805 5.5 2.0 1806 27 2.2 1807 21 16 1808 2.6 0.75 1809 5.4 1.0 1810 6.5 2.8 1811 9.1 3.2 1812 5.5 0.57 1813 13 2.3 1814 eleven 2.1 1815 24 2.9 1816 13 5.6 1817 20 19 1818 15 5.1 1819 9.1 2.2 1820 27 13

1821 6.5 14 1822 33 9.4 1823 47 24 1824 34 14 1825 19 3.3 1826 7.7 1827 6.0 1828 23 27 1829 3.9 9.4 1830 157 234 1831 242 1832 26 172 1833 13 46 1834 7.6 13 1835 BY 1836 5.4 9.1 1837 130 1838 105 1839 288 1840 296 1841 41 86 1842 117 125 1843 58 76 1844 39 120 1845 15 126 1846 97 457 1847 728 29 1848 0.54

TNF-induced systemic inflammatory response syndrome (SIRS).

RIPK1 inhibitors were evaluated for efficacy in vivo using a TNF-dependent systemic shock model, also known as systemic inflammatory response syndrome (SIRS) (Duprez et al. 2011, Immunity 35 (6): 908-918). Intravenous administration of mouse TNF induces a systemic inflammatory response characterized by a decrease in body temperature and an increase in circulating cytokines (IL-6, KC) in the blood serum. The addition of zVAD-fmk strongly sensitizes mice to TNF-induced shock via caspase inhibition (Cauwels et al., 2003). The combination of zVAD-fmk pretreatment prior to mTNF injection forms the basis of the RIPK1-dependent TNF-induced inflammatory response in this model. Female C57/BL/6 mice (aged 9 to 11 weeks) were obtained from Jackson Labs (Bar Harbor, ME). The mice were kept in the BMS vivarium with unlimited access to food and water. Mice were allowed to acclimate for at least 2 weeks and typically reach a weight of at least 21 grams before being used in any studies. The group size was 6 mice per experiment. All experiments were performed with the approval of the Institutional Animal Care and Use Committee (IACUC).

Test compounds were dosed by gavage 2 hours prior to intravenous administration of 20 μg mouse TNF (#CRT192C, Cell Sciences, Canton, MA). zVAD-fmk (16.7 mg/kg) was administered intravenously 15 min before mTNF administration. The RIPK1 kinase inhibitor, necrostatin-1s (Nec-1s), was used as a positive control and dosed at 6 mg/kg, intravenously, 30 min prior to mTNF administration. mTNF was diluted in PBS free of endotoxin and injected at 20 μg/mouse in a volume of 0.1 ml into the retroorbital sinus. All intravenous injections were performed through the retroorbital sinus, and injection sites alternated (left and right sides).

Three hours after mTNF administration, mice were assessed for hypothermia and lethality. The temperature in the rectum was recorded using an electric thermometer.

Blood samples for PK determination were collected in heparinized Microtainer blood collection tubes (Part #365965, Becton Dickinson, Franklin Lakes, NJ) and mixed well. Dry blood drops (DBS) were prepared by pipetting 10 μl whole blood in duplicate onto bioassay cards (#GR2261004, Perkin Elmer, Greenville, SC). A serum sample was obtained by collecting blood into a serum separation tube (#450472, Greiner Bio-One, Austria) and centrifuged (10 min at 10,000 rpm) to separate the serum. All blood samples were taken from the retroorbital sinus during isoflurane anesthesia.

Serum cytokine levels were assessed by ELISA. IL-6 levels were measured using the OptEIA kit (Becton Dickinson, Franklin Lakes, NJ), while KC levels were measured using the R&D Duoset kit (R&D Systems Inc., minneapolis, MN). Using these assays, percent body temperature protection and percent reduction of serum cytokines IL6 and KC were determined for the following compounds. See table. b.

Table B

Example Compound Dose % protection against lower body temperature % reduction in serum levels of KS cytokines % reduction in serum levels of IL6 cytokines 10 1.0 mg/kg 70 88 78 31-1 1.0 mg/kg 77 89 77 311 0.1 mg/kg 81 79 88 1224 1.0 mg/kg 72 65 88 1605 1.0 mg/kg 46 52 43 31-1 1.0 mg/kg 77 89 77

PI3Kδ binding analysis by HTRF.

A solution was prepared containing 0.2 nM anti-GST-Tb (Cisbio, 61GSTTLB), 40 nM fluorescein-labeled probe, and 1 nM GST-labeled PIK3Cδ complexed with PIK3R1 (Invitrogen #PV5273) in FRET buffer (20 mM HEPES, 10 mM MgCl ₂ , 0.015% Brij-35, 4 mM DTT, 0.05 mg/mL BSA). Using Formulatrix Tempest, the detection antibody/enzyme/probe solution (2 µl) was dispensed into the wells of a 1536-well plate (Black Low Binding Polystyrene 1536 Plate (Coining, 3724)) containing 10 nl of test compounds at the appropriate concentration in DMSO. The plate was incubated at room temperature for 1 hour. FRET was measured using an EnVision plate reader (excitation: 340 nM, emission: 520 nM/495 nM). The overall signal (0% inhibition) was calculated from wells containing only 10 nl DMSO. The quench signal (100% inhibition) was calculated from wells containing 10 nl of a mixture of 15 nM staurosporine and internal controls.

Percent inhibition was determined for test compounds at 11 concentrations. The IC ₅₀ value, defined as the concentration of the alternative test compound required to reduce specific probe binding by 50%, was calculated using a 4-parameter data-fitted logistic equation. The fold selectivity for RIPK1 was calculated by dividing the IC ₅₀ for PI3Kδ by the IC ₅₀ of RIPK1 HTRF. See table. C.

Table C

RPSP5 RIPK1 selectivity (fold x) Example 1С ₅₀ (nM) < Yuh Between 10 x and 100 x > 100 X 1 >1500 X 2 1192 X 3 >1500 X 8 >1500 X 9 >1500 X 10 >1500 X 17 >1500 X 26 232 X 60 >1500 X 61 >1500 X 62 >1500 X 65 1419 X 69 >1500 X 71 >1500 X 73 165 X 74 121 X 76 1155 X 77 260 X 78 45 X 81 565 X 82 >1500 X 109 >1500 X

- 45 042342

110 >1500 X 117 528 X 119 154 X 125 1100 X 129 211 X 133 162 X 140 >1500 X 153 >1500 X 160 >1500 X 165 735 X 166 140 X 167 137 X 168 247 X 169 681 X 171 280 X 181 450 X 184 1431 X 243 >1500 X 246 237 X 247 236 X 248 >1500 X 250 514 X 269 434 X 270 >1500 X 271 >1500 X 272 285 X 276 693 X 277 180 X 311 608 X 386 367 X 426 1179 X 481 14966 X 487 >15000 X 489 4132 X 491 1937 X 502 3369 X 505 >15000 X 554 >15000 X 569 545 X 615 78 X 625 100 X 645 1319 X 646 617 X 650 >15000 X 652 >15000 X 653 1937 X 656 1670 X 658 103 X 686 >15000 X

- 46 042342

690 13214 X 702 1739 X 741 580 X 781 2054 X 783 686 X 790 1089 X 833 974 X 842 1180 X 885 529 X 886 847 X 888 487 X 906 443 X 910 200 X 911 35 X 912 553 X 918 44 X 931 558 X 968 195 X 986 1169 X 990 63 X 994 553 X 1000 306 X 1081 141 X 1083 170 X 1088 558 X 1126 2238 X 1128 174 X 1138 >15000 X 1140 >15000 X 1141 >15000 X 1142 >15000 X 1143 >15000 X 1144 >15000 X 1145 >15000 X 1146 >15000 X 1147 >15000 X 1148 >15000 X 1149 >5000 X

- 47 042342

1150 >15000 X 1151 >15000 X 1152 >15000 X 1153 >15000 X 1154 >15000 X 1157 >15000 X 1158 >15000 X 1159 >15000 X 1160 >15000 X 1161 >15000 X 1162 >15000 X 1163 >15000 X 1174 928 X 1175 940 X 1220 >15000 X 1237 >15000 X 1238 >15000 X 1239 >15000 X 1240 >15000 X 1241 >15000 X 1242 >15000 X 1243 >15000 X 1244 >15000 X 1245 >15000 X 1246 >15000 X 1247 >15000 X 1248 >15000 X 1250 >15000 X 1251 >15000 X 1252 >15000 X 1254 >15000 X 1255 >15000 X 1256 >15000 X 1258 >15000 X 1259 >15000 X 1260 >15000 X 1262 >15000 X 1263 >15000 X

- 48 042342

1264 >15000 X 1266 >15000 X 1267 >15000 X 1268 >15000 X 1269 >15000 X 1270 >15000 X 1275 4974 X 1278 >15000 X 1285 5209 X 1332 128 X 1338 322 X 1344 >15000 X 1462 >15000 X 1500 >15000 X 1502 >15000 X 1506 >15000 X 1509 >15000 X 1510 >15000 X 1514 >15000 X 1515 >15000 X 1516 >15000 X 1517 >15000 X 1518 >15000 X 1519 >15000 X 1520 >15000 X 1524 >15000 X 1535 >15000 X 1541 >15000 X 1542 >15000 X 1543 >15000 X 1544 >15000 X 1548 >15000 X 1553 >15000 X 1557 13283 X 1558 >15000 X 1560 >15000 X 1562 5185 X 1563 >15000 X

- 49 042342

1564 >15000 X 1567 3166 X 1577 >15000 X 1578 >15000 X 1581 >15000 X 1595 >15000 X 1596 >15000 X 1606 437 X 1616 14779 X 1617 11000 X 1626 6268 X 1633 5107 X 1638 7849 X 1639 >15000 X 1647 7944 X 1655 5571 X 1656 5261 X 1658 9148 X 1659 >15000 X 1660 >15000 X 1689 >5000 X 1693 >15000 X 1716 12742 X 1717 >15000 X 1718 >15000 X 1719 >15000 X 1810 53 X 1811 148 X 1812 261 X 1819 1412 X 1836 >15000 X 31-1 335 X

How to get

Compounds of formula (I) and intermediates used in the preparation of compounds of formula (I) can be prepared using the methods shown in the following examples and appropriate procedures. The methods and conditions used in these examples, and the specific compounds obtained in these examples, are not intended to be limiting, but are intended to demonstrate how the compounds of formula (I) can be obtained. The starting materials and reagents used in these examples, when not prepared using the method described herein, are generally either commercially available or specified in the chemical literature, or can be obtained using methods described in the chemical literature.

The abbreviations used in this document are defined as follows: 1x for single, 2x for twice, 3x for thrice, aq or aq. for water, °C for degrees Celsius, eq for equivalent or equivalents, g for gram or grams, mg for milligram or milligrams, l for liter or liters, ml for milliliter or milliliters, µl for microliter or microliters, N for normal, M for molarity, mmol for millimoles or millimoles, min for minutes or minutes, h for hours or hours, rt for room temperature, ON for overnight, RT for retention time, atm for atmosphere, psi for psi, conc . for concentration, us. or saturated for saturation, CVs for column volume, MW for molecular weight, mp for melting point, ee for enantiomeric excess, MS or Mass Spec for mass spectrometry, ESI for electrospray ionization mass spectrometry, HR for high resolution, HRMS for high resolution mass spectrometry, LCMS or LC-MS for liquid chromatography-mass spectrometry, HPLC for high performance liquid chromatography, RP HPLC for reverse phase HPLC, TLC or tlc for thin layer chromatography, SFC for supercritical mobile phase chromatography, NMR for spectroscopy nuclear magnetic resonance, nOe for nuclear Overhauser effect spectroscopy, 1H for proton, δ for delta, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, br for broadened, MHz for megahertz, and α, β, R, S, E, and Z are stereochemical designations generally accepted in the art.

- 50 042342

Me methyl Et ethyl Pr propyl z-Pr isopropyl Bu z-Bu butyl isobutyl /-Bu Z7Z/?eZ7Z-BYTIL Ph phenyl bn benzyl Boc tert-butyloxycarbonyl AcOH or HO Ac acetic acid ASGO acetic anhydride Boc (zzz/?ezzz-bytoκci)κapbonyl B.O.P. benzotriazole-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate CBz carbobenzyloxy CH2CI2 dichloromethane CH3CN or ACN acetonitrile CDCh deutero-chloroform CHCh chloroform CS2CO3 cesium carbonate DAST diethylaminosulfur trifluoride DCE 1,2 dichloroethane DCM dichloromethane DIEA/DIPEA/Hunig base diisopropylethylamine

DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N'~ ethylcarbodiimide EDCI A-(3-dimethylaminopropyl)-A'ethylcarbodiimide hydrochloride Et3N or TEA triethylamine EtOAc ethyl acetate _Et2O diethyl ether EtOH ethanol HC1 hydrochloric acid

- 51 042342

HATU O-p-azabenzotriazole-HylLA.A.A'.A- tetramethyluronium hexafluorophosphate hex hexane HMDS hexamethyldisilazane HOBt or HOBT 1-hydroxybenzotriazole H2SO4 sulfuric acid _{K2CO3 _} potassium carbonate KOAC potassium acetate K3PO4 potassium phosphate LAH lithium aluminum hydride LG leaving group LiOH lithium hydroxide MeOH methanol Mel iodomethane _MgSO4 magnesium sulfate NaCl sodium chloride NaH sodium hydride _NaHCO3 bicarbonate of soda _{Na2CO3 _} sodium carbonate NaOH sodium hydroxide _{Na2SO3 _} sodium sulfite _{Na2SO4 _} sodium sulfate NBS N-bromosuccinimide NCS N-chlorosuccinimide _NH3 ammonia NH4CI ammonium chloride NH4OH ammonium hydroxide NIS N-iodosuccinimide NMP N-methylpyrrolidine OAC acetate OTf triflate or trifluoromethanesulfonate Pd ₂ (dba) ₃ tris(dibenzylideneacetone)dipalladium (0 Pd(OAc) ₂ palladium(II) acetate Pd/C palladium on a carbon carrier

- 52 042342

PdC12(dppf) [1,1'-bis(diphenylphosphino)- ferrocene]dichloropalladium (II) PG protecting group pin pinacol RMV para-methoxybenzyl ROSE phosphorus oxychloride i-PrOH or IP A isopropanol _SiO2 silicon oxide TV AI tetra-and-butylammonium iodide TFA trifluoroacetic acid THF tetrahydrofuran AIBN azobisisobutyronitrile ACN acetonitrile DAST diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane IPA isopropyl alcohol TBAF tetra-i-butylammonium fluoride

The compounds of the present invention can be synthesized in a variety of ways available to those skilled in the art of organic chemistry (Maffrand, J. P. et al., Heterocycles, 16(1):35-7 (1981)). General synthetic schemes for the preparation of the compounds of the present invention are described below. These schemes are illustrative and are not intended to limit the possible methods that a person skilled in the art can use to obtain the compounds disclosed in this document. Various methods for preparing the compounds of the present invention will be apparent to those skilled in the art. In addition, the various steps of the synthesis can be performed in an alternative sequence to obtain the desired compound or compounds.

Examples of compounds of the present invention prepared by the methods described in the general schemes are given in the intermediates and examples section below. Exemplary compounds are typically prepared as racemic mixtures. Obtaining homochiral examples can be performed by methods known to the person skilled in the art. For example, homochiral compounds can be obtained by separating racemic products using preparative HPLC with a chiral phase. Alternatively, exemplary compounds may be prepared by methods known to produce enantiomerically enriched products. These include, but are not limited to, the introduction of chiral auxiliary functional groups into racemic intermediates that serve to control the diastereoselectivity of the transformations to produce enantio-enriched products upon cleavage of the chiral auxiliary.

Proton magnetic resonance (1H NMR) spectra were recorded on either a Bruker Avance 400, Bruker 500, or JEOL Eclipse 500 spectrometer and are reported in ppm (parts per million) relative to the reference solvent of the sample in which they were run. HPLC and LC-MS analyzes were performed using a Shimadzu SCL-10A liquid chromatograph and an SPD UV-vis UV detector at 220 nm with MC detection performed either on a Micromass Platform LC spectrometer or on a Waters Micromass ZQ spectrometer. All flash column chromatography was performed on silica gel 60 EM Science (particle size 40-60 µm). All reagents were purchased from commercial sources and were used without further purification unless otherwise noted. All reactions were carried out in an inert atmosphere. HPLC analyzes were performed using the following conditions. All final compounds in HPLC analysis were >95% pure unless otherwise noted.

Substituents designated in the schemes and examples, for example, as R, R ¹ or R ² , etc., do not necessarily correspond to the designations of the substituents indicated in the claims.

Scheme 1 illustrates the approach to the synthesis of compounds using compound 3 as an example. Functionalization of starting material 1 can be achieved by amidation (Tetrahedron, 61:1082710852, 2005) to give bromide 2. Amidation of 1 can be carried out using an anhydride or an acid chloride in combination with a base . Suzuki coupling (Miyaura, N. and Suzuki, A. Chemical Reviews, 95:2457-2483, 1995) 2 and 4 can give compounds exemplified by 3. The Suzuki reaction can be carried out by in situ conversion of 2 to its corresponding boronate ester or boronic acid followed by coupling with 4. Initial in situ formation of boronate ester or boronic acid derived from 4 followed by coupling with bromide 2

- 53 042342 can also be effective for the formation of compounds designated as 3. In addition, a separate isolation of the boronate obtained from 2 or 4 can also be used in the transformation.

Scheme 1

The trifluoromethyl group can be incorporated into the heterocyclic portion of the molecule as described in Scheme 2. Protection of the amino group in 4 by prior iodination results in compound 6. Although p-methoxybenzyl groups are depicted in Scheme 2, a variety of protecting groups suitable for these transformations. Trifluoromethylation gives 7 by a chemoselective method. Deprotection under acidic conditions at elevated temperatures yields the substituted heterocyclic ring 8. Bromide 8 can be subjected to a Suzuki coupling reaction with phenylboronic acid or a boronate ester, exemplified by 9, to give the bound compound 10. As shown in Scheme 1, the reversibility of coupling can be practiced and known to those skilled in the art. In addition, while the phenyl and substituted analogs shown in the Scheme will all work in conversion, a six-membered heteroarene can also be used. If 9 is an ester instead of a carboxylic acid, a hydrolysis step can be carried out after the Suzuki reaction. Suitable bases may include lithium hydroxide monohydrate, sodium hydroxide, or others known to those skilled in the art. The compounds exemplified by compound 11 can be formed by amide coupling mediated by the BOP reagent as shown in the scheme, or by an alternative amide coupling reagent. The use of an anhydride or carboxylic acid chloride can also affect this conversion.

Scheme 2

oh by

An alternative substitution with a trifluoromethyl group (Scheme 2) in the heterocyclic ring can be carried out as shown in Scheme 3. From the alkyne 12, addition of an azide promoted by silver followed by a rearrangement can lead to the formation of 13. Alternatively, 13 can be formed by a three-step a protocol in which ester 14 can be hydrolyzed, amidated to form the primary amide, and dehydrated to form the nitrile at 13. As shown in Scheme 2, the heterocyclic core can be Suzuki coupled with an aryl boronate ester or boronic acid. One skilled in the art can extrapolate this to include heteroarylboronate esters and heteroarylboronic acids. This transformation can also lead to the reverse interaction of the matching partners. Formation of an amide bond under standard conditions known to those skilled in the art can lead to the formation of analogs, examples of which are compound 16.

- 54 042342

Scheme 3

Scheme 4 details the formation of a heterocyclic system that can be substituted in the 6- and 7-positions rather than the 5- and 7-positions described in the previous schemes. Ketone 17 can be converted to the corresponding difluoroalkane 18 at low temperatures using DAST. After deprotection of pyrrolidine, MnO ₂ mediated oxidation can lead to the formation of pyrrole 20. N-amination may precede cyclization to the pyrrolotriazine 22 core.

The amino group can be attached by conversion to chloride and subsequent displacement with ammonia. Bromination under standard conditions can give the heterocyclic core 24. As shown in Scheme 2, the heterocyclic core can be Suzuki coupled with an aryl boronate ester or boronic acid. One of skill in the art can transfer this to the inclusion of heteroarylboronate esters and heteroarylboronic acids. This transformation can also lead to the reverse interaction of the matching partners. Formation of an amide bond under standard conditions known to those skilled in the art can lead to analogs, exemplified by compound 26.

Scheme 4

Scheme 5 specifically describes a synthetic route for the preparation of pyridine analogs, exemplified by 32. 5-Bromopyridine such as 27 can be converted to the corresponding boronate ester 28 under anhydrous Suzuki coupling conditions. Additional coupling of Suzuki with heteroaryl bromide 29 under aqueous conditions can produce esters such as 30. Although intermediate 28 is isolated in Scheme 5, the sequence can be run as a single reactor reaction under conditions known to those skilled in the art. As described earlier, the matching partners can also be reversed for these two transformations. With esters such as 30, hydrolysis under various conditions can lead to the formation of the free acid or the corresponding lithium or sodium salt of 31. Amidation under standard conditions of coupling peptides known to those skilled in the art can lead to compounds analogous to 32.

- 55 042342

Scheme 5

Scheme 6 illustrates another route available for the preparation of compounds, exemplified by 32. Nicotinic acid derivatives such as 33 can be amidated to give 34. In addition to amide coupling under various conditions, 34 can also be prepared by coupling an anhydride or acid chloride. The conversion of 34 to the corresponding boronate ester 35 can take place under anhydrous Suzuki coupling conditions. 35 can be carefully isolated or used in situ in the subsequent Suzuki reaction with pyrrolotriazine 29. As in the previous examples, the coupling partners can be reversed in Suzuki reactions where 29 can be converted to the boronate ester (gently or in situ) and subsequently associated with bromide 34.

Scheme 6

In addition to the aryl and pyridyl coupling partners described below, five-membered rings can also be used to prepare compounds like 42. Conversion of ketone 36 to vinyl triflate 37 can occur at low temperature using Comyn's reagent as the triflate source. Conversion to the boronate ester under anhydrous Suzuki coupling conditions can give 38. Subsequent coupling of Suzuki with pyrrolotriazine such as 29 can give a related product similar to 39. Lithium hydroxide mediated hydrolysis can give the carboxylic acid or its lithium salts. Alternative bases known to those skilled in the art may be used in this hydrolysis. Amide coupling can occur with a BOP reagent as depicted in the scheme, or with alternative peptide coupling reagents known to those skilled in the art. Deprotection of the Boc may result in end analogues similar to 42.

- 56 042342

Scheme 7

In addition to the pyrrolotriazines exemplified above, a variety of other substituted pyrrolotriazines can also be prepared. They are described in the following diagrams. Chlorinated pyrrolotriazine 43 can be obtained by treating pyrrolotriazine 4 with NCS (Scheme 8). This intermediate can be used in the same manner as 4, 8, 13, 24 or 29 as described in the previous schemes.

Scheme 8

Scheme 9 illustrates the preparation of the 5-methylpyrrolotriazine core 46. Bromination of 44 at position 7 under standard conditions gives 45. The chloride can be substituted using ammonium hydroxide to give 46. This intermediate can be used in the same manner as 4, 8, 13, 24 or 29 as described in the previous diagrams.

Scheme 9

Larger groups can also be formed at the 5-position of the pyrrolotriazine, as shown in Scheme 10. Ammonium hydroxide can be used to displace the chloride from the core in 47 and produce the amine shown in 48. Treatment of 48 with alcohol in the presence of a base can cause the bromide-forming adducts to be displaced triethylammonium, of which 49 is an example. Similarly, primary or secondary amines can also displace triethylammonium bromide at elevated temperatures to form analogs like 50. These intermediates can be used in the same manner as 4, 8, 13, 24 or 29 as described in previous diagrams.

Scheme 10

Vg

As an alternative to substitution in the pyrrole moiety of the heteroarene, triazine can also be substituted (Scheme 11). Compound 51 can be coupled and cyclized to form pyrrolotriazine 52 in the presence of formadine acetate at elevated temperatures. Bromination under standard conditions can give 53. Treatment with POCl ₃ gives chloride 54. The chloride can be substituted with primary or secondary amines in the presence of a base and at elevated temperatures to give the compounds shown in Example 55. These intermediates may be used in the same manner as 4, 8, 13, 24 or 29 as described in the previous diagrams.

Scheme 11

Modifications to pyrrolotriazine can also be made at a later stage in the synthetic sequence as shown in Scheme 12. Pyridines like 56 can be Suzuki coupled with 14 to give analogs like 57. Ester hydrolysis can be done with sodium hydroxide , however, other bases known to those skilled in the art may also be effective for hydrolysis. Amide coupling under standard peptide coupling conditions can be used to prepare compounds exemplified by 59.

An alternative combination can occur using methods known to those skilled in the art, such as using an acid chloride or anhydride.

Scheme 12

U ^H 2 CO ₂ Et

In the case of nicotinic acid derivatives, which may not be commercially available, 2chloropyridine 60 can be displaced to give 61 (Scheme 13). Intermediate 61 can be converted to the boronate ester or boronic acid and used in Suzuki coupling reactions with any of the pyrrolotriazine analogs described herein. It can also be used in a similar manner with pyrrolotriazine boronate ester or boronic acid. As shown in Scheme 13, hydrolysis of the ester under standard conditions can produce acid 62. This can be coupled with any primary or secondary amines as previously described. The amide compound can then be introduced into a Suzuki reaction using the protocols described in the previous schemes.

Scheme 13

61 62

The following series of schemes describe the various ways in which a substituted pyrrolidine can be incorporated in both an achiral and a chiral manner. Scheme 14 shows the incorporation of a cisracemic or diastereomeric mixed 63. The carboxylic acid 31 can be amide coupled with 63 in the presence of a base and a BOP reagent. Alternative amide bond coupling reagents known to those skilled in the art may also be used. Deprotection of the Boc group under acidic conditions may result in secondary amine 65 as the penultimate compound. This intermediate can be coupled with sulfonyl chlorides to give the sulfonamide 66. Alternatively, 65 can be alkylated with an alkyl halide in the presence of a base at elevated temperature to give compounds like 68. One skilled in the art could also use an epoxide instead of an alkyl halide to make the hydroxyl-containing analogue 68. Coupling of amide 65 with a carboxylic acid in the presence of a coupling reagent, such as a BOP reagent or others known to those skilled in the art, can result in analogs like 70. One of skill in the art can also use 65 in additional transformations to obtain analogues of carbamate and urea. The use of chiral purification with a sulfonamide, tertiary amine or amide SFC can give the preferred isomers shown (67, 69 and 71). Chiral preparative HPLC can also separate a racemic or diastereomeric mixture.

Scheme 14

Vos

The preparation of the preferred chiral intermediate is described in Scheme 15. The carboxylic acid 33 can be coupled to the pyrrolidine 63 (cis-racemic or diastereomeric mixture) under standard amide coupling conditions with the BOP reagent. Other peptide coupling reagents known to those skilled in the art may also be used. The product 72 can be purified using chiral SFC to isolate analogues of a preferred isomer such as 73. Preferred isomers such as 73 can be confirmed by mono-compound X-ray crystallography. Preparative chiral HPLC can also be used to separate isomers. 73 can be converted to its boronate ester 74 under anhydrous Suzuki reaction conditions. The boronate ester can be carefully isolated or used in situ in a Suzuki coupling reaction with pyrrolotriazine bromide, an example of which is 29. An alternative method can also be used in which 29 is converted to its corresponding boronate ester or boronic acid and then coupled in situ or on a separate bromide step 73. The analogs shown as Example 75 can be Boc deprotected and functionalized in subsequent steps as described for Scheme 14.

Scheme 15

Chiral resolution of pyrrolidine 63 can also be carried out prior to its coupling with a carboxylic acid as described in the previous schemes. 76 can be obtained by protecting the amino group 63 with Cbz-Cl (Scheme 16). One skilled in the art could envision the use of a plurality of amine protecting groups in place of carbobenzyloxy, which would have independent dereference conditions.

- 59 042342 shields compared with Boc-carbamate. Pyrrolidine 76, either a cis-racemic or diastereomeric mixture, may be resolved into the preferred enantiomerically pure isomer 77 using a chiral SFC. Chiral preparative HPLC may be a suitable alternative for isomer isolation. Chemoselective deprotection of the Cbz group can give 78. Based on the synthesis and comparison with analogs obtained from 73, the amine 78 was found to be the preferred isomer for which the crystal structure was determined.

Scheme 16 p chiral

Cbz-CI, THF, Ίρ N-Boc SFC N-Boc

I N-Boc --------► /—/ base ^H N ^H N ² 63 Cbz 76 Cbz 77

Pd(OH) ₂ ,

-----N-Boc

H ₂ , MeOH h ₂ nV

As shown in Scheme 17, 78 can also be isolated in enantiomerically pure form using a chiral SFC of 63. A person skilled in the art can similarly use chiral preparative HPLC. By using an amide bond coupling reagent, the amide derived from 78 and 31 can be formed to give analogs exemplified by 79. In this specification, conversion to amides characterized by 71 can be accomplished by Boc deprotection and subsequent amide bond formation. Alternative peptide coupling reagents known to those skilled in the art can be used to prepare intermediates like 79 or final compounds like 71. In addition, intermediates like 80 can be alternatively functionalized as shown in Scheme 14.

Scheme 17

The chiral pyrrolidine 78 can also be linked to phenyl or substituted phenyl analogs, of which 81 is an example (Scheme 18). Amide 82 can be prepared using the BOP reagent or other peptide coupling reagents known to those skilled in the art. Subsequent removal of the Boc protecting group under acidic conditions can give 83. A secondary amine can undergo a second amide coupling mediated by a BOP reagent or alternative peptide coupling reagent to give compounds similar to 84. Intermediates characterized by 83 can also be converted to a tertiary amine, sulfonamide, urea or carbamate analogs by methods similar to those depicted in Scheme 14, or alternative methods known to those skilled in the art.

- 60 042342

Scheme 18

In some cases, the Suzuki reaction with substituted phenylboronate esters or boronic acids can proceed in higher yield with less by-product formation when combined with 7 (Scheme 19). Alternative protecting groups at 7, such as Boc, will be available and known to those skilled in the art. One skilled in the art can also prepare the boronate ester or boric acid 7 and couple it to the bromide, chloride or iodide 9. Suzuki coupling of partners related to 7 and 9 can be accomplished with isolated or in situ generated boronate esters or boronic acids. Removal of para-methoxybenzyl groups can take place in the presence of trifluoroacetic acid at high temperature under microwave irradiation. Other deprotection conditions for PMB groups are available to those skilled in the art. Esters like 86 can be hydrolyzed under basic conditions to give a carboxylic acid or carboxylate salt. Sodium hydroxide or lithium hydroxide can be used for this transformation. Carboxylic acids or carboxylates, of which 87 is an example, can be coupled with 78 under standard amide coupling conditions known to those skilled in the art. Amides like 88 can be converted to a secondary amine and linked to various functional groups using methods similar to those shown in Scheme 14.

Scheme 19

Vos

Further functionalization of the solubilized prodrug end products described herein is described in Scheme 20. The compounds shown as Example 32 can be alkylated at pyrrolotriazine using suitable electrophiles such as ditert-butyl(chloromethyl)phosphate to form intermediates characterized by 89. Alternative electrophiles may be used in place of di-tert-butyl(chloromethyl)phosphate, which may provide additional solubility in the unprotected state and will be known to those skilled in the art. When necessary for the use of an electrophile, instead of the specific conditions listed for the conversion of 32 to 89, alternative coupling conditions known to those skilled in the art may be used. Deprotection of the tert-butyl groups may result in the formation of the final prodrug 90. These conditions may be modified by methods known to those skilled in the art so as to be appropriate for the solubilizing group added in the first step.

Scheme 20

Purification of intermediates and final products was carried out using either normal or reversed phase chromatography. Normal phase chromatography on an ISCO system was performed using pre-packaged SiO ₂ cartridges eluting with gradients of either hexanes and ethyl acetate or dichloromethane and methanol unless otherwise noted. Preparative reverse phase HPLC or LC-MS was performed using C18 columns eluting with gradients of solvent A (90% water, 10% methanol, 0.1% TFA) and solvent B (10% water, 90% methanol, 0.1% TFA, UV 220 nm), or gradients of solvent A (95% water, 5% acetonitrile, 0.1% TFA) and solvent B (5% water, 95% acetonitrile, 0.1% TFA, UV 220 nm), or gradients of solvent A (98% water, 2% acetonitrile, 0.05% TFA) and solvent B (98% acetonitrile, 2% water, 0.05% TFA, UV 254 nm), or gradients of solvent A (95% water, 5% acetonitrile with 10 mM ammonium acetate) and solvent B (95% acetonitrile, 5% water with 10 mM ammonium acetate).

In most examples, two LC-MS assays were used to determine final purity.

Method A: column: Waters Acuity UPLC BEH C18, 2.1x50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; temperature: 50°C; gradient: 0-100% B over 3 min, then 0.75 min hold at 100% B; flow rate: 1.11 ml/min; detection: UV at 220 nm.

Method B: column: Waters Acquity UPLC BEH C18, 2.1x50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% TFA; mobile phase B: 95:5 acetonitrile:water with 0.1% TFA; temperature: 50°C; gradient: 0-100% B over 3 min, then 0.75 min hold at 100% B; flow rate: 1.11 ml/min; detection: UV at 220 nm.

In a smaller number of examples, HPLC analytical samples were used to determine the final purity.

Method C: column: XBridge C18, 3.0x150 mm, particles 3.5 µm; mobile phase A: 5:95 methanol:water with 10 mM ammonium bicarbonate; mobile phase B: 95:5 methanol:water with 10 mM ammonium bicarbonate; gradient: 0-100% B in 15 min; flow rate: 1 ml/min; detection: UV at 220 and 254 nm.

Method D: column: XBridge Phenyl, 3.0x150 mm, particles 3.5 µm; mobile phase A: 5:95 methanol:water with 10 mM ammonium bicarbonate; mobile phase B: 95:5 methanol:water with 10 mM ammonium bicarbonate; gradient: 0-100% B in 15 min; flow rate: 1 ml/min; detection: UV at 220 and 254 nm.

Most mass spectral analyzes were performed under the following conditions: LC-MS (ESI) m/z: [M+H]+ BEH C18, 2.11x50 mm, 1.7 µm; mobile phase A: 2:98 water:acetonitrile with 0.1% TFA; mobile phase B: 98:2 acetonitrile:water with 0.1% TFA; gradient: 0-100% B in 2 min; flow rate: 0.8 ml/min; detection: UV at 220 nm.

LC-MS methods for determining retention times:

Method 1: column: Waters XBridge C18, 2.1 mmx50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; temperature: 50°C; gradient: 0% B to 100% B over 3 min, then 0.75 min hold at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Method 2: column: Waters XBridge C18, 2.1 mmx50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; temperature: 50°C; gradient: 0% B to 100% B over 3 min, then 0.75 min hold at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Method 3: column: Waters XBridge C18, 2.1 mmx50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; temperature: 50°C; gradient: 0% B to 100% B over 3 min, then 0.50-62 042342 minute hold at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Method 4: column: Waters XBridge C18, 2.1 mm x 50 mm, particles 1.7 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; temperature: 50°C; gradient: 0% B to 100% B over 3 min, then 0.50 min hold at 100% B; flow rate: 1 ml/min; detection: MS and UV (220 nm).

Method 5: column = Waters Acquity UHPLC BEH C18, 2.1x50 mm, particles 1.7 µm; mobile phase A = 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B = 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; temperature = 50°C; gradient = 0-100% B over 3 minutes, then 0.75 minute hold at 100% B; flow rate = 1.0 ml/min; detection: UV at 220 nm.

Method 6: column = Waters Acquity UPLC BEH C18, 2.1x50 mm, 1.7 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; temperature = 50°C; gradient = 0-100% B over 3 min followed by 0.75 min hold at 100% B; flow rate: = 1.0 ml/min; detection: UV at 220 nm.

HPLC Methods:

Analytical HPLC studies were performed using Methods A and B, and reverse phase pre-purification was performed using Methods C and D.

HPLC method A: linear gradient using 5% acetonitrile, 95% water and 0.05% TFA (solvent A) and 95% acetonitrile, 5% water and 0.05% TFA (solvent B; time = 0 min, 10% B; time =15 min, 100% B) was applied on a SunFire C18 column, particles 3.5 µm, 3.5 mm x 150 mm, flow rate was 0.5 ml/min and UV detection was set at 220 nm. The LC column was maintained at ambient temperature.

HPLC method B: linear gradient using 5% acetonitrile, 95% water and 0.05% TFA (solvent A) and 95% acetonitrile, 95% water and 0.05% TFA (solvent B; time = 0 min, 10% B; time =15 min, 100% B (20 min)) was applied on an XBridge Ph column, particles 3.5 µm, 3.0 mm x 150 mm, flow rate was 0.5 ml/min, and UV detection was set at 220 nm. The LC column was maintained at ambient temperature.

HPLC method C: Waters XBridge C18 column, 19 mm x 200 mm, particles 5 µm; guard column Waters XBridge C18, 19 mm x 10 mm, particles 5 µm; mobile phase A: water with 20 mM ammonium acetate; mobile phase B: 95:5 methanol/water with 20 mM ammonium acetate; gradient: 25-65% B over 40 min, then 5 min hold at 100% B; flow rate: 20 ml/min.

HPLC method D: Waters Sunfire C18 OBD column, 50 mm x 300 mm, 10 µm particles; pre-column Waters Sunfire C18 OBD, 50 mmx50 mm, particles 10 µm; mobile phase A: 10:90 methanol/water with 0.1% trifluoroacetic acid; mobile phase B: 90:10 methanol/water with 0.1% trifluoroacetic acid; gradient: 0-100% B over 30 min, then 5 min hold at 100% B; flow rate: 150 ml/min.

NMR spectra were recorded with water suppression unless otherwise noted. When water suppression affected NMR characterization of compounds, this was noted in the text.

Example 1 3-{4-aminopyrrolo[2,1-f][1,2,4]triαzin-7-yl}-N-(3-phenylbutyl)benzamide

A: N-(3-phenylbutyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide: to a solution of 3-carboxyphenylboronic acid pinacol ester (1.0 g, 4.03 mmol), 3-phenylbutan-1-amine (0.602 g, 4.03 mmol) and Hunig's base (1.478 ml, 8.46 mmol) in DMF (12 ml) was added BOP (1.783 g, 4.03 mmol). The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted with EtOAc (150 ml), then washed with 10% LiCl solution (50 mlx2), water (50 ml) and brine (50 ml). The organics were dried over anhydrous sodium sulfate and concentrated in vacuo.

The crude material was purified by ISCO column chromatography (80 g, 0-20% EtOAc/CH ₂ Cl ₂ ) to give N-(3-phenylbutyl)-3-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2yl)benzamide (0.818 g, 2.157 mmol, 53.5% yield) as a clear viscous oil.

MS (ERI) (m/z) 380.0 (M+H).

1: In a Bohdan miniblock shaker, N-(3-phenylbutyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamide (15mg, 0.040mmol) and 7-bromopyrrolo[ 2,1-D][1,2,4]triazine-4-amine (16.9 mg, 0.079 mmol) was dissolved in DMF (400 μl). The PdCl ₂ (dppf)–CH ₂ Cl ₂ adduct (3.23 mg, 3.95 µmol) was added to the vial, followed by the addition of potassium triphosphate (59.3 µL, 0.119 mmol). The reaction mixture was closed, degassed and purged with N ₂ . After stirring for 1 hour at 100° C., the mixture was cooled to room temperature. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing

- 63 042342 reaping the desired product, were combined and dried by centrifugal evaporation to obtain the final product (6.8 mg, 17.6 μmol, 44%). MS (ERI) m/z 386.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.56-8.47 (m, 1H), 8.41 (s, 1H), 8.24 (br d, J=7.7 Hz, 1H), 7.95 (s, 1H), 7.92-7.76 (m, 2H), 7.73 (br d, J=7.7 Hz, 1H), 7.53 (t, J=7.8 Hz, 1H), 7.36-7.24 (m, 4H), 7.22-7.16 (m, 1H), 7.10 (d, J=4.5 Hz, 1H), 7.04 (d, J=4.5 Hz, 1H), 3.23 (dq, J=13.2, 6.5 Hz, 1H), 3.18-3.09 (m, 1H), 2.85-2.75 ( m, 1H), 1.84 (q, J=7.3 Hz, 2H), 1.24 (br d, J=6.8 Hz, 3H).

Example 2: 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-phenylbutyl)benzamide

2A: 7-bromo-N,N-bis(4-methoxybenzyl)pyrrolo[1,2-f][1,2,4]triazine-4-amine: 7bromopyrrolo[2,1-f][1,2 solution ,4]triazine-4-amine (120 mg, 0.563 mmol) in N,N-dimethylformamide (2.5 ml) was treated with 4-methoxybenzyl chloride (0.168 ml, 1.239 mmol), then cesium carbonate (459 mg, 1.408 mmol) was added in one portion ). The mixture was stirred at room temperature for 22 hours. The mixture was diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to give a yellow semi-solid. The material was chromatographed on a 4 g ISCO Companion silica gel column and eluted with an EtOAc/hexane (5-30%) gradient. Fractions containing the product were collected and concentrated to give 7-bromo-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f ^: ][1,2,4]triazine-4-amine (147.8 mg, 0.316 mmol, 56% yield). MS (ERI) (m/z) 453, 455 (M+H).

1H NMR (400 MHz, CDCI3) δ 8.14 (s, 1H), 7.23 (d, J=8.6 Hz, 4H), 6.93-6.88 (m, 4H), 6.61 (d, J=1.3 Hz, 2H), 4.94 (s, 4H), 3.83 (s, 6H). (Alternatively, cesium carbonate can be used instead of sodium hydride).

2B: 7-bromo-5-iodo-N,N-bis(4-methoxybenzyl)pyrrolo[1,2-f ^: ][1,2,4]triazine-4-amine: to a solution of 7bromo-N,N- bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (4.3 g, 9.49 mmol) and NIS (2.134 g, 9.49 mmol) in DMF (20 ml) were added 10 drops of TFA. The reaction mixture was stirred at room temperature for 16 h. Additional NIS (130 mg, 0.05 equiv.) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into a mixture of ice water and 1.5 M K2HPO4 (~1:1 ) to give a yellow precipitate. The precipitate was filtered off. The filter cake was washed twice with water. The filter cake was triturated with ethyl acetate to give 2.98 g of a white solid as pure product. The residual solution was concentrated and triturated with MeOH to give an additional 1.43 g of a crystalline white solid as pure product. Two portions were combined to give 7-bromo-5-iodo-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (4.41 g, 7.60 mmol, 80% yield). MS (ERI) (m/z) 579, 581 (M+H).

1H NMR (400 MHz, CDCl ₃ ) δ 8.13 (s, 1H), 7.29 (s, 1H), 7.07-7.03 (m, 4H), 6.89-6.85 (m, 4H), 4.64 (s, 4H), 3.83 (s, 6H).

2C: 7-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyrrolo[1,2-f][1,2,4]triazine-4-amine: mixture of 7-bromo-5- iodo-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (0.2 g, 0.345 mmol) and copper (I) iodide (0.072 g, 0.380 mmol) in a reaction vial with a crimp cap was placed under vacuum, then filled with nitrogen. The degassing process was repeated twice. DMF (3 ml) was added to the above solid mixture. The resulting suspension was degassed three times. Methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (0.265 g, 1.381 mmol) was added to the above suspension. The reaction vial was placed in a thermostat heated to 80°C and heated for 3 hours. The reaction mixture was cooled to room temperature, then filtered through celite. The filter cake was washed with ethyl acetate three times. The combined filtrate was washed with 5% ammonia (2x), 10% LiCl, water and brine, then concentrated to give 7-bromo-N,N-bis(4-methoxybenzyl)-5-(trifluoromethyl)pyrrolo[2,1f][1 ,2,4]triazine-4-amine (211 mg, 0.291 mmol, 84% yield). MS (ERI) (m/z) 521, 523 (m+H).

1H NMR (400 MHz, CDC13) δ 8.21 (s, 1H), 7.10 (s, 1H), 6.96-6.93 (m, 4H), 6.84-6.82 (m, 4H), 4.58 (s, 4H), 3.81- 3.79(m, 6H).

2D: 7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine: 7-bromo-N,N-bis(4methoxybenzyl)-5-(trifluoromethyl) pyrrolo[2,1-f][1,2,4]triazine-4-amine (1.2 g, 2.302 mmol) in TFA (10 ml) in a reaction vial with a crimp cap was placed in a thermostat heated to 110°C and heated in for 4 hours. The reaction mixture was concentrated. The residue was dissolved in dichloromethane and chromatographed on a 24 g ISCO Companion silica gel column eluting with an EtOAc/hexane (0-100%) gradient. Fractions containing product were collected and concentrated. The yellow oily residue was triturated with methanol to give 7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (502 mg, 1.79 mmol, 78% yield).

MS (ERI) (m/z) 281, 283 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (s, 1H), 7.38 (s, 1H).

- 64 042342

2E: 3-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)benzoic acid: to a solution of 7bromo-5-(trifluoromethyl)pyrrolo[2 ,1-1][1,2,4]triazine-4-amine (150 mg, 0.534 mmol) and 3-boronobenzoic acid (106 mg, 0.640 mmol) tribasic potassium phosphate (0.801 ml, 1.601 mmol) (2 M in H ₂ O). Nitrogen was bubbled through the reaction mixture for 5 min, and then the PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (43.6 mg, 0.053 mmol) was added. Bubbling was continued for 5 minutes. The reaction vessel was sealed and heated to 100° C. for 3 hours. After cooling to room temperature, methanol was added to cause precipitation. By isolating the precipitate, 3-(4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (100 mg, 0.310 mmol, 58.1% yield) was obtained as white solid.

MS (ERI) (m/z) 323.1 (M+H).

2: to a solution of 3-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)benzoic acid (20 mg, 0.062 mmol) and 3-phenylbutane -1-amine (13.89 mg, 0.093 mmol) in DMF (1 mL) were added Hunig's base (0.033 mL, 0.186 mmol) and BOP (30.2 mg, 0.068 mmol). The resulting mixture was stirred at room temperature for 1 hour. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (3.3 mg, 7.3 μmol, 12%).

MS (ERI) m/z 454.3 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.52 (br. s., 1H), 8.35 (s, 1H), 8.25-8.10 (m, 2H), 7.81 (d, J=7.7 Hz, 1H) , 7.65-7.48 (m, 2H), 7.38-7.21 (m, 4H), 7.20-7.12 (m, 1H), 3.30-3.10 (m, 2H), 2.84-2.71 (m, 1H), 1.83 (q, J=7.2 Hz, 2H), 1.29-1.16 (m, 4H).

Example 3: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-K-( 1 -benzyl-1 H-pyrazol4-yl )-2-fluorobenzamide

3A: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-fluorobenzoic acid: to a solution of 7-bromo-5-( trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine (500 mg, 1.779 mmol) and 5-boron-2-fluorobenzoic acid (360 mg, 1.957 mmol) 1,4-dioxane (13 ml) tribasic potassium phosphate (2.67 ml, 5.34 mmol) (2 M in H ₂ O) was added. After bubbling nitrogen through the mixture for 5 min, PdCl ₂ (dppf) (130 mg, 0.178 mmol) was added. The reaction mixture was sparged with nitrogen for an additional 5 minutes. The reaction vessel was sealed and heated to 100° C. for 3 hours. The crude mixture was filtered to remove the catalyst and concentrated. The crude residue was purified by recrystallization with MeOH to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)2-fluorobenzoic acid (500 mg, 1.396 mmol, 78% yield) as a white solid. MS (ERI) m/z 587.0 (M+H).

3: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-fluorobenzoic acid (20 mg, 0.059 mmol) and 1-benzyl-1H-pyrazole-4-amineα (15.27 mg, 0.088 mmol) in DMF (1 mL) was added Hunig's base (0.031 mL, 0.176 mmol) and BOP (28.6 mg, 0.065 mmol). The resulting mixture was stirred at room temperature for 15 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (6.4 mg, 13 μmol, 22%). MS (ERI) m/z 495.8 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ), δ 10.62 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 8.24 (br. s., 1H), 8.15 (s, 1H), 8.18 (s, 1H), 7.59 (s, 1H), 7.62 (s, 1H), 7.48 (t, J=9.2 Hz, 1H), 7.39-7.20 (m, 5H), 5.32 (s, 2H).

Example 4 3-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(2-phenoxyphenyl)methyl]benzamide

4A: 1-(tert-butyl) 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate: to a solution of 1-tert-butyl 2methyl 4-oxopyrrolidine-1,2-dicarboxylate (2 g, 8.22 mmol) in DCM (10 ml), cooled in a dry ice-acetonitrile bath, was added DAST (1.63 ml, 12.3 mmol) first dropwise, then in portions. Re

- 65 042342 the stock mixture was stirred at -40°C to room temperature over the weekend. The reaction mixture was slowly poured into saturated aqueous sodium bicarbonate cooled in an ice bath. The mixture was extracted with dichloromethane (3x) and the combined organic phases were washed with water and concentrated. The residue was purified by flash chromatography on an ISCO system (0100% ethyl acetate/hexane, 40 g silica gel column) to give 1.40 g of 1-(tert-butyl)2-methyl 4,4difluoropyrrolidine-1,2-dicarboxylate as light brown oil.

4B: methyl 4,4-difluoro-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxylate: light brown solution of 1-tert-butyl 2-methyl 4,4-difluoropyrrolidine-1,2-dicarboxylate ( 1.4 g, 5.28 mmol) in TFA (10 ml) and DCM (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and rotary evaporated several times with dichloromethane to give 2.01 g of methyl 4,4-difluoro-1-(2,2,2-trifluoroacetyl)pyrrolidine-2-carboxylate as a brown oil. Used without further purification.

4C: methyl 4-fluoro-1H-pyrrole-2-carboxylate: to a solution of methyl 4,4-difluoro-1-(2,2,2trifluoroacetyl)pyrrolidine-2-carboxylate (1.4 g, 5.36 mmol) in THF (15 ml ) manganese dioxide (2.33 g, 26.8 mmol) was added. The black reaction mixture was heated in a 75° C. incubator for 3.5 h. The reaction mixture was filtered through celite and the filtrate was concentrated and purified by flash chromatography on an ISCO system (0-70% ethyl acetate/hexane, 24 g silica gel column) to give 605 mg methyl 4-fluoro-1H-pyrrole-2-carboxylate as a white solid.

1H NMR (400 MHz, CDCI3) δ 6.74 (td, J=3.4, 1.8 Hz, 1H), 6.63 (t, J=2.0 Hz, 1H), 3.88 (s, 3H).

4D: methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate: ammonium chloride (1.57 g, 29.3 mmol), ammonium hydroxide (3.5 ml, 27.0 mmol) and 1 n. sodium hydroxide (14 ml, 4.19 mmol). Sodium hypochlorite (36 ml, 35.0 mmol) (commercial bleach) was added to the above reaction mixture over 20 minutes. Blistering was noted when bleach was added. The reaction mixture was stirred for 1.5 h at room temperature, then 0.5 ml of Bu4NOAc (1 M aqueous solution) was added. After 1 h ammonium methyltrioctyl chloride (50.8 mg, 0.126 mmol) was added and the reaction mixture was stirred for 1 h. The layers of the reaction mixture were separated and the aqueous phase of the reaction mixture was extracted with ether (2x). The combined organic phases were washed with saturated aqueous sodium bisulfite and then dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash chromatography on an ISCO system (0-80% ethyl acetate/hexane, 24 g silica gel column) gave 320 mg of methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate as white solid.

1H NMR (400 MHz, CDCl ,) δ 6.81-6.76 (m, 1H), 6.51 (d, J=2.4 Hz, 1H), 3.85 (s, 3H).

4E: 6-fluoropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one: methyl 1-amino-4-fluoro-1H-pyrrole-2carboxylate solution (597 mg, 3.78 mmol) , formamide (6462 mg, 143 mmol), and acetic acid (432 μL, 7.55 mmol) were heated at 150°C for 1.5 h. Pressure increased in the vial. The reaction mixture was split in half and heated at 150°C for 30 min. The reaction mixture was diluted with water, filtered and dried to give 6-fluoropyrrolo[2,1-f][1,2,4]triazin-4(3H)-one as a brown solid.

4F: 6-Fluoropyrrolo[2,1-T][1,2,4]triazin-4-amine: suspension of 6-fluoropyrrolo[2,1-T|[1,2,4]triazin4(3H)-one ( 410 mg, 2.68 mmol) in phosphorus oxychloride (1.25 ml, 13.4 mmol) was heated at 100°C for 6 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane, cooled in an ice water bath and water was added. The organic phase was separated and washed with water. Concentration under reduced pressure gave a residue which was dissolved in NMP (5 ml) and treated with ammonia (5 ml). After 2 h the reaction mixture was extracted with ethyl acetate (3x). The combined organic phases were washed with water and concentrated. The residue was purified by flash chromatography on an ISCO system (0-100% ethyl acetate/hexane, 40 g silica gel column) to give 180 mg of 6fluoropyrrolo[2,1-N1,2,4]triazine-4-amine as a white solid substances.

4G: 7-bromo-6-fluoropyrrolo[2,1-G][1,2,4]triazine-4-amine: to a solution of 6-fluoropyrrolo[2,1£][1,2,4]triazine-4 -amine (800 mg, 5.26 mmol) in THF (10 ml) was added NBS (234 mg, 1.32 mmol). More 6-fluoropyrrolo[2,1-G|[1,2,4]triazine-4-amine (400 mg, 2.63 mmol) was added. The reaction mixture was stirred overnight. The reaction was not complete so additional NBS (70 mg, 0.39 mmol, 0.15 eq.) was added. After 0.5 h, the reaction mixture was diluted with ethyl acetate, washed with 1.5 M aqueous sodium phosphate dibasic, washed with water, and concentrated to give 810 mg of 7bromo-6-fluoropyrrolo[2,1-G|[1,2,4]triazine-4-amine as white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.02 (s, 1H), 7.90 (br. s., 2H), 6.91 (s, 1H).

4H: 3-(4-Amino-6-fluoropyrrolo[2,1-L][1,2,4]triazin-7-yl)benzoic acid: mixture of 7-bromo-6fluoropyrrolo[2,1-G|[1 ,2,4]triazin-4-amine (0.200 g, 0.866 mmol), 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoic acid (0.258 g, 1.039 mmol) , potassium triphosphate (2 M in water) (1.299 ml, 2.60 mmol) and Ν,N-dimethylformamide (4.0 ml) were degassed using vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride - CH ₂ Cl ₂ (0.071 g, 0.087 mmol) was added, and the reaction

- 66 042342 the mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 95°C and stirred overnight. The reaction mixture was cooled to room temperature and diluted with water (2 ml) followed by the addition of 1N. aqueous hydrochloric acid (2 ml), which led to precipitation. The solid was collected by vacuum filtration and dried under reduced pressure to give 3-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (0.236 g, 0.867 mmol , 100%) as a reddish solid. MS (ERI) (m/z) 273.1 (M+H).

4: to a solution of 3-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (15 mg, 0.055 mmol) and (2-phenoxyphenyl)methanamine (16.47 mg, 0.083 mmol) in DMF (1 mL) were added Hunig's base (0.029 mL, 0.165 mmol) and BOP (26.8 mg, 0.061 mmol). The resulting mixture was stirred at room temperature for 15 minutes. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 20-60% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (18.3 mg, 32.2 μmol, 59%).

MS (ERI) m/z 453.9 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ), δ 9.03 (br. s., 1H), 8.32 (s, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.81 (d, J=7.7 Hz , 2H), 7.59 (t, J=7.7 Hz, 1H), 7.43-7.32 (m, 3H), 7.28 (t, J=7.4 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.96 (d, J=7.8 Hz, 2H), 6.92-6.82 (m, 2H), 4.49 (d, J=5.2 Hz, 2H).

Example 5 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-hydroxy-3phenylpropyl)benzamide

NC

5A: 4-amino-7-bromopyrrolo[1,2-f] [ 1,2,4]triazine-5-carbonitrile: 4-amino-7-bromopyrrolo[2,1 f] [ 1,2,4]triazine -5-Carbonitrile was prepared by nitriding 7-bromo-5-ethynylpyrrolo[2,1-f][1,2,4]triazine-4amine using the method described in Angew. Chem. Int. Ed, 52:6677-6680 (2013). A mixture of 7-bromo-5ethynylpyrrolo[2,1-f][1,2,4]triazine-4-amine (470 mg, 1.98 mmol), azidotrimethylsilane (457 mg, 3.97 mmol), silver carbonate (54.7 mg, 0.198 mmol ) and DMSO (10 ml) were placed in a crimp-cap reaction vial, the vial was purged with nitrogen, and the mixture was stirred at 100° C. for 15 h. The mixture was cooled to room temperature and diluted with water (100 ml) with vigorous stirring. The mixture was filtered to collect the product, which was washed with water and ether and dried under suction to give crude 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (400 mg ).

1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.50 (s, 1H).

Alternative way to get 5A.

5A-1: 4-amino-7-bromopyrrolo[2,1-d][1,2,4]triazine-5-carboxamide: suspension of ethyl 4-amino-7-bromopyrrolo[2,1-f][1,2, 4]triazine-5-carboxylate (5.3 g, 18.59 mmol), THF (40 ml), MeOH (20 ml) and lithium hydroxide monohydrate (4.68 g, 112 mmol) dissolved in water (20 ml), stirred at room temperature for 15 h and at 50°C for 1 h. The mixture was cooled to room temperature and acidified (pH = 2) by adding dropwise concentrated HCl, diluted with water (200 ml) and the white precipitate was collected by filtration. The product was washed with water, dried with suction and then dried further by concentrating the suspension to a solid in 20% MeOH/toluene (2 x 100 ml) under reduced pressure.

5A-2: The product from above was treated with DMF (40 ml) and DIPEA (19.48 ml, 112 mmol) and stirred for 5 minutes until most of the solid had dissolved. To the mixture were added 1-hydroxy-7-azabenzotriazole (3.80 g, 27.9 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.35 g, 27.9 mmol), the resulting yellow mixture was stirred for 5 min, then treated with chloride ammonium (3.98 g, 74.4 mmol) and stirred at room temperature for 16 h. The mixture was diluted with water (20 ml), stirred for 5 min and filtered to collect the precipitate. The collected solid was washed with saturated NaHCO ₃ (100 ml) and water (200 ml), dried with suction, and then dried under vacuum to obtain 4amino-7-bromopyrrolo[2,1-f][1,2,4]triazine- 5-carboxamide as a white solid (4.5 g, 95%).

MS (ERI) (m/z) 255.8 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 10.41 (br. s., 1H), 8.24 (br. s., 1H), 8.11 (br. s., 1H), 8.01 (s, 1H), 7.67 ( br. s., 1H), 7.48 (s, 1H). LC-MS: m/z =255.8, (M+H) ⁺ .

5A: 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (1.0 g, 3.91 mmol) was placed in a 20 ml Biotage® reaction vial and treated with phosphorus oxychloride (7.28 ml , 78 mmol). The vial was closed and heated for 20 h in a thermostat at 120°C. The resulting brown mixture was cooled to room temperature and slowly poured into 2 M NaOH (75 ml) cooled to 0°C,

- 67 042342 keeping the temperature below 35°C. The resulting mixture was stirred for 10 min and then basified to pH 7.5 with 5M NaOH. The mixture was filtered to collect a yellow solid, which was washed with water, dried with suction and dried under vacuum. The filtrate was kept at room temperature overnight, after which most of the material crystallized. The second crop was collected, washed with water, dried and combined with the first crop to give 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (0.68 g, 73% yield).

MS (ERI) m/z 237.8 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 7.50 (s, 2H).

5B: 3-(4-Amino-5-cyanopyrrolo[2,1-1][1,2,4]triazin-7-yl)benzoic acid: a mixture of 4-amino-7-bromopyrrolo[2,1-f][1 ,2,4]triazine-5-carbonitrile (0.200 g, 0.840 mmol), 3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoic acid (0.250 g, 1.008 mmol) , potassium triphosphate (2M in water) (1.260 ml, 2.52 mmol) and N,N-dimethylformamide (4.0 ml) were degassed using vacuum and nitrogen (3x). The adduct PdCl ₂ (dppf) ₂ -CH ₂ Cl ₂ (0.069 g, 0.084 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was stirred at room temperature for 5 hours. Water (4 ml) was added with stirring. Added dropwise concentrated hydrochloric acid until a precipitate formed. The solid was collected by vacuum filtration and dried under reduced pressure to give 3-(4-amino-5-cyanopyrrolo[2,1-D[1,2,4]triazin-7-yl)benzoic acid (0.212 g, 0.759 mmol, 90% yield) as a light brown solid.

MS (ERI) (m/z) 280.1 (M+H).

5: mixture of 3-(4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (0.025 g, 0.090 mmol), 3-amino-1-phenylpropane -1-ol (0.020 g, 0.134 mmol), Hunig's bases (0.047 ml, 0.269 mmol), and BOP (0.044 g, 0.098 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (14.0 mg, 33.9 μmol, 38%).

MS (ERI) m/z 413.2 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.56 (br s, 1H), 8.39 (s, 1H), 8.22-8.13 (m, 2H), 7.84 (br d, J=7.6 Hz, 1H), 7.69 (s, 1H), 7.59 (br t, J=7.7 Hz, 1H), 7.40-7.29 (m, 4H), 7.29-7.20 (m, 1H), 5.38 (br d, J=4.3 Hz, 1H) , 4.64 (br d, J=5.0 Hz, 1H), 3.49 (br s, 1H), 3.36 (br d, J=5.8 Hz, 1H), 1.91-1.84 (m, 2H).

Example 6 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4yl)benzamide

NC

A mixture of 3-(4-amino-5-cyanopyrrolo[2,1-1][1,2,4]triazin-7-yl)benzoic acid (0.025 g, 0.090 mmol), 1-benzyl-1H-pyrazole-4 -amine (0.023 g, 0.134 mmol), Hunig's base (0.047 ml, 0.269 mmol), and BOP (0.044 g, 0.098 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (37.0 mg, 85.2 μmol, 95%).

MS (ERI) m/z 434.9 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.57 (s, 1H), 8.52 (br s, 1H), 8.26-8.14 (m, 3H), 7.95 (br d, J=7.3 Hz, 1H), 7.74 (s, 1H), 7.70-7.59 (m, 2H), 7.41-7.23 (m, 6H), 5.33 (s, 2H).

Example 7 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-phenylbutyl)benzamide

NC

A mixture of 3-(4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (0.025 g, 0.090 mmol), 3-phenylbutan-1-amine (0.020 g, 0.134 mmol), Hunig's bases (0.047 ml, 0.269 mmol) and BOP (0.044 g, 0.098 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gra

- 68 042342 dient: 40-65% B over 25 minutes, then 2 minutes hold at 65% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 35-60% B over 25 min, then 2 min hold at 60% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (8.0 mg, 12.5 µmol, 14%).

MS (ERI) m/z 411.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.53 (br s, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 8.14 (br d, J=7.7 Hz, 1H), 7.81 (br d , J=7.7 Hz, 1H), 7.66 (s, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.32-7.23 (m, 5H), 7.20-7.15 (m, 1H), 3.63-3.55 ( m, 1H), 3.26-3.18 (m, 1H), 3.17-3.08 (m, 1H), 2.84-2.73 (m, 1H), 1.82 (q, J=7.2 Hz, 2H), 1.23 (br d, J =6.9 Hz, 3H).

Example 8 5-{4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl) -2methoxypyridine-3-carboxamide

8A: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide: mixture of 5-bromo-2methoxynicotinic acid (0.500 g, 2.155 mmol), 1-benzyl-1H-pyrazole-4 -amine (0.560 g, 3.23 mmol), Hunig's base (1.129 ml, 6.46 mmol) and BOP (1.048 g, 2.370 mmol) in tetrahydrofuran (12 ml) were stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water , washed with brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by purification by flash chromatography on an ISCO system (24 g column; 0-100% ethyl acetate in hexane) gave N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2methoxynicotinamide (0.689 g, 1.779 mmol, 83% yield) as a white solid.

8B: N-(1-benzyl-1H-pyrazol-4-yl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)nicotinamide: mixture of N- (1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide (0.689 g, 1.779 mmol), 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (0.542 g, 2.135 mmol) and potassium acetate (0.262 g, 2.67 mmol) in dioxane (15 mL) were degassed (3x) with vacuum/nitrogen. The adduct 1,1'bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.145 g, 0.178 mmol) was added and the mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 80°C and stirred overnight. The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography on an ISCO system (40 g column; 0-100% ethyl acetate in hexane) gave N-(1-benzyl-1H-pyrazol-4-yl)-2methoxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.501 g, 1.154 mmol, 64.8% yield) as a white solid. MS (ERI) (m/z) 435.2 (M+H).

8: mixture of 7-bromo-5-fluoropyrrolo[2,1-1][1,2,4]triazin-4-amine (0.035 g, 0.151 mmol), N-(1-benzyl-1Hpyrazol-4-yl) -2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.079 g, 0.182 mmol), potassium triphosphate (2M in water) (0.227 ml, 0.454 mmol) and dioxane (2 ml) were degassed with vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichlorideCH ₂ Cl ₂ (0.012 g, 0.015 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 95°C and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (67.0 mg, 146.1 μmol, 97%).

MS (ERI) m/z 459.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.90 (d, J=2.0 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 7.86 (s, 1H), 7.63 (s, 1H), 7.39-7.23 (m, 6H), 7.08 (s, 1H), 5.31 (s, 2H), 4.01 (s, 3H).

Example 9: 5-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)- 2methoxypyridine-3-carboxamide

- 69 042342

NC

A mixture of 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine-5-carbonitrile (0.050 g, 0.210 mmol), N-(1benzyl-1Н-pyrazol-4-yl)-2 -methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.091 g, 0.210 mmol), potassium triphosphate (2 M in water) (0.315 ml, 0.630 mmol) and dioxane (2 ml) were degassed with vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloroRide-CH ₂ C1 ₂ (0.017 g, 0.021 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 95°C and stirred overnight. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4.0 mg, 8.6 μmol, 4%).

MS (ERI) m/z 466.2 (M+H).

¹ H NMR (500 MHz, DMSO-d6) δ 10.35 (s, 1H), 8.89 (s, 1H), 8.70 (s, 1H), 8.23-8.13 (m, 2H), 7.74 (s, 1H), 7.63 (s, 1H), 7.39-7.23 (m, 5H), 5.32 (s, 2H), 4.03 (s, 3H).

Example 10: 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4chlorophenyl)- 3-hydroxypropyl]-2-methoxypyridine-3-carboxamide

10A: methyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinate: mixture of 7-bromo-5-(trifluoromethyl )pyrrolo[2,1-f][1,2,4]triazine-4-amine (1.774 g, 6.31 mmol), methyl 2methoxy-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)nicotinate (2.22 g, 7.57 mmol), potassium triphosphate (2 M in water) (9.47 ml, 18.93 mmol) and dioxane (35 ml) were degassed using vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.515 g, 0.631 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 70° C. and stirred overnight. The reaction mixture was diluted with ethyl acetate (40 ml) and water (40 ml) and stirred for 2 hours. The resulting precipitate was collected by vacuum filtration and washed well with ethyl acetate, water and ethyl acetate. The compound was dried to give methyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinate (1.34 g, 3.65 mmol, 57.8 % yield) as an off-white solid. Additional product was in the filtrate.

MS (ERI) (m/z) 300.1 (M+H).

10B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt: methyl 5-(4 -amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinate (1.34 g, 3.65 mmol) and lithium hydroxide, H ₂ O (0.153 g, 3.65 mmol) in a mixture of methanol (10 ml), tetrahydrofuran (10.00 ml) and water (5.00 ml) was stirred at room temperature overnight. The heterogeneous reaction mixture was filtered under reduced pressure and the resulting solid was dried overnight to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)-2-methoxynicotinic acid (1.05 g, 2.97 mmol, 81% yield) as a white solid.

MS (ERI) (m/z) 354.1 (M+H).

10: mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (0.023 g, 0.064 mmol ), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol, HCl (0.021 g, 0.096 mmol), Hunig base (0.033 ml, 0.192 mmol) and BOP (0.031 g, 0.070 mmol) in N,Ndimethylformamide (1.0 ml) was stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 30-70% B over 22 min, then 2 min hold at 70% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (27.1 mg, 36.2 μmol, 57%).

MS (ERI) m/z 521.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=2.4 Hz, 1H), 8.78 (d, J=2.3 Hz, 1H), 8.51 (br t, J=5.2 Hz, 1H), 8.17 ( s, 1H), 7.60 (s, 1H), 7.39 (s, 4H), 5.52 (d, J=4.3 Hz, 1H), 4.74-4.68 (m, 1H), 4.04 (s, 3H), 3.43-3.35 (m, 2H), 1.93-1.79 (m, 2H).

- 70 042342

Example 11 tert-Butyl (3S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 -amido}pyrrolidine-1-carboxylate

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (500 mg, 1.415 mmol) and (3 )-tert-butyl 3-aminopyrrolidine-1-carboxylate (264 mg, 1.415 mmol) in 1,4-dioxane (10 ml) was added Hunig's base (0.742 ml, 4.25 mmol) and BOP (689 mg, 1.557 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (18.3 mg, 32.2 μmol, 59%).

MS (ERI) m/z 522.3 (M+H).

¹ H NMR (500 MHz, DMSO-d6) δ 8.95-8.81 (m, 1H), 8.65-8.57 (m, 1H), 8.47-8.37 (m, 1H), 8.19-8.06 (m, 1H), 7.66- 7.51 (m, 1H), 4.51-4.35 (m, 1H), 4.04-3.93 (m, 3H), 3.64-3.52 (m, 1H), 3.49 -3.42 (m, 2H), 3.43 -3.15 (m, 3H ), 2.18-2.04 (m, 1H), 1.98-1.82 (m, 1H), 1.45-1.30 (m, 9H).

Example 12 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(3S)-1 -(4methylbenzoyl)pyrrolidin-3-yl]pyridine-3-carboxamide

12A: (8)-5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methokCu-N-(pyrrolidin3-yl )nicotinamide: (S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin7-yl)-2-methoxynicotinamido solution) pyrrolidine-1-carboxylate (500 mg, 0.959 mmol) pure TFA (3 mL, 38.9 mmol) was stirred at room temperature for 30 min. The reaction mixture was evaporated to remove TFA and further dried with a vacuum pump to give (S)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)-2-methoxy-N-(pyrrolidin-3-yl)nicotinamide (13.0 mg, 0.023 mmol, 65%).

MS (ERI) m/z 422.1 (M+H).

12: to a solution of (S)-5-(4-amino-5-(trifluoromethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N(pyrrolidin- 3-yl)nicotinamide (15 mg, 0.036 mmol) in THF (1.5 ml) was added Hunig's base (0.031 ml, 0.178 mmol) and 4-methylbenzoic acid (5.33 mg, 0.039 mmol) and then BOP (18.89 mg, 0.043 mmol) was added ). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 3 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (13.0 mg, 24.1 μmol, 67%).

MS (ERI) m/z 540.2 (M+H).

¹ H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J=16.0 Hz, 1H), 8.68-8.56 (m, 1H), 8.54-8.47 (m, 1H), 8.14 (d, J=13.5 Hz , 1H), 7.57 (d, J=15.4 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.29-7.19 (m, 2H), 4.36 (d, J=5.2 Hz, 1H), 4.00 (s, 1H), 3.96 (s, 2H), 3.57-3.47 (m, 1H), 3.38 (d, J=7.0 Hz, 1H), 2.32 (br. s., 3H), 2.252.09 (m, 1H), 2.05–1.98 (m, 1H).

Example 13: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methyl-N-(4,4,4trifluoro- 3-hydroxy-3-phenylbutyl)pyridine-3-carboxamide

13A: Ethyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: Ethyl 5-bromo-2-methylnicotinate was added to an oven-dried 10 ml vial (1 g, 4.10 mmol), bis(pinacolato)diborone (217 mg, 0.854 mmol) and potassium acetate (1.206 g, 12.29 mmol). 1,4-Dioxane (15 ml) was added to the vial and nitrogen gas was bubbled through the mixture for 10 minutes. into the reaction mixture

- 71 042342 PdCl ₂ (dppf (0.150 g, 0.205 mmol) was added and nitrogen gas was bubbled through the mixture for 10 minutes. The resulting mixture was heated to reflux at 80° C. overnight. The reaction mixture was filtered through a bed of celite and concentrated.The crude material was purified by flash chromatography on an ISCO system (20-80% EtOAc/hexanes) to give ethyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-nicotinate (0.9 g, 3.09 mmol, 75% yield) as a white solid MS (ESI) m/z 209.9 (weight of the corresponding boronic acid).

13B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]mriazin-7-yl)2-methylnicotinic acid: to a solution of 7-bromo-5-(trifluoromethyl )pyrrolo[2,1-^[1,2,4]triazine-4-amine (300 mg, 1.067 mmol)ethyl 2methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)nicotinate (373 mg, 1.281 mmol) (8 mL) tribasic potassium phosphate (1.601 mL, 3.20 mmol) (2 M in H2O) was added. Nitrogen was bubbled through the mixture for 5 min and then PdCl2(dppf) (78 mg, 0.107 mmol) was added. Nitrogen was bubbled through the mixture for an additional 5 minutes. The reaction vessel was sealed and heated to 100° C. for 3 hours. The reaction mixture was cooled to room temperature. Added 1 n. NaOH (10 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated. The crude material was purified by recrystallization with MeOH to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)2-methylnicotinic acid, sodium salt (300 mg, 0.890 mmol, 83% yield) as a white solid.

MS (ERI) m/z 366.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 9.27 (d, J=2.2 Hz, 1H), 9.06 (d, J=2.2 Hz, 1H), 8.10 (s, 1H), 7.44 (s, 1H), 2.93 (s , 3H).

13: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinic acid, sodium salt (25 mg, 0.074 mmol) and 4-amino-1,1,1-trifluoro-2-phenylbutan-2-ol (17.06 mg, 0.078 mmol) in 1,4-dioxane (2 ml) were added Hunig's base (0.039 ml, 0.222 mmol) and BOP (39.3 mg, 0.089 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (7.6 mg, 14.1 μmol, 19%).

MS (ERI) m/z 539.4 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.24-9.10 (m, 1H), 8.45 (t, J=5.2 Hz, 1H), 8.31-8.23 (m, 1H), 8.19 (s, 1H), 7.70- 7.56 (m, 3H), 7.51-7.40 (m, 2H), 7.39-7.31 (m, 1H), 3.35-3.24 (m, 1H), 3.01-2.87 (m, 1H), 2.54 (s, 3H), 2.36-2.20 (m, 1H).

Example 14 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzoyl-4methylpyrrolidin-3-yl) -2-methoxypyridine-3-carboxamide

14A: (3R,4R)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4 -methylpyrrolidin-1-carboxylate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (100 mg, 0.283 mmol) and (3R,4R)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (73.0 mg, 0.311 mmol) in 1,4-dioxane (3 ml) and DMF (1 ml) were added DIEA (0.148 ml , 0.849 mmol) and BOP (150 mg, 0.340 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The crude residue was purified by preparative HPLC to give (3R,4R)-benzyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-2-methoxynicotinamido)-4-methylpyrrolidine-1 carboxylate (120 mg, 0.211 mmol, 74.4% yield) as a white solid.

MS (ERI) m/z 570.3 (M+H).

14B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((3R,4R)-4methylpyrrolidine -3-yl)nicotinamide, TFA: (3R,4R)-benzyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7 solution - yl)-2-methoxynicotinamido)-4-methylpyrrolidine-1 carboxylate (100 mg, 0.176 mmol) in TFA (1 ml, 12.98 mmol) was stirred at room temperature for 2 days. The reaction mixture was concentrated and further dried with a vacuum pump. The crude material was used in the next step without purification.

14: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(4methylpyrrolidin-3-yl )nicotinamide, TFA (20 mg, 0.046 mmol) in THF (1 mL) were added benzoic acid (6.73 mg, 0.055 mmol), Hunig's base (0.024 mL, 0.138 mmol), and BOP (24.38 mg, 0.055 mmol). The resulting mixture was stirred at room temperature for 1 hour.

- 72 042342 were purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 20-60% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (10.2 mg, 18 μmol, 40%).

MS (ERI) m/z 540.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (d, J=15.9 Hz, 1H), 8.62 (br. s., 1H), 8.46 (d, J=7.9 Hz, 1H), 8.16 (d, J=17.1 Hz, 1H), 7.60 (d, J=18.3 Hz, 1H), 7.56-7.47 (m, 2H), 7.45 (br. s., 3H), 4.61 (br. s., 1H), 4.02 (s, 1H), 3.98 (s, 1H), 3.84-3.74 (m, 1H), 3.61-3.49 (m, 1H), 3.44-3.32 (m, 2H), 1.09 (d, J=6.4 Hz, 1H ), 1.02–0.88 (m, 2H).

Example 15: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3,3-dimethylbutanoyl)-4 -methylpyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

I

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(4methylpyrrolidin-3-yl)nicotinamide (15 mg, 0.034 mmol) in THF (1 mL) was added 3,3dimethylbutanoic acid (4.00 mg, 0.034 mmol), Hunig's base (0.018 mL, 0.103 mmol) and BOP (18.28 mg, 0.041 mmol). The resulting mixture was stirred at room temperature for 1 hour. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 25-65% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (8.5 mg, 11.2 μmol, 33%).

MS (ERI) m/z 534 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.89 (s, 1H), 8.63 (br. s., 1H), 8.42-8.25 (m, 1H), 8.20-8.11 (m, 1H), 7.60 ( d, J=3.7 Hz, 1H), 4.51 (d, J=17.4 Hz, 1H), 4.05-3.94 (m, 3H), 3.80-3.63 (m, 1H), 3.24-3.14 (m, 1H), 2.17 -2.08 (m, 2H), 1.06-0.91 (m, 13H).

Example 16 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-cyclohexanecarbonyl-4-methylpyrrolidin-3- yl)-2-methoxypyridine-3-carboxamide

5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-cyclohexanecarbonyl-4methylpyrrolidin-3-yl)-2- methoxypyridine-3-carboxamide: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(4- methylpyrrolidin-3-yl)nicotinamide (20 mg, 0.046 mmol) in THF (1 mL) was added cyclohexanecarboxylic acid (11.78 mg, 0.092 mmol), Hunig's base (0.024 mL, 0.138 mmol), and BOP (24.38 mg, 0.055 mmol). The resulting mixture was stirred at room temperature for 1 hour. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 25-100% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (6.9 mg, 13 μmol, 28%).

MS (ERI) m/z 546.3 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.58 (d, J=11.9 Hz, 1H), 8.44-8.30 (m, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 4.48 (br. s., 1H), 3.98 (s, 3H), 3.50 (d, J=5.2 Hz, 1H), 3.23 (d, J=9.2 Hz, 1H), 3.04 (br. s. , 1H), 2.37 (br. s., 1H), 1.73 (br. s., 1H), 1.70-1.54 (m, 5H), 1.26 (br. s., 3H), 1.21 (br. s., 1H), 1.13 (br. s., 1H), 1.05–0.91 (m, 3H).

Example 17: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4chlorophenyl)- 3-hydroxypropyl]-2-fluoropyridine-3-carboxamide

17A: methyl 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: into dried

Methyl 5-bromo-2-fluoronicotinate (1 g, 4.27 mmol), bis(pinacolato)diborone (217 mg, 0.854 mmol) and potassium acetate (1.258 g, 12.82 mmol) were added to a 10 ml oven. 1,4-dioxane (20 ml) was added to the vial and purged with nitrogen gas for 10 min. PdCl ₂ (dppf) (0.156 g, 0.214 mmol) was added to the reaction mixture, and degassing was continued for 10 min. The mixture was heated to reflux at 80° C. overnight. The reaction mixture was filtered through a pad of celite to remove the catalyst, and the filter cake was washed twice with EtOAc. The resulting organic solutions were concentrated. The crude residue was purified by flash column chromatography (ISCO, 80 g silica gel column, 20-50% EtOAc/hexanes) to give methyl 2-fluoro5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)nicotinate (1 g, 3.56 mmol, 83%) as a white solid.

MS (ERI) m/z 200.0 (M+H for boronic acid).

17B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-:H1,2,4]triazin-7-yl)-2-fluoronicotinic acid: to 7-bromo-5-(trifluoromethyl) solution pyrrolo[2,1-:H1,2,4]triazine-4-amine (300 mg, 1.067 mmol) and methyl 2fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)nicotinate (330 mg, 1.174 mmol) in 1,4-dioxane (15 mL) was added tribasic potassium phosphate (1.601 mL, 3.20 mmol) (2 M in H2O). The mixture was degassed by bubbling nitrogen for 5 minutes. PdCl ₂ (dppf) (78 mg, 0.107 mmol) was added and degassing continued for another 5 min. The reaction vessel was sealed and heated to 100°C for 3 h. NaOH (5 ml) and the reaction mixture was stirred for another 2 hours. The reaction mixture was filtered through a pad of celite to remove the catalyst and concentrated. Purification by preparative HPLC gave 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1Ni[1,2,4]triazin-7yl)-2-fluoronicotinic acid (260 mg, 0.762 mmol, 71.4% yield) as a white solid.

MS (ERI) m/z 342.0 (M+H).

Ή NMR (400 MHz, CD3OD) δ 9.03 (dd, J=8.8, 2.6 Hz, 1H), 8.97-8.92 (m, 1H), 8.06 (s, 1H), 7.34 (s, 1H).

17: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-^[1,2,4]triazin-7-yl)-2-fluoronicotinic acid (15 mg, 0.044 mmol) and ( S)-3-amino-1-(4-chlorophenyl)propan-1-ol (8.57 mg, 0.046 mmol) in 1,4dioxane (2 ml) was added Hunig's base (0.023 ml, 0.132 mmol) and BOP (23.33 mg, 0.053 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4.8 mg, 9.4 μmol, 21%).

MS (ERI) m/z 508.9 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.95 (s, 1H), 8.77 (d, J=8.8 Hz, 1H), 8.62 (br. s., 1H), 8.18 (s, 1H), 7.70 (s, 1H), 7.37 (s, 4H), 4.67 (d, J=5.2 Hz, 1H), 3.35 (d, J=5.8 Hz, 2H), 1.95-1.79 (m, 2H).

Example 18 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-X-[3-(4-fluorophenyl)-3hydroxypropyl] pyridine-3-carboxamide

18A: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1A[1,2,4]triazin-7-yl)nicotinic acid, sodium salt: to a solution of 7-bromo-5-(trifluoromethyl)pyrrolo [2,1-f][1,2,4]triazine-4-amine (300 mg, 1.067 mmol)methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinate (337 mg, 1.281 mmol) (8 mL) tribasic potassium phosphate (1.601 mL, 3.20 mmol) (2 M in H2O) was added. Nitrogen was bubbled through the mixture for 5 min, and PdCl ₂ (dppf (78 mg, 0.107 mmol) was added. Nitrogen was bubbled through for 5 min. The reaction vessel was hermetically sealed and heated to 100°C for 3 h. After cooling to room 1 N NaOH (10 ml) was added and the mixture was stirred at room temperature for 2 h. ,1-f][1,2,4]triazin-7yl)nicotinic acid (260 mg, 0.804 mmol, 75% yield) as a white solid.

MS (ERI) m/z 587.0 (M+H).

1H NMR (400 MHz, CD3OD) δ 9.35 (d, J=2.2 Hz, 1H), 9.14 (d, J=2.0 Hz, 1H), 9.02 (t, J=2.0 Hz, 1H), 8.10 (s, 1H ), 7.40 (s, 1H).

18: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)nicotinic acid, sodium salt (20 mg, 0.062 mmol) and 3-Amino-1-(4-fluorophenyl)propan-1-ol (11.52 mg, 0.068 mmol) in THF (1.5 mL) was added BOP (32.8 mg, 0.074 mmol) and Hunig's base (0.032 mL, 0.186 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase

- 74 042342

B: 95:5 acetonitrile: water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4.7 mg, 9.9 μmol, 16%).

MS (ERI) m/z 475.2 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.34 (br. s., 1H), 8.94 (br. s., 1H), 8.78 (br. s., 1H), 8.73 (br. s., 1H), 8.21 (s, 1H), 7.72 (s, 1H), 7.46-7.35 (m, 2H), 7.14 (t, J=8.6 Hz, 2H), 5.43 (br. s., 1H), 4.67 ( d, J=5.0 Hz, 1H), 3.37 (d, J=6.6 Hz, 1H), 1.88 (q, J=6.8 Hz, 2H).

Example 19 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1cyclopentanecarbonyl-4- methylpyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((3S,4S)-4methylpyrrolidine -3-yl)nicotinamide (20 mg, 0.046 mmol) in THF (1 mL) was added Hunig's base (0.024 mL, 0.138 mmol) and cyclopentanecarbonyl chloride (6.09 mg, 0.046 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain the final product (19.2 mg, 36.1 μmol, 79%).

MS (ERI) m/z 532.2 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.87 (br. s., 1H), 8.59 (d, J=4.4 Hz, 1H), 8.40 (dd, J=18.8, 7.7 Hz, 1H), 8.15 (br. s., 1H), 7.58 (br. s., 1H), 4.53 (br. s., 1H), 4.48 (br. s., 1H), 3.98 (s, 3H), 3.51 (d, J=6.7 Hz, 1H), 3.283.13 (m, 1H), 2.86-2.72 (m, 1H), 1.75 (br. s., 2H), 1.60 (br. s., 4H), 1.50 (br. s., 2H), 1.00 (t, J=6.4 Hz, 3H).

Example 20: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4chlorophenyl)- 3-hydroxypropyl]-2-methoxy-6-methylpyridine-3-carboxamide

20A: methyl 2-methoxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: methyl 5-bromo was added to an oven-dried 10 ml vial -2-methoxy-6-methylnicotinate (200 mg, 0.769 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 -dioxaborolane) (234 mg, 0.923 mmol) (bis(pinacolato)diborone) and potassium acetate (226 mg, 2.307 mmol). 1,4-dioxane (5 ml) was added to the vial and nitrogen gas was bubbled through the mixture for 10 minutes. PdCl ₂ (dppf) (28.1 mg, 0.038 mmol) was added to the reaction mixture and bubbling was continued for 10 min. The reaction mixture was heated to reflux at 65° C. overnight. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and concentrated. The crude material was purified by flash chromatography on an ISCO system (20%-50% EtOAc/hexanes) to give methyl 2-methoxy-6-methyl-5-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)nicotinate (230 mg, 0.599 mmol, 78% yield) as a white solid.

MS (ERI) m/z 308.2 (weight of the corresponding boronic acid).

20B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-6-methylnicotinic acid: to 7-bromo solution -5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.712 mmol)methyl 2-methoxy-6-methyl-5-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2yl)nicotinate (230 mg, 0.747 mmol) (30 ml) tribasic potassium phosphate (1.067 ml, 2.135 mmol) (2 M in _H2O ) was added. The reaction mixture was sparged with nitrogen for 5 min and then PdCl ₂ (dppf) (41.7 mg, 0.057 mmol) was added. Nitrogen bubbling was continued for another 5 minutes. The reaction vessel was sealed and heated to 100° C. for 12 hours. The cooled reaction mixture was filtered through a pad of celite to remove the catalyst. Sodium hydroxide (0.356 mL, 3.56 mmol) (10 M in water) was added to the filtrate, and the resulting mixture was stirred at room temperature for 2 h. The crude material was purified by recrystallization with MeOH to give 5-(4amino-5-(trifluoromethyl )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-6-methylnicotinic acid sodium salt (120 mg, 0.327 mmol, 45.9% yield) as white solid . MS (ERI) m/z 368.1 (M+H).

20: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-6-

- 75 042342 methylnicotinic acid, sodium salt (20 mg, 0.054 mmol) and (S)-3-amino-1-(4-chlorophenyl)propan1-ol (10.61 mg, 0.057 mmol) in 1,4-dioxane (2 ml ) added Hunig's base (0.029 mL, 0.163 mmol) and BOP (28.9 mg, 0.065 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (7.5 mg, 9.8 μmol, 18%).

MS (ERI) m/z 534.9 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.53-8.41 (m, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.36 (s, 4H), 4.68 (dd, J=7.5 , 4.4 Hz, 1H), 4.02 (s, 3H), 3.35 (d, J=6.1 Hz, 2H), 2.30 (s, 3H), 1.97-1.73 (m, 2H).

Example 21 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1cyclohexanecarbonyl-4- methylpyrrolidin-3-yl]-2-methylpyridin-3-carboxamide

21A: (3S,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinamido)- 4-methylpyrrolidin-1-carboxylate: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methylnicotinic acid (80 mg, 0.237 mmol) and benzyl (3S,4S)-3-amino-4methylpyrrolidine-1-carboxylate (61.1 mg, 0.261 mmol) in 1,4-dioxane (3 ml) and DMF (1 ml) were added DIEA (0.124 ml, 0.712 mmol) and BOP (126 mg, 0.285 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative HPLC to give benzyl (3S,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)2-methylnicotinamido)-4-methylpyrrolidine-1-carboxylate (80 mg, 0.137 mmol, 57.9% yield) as a white solid. MS (ERI) m/z 554.3 (M+H).

21B: 5-(4-Amino-5 -(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-((3S,4S)-4 -methylpyrrolidin-3-yl)nicotinamide: (3S,4S)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl solution )-2-methylnicotinamido)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.090 mmol) in TFA (1 ml, 12.98 mmol) was stirred at room temperature for 2 days. The reaction mixture was concentrated and further dried with a vacuum pump to give 5-(4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -((3S,4S)-4-methylpyrrolidin-3yl)nicotinamide (30 mg, 0.072 mmol, 79%). MS (ERI) m/z 420.2 (M+H).

21: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-((3S,4S) 4-methylpyrrolidin-3-yl)nicotinamide (15 mg, 0.036 mmol) in THF (1 mL) was added BOP (18.98 mg, 0.043 mmol), Hunig's base (0.019 mL, 0.107 mmol) and cyclohexanecarboxylic acid (5.04 mg, 0.039 mmol ). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 10-50% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (3.8 mg, 5.0 μmol, 14%).

MS (ERI) m/z 530.4 (M+H).

1H NMR (500 MHz, DMSO-de) δ 9.11 (br. s., 1H), 8.69 (d, J=8.2 Hz, 1H), 8.34 (br. s., 1H), 8.14 (d, J=6.1 Hz, 1H), 7.65 (d, J=5.9 Hz, 1H), 7.31 (s, 2H), 7.21 (s, 2H), 7.11 (s, 2H), 4.51 (br. s., 1H), 3.58- 3.43 (m, 2H), 2.32 (br. s., 1H), 1.76-1.60 (m, 4H), 1.58 (br. s., 1H), 1.38-1.19 (m, 4H), 1.13 (d, J =14.7 Hz, 1H), 0.99 (t, J=7.9 Hz, 3H).

Example 22 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3 ,3 difluorocyclopentanecarbonyl)-4-(fluoromethyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide

22A: (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate, TFA: to (3S,4S)benzyl 3-((tert-butoxycarbonyl)amino)-4-(fluoromethyl) solution pyrrolidine-1-carboxylate (100 mg, 0.284 mmol) in THF (3 mL) was added TFA (0.219 mL, 2.84 mmol). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated and the resulting crude material was used in the next step without purification.

MS (ERI) m/z 253.3 (M+H).

22B: (3S,4S)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methylnicotinamido)-4 -(fluoromethyl)pyrrolidine-1-carboxylate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinic acid ( 80 mg, 0.237 mmol) and (3S,4S)-benzyl 3-amino-4-(fluoromethyl)pyrrolidine-1-carboxylate, TFA (65.8 mg, 0.261 mmol) in 1,4dioxane (3 ml) and DMF (1 ml ) DIEA (0.124 mL, 0.712 mmol) and BOP (126 mg, 0.285 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Purification by preparative HPLC gave (3S,4S)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2methylnicotinamido)-4-(fluoromethyl)pyrrolidine-1-carboxylate (100 mg, 0.175 mmol, 73.8% yield) as a white solid.

MS (ERI) m/z 571.8 (M+H).

22C: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4(fluoromethyl)pyrrolidine -3-yl)-2-methylnicotinamide, TFA: (3S,4S)-benzyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine) solution -7-yl)-2-methylnicotinamido)-4-(fluoromethyl)pyrrolidine-1carboxylate (80 mg, 0.140 mmol) in TFA (0.5 ml, 6.49 mmol) (pure) was stirred at room temperature for 20 h. The reaction mixture was evaporated and further concentrated with a vacuum pump to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3S,4S )-4-(fluoromethyl)pyrrolidin-3-yl)-2-methylnicotinamide, TFA (60 mg, 0.137 mmol, 98%). The resulting crude material was used in the next step without purification. MS (ERI) m/z 437.8 (M+H).

22: to a solution of 5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4(fluoromethyl )pyrrolidin-3-yl)-2-methylnicotinamide, TFA (15 mg, 0.034 mmol) and 3,3difluorocyclopentanecarboxylic acid (6.18 mg, 0.041 mmol) in 1,4-dioxane (2 ml) were added Hunig's base (0.018 ml, 0.103 mmol) and BOP (18.20 mg, 0.041 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (5.1 mg, 9.0 μmol, 26%).

MS (ERI) m/z 570.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.15 (dd, J=6.0, 1.7 Hz, 1H), 8.87-8.69 (m, 1H), 8.34 (s, 1H), 8.16 (d, J=5.2 Hz , 1H), 7.65 (d, J=8.5 Hz, 1H), 4.74 (br. s., 1H), 4.69 (br. s., 1H), 4.65-4.54 (m, 1H), 4.54-4.46 (m , 1H), 3.89-3.68 (m, 1H), 3.20-3.06 (m, 1H), 2.91 (br. s., 1H), 2.82 (br. s., 1H), 2.55 (d, J=3.4 Hz , 3H), 2.38-2.21 (m, 2H), 2.19-1.95 (m, 3H), 1.86-1.73 (m, 1H).

Example 23: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1 -(3 ,3difluorocyclopentanecarbonyl)-4-methylpyrrolidin-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide

23A: ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)nicotinate: mixture of ethyl 5-bromo-2-(trifluoromethyl)nicotinate (0.500 g, 1.678 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (0.511 g, 2.013 mmol) and acetate potassium (0.247 g, 2.52 mmol) in 1,4-dioxane (100 mL) was degassed (3x) with vacuum/nitrogen. The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.137 g, 0.168 mmol) was added and the mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 80°C and stirred overnight. The mixture was diluted with ethyl acetate and filtered under reduced pressure. The organic layer was washed with water and brine. The organic layer was collected and the aqueous layers were extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by flash chromatography on an ISCO system (40 g column; 0-100% ethyl acetate in hexanes) gave ethyl 5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2- (trifluoromethyl)nicotinate (0.342 g, 0.991 mmol, 59.1% yield) as a white solid.

MS (ERI) m/z 264.1 (M+H boronic acid).

23B: ethyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(trifluoromethyl)nicotinate: 7-bromo-5 mixture -(trifluoromethyl)pyrrolo[2,1-£][1,2,4]triazine-4-amine (0.232 g, 0.826 mmol), ethyl 5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)-2-(trifluoromethyl)nicotinate (0.342 g, 0.991 mmol), potassium triphosphate (2 M in water) (1.239 ml, 2.477 mmol) and 1,4-dioxane (6 ml) were degassed with vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.067 g, 0.083 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 70°C and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was collected and the aqueous layers were extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. The residue was triturated with dichloromethane and dried to give ethyl 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(trifluoromethyl)nicotinate (0.218 g, 0.520 mmol, 63.0% yield) as a white solid.

MS (ERI) m/z 420.2 (M+H).

23C: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(trifluoromethyl)nicotinic acid, lithium salt: ethyl 5 mixture -(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2(trifluoromethyl)nicotinate (0.218 g, 0.520 mmol) and lithium hydroxide, H2O (0.022 g, 0.520 mmol) in a mixture of methanol (1 ml), tetrahydrofuran (1 ml) and water (0.500 ml) was stirred at room temperature overnight. The heterogeneous reaction mixture was filtered under reduced pressure and the resulting solid was dried overnight to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)-2-(trifluoromethyl)nicotinic acid, lithium salt (0.203 g, 0.519 mmol, 100% yield) as a white solid. MS (ERI) m/z 392.1 (M+H).

23D: (3S,4S)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2(trifluoromethyl) nicotinamido)-4-methylpyrrolidin-1-carboxylate: to a suspension of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-(trifluoromethyl ) nicotinic acid, lithium salt (50 mg, 0.128 mmol) and (3S,4S)-benzyl 3-amino-4-methylpyrrolidine-1-carboxylate (32.9 mg, 0.141 mmol) in 1,4-dioxane (3 ml) and DMF (1 ml) was added with DIEA (0.067 ml, 0.383 mmol) and BOP (67.8 mg, 0.153 mmol). The mixture was stirred at room temperature for 1 h. ,4]triazin-7yl)-2-(trifluoromethyl)nicotinamido)-4-methylpyrrolidine-1-carboxylate (45 mg, 0.074 mmol, 58.0% yield) as a white solid. MS (ERI) m/z 607.8 (M+H).

23E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4-methylpyrrolidin-3 -yl)-2-(trifluoromethyl)nicotinamide, TFA: (3S,4S)-benzyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4) solution ]triazin-7-yl)-2-(trifluoromethyl)nicotinamido)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.082 mmol) in TFA (1 ml, 12.98 mmol) was stirred at room temperature for 2 days. The reaction mixture was concentrated and further dried with a vacuum pump to give 5-(4-amino-5-(trifluoromethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( (3S,4S)-4methylpyrrolidin-3-yl)-2-(trifluoromethyl)nicotinamide, TFA (30 mg, 0.063 mmol, 77%). The crude product was immediately used in the next step without purification. MS (ERI) m/z 473.8 (M+H).

23: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4methylpyrrolidin-3 -yl)-2-(trifluoromethyl)nicotinamide, TFA (15 mg, 0.032 mmol) and 3,3difluorocyclopentanecarboxylic acid (5.71 mg, 0.038 mmol) in 1,4-dioxane (2 ml) were added Hunig's base (0.017 ml, 0.095 mmol ) and BOP (16.82 mg, 0.038 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4.5 mg, 7.4 μmol, 23%).

MS (ERI) m/z 606 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.44 (br. s., 1H), 8.95 (t, J=9.8 Hz, 1H), 8.70 (br. s., 1H), 8.21 (d, J=4.5 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 4.53 (d, J=19.9 Hz, 1H), 3.59-3.46 (m, 2H), 3.12-3.04 (m, 1H), 3.00 (br s., 1H), 2.34-2.18 (m, 2H), 2.14-1.92 (m, 3H), 1.76 (br. s., 1H), 0.99 (t, J=5.9 Hz, 3H).

Example 24 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(4 ,4difluorocyclohexanecarbonyl)-4-methylpyrrolidin-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4methylpyrrolidin-3-yl )-2-(trifluoromethyl)nicotinamide (15 mg, 0.032 mmol) and 4,4difluorocyclohexanecarboxylic acid (6.24 mg, 0.038 mmol) in 1,4-dioxane (2 mL), Hunig's base (0.017 mL, 0.095 mmol) and BOP ( 16.82 mg, 0.038 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10

- 78042342 mm ammonium acetate; gradient: 20-70% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4.9 mg, 7.9 μmol, 25%).

MS (ERI) m/z 620.1 (M+H).

1H NMR (500 MHz, DMSO-06) δ 9.47 (br. s., 1H), 8.95 (d, J=8.5 Hz, 1H), 8.85 (d, J=8.2 Hz, 1H), 8.72 (br. s ., 1H), 8.23 (d, J=5.3 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 4.56 (br. s., 1H), 4.52 (br. s., 1H), 2.06 (br. s., 1H), 2.01 (br. s., 2H), 1.94-1.70 (m, 5H), 1.61-1.43 (m, 2H), 1.00 (t, J=7.4 Hz, 4H).

Example 25: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1 -(4 ,4difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methylpyridine-3-carboxamide

25A: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methylnicotinamido)-4-fluoropyrrolidin-1 -carboxylate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylnicotinic acid (500 mg, 1.483 mmol) tert -butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (333 mg, 1.631 mmol) (10 ml) and DMF (2 ml) were added DIEA (0.777 ml, 4.45 mmol) BOP (787 mg, 1.779 mmol) the mixture was stirred at room temperature for 30 minutes. The crude material was purified by flash chromatography on an ISCO system (silica gel, 40 g, 5% MeOH/DCM) to give t-butyl 3-(5(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-2-methylnicotinamido)-4fluoropyrrolidine-1-carboxylate (1.0 g, 1.433 mmol, 97% yield) as a white solid.

MS (ERI) m/z 524.3 (M+H).

1H NMR (400 MHz, CD ₃ OD) δ 9.21-9.02 (m, 1H), 8.74-8.55 (m, 1H), 8.52-8.31 (m, 1H), 8.24-7.99 (m, 1H), 7.56-7.45 (m, 1H), 7.40-7.23 (m, 1H), 5.40-5.12 (m, 1H), 4.86-4.56 (m, 1H), 3.98-3.83 (m, 1H), 3.85-3.54 (m, 2H) , 2.83-2.58 (m, 3H), 1.63-1.41 (m, 9H).

The racemic material was separated into the corresponding homochiral enantiomers using the following preparative SFC conditions: Lux Cellulose-4 preparative column (5x25 cm, 5 μm); pressure BPR 100 bar; temperature 40°C; flow rate 300 ml/min; mobile phase CO ₂ /MeOH with 0.1% NH ₄ OH (80/20); detector wavelength 263 nm; the sequence of introduction of the separation program; sample 0.60 ml with a cycle time of 5.2 min; sample preparation 1.1 g/18 ml DCM + 18 ml MeOH, 30.6 mg/ml. The purity of the isolated fractions (peak 1; retention time 10.91 min and peak 2; retention time 12.27 min) was determined under the following analytical SFC conditions: Lux Cellose-4 analytical column (0.46x25 cm, 5 µm); BPR pressure 100 bar; temperature 40°C; flow rate 3.0 ml/min; mobile phase CO ₂ /MeOH with 0.1% NH4OH (80/20); wavelength of the UV detector 200-400 nm, MC mode for detecting positively charged ions, spectrogram, mV, 200-900. The absolute stereochemistry was determined by comparing the final analogues with those obtained from material for which X-ray crystallographic information was available.

25B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-methylnicotinamide, TFA: tert-butyl solution 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- methylnicotinamido)-(3R,4S)-4-fluoropyrrolidine-1 carboxylate (200 mg, 0.382 mmol) in TFA (1 ml, 12.98 mmol) (1 ml, pure) was stirred at room temperature for 30 min, then the TFA was evaporated and further dried with a vacuum pump to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4fluoropyrrolidin-3- yl)-2-methylnicotinamide, TFA (162 mg, 0.383 mmol, 100% yield) as a colorless oil, which was used directly in the next step without purification. MS (ERI) m/z 424.3 (M+H).

25: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3 -yl)-2-methylnicotinamide, TFA (15 mg, 0.035 mmol) and 4,4difluorocyclohexanecarboxylic acid (6.98 mg, 0.043 mmol) in 1,4-dioxane (2 ml) added Hunig's base (0.019 ml, 0.106 mmol) and BOP (18.80 mg, 0.043 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (7.1 mg, 12.5 μmol, 36%). MS (ERI) m/z 569.9 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.16 (8, 1H), 9.00-8.81 (m, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 7.67 (d, J=2.7 Hz, 1H), 5.31 (br d, J=12.8 Hz, 1H), 4.07 (br t, J=9.2 Hz, 1H), 3.95 (br s, 1H), 3.56 (br s, 1H), 3.25 (br d, J=10.7

- 79 042342

Hz, 1H), 2.58 (d, J=4.9 Hz, 3H), 2.05 (br d, J=7.6 Hz, 2H), 1.95-1.80 (m, 2H), 1.76 (br d, J=15.3 Hz, 1H ), 1.661.47 (m, 2H).

Example 26 2-amino-5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3- (4chlorophenyl)-3-hydroxypropyl]pyridine-3-carboxamide

26A: methyl 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: a mixture of methyl 2-amino-5-bromonicotinate (1 g, 4.33 mmol), 4 ,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.319 g, 5.19 mmol), potassium acetate (1.274 g, 12.98 mmol) in dioxane (20 ml) was degassed (3x) with vacuum/nitrogen. 1,1'-Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (0.353 g, 0.433 mmol) was added and the mixture was degassed (2x) and filled with N ₂ . The reaction mixture was immersed in an oil bath at 80°C and stirred overnight. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated. After purification by flash chromatography on a Biotage system (40 g column; 0100% ethyl acetate in hexanes), the product was triturated with ether to give methyl 2amino-5-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)nicotinate (0.6 g, 2.157 mmol, 49.8% yield) as a light tan solid.

MS (ERI) m/z 279.18 (M+H).

26B: 2-amino-5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)nicotinic acid: to a solution of 7-bromo-5- (trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine (50 mg, 0.178 mmol) and methyl 2amino-5-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)nicotinate (54.4 mg, 0.196 mmol) in 1,4-dioxane (2 mL) was added tribasic potassium phosphate (0.267 mL, 0.534 mmol) (2 M in H2O). The mixture was sparged with nitrogen for 5 min and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (14.53 mg, 0.018 mmol) was added. Bubbling was continued for another 5 minutes. The reaction vessel was sealed and heated to 100° C. for 16 hours. The reaction mixture was filtered through a pad of celite to remove the catalyst. Sodium hydroxide (0.089 mL, 0.890 mmol) (10 M in water) was added to the filtrate and the resulting mixture was stirred at room temperature for another 2 h. 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)nicotinic acid (56 mg, 0.166 mmol, 93% yield) as tan solid substances.

MS (ERI) m/z 338.97 (M+H).

¹ H NMR (400 MHz, DMSO-d6) δ 8.91-8.69 (m, 2H), 8.31-8.10 (m, 1H), 7.61-7.48 (m, 1H).

26: 2-amino-5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)nicotinic acid mixture (15 mg, 0.044 mmol), (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (9.06 mg, 0.049 mmol), BOP (23.54 mg, 0.053 mmol), Hunig's bases (0.023 ml, 0.133 mmol) in DMF (1 ml) was stirred at room temperature for 20 min. The mixture was then concentrated and subjected to preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 22-62% B over 22 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (R)-2-amino-5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine -7-yl)-N-(3-(4chlorophenyl)-3-hydroxypropyl)nicotinamide (8.8 mg, 0.017 mmol, 39.2% yield) as a white solid.

MS (ERI) m/z 506 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.84-8.71 (m, 1H), 8.55-8.46 (m, 1H), 8.30-8.23 (m, 1H), 8.16-8.04 (m, 1H), 7.45- 7.39 (m, 1H), 7.39-7.29 (m, 4H), 4.69-4.58 (m, 1H), 3.38-3.24 (m, 2H), 1.94-1.80 (m, 2H).

Example 27: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-H4-fluoro-1-(4fluorobenzoyl)pyrrolidin-3 - yl]-2-methoxypyridine-3-carboxamide

F

27A: (3R,4S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido) -4-fluoropyrrolidine-1-carboxylate: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid ( 100 mg, 0.283 mmol) (3R,4S)-tert-80 042342 butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (63.6 mg, 0.311 mmol) in 1,4-dioxane (3 ml) DMF (1 ml) DIEA (0.148 ml, 0.849 mmol) BOP (150 mg, 0.340 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The crude material was purified by preparative HPLC to give (3R,4S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triαZun-7- ul)-2-methoxynicotinαmido)-4-fluoropyrrolidine-1-carboxylateα (80 mg, 0.148 mmol, 52.4% yield) as a white solid.

MS (ERI) m/z 540.3 (M+H).

27B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrroludin-3 -yl)-2-methoxynicotinamide, TFA: (3R,4S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4] solution triαzin-7-yl)-2-methoxynicotinαmido)-4-fluoropyrrolidine-1-carboxylate (80 mg, 0.148 mmol) in TFA (0.5 mL, 6.49 mmol) (pure) was stirred at room temperature for 1 h. The reaction mixture was concentrated and further dried with a vacuum pump. The resulting crude material was carried to the next step without purification.

MS (ERI) m/z 440.3 (M+H).

27: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3 -yl)-2-methoxynicotinamide, TFA (15 mg, 0.034 mmol) and 4-fluorobenzoic acid (5.74 mg, 0.041 mmol) in 1,4-dioxane (2 mL) were added Hunig's base (0.018 mL, 0.102 mmol) and BOP (18.12 mg, 0.041 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions:

column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (1.1 mg, 2.0 μmol, 6%).

MS (ERI) m/z 562.4 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.03-8.84 (m, 1H), 8.76 (br s, 1H), 8.58 (br d, J=7.0 Hz, 1H), 8.51 (br d, J=7.3 Hz, 1H), 8.16 (br d, J=12.8 Hz, 1H), 7.73-7.57 (m, 3H), 7.44-7.24 (m, 2H), 4.60-4.83 (m, 1H), 4.04 (br d, J=4.9 Hz, 3H), 3.98 (br s, 1H), 3.94-3.76 (m, 1H), 2.56-2.53 (m, 2H), 1.00 (d, J=6.1 Hz, 1H).

Example 28: 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4chlorophenyl)- 3-methoxypropyl]-2-methoxypyridine-3-carboxamide

28A: (R)-3-(4-chlorophenyl)-3-methoxypropan-1-amine, TFA: to a solution of (R)-tert-butyl (3-(4-chlorophenyl)-3-hydroxypropyl)carbamate (50 mg, 0.175 mmol) in THF (2 ml) was added sodium hydride (14.00 mg, 0.350 mmol). After stirring for 30 min, iodomethane (0.012 mL, 0.192 mmol) was added. The resulting mixture was stirred for 1 hour. HCl (1 ml) to stop the reaction and the mixture was purified by preparative HPLC to give (R)-tert-butyl (3-(4-chlorophenyl)-3-methoxypropyl)carbamate (45 mg, 0.150 mmol, 86% yield ). The crude residue was treated with TFA (0.5 ml, 6.49 mmol) (neat). The reaction mixture was concentrated and dried under vacuum to give (R)-3-(4-chlorophenyl)-3-methoxy-propan-1-amine (30 mg, 0.150 mmol, 86% yield).

MS (ERI) (m/z) 200.1 (M+H).

28: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (10 mg, 0.028 mmol) and (R)-3-(4-chlorophenyl)-3-methoxypropαn-1-αminα (6.22 mg, 0.031 mmol) in 1,4-dioxane (2 ml) Hunig's base (0.015 ml, 0.085 mmol) and BOP (15.02 mg, 0.034 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Purification by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-90% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min; obtained (R)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7-ul)-N-(3-(4-chlorophenyl)-3 -methoxypropyl)-2methoxynicotinamide (8.4 mg, 0.015 mmol, 53.8% yield) as a white solid.

MS (ERI) m/z 535.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J=2.4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.42 (br t, J=5.5 Hz, 1H), 8.14 ( s, 1H), 7.56 (s, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.30 (dd, J=7.6, 5.2 Hz, 1H), 4.03 (s, 3H), 3.62 (br s, 1H), 3.34 (dt, J=14.6, 7.2 Hz, 2H), 3.17-3.12 (m, 3H), 1.97-1.80 (m, 2H).

Example 29: 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4chlorophenyl)- 3-methoxypropyl]-2-methoxypyridine-3-carboxamide

- 81 042342

29A: (S)-3-(4-chlorophenyl)-3-methoxypropan-1-amine, TFA: to a solution of (S)-tert-butyl (3-(4-chlorophenyl)-3-hydroxypropyl)carbamate (100 mg, 0.350 mmol) in THF (3 ml) was added sodium hydride (28.0 mg, 0.700 mmol). After stirring for 30 min, iodomethane (0.024 ml, 0.385 mmol) was added. The resulting mixture was stirred for 1 hour. HCl (2 ml) to stop the reaction and the reaction mixture was purified by preparative HPLC to give (S) tert-butyl (3-(4-chlorophenyl)-3-methoxypropyl) carbamate (90 mg, 0.300 mmol, 86% yield ). The crude residue was treated with TFA (0.5 ml, 6.49 mmol) (neat). The reaction mixture was concentrated and dried under vacuum to give (S)-3-(4-chlorophenyl)-3-methoxypropan-1-amine, TFA (60 mg, 0.300 mmol, 86% yield).

29: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (10 mg, 0.028 mmol) and (S)-3-(4-chlorophenyl)-3-methoxypropan-1-amine (6.22 mg, 0.031 mmol) in 1,4-dioxane (2 ml) Hunig's base (0.015 ml, 0.085 mmol) and BOP (15.02 mg, 0.034 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Purification by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 40-90% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min, gave (S)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3 -(4-chlorophenyl)-3-methoxypropyl)-2methoxynicotinamide (8.4 mg, 0.016 mmol, 55.5% yield) as a white solid.

MS (ERI) m/z 535 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.87 (d, J=2.4 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.40 (br t, J=5.5 Hz, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.43 (d, J=8.2Hz, 2H), 7.35 (d, J=8.5Hz, 2H), 4.31 (dd, J=7.8, 5.0Hz, 1H ), 4.03 (s, 3H), 3.46 (br s, 1H), 3.40-3.28 (m, 1H), 3.18-3.14 (m, 3H), 2.56-2.53 (m, 2H), 1.98-1.80 (m, 2H).

Example 30: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4chlorophenyl)- 3-hydroxypropyl]-2-(methylamino)pyridine-3-carboxamide

F ₃ C

I ^h ₂ n./% o Qh

N NH

I

30A: methyl 2-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: methyl 5-bromo-2 was added to an oven-dried 10 ml vial - (methylamino) nicotinate (0.6 g, 2.448 mmol), bis (pinacolato) diborone (217 mg, 0.854 mmol) and potassium acetate (0.721 g, 7.34 mmol). 1,4dioxane (20 ml) was added to the vial and purged with nitrogen gas for 10 min. PdCl ₂ (dppf) (0.090 g, 0.122 mmol) was added to the reaction mixture, and nitrogen gas was blown through the mixture for 10 min. The resulting mixture was heated to reflux at 80° C. overnight. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo. The crude residue was purified by flash chromatography on an ISCO system (40 g silica gel, 10~60% EtOAc/hexanes) to give methyl 2-(methylamino)-5-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)nicotinate (500 mg, 1.712 mmol, 69.9% yield) as a white solid.

MS (ERI) (m/z) 211.1 (M+H for boronic acid).

30B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-(methylamino)nicotinic acid: to a solution of 7-bromo- 5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazine-4-amine (100 mg, 0.356 mmol) and methyl 2-(methylamino)-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (114 mg, 0.391 mmol) in 1,4-dioxane (30 mL) was added tribasic potassium phosphate (0.534 mL, 1.067 mmol) (2 M in _H2 O). The reaction mixture was bubbled with nitrogen for 5 min, then PdCl ₂ (dppf) (20.83 mg, 0.028 mmol) was added. Nitrogen bubbling was continued for 5 minutes. The reaction vessel was sealed and heated to 100° C. for 12 hours. Water (2 ml) was added and a ground solid (methyl ester) was obtained by filtration. The resulting solid was then redissolved in MeOH (2 ml) and THF (2 ml), then sodium hydroxide (0.178 ml, 1.779 mmol) (1M in water) was added. The resulting mixture was stirred at 60° C. for 12 hours. The crude material was purified by preparative HPLC to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4] triazin-7yl)-2-(methylamino)nicotinic acid (50 mg, 0.142 mmol, 39.9% yield) as a white solid. A methoxy by-product (formed during hydrolysis) was also obtained as 5-(4amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid ( 30 mg, 0.085 mmol, 23.87% yield) as a white solid.

- 82 042342

MS (ERI) (m/z) 353.1 (M+H).

30: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2(methylamino)nicotinic acid (15 mg, 0.043 mmol ) and (S)-3-amino-1-(4-chlorophenyl)propan-1-ol (8.70 mg, 0.047 mmol) in 1,4-dioxane (2 ml) Hunig's base (0.022 ml, 0.128 mmol) was added and BOP (22.60 mg, 0.051 mmol). The resulting mixture was stirred at room temperature for 30 minutes. Purification was carried out using preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (S)-5(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) -N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2(methylamino)nicotinamide (3.8 mg, 7.24 µmol, 16.99% yield) as a white solid.

MS (ERI) m/z 520.4 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=2.1 Hz, 1H), 8.51 (br t, J=5.2 Hz, 1H), 8.36-8.23 (m, 2H), 8.13 (s, 1H ), 7.42 (s, 1H), 7.37 (s, 4H), 5.42 (d, J=4.6 Hz, 1H), 4.65 (br d, J=5.2 Hz, 1H), 3.31 (br d, J=6.4 Hz , 1H), 2.95 (d, J=4.9 Hz, 3H), 2.73-2.54 (m, 1H), 1.93-1.79 (m, 2H), 1.00 (d, J=6.1 Hz, 1H).

Example 31-1 and 31-2: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3 ,3difluorocyclobutanecarbonyl)-(3R,4S)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide and 5-[4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl]-N-[1-(3,3-difluorocyclobutanecarbonyl)(3S,4R)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

31A: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidin-1 -carboxylate: heterogeneous mixture of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (2.04 g, 5.66 mmol), tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (mixture of cis-enantiomers) (1.39 g, 6.80 mmol), Hunig's bases (2.97 ml, 17.0 mmol) and BOP (2.76 g, 6.23 mmol) in N,Ndimethylformamide (20 ml) was stirred at room temperature for 60 min (homogeneous). The mixture was diluted with ethyl acetate, washed with 10% aqueous lithium hydroxide (2x) and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with methanol with sonication and filtered to give tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (1.31 g, 2.43 mmol, 43% yield) as a light tan solid. The second portion of tert-butyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine- 1 carboxylate (0.273 g, 0.506 mmol, 9% yield) was separated. The filtrate was concentrated and purified by flash chromatography on an ISCO system (40 g column; 0-10% methanol in dichloromethane) to give (3R,4S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (0.273 g, 0.506 mmol, 9% yield).

MS (ERI) (m/z) 540.3 (M+H).

31B: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidin-1 -carboxylate: intermediate 31A was separated by chiral SFC using the following preparative conditions: column: Cellulose-4 (3x25 cm, 5 μm), BPR pressure 100 bar, temperature: 35°C, flow rate: 200 ml/min, mobile phase: CO ₂ /MeOH (60/40), detector wavelength: 220 nm, separation program: serial injection, injection: 3.5 ml with a cycle time of 3.65 min, sample preparation: 1.21 g/100 ml MeOH:DCM (1 :1), 13.1 mg/ml, throughput: 753 mg/h. Peak 1 eluted at 4.15 min and peak 2 eluted at 6.56 min. Peak 2 was concentrated under reduced pressure to give tert-butyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido )-4-(3R,4S)-fluoropyrrolidine 1-carboxylate (0.480 g, 0.890 mmol, 73.3% yield) as a white solid. Peak 1 was defined in the (3S,4R) configuration and peak 2 was defined in the (3R,4S) configuration. The determination of chirality was based on comparison with the final compounds obtained as a result of orthogonal synthesis, during which the crystal structure was obtained.

31C: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3 -yl)-2-methoxynicotinamide: tert-butyl mixture )-4-Fluoropyrrolidine-1-carboxylate (homochiral peak 2; cis-stereochemistry) (0.480 g, 0.890 mmol) and trifluoroacetic acid (16.79 mL, 218 mmol) were stirred at room temperature for 45 min. The solvent was removed under reduced pressure, and the residue was diluted with dichloromethane and washed with 1.5 M aqueous potassium phosphate dibasic solution. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2x), adjusted to pH ~10 with 2.0 M aqueous potassium phosphate dibasic, and then extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-( (3R,4S)-4-Fluoropyrrolidin-3-yl)-2-methoxysynicotinamide (0.355 g, 0.808 mmol, 91% yield) as a white solid.

MS (ERI) (m/z) 440.2 (M+H).

31-1: mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidine- 3-yl)-2-methoxynicotinamide (0.020 g, 0.046 mmol), 3,3-difluorocyclobutanecarboxylic acid (6.20 mg, 0.046 mmol), Hunig's base (0.024 ml, 0.137 mmol) and BOP (0.022 g, 0.050 mmol) in N ,N-dimethylformamide (1.0 ml) was stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 20-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-[4-amino5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1 -(3,3-difluorocyclobutanecarbonyl)-(3R,4S)-4fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide (20.0 mg, 25.5 µmol, 55%). This substance was later characterized as the (3R,4S) isomer.

MS (ERI) m/z 558.3 (M+H).

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.92 (br s, 1H), 8.84-8.75 (m, 1H), 8.58-8.49 (m, 1H), 8.22-8.17 (m, 1H), 7.67-7.61 (m, 1H), 5.45-5.19 (m, 1H), 4.88-4.58 (m, 1H), 4.05 (d, J=4.9 Hz, 3H), 4.00-3.84 (m, 1H), 3.833.69 (m , 1H), 3.45-3.36 (m, 1H), 3.31-3.24 (m, 1H), 3.24-3.11 (m, 1H), 2.90-2.70 (m, 4H).

31-2: Following a protocol similar to 31C and 31-1, peak 1 from 31B was carried further to obtain:

5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1 -(3,3difluorocyclobutanecarbonyl)-(3S,4R) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide: mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)-N-(4-fluoropyrrolidin-3-yl)-2methoxynicotinamide (0.019 g, 0.043 mmol), 3,3-difluorocyclobutanecarboxylic acid (5.89 mg, 0.043 mmol), Hunig base (0.023 ml, 0.130 mmol) and BOP ( 0.021 g, 0.048 mmol) in N,Ndimethylformamide (1.0 mL) was stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 25-65% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1-(3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide (16.4 mg, 0.029 mmol, 67%).

MS (ERI) m/z 558.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (d, J=2.1 Hz, 1H), 8.78 (dd, J=17.7, 2.1 Hz, 1H), 8.52 (br dd, J=10.2, 7.8 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.45-5.16 (m, 1H), 4.87-4.55 (m, 1H), 4.04 (d, J=6.1 Hz, 3H), 4.00-3.57 (m, 3H), 3.46-3.22 (m, 1H), 3.22-3.07 (m, 1H), 2.89-2.68 (m, 4H).

Example 32 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxypyridine-3-carboxamide

32A: 7-bromo-5-chloropyrrolo[2,1-f][1,2,4]triazine-4-amine: 7-bromopyrrolo[2,1-f][1,2,4]triazine4-amine mixture (100 mg, 0.469 mmol) and NCS (62.7 mg, 0.469 mmol) in DMF (2 mL) were stirred at room temperature for 3 h. The mixture was then diluted with water, filtered, washed with water, dried to give 7-bromo-5- chloropyrrolo[2,1-f][1,2,4]triazine-4-amine (100 mg, 0.404 mmol, 86% yield) as a white solid.

MS (ERI) m/z 248.88 (M+H).

1H NMR (400 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 6.82 (s, 1H).

32B: 5-(4-Amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, sodium salt: to 7-bromo-5-chloropyrrolo solution [2,1-1][1,2,4]triazine-4-amine (100 mg, 0.404 mmol) and methyl 2methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)nicotinate (130 mg, 0.444 mmol) in 1,4-dioxane (2 mL) was added tribasic potassium phosphate (0.606 mL, 1.212 mmol) (2 M in H2O). After bubbling

- 84 042342 nitrogen through the mixture for 5 min, was added a complex of 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) dichloromethane dichloride (33.0 mg, 0.040 mmol). Nitrogen was bubbled through the mixture for an additional 5 minutes. The reaction vessel was sealed and heated to 100° C. for 2 hours. The reaction mixture was filtered through a pad of celite to remove the catalyst. Sodium hydroxide (2.020 ml, 2.020 mmol) (10 M in water) was added to the solution and the resulting mixture was stirred at room temperature for an additional 2 hours. The product was isolated by crystallization in MeOH and filtration to give 5-(4-amino -5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, sodium salt, as a reddish solid. MS (ERI) m/z 319.95 (M+H).

32: mixture of 5-(4-amino-5-chloropyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, sodium salt (20 mg, 0.063 mmol), ( S)-3-amino-1-(4-chlorophenyl)propan-1-ol, HCl (15.28 mg, 0.069 mmol), BOP (33.2 mg, 0.075 mmol) and Hunig's base (0.033 ml, 0.188 mmol) in DMF ( 1 ml) was stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 32-72% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 14-54% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (S)-5-(4-αmino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N -(3(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (7.1 mg, 0.015 mmol, 23.29% yield) as a white solid.

MS (ERI) m/z 487.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.00-8.79 (m, 1H), 8.85-8.54 (m, 1H), 8.50-8.26 (m, 1H), 8.07-7.83 (m, 1H), 7.48-7.31 (m, 4H), 7.28-6.97 (m, 1H), 4.89-4.66 (m, 1H), 4.05-3.98 (m, 1H), 3.54-3.30 (m, 1H), 2.09-1.68 (m, 2H) .

Example 33: 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-( 1-benzyl-1H-pyrazol-4-yl)- 2methoxypyridine-3-carboxamide

A mixture of 5-(4-amino-5-chloropyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (20 mg, 0.063 mmol), 1-benzyl-1H- Pyrazole-4-amine (10.84 mg, 0.063 mmol), BOP (33.2 mg, 0.075 mmol), and Hunig's base (0.033 mL, 0.188 mmol) in DMF (1 mL) was stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 32-72% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1- benzyl-1H-pyrazol-4-yl)-2methoxynicotinamide (6.2 mg, 0.013 mmol, 20.87% yield) as a white solid.

MS (ERI) m/z 475.1 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.29-10.05 (m, 1H), 8.95-8.79 (m, 1H), 8.79-8.56 (m, 1H), 8.21-8.02 (m, 1H), 8.02- 7.84 (m, 1H), 7.73-7.55 (m, 1H), 7.41-7.21 (m, 6H), 5.42-5.17 (m, 2H), 3.28-3.24 (m, 3H).

Example 34 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ 1 -(3,3difluorocyclopentanecarbonyl)-(3R ,4S)4-Fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

34A: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidin-1 -carboxylate: heterogeneous mixture of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (2.04 g, 5.66 mmol), tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (mixture of cis-enantiomers) (1.39 g, 6.80 mmol), Hunig's bases (2.97 ml, 17.0 mmol) and BOP (2.76 g, 6.23 mmol) in N,N

- 85 042342 dimethylformamide (20 ml) was stirred at room temperature for 60 min (homogeneous). The mixture was diluted with ethyl acetate, washed with 10% aqueous lithium hydroxide (2x) and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was triturated with methanol with sonication and filtered to give tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-7 -yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (1.31 g, 2.43 mmol, 43% yield) as a light tan solid. Second portion of (3R,4S)-tert-butyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido )-4-fluoropyrrolidine-1 carboxylate (0.273 g, 0.506 mmol, 9% yield) was separated. The filtrate was concentrated and purified by flash chromatography on an ISCO system (40 g column; 0-10% methanol in dichloromethane) to give (3R,4S)-tert-butyl 3-(5-(4-amino-5-(trifluoromethyl )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (0.273 g, 0.506 mmol, 9% yield).

MS (ERI) (m/z) 540.3 (M+H).

34B: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidin-1 -carboxylate: intermediate 34A was separated by chiral SFC using the following preparative conditions: column: Cellulose-4 (3x25 cm, 5 μm), BPR pressure 100 bar, temperature: 35°C, flow rate: 200 ml/min, mobile phase: CO ₂ /MeOH (60/40), detector wavelength: 220 nm, separation program: sequential injection, injection: 3.5 ml with a cycle time of 3.65 min, sample preparation: 1.21 g/100 ml MeOH:DCM (1 :1), 13.1 mg/ml, throughput: 753 mg/h. Peak 2 was concentrated under reduced pressure to give tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido) -(3R,4S)-4-fluoropyrrolidine-1-carboxylate (0.480 g, 0.890 mmol, 73.3% yield) as a white solid. The purity of the product was >99% by HPLC with retention time = 1.22 min, column: Phenomenex Kinetex C18, 2.1 x 50 mm (1.5 min gradient); solvent A = 10% MeCN, 90% H2O, 0.1% TFA; solvent B = 90% MeCN, 10% H2O, 0.1% TFA. LC-MS M+1 = 540.3. Chiral purity: 99.5% ee.

34C: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-pyrrolidin-3 -yl)-2-methoxynicotinamide: tert-butyl mixture )-(3R,4S)-4-fluoropyrrolidine-1-carboxylate (homochiral - peak 2; cis-stereochemistry) (0.480 g, 0.890 mmol) and trifluoroacetic acid (16.79 ml, 218 mmol) were stirred at room temperature for 45 min . The solvent was removed under reduced pressure, and the residue was diluted with dichloromethane and washed with 1.5 M aqueous potassium phosphate dibasic solution. The organic layer was collected and the aqueous layer was extracted with dichloromethane (2x), adjusted to pH ~10 with 2.0 M aqueous potassium phosphate tribasic, and then extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-( (3R,4S)-4-Fluoropyrrolidin-3-yl)-2-methoxynicotinamide (0.355 g, 0.808 mmol, 91% yield) as a white solid. MS (ERI) (m/z) 440.2 (M+H).

34: mixture 3-yl)-2-methoxynicotinamide (0.020 g, 0.046 mmol), 3,3-difluorocyclopentanecarboxylic acid (8.88 mg, 0.059 mmol), Hunig's base (0.024 ml, 0.137 mmol) and BOP (0.022 g, 0.050 mmol) in N ,Ndimethylformamide (1.0 ml) was stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 10-80% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (15.0 mg, 26.2 μmol, 57%).

MS (ERI) m/z 572.3 (M+H).

1Н NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.74 (br d, J=18.3 Hz, 1H), 8.56 (br t, J=8.5 Hz, 1H), 8.14 (s, 1H ), 7.56 (s, 1H), 5.41-5.20 (m, 1H), 4.84-4.58 (m, 1H), 4.03 (d, J=6.7 Hz, 3H), 3.81-3.71 (m, 3H), 3.54- 3.37 (m, 1H), 3.29-3.11 (m, 2H), 2.31 (br dd, J=16.3, 9.0 Hz, 2H), 2.23-2.11 (m, 1H), 2.11-1.99 (m, 2H), 1.86 -1.71(m, 1h).

Example 35: 2-amino-5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-( 1-tert-butyl- 1 H -pyrazol-4-yl)pyridine-3-carboxamide

- 86 042342

A mixture of 2-amino-5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)nicotinic acid (20 mg, 0.059 mmol), 1- (tert-butyl)-1H-pyrazol-4-amine (9.88 mg, 0.071 mmol), BOP (31.4 mg, 0.071 mmol) and Hunig's base (0.031 ml, 0.177 mmol) in DMF (1 ml) was stirred at room temperature in within 20 min. The mixture was then filtered and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain 2-amino-5-(4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-N-(1-(tert-butyl)-1H-pyrazol-4-yl)nicotinamideα (11.9 mg, 0.026 mmol, 43.8% yield) as a white solid.

MS (ERI) m/z 460.1 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.43-10.12 (m, 1H), 8.96-8.71 (m, 1H), 8.63-8.37 (m, 1H), 8.19-7.94 (m, 2H), 7.72- 7.54 (m, 1H), 7.55-7.40 (m, 1H), 3.89 (s, 3H), 1.54 (s, 9H).

Example 36 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxypyridine-3-carboxamide

A mixture of 5-(4-amino-5-chloropyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (20 mg, 0.063 mmol), (R)-3- amino-1-(4-chlorophenyl)propan-1-ol, HCl (15.28 mg, 0.069 mmol), BOP (33.2 mg, 0.075 mmol) and Hunig's base (0.033 ml, 0.188 mmol) in DMF (1 ml) were stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LCMS under the following conditions: column: Waters XBridge C-18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 32-72% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (R)-5-(4-αmino-5-chloropyrrolo[2,1-f][1,2,4]triαzin-7-yl)-N -(3-(4chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (4.8 mg, 9.85 µmol, 15.74% yield) as a white solid.

MS (ERI) m/z 487 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.03-8.66 (m, 2H), 8.49-8.21 (m, 1H), 8.13-7.82 (m, 1H), 7.53-7.28 (m, 4H), 7.27-7.12 (m, 1H), 5.50-5.23 (m, 1H), 4.84-4.53 (m, 1H), 3.55-3.31 (m, 1H), 2.14-1.75 (m, 2H).

Example 37: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide (homochiral, trans-)

37A: tert-Butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidin-1 -carboxylate: a mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (0.254 g, 0.705 mmol), tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (mixture of trans-enantiomers) (0.173 g, 0.846 mmol), Hunig's bases (0.369 ml, 2.12 mmol) and BOP (0.343 g, 0.776 mmol) in N, N-dimethylformamide (3.0 ml) was stirred at room temperature for 60 min. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude material. The product was triturated with methanol with sonication and collected by vacuum filtration. The filtrate was concentrated and the residue was suspended in methanol with sonication. The solid was collected and the combined substances were dried under reduced pressure to give tert-butyl 3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (0.289 g, 0.536 mmol, 76% yield) as a white solid.

MS (ERI) (m/z) 540.3 (M+H).

37B: Intermediate 37A was separated by chiral SFC using the following preparative conditions: column: Cellulose-4 (3x25 cm, 5 μm), BPR pressure 100 bar, temperature: 35°C, flow rate: 200 ml/min, mobile phase : CO ₂ /MeOH (60/40), detector wavelength: 220 nm, pro

- 87 042342 grams separation: serial injection, injection: 1.0 ml with a cycle time of 2.9 min, sample preparation: 0.289 g/18 ml MeOH:DCM (1:1), 16.1 mg/ml, throughput: 332 mg/h . Peak 1 eluted at 4.35 min and peak 2 eluted at 4.96 min. Peak 1 was concentrated under reduced pressure to give tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)2-methoxynicotinamido )-4-Fluoropyrrolidine-1-carboxylate (homochiral, trans, absolute stereochemistry not determined) (0.135 g, 0.248 mmol, 92% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ 8.95-8.90 (m, 1H), 8.63-8.58 (m, 2H), 8.18 (s, 1H), 7.61 (s, 1H), 4.584.44 (m, 1H ), 4.02-3.97 (m, 3H), 3.72-3.62 (m, 1H), 3.60-3.51 (m, 1H), 3.50-3.38 (m, 1H), 3.30 (s, 2H), and 1.43 (s, 9H).

37C: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluoropyrrolidin-3-yl)-2methoxynicotinamide ( homochiral, trans, absolute stereochemistry not determined): mixture of tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2-methoxynicotinamido)-4fluoropyrrolidine-1-carboxylate (0.132 g, 0.245 mmol) and trifluoroacetic acid (3.00 ml, 38.9 mmol) were stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate (2x). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-( 4-Fluoropyrrolidin-3-yl)-2-methoxynicotinamide (homochiral, trans, absolute stereochemistry not determined) (0.101 g, 0.230 mmol, 94% yield) as a white solid.

MS (ERI) (m/z) 440.3 (M+H).

37: mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluoropyrrolidin-3yl)-2- methoxynicotinamide (homochiral, trans-, absolute stereochemistry not determined) (0.020 g, 0.046 mmol), 3,3-difluorocyclobutanecarboxylic acid (8.05 mg, 0.059 mmol), Hunig's base (0.024 ml, 0.137 mmol) and BOP (0.022 g, 0.050 mmol) in N,N-dimethylformαamide (1.0 mL) was stirred at room temperature for 60 min. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-80% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (15.0 mg, 26.9 μmol, 59%).

MS (ERI) m/z 558 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.92 (d, J=2.1 Hz, 1H), 8.64-8.55 (m, 2H), 8.17 (d, J=1.5 Hz, 1H), 7.59 (s, 1H) , 5.32-5.12 (m, 1H), 4.64-4.50 (m, 1H), 3.98 (s, 3H), 3.93-3.77 (m, 1H), 3.77-3.55 (m, 2H), 3.47-3.33 (m, 1H), 3.22-3.09 (m, 1H), 2.86-2.74 (m, 4H).

Example 38 5-{4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxypyridine-3-carboxamide

38A: 7-bromo-4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine: 4-chloro-5-methylpyrrolo[2,1f][1,2,4]triazine mixture (110 mg, 0.656 mmol) and NBS (117 mg, 0.656 mmol) in DCM (2 ml) and TFA (0.2 ml) were stirred at room temperature for 3 h. The mixture was diluted with water and the precipitate was filtered off, washed with water to give 7 -bromo-4-chloro-5-methylpyrrolo[2,1-f][1,2,4]triazine (150 mg, 0.609 mmol, 93% yield) as a white solid.

MS (ERI) (m/z) 247.9 (M+H).

1H NMR (400 MHz, _CDCl3 ) δ 8.24 (s, 1H), 6.86 (s, 1H), 2.69 (s, 3H).

38B: 7-bromo-5-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine: to a mixture of 7-bromo-4-chloro-5methylpyrrolo[2,1-f][1, 2,4]triazine (120 mg, 0.487 mmol) in dioxane (2 mL) was added ammonium hydroxide (0.677 mL, 4.87 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to give 7-bromo-5-methylpyrrolo[2,1-1][1,2,4]triazine-4-amine (110 mg, 0.484 mmol, 100 % yield) as a white solid.

MS (ERI) (m/z) 228.9 (M+H).

1H NMR (400 MHz, CD3OD) δ 7.97-7.64 (m, 1H), 6.57 (s, 1H), 2.57 (s, 3H).

38C: 5-(4-αmino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid: to a solution of 7-bromo-5-methylpyrrolo[2, 1-f][1,2,4]triazine-4-amine (80 mg, 0.352 mmol) and methyl 2-methoxy-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)nicotinate (114 mg, 0.388 mmol) in 1,4-dioxane (2 mL) tribasic potassium phosphate (0.528 mL, 1.057 mmol) (2 M in H2O) was added. The mixture was degassed by

- 88 042342 nitrogen bubbling through the mixture for 5 min, and then the complex 1,1'bis (diphenylphosphino) ferrocene-palladium (II) dichloromethane dichloride (28.8 mg, 0.035 mmol) was added. Nitrogen was bubbled through the mixture for an additional 5 minutes. The reaction vessel was sealed and heated to 100° C. for 3 hours. The reaction mixture was filtered through a pad of celite to remove the catalyst. Sodium hydroxide (0.176 ml, 1.762 mmol) (10 M in water) was added and the resulting mixture was stirred at room temperature for an additional 2 hours. Methanol was added and the solid was isolated by filtration to give 5-(4-amino-5 -methylpyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinic acid sodium salt (60 mg, 0.200 mmol, 56.9% yield) as a brown solid.

38: mixture of 5-(4-amino-5-methylpyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (20 mg, 0.067 mmol), (S)- 3-amino-1-(4-chlorophenyl)propan-1-ol, HCl (16.33 mg, 0.074 mmol), BOP (35.5 mg, 0.080 mmol) and Hunig's base (0.035 ml, 0.200 mmol) in DMF (1 ml) stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 μm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (S)-5-(4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-N -(3-(4-chlorophenyl)-3hydroxypropyl)-2-methoxynicotinamide (10.1 mg, 0.022 mmol, 32.4% yield) as a white solid.

MS (ERI) m/z 467.1 (M+H).

¹ H NMR (500 MHz, DMSO-d6) δ 8.86 (d, J=2.6 Hz, 1H), 8.76 (d, J=2.6 Hz, 1H), 8.38 (br t, J=5.3 Hz, 1H), 7.81 (s, 1H), 7.44-7.33 (m, 4H), 7.08 (br s, 2H), 6.88 (s, 1H), 5.40 (d, J=4.4 Hz, 1H), 4.75-4.67 (m, 1H) , 4.03 (s, 3H), 3.44-3.35 (m, 1H), 2.53 (s, 3H), 1.95-1.81 (m, 2H).

Example 39: (2S)-4-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-{[2-fluoro-5(trifluoromethoxy)phenyl]methyl} -2,5-dihydro-1H-pyrrole-2-carboxamide

39A: 1-(tert-butyl) 2-methyl (S)-4-(((trifluoromethyl)sulfonyl)oxy)-2,5-dihydro-1H-pyrrole-1,2-dicarboxylate: to mixture (S)-1- tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (4.45 g, 18.29 mmol) in THF (48.8 ml) LiHMDS (21.95 ml, 21.95 mmol) was added at -78°C. The mixture was allowed to stir at -78°C for 1 h. Then a solution of 2-[N,Nbis(trifluoromethanesulfonyl)amino]-5-chloropyridine (7.18 g, 18.29 mmol) in THF (12.20 ml) was added to the reaction mixture, which was stirred at -78°C for an additional 1 h, the Mixture was left to warm to -20°C and continued to stir at this temperature throughout the night. The reaction was stopped by adding water. The resulting mixture was extracted with diethyl ether (3x). The combined extracts were washed with 1N. aqueous sodium hydroxide, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 120 g, 0-100% EtOAc/hexanes) gave (S)-1-tert-butyl 2-methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole1,2 (2H,5H)-dicarboxylate (1.18 g, 2.99 mmol, 16% yield).

The precursor ion was not observed by LC-MS.

1H NMR (500 MHz, CDCl ₃ ) δ 5.85-5.65 (m, 1H), 5.14-4.97 (m, 1H), 4.45-4.36 (m, 1H), 4.34 (s, 1H), 3.79 (s, 3H) , 1.52-1.44 (m, 9H).

39B: 1-(tert-butyl) 2-methyl (S)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1Hpyrrole- 1,2-dicarboxylate: bis(pinacolato)diborone mixture (3.18 g, 12.51 mmol), (S)-1-tert-butyl 2methyl 4-(((trifluoromethyl)sulfonyl)oxy)-1H-pyrrole-1,2( 2H,5H)-dicarboxylate (4.27 g, 11.38 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (0.416 g, 0.569 mmol) and potassium acetate (3.35 g, 34.1 mmol) in dioxane ( 65.0 ml) was sparged with nitrogen for 5 min. The mixture was heated to 100° C. and stirred overnight. The mixture was filtered and diluted with EtOAc. The mixture was washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 120 g, EtOAc/hexanes) gave (S)-1-tert-butyl 2-methyl 4-(4,4,5,5tetramethyl-1,3,2-dioxaborolane-2- yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (3.85 g, 10.90 mmol, 96% yield).

The precursor ion was not observed by LC-MS.

1H NMR (500 MHz, CDCl ₃ ) δ 6.39-6.28 (m, 1H), 5.17-4.98 (m, 1H), 4.41-4.25 (m, 2H), 3.76-3.76 (m, 1H), 3.74 (d, J=6.4 Hz, 2H), 1.51-1.43 (m, 9H), 1.30-1.28 (m, 13H). 39C: 1-(tert-butyl) 2-methyl (S)-4-(4aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-dihydro-1H- pyrrole-1,2-dicarboxylate: 7-bromopyrrolo[2,1-1][1,2,4]triazine-4-amine mixture (250 mg, 1.174 mmol), (S)-1-tert-butyl 2-methyl 4-(4,4,5,5

- 89 042342 tetramethyl-1,3,2-dioxaborolan-2-yl)-III-pyrrol-1,2 (2H,5H) -dicarboxylate (912 mg, 2.58 mmol) and tribasic potassium phosphate (2 M in water) ( 1760 µl, 3.52 mmol) in DMF (6593 µl) was sparged with nitrogen for 5 min. The PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (96 mg, 0.117 mmol) was added to the reaction mixture and nitrogen was bubbled through for an additional 5 min. The mixture was heated to 100°C and stirred for 30 min. The reaction mixture was then diluted with EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 40 g, 40-70% EtOAc/hexanes) gave (S)-1-tert-butyl 2-methyl 4-(4-aminopyrrolo[2,1f][1,2,4 ]triazin-7-yl)-1H-pyrrole-1,2(2H,5H)-dicarboxylate (165 mg, 0.459 mmol, 39.1% yield).

MS (ERI) (m/z) 360.1 (M+H).

39D: (S)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-1-(tert-butoxycarbonyl)-2,5-dihydro-1Hpyrrol-2 -carboxylic acid, lithium salt: to a mixture of (S)-1-tert-butyl 2-methyl 4-(4-aminopyrrolo[2,1f][1,2,4]triazin-7-yl)-1H-pyrrol- 1,2(2H,5H)-dicarboxylate (165 mg, 0.459 mmol) in THF (2952 μL), MeOH (1312 μL), and water (328 μL) was added LiOH (12.09 mg, 0.505 mmol). The resulting mixture was stirred at room temperature for 3 days. The mixture was concentrated under vacuum and dried under high vacuum. The resulting residue was used in the next step without purification. MS (ERI) (m/z) 346.1 (M+H).

39E: tert-butyl (8)-4-(4-aminopyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-((2-fluoro-5(trifluoromethoxy)benzyl) carbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate: to a mixture of (S)-4-(4aminopyrrolo[2,1-f][1,2,4]triazin-7 -yl)-1 - (tert-butoxycarbonyl)-2,5-dihydro-1 H-pyrrole-2-carboxylic acid, lithium salt (15 mg, 0.043 mmol), 2-fluoro-5-(trifluoromethoxy)benzylamine (9.08 mg, 0.043 mmol) and BOP (23.05 mg, 0.052 mmol) in dioxane (2172 μl) was added Hunig's base (22.76 μl, 0.130 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was used in the next step without further purification.

MS (ERI) (m/z) 537.3 (M+H).

39: to a mixture of (3)-tert-butyl 4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-((2-fluoro-5-(trifluoromethoxy )benzyl)carbamoyl)-2,5-dihydro-1H-pyrrole-1-carboxylate (23.07 mg, 0.043 mmol) in DCM (2 ml) was added TFA (400 μl, 5.19 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated to dryness. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 18-58% B over 19 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (3.3 mg, 7.6 μmol, 18%).

MS (ERI) m/z 437.1 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.54 (t, J=6.6 Hz, 1H), 7.93 (s, 1H), 7.61 (br s, 1H), 7.34-7.24 (m, 2H), 7.24- 7.15 (m, 1H), 6.92 (d, J=4.8 Hz, 1H), 6.83 (d, J=2.2 Hz, 1H), 6.64 (d, J=4.8 Hz, 1H), 4.72-4.60 (m, 1H ), 4.45–4.30 (m, 2H), 4.28–4.09 (m, 2H), two exchangeable protons are not visible.

Example 40: cis-racemic 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[1-(cyclohexylmethyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

A mixture of (bromomethyl)cyclohexane (5.91 μl, 0.043 mmol), 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-cis-( 4-Fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA (15 mg, 0.034 mmol) and K ₂ CO ₃ (28.3 mg, 0.205 mmol) in DMF (60 µl) were heated to 60°C and stirred overnight. The reaction mixture was diluted with 0.5 ml DMF and filtered. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 40-90% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (1.9 mg, 3.5 μmol, 10%).

MS (ERI) m/z 536.2 (M+H).

Example 41-1 and 41-2: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S )-4fluoro-1-(4-fluorobenzoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide and 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1.2, 4]triazin-7-yl]-N-[(3S,4R)-4-fluoro-1-(4-fluorobenzoyl)pyrrolidin-3yl]-2-methylpyridine-3-carboxamide

- 90 042342

41-1: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-(3R,4S) fluoropyrrolidin-3-yl)-2-methylnicotinamide (Example 25) (17 mg, 0.040 mmol) and 4-fluorobenzoic acid (6.75 mg, 0.048 mmol) in 1,4-dioxane (2 ml) was added Hunig's base (0.021 ml, 0.120 mmol) and BOP (21.31 mg, 0.048 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-55% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (6.3 mg, 11.5 μmol, 29%).

MS (ERI) m/z 546.2 (M+H).

Ή NMR (500 MHz, DMSO-d6) δ 9.23-9.11 (m, 1H), 8.99-8.81 (m, 1H), 8.48-8.31 (m, 1H), 8.24-8.15 (m, 1H), 7.76-7.58 (m, 3H), 7.37-7.28 (m, 2H), 5.52-5.16 (m, 1H), 4.87-4.53 (m, 1H), 4.09-3.75 (m, 3H), 3.66-3.49 (m, 1H) , 3.47-3.35 (m, 1H), 3.22-3.10 (m, 1H), 2.62-2.53 (m, 4H), 1.07-0.91 (m, 1H).

41-2: using the opposite enantiomer 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-((3S,4R)-4- fluoropyrrolidin-3-yl)-2-methylnicotinamide, a similar sequence can be performed to give 41-2: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-N-(4-fluoropyrrolidin-3-yl)-2-methylnicotinamide (15 mg, 0.035 mmol) and 4-fluorobenzoic acid (5.96 mg, 0.043 mmol) in 1,4-dioxane (2 ml ) Hunig's base (0.019 ml, 0.106 mmol) and BOP (18.80 mg, 0.043 mmol) were added. The resulting mixture was stirred at room temperature for 30 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 10-50% B over 19 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (7.5 mg, 9.7 μmol, 28%).

MS (ERI) m/z 546.1 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.27-9.10 (m, 1H), 9.06-8.79 (m, 1H), 8.45-8.30 (m, 1H), 8.23-8.09 (m, 1H), 7.79- 7.58 (m, 3H), 7.35-7.22 (m, 2H), 5.52-5.15 (m, 1H), 4.90-4.55 (m, 1H), 4.15-3.75 (m, 2H), 3.68-3.45 (m, 1H ), 2.63-2.57 (m, 1H), 1.32-1.10 (m, 4H).

Example 42 5-{4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl) -2 methoxypyridine-3-carboxamide

A mixture of 5-(4-amino-5-methyln-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (20 mg, 0.067 mmol), 1-benzyl-1H- Pyrazole-4-amine (12.73 mg, 0.074 mmol), BOP (35.5 mg, 0.080 mmol), and Hunig's base (0.035 mL, 0.200 mmol) in DMF (1 mL) was stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 30-70% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1 - benzyl-1H-pyrazol-4-yl)-2methoxynicotinamide (6.1 mg, 0.013 mmol, 20.08% yield) as a white solid.

MS (ERI) m/z 455.1 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.27-10.00 (m, 1H), 8.98-8.84 (m, 1H), 8.84-8.60 (m, 1H), 8.33-8.07 (m, 1H), 7.92 -7.75 (m, 1H), 7.75-7.55 (m, 1H), 7.47-7.24 (m, 5H), 7.17-7.00 (m, 2H), 6.97-6.73 (m, 1H), 5.415.23 (m, 2H), 4.09-3.98 (m, 3H), 2.56-2.52 (m, 3H).

- 91 042342

Example 43: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro- 1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

F

43A: tert-Butyl (racemic) 3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (mixture of cis isomers): to a solution of tert-butyl-3-amino-4-fluoropyrrolidine-1-carboxylate ( 100 mg, 0.490 mmol, mixture of cis isomers) and N-methylmorpholine (0.108 ml, 0.979 mmol) in THF (3 ml) at 0°C was added Cbz-Cl (0.084 ml, 0.588 mmol) dropwise. The reaction mixture was heated to 23° C. and stirred for 16 hours. The reaction mixture was diluted with water (30 ml) then extracted with CH ₂ Cl ₂ (30 mlx2). The combined organic phases were washed with brine (30 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave the crude material. The crude material was purified with a silica gel column eluting with hexanes/EtOAc (100/0 to 60/40) to give t-butyl (racemic)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1 -carboxylate (165.6 mg, 0.489 mmol, 100% yield).

MS (ERI) m/z 339.1 (M+H).

¹ H NMR (400 MHz, CD ₃ OD) δ 7.42-7.29 (m, 5H), 5.19-5.08 (m, 3H), 5.08-4.95 (m, 1H), 4.41-4.24 (m, 1H), 3.82- 3.71 (m, 1H), 3.71-3.49 (m, 2H), 3.17 (td, J=10.3, 2.8 Hz, 1H), 1.48 (s, 9H).

43B: tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate: tert-butyl (racemic)-3-(((benzyloxy)carbonyl)amino)-4- fluoropyrrolidine-1-carboxylate (165.6 mg, 0.489 mmol) was separated by preparative SFC under the following conditions: preparative column: AD-H (3x25 cm, 5 µm, #repackaged); pressure BPR: 100 bar; temperature: 35°C; flow rate: 180 ml/min; mobile phase: CO ₂ /MeOH (80/20); detector wavelength: 220 nm. Peak 1 fractions were collected to give tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (61 mg, 0.180 mmol, 37% yield, chiral purity: >99.75%) . Peak 2 fractions were collected to give tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (61.5 mg, 0.182 mmol, 37.0% yield, chiral purity: >99.75 %) as the target compound. Chiral analytical conditions: analytical column: AD-H (0.46x25 cm, 5 µm); pressure BPR: 140 bar; temperature: 35°C; flow rate: 3.0 ml/min; mobile phase: CO ₂ /MeOH (85/15); detector wavelength: UV 200-400 nm. Absolute stereochemistry was determined by taking both isomers and comparing them to final compounds prepared from material for which crystallographic information was available.

MS (ERI) m/z 339.1 (M+H).

43C: tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate: suspension of a solution of tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine- 1-carboxylate (61 mg, 0.180 mmol) and Pd(OH) ₂ (12.66 mg, 0.018 mmol) in MeOH (3 mL) were stirred at 23°C in an atmosphere of balloon H ₂ (0.363 mg, 0.180 mmol) for 16 h The reaction mixture was concentrated to give tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (32 mg, 0.157 mmol, 87% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 4.97 (t, J=3.4 Hz, 1H), 4.90-4.78 (m, 1H), 5.10-4.76 (m, 1H), 3.87-3.42 (m, 4H), 3.15 -3.00 (m, 1H), 1.49 (s, 9H).

43D: tert-Butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido) -4-fluoropyrrolidine-1-carboxylate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (50 mg, 0.142 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (28.9 mg, 0.142 mmol) and DIPEA (0.074 ml, 0.425 mmol) in DMF (2 ml) was added BOP (75 mg, 0.170 mmol). The reaction mixture was stirred for 1 hour. The crude material was purified with a silica gel column eluting with hexanes/EtOAc (100/0 to 0/100) to give t-butyl (3R,4S)-3-(5-(4- amino-5-(trifluoromethyl)pyrrolo[2,1G][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (73 mg, 0.135 mmol, 96% yield) .

MS (ERI) m/z 540.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 8.99 (d, J=2.4 Hz, 1H), 8.96 (s, 1H), 8.09 (s, 1H), 7.43 (s, 1H), 5.38-5.17 (m, 1H) , 4.83 (br s, 1H), 4.18 (s, 3H), 4.03–3.92 (m, 1H), 3.84–3.63 (m, 2H), 3.29–3.18 (m, 1H), 1.51 (s, 9H).

43E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-methoxynicotinamide: to a solution of tert-butyl (3R,4S)-3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (73 mg, 0.135 mmol) in CH ₂ Cl ₂ (1 ml) was added TFA (0.261 ml, 3.38 mmol) and stirred at 23°C for 1 h. The reaction mixture was concentrated and triturated with ether (3 ml). The solid was collected as 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R,4S)-4-fluoropyrrolidine- 3-yl)-2-methoxynicotinamide, TFA (74 mg, 0.133 mmol, 98% yield).

- 92 042342

MS (ERI) m/z 440.1 (M+H).

1H NMR (500 MHz, CD3OD) δ 9.05-8.94 (m, 2H), 8.09 (s, 1H), 7.44 (s, 1H), 5.57-5.38 (m, 1H), 5.05-4.91 (m, 1H), 4.18 (s, 3H), 3.90-3.66 (m, 3H), 3.54-3.35 (m, 1H).

43: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3 -yl)-2-methoxynicotinamide, 1.0 TFA (15 mg, 0.027 mmol), 4-fluorobenzoic acid (3.80 mg, 0.027 mmol) and Hunig's base (0.017 ml, 0.095 mmol) in DMF (1 ml) was added BOP (14.39 mg , 0.033 mmol) and the mixture was stirred at 23°C for 16 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 24-64% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (10.4 mg, 15.4 µmol, 57%).

MS (ERI) m/z 562.3 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (br d, J=8.5 Hz, 1H), 8.78 (br s, 1H), 8.63-8.46 (m, 1H), 8.19 (br d, J= 13.1 Hz, 1H), 7.72-7.56 (m, 3H), 7.36-7.26 (m, 2H), 5.49-5.16 (m, 1H), 4.90-4.62 (m, 1H), 4.05 (br d, J=4.9 Hz, 6H), 3.70-3.38 (m, 1H).

Example 44 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-[4-fluoro-1-(3,3, 3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

A mixture of 3-bromo-1,1,1-trifluoropropan-2-ol (14.46 mg, 0.075 mmol), 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4] triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide, TFA (15 mg, 0.027 mmol) and K2CO3 (22.48 mg, 0.163 mmol) in DMF (60 µl) heated to 60°C and stirred overnight. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by preparative HPLC (C18, acetonitrile/water/ammonium acetate) gave 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N -(4-fluoro-1-(3,3,3-trifluoro-2hydroxypropyl)pyrrolidin-3-yl)-2-methoxynicotinamide (isolation 01, peak eluted first, racemic).

MS (ERI) m/z 552.3 (M+H).

1H NMR (500 MHz, CD3OD) δ 8.97 (q, J=2.4 Hz, 2H), 8.08 (s, 1H), 7.41 (s, 1H), 5.40-5.12 (m, 1H), 4.774.64 (m, 1H), 4.19-4.17 (m, 3H), 4.17-4.10 (m, 1H), 3.29-2.98 (m, 3H), 2.94-2.86 (m, 1H), 2.85-2.74 (m, 2H).

The racemic substance (at the alcohol center) was resolved with chiral SFC (Chiralpak AS, 5 μm, 30x250 mm, 10% MeOH (0.1% DEA) in CO ₂ , 150 bar, 35°C) to give the homochiral title compound: 5 -(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R,4S)-4-fluoro-1-(3, 3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-2-methoxynicotinamide (peak eluted first (24.10 min), absolute stereochemistry at alcohol center not determined).

44-1: MS (ERI) m/z 552.2 (M+H).

1H NMR (500 MHz, CPS1h) δ 9.02 (d, J=2.4 Hz, 1H), 8.99 (d, J=2.6 Hz, 1H), 8.55-8.44 (m, 1H), 8.13 (s, 1H), 7.28 (s, 2H), 5.87 (br s, 2H), 5.35-5.08 (m, 1H), 4.88-4.74 (m, 1H), 4.20 (s, 3H), 4.04 (ddd, J=9.8, 6.5, 3.6 Hz, 1H), 3.41-3.21 (m, 2H), 3.10-2.72 (m, 4H).

44-2: and its enantiomer (peak eluted second (25.51 min), absolute stereochemistry at the alcohol center not determined).

MS (ERI) m/z 552.3 (M+H).

1H NMR (500 MHz, CDCl ₃ ) δ 9.02 (d, J=2.4 Hz, 1H), 9.00-8.97 (m, 1H), 8.55-8.44 (m, 1H), 8.12 (s, 1H), 7.28 (s , 1H), 5.97 (br s, 2H), 5.33-5.07 (m, 1H), 4.91-4.67 (m, 1H), 4.25-4.16 (m, 3H), 4.12-4.00 (m, 1H), 3.453. 28 (m, 2H), 3.19-3.06 (m, 1H), 3.01-2.86 (m, 2H), 2.82-2.73 (m, 1H).

The other two enantiomers derived from the opposite enantiomer of pyrrolidine can be prepared in a similar manner to form two additional enantiomers:

44-3: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4-fluoro -1-(3,3,3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-2-methoxynicotinamide (peak eluted first, absolute stereochemistry at alcohol center not determined).

MS (ERI) m/z 552.2 (M+H).

1H NMR (500 MHz, CD3OD) δ 8.94 (q, J=2.5 Hz, 2H), 8.06 (s, 1H), 7.38 (s, 1H), 5.31-5.12 (m, 1H), 4.744.61 (m, 1H), 4.18-4.08 (m, 4H), 3.27-3.14 (m, 2H), 3.13-2.99 (m, 1H), 2.89 (dd, J=13.0, 2.7 Hz, 1H), 2.84-2.71 (m, 2H).

44-4: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,4S)-4-fluoro -1-(3,3,3-93 042342 trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-2-methoxynicotinamide (second eluted peak, absolute stereochemistry at alcohol center not determined).

MS (ERI) m/z 552.2 (M+H).

1H NMR (500 MHz, CD3OD) δ 8.96 (q, J=2.4 Hz, 2H), 8.06 (s, 1H), 7.39 (s, 1H), 5.31-5.12 (m, 1H), 4.754.63 (m, 1H), 4.19-4.07 (m, 4H), 3.27-3.13 (m, 2H), 3.12-3.00 (m, 1H), 2.90-2.73 (m, 3H).

Example 45: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3 ,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide

45A: Methyl d ₃ 5-bromo-2-methoxy d ₃ -nicotinate: sodium (0.514 g, 22.36 mmol) was added to CD3OD (10 ml) and stirred until the reaction was complete. Methyl 5-bromo-2-chloronicotinate (2.0 g, 7.98 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was acidified with concentrated HCl solution to pH 7, diluted with CH ₂ Cl ₂ (100 ml) and washed with water (20 ml) and brine (20 ml). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give methyl d ₃ 5-bromo-2-methoxy d ₃ -nicotinic acid (1.67 g, 6.62 mmol, 83% yield).

MS (ERI) m/z 251.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=2.6 Hz, 1H), 8.30 (d, J=2.6 Hz, 1H). 45B: 5-bromo-2-methoxy d ₃ nicotinic acid: solution of methyl d ₃ 5-bromo-2-methoxy d ₃ -nicotinate (800 mg, 3.17 mmol) and NaOH (4.76 ml, 4.76 mmol) in MeOH (15 ml ) was heated to 100°C for 30 min under the influence of microwaves. The reaction mixture was concentrated to give 5-bromo-2-methoxy d ₃ -nicotinic acid for the next reaction.

MS (ERI) m/z 235.1 (M+H).

45C: (racemic)-tert-butyl 3-(5-bromo-2-methoxy d ₃ -nicotinamido)-4-fluoropyrrolidine-1-carboxylate (mixture of cis-isomers): to a solution of 5-bromo-2-methoxy d ₃ -nicotinic acid (750 mg, 3.19 mmol), (racemic)-cis-1-boc-3-amino-4-fluoropyrrolidine (652 mg, 3.19 mmol) and DIPEA (0.669 ml, 3.83 mmol) in DMF (15 ml) BOP was added (1693 mg, 3.83 mmol). The reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated. EtOAc (150 ml) was added and the mixture was washed with water (50 ml), brine (50 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave the crude material which was triturated with water (50 ml). The solid was collected as (racemic)-tert-butyl 3-(5-bromo-2-methoxy d ₃ -nicotinamido)-4-fluoropyrrolidine-1-carboxylate (1.23 g, 2.92 mmol, 92% yield) as a mixture of cis- isomers.

MS (ERI) m/z 421.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 8.44-8.36 (m, 2H), 5.35-5.12 (m, 1H), 4.82-4.66 (m, 1H), 4.01-3.89 (m, 1H), 3.81-3.57 (m , 2H), 3.24 (td, J=10.3, 4.8 Hz, 1H), 1.50 (s, 9H).

45D: (3R,4S)-tert-butyl 3-(5-bromo-2-methoxy d ₃ -nicotinαmido)-4-fluoropyrrolidine-1-carboxylαt (chiral separation peak 2): (racemic)-tert-butyl 3- (5-bromo-2-methoxy d ₃ -nicotinamido)-4fluoropyrrolidine-1-carboxylate (1.23 g, 2.92 mmol) was separated by preparative SFC under the following conditions: preparative column: OJH (5x25 cm, 805211), BPR pressure: 100 bar; temperature: 35°C; flow rate: 280 ml/min; mobile phase: CO ₂ /MeOH (90/10); detector wavelength: 220 nm. Peak 1 fractions were collected to give tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4fluoropyrrolidine-1-carboxylate (414.6 mg, 0.984 mmol, 34% yield, chiral purity: >99%) . Peak 2 fractions were collected to give tert-butyl (3R,4S)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine 1-carboxylate (426 mg, 1.0117 mmol, 34.6% yield, chiral purity: >99%) as the target compound. Chiral analytical conditions: analytical column: OJH (0.46x25 cm, 5 µm); pressure BPR: 140 bar; temperature: 35°C; flow rate: 3.0 ml/min; mobile phase: CO ₂ /MeOH (90/10); detector wavelength: UV 220 nm. Absolute stereochemistry was determined based on crystallographic information from a closely related substrate.

MS (ERI) m/z 421.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 8.44-8.37 (m, 2H), 5.33-5.13 (m, 1H), 4.82-4.66 (m, 1H), 4.00-3.89 (m, 1H), 3.79-3.57 (m , 2H), 3.24 (td, J=10.4, 5.0 Hz, 1H), 1.50 (s, 9H).

45E: (5-(((3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-(methoxyd ₃ )pyridin-3-yl)boronic acid: degassed tert solution -butyl (3R,4S)-3-(5-bromo-2-(methoxyd ₃ )nicotinamido)-4-fluoropyrrolidine-1-carboxylate (200 mg, 0.475 mmol), 4,4,4',4',5 ,5,5',5'-octamethyl2,2'-bi(1,3,2-dioxaborolane) (157 mg, 0.617 mmol), potassium acetate (74.5 mg, 0.760 mmol) and PdCl ₂ (dppf)-CH adduct ₂ Cl ₂ (31.0 mg, 0.038 mmol) in dioxane (4 mL) was heated to 65°C for 16 h. The reaction mixture was filtered through celite. The solution was concentrated to obtain a substance which was used as is. MS (ERI) m/z 387.1 (M+H).

45F: tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- 94 042342 (methoxy^ ₃ )nicotinamido)-4-fluoropyrrolidine-1-carboxylate: degassed solution of 7-bromo-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (130 mg, 0.463 mmol), (5-(((3R,4S)-1-(tert-butoxycarbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6-(methoxy-d ₃ )pyridin-3-yl)boronic acid (184 mg, 0.476 mmol), potassium triphosphate (2 M in water) (0.694 ml, 1.388 mmol) and adduct 1,1'bis(diphenylphosphino)ferrocene palladium dichloride - CH ₂ Cl ₂ (37.8 mg, 0.046 mmol) were stirred at 70°C for 5 h. The reaction mixture was diluted with EtOAc (80 ml) and washed with 10% LiCl solution (20x2 ml) and brine (20 ml). The organics were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material, which was triturated in MeOH (2 ml). The solid was collected as the title compound. The filtrate was concentrated and purified on a silica gel column with hexanes/EtOAc (100/0 to 0/100) to give a second crop of material which was combined with the above material to give t-butyl (3R,4S)-3-(5- (4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(methoxy-d ₃ )nicotinamido)-4fluoropyrrolidine-1-carboxylate (208 mg, 0.382 mmol, 83% yield). MS (ERI) m/z 543.1 (M+H).

45G: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-(methoxy-d ₃ )nicotinamide: to a solution of tert-butyl (3R,4S)-3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-2-(methoxy-d ₃ )nicotinamido)-4-fluoropyrrolidine-1 carboxylate (208 mg, 0.383 mmol) in CH ₂ Cl ₂ (2 ml) was added TFA (0.886 ml, 11.50 mmol ) and the mixture was stirred for 1 h. The reaction mixture was concentrated and triturated with ether (3 ml). The solid was collected as 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R,4S)-4-fluoropyrrolidine- 3-yl)-2-(methoxy-d ₃ )nicotinamide, TFA (203 mg, 0.365 mmol, 95% yield).

MS (ERI) m/z 443.1 (M+H).

¹ H NMR (400 MHz, CD3OD) δ 8.99 (q, J=2.4 Hz, 2H), 8.09 (s, 1H), 7.44 (s, 1H), 5.58-5.38 (m, 1H), 5.074.92 (m , 1H), 3.93–3.74 (m, 3H), 3.55–3.47 (m, 1H).

45: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3 -yl)-2-(methoxy-d ₃ )nicotinamide, TFA (120 mg, 0.216 mmol), 3,3difluorocyclopentanecarboxylic acid (32.4 mg, 0.216 mmol) and Hunig's base (0.132 ml, 0.755 mmol) in DMF (1 ml) BOP (114 mg, 0.259 mmol) was added. The reaction mixture was stirred at 23°C for 2 hours. The crude material was purified using preparative SFC under the following conditions: preparative column: Chiralpak AD (30x250 mm, 5 μm); pressure BPR: 120 bar; column temperature: 40°C; flow rate: 100 ml/min; mobile phase: CO2/IPA (0.1% DEA) (65/35); detector wavelength: 220 nm. Fractions were collected to give:

45-1: peak 1, isomer eluted first, 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl]-N-[(3R, 4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2(deutero)methoxypyridine-3-carboxamide (9.3 mg, 0.016 mmol, 13.9%). The absolute stereochemistry with cyclopentane is unknown.

MS (ERI) m/z 575.4 (M+H).

1H NMR (500 MHz, DMSO-de) δ 8.90 (s, 1H), 8.76 (dd, J=18.3, 2.1 Hz, 1H), 8.55 (br dd, J=10.7, 7.6 Hz, 1H), 8.16 (s , 1H), 7.58 (s, 1H), 5.43-5.19 (m, 1H), 4.85-4.57 (m, 1H), 4.14-3.42 (m, 3H), 3.30-3.13 (m, 2H), 2.42-2.24 (m, 2H), 2.22-1.99 (m, 3H), 1.87-1.68 (m, 1H).

45-2: peak 2, isomer eluted second, 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl]-N-[(3R, 4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2(deutero)methoxypyridine-3-carboxamide (9.7 mg, 0.016 mmol, 14.5% yield, chiral purity: >99%). The absolute stereochemistry with cyclopentane is unknown.

MS (ERI) m/z 575.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.79 (dd, J=19.5, 2.1 Hz, 1H), 8.54 (br dd, J=11.4, 7.8 Hz, 1H), 8.17 ( s, 1H), 7.61 (s, 1H), 5.44-5.18 (m, 1H), 4.86-4.58 (m, 1H), 4.10-3.45 (m, 3H), 3.36-3.05 (m, 2H), 2.40- 2.25 (m, 2H), 2.23-1.99 (m, 3H), 1.88-1.72 (m, 1H).

Example 46 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro- 1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide

46A: methyl-d ₃ 5-bromo-2-(methoxy-d ₃ )-6-methylnicotinate: to a rapidly stirred mixture of 5-bromo-2hydroxy-6-methylnicotinic acid (1.20 g, 5.17 mmol) and iodomethane-d ₃ ( 1.931 ml, 31.0 mmol) in chloroform (100 ml) was added silver carbonate (7.13 g, 25.9 mmol). The reaction mixture was stirred in the dark [covered with aluminum foil] for 4 days. The reaction mixture was filtered through celite then concentrated to an oil. This material was loaded onto a 40 g ISCO column and purified by flash chromatography eluting with 0-75% EtOAc in hexanes. Received methyl-d ₃ 5-bromo-2-95 042342 (methoxy-d ₃ )-6-methylnicotinate (732 mg, 2.64 mmol, 51.1% yield) as a white solid.

MS (ERI) m/z 268.0 (M+H).

46B: (6-(methoxy-d ₃ )-5-((methoxy-d ₃ )carbonyl)-2-methylpyridin-3-yl)boronic acid: degassed solution of methyl d ₃ 5-bromo-2-(methoxy- d ₃ )-6-methylnicotinate (100 mg, 0.376 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (124 mg, 0.488 mmol), potassium acetate (59.0 mg, 0.601 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (24.55 mg, 0.030 mmol) in dioxane (2 ml) were heated to 65°C in for 16 hours. The reaction mixture was filtered through celite. The solution was concentrated to obtain a substance which was used as is.

MS (ERI) m/z 232.1 (M+H).

46C: methyl-d ₃ 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(methoxy-d ₃ )-6methylnicotinate : degassed solution of 7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (100 mg, 0.356 mmol), (6-(methoxy-d ₃ )- 5-((methoxy-d ₃ )carbonyl)-2-methylpyridin-3-yl)boronic acid (86 mg, 0.374 mmol), potassium triphosphate (2 M in water) (0.534 ml, 1.067 mmol) and adduct 1.1 'bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (29.1 mg, 0.036 mmol) was stirred at 70°C for 1 h. The reaction mixture was purified by flash column chromatography eluting with hexanes/EtOAc (100/0 to 0/100) to give methyl-d ₃ 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-(methoxy-d ₃ ) -6-methylnicotinate (38.4 mg, 0.099 mmol, 27.9% yield).

MS (ERI) m/z 388.1 (M+H).

¹ H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 8.07 (s, 1H), 7.32 (s, 1H), 2.34 (s, 3H). 46D: 5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(methoxy-d ₃ )-6-methylnicotinic acid, sodium salt: methyl-d ₃ solution 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-£][1,2,4]triazin-7-yl)-2-(methoxyd ₃ )-6- methyl nicotinate (38 mg, 0.098 mmol) and 1 n. a solution of NaOH (0.123 ml, 0.123 mmol) in MeOH (1 ml) was heated to 100°C for 10 min under the action of microwaves. The reaction mixture was concentrated to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-(methoxy-d ₃ )-6methylnicotinic acid , sodium salt (40 mg, 0.108 mmol, 110% yield).

MS (ERI) m/z 371.1 (M+H).

46E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-(methoxy-d ₃ )-6-methylnicotinamide: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2-(methoxy-d ₃ )-6-methylnicotinic acid, sodium salt (40 mg, 0.108 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (22.06 mg, 0.108 mmol ) and DIPEA (0.057 ml, 0.324 mmol) in DMF (1 ml) was added BOP (57.3 mg, 0.130 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (80 ml) and washed with 10% LiCl solution (2x20 ml) and brine (20 ml). The organics were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography eluting with hexanes/EtOAc (100/0 to 0/100) to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl)-2-(methoxy-d ₃ )-6-methylnicotinamide (58.8 mg, 0.106 mmol, 98%).

MS (ERI) m/z 557.1 (M+H).

1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.99 (s, 1H), 7.16 (s, 1H), 5.37-5.15 (m, 1H), 4.84 -4.66 (m, 1H), 4.02- 3.90 (m, 1H), 3.84-3.57 (m, 2H), 3.28-3.20 (m, 1H), 2.39 (s, 3H), 1.51 (s, 9H).

46F: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin3-yl )-2-(methoxy-d ₃ )-6-methylnicotinamide, TFA: to a solution of tert-butyl (3R,4S)-3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-2-(methoxy-d ₃ )-6-methylnicotinamido)-4fluoropyrrolidine-1-carboxylate (58 mg, 0.104 mmol) in CH ₂ Cl ₂ (1 ml) was added TFA (0.201 ml, 2.61 mmol) and stirred at 23°C for 1 h. The reaction mixture was concentrated and triturated with ether (2 ml). The solid was collected as 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3 -yl)-2-(methoxy-d ₃ )-6-methylnicotinamide, TFA (65.5 mg, 0.115 mmol, 110% yield).

C (ERI) m/z 457.1 (M+H).

46: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3 -yl)-2-(methoxy-d ₃ )-6-methylnicotinamide, 1.0 TFA (15 mg, 0.026 mmol), 4fluorobenzoic acid (3.68 mg, 0.026 mmol) and Hunig's base (0.016 ml, 0.092 mmol) in DMF (1 ml) BOP (13.96 mg, 0.032 mmol) was added and stirred at 23°C for 5 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 28-68% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (6.2 mg, 9.0 μmol, 34%).

MS (ERI) m/z 579.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.51-8.36 (m, 1H), 8.15 (br d, J=8.5 Hz, 1H), 8.10-8.03 (m, 1H), 7.70-96 042342

7.59 (m, 2H), 7.34-7.26 (m, 3H), 5.45-5.15 (m, 1H), 4.87-4.60 (m, 1H), 4.07-3.74 (m, 3H), 3.69-3.50 (m, 1H ),

2.34 (br d, J=5.2 Hz, 3H).

Example 47 5-(4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-neopentyl-1Hpyrazol-4-yl ) nicotinamide

47A: 1-neopentyl-4-nitro-1H-pyrazole: mixture of 1-iodo-2,2-dimethylpropane (0.705 ml, 5.31 mmol), 4nitro-1H-pyrazole (500 mg, 4.42 mmol) and K ₂ CO ₃ ( 1222 mg, 8.84 mmol) in DMF (10 ml) was heated at 70°C for 48 h. The mixture was then diluted with EtOAc. The organic layer was washed with 1 N. NaOH, water and dried over MgSO ₄ , filtered and concentrated to give 1-neopentyl-4-nitro-1Hpyrazole (800 mg, 4.37 mmol, 99% yield) as an oil.

1H NMR (400 MHz, CDCl ₃ ) δ 8.16-8.07 (m, 2H), 3.95 (s, 2H), 1.02 (s, 9H). 47B: 1-neopentyl-1Hpyrazole-4-amine: a mixture of 1-neopentyl-4-nitro-1H-pyrazole (500 mg, 2.73 mmol) and Pd/C (100 mg, 0.094 mmol) in MeOH (5 mL) was stirred in balloon hydrogen atmosphere for 5 h. The mixture was then filtered through celite and the filtrate concentrated to give 1-neopentyl-1H-pyrazol-4-amine (400 mg, 2.61 mmol, 96% yield) as an oil.

1H NMR (400 MHz, CDCl ₃ ) δ 7.21-7.16 (m, 1H), 7.04-6.99 (m, 1H), 3.81-3.68 (m, 2H), 0.96 (s, 9H).

47: mixture of 5-(4-amino-5-chloropyrrolo[2,1-L][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (20 mg, 0.063 mmol), 1-neopentyl- 1H-pyrazol-4-amine (11.50 mg, 0.075 mmol), BOP (33.2 mg, 0.075 mmol), and Hunig's base (0.033 mL, 0.188 mmol) in DMF (1 mL) was stirred at room temperature for 20 min. The mixture was then concentrated and subjected to preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 22-62% B over 22 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N -(1-neopentyl-1H-pyrazol-4yl)nicotinamide (5.9 mg, 0.013 mmol, 20.73% yield) as a white solid.

MS (ERI) m/z 455.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.19-10.12 (m, 1H), 8.91-8.83 (m, 1H), 8.79-8.66 (m, 1H), 8.04-7.96 (m, 1H), 7.96-7.91 (m, 1H), 7.66-7.57 (m, 1H), 7.26-7.16 (m, 1H), 4.06 (s, 3H), 3.89 (s, 2H), 0.92 (s, 9H).

Example 48 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1neopentyl-1H-pyrazole -4-yl)nicotinamide

48A: 1-neopentyl-4-nitro-1H-pyrazole: mixture of 1-iodo-2,2-dimethylpropane (0.705 ml, 5.31 mmol), 4nitro-1H-pyrazole (500 mg, 4.42 mmol) and K ₂ CO ₃ ( 1222 mg, 8.84 mmol) in DMF (10 ml) was heated at 70°C for 48 h. The mixture was then diluted with EtOAc. The organic layer was washed with 1 N. NaOH, water and dried over MgSO ₄ , filtered and concentrated to give 1-neopentyl-4-nitro-1Hpyrazole (800 mg, 4.37 mmol, 99% yield) as an oil.

1H NMR (400 MHz, CDCl3) δ 8.16-8.07 (m, 2H), 3.95 (s, 2H), 1.02 (s, 9H).

48B: 1-neopentyl-1H-pyrazol-4-amine: mixture of 1-neopentyl-4-nitro-1H-pyrazole (500 mg, 2.73 mmol) and Pd/C (100 mg, 0.094 mmol) in MeOH (5 mL) stirred under balloon hydrogen for 5 hours. The mixture was then filtered and concentrated to give 1-neopentyl-1H-pyrazole-4-amine (400 mg, 2.61 mmol, 96% yield) as an oil.

1H NMR (400 MHz, CDCl ₃ ) δ 7.21-7.16 (m, 1H), 7.04-6.99 (m, 1H), 3.81-3.68 (m, 2H), 0.96 (s, 9H).

48: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-neopentyl-1Hpyrazole-4 -yl)nicotinamide: a mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinic acid (20 mg, 0.057 mmol), 1-neopentyl-III-pyrazol-4-amine (10.41 mg, 0.068 mmol), BOP (30.0 mg, 0.068 mmol) and Hunig's base (0.030 ml, 0.170 mmol) in DMF (1 ml) was stirred at room temperature for 20 min. The mixture was then concentrated and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 32-72% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried.

- 97 042342 by centrifugal evaporation to obtain 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-neopentyl -1H-pyrazol-4-yl) nicotinamide (12.6 mg, 0.026 mmol,

45.6% yield) as a white solid.

MS (ERI) m/z 489.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.21-10.06 (m, 1H), 9.01-8.85 (m, 1H), 8.84-8.58 (m, 1H), 8.22-8.05 (m, 1H), 8.09-7.97 (m, 1H), 7.73-7.53 (m, 2H), 4.07 (s, 3H), 3.85 (s, 2H), 0.93 (s, 9H).

Example 49 5-(4-amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1Hpyrazol-4-yl) -2-methoxynicotinamide

49A: N-((4-Amino-7-bromopyrrolo[2,1-f][1,2,4]triαzin-5-yl)methyl)-N,N-diethylethanamine, bromide salt: N-(( 7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triαzin-5-yl)methyl)-N,N-diethylethanamine bromide salt (3.5 g, 8.20 mmol) (see WO 2015054358 ) and concentrated ammonium hydroxide (11.41 mL, 82 mmol) in dioxane (10 mL) was stirred at room temperature for 4 h. The mixture was then concentrated to give N-((4-amino-7-bromopyrrolo[2,1-f] [1,2,4]triαzin-5-yl)methyl)-N,Ndiethylethanamine bromide salt (3.3 g, 7.74 mmol, 94% yield) as an off-white solid.

MS (ERI) m/z 326.1 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.21-8.00 (m, 1H), 7.13-7.03 (m, 1H), 4.95-4.75 (m, 2H), 3.29-3.12 (m, 6H), 1.35- 1.18(m, 9H).

49B: 7-bromo-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazine-4-αmin: mixture of N-((4-amino-7bromopyrrolo[2,1-f][ 1,2,4]triazin-5-yl)methyl)-N,N-diethylethanamine, bromide salt (40 mg, 0.122 mmol) and sodium bicarbonate (51.3 mg, 0.611 mmol) in MeOH (3 ml) were heated at 75° C for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated to give 7-bromo-5(methoxymethyl)pyrrolo[2,1-f][1,2,4]triαzine-4-αmin (30 mg, 0.117 mmol, 95% yield) as a white solid.

MS (ERI) m/z 258.9. (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.96-7.90 (m, 1H), 6.86-6.76 (m, 1H), 4.76-4.60 (m, 2H), 3.32 (s, 3H).

49C: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide: 5-bromo-2methoxynicotinic acid mixture (500 mg, 2.155 mmol), 1-benzyl-1H-pyrazole-4 -amine, HCl (452 mg, 2.155 mmol), Hunig's base (1.129 ml, 6.46 mmol) and BOP (1144 mg, 2.59 mmol) in DMF (5 ml) were stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated to give N-(1-benzyl-1H-pyrazol4-yl)-5-bromo-2-methoxynicotinamide (750 mg, 1.937 mmol, 90% yield) as an oil.

MS (ERI) m/z 388.76 (M+H).

1H NMR (400 MHz, CDCl3) δ 9.76-9.34 (m, 1H), 8.70-8.57 (m, 1H), 8.44-8.31 (m, 1H), 7.65-7.60 (m, 1H), 7.42-7.29 (m , 5H), 5.36-5.31 (m, 2H), 4.21-4.17 (m, 3H).

49: 5-(4-Amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl )2-methoxynicotinamide: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide mixture (25 mg, 0.065 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.67 mg, 0.077 mmol) and potassium acetate (19.01 mg, 0.194 mmol) in dioxane (2 ml) were degassed and again filled N2. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (5.27 mg, 6.46 µmol) was added and the mixture was degassed three times and refilled with N2, then heated at 100°C for 3 h. After cooling 7-bromo-5-(methoxymethyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine (16.60 mg, 0.065 mmol), 2 M tribasic potassium phosphate (0.097 ml, 0.194 mmol) and 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (5.27 mg, 6.46 µmol), and the reaction mixture was heated at 100°C for another 5 h. The reaction mixture was filtered and then purified with using preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 26-66% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-(methoxymethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-(1 -benzyl-1H-pyrαzol-4-yl)-2-methoxynicotinamide (3.4 mg, 7.02 µmol, 10.87% yield) as a white solid.

MS (ERI) m/z 485.0 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.27-9.99 (m, 1H), 9.07-8.84 (m, 1H), 8.85-8.59 (m, 1H), 8.27-8.02 (m,

- 98 042342

1H), 8.09-7.82 (m, 1H), 7.77-7.56 (m, 1H), 7.44-7.26 (m, 5H), 7.18-6.76 (m, 1H), 5.33 (s, 2H), 4.75 (s, 2H),

4.06 (s, 3H), 3.38 (s, 3H).

Example 5 0: (S)-5-(4-amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4- chlorophenyl)3-hydroxypropyl)-2-methoxynicotinamide

50A: 7-bromo-5-(methoxymethyl)pyrrolo[2,1-1][1,2,4]1 riazin-4-amine: X-((4-amino-7-bromopyrrolo[2,1-1][ 1,2,4]triazin-5-yl)methyl)-X,X-diethylethanamine (40 mg, 0.122 mmol) and sodium bicarbonate (51.3 mg, 0.611 mmol) in MeOH (3 mL) was heated at 75°C for 3 h. The mixture was then diluted with water and extracted with EtOAc. The organics were washed with water, dried over MgSO ₄ , filtered and concentrated to give 7-bromo-5-(methoxymethyl)pyrrolo[2,1-1][1,2,4]triazine-4amine (30 mg, 0.117 mmol, 95 % yield) as a white solid.

MS (ERI) m/z 258.9 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 7.96-7.90 (m, 1H), 6.86-6.76 (m, 1H), 4.76-4.60 (m, 2H), 3.32 (s, 3H).

50B: (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide: 5-bromo-2methoxynicotinic acid mixture (200 mg, 0.862 mmol), (S)-3 -amino-1-(4-chlorophenyl)propan-1-ol, HCl (191 mg, 0.862 mmol), Hunig's base (0.452 ml, 2.59 mmol) and BOP (457 mg, 1.034 mmol) in DMF (1 ml) were stirred at room temperature for 2 hours. The mixture was diluted with water, extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated to give (S)-5-6pom-N-(3-(4chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (300 mg, 0.751 mmol, 87% yield) as a white solid.

MS (ERI) m/z 400.75-(M+H).

1H NMR (400 MHz, CDCl3) δ 8.71-8.58 (m, 1H), 8.38-8.31 (m, 1H), 7.38-7.30 (m, 4H), 4.83-4.68 (m, 1H), 4.12 (s, 3H ), 4.01-3.89 (m, 1H), 3.49-3.40 (m, 1H), 2.03-1.90 (m, 2H).

50: (S)-5-(4-Amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl) -3-hydroxypropyl)-2-methoxynicotinamide: mixture of (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2methoxynicotinamide (30 mg, 0.075 mmol), 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (22.87 mg, 0.090 mmol), potassium acetate (22.10 mg, 0.225 mmol) in dioxane (2 ml) was degassed and refilled with N2. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (6.13 mg, 7.51 µmol) was added and the mixture was degassed and refilled with N2 three times, then heated at 100°C for 3 h. After cooling to room temperature, 7-bromo-5(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (19.30 mg, 0.075 mmol), 2 M tribasic potassium phosphate (0.113 ml, 0.225 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (6.13 mg, 7.51 µmol), and the reaction mixture was heated at 100°C for another 5 h. The reaction mixture was filtered and then purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 2464% B over 22 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (S)-5-(4-amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-N-(3-(4-chlorophenyl)-3hydroxypropyl)-2-methoxynicotinamide (5.7 mg, 0.011 mmol, 15.28% yield) as a white solid.

MS (ERI) m/z 497.0 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.01-8.70 (m, 2H), 8.58-8.24 (m, 1H), 8.11-7.68 (m, 1H), 7.48-7.31 (m, 6H), 7.14-6.93 (m, 1H), 5.56-5.18 (m, 1H), 4.86-4.53 (m, 3H), 4.12-3.89 (m, 3H), 3.47-3.29 (m, 5H), 2.04-1.76 (m, 2H) .

Example 51 5-(4-amino-5-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1Hpyrazol-4-yl) -2-methoxynicotinamide

51A: (7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)methanol: 7-bromo-5-(bromomethyl)-4chloropyrrolo[2,1-f] mixture ][1,2,4]triazine (50 mg, 0.154 mmol) (see WO 2015054358), sodium bicarbonate (32.3 mg, 0.384 mmol) in acetonitrile (3 ml)/water (0.3 ml) were stirred at room temperature for - 99 042342 for 3 days. The mixture was then extracted with EtOAc. The organic layer was washed with water, dried over

MgSO ₄ , filtered and concentrated to give a yellow solid which was then purified by flash chromatography on a Biotage system eluting with 40% EtOAc/hexanes to give (7-bromo-4-chloropyrrolo[2,1-f][1 ,2,4]triazin-5-yl)methanol (34 mg, 0.130 mmol, 84% yield) as a light yellow solid. MS (ERI) m/z 263.8 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 8.59-8.46 (m, 1H), 7.35-7.23 (m, 1H), 5.48-5.35 (m, 1H), 4.97-4.84 (m, 2H).

51B: (4-Amino-7-bromopyrrolo[2,1-P][1,2,4]triazin-5-yl)methanol: mixture of (7-bromo-4-chloropyrrolo[2,11][1,2 ,4]triazin-5-yl)methanol (130 mg, 0.495 mmol) and ammonium hydroxide (0.19 ml, 4.95 mmol) in dioxane (2 ml) were stirred at room temperature for 3 h. The mixture was then concentrated to give (4- amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methanolα (120 mg, 0.494 mmol, 100% yield) as a white solid.

MS (ERI) m/z 245.0 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 8.01-7.84 (m, 3H), 6.85-6.73 (m, 1H), 6.28-6.07 (m, 1H), 4.86-4.60 (m, 2H).

51: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide mixture (30 mg, 0.077 mmol), 4,4,4',4',5,5,5' ,5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (23.61 mg, 0.093 mmol) and potassium acetate (22.81 mg, 0.232 mmol) in dioxane (2 mL) were degassed and refilled with N2. 1,1'Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (6.33 mg, 7.75 µmol) was added and the mixture was degassed and refilled with N2 three times, then heated at 100°C for 3 h. After cooling to room temperature, (4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methanol (22.60 mg, 0.093 mmol), 2 M tribasic potassium phosphate (0.116 ml, 0.232 mmol) and 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (6.33 mg, 7.75 µmol), and the reaction mixture was heated at 100°C for 5 h. LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 18-58% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 4-43% B over 26 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-(hydroxymethyl)pyrrolo[2,1-P][1,2,4]triazin-7yl)-N-(1 -benzyl-1H-pyrazol-4-yl)-2-methoxynicotinamide (3.0 mg, 8.24%) as a white solid.

MS (ERI) m/z 471.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.28-10.09 (m, 1H), 9.04-8.87 (m, 1H), 8.82-8.66 (m, 1H), 8.13-8.07 (m, 1H), 7.83 (br s, 1H), 7.43-7.23 (m, 5H), 7.10-6.96 (m, 1H), 5.43-5.22 (m, 2H), 4.91-4.57 (m, 2H), 4.05 (s, 3H).

Example 52: (S)-5-(4-Amino-5-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4chlorophenyl)- 3-hydroxypropyl)-2-methoxynicotinamide

52A: (7-bromo-4-chloropyrrolo[2,1-1][1,2,4]triazin-5-yl)methanol: 7-bromo-5-(bromomethyl)-4chloropyrrolo[2,1-f] mixture ][1,2,4]triazine (50 mg, 0.154 mmol) and sodium bicarbonate (32.3 mg, 0.384 mmol) in acetonitrile (3 mL)/water (0.3 mL) were stirred at room temperature for 3 days. The mixture was then extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered and concentrated to give a yellow solid. The crude material was purified by flash chromatography on a Biotage system eluting with 40% EtOAc/hexanes to give (7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)methanol (34 mg, 0.130 mmol, 84% yield) as a light yellow solid.

MS (ERI) m/z 263.8 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.59-8.46 (m, 1H), 7.35-7.23 (m, 1H), 5.48-5.35 (m, 1H), 4.97-4.84 (m, 2H).

52B: (4-Amino-7-bromopyrrolo[2,1-1][1,2,4]triazin-5-yl)methanol: mixture of (7-bromo-4-chloropyrrolo[2,11][1,2 ,4]triazin-5-yl)methanol (130 mg, 0.495 mmol) and ammonium hydroxide (0.19 ml, 4.95 mmol) in dioxane (2 ml) were stirred at room temperature for 3 h. The mixture was then concentrated with

- 100 042342 obtaining (4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methanol (120 mg, 0.494 mmol, 100% yield) as a white solid.

MS (ERI) m/z 245.0 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.01-7.84 (m, 3H), 6.85-6.73 (m, 1H), 6.28-6.07 (m, 1H), 4.86-4.60 (m, 2H).

52: mixture of (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (30 mg, 0.075 mmol), 4,4,4',4',5, 5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (22.87 mg, 0.090 mmol), potassium acetate (22.10 mg, 0.225 mmol) in dioxane (2 mL) was degassed and again filled N2. 1,1'Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (6.13 mg, 7.51 µmol) was added and the mixture was degassed and refilled with N2 three times. The reaction mixture was heated at 100°C for 3 h. After cooling to room temperature, (4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5yl)methanol (21.89 mg, 0.090 mmol), 2 M tribasic potassium phosphate (0.113 ml, 0.225 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (6.13 mg, 7.51 μmol), and the reaction mixture was heated at 100°C C for another 5 hours. The reaction mixture was filtered and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (S)-5-(4-amino-5-(hydroxymethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)- N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (3.4 mg, 7.04 µmol, 9.38% yield) as a white solid.

MS (ERI) m/z 493.1 (M+H).

¹ H NMR (500 MHz, DMSO-d6) δ 8.93-8.83 (m, 1H), 8.83-8.73 (m, 1H), 8.43-8.30 (m, 1H), 7.94-7.86 (m, 1H), 7.78- 7.69 (m, 2H), 7.42-7.28 (m, 4H), 7.03-6.92 (m, 1H), 6.10-5.96 (m, 1H), 5.45-5.34 (m, 1H), 4.84-4.76 (m, 2H ), 4.75-4.66 (m, 1H), 4.05 (s, 3H), 3.47-3.36 (m, 2H), 1.97-1.76 (m, 2H).

Example 53 5-(4-amino-5-(aminomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol4-yl) -2-methoxynicotinamide

53A: 5-(Aminomethyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine: N-((4-amino-7-bromopyrrolo[2,1-f][1 ,2,4]triazin-5-yl)methyl)-N,N-diethylethanamine, bromide salt (70 mg, 0.172 mmol) and concentrated ammonium hydroxide (0.5 ml, 12.84 mmol) in dioxane (2 ml) were heated at 75° C for 16 hours. The mixture was then concentrated to give 5-(aminomethyl)-7-bromopyrrolo[2,1-1][1,2,4]triazine-4-amine (40 mg, 96%) as a white solid.

MS (ERI) m/z 243.9 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.98 (s, 1H), 6.96 s, 1H), 4.33 (s, 2H).

53: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide mixture (25 mg, 0.065 mmol), 4,4,4',4',5,5,5' ,5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.67 mg, 0.077 mmol), potassium acetate (19.01 mg, 0.194 mmol) in dioxane (2 mL) was degassed and refilled with N2. 1,1'Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (5.27 mg, 6.46 µmol) was added and the mixture was degassed and refilled with N2 three times. The reaction mixture was heated at 100°C for 3 h. After cooling to room temperature, 5-(aminomethyl)-7-bromopyrrolo[2,1-1][1,2,4]triazine4-amine (15.63 mg, mmol), 2 M tribasic potassium phosphate (0.097 mL, 0.194 mmol), 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (5.27 mg, 6.46 μmol), and the reaction mixture was heated at 100°C for for 5 hours. The reaction mixture was filtered and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 6-46% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-(aminomethyl)pyrrolo[2,1-1][1,2,4]triazin7-yl)-N-(1 -benzyl-1H-pyrazol-4-yl)-2-methoxynicotinamide (8.7 mg, 0.019 mmol, 28.7% yield) as a white solid.

MS (ERI) m/z 470.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.25-10.07 (m, 1H), 8.97-8.85 (m, 1H), 8.80-8.60 (m, 1H), 8.20-8.09 (m, 1H), 8.05-7.89 (m, 1H), 7.70-7.63 (m, 1H), 7.37-7.25 (m, 4H), 7.24-7.19 (m, 1H), 5.42-5.23 (m, 2H), 4.524.32 (m, 2H) , 4.08 (s, 3H).

Example 54: (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-5-(4-((2-hydroxyethyl)amino)pyrrolo[2,1f][1,2,4]triazine -7-yl)-2-methoxynicotinamide:

- 101 042342

54A: pyrrolo[2,1-f][1,2,4]triazin-4-ol: To a stirred solution of methyl 1-amino-1H-pyrrole-2carboxylate (3 g, 21.41 mmol) in ethanol (60 ml) was added formamidine acetate (22.29 g, 214 mmol) at room temperature. The reaction mixture was stirred at 85° C. for 16 hours. The reaction was evaporated to dryness. The mixture was diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated to give a brown solid which was washed with ether to give pyrrolo[2,1-1][1,2,4]triazin-4-ol (2.6 g, 19.24 mmol, 90 % yield) as a light brown solid.

MS (ERI) m/z 136.0 (M+H).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.95-7.73 (m, 1H), 7.70-7.41 (m, 1H), 6.98-6.73 (m, 1H), 6.63-6.40 (m, 1H).

54B: 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol: to a mixture of pyrrolo[2,1-f][1,2,4]triazin-4-ol (2.8 g , 20.72 mmol) in CH ₂ Cl ₂ (40 ml) at 0°C was added acetic acid (20 ml) followed by slow addition of NBS (3.32 g, 18.65 mmol). The reaction mixture was stirred at 0°C for 1 h. Saturated aqueous NaHCO ₃ was added to the reaction mixture. The mixture was extracted with EtOAc and washed with saturated aqueous NaHCO ₃ (5x). The organics were dried over MgSO ₄ , filtered and concentrated to give 7-bromopyrrolo[2,1-1][1,2,4]triazin-4-ol (3.9 g, 18.22 mmol, 88% yield) as a tan solid .

MS (ERI) m/z 214.0 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.19-11.66 (m, 1H), 8.50-7.64 (m, 1H), 7.43-6.86 (m, 1H), 6.86-6.35 (m, 1H).

54C: 7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine: mixture of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-ol (3.9 g, 18.22 mmol), POCl ₃ (5.10 ml, 54.7 mmol) and Hunig's base (3.18 ml, 18.22 mmol) in PhCH ₃ (50 ml) were heated at the boil under reflux for 16 h. The reaction mixture was concentrated and cooled to 0 °C Saturated aqueous NaHCO ₃ was added and a light brown precipitate formed. The precipitate was separated by filtration, washing with water and drying under vacuum to give 7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (3.7 g, 15.92 mmol, 87% yield) as a tan solid.

MS (ERI) m/z 233.8 (M+H).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51-8.33 (m, 1H), 7.12-7.08 (m, 1H), 7.08-7.03 (m, 1H).

54D: 2-((7-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)amino)ethanol: a mixture of 2-aminoethanol (0.286 ml, 4.73 mmol), 7-bromo-4 -chloropyrrolo[2,1-f][1,2,4]triazine (1 g, 4.30 mmol) and Hunig's base (0.902 ml, 5.16 mmol) in THF (10 ml) were heated at 70°C for 16 h. The mixture was diluted with EtOAc and washed with dilute HCl and water. The organics were dried over MgSO ₄ , filtered and concentrated to give 2-((7-bromopyrrolo[2,1-f][1,2,4]truazin-4-yl)amino)ethanol (1 g, 3.89 mmol, 90 % yield) as a reddish solid.

MS (ERI) m/z 258.9 (M+H).

¹ H NMR (400 MHz, CDCl3) δ 8.21-8.06 (m, 1H), 8.06-8.03 (m, 1H), 6.85-6.60 (m, 2H), 6.17-5.80 (m, 1H), 3.99-3.89 ( m, 2H), 3.88-3.80 (m, 2H).

54E: 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid: methyl mixture 2-methoxy-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) nicotinate (100 mg, 0.341 mmol) and 1 n. NaOH (1.706 ml, 1.706 mmol) in MeOH (1 ml) was stirred at room temperature for 1 h. The mixture was concentrated and the pH was adjusted to 5 using 1 N NaOH. HCl. The resulting white solid was filtered and washed with water to give 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)nicotinic acid as the title compound.

1H NMR (400 MHz, CDCl ₃ ) δ 9.08-8.77 (m, 1H), 8.82-8.66 (m, 1H), 4.23 (s, 3H), 1.35 (s, 12H).

54F: (8)-N3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide: mixture of 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinic acid (30 mg, 0.107 mmol), (S)-3-amino-1- (4-chlorophenyl) propan-1-ol, HCl (23.87 mg, 0.107 mmol), Hunig's base (0.056 ml, 0.322 mmol) and BOP (57.0 mg, 0.129 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The mixture was diluted with water, extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated to give (8)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2methoxy-5-(4.4.5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (40 mg, 0.090 mmol, 83% yield) as a white solid.

MS (ERI) (m/z) 367.0 (M+H).

54: mixture (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)nicotinamide (40 mg, 0.090 mmol), 2-((7-bromonirrolo[2,1-f][1,2,4]triazine-4

- 102 042342 yl)amino)ethanol (23.02 mg, 0.090 mmol), 2 M tribasic potassium phosphate (0.134 ml, 0.269 mmol) in dioxane (2 ml) was degassed and refilled with N ₂ . The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (7.31 mg, 8.95 μmol) was added to the reaction mixture, and the reaction mixture was heated at 100°C for 2 h. LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 18-58% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-5-(4-((2hydroxyethyl)amino)pyrrolo[2,1 -f][1,2,4]triazin-7-yl)-2-methoxynicotinamide (16.9 mg, 0.034 mmol, 38.0% yield) as a white solid.

MS (ERI) m/z 497.3 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.94-8.82 (m, 1H), 8.81-8.69 (m, 1H), 8.51-8.33 (m, 1H), 8.29-8.09 (m, 1H), 8.06- 7.88 (m, 1H), 7.44-7.31 (m, 4H), 7.12-6.97 (m, 2H), 5.56-5.39 (m, 1H), 4.77-4.62 (m, 1H), 4.05 (s, 3H), 3.71-3.55 (m, 4H), 3.46-3.24 (m, 2H), 2.06-1.81 (m, 2H).

Example 55: N-(1-benzyl-1H-pyrazol-4-yl)-5-(4-((2-hydroxyethyl)amino)pyrrolo[2,1-f][1,2,4]triazine-7 -yl)-2-methoxynicotinamide

55A: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide: 5-bromo-2-methoxynicotinic acid mixture (500 mg, 2.155 mmol), 1-benzyl-1H-pyrazole -4-amine, HCl (452 mg, 2.155 mmol), Hunig's base (1.129 ml, 6.46 mmol) and BOP (1144 mg, 2.59 mmol) in DMF (5 ml) were stirred at room temperature for 2 h. The reaction mixture was diluted water, extracted with EtOAc, dried over MgSO ₄ , filtered and concentrated to give N-(1-benzyl-1H-pyrazol-4-yl)-5bromo-2-methoxynicotinamide (750 mg, 1.937 mmol, 90% yield) as an oil .

MS (ERI) m/z 388.8 (M+H).

1H NMR (400 MHz, CDCl ₃ ) δ 9.76-9.34 (m, 1H), 8.70-8.57 (m, 1H), 8.44-8.31 (m, 1H), 7.65-7.60 (m, 1H), 7.42-7.29 ( m, 5H), 5.36-5.31 (m, 2H), 4.21-4.17 (m, 3H).

55: N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide mixture (30 mg, 0.077 mmol), 4,4,4',4',5,5,5' ,5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) (23.61 mg, 0.093 mmol) and potassium acetate (22.81 mg, 0.232 mmol) in dioxane (2 mL) were degassed and refilled with N2. The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (6.33 mg, 7.75 µmol) was added to the mixture, and the reaction mixture was heated at 100°C for 3 h. After cooling to room temperature, 2- ((7-bromopyrrolo[2,1-1][1,2,4]triazin-4-yl)amino)ethan-1-ol (23.90 mg, 0.093 mmol) and tribasic potassium phosphate (0.116 ml, 0.232 mmol) , and the reaction mixture was degassed and refilled with N2. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane dichloride complex (6.33 mg, 7.75 µmol) was added to the mixture, and the reaction mixture was heated at 100°C for another 12 h. The mixture was then filtered and purified with preparative HPLC to give N-(1-benzyl-1H-pyrazol-4-yl)-5-(4-((2hydroxyethyl)amino)pyrrolo[2,1-1][1,2,4]triazin-7- yl)-2-methoxynicotinamide (2 mg, 4.13 µmol, 5.33% yield) as a white solid.

MS (ERI) m/z 485.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.20-10.02 (m, 1H), 8.97-8.87 (m, 1H), 8.81-8.69 (m, 1H), 8.24-8.15 (m, 1H), 8.14- 8.06 (m, 1H), 8.04-7.91 (m, 1H), 7.72-7.52 (m, 1H), 7.40-7.24 (m, 5H), 7.12-7.02 (m, 2H), 5.405.20 (m, 2H ), 4.06 (s, 3H), 3.73–3.50 (m, 4H).

Example 56: N-(1-benzyl-1H-pyrazol-4-yl)-2-methoxy-5-(4-((2-methoxyethyl)amino)pyrrolo[2,1f][1,2,4]triazine -7-yl)nicotinamide

56A: 7-bromo-N-(2-methoxyethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine: a mixture of 2-methoxyethanamine (71.1 mg, 0.946 mmol), 7-bromo- 4-chloropyrrolo[2,1-1][1,2,4]triazine (200 mg, 0.860 mmol), Hunig's base (0.180 ml, 1.032 mmol) in THF (5 ml) was heated at 70°C for 16 h The mixture was diluted with water. The brown solid was filtered, washed with water and dried to give 7-bromo-N-(2methoxyethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (199 mg, 0.734 mmol, 85% yield ) as a reddish solid.

- 103 042342

MS (ERI) m/z 272.92 (M+H).

1H NMR (400 MHz, CD3OD) δ 7.98-7.88 (m, 1H), 7.00-6.92 (m, 1H), 6.74-6.68 (m, 1H), 3.83-3.73 (m, 2H), 3.68-3.61 (m , 2H), 3.40 (s, 3H).

56B: 2-methoxy-5-(4-((2-methoxyethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)nicotinic acid: to 7-bromo-N solution -(2-methoxyethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (130 mg, 0.480 mmol) and methyl 2-methoxy-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (141 mg, 0.480 mmol) in 1,4dioxane (2 mL) was added tribasic potassium phosphate (0.719 mL, 1.439 mmol) (2 M in H2O). After bubbling nitrogen through the mixture for 5 min, 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (39.2 mg, 0.048 mmol) was added. Nitrogen sparging was continued for an additional 5 minutes. The reaction vessel was sealed and heated to 100° C. for 16 hours. The reaction mixture was filtered through a pad of celite to remove the catalyst. NaOH (0.240 ml, 2.398 mmol) (10 M in water) was added and the mixture was stirred at room temperature for 2 h. Methanol was added and the solid was isolated by filtration to give 2-methoxy-5-(4-((2- methoxyethyl)amino)pyrrolo[2,1-1][1,2,4]triazin-7-yl)nicotinic acid (100 mg, 61%) as a tan solid.

MS (ERI) m/z 344.03 (M+H).

56: 2-methoxy-5-(4-((2-methoxyethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl)nicotinic acid mixture (20 mg, 0.058 mmol) , 1-benzyl-1H-pyrazole-4-amine (12.11 mg, 0.070 mmol), BOP (30.9 mg, 0.070 mmol) and Hunig's base (0.031 ml, 0.175 mmol) in DMF (1 ml) was stirred at room temperature for 20 minutes. The mixture was concentrated and purified by preparative LC-MS: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 8-48% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give N-(1-benzyl1H-pyrazol-4-yl)-2-methoxy-5-(4-((2-methoxyethyl)amino)pyrrolo[2.1 -f][1,2,4]triazin-7yl)nicotinamide (9.4 mg, 0.019 mmol, 32.4% yield) as a white solid.

MS (ERI) m/z 499.2 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.98-8.89 (m, 1H), 8.79-8.70 (m, 1H), 8.33-8.24 (m, 1H), 8.17-8.06 (m, 1H), 8.03-7.92 (m, 1H), 7.67-7.61 (m, 1H), 7.41-7.25 (m, 5H), 7.14-7.01 (m, 2H), 5.35-5.26 (m, 2H), 4.09-4.01 (m, 3H) , 3.77-3.64 (m, 2H), 3.63-3.53 (m, 2H), 3.35-3.30 (m, 1H).

Example 57: (S)-5-(4-amino-5-(((2-hydroxyethyl)amino)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N (3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide:

57A: N-((4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethaneαminium bromide salt: N-(( 7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethanamine, bromide salt (3.5 g, 8.20 mmol) and concentrated ammonium hydroxide ( 11.41 ml, 82 mmol) in dioxane (10 ml) was stirred at room temperature for 4 h. The mixture was then concentrated to give N-((4-amino-7-bromopyrrolo[2,1-f][1,2,4 ]triazin-5-yl)methyl)-N,N-diethylethanamine bromide salt (3.3 g, 7.74 mmol, 94% yield) as an off-white solid.

MS (ERI) m/z 326.1 (M+H).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.21-8.00 (m, 1H), 7.13-7.03 (m, 1H), 4.95-4.75 (m, 2H), 3.29-3.12 (m, 6H), 1.35- 1.18(m, 9H).

57B: 2-(((4-amino-7-bromopyrrolo[2,1-1][1,2,4]triazin-5-yl)methyl)amino)ethan-1-ol: mixture of N-((4amino -7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethanamine (40 mg, 0.122 mmol) and 2-aminoethan-1-ol (0.1 ml, 1.222 mmol) in dioxane (1 ml) was heated at 75°C for 72 h. The mixture was then diluted with EtOAc and washed with water. The organics were dried over MgSO ₄ , filtered and concentrated to give 2-(((4-amino-7-bromopyrrolo[2,1-1][1,2,4]triazin-5-yl)methyl)amino)ethan1- ol (26 mg, 0.091 mmol, 74.3% yield) as a light orange solid.

MS (ERI) m/z 287.8 (M+H).

1H NMR (400 MHz, CDCI3) δ 8.02-7.73 (m, 1H), 6.67-6.35 (m, 1H), 4.10-3.99 (m, 2H), 3.86-3.78 (m, 2H), 2.99-2.74 (m , 2H).

57: mixture of (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (25 mg, 0.063 mmol), 4,4,4',4',5, 5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.06 mg, 0.075 mmol) and potassium acetate (18.42 mg, 0.188 mmol) in dioxane (2 ml) were degassed and again filled N2. A complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (5.11 mg, 6.26 μmol) was added to the mixture, and the reaction was degassed and refilled with N2. The reaction mixture was heated at 100°C for 6 h.

- 104 042342

The mixture was cooled to room temperature, and tribasic potassium phosphate (0.094 ml, 0.188 mmol), 2-(((4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl) was added methyl)amino)ethan-1-ol (17.90 mg, 0.063 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (5.11 mg, 6.26 µmol). The reaction mixture was degassed and refilled with N2 and heated for 6 hours. The reaction mixture was cooled to room temperature, filtered and purified by preparative HPLC to give (S)-5-(4-amino-5-(((2-hydroxyethyl) amino)methyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (9.7 mg, 0.018 mmol, 29.5% yield) as a white solid.

MS (ERI) m/z 526.0 (M+H).

Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.97-8.90 (m, 1H), 8.79-8.72 (m, 1H), 8.47-8.28 (m, 1H), 8.05-7.92 (m, 1H), 7.43- 7.37 (m, 4H), 7.33-7.24 (m, 1H), 4.79-4.68 (m, 1H), 4.62-4.44 (m, 2H), 4.07 (s, 3H), 3.77-3.68 (m, 2H), 3.50-3.34 (m, 2H), 3.18-3.01 (m, 2H).

Example 58 5-(4-amino-5-(((2-hydroxyethyl)amino)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1benzyl- 1H-pyrazol-4-yl)-2-methoxynicotinamide:

But

N-(1-benzyl-1H-pyrazol-4-yl)-5-bromo-2-methoxynicotinamide mixture (25 mg, 0.065 mmol), 4,4,4',4',5,5,5',5 '-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.67 mg, 0.077 mmol), potassium acetate (19.01 mg, 0.194 mmol) in dioxane (2 mL) was degassed and refilled with N ₂ . The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (5.27 mg, 6.46 µmol) was added and the reaction mixture was degassed three times and refilled with N2. The reaction mixture was heated at 100° C. for 3 h. )amino)ethan-1-ol (18.47 mg, 0.065 mmol), 2 M tribasic potassium phosphate (0.097 ml, 0.194 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride complex (5.27 mg , 6.46 µmol) and the reaction mixture was heated at 100°C for 5 h. The reaction mixture was cooled to room temperature and purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 1-41% B over 25 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-(((2-hydroxyethyl)amino)methyl)pyrrolo[2,1-f][1,2,4]triazine -7-yl)-N-(1benzyl-1H-pyrazol-4-yl)-2-methoxynicotinamide (11.1 mg, 0.022 mmol, 33.5% yield) as a white solid.

MS (ERI) m/z 514.1 (M+H).

Ή NMR (500 MHz, DMSO-d ₆ ) δ 10.24-10.06 (m, 1H), 8.96-8.87 (m, 1H), 8.77-8.57 (m, 1H), 8.16-8.05 (m, 1H), 8.08- 7.96 (m, 1H), 7.78-7.51 (m, 1H), 7.42-7.25 (m, 6H), 5.39-5.23 (m, 2H), 4.64-4.49 (m, 2H), 4.164.01 (m, 3H ), 3.78-3.61 (m, 2H), 3.17-2.98 (m, 2H).

Example 59 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxy-3-phenylpropyl)benzamide:

59A: mixture of 7-bromopyrrolo[2,1-1][1,2,4]triazine-4-amine (0.200 g, 0.939 mmol), 3-(4,4,5,5tetramethyl-1,3,2- dioxaborolan-2-yl)benzoic acid (0.279 g, 1.127 mmol), potassium triphosphate (2 M in water) (1.408 ml, 2.82 mmol) and N,N-dimethylformamide (4.0 ml) were degassed using vacuum and nitrogen (3x) . 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.069 g, 0.094 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immediately immersed in an oil bath at 95°C and stirred overnight. The reaction mixture was cooled to room temperature and then diluted with water (2 ml) followed by the addition of 1N. aqueous hydrochloric acid (2 ml), which led to precipitation. The solid was collected by vacuum filtration and dried under reduced pressure to give 3-(4-aminopyrrolo[2,1-1][1,2,4]triazin-7yl)benzoic acid (0.117 g, 0.460 mmol, 49.0% yield) in as a gray solid.

MS (ERI) m/z 255.1 (M+H).

59: mixture of 3-(4-aminopyrrolo[2,1-1][1,2,4]triazin-7-yl)benzoic acid (0.025 g, 0.098 mmol), 3-amino-1-phenylpropan-1-ol (0.022 g, 0.147 mmol), Hunig's bases (0.052 ml, 0.295 mmol), and BOP (0.048 g, 0.108 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions:

- 105 042342 column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 10-55%

B for 20 min, then 3 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (34.0 mg, 87 μmol, 88%).

MS (ERI) m/z 388.2 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.53 (br s, 1H), 8.42 (s, 1H), 8.23 (br d, J=7.7 Hz, 1H), 7.94 (s, 1H), 7.89- 7.65 (m, 3H), 7.54 (br t, J=7.8 Hz, 1H), 7.41-7.28 (m, 4H), 7.27-7.17 (m, 1H), 7.13-6.99 (m, 2H), 4.65 (br s, 1H), 3.59-3.43 (m, 2H), 3.40-3.29 (m, 1H), 1.97-1.78 (m, 2H).

Example 60 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)benzamide:

A mixture of 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)benzoic acid (0.025 g, 0.098 mmol), 1benzyl-1H-pyrazol-4-amine (0.026 g, 0.147 mmol), Hunig's bases (0.052 ml, 0.295 mmol), and BOP (0.048 g, 0.108 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 15-100% B over 20 min, then 2 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (30.0 mg, 72 μmol, 73%).

MS (ERI) m/z 410.3 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.69-10.42 (m, 1H), 8.54 (s, 1H), 8.26 (br d, J=7.6 Hz, 1H), 8.15 (s, 1H), 7.95 (s , 1H), 7.90-7.69 (m, 3H), 7.68-7.55 (m, 2H), 7.43-7.21 (m, 5H), 7.16-6.97 (m, 2H), 5.32 (s, 2H).

Example 61 5-(4-Amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylbutyl)nicotinamide:

F

61A: mixture of 7-bromo-6-fluoropyrrolo[2,1-f][1,2,4]triazine-4-amine (0.131 g, 0.569 mmol), methyl 2methoxy-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.200 g, 0.682 mmol), potassium triphosphate (2 M in water) (0.853 ml, 1.706 mmol) and dioxane (4.0 ml) were degassed with vacuum and nitrogen (3x). The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.046 g, 0.057 mmol) was added and the reaction mixture was degassed (2x). The reaction mixture was immersed in an oil bath at 95°C and stirred overnight. The reaction mixture was diluted with ethyl acetate, then washed with water and brine. The organic layer was collected and the aqueous layers were successively extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was triturated with dichloromethane, sonicated, and isolated to give methyl 5-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinate (0.052 g, 0.164 mmol , 28.8% yield) as a tan solid.

MS (ERI) m/z 318.1 (M+H).

61B: heterogeneous mixture of methyl 5-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinate (0.052 g, 0.164 mmol) and lithium hydroxide, H2O ( 6.88 mg, 0.164 mmol) in a mixture of methanol (1 ml), tetrahydrofuran (1 ml) and water (0.500 ml) was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dried well to give 5-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (0.051 g, 0.164 mmol, 100% yield) as a light brown solid. The compound was used without further purification.

MS (ERI) m/z 304.1 (M+H).

61: mixture of 5-(4-amino-6-fluoropyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (0.025 g, 0.081 mmol), 3 -phenylbutan-1-amine (0.018 g, 0.121 mmol), Hunig's base (0.042 ml, 0.242 mmol) and BOP (0.039 g, 0.089 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min . The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 40-80% B over 20 min, then 8 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (10.4 mg, 24 μmol, 29%).

- 106 042342

MS (ERI) m/z 435.2 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.76 (s, 1H), 8.57 (d, J=1.4 Hz, 1H), 8.29 (br t, J=5.1 Hz, 1H), 7.99 (s, 1H) , 7.87 (br s, 2H), 7.36-7.12 (m, 5H), 6.90 (s, 1H), 4.02 (s, 3H), 3.32-3.11 (m, 2H), 2.88-2.73 (m, 1H), 1.82 (q, J=7.2 Hz, 2H), 1.23 (br d, J=6.9 Hz, 3H).

Example 62 5-(4-Amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl) -2 methoxynicotinamide

A mixture of 5-(4-amino-6-fluoropyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, lithium salt (0.025 g, 0.081 mmol), 1-benzyl -1H-pyrazole-4-amine (0.021 g, 0.121 mmol), Hunig's base (0.042 ml, 0.242 mmol) and BOP (0.039 g, 0.089 mmol) in N,N-dimethylformamide (1.0 ml) were stirred at room temperature for 60 min. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 20-60% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (11.2 mg, 23 μmol, 29%). MS (ERI) m/z 459.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.79 (s, 1H), 8.59 (d, J=2.0 Hz, 1H), 8.15 (s, 1H), 8.01 (s, 1H) , 7.89 (br s, 2H), 7.64 (s, 1H), 7.45-7.20 (m, 5H), 6.91 (s, 1H), 5.31 (s, 2H), 4.04 (s, 3H).

Example 63: (S)-5-(4-amino-5-(aminomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl )-3hydroxypropyl)-2-methoxynicotinamide

Mixture of (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (25 mg, 0.063 mmol), 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (19.67 mg, 0.077 mmol), potassium acetate (19.01 mg, 0.194 mmol) in 1,4-dioxane (2 ml) degassed and refilled with N2. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (5.27 mg, 6.46 µmol) was added and the solution was degassed three times and refilled with N ₂ . The reaction mixture was then heated at 100°C for 6 hours. The mixture was cooled to room temperature and 5-(aminomethyl)-7-bromopyrrolo[2,11][1,2,4]triazine-4-amine (15.14 mg, 0.063 mmol), tribasic potassium phosphate (0.097 ml, 0.194 mmol) (2 M in water), and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (5.27 mg, 6.46 µmol). The reaction mixture was heated at 100° C. for 5 hours. The mixture was cooled to room temperature and filtered through celite. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 7-47% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (S)-5-(4-amino-5-(aminomethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)- N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (4.7 mg, 9.75 µmol, 16% yield).

MS (ERI) m/z 482.0 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.10-8.84 (m, 1H), 8.82-8.54 (m, 1H), 8.50-8.31 (m, 1H), 8.05-7.69 (m, 1H), 7.43-7.35 (m, 4H), 7.16-7.11 (m, 1H), 4.79-4.67 (m, 1H), 4.32-4.26 (m, 2H), 4.06 (s, 3H), 3.48-3.32 (m, 2H), 1.98 -1.80 (m, 2H).

Example 64: (7-(5-(((3R,4S)-1-(3,3-difluorocyclobutane-1-carbonyl)-4-fluoropyrrolidin-3yl)carbamoyl)-6-methoxypyridin-3-yl)-4 -imino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-3(4H)yl)methyl dihydrogen phosphate:

"Alo

O / \A J Η HO-V° ^F

HE

To a mixture of 5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3, 3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (300 mg, 0.538 mmol),

- 107 042342 potassium iodide (313 mg, 1.884 mmol) and potassium carbonate (223 mg, 1.614 mmol) in acetonitrile (6 ml) were added di-tert-butyl(chloromethyl)phosphate (487 mg, 1.884 mmol) and the mixture was heated at 55° C. for 15 hours. The mixture was then cooled to room temperature, filtered through a pad of celite and washed with about 100 ml of acetonitrile. The filtrate was then concentrated in vacuo to give a yellow oil. The resulting yellow oil was dissolved in 3 ml of acetone and 3 ml of water. The resulting mixture was heated at 50° C. for 2 hours. The solution changed color from yellow to light yellow. The mixture was then filtered and purified by preparative HPLC: preparative column: Waters Sunfire C18 OBD, 5 mm, 30x150 mm, solvent A: 10% MeCN/90% water, 0.1% TFA; solvent B: 90% MeCN/10% water, 0.1% TFA; flow rate: 50 ml/min; gradient: 10% B - 60% B in 15 min, 60% B - 100% B in 0.5 min, then hold at 100% B for 3.5 min. Fractions containing the target product were collected and dried by lyophilization to obtain 6-methoxypyridin-3-yl)-4-imino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-3(4H)-yl)methyl dihydrogen phosphate (145 mg, 0.217 mmol, 56.5 % yield) as a white solid.

MS (ERI) m/z 668.0 (M+H).

1H NMR (500 MHz, CD ₃ OD) δ 8.96-8.86 (m, 2H), 8.59-8.50 (m, 1H), 7.76-7.66 (m, 1H), 5.97-5.89 (m, 2H), 5.43-5.22 (m, 1H), 4.98-4.74 (m, 1H), 4.22-4.17 (m, 3H), 4.17-4.09 (m, 1H), 3.98-3.69 (m, 2H), 3.53-3.35 (m, 1H) , 3.27-3.17 (m, 1H), 2.91-2.79 (m, 4H).

Example 65 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1Hpyrazol-4-yl) -2-methoxybenzamide

65A: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-C[1,2,4]triazin-7-yl)-2-methoxybenzoic acid: to a solution of 7-bromo-5-(trifluoromethyl )pyrrolo[2,1-C[1,2,4]triazine-4-amine (200 mg, 0.712 mmol) and 5boron-2-methoxybenzoic acid (167 mg, 0.854 mmol) in DMF (3 ml) was added potassium phosphate tribasic (1.067 ml, 2.135 mmol) (2 M in H2O). The reaction mixture was degassed by bubbling nitrogen (5 min). The PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (58.1 mg, 0.071 mmol) was added and nitrogen bubbling was continued for another 5 min. The reaction vessel was sealed and heated to 90°C for 12 hours. Methanol was added and the solid was isolated to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-d][1,2,4] triazin-7-yl)-2-methoxybenzoic acid (160 mg, 0.431 mmol, 60.6% yield) as a white solid.

MS (ERI) m/z 353.1 (M+H).

1H NMR (400 MHz, CD3OD) d 8.46 (d, J=2.3 Hz, 1H), 8.21-8.15 (m, 1H), 8.03 (s, 1H), 7.21 (d, J=2.6 Hz, 2H), 4.01 (s, 3H).

65: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-d][1,2,4]triazin-7-yl)-2-methoxybenzoic acid (20 mg, 0.057 mmol) and 1-benzyl-1H-pyrazole-4-amine (14.75 mg, 0.085 mmol) in DMF (1 mL) was added DIEA (0.030 mL, 0.170 mmol) and BOP (27.6 mg, 0.062 mmol). The mixture was stirred at room temperature for 15 minutes. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 25-75% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N- (1-benzyl-1 H-pyrazol-4yl)-2-methoxybenzamide (1.5 mg, 0.020 mmol, 35%).

MS (ERI) m/z 508.0 (M+H).

1H NMR (500 MHz, DMSO-d ₆ ) d 10.23 (s, 1H), 8.32 (s, 1H), 8.16-8.05 (m, 3H), 7.62 (s, 1H), 7.46 (s, 1H), 7.40 -7.21 (m, 6H), 5.29 (s, 2H), 3.92 (s, 2H).

Example 66 5-{4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3- difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

To a solution of 5-(4-amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3yl)-2 -methoxynicotinamide, 1.0 TFA (14 mg, 0.028 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (3.79 mg, 0.028 mmol) and DIPEA (0.017 ml, 0.097 mmol) in DMF (1 ml) was added BOP (14.76 mg , 0.033 mmol). The reaction mixture was stirred at room temperature for 2 hours. Crude material

- 108 042342 was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 9-49% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-{4-amino-5fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S )-1-(3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide, TFA (8.7 mg, 0.013 mmol, 46%). MS (ERI) m/z 508.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=1.8 Hz, 1H), 8.82-8.71 (m, 1H), 8.54 (br dd, J=7.0, 4.9 Hz, 1H), 7.90 (s , 1H), 7.09 (s, 1H), 5.44-5.16 (m, 1H), 4.87-4.57 (m, 1H), 4.03 (d, J=6.4 Hz, 3H), 3.99-3.23 (m, 4H), 3.17 (s, 1H), 2.93-2.63 (m, 4H).

Example 67: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3 ,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-4-fluoro-2-methylbenzamide

F

67A: Methyl 5-(4-(bis(4-methoxybenzyl)amino)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)4-fluoro-2- methyl benzoate: degassed solution of methyl 4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (174 mg, 0.591 mmol), potassium triphosphate (2 M in water) (0.806 ml, 1.611 mmol), adduct 1,1'-bis (diphenylphosphino) ferrocene palladium dichloride - CH ₂ Cl ₂ (43.9 mg, 0.054 mmol) and 7-bromo-N, N-bis (4-methoxybenzyl )-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (280 mg, 0.537 mmol) in DMF (10 ml) was divided into 4 equal portions, which were stirred at 135 °C for 60 minutes under the influence of microwaves. The reaction mixture was diluted with EtOAc (150 ml), then washed with 10% lithium chloride solution (50x2 ml) and brine (50 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave a crude material which was purified with a silica gel column eluting with hexanes/EtOAc (100/0 to 80/20) to give methyl 5-(4-(bis(4methoxybenzyl)amino)-5-(trifluoromethyl )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate (232.5 mg, 0.359 mmol, 66.9% yield).

MS (ERI) m/z 609.2 (M+H).

1H NMR (400 MHz, CDCl ₃ ) δ 8.53 (d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.05-6.97 (m, 5H), 6.87 (d, J=8.6 Hz, 5H), 4.64 (s, 4H), 3.94 (s, 3H), 3.83 (s, 6H), 2.71 (s, 3H).

67B: methyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate: methyl 5-( 4-(bis(4-methoxybenzyl)amino)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4fluoro-2-methylbenzoate (232 mg, 0.381 mmol ) in TFA (2 ml) was heated to 130°C for 25 min under the influence of microwaves. The reaction mixture was concentrated and diluted with water (50 ml). The organics were washed with 1.5 M Na ₂ HPO ₄ solution (20 mlx2), water (20 ml) and brine (20 ml). The organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude material which was purified with a silica gel column eluting with hexanes/EtOAc (100/0 to 20/80) to give methyl 5-(4-amino- 5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate (151 mg, 0.398 mmol, 104% yield).

MS (ERI) m/z 375.1 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J=7.6 Hz, 1H), 8.12 (s, 1H), 7.42 (d, J=11.3 Hz, 1H), 7.37 (s, 1H), 3.84 (s, 3H), 2.61 (s, 3H).

67C: Sodium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate, sodium salt: methyl solution 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4fluoro-2-methylbenzoate (151 mg, 0.410 mmol) and 1 M solution NaOH (0.615 mL, 0.615 mmol) in MeOH (2 mL) was heated to 100°C under microwave for 30 min. The reaction mixture was concentrated to give sodium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate, sodium salt (151 mg, 0.401 mmol, 98% yield).

67D: tert-butyl (3R,4S)-3 -(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl)-4 -fluoro2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-!][1,2,4]triazin-7-yl)- 4-fluoro-2-methylbenzoic acid, sodium salt (151 mg, 0.426 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (96 mg, 0.469 mmol) and DIPEA (0.223 ml, 1.279 mmol) BOP (226 mg, 0.511 mmol) was added to DMF (3 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc (80 ml), then washed with 10% lithium chloride solution (30x2 ml) and brine (30 ml). The organics were dried over Na ₂ SO ₄ . Filtration and concentration gave a crude material which was purified on a silica gel column with hexanes/EtOAc (100/0 to 20/80) to give t-butyl (3R,4S)-3-(5-(4-amino- 5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzamido)-4- 109 042342 fluoropyrrolidine-1-carboxylate (163.7 mg, 0.303 mmol, 71.1% yield).

MS (ERI) m/z 542.1 (M+H).

67E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)-4fluoropyrrolidine -3-yl)-2-methylbenzamide, TFA: tert-butyl (3K,48)-3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-4-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1 carboxylate (163.7 mg, 0.303 mmol) in TFA (2 mL) was stirred at 23°C for 1 h. The reaction mixture was concentrated and triturated with ether (10 ml). The solid was collected as 5-(4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)-4 -fluoropyrrolidin-3-yl)2-methylbenzamide, TFA (150 mg, 0.271 mmol, 89% yield).

MS (ERI) m/z 441.0.

67: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S) -4-fluoropyrrolidin-3-yl)-2-methylbenzamide, TFA (15 mg, 0.027 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (4.05 mg, 0.030 mmol) and DIPEA (0.024 ml, 0.135 mmol) in DMF (1 ml ) was added BOP (14.36 mg, 0.032 mmol). The reaction mixture was stirred at room temperature for 2 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 26% B, 26-66% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N- ((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-4-fluoro-2-methylbenzamide (6.4 mg, 0.011 mmol, 42%).

MS (ERI) m/z 559.3 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.56 (br dd, J=14.6, 7.1 Hz, 1H), 8.08 (s, 1H), 7.82-7.75 (m, 1H), 7.347.24 (m, 2H), 5.39-5.13 (m, 1H), 4.76-4.45 (m, 1H), 3.95-3.78 (m, 2H), 3.77-3.56 (m, 2H), 3.21-3.03 (m, 1H), 2.89- 2.67 (m, 4H), 2.44 (d, J=2.7 Hz, 3H).

Example 68 5-{4-amino-5-[(2-acetamidoethyl)carbamoyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)3 - (4-chlorophenyl)-3-hydroxypropyl]-2-methoxypyridine-3-carboxamide

68A: (8)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide: 5-bromo-2methoxynicotinic acid solution (0.50 g, 2.155 mmol), BOP (1.144 g, 2.59 mmol), (S)-3-amino-1-(4chlorophenyl)propan-1-ol (0.527 g, 2.370 mmol) and triethylamine (1.051 ml, 7.54 mmol) in DMF (10.77 ml) was stirred at room temperature for 75 min. DMF was removed under vacuum. EtOAc and 10% LiCl aqueous solution were added. The layers were separated and the EtOAc layer was washed with 10% aqueous LiCl, saturated aqueous NaHCO ₃ , brine, dried over Na ₂ SO ₄ and evaporated in vacuo to give a tan oil (1.56 g). The crude product was dissolved in CH ₂ Cl ₂ and purified by flash column chromatography (Teledyne-Isco RediSep Rf, 24 g column; eluting with 0-100% EtOAc in hexanes) to give (S)-5-bromo-N-(3 -(4-chlorophenyl)-3-hydroxypronyl)-2methoxynicotinamide (0.785 g, 91%) as a white solid.

MS (ERI) m/z 402.9 (M+H).

68B: (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )nicotinamide: mixture of (S)-5-bromo-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2methoxynicotinamide (0.7847 g, 1.963 mmol), 4,4,4',4',5,5 ,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.598 g, 2.356 mmol) and potassium acetate (0.289 g, 2.95 mmol) in dioxane (9.67 ml) were degassed (4x ) vacuum/nitrogen. The adduct 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride-CH ₂ Cl ₂ (0.160 g, 0.196 mmol) was added and the mixture was again degassed with vacuum/nitrogen (2x). The reaction mixture was immersed in an oil bath at 80°C and stirred overnight. After cooling to room temperature, the reaction mixture was filtered through celite, washing with dioxane. The filtrate was evaporated to dryness under vacuum. Ether was added followed by 2 minutes of sonication. The mixture was filtered through Celite and the filtrate was evaporated in vacuo to give a brown oil (1.57 g). The crude material was dissolved in CH ₂ Cl ₂ and filtered through a 25 mm syringe filter with a 0.45 μm nylon membrane. Silica gel flash chromatography (Teledyne-Isco RediSep Rf, 40 g column; eluting with 0-100% EtOAc in hexanes) gave (S)-N-(3-(4-chlorophenyl)-3hydroxypropyl)-2-methoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.492 g, 1.102 mmol, 56%) as an off-white solid.

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MS (ERI) m/z 447.1/449.1 (M+H).

68C: ethyl (S)-4-amino-7-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-6-methoxypyridin-3yl)pyrrolo[2,1-f][1, 2,4]triazine-5-carboxylate: mixture of ethyl 4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazine5-carboxylate (0.262 g, 0.92 mmol) and (S)-N- (3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxy-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.4921 g, 1.102 mmol) in potassium triphosphate (2.0 M aqueous solution) (1.380 mL, 2.76 mmol) was degassed with N2. The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (0.075 g, 0.092 mmol) was added, followed by degassing. The reaction mixture was heated at 105°C for 2.5 h. The reaction mixture was diluted with EtOAc (25 ml). The layers were separated and the organics were washed with saturated aqueous sodium bicarbonate (2x) and brine, dried over Na ₂ SO ₄ , filtered and evaporated in vacuo to give an oil (0.48 g). The crude material was suspended in ether and sonicated for 2 minutes. The solid was collected by filtration, washed with ether and dried under vacuum to give a pale green solid. The material was triturated with methanol (including the ethereal filtrate freed from ether) to give ethyl (S)-4-amino-7-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-6-methoxypyridine-3- yl)pyrrolo[2,1-f][1,2,4]triazine-5carboxylate (0.327 g, 0.623 mmol, 68%) as a light gray powder.

MS (ERI) m/z 525.0/527.0 (M+H).

¹ H NMR (400 MHz, DMSO-d6) δ 9.25-9.11 (m, 1H), 8.88 (br s, 1H), 8.72 (s, 1H), 8.57-8.37 (m, 2H), 8.12 (s, 1H ), 7.56 (s, 1H), 7.40 (s, 4H), 5.52 (br d, J=3.9 Hz, 1H), 4.72 (br d, J=3.2 Hz, 1H), 4.37 (q, J=7.1 Hz , 2H), 4.04 (s, 3H), 3.39 (br d, J=5.6 Hz, 2H), 2.01-1.73 (m, 2H), 1.37 (br t, J=7.0 Hz, 3H).

68D: (S)-4-amino-7-(5-((3-(4-chlorophenyl)-3-hydroxypropyl)carbamoyl)-6-methoxypyridin-3yl)pyrrolo[2.1-1][1.2 ,4]triazine-5-carboxylic acid: thick suspension of ethyl (S)-4-amino-7-(5-((3-(4chlorophenyl)-3-hydroxypropyl)carbamoyl)-6-methoxypyridin-3-yl)pyrrolo [2,1-Ni1,2,4]triazine-5carboxylate (0.327 g, 0.623 mmol) in THF (1.87 ml), ethanol (1.87 ml) and sodium hydroxide (1.0 N) (1.869 ml, 1.869 mmol) was stirred at room temperature for 16 hours. The reaction solution was immersed in an ice bath at 0°C and slowly added 1N. HCl to pH 7. The precipitate was collected by filtration, washed with water and dried under vacuum. The filtrate was concentrated in vacuo to remove ethanol and THF and the second crop was collected and combined with the first crop. The solid was suspended in ether, sonicated for 2 minutes, collected by filtration, washed with ether and dried under vacuum to give (S)-4-amino-7-(5-((3-(4chlorophenyl)-3-hydroxypropyl )carbamoyl)-6-methoxypyridin-3-yl)pyrrolo[2,1-H1,2,4]triazine-5carboxylic acid (0.241 g, 0.485 mmol, 78%) as a light tan solid.

MS (ERI) m/z 497.0/499.0 (M+H).

1H NMR (400 MHz, DMSO-d6) δ 9.92-9.58 (m, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.2 Hz, 1H), 8.51 (br t, J =5.2 Hz, 1H), 8.33 (br s, 1H), 8.08 (s, 1H), 7.50 (s, 1H), 7.40 (s, 4H), 5.52 (br d, J=3.1 Hz, 1H), 4.71 (br s, 1H), 4.04 (s, 3H), 3.44-3.39 (m, 2H), 1.86 (dt, J=14.6, 7.2 Hz, 2H). 68: solution of (S)-4-amino-7-(5-((3-(4chlorophenyl)-3-hydroxypropyl)carbamoyl)-6-methoxypyridin-3-yl)pyrrolo[2,1-N1,2,4 ]triazine-5carboxylic acid (10.0 mg, 0.020 mmol), BOP (10.68 mg, 0.024 mmol), N-(2-aminoethyl)acetamide (2.261 mg, 0.022 mmol), and triethylamine (9.82 μL, 0.070 mmol) in DMF (201 µl) was stirred at room temperature for 16 h. The reaction mixture was diluted with methanol and filtered through a syringe filter with a 0.45 µm nylon membrane. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 18-58% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain (S)-N-(2-acetamidoethyl)-4-amino-7-(5-((3-(4-chlorophenyl)-3hydroxypropyl)carbamoyl)- 6-methoxypyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazine-5-carboxamide (3.3 mg, 28%). MS (ERI) m/z 581.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 10.46-10.18 (m, 1H), 8.94 (d, J=2.1 Hz, 1H), 8.75 (br t, J=5.3 Hz, 1H), 8.67 (d, J =2.4 Hz, 1H), 8.55 (br t, J=5.3 Hz, 1H), 8.19 (br s, 1H), 8.04 (br t, J=5.6 Hz, 1H), 8.02 (s, 1H), 7.72 ( s, 1H), 7.39 (s, 4H), 4.71 (br s, 1H), 4.05 (s, 3H), 3.49-3.42 (m, 1H), 3.42-3.31 (m, 2H), 3.25-(q, J=6.3 Hz, 2H), 1.94-1.85 (m, 2H), 1.83 (s, 3H).

Connections in the table. 1 was prepared by the methods detailed in examples 4 and 61. The compounds are racemic.

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Example Name R The ion mass observed in MS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 69 3-{4-Amino-6fluoropyrrolo[2,11][1,2,4]triazin-7yl}-M-(3phenylbutyl)benzamide d 404.2 8.50 (brt, >5.2 Hz, 1H), 8.34 - 8.28 (m, 1H), 8.06 - 7.96 (m, 2H), 7.86 (br s, 2H), 7.78 (br d, >7.7 Hz, 1H), 7.62 -7.54 (m, 1H), 7.34 - 7.22 (m, 4H), 7.21 -7.12(m, 1H), 6.966.86 (m, 1H), 3.53 - 3.47 (m, 1H), 3.26 - 3.08 (m, 2H), 2.85 -2.74(m, 1H), 2.55 (m, 3H), 1.87 - 1.77 (m, 2H) 70 3-{4-Amino-6fluoropyrrolo[2,1f] [1,2,4]triazin-7yl } -N-(3-hydroxy3phenylpropyl)benza MFA He 405.9 8.58-8.51 (m, 1H), 8.33 8.28 (m, 1H), 8.05 - 7.95 (m, 2H), 7.88 - 7.80 (m, 2H), 7.79 - 7.73 (m, 1H), 7.64 - 7.55 (m, 1H), 7.40 - 7.27 (m, 4H), 7.25 - 7.17(m, 1H), 6.93 - 6.86 (m, 1H), 5.46 - 5.40 (m, 1H), 4.68 - 4.58 (m, 1H), 3.39 - 3.29 (m, 2H), 1.93 - 1.82 (m, 2H) 71 3-{4-amino-6fluoropyrrolo[2,1f] [ 1,2,4]triazin-7 yl}-M-(1-benzyl- 1H-pyrazol-4yl)benzamide 428.2 10.64 - 10.58 (m, 1H), 8.41 (s, 1H), 8.17-8.12 (m, 1H), 8.06 (br d, >7.7 Hz, 1H), 7.99 (s, 1H), 7.92 - 7.79 (m, 3H), 7.68 - 7.60 (m, 2H), 7.39 - 7.22 (m, 5H), 6.94 - 6.88 (m, 1H), 5.33 - 5.25 (m, 2H)

Connections in the table. 2 was made by the methods detailed in Example 2. Where a tertiary amide was made, all of the amine will be shown. When the diastereomers have been separated, they are included as separate data.

table 2

Example Name R Ion mass observed in MS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 72 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-H-(3- hydroxy-3phenylpropyl)b benzamide HE 455.9 8.55 (brt, >5.1 Hz, 1H), 8.39 (s, 1H), 8.22 (br d, >7.7 Hz, 1H), 8.16 (s, 1H), 7.83 (brd, >7.6 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.40 7.28 (m , 4H), 7.27-7.17 (m, 1H), 4.70-4.61 (m, 1H), 3.53-3.49 (m, 2H), 3.40-3.31 (m, 1H), 1.95 1.83 (m, 2H) 73 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-mi]-N-[(3R)3-(4chlorophenyl)-3hydroxypropyl]benzamide He 489.9 8.55 (br s, 1H), 8.40 (br s, 1H), 8.27-8.13 (m, 2H), 7.83 (brd, >5.3 Hz, 1H), 7.57 (br s, 2H), 7.38 (br s, 4H ), 4.66 (br s, 1H), 2.59 2.53 (m, 1H), 1.96-1.81 (m, 2H) (peaks lost with solvent suppression)

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74 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7-yl]/-[3-(4fluorophenyl)-3hydroxypropyl]benzamide OH ^a _F 474.2 8.60-8.51 (m, 1H), 8.45 8.36 (m, 1H), 8.27 - 8.20 (m, 1H), 8.17 (s, 1H), 7.907.80 (m, 1H), 7.65 - 7.54 (m, 2H) , 7.45 - 7.36 (m, 2H), 7.14 (brt, 1=8.8Hz, 2H), 5.46 - 5.37 (m, 1H), 4.70-4.61 (m, 1H), 3.493.29 (m, 1H), 1.93 - 1.82 (m, 2H) 75 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl]/-[1(cyclopropylmethyl)-1Hpyrazol-4yl]benzamide G/ 441.9 10.56 - 10.52 (m, 1H), 8.57 -8.51 (m, 1H), 8.26 (brd, 1=7.7Hz, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.95 (brd, 1= 7.7Hz, 1H), 7.70-7.58 (m, 3H), 3.96 (br d, J=7.1 Hz, 2H), 1.28-1.19 (m, 1H), 0.58 - 0.50 (m, 2H), 0.40 - 0.32 ( m, 2H) 76 3-[4-amino-5(trifluoromethyl)pyrrolo[2.11][1.2.4]triazin-7-yl]/-(1benzyl-1Hpyrazol-4yl)benzamide, 2 TFA 478.3 10.62 - 10.53 (m, 1H), 8.51 (s, 1H), 8.24 (br d, J=7.7 Hz, 1H), 8.11 (s, 2H), 7.987.90 (m, 1H), 7.70 - 7.61 (m , 2H), 7.59 (s, 1H), 7.40 7.22 (m, 5H), 5.32 (s, 2H) 77 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-mi]-N-[(3S)3-(4chlorophenyl)-3hydroxypropyl]benzamide Oh 490.1 8.60 - 8.53 (m, 1H), 8.43 8.33 (m, 1H), 8.26-8.13 (m, 2H), 7.87 - 7.78 (m, 1H), 7.64-7.51 (m, 2H), 7.37 (br s, 4H ), 5.55 - 5.45 (m, 1H), 4.71 -4.60 (m, 1H), 3.41-3.31 (m, 1H), 1.93 - 1.80 (m, 2H) 78 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-nn]-N-[(3S)1benzylpyrroli din-3yl]benzamide 481.2 8.57 (brd, 1=6.9Hz, 1H), 8.39 (s, 1H), 8.26-8.19 (m, 1H), 8.19-8.13 (m, 1H), 7.88 - 7.83 (m, 1H), 7.64 7.52 (m , 2H), 7.38 - 7.27 (m, 4H), 7.28-7.18 (m, 1H), 4.48 -4.35 (m, 1H), 3.41 -3.32 (m, 1H), 2.85 (s, 1H), 2.69-2.59 (m, 1H), 2.48-2.41 (m, 3H), 2.25 2.12 (m, 1H), 1.82 (brdd, J=13.1, 7.1 Hz, 1H) 79 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7-mi]-N-[(3S)1benzoylpyrrole idin-3yl]benzamide 'A 494.9 8.79 - 8.65 (m, 1H), 8.46 8.33 (m, 1H), 8.26-8.12 (m, 2H), 7.93 - 7.76 (m, 1H), 7.65 - 7.39 (m, 7H), 4.61 -4.35 (m, 1H), 3.863.67 (m, 1H), 3.62-3.58 (m, 1H), 3.42-3.31 (m, 1H), 3.20-3.13 (m, 1H), 2.30-2.11 (m, 1H), 1.90 ( s, 1H)

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80 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7-mi]-N-[(3S)1benzylpiperide in-3yl]benzamide Chie 495.1 8.35 (s, 1H), 8.27 (brd, >7.9Hz, 1H), 8.23-8.18 (m, 1H), 8.18-8.13 (m, 1H), 7.87 - 7.79 (m, 1H), 7.62 - 7.53 (m , 2H), 7.36 7.28 (m, 4H), 7.27 - 7.20 (m, 1H), 4.03 - 3.93 (m, 1H), 3.55 - 3.46 (m, 1H), 3.42 - 3.33 (m, 1H), 2.93 2.84 (m, 1H), 2.77 - 2.68 (m, 1H), 1.98 - 1.88 (m, 2H), 1.87 - 1.79 (m, 1H), 1.75 - 1.66 (m, 1H), 1.601.48 (m, 1H) , 1.42-1.29 (m, 1H) 81 7-{3-[(3R)-3[(4fluorophenyl)methyl]piperidine1carbonyl]pheny l}-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-4-amine W 498.2 8.22-8.12 (m, 1H), 8.11 8.01 (m, 2H), 8.00 - 7.90 (m, 1H), 7.61 -7.48 (m, 2H), 7.47 - 7.33 (m, 1H), 7.31 -7.18 (m, 2H), 7.167.05 (m, 1H), 7.02 - 6.88 (m, 1H), 6.65 (br s, 1H), 4.42-4.14 (m, 1H), 3.11 2.97 (m, 1H), 2.89 - 2.76 (m, 1H), 2.73 -2.54 (m, 2H), 2.30-2.15 (m, 1H), 1.78 (m, 2H) , 1.65-1.57 (m, 1H), 1.54-1.34 (m, 1H), 1.32-1.16 (m, 1H) 82 7-{3-[(3S)-3[(4fluorophenyl)methyl]piperidine1carbonyl]pheny l}-5(trifluoromethyl)pyrrolo[2,11(][1,2,4]triazine-4-amine VO, 497.9 8.16 (s, 1H), 8.12-8.02 (m, 2H), 8.00 - 7.93 (m, 1H), 7.54 (br s, 2H), 7.47 - 7.34 (m, 1H), 7.33 - 7.20 (m, 2H) , 7.18-7.07 (m, 1H), 6.97 (br s, 1H), 6.73 - 6.61 (m, 1H), 4.45 - 4.29 (m, 1H), 3.62-3.50 (m, 1H), 3.11 -2.98 (m , 1H), 2.89 2.77 (m, 1H), 2.74 - 2.56 (m, 2H), 2.30 - 2.18 (m, 1H), 1.79 (m, 2H), 1.61 (br s, 1H), 1.54 - 1.35 (m , 1H), 1.32-1.18 (m, 1H)

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83 3-[4-amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine -7-yl]-M[(3R,4S)-4fluoro-1-(4hydroxyoxane4carbonyl)pyrr olidin-3yl]benzamide VFS 537.4 8.77 - 8.65 (m, 1H), 8.44 (s, 1H), 8.24 (br d, J=7.9Hz, 1H), 8.16 (s, 1H), 7.90 (brd, 1=7.6Hz, 1H), 7.61 ( t, J=7.9 Hz, 1H), 7.56 (s, 1H), 5.53 (s, 1H), 5.35-5.10 (m, 1H), 4.68 - 4.48 (m, 1H), 4.45 4.28 (m, 1H), 4.04-3.10 (m, 5H), 2.10-1.95 (m, 1H), 1.90-1.79 (m, 1H), 1.66-1.44 (m, 2H); 1 CH of pyrrolidine was not fully observed due to water suppression 84 3-[4-amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine -7-yl]-M[(3R,4S)-4fluoro-1-(1hydroxycyclopentanecarbonyl l)pyrrolidin3-yl]benzamide 521.2 8.75 (br dd, J=18.9, 6.7 Hz, 1H), 8.43 (s, 1H), 8.23 (br d, 1=7.6Hz, 1H), 8.15 (s, 1H), 7.91 (brd, 1=7.9Hz , 1H), 7.62 (t, >7.8Hz, 1H), 7.55 (s, 1H), 5.36 (s, 1H), 5.33 - 5.14 (m, 1H), 4.73 - 4.49 (m, 1H), 4.37 -3.67 (m, 3H), 3.52 (brt, 1=11.0Hz, 1H), 2.12 (br d, >6.7Hz, 1H), 2.00 - 1.83 (m, 1H), 1.80- 1.50 (m, 6H) 85 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-M[(3R,4S)-4φτορ-1-[Υ)3,3,3-trifluoro- 2- hydroxypropanoyl]pyrrolide in-3yl]benzamide Ycf ₃ η but 535.3 8.79 (br dd, J=16.2, 7.0 Hz, 1H), 8.42 (br s, 1H), 8.22 (brd, 1=7.6Hz, 1H), 8.14 (s, 1H), 7.89 (br d, J=7.6 Hz, 1H), 7.61 (t, >7.8Hz, 1H), 7.54 (s, 1H), 7.08 6.80 (m, 1H), 5.39-5.17 (m, 1H), 4.99-4.81 (m, 1H), 4.78 -4.58 (m, 1H), 4.21 (brt, J=9.3 Hz, 1H), 4.18-4.08 (m, 1H), 3.95 - 3.80 (m, 1H), 3.71 -3.48 (m, 1H)

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86 3-[4-amino-5(trifluoromethyl)pyrrolo[2, ΙΟΙ 1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(3,4difluorobenzoyl)-4fluoropyrrolidine n-3yl]benzamide 7%F 549.2 8.75 - 8.52 (m, 1H), 8.48 8.33 (m, 1H), 8.21 (br s, 1H), 8.13 (br s, 1H), 7.88 (brd, J=15.4 Hz, 1H), 7.60 (br s, 2H), 7.54 - 7.45 (m, 2H), 7.42 (br s, 1H), 5.485.08 (m, 1H), 4.90 - 4.53 (m, 1H), 4.08 -3.59 (m, 4H) 87 3-[4-amino-5(trifluoromethyl) pyrrolo[2, ΙΟ [1,2,4]triazin-7-yl]-Н- [(3R,4S)-4fluoro-1-(2hydroxy-2methylpropanoyl)pyrrolidin3-yl]benzamide, TFA l//n but 495.1 8.64-8.51 (m, 1H), 8.45 (br s, 1H), 8.24 (br d, J=7.7 Hz, 1H), 8.16 (s, 1H), 7.92 (brd, J=7.4 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.54 (s, 1H), 5.41 5.12 (m, 1H), 4.72 - 4.50 (m, 1H), 4.47 - 4.25 (m, 1H), 4.10-3.42 (m, 3H), 1.38 - 1.29 (m, 6H); water suppression closes one CH pyrrolidine 88 3-[4-amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazin-7-yl]-M- [(3R,4S)-4fluoro-1-(3fluoro-2,2dimethylpropan oil)pyrrolidi n-3yl]benzamide ^F \__, o '/' F 511.1 8.59 (brd, 4=6.2Hz, 1H), 8.45 (br s, 1H), 8.24 (br d, J=7.5 Hz, 1H), 8.16 (br s, 1H), 7.92 (br d, J=7.3 Hz , 1H), 7.61 (t, >7.9Hz, 1H), 7.53 (br s, 1H), 5.36–5.14 (m, 1H), 4.76–4.57 (m, 1H), 4.56–4.31 (m, 2H), 4.09-3.57 (m, 3H), 1.25 (br s, 3H), 1.23 (br s, 3H); water suppression closes one CH pyrrolidine 89 3-[4-amino-5(trifluoromethyl)pyrrolo[2, ΙΟ[1,2,4]triazine -7-ππ]-N[(3R,4S)-4fluoro-1-(2methylpropanoyl)pyrrolidin3-yl]benzamide 479.1 8.69 - 8.56 (m, 1H), 8.42 (br s, 1H), 8.22 (br d, 1=8.1Hz, 1H), 8.15-8.09 (m, 1H), 7.89 (br s, 1H), 7.64 - 7.57 (m, 1H), 7.51 (brs, 1H), 5.42-5.13 (m, 1H), 4.83 - 4.50 (m, 1H), 4.00 (br t, J=9.2 Hz, 1H), 3.93-3.77 (m, 2H), 3.76-3.71 (m, 1H), 2.76-2.59 (m, 1H), 1.02 (br s, 6H)

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90 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-X[(3R,4S)-l-(3,3dimethylbutanoyl)-4fluoropyrrolidine n-3yl]benzamide, TFA A--\ .o // 506.9 8.68 - 8.53 (m, IH), 8.43 (br s, IH), 8.23 (br d, J=7.6 Hz, IH), 8.15 (s, IH), 7.91 (br d, >7.7Hz, IH), 7.61 (brt, >7.7Hz, IH), 7.52 (s, IH), 5.41-5.13 (m, IH), 4.80 4.49 (m, IH), 4.07-3.48 (m, 4H), 2.28 - 2.07 (m, 2H ), 1.01 (s, 9H) 91 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-X[(3R,4S)-4fluoro-1-(2fluorobenzoyl)p irrolidin-3yl]benzamide ^F >-^\ /° T N-\ /=\ ⁿ 531.1 8.73-8.51 (m, IH), 8.48 8.34 (m, IH), 8.22 (br dd, J=18.1, 7.7 Hz, IH), 8.13 (brd, 1=11.9Hz, IH), 7.95 7.82 (m, IH ), 7.65 - 7.41 (m, 4H), 7.34 - 7.26 (m, 2H), 5.46-5.12 (m, IH), 4.88 -4.56 (m, IH), 4.06 3.50 (m, 4H) 92 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl]-Н- [(3R,4S)-4fluoro-1-(3fluorobenzoyl)p irrolidin-3yl]benzamide F 531.1 8.75-8.51 (m, IH), 8.47 8.33 (m, IH), 8.20 (br s, IH), 8.11 (br s, IH), 7.95 7.82 (m, IH), 7.59 (brd, >6.2Hz, IH ), 7.55-7.44 (m, 2H), 7.41-7.26 (m, 3H), 5.46-5.14 (m, IH), 4.85-4.55 (m, IH), 4.08 3.60 (m, 4H) 93 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-X[(3R,4S)-4fluoro-1-(1fluorocyclobuta ncarbonyl)pyrolidin-3yl]benzamide M 509.1 8.63 (brd, J=5.3Hz, IH), 8.42 (br s, IH), 8.22 (br d, >7.0Hz, IH), 8.14 (s, IH), 7.90 (brd, 4=7.6Hz, IH) , 7.60 (t, >7.8Hz, IH), 7.51 (s, IH), 5.40-5.12 (m, IH), 4.82-4.55 (m, IH), 3.99 - 3.55 (m, 4H), 2.78 - 2.65 (m, IH), 2.65 -2.56 (m, IH), 2.48 - 2.23 (m, 2H), 1.88 (br dd, J=10.1, 3.9 Hz, IH), 1.67 - 1.47 (m, IH)

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94 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-ππ]-N[(3R,4S)-l-(3,5difluoropyridium n-4-carbonyl)4fluoropyrrolidium n-3yl]benzamide H Ά R N 550.0 8.78 - 8.57 (m, 3H), 8.45 8.33 (m, 1H), 8.19 (brdd, J=17.5, 7.7 Hz, 1H), 8.10 (brd, 1=11.8Hz, 1H), 7.927.80 (m, 1H ), 7.64 - 7.53 (m, 1H), 7.48 (brd, J=19.7 Hz, 1H), 5.46-5.15 (m, 1H), 4.88 - 4.66 (m, 1H), 4.10-3.80 (m, 4H) 95 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-X[(3R,4S)-4fluoro-1-[1(trifluoromethyl)cyclobutanecarbonyl]pyrroles 7/ /D ³ 559.2 8.62 (br s, 1H), 8.44 (br s, 1H), 8.29 - 8.21 (m, 1H), 8.16 (s, 1H), 7.92 (brd, J=7.1 Hz, 1H), 7.62 (t, J= 7.8 Hz, 1H), 7.53 (s, 1H), 5.40 5.17 (m, 1H), 4.84 - 4.54 (m, 1H), 3.87 -3.52 (m, 4H), 2.84-2.63 (m, 2H), 2.48 - 2.35 (m, 2H), 2.08 1.95 (m, 1H), 1.81 (brd, din-3 yl]benzamide J=9.5Hz, 1H) 3-[4-amino-5(trifluoromethyl) 8.72 (br dd, J=16.2, 7.0 Hz, pyrrolo[2,1- 1H), 8.46 (s, 1H), 8.27 (br d, P[1,2,4]triazine J=6.1 Hz, 1H), 8.19 (br s, -7-yl]-X- a ⁰ 1H), 7.93 (br d, J=7.6 Hz, 96 [(3R,4S)-4- 497.1 1H), 7.63 (t, >7.8Hz, 1H), fluoro-1-(2- _F -v 7.58 (s, 1H), 5.40-5.16 (m, fluoro-2- 1H), 4.83 -4.58 (m, 1H), methyl propanoic 4.24-3.36 (m, 4H), 1.62- l) pyrrolidine- 1.49(m, 6H). 3-yl]benzamide 3-[4-amino-5(trifluoromethyl) 8.75 (br dd, J=18.8, 6.9 Hz, pyrrolo[2,1- 1H), 8.47 (s, 1H), 8.27 (br d, 1][1,2,4]triazine >7.6Hz, 1H), 8.18(s, 1H), -7-yl]-X- 7.93 (brd, >7.0Hz, 1H), 97 [(3R,4S)-4- Vf 495.2 7.63 (brt, >7.8Hz, 1H), fluoro-1-(1- <r ^F 7.58(s, 1H), 5.44-5.19(m, fluorocycloprop 1H), 4.87-4.60 (m, 1H), ancarbonyl)pi 4.29-3.29 (m, 4H), 1.46- rrolidin-3yl]benzamide 1.08 (m, 4H).

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98 3-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl]-M- [(3R,4S)-4fluoro-1-(3,3,3trifluoropropane oil)pyrrolidi n-3yl]benzamide, TFA H F ₃ C 519.2 8.67 (br dd, J=18.7, 6.9 Hz, 1H), 8.43 (s, 1H), 8.23 (br d, 1=7.7Hz, 1H), 8.14 (s, 1H), 7.90 (brd, >7.8Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 7.52 (s, 1H), 5.41-5.18 (m, 1H), 4.80-4.55 (m, 1H). 99 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-M[(3R,4S)-4fluoro-1-[1(trifluoromethyl)cyclopentane rbonyl]pyrrole idin-3yl]benzamide ^F V-% /° An ^cf _s 573.2 8.74 (brd, >5.2Hz, 1H), 8.45 (s, 1H), 8.25 (br d, J=5.2Hz, 1H), 8.17 (s, 1H), 7.91 (brd, J=7.3Hz, 1H), 7.62 (brt, >7.8Hz, 1H), 7.56 (s, 1H), 5.35 -5.14 (m, 1H), 4.78 -4.54 (m, 1H), 4.29-3.29 (m, 4H), 2.46 - 1.48(m, 8H). 100 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-M[(3R,4S)-4fluoro-1-(3fluorocyclobuta ncarbonyl)pyrolidin-3yl]benzamide F 509.0 8.78 - 8.65 (m, 1H), 8.45 (s, 1H), 8.26 (br d, J=7.6Hz, 1H), 8.18 (s, 1H), 7.91 (brd, 1=7.9Hz, 1H), 7.61 ( brt, 1=7.6Hz, 1H), 7.58 (s, 1H), 5.41-4.99 (m, 2H), 4.83-4.54 (m, 1H), 3.90-3.79 (m, 1H), 3.79-3.54 (m, 2H ), 3.54-3.40 (m, 1H), 2.54 (s, 2H), 2.49-2.31 (m, 3H) 101 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-M[(3R,4S)-4fluoro-1-(3fluorocyclobuta ncarbonyl)pyrolidin-3yl]benzamide F 509.0 8.68 - 8.54 (m, 1H), 8.45 (s, 1H), 8.25 (br d, J=7.7Hz, 1H), 8.16 (s, 1H), 7.92 (brd, 1=7.7Hz, 1H), 7.66- 7.58 (m, 1H), 7.54 (s, 1H), 5.41 5.15 (m, 1H), 5.12-4.87 (m, 1H), 4.84 -4.55 (m, 1H), 3.95 - 3.56 (m, 3H), 3.55 - 3.40 (m, 1H), 2.86 2.67 (m, 1H), 2.64 - 2.54 (m, 2H), 2.38 - 2.15 (m, 2H)

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102 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazin-7-yl]-M- [(3R,4S)-4fluoro-1-(4fluorocyclohex ancarbonyl)pyrrolidin-3yl]benzamide R F 537.2 8.75 - 8.65 (m, 1H), 8.45 (s, 1H), 8.26 (br d, J=7.9 Hz, 1H), 8.17 (s, 1H), 7.91 (br d, J=7.9 Hz, 1H), 7.62 (td, J=7.6, 3.1Hz, 1H), 7.57 (s, 1H), 5.42-5.14 (m, 1H), 4.95.4.54 (m, 2H), 4.05 (br t, J=9.3 Hz, 1H) , 3.98-3.48 (m, 3H), 3.17 (d, >5.2Hz, 1H), 2.00-1.86 (m, 2H), 1.72-1.43 (m, 5H); 1 CH pyrrolidine was not observed due to water suppression 103 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazin-7-yl]-M- [(3R,4S)-4fluoro-1-(4fluorocyclohex ancarbonyl)pyrrolidin-3yl]benzamide F 537.3 8.76 - 8.64 (m, 1H), 8.45 (s, 1H), 8.26 (br d, J=7.9 Hz, 1H), 8.17 (s, 1H), 7.947.88 (m, 1H), 7.66 - 7.58 (m , 1H), 7.57 (s, 1H), 5.42 5.14 (m, 1H), 4.87 - 4.40 (m, 2H), 4.04 (br t, J=9.2 Hz, 1H), 3.97 - 3.83 (m, 1H), 3.82-3.73 (m, 1H), 3.73 - 3.58 (m, 1H), 2.47 2.33 (m, 1H), 2.06 (br d, J=5.5 Hz, 2H), 1.91 - 1.68 (m, 2H), 1.58 - 1.32(m, 4H) 104 105 106 107 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazin-7-yl]^- [(3R,4S)-4fluoro-1-(4fluorobenzoyl)p irrolidin-3yl]benzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazine -7-yl]-M[(3R,4S)-l-(4,4difluorocyclohe xancarbonyl)4fluoropyrrolidine n-3yl]benzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazine -7-yl]-M[(3R,4S)-l-(3,3difluorocyclop entancarbonyl)- 4fluoropyrrolidi n-3yl]benzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazine -7-ππ]-N[(3R,4S)-l-(2,2difluorocycloprop opanecarbonyl)4fluoropyrrolidine n-3yl]benzamide ^F S^-\ .0 F ^F Sx P K F 531.4 555.4 541.2 513.3 8.74 - 8.50 (m, 1H), 8.49 8.35 (m, 1H), 8.23 (br s, 1H), 8.14 (s, 1H), 7.977.82 (m, 1H), 7.67 - 7.55 (m, 3H), 7.52 (br s, 1H), 7.28 (brt, .1=8.8 Hz, 2H), 5.45-5.15 (m, 1H), 4.86 4.56 (m, 1H), 3.93 (br s, 1H), 3.83 (br d , 1=17.5Hz, 1H), 3.76-3.61 (m, 1H), 3.46-3.38 (m, 1H) 8.80 - 8.68 (m, 1H), 8.43 (s, 1H), 8.24 (br d, J=7.3 Hz, 1H), 8.15 (s, 1H), 7.90 (brd, 1=7.6Hz, 1H), 7.61 (td, J=7.6, 4.6 Hz, 1H), 7.55 (s, 1H), 5.45 -5.13 (m, 1H), 4.85 -4.55 (m, 1H), 4.06 (br t, 1=9.2Hz, 1H), 4.00- 3.89 (m, 1H), 3.88 -3.68 (m, 1H), 3.68 - 3.36 (m, 1H), 2.72 - 2.57 (m, 1H), 2.05 (br s, 2H), 1.95 - 1.70 (m, 4H) , 1.58 (br d, J=6.4 Hz, 2H) 8.62 (br dd, J=17.6, 6.9 Hz, 1H), 8.45 (s, 1H), 8.26 (br d, >7.8Hz, 1H), 8.17 (s, 1H), 7.92 (brd, >7.8Hz, 1H ), 7.62 (td, J=7.7, 3.5 Hz, 1H), 7.55 (s, 1H), 5.44-5.13 (m, 1H), 4.83-4.60 (m, 1H), 4.12-3.98 (m, 1H), 3.98 3.83 (m, 2H), 3.82-3.58 (m, 2H), 2.41 -2.26 (m, 2H), 2.24 -2.14 (m, 1H), 2.13 -2.06 (m, 2H), 1.93 - 1.75(m, 1H) 8.87 - 8.72 (m, 1H), 8.46 (br s, 1H), 8.26 (br d, J=7.6 Hz, 1H), 8.17 (s, 1H), 7.97 7.88 (m, 1H), 7.63 (td, J =7.7, 2.6 Hz, 1H), 7.59 7.55 (m, 1H), 5.46-5.17 (m, 1H), 4.91-4.63 (m, 1H), 4.28-4.08 (m, 1H), 4.07-3.91 (m, 1H), 3.90 3.80 (m, 1H), 3.78-3.62 (m, 1H), 3.12-2.84 (m, 1H), 2.03 - 1.81 (m, 2H)

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108 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine -7-yl]-X[(3R,4S)-l-(3,3difluorocyclobu tankcarbonyl)4fluoropyrrolidine n-3yl]benzamide ^F V^X /° l Χ/Λ /-7 n Y- _F F 527.0 8.76 (br dd, J=19.2, 7.0Hz, 1H), 8.42 (s, 1H), 8.22 (br d, 1=7.6Hz, 1H), 8.14 (s, 1H), 7.89 (brd, 1=7.6Hz , 1H), 7.61 (td, J=7.8, 2.1Hz, 1H), 7.54 (s, 1H), 5.39-5.13 (m, 1H), 4.83-4.53 (m, 1H), 3.90 (brt, J=9.2 Hz, 1H)

Connections in the table. 3 was made by the methods detailed in Example 31. Where a tertiary amide was made, all of the amine will be shown. When the diastereomers were separated, they were included as separate data.

Table 3

Example Name R Observe May in MS the mass of the ion Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 109 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazin-7yl ]-2-methoxy-H(3ph enylbutyl)pyride in-3-carboxamide G 484.9 8.92 - 8.85 (m, 1H), 8.75 8.68 (m, 1H), 8.32 - 8.24 (m, 1H), 8.20 - 8.13 (m, 1H), 7.62 - 7.55 (m, 1H), 7.34 - 7.24 (m, 4H), 7.22 7.14 (m, 1H), 4.02 (s, 3H), 3.24-3.14 (m, 1H), 2.86 2.75 (m, 1H), 2.55 (s, 2H), 1.87-1.77 (m, 2H) , 1.271.20 (m, 3H) 110 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-(1-benzyl1H-pyrazol-4-yl)2-methoxypyridine3-carboxamide GO 509.1 10.30 (s, 1H), 8.97-8.86 (m, 1H), 8.78 - 8.66 (m, 1H), 8.24 - 8.07 (m, 2H), 7.67 - 7.56 (m, 2H), 7.41 7.19 (m, 5H) , 5.38 - 5.26 (m, 2H), 4.06 -3.97 (m, 3H)

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111 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2-MeTOKCH-N [3-(2methylpropoxy)propyl]pyridine-3 carboxamide 466.9 8.86 (d, 1=2.1Hz, 1H), 8.72 (d, J=2.1Hz, 1H), 8.38 (br. s., 1H), 8.15 (s, 1H), 7.57 (s, 1H), 4.01 ( s, 3H), 3.43 (t, J=6.1Hz, 1H), 3.36 (d, J=6.1Hz, 2H), 3.14 (d, 1=6.6Hz, 2H), 1.85-1.69 (m, 3H), 0.84 (d, J=6.6 Hz, 6H). 112 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-[3-(tert-butoxy)propyl]-2methoxypyride in-3 carboxamide 466.9 8.88 (d, J=2.0Hz, 1H), 8.75 (d, J=2.0Hz, 1H), 8.30 (t, J=5.2Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 4.02 (s, 3H), 1.71 (t, 1=6.4Hz, 2H), 1.14 (s, 9H). FROM 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-[3-(4fluorophenoxy)propyl]-2methoxypyride in-3 carboxamide 0 "P 505.2 8.88 (d, J=2.2Hz, 1H), 8.73 (d, J=2.2Hz, 1H), 8.45 (t, J=5.4Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.12 (t, J=8.8 Hz, 2H), 6.96 (dd, J=8.9, 4.3 Hz, 2H), 4.10-3.96 (m, 5H), 3.53 - 3.42 (m, 1H), 2.05 - 1.93 (m, 2H). 114 in- 3 carboxamide 472.9 10.33 - 10.27 (m, 1H), 8.98 - 8.90 (m, 1H), 8.81 -8.74 (m, 1H), 8.23 -8.16 (m, 1H), 8.15-8.08 (m, 1H), 7.68 -7.56 (m, 2H), 4.10- 4.01 (m, 3H), 3.96 (d, J=7.1 Hz, 2H), 1.30-1.17 (m, 1H), 0.60 - 0.48 (m, 2H), 0.37 (br d, J=4.5 Hz, 2H) 115 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1] [ 1,2,4]triazin-7yl ] -2-MeTOKCH-N [1-(2,2,2trifluoroethyl)-1Hpyrazol-4yl]pyridine-3 carboxamide ^CFs ID ⁿ 501.1 10.49 - 10.39 (m, 1H), 9.00 - 8.91 (m, 1H), 8.80 - 8.71 (m, 1H), 8.30 - 8.22 (m, 1H), 8.21 - 8.14 (m, 1H), 7.78 - 7.70 (m , 1H), 7.68 7.58 (m, 1H), 5.21 - 5.08 (m, 2H), 4.09 - 3.98 (m, 3H)

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116 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazine-7- HE 487 1 8.94 - 8.85 (m, 1H), 8.82 8.71 (m, 1H), 8.63 - 8.48 (m, 1H), 8.26 - 8.08 (m, 1H), 7.64 - 7.53 (m, 1H), 7.42 - 7.32 (m, 4H), 7.29 - 117 yl]-M-(3-hydroxy3-phenylpropyl)-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7yl]-N-(3-hydroxy3-phenylpropyl)-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7wi]-N-{[(1S,2S)-2- 1 o s 71 487.2 7.18 (m, 1H), 5.54-5.40 (m, 2H), 4.79 - 4.60 (m, 1H), 409-3.95 (m, 6H), 3.55 - 3.33 (m, 1H), 1.95 1.76 (m, 2H ) 8.94 - 8.85 (m, 1H), 8.82 8.71 (m, 1H), 8.63 - 8.48 (m, 1H), 8.26 - 8.08 (m, 1H), 7.64 - 7.53 (m, 1H), 7.42 - 7.32 (m, 4H), 7.29 7.18 (m, 1H), 5.54-5.40 (m, 2H), 4.79 - 4.60 (m, 1H), 4.09-3.95 (m, 6H), 3.55 - 3.33 (m, 1H), 1.95 1.76 (m, 2H) 8.89 (s, 1H), 8.75 (s, 1H), 8.55 (br. s., 1H), 8.15 (s, 1H), 7.84 (s, 1H), 7.78 (s, 118 [3,5bis(trifluoromethyl)phenyl]cyclopropyl]methyl}-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7- For CF ₃ 619.3 2H), 7.60 (s, 1H), 3.99 (s, 3H), 2.22 (d, J=4.0 Hz, 1H), 1.56 (br. s., 1H), 1.23 (br. s., 2H), 1.14 (d, >5.2Hz, 1H). 8.91 -8.86 (m, 1H), 8.75 - 8.63 (m, 1H), 8.39 (br d, J=7.2 Hz, 1H), 8.16 (s, 1H), 7.63 - 7.57 (m, 1H), 7.33 (br d, >3.6Hz, 4H), 7.30- 7.22 119 m]-N-[(3S)-1benzylpyrrolidin3-yl]-2methoxypyride in-3 carboxamide 512 (m, 1H), 4.42 - 4.34 (m, 1H), 4.03 (s, 3H), 3.683.52 (m, 1H), 2.76 - 2.66 (m, 2H), 2.49-2.41 (m, 3H), 2.30 -2.17 (m, 1H), 1.72 (brd, J=6.1Hz, 1H)

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120 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R)-lbenzylpyrrolidin3-yl]-2methoxypyride in-3 carboxamide 512.2 8.91 - 8.85 (m, 1H), 8.72 8.66 (m, 1H), 8.43 - 8.36 (m, 1H), 8.19-8.13 (br, 1H), 7.63 - 7.56 (m, 1H), 7.37 - 7.30 (m, 4H), 7.29 7.21 (m, 1H), 4.44 - 4.34 (m, 1H), 3.69 - 3.54 (br, 1H), 2.75 - 2.67 (m, 2H), 2.49-2.41 (w, W), 2.302.17 (m, 1H), 1.76-1.68 (m, 1H) 121 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7- nn]-N-[(3S)-lbenzoylpyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide 526.2 8.92 - 8.86 (m, 1H), 8.67 8.48 (m, 2H), 8.21-8.13 (m, 1H), 7.60 (brd, J=15.9 Hz, 1H), 7.55 - 7.48 (br, 2H), 7.47 - 7.39 (w, W), 4.59-4.52 (m, 1H), 4.444.34 (m, 1H), 4.04-3.94 (w, W), 3.81-3.66 (w, 1H), 3.61-3.33 (w, 1H) , 2.25-2.12 (m, 1Н), 2.06- 1.91 (m, 1H) (peaks lost with solvent suppression) 122 7-{5-[(3S)-3-[(4fluorophenyl)methyl]piperidine-1carbonyl]-6methoxypyride in-3yl}-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine- 4amine 0 b 528.9 8.92 - 8.78 (m, 1H), 8.35 8.24 (m, 1H), 8.21 - 8.09 (m, 1H), 7.65 - 7.52 (br, 1H), 7.33 - 7.21 (m, 1H), 7.12 (brt, >8.7 Hz, 1H), 7.04 (br s, 1H), 6.98 - 6.84 (m, 1H), 6.57 (br s, 1H), 4.47-4.11 (m, 1H), 4.01 3.79 (br, 3H), 3.50-3.40 (m, 1H), 3.32-3.06 (br, 1H), 3.06-2.84 (m, 1H), 2.79-2.56 (m, 2H), 2.402.14 (m, 1H), 1.85-1.65 (br, W) , 1.63-1.52 (w, 1H), 1.49-1.33 (m, 1H), 1.29-1.15 (m, 1H)

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123 7-{5-[(3R)-3-[(4fluorophenyl)methyl]piperidine-1carbonyl]-6methoxypyride in-3yl}-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine- 4amine Ύτα, 528.9 8.92 - 8.79 (m, 1H), 8.37 8.24 (m, 1H), 8.22-8.11 (m, 1H), 7.63 -7.54 (m, 1H), 7.27 (br s, 1H), 7.187.08 (m, 1H ), 7.08 - 6.99 (m, 1H), 6.99 -6.83 (m, 1H), 6.63 - 6.50 (m, 1H), 4.55-4.11 (m, 1H), 3.99 3.81 (m, 3H), 3.31 -2.84 ( m, 2H), 2.79 - 2.58 (m, 2H), 1.86 - 1.66 (m, 3H), 1.65 - 1.53 (m, 1H), 1.501.36 (m, 1H), 1.25 (brd, >10.4Hz, 1H ) 124 7-[5-(3benzylpyrrolidine1-carbonyl)-6methoxypyride in-3 yl]-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-4amine O 497.2 8.90-8.83(m, 1H), 8.35(dd, J=9.3, 2.0 Hz, 1H), 8.19-8.12(m, 1H), 7.63-7.55 (m, 1H), 7.36 - 7.09 (m, 5H), 4.00 - 3.91 (m, 3H), 3.65 - 3.39 (m, 1H), 3.323.09 (m, 2H), 2.97 - 2.89 (m, 1H) , 2.75 - 2.67 (m, 1H), 2.65 - 2.57 (m, 1H), 2.48 - 2.41 (m, 1H), 1.89 (br s, 1H), 1.70 - 1.53 (m, 1H) 125 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-T4-[3-(4fluorophenyl)-3hydroxypropyl] 2-methoxypyridine3-carboxamide He 505.2 1HNMR(400 MHz, CD3OD) δ 8.93 (q, J=2.5 Hz, 2H), 8.04 (s, 1H), 7.59 (s, 1H), 7.38 (dd, J=8.5, 5.4 Hz, 2H), 7.29 ( s, 1H), 7.02 (t, >8.8Hz, 2H), 4.884.77 (m, 1H), 4.21 -4.13 (m, 3H), 2.04 (d, J=6.5 Hz, 2H) 126 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-methoxy-X[(2-phenyloxan-3 yl)methyl]pyridine3-carboxamide he ^a _F 1H NMR (400 MHz, CD3OD) δ 8.93 (q, J=2.5 Hz, 2H), 8.04 (s, 1H), 7.59 (s, 1H), 7.38 (dd, J=8.5, 5.4 Hz, 2H), 7.29 (s, 1H), 7.02 (t, >8.8Hz, 2H), 4.884.77 (m, 1H), 4.21 -4.13 (m, 3H), 2.04 (d, J=6.5Hz, 2H) 127 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-methoxy-X[(2-phenyloxan-3 yl)methyl]pyridine3-carboxamide 0 527.2 8.83 (d, 1=2.1Hz, 1H), 8.63 (d, J=2.1Hz, 1H), 8.13 (s, 1H), 8.03 (d, J=5.5Hz, 1H), 7.55 (s, 1H), 7.40 - 7.28 (m, 4H), 7.21 (d, J=6.1 Hz, 1H), 4.67 (s, 1H), 4.12 (d, J=7.3 Hz, 1H), 3.97 (s, 3H), 2.902.78 (m, 1H), 2.23 (br. s., 1H), 2.00-1.86 (m, 2H), 1.82 (d, J=12.5 Hz, 1H), 1.37 (d, J=13.1 Hz, 1H). 128 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-methoxy-X[(2-phenyloxan-3 yl)methyl]pyridine3-carboxamide 527.1 8.83 (d, 1=2.1Hz, 1H), 8.63 (d, J=2.1Hz, 1H), 8.13 (s, 1H), 8.03 (d, J=5.5Hz, 1H), 7.55 (s, 1H), 7.40 - 7.28 (m, 4H), 7.21 (d, J=6.1 Hz, 1H), 4.67 (s, 1H), 4.12 (d, J=7.3 Hz, 1H), 3.97 (s, 3H), 2.902.78 (m, 1H), 2.23 (br. s., 1H), 2.00-1.86 (m, 2H), 1.82 (d, J=12.5 Hz, 1H), 1.37 (d, J=13.1 Hz, 1H). 129 7-(5-{3-[(3fluorophenyl)methyl]piperidine-1carbonyl}-6methoxypyride in-3yl)-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-4- amine 529.3 8.91-8.83 (m, 1H), 8.398.31 (m, 1H), 8.19-8.12 (m, 1H), 7.62 -7.56 (m, 1H), 7.35 - 7.09 (m, 5H), 3.99-3.91 (m , 3H), 3.663.37 (m, 3H), 3.32-3.10 (m, 2H), 2.98-2.88 (m, 1H), 2.76-2.67 (m, 1H), 2.64-2.57 (m, 1H), 2.48 2.41 (m, 1H), 2.01 - 1.82 (m, 1H), 1.69 - 1.53 (m, 1H)

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130 7-(6-methoxy-5-{3[(4methylphenyl)methyl]piperidine-1carbonyl}pyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-4- amine / 525.2 8.94 - 8.77 (m, 1H), 8.34 8.09 (m, 2H), 7.67 - 7.49 (m, 1H), 7.16-7.04 (t, 2H), 6.96-6.81 (m, 1H), 6.76 - 6.67 (m, 1Н), 6.59 6.47 (m, 1Н), 4.48 - 4.09 (m, 1Н), 3.98 - 3.80 (t, ZN), 3.31 - 3.07 (m, 1Н), 3.05 -2.85 (m, 1Н), 2.77 2.59 ( m, 1H), 2.45-2.36 (m, 1H), 2.31-2.21 (t, 2H), 2.19-2.08 (t, 1H), 1.99-1.90 (t, 1H), 1.86 1.65 (t, 3H), 1.62 -1.51 (t, 1H), 1.47-1.31 (t, 1H), 1.27-1.13 (t, 1H) 131 132 133 134 7-(6-methoxy-5-{3[(4methoxyphenyl)methyl]piperidine-1carbonyl}pyridine-3-yl)-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazine-4amine 7-(5-{3-[(4chlorophenyl)methyl]piperidin-1carbonyl}-6methoxypyride in-3yl)-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-4amine 7-{5-[(3S)-3-[(3fluorophenyl)methyl]piperidine-Hcarbonyl]-6methoxypyride in-3yl}-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine -4amine 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazin-7yl]-H-[3-(3,4difluorophenyl)-3hydroxypropyl] 2-methoxypyridine3-carboxamide 'Ag I 4 r r P " \ 541.2 544.9 529 522.8 8.96 - 8.79 (t, 1H), 8.36 8.23 (t, 1H), 8.21 - 8.10 (t, 1H), 7.68 - 7.53 (t, 1H), 7.19-7.07 (t, 1H), 6.96 - 6.83 (t, 1H), 1Н), 6.79 (br d, J=7.7 Hz, 1Н), 6.68 (br d, J=7.5 Hz, 1Н), 6.42 - 6.32 (t, 1Н), 4.49 -4.14 (t, 1Н), 4.02-3.80 (t, GL), 3.73 (s, GL), 3.32-3.21 (t, 1Н), 3.20-3.07 (t, 1Н), 3.06-2.81 (t, 1Н), 2.792.61 (t, 1Н), 2.47 - 2.33 (t, 1H), 2.32 -2.10 (t, 1H), 1.85 - 1.62 (t, 2H), 1.59 (br s, 2H), 1.33 - 1.11 (t, 1H) 8.96 - 8.77 (t, 1H) , 8.36 8.10 (t, 2H), 7.66-7.52 (t, 1H), 7.37 (brd, J=7.9 Hz, 1H), 7.30 - 7.23 (t, 1H), 7.20-7.12 (t, 1H), 7.04 ( brd, J=7.3 Hz, 1Н), 6.96 - 6.87 (t, 1Н), 6.84 6.74 (t, 1Н), 4.47-4.11 (t, 1Н), 3.99 -3.82 (t, ZN), 3.33 -3.22 (t , 1H), 3.19–2.86 (t, 1H), 2.83–2.58 (t, 2H), 2.40–2.15 (t, 1H), 1.88–1.66 (t, 3H), 1.66–1.34 (t, 1H), 1.33– 1.17 (t, 1H) 8.88 (br s, 1H), 8.37 - 8.24 (t, 1H), 8.22 - 8.07 (t, 1H), 7.64 - 7.52 (t, 1H), 7.33-7.21 (t, 1H), 7.13 (br t, J=8.6 Hz, 2Н), 7.08 - 7.00 (t, 1Н), 7.00 -6.88 (t, ZN), 6.56 (br s, ZN), 4.47 4.12 (t, 1Н), 4.00- 3.79 (t, 3H), 3.31-3.21 (t, 1H), 3.19-2.84 (t, 1H), 2.80-2.63 (t, 1H), 2.362.25 (t, 1H), 2.25-2.13 (t, 1H ), 1.85 - 1.65 (t, 2H), 1.63 - 1.54 (t, 1H), 1.51 - 1.34 (t, 1H), 1.341.15 (t, 2H) 1HNMR (400 MHz, CD ₃ OD) δ 8.97 - 8.87 (t, 2H), 8.02 (s, 1H), 7.38 (s, 2H), 7.29 - 7.21 (t, 1H), 7.14-7.03 (t, 2H), 4.74 (dd, J=8.7, 4.0 Hz, 1H ), 4.22 -4.11 (t, GL), 3.77-3.61 (t, 1Н), 3.56 -3.45 (t, 1Н), 2.12-1.84 (t, 2Н)

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135 136 137 138 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7- ηπ]-N-[3-(3,4difluorophenyl)-3hydroxypropyl] 2-methoxypyridine3-carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1D][1,2,4]triazin-7yl]-N-( 1 -benzyl-2 oxopyrrolidin-3 yl)-2methoxypyride in-3 carboxamide, 2 TFA 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-N-(1-benzyl-5oxopyrrolidine-3- yl)-2methoxypyride in-3carboxamide 7-[5-(3-benzyl-4,4difluoropiperidine1-carbonyl)-6methoxypyride in-3 - silt]-5- (trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazine-4amine, 2 TFA Oh o// Vo d 522.7 526.1 526.1 547.3 1Н NMR (400 MHz, CD3OD) δ 8.97 - 8.87 (m, 2Н), 8.02 (s, 1Н), 7.38 (s, 2H), 7.29 - 7.21 (m, 1H), 7.14-7.03 (m, 2H), 4.74 (dd, J=8.7, 4.0 Hz, 1H), 4.22 -4.11 (m, 3H), 3.77-3.61 (m, 1H), 3.56 -3.45 (m, 1H), 2.12 - 1.84 (m, 2H) 8.92 (d, J=2.6Hz, 1H), 8.83 (d, >2.2Hz, 1H), 8.58 (d, >7.0Hz, 1H), 8.18 (s, 1H), 7.58 (s, 1H), 7.40 - 7.34 (m, 2H), 7.33 - 7.24 (m, 3H), 4.65 -4.59 (m, 1H), 4.45 (s, 2H), 4.09 (s, 3H), 3.323.24 (m, 2H, partially suppressed), 2.48 - 2.41 (m, 1H), 2.09-2.01 (m, 1H) 8.90 (d, J=2.6Hz, 1H), 8.63 (d, >2.6Hz, 1H), 8.51 (br d, >6.6Hz, 1H ), 8.16 (s, 1H), 7.55 (s, 1H), 7.38 7.31 (m, 2H), 7.31-7.25 (m, 3H), 4.61 -4.55(m, 1H), 4.49 - 4.44 (m, 1H) , 4.39 (d, >15.0Hz, 1H), 4.01 (s, 3H), 3.64 (dd, J=10.1, 7.5 Hz, 1H), 3.273.16 (m, 1H, predominantly suppressed), 2.77 (dd, J =17.1, 8.6 Hz, 1H), 2.47 (d, J=5.5 Hz, 1H) 8.93 (br s, 1H), 8.43 - 8.32 (m, 1H), 8.24-8.12 (m, 2H), 7.76-7.51 ( m, 2H), 7.40–7.23 (m, 4H), 7.11 (br s, 1H), 7.05–6.96 (m, 1H), 6.91–6.81 (m, 1H), 6.766.67 (m, 1H), 4.61 - 4.37 (m, 1H), 4.33 - 4.22 (m, 1H), 4.19-4.00 (m, 1H), 3.99-3.93 (m, 2H), 3.88 3.79 (m, 1H), 3.67 (br s, 1H ), 3.30-3.12 (m, 1H), 3.09-2.91 (m, 2H), 2.42 2.20 (m, 3H), 2.13-1.94 (m, 2H) 139 7-[5-(2- benzylmorpholine-4carbonyl)-6methoxypyride in-3yl]-5- (trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazine-4amine, TFA E % 513 8.91 (s, 1H), 8.36 (br s, 1H), 8.16 (s, 1H), 7.60 (s, 2H), 7.37 - 6.92 (m, 5H), 4.33 (br s, 1H), 4.02-3.87 ( m, 2H), 3.87-3.72 (m, 1H), 3.72 3.57 (m, 1H), 3.49-3.39 (m, 1H), 3.18 (brd, J=4.9 Hz, 2H), 2.95 (br s, 1H) , 2.84 (brd, >5.8 Hz, 1H), 2.58 -2.54 (m, 3H) 140 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7Hn]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl] 2-methoxypyridine3-carboxamide He 521.2 8.89 (d, J=2.3Hz, 1H), 8.78 (d, J=2.4Hz, 1H), 8.51 (brt, J=5.3Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.39 (s, 4H), 5.52 (d, J=4.3 Hz, 1H), 4.74 - 4.68 (m, 1H), 4.04 (s, 3H), 3.42-3.35 (m, 2H), 1.92- 1.79(m, 2H).

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141 5-[4-amino-5(trifluoromethyl)pyr rolo[2, ΙΟ [1,2,4]triazin-7yl ]-2-MeTOKCH-N (4,4,4-trifluoro-3hydroxy-3phenylbutyl)pyride in-3-carboxamide f 555.2 1HNMR, racemic compound (400 MHz, CDC1 ₃ ) δ 8.88 (d, J=2.4 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H), 8.28 (t, >5.8 Hz, 1H), 8.12 (s , 1H), 7.63 (d, J=7.7 Hz, 2H), 7.44 - 7.34 (m, 3H), 7.34-7.29 (m, 1H), 4.19 (s, 3H), 3.58 (dt, J=14.0, 7.0 Hz, 1H), 3.52 - 3.36 (m, 1H), 2.72 (dt, J=14.3, 7.3 Hz, 1H), 2.41 (dt, J=14.6, 5.7 Hz, 1H) 142 5-[4-amino-5(trifluoromethyl)pyr rolo[2, ΙΟ [1,2,4]triazin-7yl] -2-methoxy-K (4,4,4-trifluoro-3hydroxy-3phenylbutyl) pyride in-3-carboxamide f 555.2 1HNMR, racemic compound (400 MHz, CDCh) δ 8.88 (d, J=2.4 Hz, 1H), 8.91 (d, J=2.3 Hz, 1H), 8.28 (t, 4=5.8 Hz, 1H), 8.12 (s , 1H), 7.63 (d, J=7.7 Hz, 2H), 7.44 - 7.34 (m, 3H), 7.34-7.29 (m, 1H), 4.19 (s, 3H), 3.58 (dt, J=14.0, 7.0 Hz, 1H), 3.52 - 3.36 (m, 1H), 2.72 (dt, J=14.3, 7.3 Hz, 1H), 2.41 (dt, J=14.6, 5.7 Hz, 1H) 143 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1Ι] [1,2,4]triazin-7yl] -2-MeTOKCH-N {2[methyl(phenyl)amine o]ethyl } pyridine-3 carboxamide R — 486.1 8.98 - 8.82 (m, 1H), 8.82 8.61 (m, 1H), 8.47 - 8.25 (m, 1H), 8.24 - 8.00 (m, 1H), 7.62 - 7.43 (m, 1H), 7.23 - 7.06 (m, 2H), 6.92 6.78 (m, 2H), 6.65 - 6.52 (m, 1H), 4.08 -3.98 (m, 3H), 3.60-3.44 (m, 2H), 3.22-3.14 (m, 2H), 3.97 (s , 3H). 144 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazin-7yl]-M-(1-tert-butyl-1H-pyrazol4-yl)-2methoxypyride in-3 carboxamide A' ⁿ 475.1 10.30-9.91 (m, 1H), 9.168.86 (m, 1H), 8.86-8.69 (m, 1H), 8.28-8.13 (m, 1H), 8.13-7.91 (m, 1H), 7.76-7.46 (m , 2H), 3.323.06 (m, 3H), 1.59 (s, 9H).

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145 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-[3-(4chlorophenyl)-3hydroxybutyl]-2methoxypyride in-3 carboxamide HE ΌΙ 535.0 8.91-8.80 (m, 1Н), 8.788.66 (m, 1Н), 8.54 - 8.43 (m, 1Н), 8.22 - 8.06 (br, 1Н), 7.64 - 7.53 (m, 1Н), 7.52 - 7.46 (m, 2H), 7.39 7.32 (m, 2H), 7.29 - 7.23 (m, 1H), 7.18 - 7.13 (t, 1H), 7.08 - 7.03 (m, 1H), 4.11 -3.97 (t, 3H), 3.68 3.47 (m, 1H), 3.33 -3.12 (m, 2H), 2.11 - 1.88 (t, 2H), 1.31 -1.16 (m, 1H) 146 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-X-[3-(4chlorophenyl)-3hydroxy-4methylpentyl]-2methoxypyride in-3 carboxamide __1 he ^v kJ ΌΙ 563.1 8.93 - 8.82 (m, 1H), 8.81 8.66 (t, 1H), 8.41 - 8.24 (m, 1H), 8.26 - 8.09 (t, 1H), 7.67 - 7.54 (w, 1H), 7.50 - 7.42 (m, 2H), 7.39 7.32 (m, 2H), 4.96 - 4.85 (t, 1H), 4.11 - 3.99 (t, 3H), 3.93 - 3.84 (br, 1H), 3.48 - 3.35 (m, 1H), 3.243.01 (m, 2H), 2.23-2.11 (t, 1H), 2.09-1.91 (t, 2H), 0.95-0.84 (t, 3H), 0.70-0.54 (t, 3H) 147 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7- yl]-M-[3-(4chlorophenyl)-3hydroxypentyl]-2methoxypyride in-3 carboxamide 1 he ΌΙ 549.4 8.95 - 8.82 (t, 1H), 8.76 8.65 (t, 1H), 8.37 - 8.24 (t, 1H), 8.17-8.08 (t, 1H), 7.58 - 7.47 (t, 1H), 7.48 - 7.41 (t, 2Н), 7.38 7.30 (t, 2Н), 4.11 -4.01 (t, GL), 3.24-3.13 (t, 1Н), 2.58 -2.54 (t, 1Н), 2.16-2.03 (t, 1Н), 2.03 1.92 ( t, 1H), 1.84–1.68 (t, 2H), 0.73–0.62 (t, 3H) 148 149 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-I-[3-(4chlorophenyl)-3oxopropyl]-2methoxypyride in-3 carboxamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7yl]-I-[3-(4fluorophenyl)-3oxopropyl]-2methoxypyride in-3 carboxamide G G ΌΙ L F 519.2 503.1 8.89 (d, 1=2.1Hz, 1H), 8.81 (d, J=2.4Hz, 1H), 8.52 (brt, J=5.5Hz, 1H), 8.17 (s, 1H), 8.02 (d, J=8.5 Hz, ZN), 7.66 -7.58(t, ZN), 4.03 (s, ZN), 3.68 (q, J=6.3 Hz, 2Н), 2.66 -2.55 (t, 1Н) 8.94 - 8.86 (t, 1H), 8.84 8.79 (t, 1H), 8.60 - 8.50 (t, 1H), 8.21 - 8.15 (t, 1H), 8.13-8.06 (t, 2H), 7.66 - 7.55 (t, 1H), 1Н), 7.42 7.32 (t, 2Н), 4.11 -3.98 (t, GL), 3.72 -3.64 (t, 2Н), 3.39 -3.29 (t, 1Н), 2.59-2.54 (t, 1Н) 150 7-[5-(3-benzyl-1,3diazinan-1carbonyl)-6methoxypyride in-3yl]-5- (trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazine-4amine 512.2 8.95 - 8.76 (t, 1H), 8.42 8.30 (t, 1H), 8.17 (d, 1=17.6 Hz, 1H), 7.68-7.58 (t, 1H), 7.39 - 7.26 (t, 2H), 7.05 (br d, J=7.0 Hz, 1H), 6.98 - 6.86 (t, 2H), 4.35 (s, 1H), 4.01 (s, 1H), 3.88 (s, 1H), 3.93 - 3.36 (m, 6H), 3.18 (d, >5.2Hz, 1H), 2.94-2.61 (m, 3H).

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Connections in the table. 4 was obtained by methods similar to those detailed in examples 1 and 51.

When the diastereomers were separated, they were included as separate data.

Table 4

O R

Vnh £W Wo

H ₂ N^/N \=N ^x

Example Name R Ion mass observed in MS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 151 5-{4aminopyrrolo[2, 11][1,2,4]triazin7-yl } -2-methoxyN-(3phenylbutyl)pyridine-3 carboxamide 417.2 8.91-8.84 (m, 1H), 8.748.68 (m, 1H), 8.34 - 8.25 (m, 1H), 7.97 - 7.66 (m, 3H), 7.33 - 7.21 (m, 4H), 7.20-7.12 (m , 1H), 7.11 7.05 (m, 1H), 7.02 (d, J=4.5 Hz, 1H), 4.00 (s, 3H), 3.253.14 (m, 2H), 2.84-2.74 (m, 1H), 1.87 - 1.75 (m, 2H) 152 5-{4aminopyrrolo[2, 1- f] [1,2,4]triaz in7-yl}-H-(3hydroxy-3phenylpropyl)-2methoxypyridine3-carboxamide he ^0 419.1 8.94-8.88 (m, 1H), 8.83 8.76 (m, 1H), 8.59-8.53 (m, 1H), 7.97-7.67 (m, 3H), 7.40-7.29 (m, 4H), 7.26-7.18 (m, 1H), 7.107.06 (m, 1H), 7.06 - 6.98 (m, 1H), 4.73 - 4.66 (m, 1H), 4.05 - 3.98 (m, 3H), 3.53 - 3.44 (m, 1H), 3.42 3.32 (m, 1H), 1.93 - 1.80 (m, 2H) 153 5-{4aminopyrrolo[2, 1-1][1,2,4]triazin7- _yl }-H-(1benzyl-1Hpyrazol-4-yl)-2methoxypyridine3-carboxamide /-ABOUT 440.9 10.39 - 10.27 (m, 1H), 9.01 - 8.89 (m, 1H), 8.82 - 8.69 (m, 1H), 8.20 - 8.09 (m, 1H), 8.02 - 7.72 (m, 3H), 7.68 - 7.57 (m , 1H), 7.43 7.21 (m, 5H), 7.13 (br d, J=4.0 Hz, 1H), 7.04 (br d, >4.0 Hz, 1H), 5.42-5.25 (m, 2H), 4.11 -3.94 ( m, 3H) 154 5-{4aminopyrrolo[2, 11][1,2,4]triazine7-mi}-N-[(3R,4S)1-(3,3difluorocyclobutanencarbonyl)-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide, TFA F 490.2 8.94 (s, 1H), 8.80 (dd, J=18.8, 2.3 Hz, 1H), 8.578.50 (m, 1H), 8.05 (d, J=2.4 Hz, 1H), 7.18 (br s, 1H), 5.42-5.21 (m, 1H), 4.86 4.61 (m, 1H), 4.09-3.11 (m, 8H), 2.88 - 2.69 (m, 4H)

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155 156 5-{4aminopyrrolo[2, 11][1,2,4]triazine7-mi}-N-[(3R,4S)4-fluoro-1-(oxane- 4carbonyl)pyrrole idin-3-yl]-2methoxypyridine3-carboxamide 5-{4aminopyrrolo[2, 11][1,2,4]triazin7-mi}-N-[(3R,4S)1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide F^, X y, 484.2 476.1 8.94 (s, 1H), 8.88 - 8.78 (br, 1H), 8.45 (br dd, J=17.2, 7.4 Hz, 1H), 7.94 (s, 1H), 7.09 (d, J=4.5 Hz, 1H), 7.04 (d, J=4.3 Hz, 1H), 5.43 - 5.20 (m, 1H), 4.86 - 4.60 (m, 1H), 4.19-3.16 (m, 11H), 2.80 -2.65 (m, 1H), 1.671. 49 (m, 4H) 8.98 - 8.93 (m, 1H), 8.89 8.79 (m, 1H), 8.55 - 8.42 (m, 1H), 7.94 (s, 1H), 7.09 (br d, J=4.3 Hz, 1H), 7.04 (d, 3=4.4Hz, 1H), 5.485.22 (m, 1H), 4.92 - 4.65 (m, 1H), 4.35 -3.27 (m, 7H), 3.11 -2.83 (m, 1H), 2.02 - 1.79 (m, 2H) 157 158 5-{4aminopyrrolo[2, 1£][1,2,4]triazine7-mi}-N-[(3R,4S)4-fluoro-1-(3fluorocyclobutane arbonyl)pyrrolidin-3-yl]-2methoxypyridine3- carboxamide 5-{4aminopyrrolo[2, 11][1,2,4]triazine7-mi}-N-[(3R,4S)1-(4,4difluorocyclohexancarbonyl)-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide F^^ P^^x At p N— 1F F 472.1 518.0 8.96 (d, J=2.1 Hz, 1H), 8.82 (dd, J=15.3,2.1 Hz, 1H), 8.51 (br dd, J=15.6, 7.6 Hz, 1H), 7.96 (s, 1H), 7.93 7.71 (m, 2H), 7.12 (d, J=4.3 Hz, 1H), 7.05 (d, J=4.3 Hz, 1H), 5.45-5.21 (m, 1H), 5.11 -4.89 (m, 1H), 4.85 - 4.57 (m, 1H), 4.04 (d, J=4.3 Hz, ZH), 4.00-3.15 (m, 4H), 2.85 - 2.69 (m, 1H), 2.61-2.48 (m, 2H, absorbed by DMSO), 2.36 - 2.16(m, 2H) 8.93 (s, 1H), 8.86 - 8.78 (m, 1H), 8.55 (dd, J=13.6, 7.5 Hz, 1H), 7.94 (s, 1H), 7.10 (d, J=4.6 Hz, 1H), 7.05 7.01 (m, 1H), 5.43-5.18 (m, 1H), 4.87 -4.58 (m, 1H), 4.16-3.14 (m, 7H), 2.13 - 1.71 (m, 7H), 1.65 - 1.51(m, 2H) 159 5-{4aminopyrrolo[2, 11][1,2,4]triazine7-mi}-N-[(3R,4S)4-fluoro-1-(4fluorobenzoyl)pyrrolide in-3-yl]-2methoxypyridine3-carboxamide £ ί F 494.1 8.95 - 8.90 (m, 1H), 8.79 (br s, 1H), 8.64 - 8.50 (m, 1H), 7.93 (br d, J=12.2 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.33 7.24 (m, 2H), 7.13-7.06 (m, 1H), 7.05 - 6.99 (m, 1H), 5.48-5.16 (m, 1H), 4.89-4.59 (m, 1H), 4.06 3.46 (m, 7H)

Connections in the table. 5 was prepared by methods similar to those detailed in Example 31. The listed compounds are racemic.

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Table 5

R

Example Name “R” structure Observe May in MS the mass of the ion Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 160 161 5-[4-amino-5(trifluoromethyl)pyrrolo[2, Ι- Ο [1,2,4]triazin-7yl]-2-methoxy-M(zphenylbutyl)benza MFA 5-[4-amino-5(trifluoromethyl)pyrrolo[2, Ι- Ο [1,2,4]triazin-7yl]-H-(3hydroxy-3phenylpropyl)-2methoxybenzamide He 484.3 486.3 8.32 - 8.26 (m, 1H), 8.25-8.18 (m, 1H), 8.09 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.40 (s, 1H), 7.33 - 7.26 (m, 2H), 7.23 (d, J=6.9 Hz, ZH), 7.19-7.13 (m, 1H), 3.90 (s, 1H), 3.25 -3.09 (m, 2H), 2.85 -2.69 (m, 1H), 1.79 (q, J=7.1 Hz, 2H), 1.21 (d, J=6.9 Hz, ZN). 8.46 (br. s., 1H), 8.41-8.31 (m, 1H), 8.17-8.04 (m, 2H), 7.44 (s, 1H), 7.39 - 7.29 (m, 4H), 7.29-7.18 (m, 2H), 5.46 (d, 3=4.1Hz, 1H), 4.76 - 4.63 (m, 1H), 3.94 (s, 2H), 3.50(br. s., 2H), 3.37 (br. s., 1H) , 1.95 - 1.75 (m, 2H). 162 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 0 [ 1,2,4]triazin-7yl ] -2-methoxy-H [(2phenoxyphenyl)methyl] benzamide 0^^ and 534 8.71 (t, J=5.8Hz, 1H), 8.39 (d, 3=1.9Hz, 1H), 8.19-8.04 (m, 2H), 7.50 - 7.41 (m, 2H), 7.38 (t, 1=7.8Hz , 2H), 7.32-7.24 (m, 2H), 7.21-7.15 (m, 1H), 7.11 (t, J=7.3 Hz, 1H), 6.99 (d, J=8.1 Hz, 2H), 6.89 (d, J=8.0 Hz, 1H), 4.52 (d, J=5.8 Hz, 2H), 3.90 (s, 2H). 163 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazine-7m]-N-{[2(cyclopropylmethoxy)phenyl]methyl}-2methoxybenzamide x/ o^d 512.1 8.60 (t, J=5.7 Hz, 1H), 8.47 8.38 (m, 1H), 8.19-8.05 (m, 2H), 7.44 (s, 1H), 7.35-7.16 (m, 3H), 7.02 - 6.85 (m , 2H), 4.51 (d, >5.8Hz, 2H), 3.96 (s, 3H), 3.90 (d, J=6.7 Hz, 2H), 1.26 (br. s., 1H), 0.57 (d, >7.4 Hz, 2H), 0.36 (d, J=4.5 Hz, 2H). 164 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazin-7yl]-K-[(3chloropyrazin-2yl)methyl]-2methoxybenzamide 477.9 9.11 (br. s., 1H), 8.68 (s, 1H), 8.58 (br. s., 1H), 8.47 (br. s., 1H), 8.15 (br. s., 2H), 7.47 (s , 1H), 7.34 (d, J=8.7 Hz, 1H), 4.79 (d, J=4.6 Hz, 2H), 4.03 (s, 3H).

Connections in the table. 6 was prepared by the methods detailed in Examples 13, 21 and 22. Where a tertiary amide was prepared, all of the amine will be shown. Compounds without defined stereochemistry were isolated as racemic or diastereomeric mixtures.

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Table 6

F ₃ C _X ^.

ΊΟ

Η ₂ Ν^/ Ν

Ρ,.Ν

Example Name R The ion mass observed in MS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 165 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine7-mi]-N-[(3R)-3(4-chlorophenyl)3- hydroxypropyl]-2- methylpyridine3-carboxamide He 505.2 9.22 - 9.09 (m, 1H), 8.55 - 8.43 (m, 1H), 8.40-8.31 (m, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.447.34 (m, 5H), 5.41 (d, J=4.6 Hz, 1H), 4.73 - 4.63 (m, 1H), 3.35 (br. s., 2H), 1.85 (q, >6.8 Hz, 2H). 166 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-H-(1benzyl-1Hpyrazol-4-yl)-2methylpyridine3-carboxamide /-ABOUT 493.1 10.62 (s, 1H), 9.23 (s, 1H), 8.52 (s, 1H), 8.20 (s, 1H), 8.16 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.43 -7.19 (m, 5H), 5.33 (s, 2H), 2.60 (s, 3H). 167 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.11][1.2.4]triazin7-yl]-H-(3hydroxy-3phenylpropyl)- 2- methylpyridine3-carboxamide He 471.3 9.16 (s, 1H), 8.49 (br. s., 1H), 8.36 (s, 1H), 8.19 (s, 1H), 7.69 (s, 1H), 7.43 - 7.28 (m, 4H), 7.28-7.19 (m, 1H), 4.66 (d, >4.9Hz, 1H), 3.45–3.24 (m, 1H), 2.56 (s, 3H), 1.92–1.81 (m, 2H). 168 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine- 7-yl]-X-[3-(4fluorophenyl)-3hydroxypropyl]-2methylpyridine3-carboxamide HE 489.1 9.15 (s, 1H), 8.54 - 8.44 (m, 1H), 8.35 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 7.47 - 7.34 (m, 2H), 7.15 (t, J=8.7Hz, 2H), 5.37(d, J=4.3Hz, 1H), 4.67(d, J=4.9Hz, 1H), 2.56(s, 3H), 1.85(q, J=7.0Hz, 2H) .

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169 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine7-nn]-N-[(3S)-3(4-chlorophenyl)3- hydroxypropyl]-2methylpyridine3-carboxamide HE 505.1 9.22 - 9.09 (m, 1H), 8.52 - 8.43 (m, 1H), 8.39-8.31 (m, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 7.39 (s, 5H), 5.50 - 5.35 (m, 1H), 4.67 (d, J=4.9 Hz, 1H), 3.32 (br. s., 1H), 1.85 (q, А6.7Hz, 2H). 170 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-H-[1(cyclopropylmethyl)-1Hpyrazol-4-yl]-2methylpyridine3-carboxamide go Ju ⁿ 457.2 10.58 (s, 1H), 9.31 -9.18 (m, 1H), 8.53 (s, 1H), 8.21 (s, 1H), 8.11 (s, 1H), 7.74 (s, 1H), 7.53 (s, 1H) , 3.97 (d, J=7.0Hz, 2H), 2.61 (s, 3H), 1.24 (br. s., 1H), 0.53 (d, А7.0Hz, 2H), 0.37 (d, J=4.3Hz, 2H). 171 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-2-methylN-(3phenylbutyl)pyridine-3 carboxamide, 2 TFA G 469.1 9.12 (s, 1H), 8.57 - 8.45 (m, 1H), 8.31 (s, 1H), 8.16 (s, 1H), 7.65 (s, 1H), 7.34 - 7.21 (m, 4H), 7.21 -7.13 ( m, 1H), 2.88 2.76 (m, 1H), 2.54 (d, J=3.4 Hz, 4H), 1.81 (q, J=7.3 Hz, 2H), 1.23 (d, J=6.7 Hz, ZN). 172 7-{5-[(3S)-3-[(4fluorophenyl)methyl l]piperidine-1carbonyl]-6methylpyridin3-yl}-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine4-amine, 2.TFA 'Ό'Χι, 513.3 9.32 -9.03 (m, 1H), 8.35-8.11 (m, 2H), 7.76 - 7.57 (m, 1H), 7.38-7.21 (m, 2H), 7.19-7.09 (m, 2H), 7.08 - 6.95 (m , 1H), 6.93 - 6.79 (m, 1H), 6.49 - 6.37 (m, 1H), 4.54 - 4.22 (m, 1H), 3.34 -3.06 (m, 1H), 2.83 -2.61 (m, 2H), 2.55 (s, 3H), 2.46 2.31 (m, 3H), 2.23 - 2.07 (m, 1H), 1.90 - 1.67 (m, 2H), 1.651.37 (m, 1H), 1.33 - 1.19 (m, 1H)

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173 7-{5-[(3S)-3-[(3fluorophenyl)methyl l]piperidine-1carbonyl]-6methylpyridin3-yl}-5(trifluoromethyl)pyrrolo[2.11D][1.2.4]triazine4-amine 513 9.12 (br s, 1H), 8.30 - 8.08 (m, 2H), 7.72 - 7.59 (m, 1H), 7.32 7.22 (m, 1H), 7.18-7.09 (m, 1H), 7.04 - 6.77 (m, 2H ), 6.47 6.34 (m, 1H), 4.56-4.18 (m, 1H), 3.32-3.12 (m, 1H), 3.11 2.94 (m, 1H), 2.82 - 2.62 (m, 1H), 2.60 - 2.55 (m , 3H), 2.46 2.29 (m, 3H), 2.18-2.07 (m, 1H), 1.89 - 1.67 (m, 2H), 1.63 1.43 (m, 1H), 1.34-1.13 (m, 1H) 174 7-{5-[(3R)-3-[(4fluorophenyl)methyl l]piperidine-1carbonyl]-6methylpyridin3-yl}-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine4-amine 513.3 9.19-9.02 (m, 1H), 8.32-8.10 (m, 2H), 7.74 - 7.59 (m, 1H), 7.35 - 7.22 (m, 1H), 7.13 (brt, J=8.6 Hz, 1H), 7.04 - 6.82 (m, 2H), 6.48 -6.37 (m, 1H), 4.544.26 (m, 1H), 3.33 - 3.23 (m, 1H), 3.20 -2.93 (m, 2H), 2.83 2.59 (m, 2H) , 2.46 - 2.33 (m, 3H), 1.94 (br d, J=6.7 Hz, 2H), 1.64 - 1.36 (m, 1H) 175 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-X[(3S,4S)-1cyclopentanecar bonyl-4methylpyrrolide in-3-yl]-2methylpyridin3- carboxamide, 2TFA 515.9 9.17 (br. s., 1H), 8.79-8.60 (m, 1H), 8.37 (s, 1H), 8.18 (d, J=6.1 Hz, 1H), 7.69 (d, J=9.2 Hz, 1H), 4.70 - 4.46 (m, 1H), 3.79 (dd, J=10.7, 5.9 Hz, 1H), 3.71 - 3.60 (m, 1H), 3.27-3.13 (m, 1H), 3.08 -2.97 (m, 1H), 2.93 (q, J=7.3 Hz, 1H), 2.78 (br. s., 1H), 1.84 - 1.70 (m, 2H), 1.70-1.55 (m, 4H), 1.50 (br. s., 2H), 1.16 (t, J=7.2 Hz, 2H), 1.01 (t, J=6.7 Hz, 3H). 176 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-2-methyl- N-[1-(2,2,2trifluoroethyl)1H-pyrazol-4yl]pyridine-3 carboxamide _r CF ₃ Ων 485.2 10.77 (br. s., 1H), 9.25 (d, J=1.9Hz, 1H), 8.55 (d, >1.9Hz, 1H), 8.26 (s, 1H), 8.21 (s, 1H), 7.75 (s , 1H), 7.67 (s, 1H), 5.14 (q, >9.0Hz, 2H), 2.61 (s, 3H).

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177 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine7-m]-N-[(3S)-3(4-chlorophenyl)3methoxypropyl]-2- methylpyridine3-carboxamide 519.2 9.15 (d, J=1.8 Hz, 1H), 8.52 (br t, J=5.3 Hz, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.73 (s, 1H) , 7.68 (s, 1H), 7.48 - 7.39 (m, J=8.5 Hz, 2H), 7.39-7.31 (m, J=8.5 Hz, 2H), 4.29 (dd, J=7.8, 5.0 Hz, 1H), 3.90 (s, 1H), 3.42 (s, 1H), 3.35 -3.22 (m, 1H), 3.14 (s, 2H), 2.80 - 2.65 (m, 1H), 2.58 -2.54 (m, 3H), 1.94 ( dt, J=13.7, 6.9 Hz, 1H), 1.86-1.72 (m, 1H). 178 179 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin7-yl]-2-methyl- N-[2-(3phenylpyrrolide in-1yl)ethyl]pyridi n-3carboxamide, TFA methyl- N-[2-(3phenylpiperidi n-1yl)ethyl]pyr go n-3carboxamide, TFA And 510.2 524.4 9.17 (d, J=1.8Hz, 1H), 8.81 (br t, >5.6Hz, 1H), 8.42 (d, J=1.8Hz, 1H), 8.15 (s, 1H), 7.63 (s, 1H), 7.35 (br d, J=4.3 Hz, 5H), 7.30 -7.20 (m, 2H), 3.82 - 3.60 (m, 5H), 3.46 (br s, 2H), 2.91 (br d, J=5.5 Hz, 1H ), 2.66 - 2.54 (m, 4H), 2.48 - 1.84 (m, 2H) 9.15 (d, J = 2.2 Hz, 1H), 8.79 (t, J = 6.0 Hz, 1H), 8.37 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.62 (s, 1H), 7.29 (ddt, J = 21.4, 14.2, 7.4 Hz, 6H), 3.31 (s, 1H), 3.16 (d, J = 12.8 Hz, 1H), 3.01 (s, 2H), 2.56 (s, 3H), 1.99 (s, 1H), 1.88 (t, J = 16.9 Hz, 2H), 1.69 (d, J = 12.6 Hz, 1H)

Connections in the table. 7 was made by the methods detailed in Example 23. Where a tertiary amide was made, all of the amine will be shown.

Table 7

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 180 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl] 2( trifluoro methyl l)pyridine-3 carboxamide HE 559.3 9.47 - 9.42 (m, 1H), 8.79 (br s, 1H), 8.67 (br s, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.42 - 7.32 (m, 6H), 5.54 ( brs, 1H), 4.69-4.61 (m, 2H), 3.31 (q, J=6.5 Hz, 2H), 1.81 (q, J=6.8 Hz, 2H)

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181 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl] 2(trifluoromethyl)pi ridin-3 carboxamide, 2 TFA HE ^^Cl 559.1 9.47 (br s, 1H), 8.83 - 8.74 (m, 1H), 8.74 - 8.67 (m, 1H), 8.26 (br s, 1H), 7.93 (br s, 1H), 7.33 (s, 4H), 5.47 (br s, 1H), 4.66 (br d, J=4.9 Hz, 2H), 3.32 (q, J=6.1 Hz, 1H), 1.88 - 1.76 (m, 2H) 182 7-{5-[(3S)-3-[(4fluorophenyl)methyl]piperidine-1carbonyl]-6(trifluoromethyl)pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2 ,4]triazine-4amine ^x Oa _F 567.2 9.52 - 9.33 (m, 1H), 8.68 - 8.49 (m, 1H), 8.32 - 8.14 (m, 1H), 7.96 -7.78 (m, 1H), 7.56-7.41 (m, 1H), 7.32-7.21 (m , 1H), 7.15- 7.06 (m, 1H), 6.98 - 6.77 (m, 1H), 6.42 - 6.29 (m, 1H), 4.51 -4.18 (m, 1H), 3.29 - 3.04 (m, 1H), 3.00 -2.84 (m, 1H ), 2.82–2.58 (m, 1H), 2.47–2.23 (m, 1H), 2.17– 2.00 (m, 1H), 1.93 - 1.64 (m, 2H), 1.62 - 1.47 (m, 1H), 1.43 - 1.15 (m, 2H) 183 7-{5-[(3R)-3-[(4fluorophenyl)methyl]piperidine-1carbonyl]-6(trifluoromethyl)pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2 ,4]triazine-4amine 567.4 9.55 - 9.42 (m, 1H), 8.72 - 8.54 (m, 1H), 8.33 - 8.19 (m, 1H), 7.98 - 7.87 (m, 1H), 7.28 (br dd, J=8.1, 5.8 Hz, 1H) , 7.18-7.09 (m, 1H), 7.03 - 6.78 (m, 1H), 6.50 - 6.35 (m, 1H), 4.54 - 4.21 (m, 1H), 3.72 -3.47 (m, 2H), 3.32-3.10 ( m, 1H), 3.06-2.90 (m, 1H), 2.86-2.55 (m, 2H), 1.91-1.69 (m, 2H), 1.63-1.42 (m, 1H), 1.37-1.14 (m, 1H) 184 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-I-(1-benzyl1H-pyrazol-4-yl)2(trifluoromethyl)pyridine- 3 carboxamide rO 547.4 10.94 - 10.84 (m, 1H), 9.56 (s, 1H), 8.88 (s, 1H), 8.27 (s, 1H), 8.21 - 8.10 (m, 1H), 7.97 (s, 1H), 7.55 (s, 1H), 7.41 - 7.24 (m, 5H), 5.33 (s, 2H)

Connections in the table. 8 was prepared by the methods detailed in Example 44. All compounds are cis-racemic at fluoropyrrolidine. In some cases mixtures of diastereomers have been isolated.

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Table 8 h ₂ n

-R

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 185 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-I-{1-[(3,3difluorocyclobutyl)methyl]-4fluoropyrrolidin-3yl}- 2 methoxypyridine-3 carboxamide, 2 TFA ''T 544.2 No data 186 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-{4-fluoro-1[(oxolan-3yl)methyl]in-3 pyrrolide -yl}-2methoxypyridine-3 carboxamide 524.1 8.92 (d, J=2.4 Hz, 1H), 8.88 - 8.84 (t, 1H), 8.44 (brs, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.35 - 5.03 (t, 1H) , 4.53 (br dd, J=10.9, 4.2 Hz, 1H), 4.05 (s, ZH), 3.80 - 3.67 (m, 2H), 3.62 (q, J=7.7 Hz, 1H), 3.40 3.36 (m, 1H ), 3.16 - 2.54 (m, 4H), 2.47 - 2.27 (m, 3H), 2.01 - 1.92 (m, 1H), 1.59-1.51 (m, 1H) 187 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-N-[4-fluoro-1-(3-methoxypropyl)pyrrolide in-3-yl ]-2methoxypyridine-3 carboxamide 512.2 8.92 (d, J=2.4 Hz, 1H), 8.88 - 8.84 (m, 1H), 8.45 (brs, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.41 - 5.06 (m, 1H) , 4.67 - 4.42 (m, 1H), 4.05 (s, 3H), 4.05 - 4.03 (m, 1H), 3.393.35 (m, 2H), 3.31-3.24 (m, 1H), 3.23 (s, 3H) , 3.14 - 2.70 (m, 2H), 2.70 - 2.53 (m, 2H), 1.73 - 1.67 (m, 2H) 188 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-H-{1-[2-(2,2difluorocyclopropyl)ethyl]-4fluoropyrrolidine-3 yl]-2methoxypyridine-3 carboxamide, 2 TFA a f 544.2 8.94 (d, J=2.1 Hz, 1H), 8.86 - 8.76 (m, 1H), 8.63 (br d, J=1.8 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.655. 25 (m, 1H), 5.18 - 4.62 (m, 1H), 4.14 - 3.96 (m, 4H), 3.80 - 3.20 (m, 5H), 1.99 - 1.83 (t, 1H), 1.821.66 (m, 2H ), 1.65-1.51 (m, 1H), 1.35 - 1.17 (m, 1H)

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189 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-I-[1(cyclobutylmethyl)-4fluoropyrrolidin-3yl]-2methoxypyridine-3 carboxamide, 2.TFA 508.1 No data 190 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7ηπ]-N-[1-(2cyclopropylethyl)4-fluoropyrrolidin3-yl]-2methoxypyridine-3 carboxamide .2 TFA 508.2 8.94 (d, J=2.3 Hz, 1Н), 8.80 (br d, >10.7 Hz, 1Н), 8.63 (br s, 1Н), 8.18 (s, 1Н), 7.63 (s, 1Н), 5.585.29 ( t, 1H), 5.17 - 4.62 (m, 1H), 4.05 (s, ZH), 4.01-3.87 (m, 1H), 3.78-3.18 (m, 5H), 1.55 (brd, J=3.1 Hz, 2H) , 0.71 (br s, 1Н), 0.50–0.42 (t, 2Н), 0.13 (br s, 2Н) 191 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-T4-{4-fluoro-1[(oxan-2yl)methyl]in-3 pyrrolide -yl}-2methoxypyr idine-3 carboxamide 538.2 8.92 (d, J=2.4 Hz, IH), 8.86 (s, IH), 8.45 (br s, IH), 8.18 (s, IH), 7.63 (s, IH), 5.41-4.97 (m, IH), 4.69 - 4.36 (m, IH), 4.05 (s, 3H), 3.87 (br d, J=10.4 Hz, IH), 3.63 3.39 (m, 2H), 3.21 - 2.54 (m, 6H), 1.77 (brd, J=8.1 Hz, IH), 1.651.54 (m, IH), 1.52 - 1.35 (m, 3H), 1.31-1.08 (m, IH) 192 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine-7ηπ]-N-[1-(2ethoxyethyl)-4fluoropyrrolidin-3yl]-2methoxypyridine-3 carboxamide 512.2 8.92 (d, J=2.4 Hz, IH), 8.85 (d, J=2.4 Hz, IH), 8.46 (br s, IH), 8.18 (s, IH), 7.63 (s, IH), 5.36-4.99 ( m, IH), 4.68 - 4.39 (m, IH), 4.05 (s, 3H), 3.53 - 3.47 (m, 2H), 3.44 (q, J=7.0 Hz, 2H), 3.24 - 2.59 (m, 6H) , 1.12(1.1=7.0Hz, ZN)

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193 5-[4-Amino-5(trifluoromethyl)pyrolo[2, ΙΟ [1,2,4]triazine-7Ηπ]-Ν-{4-φτορ-1[4,4,4-trifluoro-3(trifluoromethyl) butyl]pyrrolidin-3yl}-2methoxypyr idine-3 carboxamide CF ₃ V^^CF ₃ 618.1 No data 194 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10 [1,2,4]triazine-7- il]-X-[1- (cyclopentylmethyl )-4fluoropyrrolidin-3 yl]-2methoxypyridine-3 carboxamide 522.1 No data 195 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, ΙΟ[1,2,4]triazin-7yl]-M-{4-fluoro-1[(oxolan-2yl)methyl]pyrrolide in-3- yl}-2methoxypyr idine-3 carboxamide 524.2 No data 196 5-[4-amino-5(trifluoromethyl)pyrrolo[2,10 [1,2,4]triazin-7yl]-X-{1-[(2,2difluorocyclopropyl)methyl]-4fluoropyrrolidin-3yl}- 2methoxypyr idine-3 carboxamide 530.2 8.93 (d, J=2.3 Hz, 1H), 8.89 - 8.82 (m, 1H), 8.49 (br s, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.38 - 5.11 (br, 1H ), 4.68 - 4.42 (m, 1Н), 4.05 (s, ZN), 3.25 -2.57 (m, 6Н), 2.04 - 1.76 (m, 1H), 1.72 - 1.48 (m, 1H), 1.38-1.13 (m, 1H)

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197 198 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-X-[1(cyclopropylmethyl)-4fluoropyrrolidin-3yl]-2methoxypyridine-3 carboxamide 5 -[4-Amino-5(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7yl]-X-[4-fluoro-1(4,4,4trifluorobutyl)pyrrolidin-3-yl ]-2methoxypyr idine-3 carboxamide, 2 TFA V^CF ₃ 494 550.2 8.92 (d, J=2.6Hz, 1H), 8.87 (d, J=2.6Hz, 1H), 8.37 (br d, J=7.3Hz, 1H), 8.17 (s, 1H), 7.57 (s, 1H) , 5.35 - 5.04 (m, 1H), 4.70 - 4.40 (m, 1H), 4.08 (s, 3H), 3.18-3.06 (m, 1H, partially suppressed), 3.04-2.97 (m, 1H), 2.91 - 2.75 (m, 1H), 2.64 (t, J=8.4 Hz, 1H), 2.37 (d, J=6.6 Hz, 2H), 0.96 - 0.77 (m, 1H), 0.49 0.44 (m, 2H), 0.14 - 0.10 (m, 2H) 8.94 (d, J=2.4 Hz, 1H), 8.81 (br s, 1H), 8.63 (br s, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.65 - 5.23 (m, 1H) , 5.17-4.63 (m, 1H), 4.05 (s, 3H), 3.83-3.10 (m, 6H), 2.45-2.27 (m, 2H), 1.95-1.79 (m, 2H) 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7- 199 silt]-H-(1- cyclopentyl-4fluoropyrrolidine-3 - silt) -2- methoxypyridine-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7ππ]-Ν-{4-φτορ-1- 508.1 No data 200 [(3-methyloxetan3yl)methyl]pyrrolide in-3-yl}-2methoxypyridine-3-carboxamide, 2 TFA 524.2 No data

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201 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7- yl]-X-{1-[(1,3benzoxazol-2yl)methyl]-4fluoropyrrolidin-3 yl 1-2methoxypyridine-3 carboxamide Z/D oJA 571.1 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.16 (s, 1H), 7.80 7.69 (m, 2H), 7.57 (s, 1H), 7.43 7.35 (m , 2H), 5.35 - 5.16 (m, 1H), 4.66 - 4.56 (m, 1H), 4.14 - 4.08 (m, 2H), 4.07 (s, 3H), 3.41-3.03 (m, 3H), 2.86 (1 ,7=8.6 Hz, 1H). 202 203 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1Ι] [1,2,4]triazin-7yl]-M-{4-fluoro-1[(quinolin-4yl)methyl]in-3 pyrrolide -yl}-2methoxypyridine-3-carboxamide -3yl)methyl] pyrrolide in-3-yl}-2methoxypyridine-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M- (4-fluoro-1{[6- and Au A? 581.1 531.1 8.91 (d, >2.6Hz, 1H), 8.87 (d, J=4.4Hz, 1H), 8.83 (d, J=2.6Hz, 1H), 8.37 (br d, J=7.0Hz, 1H), 8.29 ( d, J=8.4 Hz, 1H), 8.05 (d, J=8.4 Hz, 1H), 7.79 - 7.74 (m, 1H), 7.64 (t, J=7.2 Hz, 1H), 7.57 - 7.54 (m, 2H ), 5.34 - 5.16 (m, 1H), 4.66 4.56 (m, 1H), 4.26 - 4.17 (m, 2H), 4.05 (s, 3H), 3.14 - 2.87 (m, 3H), 2.75 (t, J= 8.3Hz, 1H), 8.92 (d, 7=2.2Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.54 (s, 1H), 8.48 (dd, 7=4.8, 1.5Hz, 1H), 8.16 (s, 1H ), 7.74 (br d, 7=7.7 Hz, 1H), 7.57 (s, 1H), 7.37 (dd, 7=7.7, 4.8 Hz, 1H), 5.33-5.13 (m, 1H), 4.62 4.52 (m, 1H), 4.08 (s, 3H), 3.80 3.66 (m, 2H), 3.20 - 2.76 (m, 3H), 2.64 (t, 7=8.4 Hz, 1H). 8.93 (d, 7=2.6Hz, 1H), 8.82 (d, 7=2.2Hz, 1H), 8.47 (br d, 7=7.0Hz, 1H), 8.19 - 8.13 (m, 2H), 7.89 - 204 (trifluoromethyl)pyridine-2yl]methyl}pyrroli din-3 -yl)-2methoxypyridine-3carboxamide, 2 TFA NU CF ₃ 599.1 7.80 (m, 2H), 7.57 (s, 1H), 5.49 5.23 (m, 1H), 4.91 - 4.68 (m, 1H), 4.35 (br s, 2H), 4.07 (s, 3H), 3.69 3.02 (m , 4H).

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205 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7yl]/-{4-fluoro-1[(6-methylpyridin2yl)methyl]pyrrolide in-3-yl }-2methoxypyr idine-3 carboxamide v/ 545.2 8.92 (d, 7=2.6 Hz, 1H), 8.85 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H), 7.65 (t, 7= 7.7 Hz, 1H), 7.57 (s, 1H), 7.23 (d, 7=7.7 Hz, 1H), 7.12 (d, 7=7.7 Hz, 1H), 5.36 - 5.09 (m, 1H), 4.65 4.50 (m , 1H), 4.08 (s, 3H), 3.81 3.74 (m, 2H), 3.13 (dd, 7=11.7, 4.8 Hz, 1H), 2.96 - 2.86 (m, 1H), 2.70 (t, 7=8.4 Hz , 1H), 2.46 (s, 3H). 206 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-[4-fluoro-1[(1,3-thiazol-4yl)methyl] pyrrolide in-3-yl}-2- Ν=/ 537 9.04 (d, 7=1.8Hz, 1H), 8.92 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.2Hz, 1H), 8.35 (br d, 7=7.7Hz, 1H), 8.16 (s, 1H), 7.58 - 7.52 (m, 2H), 5.32 - 5.11 (m, 1H), 4.64 - 4.45 (m, 1H), 4.07 (s, 3H), 3.92 - 3.85 (m, 2H), 3.25 - 3.11 (m, 1H), 3.08 -3.04 (m, 1H), 2.98 - 2.88 (m, 1H), 2.70 (t, methoxypyridine-3 carboxamide 7=8.8Hz, 1H). 5-[4-amino-5(trifluoromethyl)pyr 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, rollo[2,1- 7=2.6 Hz, 1H), 8.36 (br d, 7=7.0 £][1,2,4]triazine-7- Hz, 1H), 8.17 (s, 1H), 7.57 (s, 1H), il]/-{1-[(5- 5.34 - 5.12 (m, 1H), 4.65 - 4.51 (m, 207 cyclopropyl-1,3,4- 1 ,N ^S 578.2 1H), 4.12 (d, 7=2.9 Hz, 2H), 4.08 thiadiazole-2- (s, 3H), 3.31 -3.14(m, 1H), 3.13- yl)methyl]-4- 3.04 (m, 1H), 3.04 - 2.91 (m, 1H), fluoropyrrolidine-3 - 2.77 (t, 7=8.8Hz, 1H), 2.49 - 2.44 il}-2- (m, 1H), 1.25 - 1.17 (m, 2H), 1.05 - methoxypyridine-3 - 0.97 (m, 2H). carboxamide 5-[4-amino-5- (trifluoromethyl)pyr 8.92 (d, 7=2.6 Hz, 1H), 8.85 (d, rollo[2,1- 7=2.2 Hz, 1H), 8.36 (br d, 7=7.3 1][1,2,4]triazine-7- Hz, 1H), 8.17 (s, 1H), 7.57 (s, 1H), yl]/-{4-fluoro-1- 7.27 (s, 1H), 5.31-5.09 (m, 1H), 208 [(2-methyl-1,3- 551 4.61 - 4.43 (m, 1H), 4.07 (s, 3H), thiazole-4- 3.80 - 3.73 (m, 2H), 3.26 - 3.09 (m, yl)methyl]pyrrolide 1H), 3.07 -3.02 (m, 1H), 2.96 - in-3-yl}-2- 2.86 (m, 1H), 2.69 (t, 7=8.6 Hz, methoxypyridine-3 - 1H), 2.64 (s, 3H). carboxamide

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209 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-{1-[(3,5dimethyl-1,2oxazol-4yl)methyl]- 4fluoropyrrolidin-3 yl}-2methoxypyridine-3 carboxamide, 2 TFA 549.2 8.93 (d, 7=2.6Hz, 1H), 8.83 (d, J=2.2Hz, 1H), 8.47 (br d, 7=7.0Hz, 1H), 8.17 (s, 1H), 7.58 (s, 1H) , 5.52 - 5.22 (m, 1H), 4.93 - 4.64 (m, 1H), 4.07 (s, 3H), 4.00 - 3.12 (m, 6H), 2.45 (s, 3H), 2.28 (s, 3H). 210 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-M-{4-fluoro-1[(pyridin-2yl)methyl]in-3 pyrrolide -yl}-2methoxypyr idine-3 carboxamide R 531.2 8.92 (d, J=2.2 Hz, 1H), 8.85 (d, J=2.2 Hz, 1H), 8.51 (br s, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H ), 7.78 (t, 7=7.7 Hz, 1H), 7.57 (s, 1H), 7.45 (br d, 7=7.3 Hz, 1H), 7.33 7.17 (m, 1H), 5.35-5.11 (m, 1H) , 4.63 - 4.53 (m, 1H), 4.08 (s, 3H), 3.88 - 3.79 (m, 2H), 3.15 - 2.84 (m, 3H), 2.71 (brt, 7=8.3 Hz, 1H). 211 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-M-{1-[(3,4difluorophenyl)methyl]-4fluoropyrrolidin-3yl} -2methoxypyr idine-3 carboxamide F 566.1 8.92 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.36 (br d, 7=7.0Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.43 - 7.31 (m, 2H), 7.20 (br s, 1H), 5.35 - 5.12 (m, 1H), 4.65 - 4.47 (m, 1H), 4.08 (s, 3H), 3.71 (br d, 7= 8.4 Hz, 2H), 3.26 - 2.76 (m, 3H), 2.70 2.56 (m, 1H).

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212 5-[4-amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazin-7yl]-X-{1-[(1cyclopropyl-1H1,2,3,4-tetrazol-5yl )methyl]-4fluoropyrrolidin-3 yl}-2methoxypyridine-3 carboxamide Υ η ,Ν Ν-ν 562.2 8.92 (d, 7=2.6Hz, 1H), 8.84 (d, J=2.2Hz, 1H), 8.37 (br d, 7=7.7Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 5.34 - 5.14 (m, 1H), 4.66 - 4.56 (m, 1H), 4.20 - 4.12 (m, 2H), 4.07 (s, 3H), 3.87 (tt, 7=7.3, 3.7 Hz, 1H), 3.29 - 3.07 (m, 2H), 3.06 - 2.95 (m, 1H), 2.79 (t, 7=8.4 Hz, 1H), 1.28 1.19 (m, 4H). 213 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-T4-{4-fluoro-1[(4fluorophenyl)methyl]pyrrolidin-3-yl} 2-methoxypyridine3-carboxamide R 548.1 8.91 (d, 7=2.6Hz, 1H), 8.83 (d, 7=2.6Hz, 1H), 8.36 (br d, 7=7.0Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H) , 7.41 - 7.27 (m, 2H), 7.15 (t, 7=8.8 Hz, 2H), 5.33 - 5.11 (m, 1H), 4.67 4.45 (m, 1H), 4.07 (s, 3H), 3.75 3.65 (m , 2H), 3.34 - 2.74 (m, 3H), 2.68 - 2.57 (m, 1H). 214 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1ί][1,2,4]triazin-7yl]-H-{1-[(2cyanophenyl)methyl]-4fluoropyrrolidin-3yl}-2methoxypyridine -3 carboxamide CN 555.1 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H), 7.81 (d, 7= 7.0 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.65 - 7.61 (m, 1H), 7.57 (s, 1H), 7.49 (t, 7=7.5 Hz, 1H), 5.39 - 5.13 (m, 1H ), 4.66 - 4.51 (m, 1H), 4.08 (s, 3H), 3.95 - 3.84 (m, 2H), 3.19 - 3.09 (m, 1H), 3.06 - 2.98 (m, 1H), 2.96 - 2.80 (m, 1H), 2.69 (t, 7=8.3 Hz, 1H). 215 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 0 [1,2,4]triazin-7yl]-N-(1-benzyl-4fluoropyrrolidin-3 yl)-2methoxypyridine-3 carboxamide 530.1 8.91 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.36 (br d, 7=8.1Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.34 (d, 7=4.4 Hz, 4H), 7.31 -7.18 (m, 1H), 5.34-5.11 (m, 1H), 4.64 4.45 (m, 1H), 4.08 (s, 3H), 3.76 3.62 (m , 2H), 3.17 - 3.02 (m, 1H), 2.95 (dd, 7=8.8, 7.7 Hz, 1H), 2.89 2.74 (m, 1H), 2.61 (t, 7=8.3 Hz, 1H).

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216 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-PM-(4-fluoro-1{[4(trifluoromethyl)phenyl]methyl}pyrroli din-3-yl)-2methoxypyr idine-3 carboxamide Λ o 598.1 8.91 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.2 Hz, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H), 7.69 (d, 7= 8.1 Hz, 2H), 7.59 - 7.55 (m, 3H), 5.34 - 5.13 (m, 1H), 4.68 - 4.48 (m, 1H), 4.08 (s, 3H), 3.84 - 3.77 (m, 2H), 3.19 -3.04 (m, 1H), 3.03 2.94 (m, 1H), 2.92 - 2.77 (m, 1H), 2.65 (t, 7=8.4 Hz, 1H). 217 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-T4-{4-fluoro-1[(2fluorophenyl)methyl]pyrrolidin-3-yl} 2-methoxypyridine3-carboxamide F Yb 548.2 8.91 (d, 7=2.4Hz, 1H), 8.84 (d, 7=2.4Hz, 1H), 8.43 (br d, 7=7.5Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H) , 7.45 (br t, 7=7.0 Hz, 1H), 7.39 7.30 (m, 1H), 7.24 - 7.14 (m, 2H), 5.37-5.11 (m, 1H), 4.61 - 4.46 (m, 1H), 4.05 (s, 3H), 3.75 (s, 2H), 3.18 - 3.03 (m, 1H), 2.95 (t, 7=8.2 Hz, 1H), 2.89 - 2.75 (m, 1H), 2.62 2.58 (m, 1H) . 218 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-PM-{ 1-[(2-bromo1,3-thiazol-5yl)methyl]- 4fluoropyrrolidin-3 yl}-2methoxypyr idine-3 carboxamide Br 615 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.35 (br d, 7=7.3 Hz, 1H), 8.17 (s, 1H), 7.58 (d, 7= 6.2 Hz, 2H), 5.32 - 5.11 (m, 1H), 4.66 - 4.45 (m, 1H), 4.08 (s, 3H), 3.99 - 3.91 (m, 2H), 3.14 - 3.07 (m, 1H), 3.03 (dd, 7=9.2, 7.7 Hz, 1H), 2.96 - 2.84 (m, 1H), 2.69 (t, 7=8.3 Hz, 1H). 219 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1] [ 1,2,4]triazin-7yl]-PM-{1-[(1benzyl-1nimidazol-5yl)methyl]-4fluoropyrrolidin-3 yl}-2methoxypyridine-3 carboxamide N~\ ^N=/ o 610.2 8.92 (d, 7=2.2Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.32 (br d, 7=7.0Hz, 1H), 8.17 (s, 1H), 7.72 (s, 1H) , 7.57 (s, 1H), 7.42 - 7.23 (m, 3H), 7.23 - 7.17 (m, 2H), 6.87 (s, 1H), 5.27 (s, 2H), 5.25 - 5.09 (m, 1H), 4.55 - 4.45 (m, 1H), 4.06 (s, 3H), 3.58-3.51 (m, 2H), 3.08 - 2.94 (m, 1H), 2.92 - 2.86 (m, 1H), 2.83 2.69 (m, 1H), 2.55 (br t, 7=8.6 Hz, 1H).

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220 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-L1-{1-[(1-ethyl1H-imide azol-5yl)methyl] -4fluoropyrrolidin-3 yl}-2methoxypyr idine-3 carboxamide 548.2 8.92 (d, 7=2.6Hz, 1H), 8.85 (d, 7=2.6Hz, 1H), 8.34 (br d, 7=6.2Hz, 1H), 8.16 (s, 1H), 7.57 (s, 2H) , 5.40 - 5.08 (m, 1H), 4.66 - 4.42 (m, 1H), 4.07 (s, 3H), 4.02 (d, 7=7.0 Hz, 2H), 3.68 (br s, 2H), 3.11 - 2.98 ( m, 1H), 2.96 - 2.88 (m, 1H), 2.87 - 2.75 (m, 1H), 2.67 - 2.56 (m, 1H), 1.35 (t, 7=7.2 Hz, ZN). 221 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazin-7yl]-M-{ 1-[(3-bromo1,2-oxazol-5yl)methyl]-4fluoropyrrolidine -3 yl}-2methoxypyr idine-3 carboxamide °'N 599 8.92 (d, 7=2.6Hz, 1H), 8.83 (d, 7=2.2Hz, 1H), 8.36 (br d, 7=7.7Hz, 1H), 8.17 (s, 1H), 7.57 (s, 1H) , 6.75 (s, 1H), 5.32-5.12 (m, 1H), 4.64 - 4.49 (m, 1H), 4.07 (s, 3H), 3.99 - 3.89 (m, 2H), 3.18 - 3.10 (m, 1H) , 3.07 (t, 7=8.4 Hz, 1H), 3.01 2.87 (m, 1H), 2.74 (t, 7=8.4 Hz, 1H). 222 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-{l-[(l,3benzothiazol-2yl)methyl]-4fluoropyrrolidin-3yl }-2methoxypyr idine-3 carboxamide /xA S ZA 587.1 8.93 (d, 7=2.6 Hz, 1H), 8.85 (d, 7=2.6 Hz, 1H), 8.41 (br d, 7=7.0 Hz, 1H), 8.16 (s, 1H), 8.07 (d, 7= 7.7 Hz, 1H), 7.95 (d, 7=8.4 Hz, 1H), 7.58 (s, 1H), 7.54 - 7.46 (m, 1H), 7.45 - 7.40 (m, 1H), 5.37 5.17 (m, 1H) , 4.72 - 4.58 (m, 1H), 4.26 - 4.19 (m, 2H), 4.10 (s, 3H), 3.39 - 3.02 (m, 3H), 2.89 (t, 7=8.8 Hz, 1H). 223 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazin-7yl]-LF(4-fluoro-1{[1-(2methoxyethyl)-1nimidazol-5yl]methyl} pyrroly din-3 -yl)-2methoxypyr idine-3 carboxamide MeO 578.2 8.92 (d, 7=2.6Hz, 1H), 8.85 (d, 7=2.6Hz, 1H), 8.35 (br d, 7=7.3Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.54 (s, 1H), 6.79 (s, 1H), 5.32 5.11 (m, 1H), 4.62 - 4.47 (m, 1H), 4.16 (t, 7=5.5 Hz, 2H), 4.07 (s, 3H) , 3.72 - 3.64 (m, 2H), 3.63 (t, 7=5.5 Hz, 2H), 3.25 (S, 3H), 3.09 - 2.95 (m, 1H), 2.93 - 2.87 (m, 1H), 2.87 2.76 ( m, 1H), 2.59 (t, 7=8.4 Hz, 1H).

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224 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7yl]-H-{1-[(4xl orphenyl)methyl]4-fluoropyrrolidin3-yl}- 2methoxypyr idine-3 carboxamide l O 564 8.91 (d, 7=2.2 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.36 (br d, 7=8.1 Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H) , 7.44 - 7.31 (m, 4Н), 5.33 - 5.09 (br, 1Н), 4.63 - 4.48 (m, 1Н), 4.08 (s, ЗН), 3.73 - 3.65 (m, 2Н), 3.153.02 (m, 1Н), 2.98 - 2.92 (m, 1Н), 2.87 - 2.77 (m, 1Н), 2.62 (t, 7=8.3 Hz, 1Н). 225 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7Ηπ]-Ν-{4-φτορ-1[(quinolin-2yl)methyl] pyrrolide in-3 -yl}-2methoxypyr idine-3 carboxamide ABOUT 581.1 8.92 (d, 7=2.2 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.38 (br d, 7=8.1 Hz, 1H), 8.34 (d, 7=8.4 Hz, 1H), 8.16 (s, 1H), 8.01-7.97 (m, 1H), 7.96 (br d, 7=8.4 Hz, 1H), 7.78 7.72 (t, 1H), 7.64 (d, 7=8.4 Hz, 1H), 7.61 - 7.56 (t, 2H), 5.33 - 5.17 (t, 1H), 4.68 - 4.55 (t, 1H), 4.08 (s, 3H), 4.06 - 3.98 (t, 2H), 3.28 - 3.19 (t, 1H), 3.13 - 3.06 (t, 1H), 3.04 - 2.90 (t, 1H), 2.76 (t, 7=8.6 Hz, 1H). 226 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7Ηπ]-Ν-{4-φτορ-1[(quinolin-8yl)methyl] pyrrolide in-3 -yl}-2methoxypyr idine-3 carboxamide Lu 581.1 8.94 (dd, 7=4.2, 1.7 Hz, 1H), 8.91 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.40 - 8.35 (t, 2H), 8.16 (s , 1Н), 7.89 (d, 7=8.1 Hz, 1Н), 7.85 (d, 7=6.2 Hz, 1Н), 7.62 (t, 7=7.5 Hz, 1Н), 7.57 (s, 1Н), 7.55 (dd , 7=8.3, 4.2 Hz, 1H), 5.34 - 5.14 (t, 1H), 4.64 - 4.54 (t, 1H), 4.42 (s, 2H), 4.07 (s, 3H), 3.26-3.17 (t, 1H ), 3.12 -3.05 (t, 1H), 3.022.91 (t, 1H), 2.76 (t, 7=8.4 Hz, 1H). 227 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ηπ]-Ν-{1-[(3cyanophenyl)methyl]-4fluoropyrrolidin-3 yl}-2methoxypyridine -3 carboxamide z o g 555 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.2 Hz, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H), 7.77 (s, 1H) , 7.72 (br d, 7=7.7 Hz, 1H), 7.71 7.68 (t, 1H), 7.59 - 7.55 (t, 2H), 5.33 - 5.09 (t, 1H), 4.65 - 4.52 (t, 1H), 4.08 (s, ZN), 3.82 - 3.73 (t, 2H), 3.18 -3.04 (t, 1H), 3.002.95 (t, 1H), 2.91 -2.78 (t, 1H), 2.65 (t, 7=8.3 Hz , 1H).

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228 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-H-(4-fluoro-1{[3(trifluoromethyl)phenyl]methyl}pyrroli din-3-yl)-2methoxypyr idine-3 carboxamide SO o r 598.1 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.3 Hz, 1H), 8.16 (s, 1H), 7.69-7.58 (m, 4H), 7.57 (s, 1H), 5.33–5.15 (m, 1H), 4.66–4.51 (m, 1H), 4.07 (s, 3H), 3.85–3.78 (m, 2H), 3.15–3.04 (t, 1H ), 3.00 - 2.96 (t, 1H), 2.90 - 2.81 (t, 1H), 2.66 (t, 7=8.6 Hz, 1H). 229 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7 _Ηπ ]-N-{1-[(2,6dichlorophenyl)methyl]-4fluoropyrrolidin-3yl} -2methoxypyr idine-3 carboxamide CI 598 8.91 (d, 7=2.2 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.34 (br d, 7=8.1 Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H) , 7.48 (d, 7=8.1 Hz, 2H), 7.38 - 7.31 (t, 1H), 5.33 - 5.11 (t, 1H), 4.57 4.47 (t, 1H), 4.06 (s, 3H), 3.97 (s, 2Н), 3.30 -3.16 (t, 1Н), 3.083.03 (t, 1Н), 2.99 -2.89 (t, 1Н), 2.73 (t, 7=8.3 Hz, 1Н). 230 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-T4-{4-fluoro-1[(5-fluoro-pyridin-3yl)methyl ]in-3-yl pyrrolide}-2methoxypyr idine-3 carboxamide, 2 TFA F 549.1 8.93 (d, 7=2.4 Hz, 1H), 8.81 (d, 7=2.4 Hz, 1H), 8.70 - 8.49 (t, 2H), 8.17 (s, 1H), 8.01-7.77 (t, 1H), 7.61 (s, 1H), 7.27 - 6.95 (t, 1H), 5.56 - 5.16 (t, 1H), 4.88 - 4.45 (t, 1H), 4.05 (s, 3H), 4.01 - 3.94 (t, 2H), 3.67 -3.57 (t, 1H), 3.543.46 (t, 1H), 3.39 - 3.28 (t, 1H), 3.13 -3.05 (t, 1H). 231 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7yl]-T4-{4-fluoro-1[(pyridin-4yl)methyl] pyrrolide in-3- yl}-2methoxypyr idine-3 carboxamide 531.2 8.92 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.53 (d, 7=5.9Hz, 2H), 8.37 (br d, 7=8.1Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.35 (d,7=5.9 Hz, 2H), 5.34 - 5.10 (t, 1H), 4.67 4.50 (t, 1H), 4.08 (s, 3H), 3.79 3.71 (t, 2H), 3.12 - 3.05 (t, 1H), 3.01 - 2.96 (t, 1H), 2.93 - 2.76 (t, 1H), 2.67 (t, 7=8.4 Hz, 1H).

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232 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazine-7Ηπ]-N-(4-φτορ-1{[2(trifluoromethyl)phenyl]methyl}pyrrolidine -3-yl)-2methoxypyr idine-3 carboxamide T 598.2 8.92 (d, 7=2.6 Hz, 1H), 8.85 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.7 Hz, 1H), 8.16 (s, 1H), 7.79 (d, 7= 7.7 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.57 (s, 1H), 7.48 - 7.47 (m, 1H), 5.35-5.11 (m, 1H), 4.66 - 4.56 (m, 1H), 4.08 (s, 3H), 3.93 - 3.85 (m, 2H), 3.18 - 3.07 (m, 1H), 2.99 (t, 7=8.3 Hz, 1H), 2.93 - 2.83 (m, 1H), 2.70 (t, 7 =8.3 Hz, 1H). 233 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazin-7yl]-T4-{4-fluoro-1[(4methylphenyl)methyl]pyrrolidin-3-yl} 2 -methoxypyridine3-carboxamide 544.2 8.92 (d, 7=2.2Hz, 1H), 8.85 (d, 7=2.2Hz, 1H), 8.35 (br d, 7=7.7Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.25 - 7.18 (m, 7=7.7 Hz, 2H), 7.18 - 7.12 (m, 2H), 5.31 - 5.08 (m, 1H), 4.54 (td, 7=13.8, 7.0 Hz, 1H), 4.08 (s , 3H), 3.69 - 3.61 (m, 2H), 3.15 2.98 (m, 1H), 2.96 - 2.90 (m, 1H), 2.85 -2.74 (m, 1H), 2.59 (br t, 7=8.6 Hz, 1H ), 2.30 (s, 3H). 234 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-X-{1-[(2,5difluorophenyl)methyl]-4fluoropyrrolidin-3yl} -2methoxypyr idine-3 carboxamide F 566.2 8.92 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.6Hz, 1H), 8.36 (br d, 7=7.3Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.31 - 7.26 (m, 1H), 7.23 (td, 7=9.2, 4.4 Hz, 1H), 7.19 - 7.12 (m, 1H), 5.32 - 5.14 (m, 1H), 4.63 - 4.53 (m, 1H) , 4.07 (s, 3H), 3.81 -3.71 (m, 2H), 3.15 -3.05 (m, 1H), 3.022.98 (m, 1H), 2.93 - 2.80 (m, 1H), 2.67 (t, 7= 8.6 Hz, 1H). 235 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1D[1,2,4]triazin-7yl]-M-[4-fluoro-1[(4-fluoro-3methylphenyl)methyl]pyrrolidine-3 -yl } 2-methoxypyridine3-carboxamide ΊΤ ^F 562.2 8.91 (d, 7=2.6Hz, 1H), 8.84 (d, 7=2.4Hz, 1H), 8.42 (br d, 7=7.3Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H) , 7.24 (br d, 7=7.0 Hz, 1H), 7.20 7.14 (m, 1H), 7.14 - 7.06 (m, 1H), 5.34 - 5.10 (m, 1H), 4.62 - 4.40 (m, 1H), 4.05 (s, 3H), 3.71 - 3.55 (m, 2H), 3.14 - 2.99 (m, 1H), 2.92 (br s, 1H), 2.84 - 2.72 (m, 1H), 2.62 2.54 (m, 1H), 2.29 - 2.18 (m, 3H).

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236 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7ππ]-N-(4-φτορ-1{[3-fluoro-4(trifluoromethoxy)phenyl ] methyl } pyrrole idin-3 -yl)-2methoxypyr idine-3 carboxamide ^YOCF _3F 632.2 8.92 (d, 7=2.4Hz, 1H), 8.83 (d, 7=2.4Hz, 1H), 8.44 (d, 7=7.6Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.57 - 7.45 (m, 2H), 7.30 (d, 7=8.2 Hz, 1H), 5.33-5.13 (m, 1H), 4.71 4.49 (m, 1H), 4.05 (s, 3H), 3.81 3.68 (m, 2Н), 3.19 - 3.02 (m, 1Н), 2.95 (t, 7=8.2 Hz, 1Н), 2.90 - 2.76 (br, 1Н), 2.64 (t, 7=8.4 Hz, 1Н). 237 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ππ]-Ν-{4-φτορ-1[(zmethylphenyl)methyl]pyrrolidin-3-yl } 2-methoxypyridine3-carboxamide At 544.2 8.92 (d, 7=2.6 Hz, 1H), 8.85 (d, 7=2.6 Hz, 1H), 8.36 (br d, 7=7.7 Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.28 - 7.18 (gp, 1H), 7.16 - 7.10 (br, 2H), 7.08 (br d, 7=7.7 Hz, 1H), 5.31 - 5.10 (m, 1H), 4.64 - 4.45 (m, 1H), 4.08 (s, ZH), 3.73 - 3.57 (m, 2H), 3.14 - 3.02 (gp, 1H), 3.00 - 2.91 (br, 1H), 2.88 - 2.73 (m, 1H), 2.60 (s, 1H), 2.31(s, 3N). 238 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-M-{1-[(3,5difluorophenyl)methyl]-4fluoropyrrolidin-3yl} -2methoxypyr idine-3 carboxamide p F 566.2 8.92 (d, 7=2.2 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.7 Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H) , 7.06 (br d, 7=6.6 Hz, ZN), 5.34 5.13 (br, 1Н), 4.70 - 4.49 (m, 1Н), 4.08 (s, ЗН), 3.80 - 3.67 (m, 2Н), 3.18 - 3.04 (gp, 1H), 3.02 - 2.94 (br, 1H), 2.92 - 2.79 (m, 1H), 2.68 2.64 (m, 1H). 239 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazin-7yl]-H-{1-[(5bromopyridin-3yl)methyl]-4fluoropyrrolidin-3yl} -2 methoxypyr idine-3 carboxamide, 2 TFA νφ Vg 609 8.97 - 8.90 (gp, 1H), 8.86 - 8.79 (br, 1H), 8.75 - 8.39 (w, W), 8.17(s, 1H), 8.10 -8.00 (m, 1H), 7.62 (s, 1H), 5.52 - 5.09 (t, 1H), 4.73 4.44 (t, 1H), 4.05 (s, 3H), 3.94 3.66 (t, 1H), 3.55 - 3.12 (t, 5H).

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240 In -3-yl}-2methoxypyr idine-3 carboxamide 580.1 8.91 (d, 7=2.2 Hz, 1H), 8.83 (d, 7=2.6 Hz, 1H), 8.34 (br d, 7=7.3 Hz, 1H), 8.28 (d, 7=8.1 Hz, 1H), 8.15 (s, 1H), 7.93 (d, 7=7.7 Hz, 1H), 7.85 (d, 7=8.1 Hz, 1H), 7.59 7.49 (m, 4H), 7.49 - 7.45 (t, 1H), 5.35 - 5.13 (t, 1H), 4.63 - 4.48 (t, 1H), 4.17 - 4.10 (t, 2H), 4.04 (s, 3H), 3.17 - 3.08 (t, 1H), 3.03 2.99 (t, 1H), 2.95 - 2.85 (t, 1H), 2.67 (t, 7=8.4 Hz, 1H). 241 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazin-7yl]-I-{1-[(4cyanophenyl)methyl]-4fluoropyrrolidin-3yl}- 2methoxypyr idine-3 carboxamide O 555.1 8.92 (d, 7=2.6 Hz, 1H), 8.84 (d, 7=2.6 Hz, 1H), 8.37 (br d, 7=7.0 Hz, 1H), 8.16 (s, 1H), 7.79 (d, 7= 8.1 Hz, 2H), 7.57 (d, 7=3.3 Hz, 2H), 7.55 (s, 1H), 5.33 - 5.14 (t, 1H), 4.66 - 4.52 (t, 1H), 4.08 (s, 3H), 3.86 - 3.74 (t, 2H), 3.133.05 (t, 1H), 3.00 - 2.95 (t, 1H), 2.92 - 2.78 (t, 1H), 2.68 - 2.63 (t, 1H). 242 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazine-7ππ]-Ν-{4-φτορ-1[(5-methyl-1,2oxazol- 3yl)methyl]pyrrolide in-3-yl}-2methoxypyr idine-3 carboxamide 535.1 8.92 (d, J=2.2Hz, 1H), 8.84 (d, J=2.6Hz, 1H), 8.36 (br d, J=8.1Hz, 1H), 8.17 (s, 1H), 7.57 (s, 1H) , 6.20 (s, 1H), 5.30 - 5.12 (m, 1H), 4.61 4.49 (m, 1H), 4.07 (s, 3H), 3.79 3.66 (m, 2H), 3.21-3.08 (m, 1H, partially suppressed ), 3.05 - 2.98 (m, 1H), 2.95 - 2.82 (m, 1H), 2.68 (t, 1=8.4Hz, 1H), 3.41 (s, 3H)

Connections in the table. 9 was prepared by the methods detailed in Example 3. For tertiary amides, the full amine is designated as the R group. In cases with uncertain stereochemistry, the compounds were isolated as racemic or diastereomeric mixtures.

Table 9

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 243 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ππ]-2-φτορ-N-(3phenylbutyl)benzamide 472.1 8.43 (br. s., 1H), 8.21 (d, J=5.4 Hz, 1H), 8.15 (br. s., 2H), 7.56 (s, 1H), 7.41 (t, J=9.1 Hz, 1H) , 7.29 (d, J=7.2 Hz, 2H), 7.27 - 7.22 (m, 2H), 7.19 (d, J=7.0 Hz, 1H), 3.26 - 3.07 (m, 2H), 2.80 (d, J=6.8 Hz, 1H), 1.80 (d, J=7.1 Hz, 2H), 1.23 (d, J=6.6 Hz, ZN) 244 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7ππ]-2-φτορ-N-[(2phenoxyphenyl)methyl]benzamide λ o 521.8 8.89 (br. s., 1H), 8.26 (d, J=4.9 Hz, 1H), 8.19 (dd, J=6.0, 2.5 Hz, 1H), 7.56 (s, 1H), 7.49 - 7.41 (m, 2H ), 7.37 (t, J=7.8Hz, 2H), 7.30 (t, 1=7.6Hz, 1H), 7.19 (t, J=7.4Hz, 1H), 7.10(1, J=7.3Hz, 1H), 7.00 (d, J=8.0Hz, 2H), 6.89 (d, J=8.0Hz, 1H), 4.51 (d, J=5.6Hz, 2H)

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245 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ιιπ]-2-φτορ-Ν-(3hydroxy-3phenylpropyl)benza MFA HE 474.1 8.44 (br. s., 1H), 8.26 (d, J=4.8 Hz, 1H), 8.17 (s, 2H), 7.57 (s, 1H), 7.48 - 7.42 (m, 1H), 7.39 - 7.29 (m, 4H), 7.27 - 7.18 (m, 1H), 4.66 (d, J=4.5Hz, 1H), 1.86 (q, J=6.6Hz, 2H) 246 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7nn]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl] 2-fluorobenzamide He 508.2 8.43 (br. s., 1H), 8.29 - 8.22 (m, 1H), 8.21 - 8.13 (m, 2H), 7.57 (s, 1H), 7.47 - 7.35 (m, 4H), 5.45 (d, >4.6 Hz, 1H), 4.72–4.63 (m, 1H), 3.36–3.27 (m, 1H), 1.91–1.79 (m, 2H). 247 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-N-[3-(4fluorophenyl)-3hydroxypropyl]benzamide he ^a _F 492.3 8.44 (br. s., 1H), 8.26 (d, J=6.7 Hz, 1H), 8.21 - 8.14 (m, 2H), 7.56 (s, 1H), 7.46-7.35 (m, 3H), 7.15 (t , J=8.7 Hz, 2H), 5.41 (d, J=4.3 Hz, 1H), 4.73 - 4.64 (m, 1H), 3.34 (d, J=6.4 Hz, 1H), 1.85 (q, J=6.8 Hz , 2H). 248 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl] 2-fluorobenzamide )Ό ___/ ΞΓ O O 508.1 8.43 (br. s., 1H), 8.25 (d, >6.7 Hz, 1H), 8.17 (s, 2H), 7.56 (s, 1H), 7.47 - 7.33 (m, 4H), 5.46 (d, J= 4.3 Hz, 1H), 4.73 - 4.61 (m, 1H), 3.34 (d, J=4.9 Hz, 1H), 1.91 - 1.77 (m, 2H). 249 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-M(4,4,4-trifluoro-3hydroxy-3phenylbutyl)benzamide 542.2 8.44 - 8.29 (m, 1H), 8.23 - 8.11 (m, 3H), 7.66 - 7.59 (m, 2H), 7.58 - 7.53 (m, 1H), 7.47 - 7.34 (m, 4H), 3.45 - 3.37 (m , 2H), 3.363.27 (m, 1H), 3.20-3.12 (m, 1H), 3.02-2.91 (m, 1H), 2.35 - 2.21 (m, 1H) 250 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-M-[(2phenyloxan-3yl)methyl]benzamide 514.1 8.19 (br. s., 1H), 8.15 (br. s., 3H), 7.53 (s, 1H), 7.45 - 7.29 (m, 5H), 7.23 (d, J=6.7 Hz, 1H), 4.68 ( br. s., 1H), 4.13 (d, >6.7Hz, 1H), 2.72 (d, J=13.4 Hz, 1H), 2.24 (br. s., 1H), 1.97 (d, J=13.1 Hz, 1H), 1.91 (br. s., 1H), 1.79 (br. s., 1H), 1.37 (d, >13.1Hz, 1H). 251 tert-butyl (3S)-3{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2fluorobenzamido}pyrrolidine-1carboxylate 10 531.1 8.81 - 8.66 (m, 1H), 8.25 - 8.08 (m, 3H), 7.56 - 7.48 (m, 1H), 7.48 - 7.32 (m, 1H), 4.48 -4.34 (m, 2H), 3.21-3.13 (m , 3H), 2.57 2.53 (m, 2H), 2.17 - 2.05 (m, 1H), 1.98 - 1.80 (m, 1H), 1.45 - 1.28 (m, 9H)

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252 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7ππ]-2-φτορ-Ν[(3R,4S)-4^to _P -1(3fluorocyclobutane pbonyl)pyrrolidi n-3-yl]benzamide B. -Ν Ρ % F 527.2 8.75 (br dd, J=13.6, 7.2 Hz, 1H), 8.28 - 8.20 (m, 2H), 8.18 (s, 1H), 7.58 (d, J=2.4 Hz, 1H), 7.45 (t, J=9.3 Hz, 1H), 5.38 - 5.02 (m, 2H), 4.79 - 4.56 (m, 1H), 3.943.16 (m, 4H), 3.24 - 3.16 (m, 1H), 2.59 - 2.32 (m, 5H, absorbed DMSO) 253 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ππ]-2-φτορ-N[(3K,48)-4-fluoro-1(sfluorocyclobutane pbonyl )pyrrolidi n-3-yl]benzamide F^_ 4F 527.2 8.62 (br d, J=7.0 Hz, 1H), 8.25 (br d, J=4.5 Hz, 1H), 8.18 (dt, J=5.8, 2.7 Hz, 1H), 8.14 (s, 1H), 7.51 (s , 1H), 7.45 - 7.38 (m, 1H), 5.38 5.18 (m, 1H), 5.07 - 4.88 (m, 1H), 4.79 - 4.52 (m, 1H), 3.93 - 3.14 (m, 4H, absorbed by water) , 2.65 2.37 (m, 2H, absorbed by DMSO), 2.85 - 2.68 (m, 1H), 2.33 - 2.13 (m, 2H) 254 255 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-1(3,3difluorocyclobutane carbonyl)-4fluoropyrrolidine-3 yl]-2fluorobenzamide 4fluoropyrrolidin-3 yl]-2fluorobenzamide, TFA F^ F τ F 545.0 573.1 8.62 (br d, J=7.0 Hz, 1H), 8.25 (br t, J=5.3 Hz, 1H), 8.21 -8.16(m, 1H), 8.14 (s, 1H), 7.51 (s, 1H), 7.45 -7.37 (m, 1H), 5.39-5.18 (m, 1H), 4.81-4.53 (m, 1H), 3.93 3.27 (m, 4H, absorbed by water), 3.21 -3.09(m, 1H), 2.87-2.68 ( m, 4H) 8.76 (br dd, J=18.6, 7.3 Hz, 1H), 8.29 - 8.20 (m, 2H), 8.18 (s, 1H), 7.58 (br s, 1H), 7.49-7.41 (m, 1H), 5.42- 5.17 (m, 1H), 4.85 4.57 (m, 1H), 4.15-3.23 (m, 4H), 2.06 (brd, 1=11.6Hz, 2H), 1.991.68 (m, 5H), 1.59 (brd, J =11.6Hz, 2H)

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256 257 258 259 260 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7yl]-2-fluoro-H[(3K,48)-4-fluoro-1(4fluorobenzoyl)pyrro LIDIN-3 yl] benzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-l(3,3difluorocyclopenta ncarbonyl)-4fluoropyrrolidine-3 yl]-2fluorobenzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ππ]-2-φτορ-Ν[(3K,48)-4-fluoro-1(oxane- 4carbonyl)pyrrolide in-3-yl]benzamide 2,2difluorocyclopropane ncarbonyl)-4fluoropyrrolidin-3 yl]-2fluorobenzamide ^F \___ O F A \ .o A m. 549.3 559.2 539.2 531.3 500.3 8.73 - 8.54 (m, 1H), 8.30-8.11 (m, ZH), 7.62 (br d, Т=5.9Hz, 2H), 7.50 (br s, 1H), 7.41 (br s, 1H), 7.33 - 7.22 (m, 2H), 5.45 - 5.17 (m, 1H), 4.83 - 4.56 (m, 1H), 4.03 - 3.33 (m, 4H, absorbed by water) 8.62 (br d, J=5.8Hz, 1H), 8.25 (br t, 3=6.1Hz, 1H), 8.21 -8.16(m, 1H), 8.14 (s, 1H), 7.51 (s, 1H), 7.42 (td, J=9.4, 3.7 Hz, 1H), 5.42 -5.18(m, 1H), 4.82 - 4.54 (m, 1H), 4.09 -3.83 (m, 2H), 3.75 3.41 (m, W, absorbed by water) , 3.26 -3.07 (m, 1H), 2.702.45(m, 2H, absorbed by DMSO), 2.41 -2.00 (m, 4H), 1.91 - 1.69 (m, 1H) 8.74 (br dd, J=11.1, 7.8 Hz, 1H), 8.30 - 8.20 (m, 2H), 8.19 (s, 1H), 7.59 (d, J=3.4 Hz, 1H), 7.45 (td, J=9.3 , 3.1Hz, 1H), 5.41 -5.17 (m, 1H), 4.83 - 4.56 (m, 1H), 4.15 - 2.98 (m, 8H, absorbed by water), 2.78 -2.63 (m, 1H), 1.67-1.52 ( m, 4H) 8.77 - 8.60 (m, 1H), 8.28 - 8.22 (m, 1H), 8.21 - 8.15 (m, 1H), 8.14 (s, 1H), 7.50 (s, 1H), 7.45 - 7.37 (m, 1H), 5.45 - 5.18 (m, 1H), 4.84 - 4.58(m, 1H), 4.26 - 3.48 (m, 4H, absorbed by water), 3.06 2.77 (m, 1H), 1.99 - 1.77 (m, 2H) 8.13 (s, 2H), 8.10-7.98 (m, 1H), 7.51 (brd, >8.7Hz, 1H), 7.446.98 (m, 6H), 4.0 - 2.65 (m, 9H, absorbed by water)

Connections in the table. 10 was obtained by the methods detailed in examples 11 and 12. In cases with uncertain stereochemistry, the compounds were isolated as diastereomeric mixtures.

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Table 10

Example Name R May observed in MS the mass of the ion Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 261 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3S)-l-(3,3dimethylbutanoyl)pyrrolidin-3-yl] - 2- methoxypyridine3-carboxamide 520.0 8.85 (s, 1H), 8.59 (s, 1H), 8.13 (s, 1H), 7.55 (s, 1H), 4.52 - 4.34 (m, 1H), 3.97 (s, 3H), 3.61 -3.51 (m, 1H), 3.48 - 3.40 (m, 1H), 3.40 - 3.29 (m, 1H), 2.21 - 2.07 (m, 3H), 2.02 1.95 (m, 1H), 0.97 (d, J=6.4 Hz, JH) 262 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2-methoxy-M- [(3S)-l-[3,3,3trifluoro-2-methyl2(trifluoromethyl)propanoyl]pyrrolide in-3-yl]pyridine3-carboxamide ^^CF ₃ CF ₃ 613.9 8.89 (s, 1H), 8.62 (s, 1H), 8.50 (d, J=5.9 Hz, 1H), 8.15 (s, 1H), 7.59 (s, 1H), 4.48 (br. s., 1H), 3.98 (s, 4H), 1.85 (br. s.,4H), 1.31 - 1.11 (m, 2H) 263 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3S)-lcyclohexanecarbonylpyrrolidine-3 - silt]-2- methoxypyridine3-carboxamide 532.1 8.88 (d, J=1.8 Hz, 1H), 8.62 (br. s., 1H), 8.53 - 8.39 (m, 1H), 8.15 (s, 1H), 7.58 (s, 1H), 4.49 (d, J =5.5 Hz, 1H), 3.98 (s, 3H), 3.60 - 3.52 (m, 1H), 3.37 - 3.26 (m, 1H), 2.42 - 2.31 (m, 1H), 2.08 (dd, J=13.7, 7.3 Hz, 1H), 1.96 - 1.85 (m, 1H), 1.68 (br. s., 4H), 1.61 (br. s., 1H), 1.38-1.19 (m, 6H), 1.15 (d, J=9.2 Hz, 1H) 264 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3S)-lcyclopentanecarbonylpyrrolidin-3yl]-2methoxypyridine3-carboxamide 518.3 8.89 (s, 1H), 8.63 (s, 1H), 8.55 - 8.40 (m, 1H), 8.16 (d, J=2.4Hz, 1H), 7.59 (s, 1H), 4.50 (d, J=5.2Hz , 1H), 4.47 4.39 (m, 1H), 3.99 (d, J=2.1 Hz, ZH), 3.70 - 3.54 (m, 1H), 3.40 - 3.26 (m, 1H), 2.91 - 2.75 (m, 1H) , 2.16 - 2.07 (m, 1H), 1.96 - 1.88 (m, 1H), 1.77 (d, J=7.9 Hz, 2H), 1.63 (br. s., 4H), 1.52 (br. s., 2H) 265 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3S)-lcyclobutanecarbon ylpyrrolidin-3yl]-2methoxypyridine3-carboxamide 504.3 8.89 (s, 1H), 8.62 (s, 1H), 8.44 (dd, 1=12.7, 6.9 Hz, 1H), 8.16 (d, J=3.1 Hz, 1H), 7.59 (s, 1H), 4.51 - 4.37 (m, 1H), 3.99 (s, 3H), 3.66 - 3.53 (m, 1H), 3.35 - 3.18 (m, 2H), 2.25 - 2.03 (m, 5H), 2.02 - 1.94 (m, 1H), 1.94 - 1.83 (m, 2H), 1.74 (br. s., 1H)

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266 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3S)-1-(3,3difluorocyclobutane carbonyl)pyrrole idine-3- yl]-2methoxypyridine3-carboxamide A F 540.4 8.89 (t, J=2.1Hz, 1H), 8.62 (dd, J=4.9, 2.3Hz, 1H), 8.50 (t, J=8.1Hz, 1H), 8.17 (d, J=2.8Hz, 1H), 7.66 7.55 (m, 1H), 4.58 - 4.38 (m, 1H), 3.99 (s, 3H), 3.70 (dd, 1=10.6, 6.3 Hz, 1H), 3.49-3.41 (m, 2H), 3.20 - 3.06 (m, 1H), 2.86 - 2.69 (m, 4H), 2.25 2.07 (m, 1H), 2.06 - 1.86 (m, 1H) 267 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-N-[(3S)-1-(3,3 difluorocyclopenta ncarbonyl)pyrrole idine-3 -yl]-2methoxypyridine3-carboxamide ^{F ?} \/ ^F 554.0 8.89 (s, 1H), 8.62 (br. s., 1H), 8.48 (dd, J=16.6, 6.9 Hz, 1H), 8.16 (d, J=2.4 Hz, 1H), 7.59 (s, 1H), 4.51 (d, J=5.8 Hz, 1H), 4.44 (br. s., 1H), 3.99 (s, 3H), 3.86 - 3.74 (m, 1H), 3.62 (br. s., 1H), 3.24 - 3.07 (m, 1H), 2.34 - 2.24 (m, 2H), 2.17 - 1.99 (m, 4H), 1.99 - 1.88 (m, 1H), 1.87 - 1.72 (m, 1H).

Connections in the table. 11 was obtained by the methods detailed in example 17. In cases with uncertain stereochemistry, the compounds were isolated as a racemic mixture.

Table 11

O ^R

Anh ii ah/ ^f

Η ₂ ΝΑα \=N N>

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 268 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-P-[1(cyclopropylmethyl)-1H-pyrazol-4-yl]2-fluoropyridin- 3 carboxamide 461.3 0.75 (br. s., 1H), 9.06 (d, J=1.9 Hz, 1H), 8.93 (dd, J=8.8, 2.3 Hz, 1H), 8.23 (s, 1H), 8.13 (s, 1H), 7.80 (s, 1H), 7.57 (s, 1H), 3.97 (d, >7.2Hz, 2H), 1.23 (t, J=7.4Hz, 1H), 0.62 - 0.48 (m, 2H), 0.37 (q, >4.7Hz, 2H) 269 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7mi]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl]-2fluoropyridine-3carboxamide HE 509.0 8.99 (s, 1H), 8.81 (d, J=8.1 Hz, 1H), 8.62 (br. s., 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.39 (s, 4H), 4.68 (d, >4.9Hz, 1H), 3.48 (br. s., 1H), 1.95 - 1.73 (m, 2H) 270 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-H-(1-benzyl-1Hpyrazol-4-yl)-2fluoropyridine-3carboxamide de r- ^N Λ' ^Ν 497.2 10.80 (br. s., 1H), 9.03 (br. s., 1H), 8.90 (d, J=8.6 Hz, 1H), 8.17 (s, 1H), 8.21 (s, 1H), 7.77 (br. s., 1H), 7.61 (s, 1H), 7.43-7.19 (m, 5H), 5.33 (s, 2H)

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271 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-M-(3phenylbutyl)pyridi n-3-carboxamide 473.1 8.96 (br. s., 1H), 8.75 (d, J=8.2 Hz, 1H), 8.59 (br. s., 1H), 7.72 (s, 1H), 7.40 - 7.22 (br, 3H), 7.22 - 7.12(br, 2H), 3.18 (br. s., 1H), 2.82 (d, J=13.7 Hz, 2H), 1.82 (d, J=7.0 Hz, 1H), 1.62 (d, J=7.0 Hz, 1H), 1.24 (d, J=6.4Hz, 2H), 1.17 (d, J=6.4Hz, 2H) 272 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-M-[3-(4fluorophenyl)-3hydroxypropyl]pyridine-3 carboxamide He 493.0 8.98 (s, 1H), 8.81 (d, J=8.9 Hz, 1H), 8.61 (br. s., 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.40 (t, J=6.9 Hz, 2H), 7.15 (t, J=8.5 Hz, 2H), 5.42 (d, J=4.3 Hz, 1H), 4.68 (d, J=5.2 Hz, 1H), 1.86 (q, J=6.7 Hz, 2H). 273 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-N-(4,4,4trifluoro-3hydroxy-3phenylbutyl)pyridi n- 3-carboxamide 543.3 9.00 (s, 1H), 8.77 (d, J=8.8 Hz, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.63 (d, J=7.6 Hz, 2H), 7.50 7.42 (m, 2H), 7.42-7.31 (m, 1H), 2.99 (br. s., 1H), 2.36 - 2.23 (m, 1H), 1.62 (s, 1H).

Connections in the table. 12 was prepared by the methods detailed in Example 18. For tertiary amides, the full amine is shown as the R group. When the diastereomers were separated, they were included as separate data. Indeterminate stereochemistry means isolation as a racemic or diastereomeric mixture.

Table 12

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 274 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7Hi]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl]pyridine- 3 carboxamide HE 491.1 9.35 (s, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.72 (br. s., 1H), 8.22 (s, 1H), 7.73 (s, 1H), 7.53 - 7.34 (m , 4H), 5.45 (br. s., 1H), 4.76–4.58 (m, 1H), 1.97–1.78 (m, 2H). 275 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1Ι] [1,2,4]triazine-7- yl]-M-(3phenylbutyl)pyridium n-3-carboxamide 455.3 9.34 (s, 1H), 8.93 (s, 1H), 8.76 (br. s., 1H), 8.67 (br. s., 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.36 7.23 (m, 4H), 7.22-7.13 (m, 1H), 3.31-3.09 (m, 2H), 2.882.75 (m, 1H), 1.95 - 1.78 (m, 2H), 1.24 (d, >6.7Hz, ZN).

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276 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-N-(1-benzyl-1Hpyrazol-4yl)pyridine-3carboxamide r-N 479.1 9.38 (s, 1Н), 9.06 (s, 1Н), 8.92 (br. s., 1Н), 8.22 (s, 1Н), 8.18 (s, 1Н), 7.76 (s, 1Н), 7.66 (s, 1Н ), 7.42 - 7.18 (m, 5H), 5.34 (s, 2H). 277 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]/-[(38)-3-(4chlorophenyl)-3hydroxypropyl]pyridine-3 carboxamide HE 491.0 9.35 (s, 1Н), 8.94 (s, 1Н), 8.78 (br. s., 1Н), 8.69 (br. s., 1Н), 8.21 (s, 1Н), 7.72 (s, 1Н), 7.38 ( br. s., 4H), 5.43 (d, J=4.3 Hz, 1H), 4.67 (d, J=4.9 Hz, 1H), 1.88 (d, J=6.7 Hz, 2H). 278 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]/-[(3R,48)-4fluoro-1-(2-fluoro-2methylpropanoyl)pi rrolidin-3yl] pyridine-3 carboxamide m 498.0 9.39 (s, 1Н), 9.03 (s, 1Н), 8.84 (s, 2Н), 8.21 (s, 1Н), 7.70 (s, 1Н), 5.45-5.19 (m, 1Н), 4.844.62 (m, 1H), 4.24 -3.20 (m, 4H, absorbed by water), 1.58 (s, 3H), 1.54 (s, 3H) 279 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]/-[(3R,48)-4fluoro-1-[(2C)-3,3 ,3trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]pyridine-3 carboxamide m, • He 550.2 9.42 (br s, 1Н), 9.05 (br s, 1Н), 9.02-8.92 (m, 1H), 8.88 (brs, 1H), 8.25 (br s, 1H), 7.77 (br s, 1H), 5.41 - 5.22 (m, 1H), 4.80 4.59 (m, 1H), 4.54 - 3.39 (m, 4H, absorbed by water), 1.58 (br s, 3H)

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280 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-1(4,4- 556.2 9.39 (s, 1Н), 9.03 (s, 1Н), 9.00 8.89 (m, 1Н), 8.85 (s, 1Н), 8.23 (s, 1Н), 7.74 (s, 1Н), 5.43 -5.19 (m, 1Н ), 4.89–4.60 (m, 1Н), 4.18–3.27 (m, 4Н, absorbed difluorocyclohexane A water), 2.07 (br d, J=7.9 Hz, carbonyl)-4fluoropyrrolidine-3 - F 2Н), 1.98-1.71 (m, 5Н), 1.68- 1.52 (m, 2H) yl] pyridine-3 carboxamide 5-[4-amino-5- — (trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7^]-N-[(3R,4S)-l- -A 9.37 (br s, 1H), 9.12-8.96 (t, 2H), 8.84 (brs, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 5.46 - 5.20 (t, 281 (2,2- d F 513.9 1H), 4.91 -4.62 (m, 1H), 4.29- difluorocyclopropane b A 3.39 (m, 4H, absorbed by water), carbonyl) -4- 3.10-2.84 (m, 1H), 2.03-1.81 fluoropyrrolidine-3 - (m, 2H) yl] pyridine-3 carboxamide 5-[4-amino-5- — (trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-l- 9.38 (s, 1H), 9.02 (s, 1H), 8.91 8.78 (m, 2H), 8.21 (s, 1H), 7.70 (s, 1H), 5.43 -5.19 (m, 1H), 4.88 282 (3,3- <· at 527.9 -4.56(w, 1h), 3.97 -3.26(w, difluorocyclobutane With A 4H, absorbed by water), 2.91 - arbonyl) -4- F 2.70 (w, W), 2.60 - 2.46 (m, 2H, fluoropyrrolidine-3 - absorbed by DMSO) yl] pyridine-3 carboxamide 5-[4-amino-5- — (trifluoromethyl)pyrr 9.38 (s, 1H), 9.05 - 8.93 (m, 2H), olo[2,1- 8.84 (s, 1Н), 8.21 (s, 1Н), 7.72 f] [ 1,2,4]triazine-7- P (s, 1H), 5.43 -5.19 (m, 1H), 4.87 №i]-N-[(3R,4S)-l- -4.58(w, 1h), 4.14 -3.38(w, 283 (3,3- 542.0 4H, absorbed by water), 3.29 - difluorocyclopentane At 3.08 (m, 1H), 2.40 - 2.25 (w, carbonyl)-4fluoropyrrolidin-3 yl]pyridine-3 carboxamide, TFA 2Н), 2.23 - 1.98 (br, ZN), 1.89- 1.73 (m, 1H)

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284 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(4fluorobenzoyl)pyrrolidin-3 yl] pyridine-3 carboxamide, TFA T F 532.1 9.36 (br d, J=12.5 Hz, 1H), 9.07 - 9.00 (m, 1H), 8.99 - 8.92 (m, 1H), 8.88 - 8.76 (m, 1H), 8.20 (br d, J=8.9 Hz, 1H), 7.71 (brd, J=13.1Hz, 1H), 7.63 (brd, J=7.6Hz, 2H), 7.30 (brt, 1=8.2Hz, 2H), 5.47-5.16 (m, 1H), 4.884 .60 (m, 1H), 4.12 - 3.54 (m, 4H, absorbed by water) 285 7-{5-[(3R)-3-[(4fluorophenyl)methyl]piperidin-1 carbonyl]pyridin3-yl}-5(trifluoromethyl)pyrr olo[2.11][1.2.4]triazine- 4amine ra _F 499.2 9.26 (br s, 1H), 8.63 - 8.33 (m, 2H), 8.21 (s, 1H), 7.75 (brd, J=19.8 Hz, 1H), 7.28 (br s, 1H), 7.15 (brd, J= 8.2 Hz, 1H), 6.99 (brs, 1H), 6.65 (brs, 1H), 3.572.20 (m, 6H, absorbed by DMSO), 1.89 - 1.59 (m, 3H), 1.57-1.38 (m, 1H), 1.27 (brd, J=7.0Hz, 1H) 286 7-{5-[(3S)-3-[(4fluorophenyl)methyl]piperidin-1 carbonyl]pyridin3-yl}-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine- 4amine, TFA ηχ 499.1 9.22 (br s, 1H), 8.63 - 8.23 (m, 2H), 8.16 (s, 1H), 7.66 (br s, 1H), 7.37 - 6.87 (m, 3H), 6.74 6.51 (m, 1H), 3.86 - 3.46 (m, 3H, absorbed by water), 2.98 - 2.24 (m, 2H, absorbed by DMSO), 1.95 - 1.12 (m, 6H) 287 7-[5-(2benzylmorpholine-4carbonyl)pyridine- 3-yl]-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-4amine ΧΌ 483.0 9.28 (s, 1H), 8.64 - 8.41 (m, 2H), 8.20 (s, 1H), 7.74 (br s, 1H), 7.40-7.18 (m, 3H), 7.15-6.89 (m, 2H), 4.05 -2.41 (m, 9H, absorbed by DMSO)

Connections in the table. 13 was obtained by the methods detailed in example 20. In cases with uncertain stereochemistry, the compounds were isolated as a racemic mixture.

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Table 13

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 288 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl]-2-methoxy-6methyl-M-(4,4,4trifluoro-3hydroxy-3phenylbutyl)pyridium n-3-carboxamide O 569.3 8.28 (t, J=5.3Hz, 1H), 8.02 (s, 1H), 8.06 (s, 1H), 7.59 (d, J=7.6Hz, 2H), 7.39 (t, J=7.5Hz, 2H), 7.35 - 7.29 (m, 1H), 7.25 (s, 1H), 4.00 (s, 3H), 3.63 (br. s., 1H), 3.24 (d, 1=4.9Hz, 1H), 3.11 (d, J =5.8 Hz, 1H), 2.29 (s, 3H), 2.25 -2.13 (m, 1H) 289 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1C[1,2,4]triazine-7Ni]-N-[(3R)-3-(4chlorophenyl)-3hydroxypropyl]-2methoxy-6methylpyr idine-3 carboxamide He 535.3 8.47 (t, J=5.2Hz, 1H), 8.10 (s, 1H), 8.03 (s, 1H), 7.36 (s, 4H), 7.26 (s, 1H), 4.68 (dd, J=7.6, 4.6Hz , 1H), 4.02 (s, 3H), 3.35 (d, J=5.8 Hz, 2H), 2.30 (s, 3H), 1.92 - 1.72 (m, 2H). 290 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7- yl]-H-[1(cyclopropylmethyl)-1H-pyrazol-4-yl] 2-methoxy-6methylpyridine-3 carboxamide 487.1 10.17 (s, 1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 3.93 (d, J=7.3 Hz, 2H), 2.33 (s , 3H), 1.22 (br. s., 2H), 0.51 (d, J=7.3 Hz, 2H), 0.34 (d, J=4.3 Hz, 2H).

Connections in the table. 14 were prepared by the methods detailed in Example 21. When the diastereomers were separated, they were included as separate data. Indeterminate stereochemistry indicates isolation of the compound as a mixture of diastereomers.

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Table 14

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 291 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7wi]-N-[(3S,4S)-lbenzoyl-4methylpyrrolidin-3 yl]-2-methylpyridine3- carboxamide 524.1 9.19 (s, 1H), 8.70 (t, J=8.4 Hz, 1H), 8.43 (s, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7.57 - 7.36 (m, 7H), 2.59 (s, 3H), 1.73 (br. s., 2H), 1.08 (d, J=6.7 Hz, 2H), 0.97 (d, J=6.7 Hz, 2H). 292 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazine-7m]-N-[(3S,4S)-1-(3,3difluorocyclobutane pbonyl)-4methylpyrrolidine-3 yl]-2-methylpyridine3-carboxamide h 538.1 9.16 (d, >5.2Hz, 1H), 8.73-8.56 (m, 1H), 8.38 (s, 1H), 8.17 (d, J=5.5Hz, 1H), 7.68 (d, J=9.8Hz, 1H) , 4.57 (d, J=13.4 Hz, 1H), 3.62 - 3.36 (m, 1H), 3.15 - 2.98 (m, 2H), 2.86 - 2.67 (m, 4H), 2.56 (s, 4H), 1.01 (d , J=6.7 Hz, ZN). 293 5-[4-amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7wi]-N-[(3S,4S)-1-(4,4difluorocyclohexane arbonyl)-4methylpyrrolidine-3 yl]-2-methylpyridine3-carboxamide b: 566.5 8.71 (d, J=8.5 Hz, 1H), 8.63 (d, J=8.2 Hz, 1H), 8.36 (s, 1H), 7.67 (d, >7.6 Hz, 1H), 4.59 (br. s., 1H ), 4.53 (br. s., 1H), 3.77 -3.65 (m, 1H), 3.02 (t, J=10.5 Hz, 1H), 2.55 (s, 3H), 2.06 (s, 1H), 2.02 (br s., 2H), 1.87 (d, 1=14.0 Hz, 1H), 1.84 - 1.70 (m, 3H), 1.56 (d, J=12.2 Hz, 2H), 1.30 - 1.22 (m, 3H), 1.02 (t, J=7.3 Hz, ZN). 294 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazine-7m]-N-[(3S,4S)-1-(3,3difluorocyclopentane arbonyl)-4methylpyrrolidine-3 yl]-2-methylpyridine3-carboxamide ^F Ύ Yf 552.5 9.14 (d, J=4.3Hz, 1H), 8.76 - 8.59 (m, 1H), 8.36 (s, 1H), 8.16 (d, J=4.6Hz, 1H), 7.66 (d, J=8.5Hz, 1H ), 4.63 - 4.48 (m, 1H), 3.80 (br. s., 1H), 3.43 (br. s., 1H), 3.22 - 3.06 (m, 2H), 2.55 (d, J=4.6 Hz, ZN ), 2.39 - 2.19 (m, 2H), 2.04 (d, J=17.1 Hz, VN), 1.79 (d, J=8.5 Hz, 1H), 1.01 (t, J=6.1 Hz, VN)

Connections in the table. 15 was obtained by the methods detailed in examples 14 and 19. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 15

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 295 296 297 298 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1- f] [ 1,2,4]triazine-7mi]-N-[(3S,4S)-lbenzoyl-4- methylpyrrolidin3-yl]-2- methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1- 1][1,2,4]triazine-7m]-N-[(3S,4S)-1cyclohexanecarboni l-4- methylpyrrolidin3-yl]-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7- mi]-N-[(3S,4S)-l- (3,3difluorocyclopentane carbonyl)-4- methylpyrrolidin3-yl]-2- methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1- 1][1,2,4]triazine-7mi]-N-[(3S,4S)-l(3,3difluorocyclobutane arbonyl)-4- methylpyrrolidin3-yl]-2- methoxypyride in-3 carboxamide FjV-f 540.3 546.4 567.9 554.4 8.87 (dd, J=15.9, 2.1 Hz, 1H), 8.59 (d, J=1.9 Hz, 1H), 8.56 - 8.47 (m, 1H), 8.42 (d, J=7.9 Hz, 1H), 8.14 (d , J=17.4 Hz, 1H), 7.64 - 7.41 (m, 6H), 4.61 (br. s., 1H), 4.46 (br. s., 1H), 4.00 (s, 2H), 3.96 (s, 1H ), 3.86 - 3.72 (m, 2H), 3.40 - 3.19 (m, 1H), 1.07 (d, J=6.8 Hz, 1H), 0.95 (d, J=6.7 Hz, 2H). 8.88 (br. s., 1H), 8.60 (d, J=11.4 Hz, 1H), 8.47 - 8.30 (m, 1H), 8.16 (br. s., 1H), 7.60 (br. s., 1H) , 7.26 (br. s., 1H), 7.16 (br. s., 1H), 7.06 (br. s., 1H), 4.55 (br. s., 1H), 4.49 (br. s., 1H) , 3.98 (s, 3H), 2.42 (d, J=13.0 Hz, 1H), 2.38 2.26 (m, 1H), 1.75 - 1.53 (m, 5H), 1.42 - 1.20 (m, 4H), 1.14 (br. s„ 1H), 1.00 (t, 4=7.4Hz, ZN). 8.87 (br. s., 1H), 8.64 - 8.54 (m, 1H), 8.48 - 8.35 (m, 1H), 8.15 (s, 1H), 7.59 (br. s., 1H), 4.63 - 4.44 (m , 1H), 3.98 (s, 3H), 3.26 - 3.03 (m, 2H), 2.55 (s, 2H), 2.39 - 2.21 (m, 2H), 2.11 (d, J=17.5 Hz, 1H), 2.04 ( d, J=14.0 Hz, 2H), 1.77 (br. s., 2H), 1.06 - 0.95 (m, 3H) 8.88 (br. s., 1H), 8.64 - 8.55 (m, 1H), 8.48 - 8.35 (m, 1H), 8.16 (d, J=2.6 Hz, 1H), 7.60 (d, J=3.3 Hz, 1H ), 4.56 (br. s., 1H), 4.52 (br. s., 1H), 4.04 - 3.94 (m, 3H), 3.14-3.02 (m, 2H), 2.77 (dd, J=15.7, 8.1 Hz , 5H), 1.07 - 0.97 (m, 4H).

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299 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7m]-N-[(3S,4S)-1(4,4difluorocyclohexane carbonyl)-4methylpyrrolidin3-yl ]-2methoxypyridine-3 carboxamide YY ^F 582.2 8.88 (d, 1=1.8Hz, 1H), 8.60 (dd, J=14.2, 2.0Hz, 1H), 8.46 - 8.31 (m, 1H), 8.15 (s, 1H), 7.58 (s, 1H), 4.65 4.45 (m, 1H), 4.03 - 3.95 (m, 3H), 3.74 (br. s., 1H), 3.55 (br. s., 1H), 3.40 (br. s., 1H), 3.25 (t, J=9.6Hz, 1H), 3.11-2.98 (m, 1H), 2.04 (d, J=15.6Hz, 2H), 1.93 - 1.71 (m, 4H), 1.56 (d, J=10.7Hz, 2H), 1.01 (t, J=6.9 Hz, ZN).

Connections in the table. 16 was obtained by the methods detailed in examples 27, 31, 34 and 43. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

Table 16

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 300 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-1-(4,4difluorocyclohexane pbonyl)-4fluoropyrrolidin-3 yl]-2methoxypyridine-3 carboxamide V 586.0 8.92 (s, 1H), 8.81 (s, 1H), 8.76 (s, 1H), 8.62 - 8.49 (m, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 4.91 - 4.61 (m, 1H), 4.11 (s, 1H), 4.04 (d, J=8.2 Hz, ZH), 3.93 - 3.82 (m, 1H), 3.32 3.12 (m, 1H), 3.00 (s, 1H), 2.05 (br. s., 2H), 1.96-1.72 (m, 4H), 1.58 (d, J=12.5 Hz, 2H).

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301 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[4-φτορ-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3yl]-2methoxypyride in-3 carboxamide % 568.4 Ή NMR (400 MHz, CD ₃ OD) δ 9.01 - 8.90 (m, 2H), 8.72 - 8.37 (m, 1H), 8.10 -7.99 (m, 1H), 7.347.18 (m, 1H), 5.46 - 5.13 (m, 1H), 4.95 - 4.70 (m, 2H), 4.21 - 4.08 (m, 4H), 4.03 - 3.74 (m, 2H), 3.51 - 3.38 (m, 1H), 2.55 - 2.33 (m, 1H), 2.21 - 2.01 (m, 2H), 1.95 - 1.80 (m, 2H), 1.72 - 1.38 (m, 4H) 302 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[4-φτορ-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3yl]- 2methoxypyride in-3 carboxamide 568.3 Ή NMR (400 MHz, CD ₃ OD) δ 9.06 - 8.91 (m, 2H), 8.72 - 8.43 (m, 1H), 8.14 -7.98 (m, 1H), 7.32 7.22 (m, 1H), 5.53 - 5.28 ( m, 1H), 5.28 - 5.15 (m, 1H), 5.04 - 4.70 (m, 1H), 4.27 - 4.09 (m, 4H), 4.04 3.81 (m, 2H), 3.80 - 3.60 (m, 1H), 3.54 - 3.39 (m, 1H), 2.51 - 2.30 (m, 1H), 2.26 - 2.09 (m, 2H), 1.981.80 (m, 2H), 1.70 - 1.40 (m, 4H) 303 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-1-(2,2difluorocyclopropane pbonyl)-4fluoropyrrolidin-3 - silt]-2- methoxypyride in-3 carboxamide F Alf 544.5 8.98 - 8.86 (m, 1H), 8.71 - 8.54 (m, 2H), 8.24 - 8.07 (m, 1H), 7.67 7.52 (m, 1H), 5.44 - 5.11 (m, 1H), 4.72 - 4.50 (m, 1H), 4.20 - 4.03 (m, 1H), 4.03 -3.94 (m, 3H), 3.923.54 (m, 2H), 3.55 - 3.36 (m, 1H), 3.12 - 2.84 (m, 1H), 2.04 - 1.76 (m, 2H), 1.34-1.17 (m, 1H). 304 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-1-(2,2difluoro-1- methylcyclopropanecarbonyl)-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide A F 558.2 8.92 - 8.88 (m, 1H), 8.75 (d, J=2.0 Hz, 1H), 8.56 - 8.42 (m, 1H), 8.14 (s, 1H), 7.55 (s, 1H), 5.48 - 5.22 (m, 1H), 4.90 - 4.58 (m, 1H), 4.19 3.99 (m, 4H), 3.98 - 3.57 (m, 3H), 1.94 - 1.70 (m, 1H), 1.53 (br s, 1H), 1.41 (brd, J=8.3 Hz, ZN)

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305 306 307 308 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3R,4S)-l-(3,4difluorobenzoyl)-4fluoropyrrolidine- 3- yl]-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-1-(2,6difluorobenzoyl)-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 5-[4-amino- 5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3R,4S)-4^Top-l[(28)-3,3,3-trifluoro- 2hydroxy-2methylpropanoyl]pyrr olidin-3-yl]-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-4-φτop-l(4methylpentanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide T T F /0 X^CF ₃ '' OH 580.2 580.0 580.2 538.1 8.95 - 8.87 (m, 1H), 8.76 (d, J=2.1Hz, 1H), 8.60 - 8.47 (m, 1H), 8.16 (d, J=12.5Hz, 1H), 7.71 - 7.62 (m, 1H) , 7.59 (brd, 1=13.1Hz, 1H), 7.56-7.48 (m, 1H), 7.45 (br d, J=8.9 Hz, 1H), 5.48 - 5.15 (m, 1H), 4.87 - 4.60 (m, 1H), 4.03 (d, J=3.1 Hz, ZH), 4.01 - 3.92 (m, 1H), 3.88 3.75 (m, 1H), 3.71 - 3.48 (m, 1H); 1 CH suppressed 8.91 (dd, J=15.9, 2.4 Hz, 1H), 8.80 - 8.68 (m, 1H), 8.61 - 8.49 (m, 1H), 8.16 (d, J=15.6 Hz, 1H), 7.64 - 7.54 (m, 2H), 7.25 (brt, J=8.5 Hz, 2H), 5.49 - 5.17 (m, 1H), 4.94 - 4.68 (m, 1H), 4.14 - 3.93 (m, 4H), 3.92 - 3.83 (m, 1H), 3.82 - 3.61 (m, 1H), 3.59 -3.44 (m, 1H) 8.92 (d, 1=1.8Hz, 1H), 8.76 (dd, J=5.3, 2.3Hz, 1H), 8.59 - 8.47 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.05 (d, J=8.5 Hz, 1H), 5.39 - 5.14 (m, 1H), 4.80 - 4.54 (m, 1H), 4.42 4.34 (m, 1H), 4.33 - 4.20 (m, 1H), 4.03 (s, 3H), 3.80 - 3.67 (m, 1H), 3.60 (brt, 3=11.0Hz, 1H), 1.52 (d, >10.7Hz, ZN) 8.88 (s, 1H), 8.74 (dd, J=16.3, 2.3 Hz, 1H), 8.54 (dd, J=11.7, 7.5 Hz, 1H), 8.13 (s, 1H), 7.56 (s, 1H), 5.41 - 5.15 (m, 1H), 4.84 - 4.53 (m, 1H), 4.02 (d, J=5.2 Hz, ZN), 3.99 - 3.83 (m, 1H), 3.81-3.62 (m, 1H), 3.43 (t , >10.2Hz, 1H), 3.24-3.11 (m, 1H), 2.30-2.12 (m, 2H), 1.52 (dquin, J=13.1, 6.7 Hz, 1H), 1.44 1.31 (m, 2H), 0.85 ( d, 3=6.4Hz, 6H)

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309 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(ЗR,4S)-4-φτop-l(5-fluoropyridine -2 carbonyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide A/A h A 563.0 8.92 (dd, J=7.1, 2.1 Hz, 1H), 8.77 (dd, J=11.3, 2.1 Hz, 1H), 8.658.58 (m, 1H), 8.51 - 8.43 (m, 1H), 8.16 (d, J=8.2 Hz, 1H), 7.94 (dd, J=8.7, 4.7 Hz, 1H), 7.89 - 7.82 (br, 1H), 7.57 (d, J=8.6 Hz, 1H), 5.43 5.22 (m, 1H) , 4.87 - 4.65 (m, 1Н), 4.35 - 4.20 (t, 1Н), 4.19 - 4.09 (t, 1Н), 4.09 - 4.02 (t, ZN), 3.99 - 3.86 (t, 1H), 3.82 - 3.50 (t, 1H) 310 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-4-φτop-lpropanoylpyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide /— 496.4 8.90 (d, J=2.1 Hz, 1H), 8.76 (dd, J=15.9, 2.1 Hz, 1H), 8.52 (brdd, J=12.5, 7.6 Hz, 1H), 8.16 (s, 1H), 7.59 (s , 1Н), 5.44-5.17 (t, 1Н), 4.86 - 4.54 (t, 1Н), 4.03 (d, J=4.6 Hz, ZN), 3.96 (t, J=9.2 Hz, 1Н), 3.92 - 3.83 ( t, 1Н), 3.78 - 3.59 (t, 1Н), 3.45 -3.15 (t, 1Н), 2.39 2.14 (t, 2Н), 0.99 (td, J=7.4, 3.5 Hz, ZN) 311 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3^48)-4-φτορ-1[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrr olidin-3 -yl]-2methoxypyride in-3 carboxamide /C/ ^CF 3 'he 580.2 8.96 - 8.88 (t, 1H), 8.76 (dd, J=11.0, 2.1 Hz, 1H), 8.60 - 8.47 (t, 1H), 8.16 (s, 1H), 7.60 (d, J=3.1 Hz, 1H) , 7.13 (d, J-4.3 Hz, 1Н), 4.76 - 4.57 (t, 1Н), 4.52 - 4.45 (t, 1Н), 4.39 - 4.26 (t, 1Н), 4.03 (d, J=2.1 Hz, ZN ), 3.99 - 3.33 (t, 2H), 1.53 (s, 3H) partial suppression 312 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3M8)-4-φτορ-1[1(trifluoromethyl)cyclohexanecarbonyl ]pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide, TFA ^^0 618.1 8.89 (d, J=2.1 Hz, 1H), 8.74 (br s, 1H), 8.62 - 8.48 (t, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 5.44-5.14 (m, 1H ), 4.83 - 4.60 (m, 1H), 4.02 (s, 3H), 3.97 - 3.36 (m, SA, partial suppression), 2.45 - 2.37 (m, 1H), 1.76 - 1.47 (m, 4H), 1.41 ( br s, 1H), 1.33 - 0.99 (m, 4H)

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313 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(2-methylpyridine- 4carbonyl)pyrrolidin -3-yl]-2methoxypyride in-3 carboxamide DH 559.2 8.88 (dd, J=11.6, 2.1 Hz, 1H), 8.73 (dd, J=8.7, 2.3 Hz, 1H), 8.62 - 8.48 (m, 2H), 8.13 (d, J=13.7 Hz, 1H), 7.56 (d, J=15.3 Hz, 1H), 7.36 (d, J=11.9 Hz, 1H), 7.29 (dd, J=12.2, 4.9 Hz, 1H), 5.45 -5.15 (m, 1H), 4.84 - 4.60 (m, 1Н), 4.06 - 3.98 (t, SA), 3.97 - 3.41 (t, SA, partial suppression), 2.54 (s, SA) 5-[4-amino-5- 8.93 (d, J=2.4 Hz, 1Н), 8.80 (br s, 314 (trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(3-fluoro-2,2- 542.2 1Н), 8.52 (brd, J=6.1 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.39-5.17 (m, 1H), 4.88 - 4.62 (m, 1H), 4.58 4.30 ( m, 2H), 4.06 (s, 3H), 1.27 - dimethylpropanoyl)pi 1.22 (m, 6H); 4 CH pyrrolidine rrolidin-3-yl]-2- not observed due to suppression methoxypyridine-3 - water carboxamide 5-[4-amino-5- 8.90 (d, J=2.4 Hz, 1H), 8.76 (br d, (trifluoromethyl)pyrro J=2.4 Hz, 1H), 8.57 - 8.46 (m, 1H), lo[2,1- 8.15 (s, 1H), 7.58 (s, 1H), 5.38 - f] [ 1,2,4]triazin-7-yl]- 5.16 (m, 1H), 4.74 - 4.53 (m, 1H), Ν-[(3Κ,48)-4-φτορ-1- . He 4.45 - 4.34 (m, 1H), 4.32 - 4.20 (m, 315 (1- G \ 552.0 1H), 4.03 (s, 3H), 3.99 - 3.79 (m, hydroxycyclopentane 1H), 3.77 -3.60 (m, 1H), 2.16- carbonyl)pyrrolidine 2.05 (m, 1H), 1.99 - 1.83 (m, 1H), -3-yl]-2- 1.79-1.61 (m, 4H), 1.56 (brd, methoxypyride in-3 carboxamide, TFA J=2.7Hz, 2H) 5-[4-amino-5- 8.90 (d, 1=2.1Hz, 1H), 8.75 (d, J=2.1Hz, 1H), 8.52 (br dd, J=13.7, (trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]- Ν-[(3Κ,48)-4-φτορ-1- xA ^0H 7.6 Hz, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 5.35 - 5.18 (m, 1H), 4.74 4.56 (m, 1H), 4.16 - 4.07 (m, 1H), 316 (1- A 538.3 4.03 (s, 3H), 3.99-3.81 (m, 1H), hydroxycyclobutane V 3.80 - 3.62 (m, 1H), 3.47 - 3.27 (m, arbonyl)pyrrolidine- 1H), 2.62 - 2.55 (m, 1H), 2.47 - 3-yl]-2- 2.38 (m, 1H), 2.12 - 2.03 (m, 1H), methoxypyride in-3 - 2.03 - 1.93 (m, 1H), 1.77 - 1.65 (m, carboxamide, TFA 1H), 1.53 - 1.40 (m, 1H)

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317 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(3-hydroxy-3 methylbutanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 540.1 8.88 (br s, 1H), 8.74 (br d, J=13.1 Hz, 1H), 8.57 (br d, J=6.4 Hz, 1H), 8.14 (s, 1H), 7.56 (s, 1H), 5.43 5.17 (m, 1H), 4.83 - 4.55 (m, 1H), 4.14-3.11 (m. 7 H, absorbed by water), 2.47 - 2.31 (m, 2H), 1.19 (br s, 6H) 318 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1[(28)-3,3,3-trifluoro-2hydroxypropanoyl]p irrolidin-3-yl ]-2methoxypyride in-3 carboxamide ^he CF ₃ 566.2 8.91 (d, J=1.8 Hz, 1H), 8.76 (br s, 1H), 8.61 - 8.50 (m, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 5.44 - 5.20 (m, 1H ), 4.94 (br d, J=5.8 Hz, 1H), 4.83 - 4.60 (m, 1H), 4.20 - 3.97 (m, 4H), 3.95 - 3.85 (m, 2H), 3.82 - 3.66 (m, 1H) , 3.55 (brt, 1=10.7Hz, 1H) 319 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(2-hydroxy-2methylbutanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 540.3 8.91 (s, 1H), 8.77 (brs, 1H), 8.44 (brs, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 5.37-5.15 (m, 1H), 5.084.99 (m , 1H), 4.73 - 4.24 (m, 2H), 4.05 (s, 3H), 3.93 - 3.85 (m, 1H), 3.81 - 3.62 (m, 1H), 3.56 - 3.45 (m, 1H), 1.79 - 1.66 (m, 1H), 1.57 (dq, J=13.9, 7.2 Hz, 1H), 1.33 - 1.26 (m, 3H), 0.88 - 0.77 (m, 3H) 320 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]Ν-[(3Κ,48)-4-φτορ-1(ΐ- hydroxycyclopropane carbonyl)pyrrolidin -3-yl]-2methoxypyride in-3 carboxamide 524.2 8.92 (d, J=2.2Hz, 1H), 8.78 (d, J=1.8Hz, 1H), 8.47 (br d, J=4.3Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H) , 5.44 -5.19(m, 1H), 4.80-4.58 (m, 1H), 4.51 - 3.34 (m, 7H, absorbed by water), 1.19 - 1.08 (m, 1H), 0.98 0.84 (m, 2H), 0.82 - 0.71(m, 1H)

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321 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(ЗR,4S)-4-φτop-l[(2C)- 2-hydroxy-4methylpentanoyl]pyrr olidin-3-yl]-2methoxypyride in-3 carboxamide 554.3 8.92 (s, 1H), 8.79 (br d, J=10.3 Hz, 1H), 8.46 (br dd, J=19.2, 7.3 Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 5.44 - 5.19 (m, 1H), 4.84 - 4.57 (m, 1H), 4.26 - 3.34 (m, 8H, absorbed by water), 1.86 - 1.72 (m, 1H), 1.52 1.30 (m, 2H), 0.92 (br d , J=6.2Hz, 6H) 322 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(ЗR,4S)-4-φτop-l[(2R)-3,3,3-trifluoro-2 hydroxypropanoyl] p irrolidin-3 - yl]-2methoxypyride in-3carboxamide X^CF ₃ he 566.0 8.93 (d, J=2.4 Hz, 1H), 8.79 (dd, J=6.9, 2.2 Hz, 1H), 8.48 (br dd, J=18.2, 7.4 Hz, 1H), 8.17 (s, 1H), 7.58 ( s, 1H), 5.45 - 5.23 (m, 1H), 5.00 - 4.85 (m, 1H), 4.84 - 4.64 (m, 1H), 4.36 -3.26 (m, 7H) 323 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3M8)-4-φτορ-1[(2 8)-2 -hydroxy-3,3 dimethylbutanoyl] pyrrolide in-3 -yl] -2methoxypyride in-3 carboxamide HE 554.3 8.93 (s, 1H), 8.82 - 8.75 (m, 1H), 8.45 (br dd, J=12.8, 7.4 Hz, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 5.41 5.21 (m, 1H), 4.77 - 4.61 (m, 1H), 4.28 - 3.24 (m, 8H), 0.94 (s, 9H) 324 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3^48)-4-φτορ-1[(2 8) -2-hydroxy-4methylpentanoyl]pyrr olidin-3 -yl]-2methoxypyride in-3 carboxamide 554.3 8.93 (d, J=2.2 Hz, 1H), 8.82 - 8.76 (m, 1H), 8.46 (br dd, J=18.4, 7.4 Hz, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 5.42 - 5.20 (m, 1H), 4.84 - 4.61 (m, 1H), 4.28 - 3.16 (m, 8H, absorbed by water), 1.85 - 1.71 (m, 1H), 1.52 1.34 (m, 2H), 0.97-0.87 (m, 6H)

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325 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(oxolane-2carbonyl) pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide At 538.3 8.90 (s, 1H), 8.80 - 8.72 (m, 1H), 8.54 - 8.39 (m, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 5.43 - 5.20 (m, 1H), 4.82 - 4.59 (m, 1H), 4.57 - 4.44 (t, 1H), 4.24 - 3.40 (m, 9H, absorbed by water), 2.12 - 1.94 (m, 2H), 1.92 - 1.76 (m, 2H) 326 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(oxane-2carbonyl) pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide Ό 552.2 8.90 (br s, 1H), 8.81 - 8.72 (m, 1H), 8.53-8.41 (m, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 5.42 - 5.20 (m, 1H), 4.82 - 4.52 (m, 1H), 4.27 - 3.40 (t, YuN, absorbed by water), 1.89 - 1.40 (m, 6H) 327 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(oxane-3carbonyl) pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide 552.2 8.93 (br s, 1Н), 8.84 - 8.74 (m, 1Н), 8.52 (brdd, 1=15.9, 7.3 Hz, 1Н), 8.18 (s, 1Н), 7.62 (s, 1Н), 5.435.18 (m , 1Н), 4.86 - 4.55 (m, 1Н), 4.22- 3.14 (m, IN), 2.70 (brd, J=10.4 Hz, 1Н), 1.97- 1.78 (t, 1Н), 1.59 (br s, ZN) 328 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(2,6, 6-trimethyloxane2carbonyl)pyrrolidin -3-yl]-2methoxypyride in-3 carboxamide 594.4 8.93 (dd, J=9.5, 2.1 Hz, 1H), 8.85 8.71 (m, 1H), 8.59 - 8.47 (m, 1H), 8.18 (d, 3=1.2Hz, 1H), 7.61 (d, J=4.6 Hz, 1Н), 5.43 - 5.19 (m, 1Н), 4.98 - 4.49 (m, 2Н), 4.05 (d, J=11.6 Hz, ZN), 3.96-3.14 (br, ZN), 2.27 (brd, J= 9.5 Hz, 1Н), 1.84-1.66 (br, 1Н), 1.55 - 1.40 (m, 2Н), 1.37 0.97 (br, 11Н)

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329 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(ЗR,4S)-4-φτop-l(3-methyloxetan- 3 carbonyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide 538.4 8.92 (d, J=2.3 Hz, 1H), 8.79 (br d, 1=16.6 Hz, 1H), 8.43 (br s, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 5.40- 5.19 (m, 1H), 4.89 (br d, J=5.8 Hz, 1H), 4.86 - 4.62 (t, 2H), 4.32 - 4.19 (t, 2H), 4.06 (s, 3H), 3.94 - 3.63 (t, 2H), 3.59 - 3.29 (t, 2H), 1.58 (br d, J=7.2 Hz, ZN) 330 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(ЗR,4S)-4-φτop-l(ΐfluorocyclobutanecarbonyl)pyrrolidine -3 yl]-2methoxypyride in-3 carboxamide 540.4 8.91 (s, 1H), 8.76 (d, 1=2.1Hz, 1H), 8.53 (br dd, 1=14.0, 7.6 Hz, 1H), 8.16 (d, J=1.8 Hz, 1H), 7.60 (s, 1H), 5.39-5.19 (m, 1H), 4.85 4.62 (m, 1H), 4.03 (s, 3H), 3.99 3.93 (m, 1H), 3.93 - 3.85 (m, 1H), 3.85 - 3.78 (m, 1H), 3.77 - 3.65 (m, 1H), 2.78 - 2.56 (m, 2H), 2.47 2.23 (m, 2H), 1.87 (dt, 1=10.4, 3.8 Hz, 1H), 1.63 - 1.49 (m, 1H ) 331 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,4δ)-4-φτορ-1(ΐfluorocyclopropanecarb onyl)pyrrolidin-3yl]-2methoxypyride in-3 carboxamide 526.1 8.91 (d, J=2.4 Hz, 1H), 8.76 (br s, 1H), 8.60 - 8.49 (m, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 5.45-5.19 (m, 1H ), 4.91 -4.63 (m, 1H), 4.30 - 4.18 (m, 1H), 4.03 (s, 3H), 3.98 - 3.86 (m, 1H), 3.80 (br s, 1H), 3.76 3.63 (m, 1H), 1.46 - 1.20 (m, 3H), 1.20 - 1.05 (m, 1H) 332 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazin-7-yl]- N-[(3R,4S)-1(dimethylcarbamoyl)4-fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide A 1 511.2 8.90 (d, J=2.1Hz, 1H), 8.78 (d, J=2.1Hz, 1H), 8.48 (br d, J=7.3Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H) , 5.33 - 5.14 (m, 1H), 4.68 - 4.49 (m, 1H), 4.04 (s, 3H), 3.88 - 3.73 (m, 1H), 3.63 (t, J=9.2 Hz, 1H), 2.76 (s , 6H); 2CH pyrrolidine was not observed due to water suppression

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333 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(pyrrolidine-1carbonyl) pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide, TFA A 537.2 8.90 (d, >2.1Hz, 1H), 8.77 (d, J=2.1Hz, 1H), 8.49 (br d, J=7.6Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 5.33 - 5.13 (m, 1H), 4.70 - 4.53 (m, 1H), 4.04 (s, 3H), 3.85 - 3.77 (m, 1H), 3.71 (br t, J=9.2 Hz, 1H), 3.403.27 (m, 2H), 3.26 - 3.17 (m, 2H), 1.88 - 1.77 (m, 2H), 1.76 - 1.64 (m, 2H); 2 CH pyrrolidine was not observed due to suppression water 334 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]Ν-[(3Κ,48)-4-φτορ-1(3,3,3- trifluoropropanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide X^ ^CF 3 550.1 8.92 (d, J=2.1 Hz, 1H), 8.78 (dd, J=14.0, 2.1 Hz, 1H), 8.56 (br dd, J=13.6, 7.5 Hz, 1H), 8.18 (s, 1H), 7.61 ( s, 1H), 5.45-5.19 (m, 1H), 4.86 - 4.56 (m, 1H), 4.13 - 3.13 (m, 9H) 335 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(3methylbutanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 524.2 8.94 (d, J=2.1 Hz, 1H), 8.80 (dd, J=14.6, 2.4 Hz, 1H), 8.52 (br dd, J=14.3, 7.6 Hz, 1H), 8.19 (s, 1H), 7.63 ( s, 1H); ), 0.99 - 0.84 (m, 6H) 336 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(pyridine-3-carbonyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide X N 545.2 8.89 (br s, 1H), 8.74 (br s, 2H), 8.67 (brd, J=3.5 Hz, 1H), 8.578.43 (m, 1H), 8.13 (br d, J=9.1 Hz, 1H), 7.97 (br s, 1H), 7.57 - 7.46 (m, 2H), 5.49 - 5.20 (m, 1H), 4.89 - 4.64 (m, 1H), 4.05 (brs, 3H), 3.99 - 3.45(m, 4H)

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337 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]- N-[(3R,4S)-4-φτop-l(3,3,3-trifluoro-2,2dimethylpropanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide, TFA 578.2 8.93 (d, J=2.4 Hz, 1H), 8.80 (br s, 1H), 8.53 (brd, J=5.5 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.43-5.19 ( m, 1H), 4.87 - 4.60 (m, 1H), 4.05 (s, 3H), 4.01 - 3.14(m, 4H, absorbed by water), 1.49 (s, 3H), 1.45 (s, 3H) 338 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R, 48)-1-(3,3dimethylbutanoyl)-4fluoropyrrolidine-3 - silt]-2- methoxypyride in-3 carboxamide 538.3 8.91 (s, 1H), 8.78 (br d, J=12.8 Hz, 1H), 8.45 (br dd, J=14.6, 7.5 Hz, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 5.41 - 5.18 (m, 1H), 4.84 - 4.54 (m, 1H), 4.11 - 3.17 (m, 9H, absorbed by water), 1.02 (s, 9H) 339 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3M8)-4-φτορ-1(2-hydroxy-2methylpropanoyl) pyrr olidin-3 -yl]-2methoxypyride in-3 carboxamide, TFA 526.0 8.94 (d, J=1.8 Hz, 1H), 8.79 (br s, 1H), 8.59 - 8.45 (m, 1H), 8.19 (s, 1H), 7.63 (s, 1H), 5.39-5.17 (m, 2H ), 4.77 - 4.54 (m, 1H), 4.51 - 4.27 (m, 1H), 4.05 (s, 3H), 3.97 3.55 (m, 2H), 2.94 (br d, J=7.6 Hz, 1H), 1.35 - 1.27 (m, 6H) 340 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3^48)-4-φτορ-1(3methoxypropanoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 526.1 8.94 (d, J=1.8 Hz, 1H), 8.80 (dd, J=14.6, 2.1 Hz, 1H), 8.53 (br dd, J=14.5, 7.5 Hz, 1H), 8.19 (s, 1H), 7.63 ( s, 1H), 5.42 - 5.20 (m, 1H), 4.86 - 4.55 (m, 1H), 4.12 - 3.28 (m, 12H, absorbed by water), 2.60 - 2.43 (m, 2H, absorbed by DMSO)

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341 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3R,4S)-1-(2,5difluorobenzoyl)-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide, TFA 580.1 8.93 (dd, J=14.1, 2.1 Hz, 1H), 8.82 - 8.70 (m, 1H), 8.56 - 8.39 (m, 1H), 8.16 (d, >13.8Hz, 1H), 7.57 (d, J=16.7 Hz, 1Н), 7.38 (br d, J=5.0 Hz, ZN), 5.52 - 5.18 (m, 1Н), 4.92 4.65 (m, 1H), 4.06 (d, J=17.8 Hz, ZN), 3.99 -3.22 (m, 4H) 342 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3^48)-4-φτορ-1(sfluorobenzoyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide h 562.1 8.91 - 8.84 (m, 1H), 8.76 - 8.68 (m, 1H), 8.65 - 8.53 (m, 1H), 8.12 (d, >13.7Hz, 1H), 7.58 -7.48 (m, 2H), 7.43 - 7.28 (m, 3H), 5.47 5.16 (m, 1H), 4.87 - 4.60 (m, 1H), 4.07 - 3.26 (m, 7H, absorbed by water) 343 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3^48)-4-φτορ-1- (2fluorobenzoyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 00 562.2 8.90 (br d, J=14.7 Hz, 1H), 8.80 8.69 (m, 1H), 8.56 - 8.41 (m, 1H), 8.14 (br d, J=15.3 Hz, 1H), 7.587.43 (m, 3H ), 7.36 - 7.25 (m, 2H), 5.50 - 5.17 (m, 1H), 4.91 - 4.63 (m, 1H), 4.13 - 3.33 (m, 7H, absorbed by water) 344 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3M8)-4-φτορ-1(2-methyl-2phenylpropanoyl) pyrr olidin-3-yl]-2methoxypyride in-3 carboxamide 586.4 8.89 (brd, >7.6Hz, 1H), 8.75 8.65 (m, 1H), 8.48 - 8.25 (m, 1H), 8.16 (brs, 1H), 7.58 (brd, J=5.8Hz, 1H), 7.43 - 7.33 (m, 2H), 7.30 7.20 (m, 3H), 5.25 - 4.91 (m, 1H), 4.62 - 4.28 (m, 1H), 4.00 (br d, J=19.5 Hz, ZN), 3.93 -3.02 (m , 4H), 1.49 (br s, 3H), 1.43 (brd, >12.8Hz, ZN)

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345 346 347 348 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(2methylpropanoyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrro lo[2,1- f] [ 1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(oxetane-3carbonyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide 5-[4 -amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]N-[(3Κ,48)-4-φτορ-1(2-fluoro-2methylpropanoyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide, TFA 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl)N-(4-φτορ-1-(3fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl)-2methoxynicotinamide A ^L o V h 509.9 524.0 528.4 540.3 (isomers) 8.94 (d, J=2.3 Hz, 1H), 8.84 - 8.76 (m, 1H), 8.51 - 8.34 (m, 1H), 8.17 (s, 1H), 7.59 (s, 1H), 5.44-5.15 (m, 1H), 4.89 - 4.56 (m, 1H), 4.08 (br d, >3.6Hz, ZH), 3.98-3.15 (m, 4H), 2.78 - 2.60 (m, 1H), 1.09 0.98 (m, 6H) 8.93 (d, J=2.2 Hz, 1H), 8.80 (dd, J=12.5, 2.3 Hz, 1H), 8.49 - 8.39 (t, 1H), 8.17 (s, 1H), 7.58 (s, 1H), 5.44 - 5.21 (t, 1H), 4.83 - 4.58 (t, 5H), 4.17-3.18 (t, 8H) 8.93 (s, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.59 - 8.49 (t, 1H ), 8.18 (s, 1Н), 7.61 (s, 1Н), 5.40–5.17 (t, 1Н), 4.87–4.62 (t, 1Н), 4.28–4.17 (t, 1Н), 4.13–3.99 (t, 4Н) , 3.98 - 3.86 (t, 1H), 3.81 - 3.52 (t, 1H), 1.63 - 1.48 (t, 6H) (400 MHz, CD ₃ OD) δ 9.01 - 8.88 (t, 2H), 8.69 - 8.46 (t , 1Н), 8.11 8.02 (t, 1Н), 7.37 - 7.24 (t, 1Н), 5.41 - 5.29 (t, 1Н), 5.24 - 5.16 (t, 1Н), 5.08 -4.96 (t, 1Н), 4.94 4.73 (t, 2H), 4.23 - 4.04 (t, 4H), 4.02 - 3.91 (t, 1H), 3.90 - 3.63 (t, 2H), 2.79 - 2.37 (t, 5H) 349 5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl)N-(4-φτορ-1-(3fluorocyclobutane-1 carbonyl)pyrrolidine -3- yl)-2methoxynicotinamide h 540.3 (isomers) (400 MHz, CD3OD) δ 9.01 - 8.87 (t, 2H), 8.65 - 8.40 (t, 1H), 8.10 7.98 (t, 1H), 7.31-7.15 (t, 1H), 5.42 - 5.05 (t, 2H) , 4.94 - 4.68 (t, 1H), 4.22-4.11 (t, 4H), 4.09 3.98 (t, 1H), 3.97 - 3.88 (t, 1H), 3.85 - 3.61 (t, 2H), 2.75 - 2.37 (t , 4H)

Connections in the table. 17 was obtained by the methods detailed in examples 25 and 41. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 17

Example Name R Observe May in MS the mass of the ion Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 350 351 352 353 354 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazine-7ra]-N-[(3R,4S)-l(3,3difluorocyclobutanencarbonyl)-4fluoropyrrolidine- 3-yl]-2methylpyridine-3 carboxamide 3,3difluorocyclopenta ncarbonyl)-4fluoropyrrolidin3-yl]-2methylpyridine-3 carboxamide ,4S)-l(3,3difluorocyclopenta ncarbonyl)-4fluoropyrrolidine- 3-yl]-2methylpyridine-3 carboxamide 1-(2methylpropanoyl)p irrolidin-3 -yl] 2-methylpyridine3-carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 0[1,2,4]triazin-7yl]-I-[1-(2,2difluorocycloprop ancarbonyl)-4fluoropyrrolidine- 3-yl]-2methylpyridine-3 carboxamide F ^F GU- F ^F GU- ^F A ^F W ^F 541.9 556.0 (isomers) 556.0 (isomers) 494.4 528.2, (isomers) 9.21 - 9.11 (m, 1H), 9.04 - 8.87 (m, 1H), 8.43 - 8.32 (m, 1H), 8.22 - 8.10 (m, 1H), 7.73 - 7.55 (m, 1H), 4.87 4.55 (m, 1H), 3.98 - 3.79 (m, 1H), 3.72 - 3.65 (m, 1H), 3.46 - 3.36 (m, 1H), 3.34 - 3.25 (m, 1H), 3.21 - 3.07 (m, 1H), 2.89 - 2.68 (m, 3H), 2.61 2.53 (m, 4H), 2.53 - 2.46 (m, 3H). cyclopentane isomers 9.24–9.10 (m, 1H), 9.03–8.82 (m, 1H), 8.44–8.32 (m, 1H), 8.25–8.13 (m, 1H), 7.74–7.61 (m, 1H), 5.51–5.16 ( m, 1H), 4.88 - 4.53 (m, 1H), 4.15 - 3.98 (m, 1H), 3.98 - 3.80 (m, 1H), 3.78 3.65 (m, 1H), 3.56 - 3.42 (m, 1H), 3.36 - 3.10 (m, 2H), 2.61 - 2.57 (m, 3H), 2.39 - 2.23 (m, 2H), 2.22 - 1.98 (m, 3H), 1.91 - 1.71 (m, 1H), 1.07 - 0.94(m, 1H) cyclopentane isomers 9.24–9.10 (m, 1H), 9.03–8.82 (m, 1H), 8.44–8.32 (m, 1H), 8.25–8.13 (m, 1H), 7.74–7.61 (m, 1H), 5.51–5.16 ( m, 1H), 4.88 - 4.53 (m, 1H), 4.15 - 3.98 (m, 1H), 3.98 - 3.80 (m, 1H), 3.78 3.65 (m, 1H), 3.56 - 3.42 (m, 1H), 3.36 - 3.10 (m, 2H), 2.61 - 2.57 (m, 3H), 2.39 - 2.23 (m, 2H), 2.22 - 1.98 (m, 3H), 1.91 - 1.71 (m, 1H), 1.07 - 0.94(m, 1H) 9.27 - 9.11 (m, 1H), 9.01 - 8.84 (m, 1H), 8.52 - 8.36 (m, 1H), 8.25 - 8.11 (m, 1H), 7.80 - 7.63 (m, 1H), 5.44 5.17 (m, 1H), 4.84 - 4.52 (m, 1H), 4.08 - 3.97 (m, 1H), 3.96 - 3.41 (m, 2H), 2.74 - 2.56 (m, 4H), 1.09 - 0.93 (m, 6H). cyclopropyl isomers 9.28 - 9.12 (m, 1H), 9.05 - 8.84 (m, 1H), 8.46 - 8.33 (m, 1H), 8.26 - 8.12 (m, 1H), 7.79 - 7.60 (m, 1H), 5.50 - 5.18 ( m, 1H), 4.87 - 4.56 (m, 1H), 4.35 - 4.00 (m, 1H), 3.96 - 3.57 (m, 2H), 3.58 3.45 (m, 1H), 3.39 - 2.81 (m, 2H), 2.63 - 2.56 (m, 3H), 2.02 - 1.80 (m, 2H), 1.05 -0.96 (m, 1H)

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355 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-hp . F 528.2, (isomers) cyclopropyl isomers 9.28 - 9.12 (t, 1H), 9.05 - 8.84 (m, 1H), 8.46 - 8.33 (m, 1H), 8.26 - 8.12 (m, 1H), 7.79 - 7.60 (br, 1H), 5.50 - 5.18 ( t, 1H), 4.87 - 4.56 (m, 1H), 4.35 - 4.00 (t, 1H), 3.96 - 3.57 (m, 2H), 3.58 3.45 (m, 1H), 3.39 - 2.81 (m, 2H), 2.63 - 2.56 (w, W), 2.02 - 1.80 (t, 2H), 1.05 -0.96 (m, 1H) 356 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-H-[4-fluoro-1(sfluorocyclobutane pbonyl)pyrrolidi n-3-yl]- 2methylpyridine-3 carboxamide U, 524.1 Ή NMR (400 MHz, CD ₃ OD) δ 9.20 - 9.09 (m, 1H), 8.57 - 8.37 (m, 1H), 8.12 - 7.98 (m, 1H), 7.39 - 7.31 (br, 1H), 5.45 - 5.15 (m, 1H), 4.93 - 4.59 (m, 2H), 4.13 - 3.85 (m, 2H), 3.85 - 3.56 (t, 2H), 3.47 - 3.38 (m, 1H), 2.75 - 2.70 (br, W), 2.69 - 2.32 (w, 6H), 1.22- 1.05 (m, 1H) 357 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-N-[4-fluoro-1(sfluorocyclobutane pbonyl)pyrrolidi n-3-yl]- 2methylpyridine-3 carboxamide h 524.1 Ή NMR (400 MHz, CD3OD) 5 9.13 (dd, 7=11.2, 2.0 Hz, 1H), 8.45 (dd, 7=7.2, 2.1 Hz, 1H), 8.05 (d, 7=1.2 Hz, 1H), 7.36 (s, 2Н), 7.34 (d, 7=5.5 Hz, 1Н), 5.34 - 5.05 (t, 2Н), 4.86 - 4.56 (t, 1Н), 4.07 - 3.57 (t, ZN), 3.45 - 3.37 (t, 1H), 3.29-3.14 (t, 1H), 2.71 (s, 3H), 2.67 - 2.37 (t, 4H) 358 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-H-[1-(4,4difluorocyclohexancarbonyl)-4fluoropyrrolidin3-yl]-2methylpyridin-3 carboxamide A; 570.2 9.24 - 9.09 (t, 1H), 9.04 - 8.84 (t, 1H), 8.48 - 8.30 (t, 1H), 8.22 - 8.12 (t, 1H), 7.73 - 7.57 (t, 1H), 5.48 5.16 (t, 1H), 4.87 - 4.46 (t, 1H), 4.20 - 3.77 (t, 2H), 3.71 - 3.52 (t, 2H), 3.31 - 3.11 (t, 1H), 2.60 - 2.56 (t, 3H), 2.16 - 1.96 (t, 2H), 1.96 1.70 (t, 4H), 1.63–1.47 (t, 2H), 1.29–1.17 (t, 1H), 1.03–0.91 (t, 1H)

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359 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-T4-[4-fluoro-1(4fluorocyclohexane arbonyl)pyrrolide in-3-yl]- 2methylpyridine-3 carboxamide η 552.4 9.25 - 9.13 (m, IH), 8.98 - 8.80 (m, IH), 8.49 - 8.33 (m, IH), 8.26 - 8.13 (m, IH), 7.78 - 7.59 (m, IH), 5.47 5.15 (m, IH), 4.81 - 4.40 (m, 2H), 4.13 - 3.80 (m, 2H), 3.72 - 3.41 (m, IH), 3.32 - 3.06 (m, IH), 2.59 (d, >6.4 Hz, ZN), 2.48 - 2.30 (m, IH), 2.18-1.94 (m, 2H), 1.90 - 1.72 (m, 2H), 1.55 - 1.35 (m, 4H), 1.09 - 0.91 (m, IH) 360 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-M-[4-fluoro-1(4- 552.4 9.25 - 9.13 (m, IH), 8.98 - 8.80 (m, IH), 8.49 - 8.33 (m, IH), 8.26 - 8.13 (m, IH), 7.78 - 7.59 (m, IH), 5.47 5.15 (m, IH), 4.81 - 4.40 (m, 2H), 4.13 -3.80 (m, 2H), 3.72-3.41 (m, IH), 3.32 - 3.06 (m, IH), 2.59 (d, 361 fluorocyclohexane arbonyl)pyrrolide in-3-yl]-2methylpyridin-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7mi]-N-[(3R,4S)-4- fluoro-1-[(2K)-3,3,3- X^CF ₃ 550.1 J=6.4 Hz, ZN), 2.48 - 2.30 (m, IH), 2.18 - 1.94 (m, 2H), 1.90 - 1.72 (m, 2H), 1.55 - 1.35 (m, 4H), 1.09 - 0.91 (m, IH) 9.19 (dd, J=4.6, 1.8 Hz, IH), 8.97 8.86 (m, IH), 8.41 (dd, J=6.1, 1.8 Hz, IH), 8.21 (s, IH), 7.70 (d, J=2.4 Hz, IH), 6.95 - 6.73 (m, IH), 5.47 5.20 (m, IH), 5.06 - 4.86 (m, IH), 362 trifluoro-2hydroxypropanoyl] pyrrolidin-3 yl]-2methylpyridine-3 carboxamide, TFA 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- C[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(1- HE SA 536.3 4.82 - 4.60 (m, IH), 4.26 (br t, J=9.2 Hz, IH), 4.22 - 4.10 (m, IH), 3.98 3.82 (m, IH), 3.82 - 3.69 (m, IH), 2.59 ( s, 3H) 9.15 (s, IH), 8.93 (br dd, J=17.5, 6.9 Hz, IH), 8.39 (s, IH), 8.16 (s, IH), 7.66 (s, IH), 5.38-5.13 (m, IH ), 4.72 - 4.47 (m, IH), 4.37 - 4.29 (m, IH), 4.28-4.17 (m, IH), 3.34 (brt, J=11.1 Hz, IH), 2.57 (s, 3H), 2.16 - hydroxycyclopene tankcarbonyl)pyrr olidin-3 -yl]-2methylpyridine-3 carboxamide, TFA 2.04 (m, IH), 1.96 - 1.81 (m, IH), 1.78 - 1.60 (m, 4H), 1.55 (br s, 2H); 1 CH pyrrolidine closed due to water suppression

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363 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4- fluoro-1-(1hydroxycyclobut ancarbonyl)pyrrolidin-3-yl]-2methylpyride in-3 carboxamide, TFA 522.3 9.18 (s, 1H), 8.93 (brt, J=7.2 Hz, 1H), 8.42 (br d, J=3.7 Hz, 1H), 8.19 (s, 1H), 7.68 (s, 1H), 5.38 - 5.18 ( m, 1H), 4.70 - 4.53 (m, 1H), 4.10 - 3.94 (m, 1H), 3.90 - 3.72 (m, 1H), 3.55 - 3.28 (m, 1H), 2.58 (s, 4H), 2.48 2.33 (m, 1H), 2.14 - 2.04 (m, 1H), 1.99 (br d, J=8.2 Hz, 1H), 1.74 (br d, > 4.9Hz, 1H), 1.53 - 1.39 (m, 1H); 1 CH of pyrrolidine closed due to water suppression 364 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7ra]-N-[(3R,4S)-4fluoro-1-(3methylbutanoyl)pyrrolide in- 3 -yl]-2methylpyride in-3 carboxamide, TFA 508.2 9.14 (s, 1H), 8.80(brdd, J=12.1,7.1 Hz, 1H), 8.35 (s, 1H), 8.16 (s, 1H), 7.61 (s, 1H), 5.43 -5.19 (m, 1H) , 4.78-4.51 (m, 1H), 3.97 (brt, J=9.2 Hz, 1H), 3.92 - 3.82 (m, 1H), 3.82 3.65 (m, 1H), 2.58 (d, J=1.9 Hz, ZN) , 2.25 - 2.09 (m, 2H), 2.05 - 1.94 (m, 1H), 0.94 - 0.87 (m, 6H); 1 CH pyrrolidine closed due to water suppression 365 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1(][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[(28)-2hydroxy -4methylpentanoyl] and irrolidin-3-yl]2-methylpyridine3-carboxamide 538.3 9.16 (br s, 1H), 8.88 (brt, J=8.1 Hz, 1H), 8.38 (s, 1H), 8.18 (d, J=1.5 Hz, 1H), 7.68 (s, 1H), 5.43-5.16 ( m, 1H), 4.92 (br t, J=7.0 Hz, 1H), 4.77 4.53 (m, 1H), 4.27 - 4.06 (m, 2H), 4.06 -3.93 (m, 1H), 3.89 (s, 1H) , 3.83 - 3.72 (m, 1H), 2.57 (s, 3H), 1.74 (br d, J=5.5 Hz, 1H), 1.47 - 1.25 (m, 2H), 0.89 (br t, J=6.4 Hz, 6H ) 366 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7nn]-N-[(3R,4S)-4- φτop-l-[(2R)-3,3,3trifluoro-2hydroxy-2methylpropanoyl] and irrolidin-3-yl] 2-methylpyridine3-carboxamide X/CF ₃ 'he 564.2 9.17 (s, 1H), 8.94-8.83 (m, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.68 (s, 1H), 5.39 - 5.16 (m, 1H), 4.70 - 4.54 ( m, 1H), 4.45 - 4.37 (m, 1H), 4.36 4.24 (m, 1H), 4.06 - 3.91 (m, 1H), 3.87 - 3.80 (m, 1H), 2.57 (s, 3H), 1.52 (s , 3H)

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367 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-l(2,5difluorobenzoyl)-4fluoropyrrolidine- 3-yl]-2methylpyride in-3 carboxamide LL th 564.2 9.18 (dd, J=16.8, 1.5 Hz, 1H), 8.96 8.79 (m, 1H), 8.45 - 8.30 (m, 1H), 8.19 (d, J=15.0 Hz, 1H), 7.72 - 7.63 (m, 1H ), 7.39 (br d, J=4.6 Hz, ZN), 5.45 - 5.18 (m, 1H), 4.85 - 4.59 (m, 1H), 4.05 - 3.96 (m, 1H), 3.86 - 3.72 (m, 1H) , 3.65 (br t, J=9.2 Hz, 1H), 3.57 - 3.44 (m, 1H), 2.54 (s, 3H) 368 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4- φτop-l-[(2R)-2- hydroxy-4methylpentanoyl]p irrolidin-3-yl]2-methylpyridine3-carboxamide 538.2 9.19 (br s, 1H), 8.96 - 8.84 (m, 1H), 8.41 (br s, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 5.51 - 5.18 (m, 1H), 5.07 - 4.92 (m, 1H), 4.80 - 4.53 (m, 1H), 4.22 4.07 (m, 1H), 4.07 - 3.98 (m, 1H), 3.95 - 3.85 (m, 2H), 3.81 - 3.49 (m, 1H) , 2.60 (s, 3H), 1.84-1.71 (m, 1H), 1.46 - 1.29 (m, 2H), 0.97 - 0.87 (m, 6H) 369 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4- fluoro-G(1fluorocyclopropane carbonyl)pyrrolidin-3-yl]-2methylpyride in-3 carboxamide 510.2 9.20 (s, 1H), 8.92 (br dd, J=17.2, 7.5 Hz, 1H), 8.41 (brs, 1H), 8.21 (s, 1H), 7.70 (s, 1H), 5.49 - 5.22 (m, 1H ), 4.86 - 4.58 (m, 1H), 4.22 (br d, J=7.0 Hz, 1H), 4.14 - 3.99 (m, 1H), 3.94 - 3.70 (m, 2H), 2.60 (s, 3H), 1.46 - 1.28 (m, 3H), 1.15 (brd, J=10.1Hz, 1H) 370 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[(28)-3,3,3trifluoro-2hydroxypropanoyl] pyrrolidin-3 yl]-2methylpyride in- 3 carboxamide ^° ⁿ CF ₃ 550.2 9.15 (br s, 1H), 8.88 - 8.77 (m, 1H), 8.36 (br s, 1H), 8.16 (s, 1H), 7.62 (s, 1H), 5.46 - 5.19 (m, 1H), 4.88 ( br s, 1H), 4.80 - 4.55 (m, 1H), 4.21 - 3.51 (m, 5H), 2.58 (s, 3H)

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371 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 0 [ 1,2,4]triazin-7mi]-N-[(3R,4S)-4fluoro-G(1fluorocyclobutane pbonyl)pyrrolidi n-3-yl]-2methylpyride in-3 carboxamide ΐ 524.2 9.16 (br s, 1H), 8.94 - 8.85 (m, 1H), 8.38 (brd, J=6.1 Hz, 1H), 8.18 (brd, J=1.8 Hz, 1H), 7.67 (br d, J=4.6 Hz , 1Н), 5.43 - 5.18 (m, 1H), 4.79 - 4.58 (m, 1H), 3.98 - 3.64 (m, 4H), 2.78 - 2.54 (m, 4H), 2.45 - 2.23 (m, 2H), 1.86 ( brdd, J=10.1, 3.7 Hz, 1H), 1.59 - 1.45 (m, 1H); 1 CH cyclobutyl under solvent 372 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 0 [ 1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[(28)-3,3,3trifluoro-2hydroxy-2- methylpropanoyl] and irrolidin-3 -yl] 2-methylpyridine3-carboxamide, TFA /Acf ₃ '' he 564.2 9.18 (br s, 1H), 8.97 - 8.83 (m, 1H), 8.41 (br s, 1H), 8.19 (s, 1H), 7.69 (s, 1H), 5.42 - 5.14 (m, 1H), 4.78 - 4.47 (m, 1H), 4.38-4.17 (m, 1H), 4.103.80 (m, 2H), 3.78 - 3.59 (m, 1H), 2.58 (s, 3H), 1.53 (s, 3H) 373 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[(28)-2hydroxy- 3,3dimethylbutanoyl]pyrrolidin-3-yl]2-methylpyridine3-carboxamide He 538.3 9.17 (br s, 1H), 8.93 - 8.83 (m, 1H), 8.42 - 8.36 (m, 1H), 8.19 (s, 1H), 7.68 (d, J=3.7 Hz, 1H), 5.41 - 5.17 (m , 1H), 4.98-4.83 (m, 1H), 4.75-4.51 (m, 1H), 4.20-4.00 (m, 1H), 3.87-3.71 (m, 2H), 3.70-3.55 (m, 1H), 2.58 ( s, 3H), 0.91 (br d, J=4.0 Hz, 9H) 374 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(2-fluoro-2methylpropanoyl) p irrolidin-3-yl] 2-methylpyridine 3-carboxamide 0 512.2 9.17 (brd, J=2.1 Hz, 1H), 8.87 (br dd, J=13.9, 7.2 Hz, 1H), 8.39 (br s, 1H), 8.19 (s, 1H), 7.68 (d, J=3.1 Hz , 1H), 5.40 - 5.18 (m, 1H), 4.81 - 4.54 (m, 1H), 4.22 - 3.52 (m, 4H), 2.58 (s, 3H), 1.58 - 1.48 (m, 6H)

Connections in the table. 18 was obtained by the methods detailed in example 45. When the diastereomers were separated, they were included as separate data.

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Table 18

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 375 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-l-(4,4difluorocyclohexane pbonyl)-4fluoropyrrolidine- 3- silt]-2- (deutero)methoxypyr idine-3-carboxamide 589.2 8.94 (d, 1=1.8Hz, 1H), 8.868.76 (m, 1H), 8.61 - 8.46 (m, 1H), 8.19 (s, 1H), 7.63 (s, 1H), 5.46-5.19 (m, 1H), 4.92 - 4.57 (m, 1H), 4.21 - 3.16 (m, 4H), 2.71 -2.58 (m, 1H), 2.07 (br d, J=12.5 Hz, 2H), 1.99 - 1.72 (m, 4H ), 1.68 - 1.52 (m, 2H) 376 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(4fluorobenzoyl)pyrrolidin-3 -yl]-2(deutero)methoxypyr idine-3-carboxamide 565.4 8.93 (brd, J=8.5 Hz, 1H), 8.78 (br s, 1H), 8.62 - 8.48 (m, 1H), 8.18 (brd, J=13.1 Hz, 1H), 7.70 -7.58(m, 3H), 7.36 - 7.26 (m, 2H), 5.48-5.19 (m, 1H), 4.89 4.64 (m, 1H), 4.09 -3.77 (m, 3H), 3.70 -3.50 (m, 1H) 377 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-l-(2,2difluorocyclopropane carbonyl)-4fluoropyrrolidine- 3- silt]-2- (deutero)methoxypyr idine-3-carboxamide F 547.2 8.93 (dd, J=5.2, 2.4 Hz, 1H), 8.86 - 8.73 (m, 1H), 8.63 - 8.48 (m, 1H), 8.18 (d, J=0.9 Hz, 1H), 7.62 (d, >2.7 Hz, 1H), 5.465.23 (m, 1H), 4.91–4.62 (m, 1H), 4.18–3.60 (m, 4H), 3.042.86 (m, 1H), 2.03–1.81 (m, 2H).

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378 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-l-(2,2difluorocyclopropane arbonyl)-4fluoropyrrolidine- 3 yl]-2(deutero)methoxypyr idin-3-carboxamide . F 527.2 8.92 (s, 1H), 8.77 (s, 1H), 8.63 8.50 (m, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.48-5.19 (m, 1H), 4.94-4.63 (m , 1H), 4.35 - 3.26 (m, 4H), 3.15-2.97 (m, 1H), 2.02 - 1.75 (m, 2H) 379 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7Hn]-N-[(3R,4S)-4fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidine-3 - yl]-2(deutero)methoxypyr idin-3-carboxamide 543.2 8.93 (d, J=2.3 Hz, 1H), 8.78 (dd, J=11.9, 2.4 Hz, 1H), 8.54 (brdd, J=13.6, 7.6 Hz, 1H), 8.18 (s, 1H), 7.63 (s , 1H), 5.40–5.01 (m, 2H), 4.86–4.58 (m, 1H), 3.96–3.15 (m, 5H), 2.60–2.33 (m, 4H, absorbed by DMSO) 380 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7m]-N-[(3R,4S)-4fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3yl ]-2(deutero)methoxypyride in-3-carboxamide 543.1 8.92 (d, J=2.4Hz, 1H), 8.78 (dd, J=10.8, 2.4Hz, 1H), 8.51 (dd, J=13.0, 7.6Hz, 1H), 8.18 (s, 1H), 7.62 (s , 1H); -2.68 (m, 1H), 2.61 -2.53 (m, 1H), 2.35 -2.03 (m, 4H) 381 5-[4-amino-5(trifluoromethyl)pyrro lo[2,1- f] [ 1,2,4]triazin-7Hn]-N-[(3R,4S)-4fluoro-1 -(2-fluoro-2methylpropanoyl)pyrrolide in-3-yl]-2(deutero)methoxypyridine- 3-carboxamide 531.2 8.92 (s, 1H), 8.77 (s, 1H), 8.60 8.46 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.43-5.16 (m, 1H), 4.86-4.55 (m , 1H), 4.28 - 3.16 (m, 4H), 1.61-1.47 (m, 6H)

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382 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7Ni]-N-[(3R,4S)-4fluoro-1-(2methylpropanoyl)pyrrolide in-3-yl]-2(deutero)methoxypyr idin-3-carboxamide V 513.0 8.92 (d, J=2.1 Hz, 1H), 8.79 (dd, J=14.0.2.1 Hz, 1H), 8.53 (br dd, J=18.3, 7.6 Hz, 1H), 8.17 (s, 1H), 7.61 ( s, 1H), 5.44-5.19 (m, 1H), 4.85-4.58 (m, 1H), 4.12-3.15 (m, 4H, absorbed by water), 2.76-2.61 (m, 1H), 1.08-0.97 (m, 6H) 383 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7m]-N-[(3R,4S)-1-(2,5difluorobenzoyl)-4fluoropyrrolidine-3 yl]-2(deutero)methoxypyr idine-3-carboxamide, TFA dou 583.0 8.91 (brd, 1=13.8Hz, 1H), 8.82 - 8.67 (m, 1H), 8.56 - 8.40 (m, 1H), 8.15 (brd, 1=13.6Hz, 1H), 7.55 (brd, J=16.2Hz , 1H), 7.36 (br d, >3.7Hz, ZH), 5.50–5.18 (m, 1H), 4.94–4.62 (m, 1H), 4.11–3.15 (m, 4H, absorbed by water) 384 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[(28)-3, 3,3trifluoro-2-hydroxy2methylpropanoyl] pyrrolide in-3-yl]-2(deutero)methoxypyridine-3-carboxamide X^CF ₃ T*on 583.0 8.93 (s, 1H), 8.78 (br d, J=3.4 Hz, 1H), 8.61 - 8.47 (m, 1H), 8.19 (s, 1H), 7.63 (s, 1H), 7.06 (brd, J=7.3 Hz, 1H), 5.44-5.16 (m, 1H), 4.84-4.56 (m, 1H), 4.43 - 3.15 (m, 4H, absorbed by water), 1.54 (br d, J=10.7 Hz, SA) 385 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(3-hydroxy3methylbutanoyl)pyrrolidine -3-yl]-2(deutero)methoxypyr idin-3-carboxamide, TFA 543.1 8.92 (d, J=2.1 Hz, 1H), 8.79 (dd, J=12.1,2.3 Hz, 1H), 8.53 (brdd, J=11.6, 7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s , 1H), 5.42 - 5.20 (m, 1H), 4.85 - 4.57 (m, 1H), 4.15 - 3.15 (m, 4H, absorbed by water), 2.48-2.31 (m, 2H), 1.20 (s, 6H)

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386 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7m]-N-[(3R,4S)-4φτop-l-[(2R)-3, 3,3trifluoro-2-hydroxy2methylpropanoyl] pyrrolide in-3-yl]-2(deutero)methoxypyridine-3-carboxamide X^CF ₃ ron 583.1 8.91 (br s, 1H), 8.78 (br d, J=6.7 Hz, 1H), 8.52 - 8.38 (m, 1H), 8.16 (s, 1H), 7.56 (br s, 1H), 5.39-5.18 (m , 1H), 4.76 - 4.60 (m, 1H), 4.56-4.27 (m, 1H), 4.10-3.70 (m, 3H), 1.55 (s, 3H) 387 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(3methylbutanoyl)pyrrolidin-3 -yl]-2(deutero)methoxypyride in-3-carboxamide, TFA 527.3 8.93 (s, 1H), 8.79 (brd, 1=14.6 Hz, 1H), 8.52 (br dd, J=14.0, 7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.42- 5.17 (m, 1H), 4.87 4.57 (m, 1H), 4.09-3.15 (m, 4H, absorbed by water), 2.21 1.97 (m, 3H), 0.97 -0.87 (m, 6H) 388 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-l-(3,3dimethylbutanoyl)-4fluoropyrrolidine-3 yl]-2(deutero)methoxypyr idin-3-carboxamide 541.1 8.93 (d, J=1.8 Hz, 1H), 8.79 (dd, J=13.7, 2.1 Hz, 1H), 8.52 (brdd, J=14.6, 7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s , 1H), 5.42-5.15 (m, 1H), 4.85-4.51 (m, 1H), 4.08 - 3.15 (m, 6H, absorbed by water), 1.02 (s, 9H) 389 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(2fluorobenzoyl)pyrrolidin-3 -yl]-2(deutero)methoxypyr idine-3-carboxamide, TFA I 565.2 8.91 (brd, >15.6Hz, 1H), 8.80 - 8.70 (m, 1H), 8.64 - 8.49 (m, 1H), 8.16 (brd, >15.9Hz, 1H), 7.63 - 7.44 (m, 3H), 7.37 - 7.29 (m, 2H), 5.49-5.18 (m, 1H), 4.90-4.64 (m, 1H), 4.08 - 3.32 (m, 4H, absorbed by water) 390 5-(4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi)-N-((3R,4S)-l-(3,3difluorocyclobutane-1 carbonyl)- 4fluoropyrrolidin-3 yl)-2-(methoxyd3)nicotinamide A 561.2 8.94 (d, J=2.4 Hz, 1H), 8.898.68 (m, 1H), 8.61-8.51 (m, 1H), 8.19 (s, 1H), 7.63 (s, 1H), 7.29-6.93 (m, 1H), 5.46 - 5.11 (m, 1H), 4.93 - 4.49 (m, 1H), 4.16-3.54 (m, 3H), 3.32-3.23 (m, 1H), 3.23-3.13 (m, 2H), 2.91 - 2.69(m, 4H).

Connections in the table. 19 was obtained by the methods detailed in examples 67 and 31. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 19

ABOUT

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 391 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1£][1,2,4]triazin-7yl]-2-fluoro-M[(3R,4S)-4-φτop-l-( 2fluorobenzoyl)pyrrole idin-3-yl]-4methylbenzamide I 563.1 8.72-8.50 (m, 1H), 8.03 (br d, J=13.4 Hz, 1H), 7.62-7.40 (m, 3H), 7.37-7.26 (m, 3H), 7.25-7.16 (m, 1H), 5.41 - 5.10 (m, 1H), 4.81 - 4.52 (m, 1H), 4.01 - 3.35 (m, 4H), 2.14 (d, 1=13.7Hz, ZN) 392 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-l(3,3difluorocyclopentane arbonyl)-4fluoropyrrolidine-3 yl]-2-fluoro-4methylbenzamide F g ν 573.3 8.62 (br d, J=4.6 Hz, 1H), 8.01 (s, 1H), 7.58 (dd, J=7.2, 4.4 Hz, 1H), 7.32 (dd, J=11.3, 3.7 Hz, 1H), 7.21 (s, 1H), 5.37 - 5.10 (m, 1H), 4.75 - 4.46 (m, 1H), 4.06 - 3.04 (m, 6H), 2.38 2.21 (m, 2H), 2.14 (br d, J=1.5 Hz, ZN), 2.07 - 1.96 (m, 2H), 1.84 - 1.67 (m, 1H) 393 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-N[(3R,4S)-4-φτop-l-(3methylbutanoyl )pyrr olid in-3-yl]-4methylbenzamide 1 525.4 8.62 (br d, J=4.3 Hz, 1H), 8.06 (br s, 1H), 7.59 (dd, J=7.2, 4.1 Hz, 1H), 7.33 (br dd, J=11.4, 2.3 Hz, 1H), 7.22 (s, 1H), 5.36 - 5.10 (m, 1H), 4.75 - 4.45 (m, 1H), 3.98 - 3.74 (m, 1H), 3.66 (br s, 2H), 3.49 - 3.19 (m, 1H), 2.21 - 2.05 (m, 5H), 2.04 - 1.92 (m, 1H), 0.95 - 0.82 (m, 6H) 394 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-fluoro-I[(3^48)-4-fluoro-1[(2R )-3,3,3-trifluoro2-hydroxy-2methylpropanoyl]pyrrolide in-3-yl]-4methylbenzamide / 'He 581.3 8.59 (br dd, J=14.6, 7.0 Hz, 1H), 8.03 (s, 1H), 7.60 (t, J=6.7 Hz, 1H), 7.33 (br d, J=11.3 Hz, 1H), 7.22 (s , 1H), 5.34 - 5.10 (m, 1H), 4.67 - 4.48 (m, 1H), 4.43 - 4.21 (m, 1H), 4.07 - 3.30 (m, 2H), 2.15 (s, 3H), 1.51 (s , 3H); 2 CH pyrrolidine was not fully observed due to water suppression

Connections in the table. 20 was obtained by the methods detailed in examples 67 and 31. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 20

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 395 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ- 1-(1hydroxycyclobuta ncarbonyl)pyrroli din-3-yl]benzamide 559.0 8.93 (br t, J=7.2 Hz, 1H), 8.09 (s, 1H), 7.90 (br dd, J=7.5, 3.8 Hz, 1H), 7.68 (br dd, J=9.8, 2.4 Hz, 1H), 7.36 (s, 1H), 6.00 (d, J=3.4 Hz, 1H), 5.30 5.12 (m, 1H), 4.65 - 4.45 (m, 1H), 4.04 - 3.93 (m, 1H), 3.83 - 3.60 (m , 2H), 3.50 - 3.25 (m, 1H), 2.49 - 2.31 (m, 2H), 2.12 - 2.01 (m, 1H), 1.96 (br d, J=8.9 Hz, 1H), 1.78 - 1.66 (m, 1H), 1.51-1.38 (m, 1H) 396 397 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ1-( 3-Hydroxy-3-methylbutanoyl)pyrolidin-3yl] benzamide -[(3Κ,48)-4-φτορ1-(1- hydroxycyclopent ancarbonyl)pyrrole idin-3yl]benzamide, TFA ₍ he 561.0 573.0 8.94 (brdd, J=18.3.7.3 Hz, 1H), 8.11 (s, 1H), 7.91 (dd, 1=7.3, 4.0 Hz, 1H), 7.71 (d, J=9.8 Hz, 1H), 7.37 (s , 1H), 5.38 - 5.12 (m, 1H), 4.82 (d, J=3.7 Hz, 1H), 4.74 - 4.45 (m, 1H), 4.02 (br t, J=9.2 Hz, 1H), 3.95 - 3.77 (m, 1H), 3.74 - 3.52 (m, 1H), 3.27-3.12 (m, 1H), 2.46 - 2.25 (m, 2H), 1.18 (s, 6H) 8.80 (br s, 1H), 8.09 (s, 1H), 7.92 (br d, J=7.3 Hz, 1H), 7.64 (br d, J=9.9 Hz, 1H), 7.34 (s, 1H), 5.37 - 5.11 (m, 1H), 4.65 - 4.43 (m, 1H), 4.07 - 3.56 (m, 4H), 2.19 - 2.04 (m, 1H), 2.00 - 1.85 (m, 1H), 1.79 - 1.49 (m, 6H )

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398 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl] -2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ1-( 3methylbutanoyl)pyrolidin-3yl]benzamide 545.0 8.81 (br dd, J=11.5, 7.4 Hz, 1H), 8.09 (s, 1H), 7.92 (br d, J=7.5 Hz, 1H), 7.64 (br d, J=9.8 Hz, 1H), 7.34 ( s, 1H), 5.35-5.11 (m, 1H), 4.73 - 4.47 (m, 1H), 3.92 (brt, J=9.1 Hz, 1H), 3.87 - 3.79 (m, 1H), 3.78 - 3.72 (m, 1H), 3.22 (brt, 3=11.0Hz, 1H), 2.152.07 (m, 2H), 2.03 - 1.95 (m, 1H), 0.90 (br d, 1=5.4Hz, 6H) 399 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl] -2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ1-( 2fluorobenzoyl)pyrrolidin-3yl]benzamide And 583.0 8.92 - 8.73 (m, 1H), 8.09 (d, J=16.3 Hz, 1H), 7.99 - 7.84 (m, 1H), 7.70 7.59 (m, 1H), 7.52 (br s, 1H), 7.44 (q, J=7.3 Hz, 1H), 7.36 (s, 1H), 7.33 7.27 (m, 2H), 5.41 - 5.11 (m, 1H), 4.82-4.55 (m, 1H), 3.99 (br dd, J=11.3, 9.3Hz, 1H), 3.91 - 3.80 (m, 1H), 3.58 (brt, 1=9.2Hz, 1H), 3.53 3.42 (m, 1H) 400 5-[4-amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl]-2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ- l-[(2R)-3,3,3- trifluoro-2hydroxypropanoyl]pyrrolidin-3yl]benzamide ^CF ₃ OH 587.2 8.12 (s, 1H), 7.96 (br dd, J=7.2, 4.1 Hz, 1H), 7.68 (d, J=10.0 Hz, 1H), 7.37 (s, 1H), 5.41 - 5.18 (m, 1H), 4.98 - 4.82 (m, 1H), 4.76 - 4.54 (m, 1H), 4.23 (brt, J=9.3 Hz, 1H), 4.18 - 4.04 (m, 1H), 3.81 - 3.68 (m, 1H), 3.49 ( br t, 1=10.6Hz, 1H) 401 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl] -2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ1-( 2-fluoro-2methylpropanoyl)pyrrolidin-3yl]benzamide 549.0 8.88 - 8.76 (m, 1H), 8.10 (s, 1H), 7.93 (br d, J=7.6 Hz, 1H), 7.65 (d, J=10.0 Hz, 1H), 7.35 (s, 1H), 5.39 - 5.12 (m, 1H), 4.76 - 4.47 (m, 1H), 4.23 - 4.09 (m, 1H), 4.08 - 3.95 (m, 1H), 3.94 3.82 (m, 1H), 3.80 - 3.65 (m, 1H) , 1.59 - 1.46 (m, 6H)

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402 5-[4-amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl]-2-chloro-4-fluoroΝ-[(3Κ,48)-4-φτορ- l-[(2R)-3,3,3- trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide 'em 601.2 8.87 - 8.76 (m, 1H), 8.10 (br s, 1H), 7.93 (br d, J=6.6 Hz, 1H), 7.65 (br d, J=9.8 Hz, 1H), 7.35 (s, 1H), 5.34 5.12 (m, 1H), 4.66 - 4.48 (m, 1H), 4.40 (br t, J=9.3 Hz, 1H), 4.36 - 4.23 (m, 1H), 4.06 - 3.89 (m, 1H), 3.87 3.80 (m, 1H), 3.79 - 3.66 (m, 1H), 1.52 (br s, 3H) 403 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl]-2-chloro-4-fluoroN-[(3R,4S)-4-(j) Top1-(3,3,3trifluoropropanoyl)pyrrolidin-3yl]benzamide ^cf ₃ 571.1 8.85 (br dd, J=19.9, 7.2 Hz, 1H), 8.09 (br d, J=2.0 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.65 (br d, J=9.7 Hz, 1H), 7.34 (s, 1H), 5.39 - 5.13 (m, 1H), 4.74 4.48 (m, 1H), 3.99 (br t, J=8.9 Hz, 1H), 3.93 - 3.77 (m, 2H), 3.75 - 3.63 ( m, 1H), 3.31 - 3.18 (m, 1H); 1 CH pyrrolidine closed due to water suppression 404 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f][1,2,4]triazin-7yl]-2-chloro-4-fluoroN-[(3R,4S)-4-4)Top1 -(3-fluoropyridine2carbonyl)pyrrolide in-3-yl]benzamide 584.0 8.92 - 8.74 (m, 1H), 8.48 (br s, 1H), 8.11 (d, >15.6Hz, 1H), 8.01 -7.88 (m, 1H), 7.86 (t, >9.2 Hz, 1H), 7.71 7.56 (m, 2H), 7.35 (br d, J=19.7 Hz, 1H), 5.45 - 5.15 (m, 1H), 4.87 - 4.56 (m, 1H), 4.04 (br dd, J=11.7, 9.0 Hz, 1H ), 3.88 - 3.80 (m, 1H), 3.80 - 3.41 (m, 2H) 405 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2-chloro-4-fluoroN-[(3R,4S)-4-4)Top1 -(4fluorobenzoyl)pyrrolidin-3yl]benzamide XX^F 583.0 8.93 - 8.71 (m, 1H), 8.08 (br s, 1H), 8.00 - 7.81 (m, 1H), 7.64 (br d, J=2.6 Hz, 1H), 7.59 (br dd, J=8.4, 5.6 Hz , 2H), 7.33 (br s, 1H), 7.26 (br t, J=8.8 Hz, 2H), 5.42 - 5.12 (m, 1H), 4.80 4.51 (m, 1H), 4.11 -3.62 (m, ZH) ; 1 CH pyrrolidine closed due to water suppression

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406 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7- yl]-2-chloro-M[(3R,4S)-l-(3,3difluorocyclobutane arbonyl)-4fluoropyrrolidin-3 yl]-4-fluorobenzamide Lf F 579.1 8.83 (brt, J=8.5 Hz, 1H), 8.10 (s, 1H), 7.93 (dd, J=7.4, 2.6 Hz, 1H), 7.65 (br d, J=9.6 Hz, 1H), 7.35 (s, 1H), 5.39 5.14 (m, 1H), 4.79 - 4.50 (m, 1H), 3.95 - 3.81 (m, 1H), 3.78 - 3.61 (m, 3H), 3.21 - 3.04 (m, 1H), 2.87 - 2.66 (m, 4H) 407 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1- 1][1,2,4]triazin-7yl]-2-chloro-X[(3R,4S)-1-(4,4difluorocyclohexane carbonyl)-4fluoropyrrolidin-3yl]-4-fluorobenzamide Ύ Lf F 607.1 8.82 (br dd, J=16.3, 7.5 Hz, 1H), 8.09 (s, 1H), 7.92 (br d, J=7.5 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.35 (s, 1H) , 5.39 - 5.10 (m, 1H), 4.78 - 4.45 (m, 1H), 4.03 (brt, J=9.3 Hz, 1H), 3.95 - 3.78 (m, 2H), 3.75 - 3.67 (m, 1H), 2.68 - 2.57 (m, 1H), 2.03 (s, 2H), 1.93 - 1.69 (m, 4H), 1.65 - 1.50 (m, 2H) 408 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f][ 1,2,4]triazine-7- yl]-2-chloro-M[(3R,4S)-1-(2,2difluorocyclopropane carbonyl)-4fluoropyrrolidin-3 yl]-4-fluorobenzamide AG* F F 565.1 8.93 - 8.78 (m, 1H), 8.13 (s, 1H), 7.97 (br d, J=7.6 Hz, 1H), 7.69 (br d, J=9.9 Hz, 1H), 7.37 (s, 1H), 5.44 - 5.15 (m, 1H), 4.86 - 4.53 (m, 1H), 4.29 - 3.43 (m, 4H), 3.09 - 2.82 (m, 1H), 2.02 1.79 (m, 2H) 409 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7yl]-2-chloro-4-fluoroN-[(3R,4S)-4-4)Top1 -(3fluorocyclobutanecar bonyl)pyrrolidin3-yl]benzamide 561.1 8.93 (dd, J=16.8, 7.3 Hz, 1H), 8.11 (s, 1H), 7.91 (dd, J=7.5, 4.7 Hz, 1H), 7.71 (d, J=9.8 Hz, 1H), 7.37 (s , 1H), 5.36 - 4.98 (m, 2H), 4.78 - 4.47 (m, 1H), 3.94 - 3.13 (m, 5H), 2.49 - 2.29 (m, 4H) 410 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7- yl]-2-chloro-M[(3R,4S)-l-(3,3difluorocyclopentane carbonyl)-4fluoropyrrolidin-3 yl]-4-fluorobenzamide F L/ ^F 593.0 No data

Connections in the table. 21 was obtained by the methods detailed in examples 67 and 31. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 21

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 411 5-[4-amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7 yl]-4-fluoro-M[(3K,48)-4-fluoro-1-( 3fluorocyclobutanecarb onyl)pyrrolidin-3 yl]-2-methylbenzamide 541.4 8.55 (brdd, >11.5, 7.1 Hz, 1H), 8.07 (s, 1H), 7.77 (br d, >7.2 Hz, 1H), 7.31 - 7.24 (m, 2H), 5.38 - 5.13 (m, 1H), 5.08 - 4.84 (m, 1H), 4.73 - 4.47 (m, 1H), 3.92 - 3.77 (m, 2H), 3.77 3.61 (m, 2H), 2.72 (td, >16.7, 8.3 Hz, 1H), 2.43 ( s, 3H), 2.32 - 2.13 (m, 2H); 2 CH cyclobutyl closed due to water suppression 412 413 414 415 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1(][1,2,4]triazin-7yl]-4-fluoro-bT [(3K,48)-4-fluoro-1-( 2fluorobenzoyl)pyrrole idin-3-yl]-2methylbenzamide 4S)-4-φτop-l-(3hydroxy-3methylbutanoyl)pyrr olidin-3-yl]-2methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrr olo[2.11][1.2.4]triazine- 7Ηπ]-4-φτορ-Ν[(3R,48)-4-fluoro-1[(2R)-3,3,3-trifluoro2-hydroxy-2methylpropanoyl] pyrrolide in-3-yl]-2methylbenzamide 5-[ 4-Amino-5(trifluoromethyl)pyrr olo[2,1(][1,2,4]triazin-7yl]-4-fluoro-M[(3K,48)-4-fluoro-1[(2R)- 3,3,3-trifluoro2hydroxypropanoyl]pyrrolidin-3-yl]-2methylbenzamide (0 he ?^srz 'he A/CF ₃ OH 563.3 541.4 581.3 567.3 8.78 - 8.59 (m, 1H), 8.09 (brd, >16.5 Hz, 1H), 7.84 - 7.69 (m, 1H), 7.58 - 7.49 (m, 1H), 7.48 - 7.41 (br, 1H), 7.37 - 7.25 (m, 4H), 5.44 - 5.09 (br, 1H), 4.84 - 4.53 (m, 1H), 4.06 3.30 (t, W), 2.47 - 2.35 (t, W); 1 CH of pyrrolidine was not observed due to water suppression 8.70 (br dd, >13.9, 7.2 Hz, 1H), 8.08 (s, 1H), 7.74 (dd, >7.2, 2.0 Hz, 1H), 7.33 - 7.27 (m, 2H), 5.40 - 5.08 (m, 1H ), 4.85 (d, >5.5 Hz, 1H), 4.73 4.44 (m, 1H), 4.00 (br t, J=9.2 Hz, 1H), 3.96 - 3.75 (m, 1H), 3.43 (brt, >10.2 Hz , 1H), 3.24 (brt, >11.0 Hz, 1H), 2.46 - 2.24 (m, 5H), 1.17 (s, 6H) 8.72 - 8.59 (m, 1H), 8.10 (s, 1H), 7.78 (br d, >5.8 Hz, 1H), 7.36 - 7.27 (m, 2H), 5.35 - 5.13 (m, 1H), 4.67 4.48 (m , 1H), 4.42 - 4.23 (m, 1H), 4.03 - 3.85 (m, 1H), 3.84 - 3.71 (m, 1H), 3.70 - 3.56 (m, 1H), 2.43 (s, 3H), 1.51 (brd , >2.1Hz, ZN) 8.72 (br dd, >18.9, 7.3 Hz, 1H), 8.08 (s, 1H), 7.75 (dd, >7.3, 3.1 Hz, 1H), 7.34 - 7.26 (m, 2H), 6.99 - 6.76 (m, 1H ), 5.42 - 5.14 (m, 1H), 5.00 - 4.79 (m, 1H), 4.74 - 4.52 (m, 1H), 4.23 3.23 (m, 4H), 2.42 (s, 3H)

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416 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-4-fluoro-M[(3K,48)-4-fluoro-1-(2hydroxy -2methylpropanoyl)pyrrolide in-3 -yl]-2methylbenzamide HE 527.3 8.71 - 8.58 (m, 1H), 8.10 (s, 1H), 7.77 (br d, J=7.3 Hz, 1H), 7.36 - 7.26 (m, 2H), 5.39 - 5.10 (m, 2H), 4.64 4.42 ( m, 1H), 4.39 - 4.21 (m, 1H), 4.02-3.81 (m, 1H), 3.79 - 3.71 (m, 1H), 3.69-3.57 (m, 1H), 2.43 (s, 3H), 1.35 - 1.25(m, 6H) 417 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1(3,3difluorocyclopentane arbonyl)-4fluoropyrrolidine-3 yl]-4-fluoro-2methylbenzamide, TFA Al ^F L/ ^F 573.4 8.68 (br dd, J=18.3, 7.0 Hz, 1H), 8.09 (s, 1H), 7.76 (br d, J=7.0 Hz, 1H), 7.35 - 7.27 (m, 2H), 5.42 - 5.11 (m, 1H), 4.79 - 4.45 (m, 1H), 4.05 - 3.49 (m, 3H), 3.34 - 3.06 (m, 1H), 2.43 (br d, J=4.0 Hz, ZN), 2.37 - 2.23 (m, 2H ), 2.21 - 1.94 (m, 3H), 1.86 - 1.69 (m, 1H); 1 CH pyrrolidine was not observed due to water suppression 418 5-[4-amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazin-7yl]-4-fluoro-M[(3R,4S)-4-φτop-l-(3fluorocyclobutanecarb onyl)pyrrolidin-3 yl]-2-methylbenzamide 541.1 8.67 (br dd, J=14.2, 7.2 Hz, 1H), 8.09 (s, 1H), 7.75 (br dd, J=7.2, 2.3 Hz, 1H), 7.34 - 7.26 (m, 2H), 5.37 - 4.97 ( m, 2H), 4.75 - 4.45 (m, 1H), 3.87 3.12 (m, 5H), 2.49 - 2.29 (m, 7H)

Connections in the table. 22 was obtained by the methods detailed in examples 67 and 31. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 22

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 419 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-1(3,3difluorocyclobutane pbonyl)-4fluoropyrrolidine-3 yl]-4-fluorobenzamide h 545.2 8.79 (brdd, 1=17.1, 7.0 Hz, 1H), 8.32 (br d, J=6.1 Hz, 1H), 8.13 (s, 1H), 8.08 (br s, 1H), 7.53 (br t, J=8.2 Hz, 1H), 7.42 (s, 1H), 5.41-5.15 (m, 1H), 4.83 - 4.52 (m, 1H), 3.98 3.68 (m, 2H), 3.54 - 3.39 (m, 1H), 3.19 (brdd , 1=11.4, 5.0 Hz, 1H), 2.92 - 2.67 (m, 4H); 1 CH pyrrolidine closed due to water suppression 420 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-4-fluoro-M[(3^4δ)-4-φτορ-1-(2methylpropanoyl )pyrrolidin-3yl]benzamide, TFA 497.1 8.71 (br dd, 1=18.9, 7.0 Hz, 1H), 8.30 (brd, 1=4.9Hz, 1H), 8.10 (s, 1H), 8.06 (br s, 1H), 7.49 (dt, J=9.1, 4.5 Hz, 1H), 7.39 (s, 1H), 5.39 - 5.12 (m, 1H), 4.81 - 4.50 (m, 1H), 3.99 (br t, J=9.0 Hz, 1H), 3.90 (brd, J= 7.0 Hz, 1H), 3.86 - 3.75 (m, 1H), 3.74 - 3.54 (m, 1H), 2.76 - 2.58 (m, 1H), 1.07-0.92 (m, 6H) 421 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-4-fluoro-M[(3R,4S)-4-φτop-l-(4fluorobenzoyl )pyrrole idin-3-yl]benzamide, TFA h, 549.2 8.83 - 8.62 (m, 1H), 8.36 - 8.21 (m, 1H), 8.13 - 7.97 (m, 2H), 7.61 (br s, 2H), 7.54 - 7.42 (m, 1H), 7.37 (br d, 1 =12.8 Hz, 1H), 7.28 (br t, J=8.7 Hz, 2H), 5.42-5.11 (m, 1H), 4.85 - 4.50 (m, 1H), 4.08 - 3.57 (m, 2H); 2 CH pyrrolidine closed due to water suppression

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422 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7ππ]-4-φτορ-Ν[(ЗR,4S)-4-φτop-l(3, 3,3trifluoropropanoyl)p irrolidin-3yl]benzamide X^cf ₃ 537.2 8.84 - 8.70 (m, 1H), 8.29 (br d, J=4.9 Hz, 1H), 8.09 (s, 1H), 8.05 (br s, 1H), 7.49 (brt, J=8.7 Hz, 1H), 7.38 (br s, 1H), 5.43 - 5.15 (m, 1H), 4.82 - 4.49 (m, 1H), 3.98 (brt, J=8.9 Hz, 1H), 3.95 - 3.74 (m, 2H), 3.73 3.61 (m , 1H), 3.40 (brt, J=10.5 Hz, 1H); 1 CH pyrrolidine closed due to water suppression 423 424 425 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazine-7m]-N-[(3R,4S)-1(2,2difluorocyclopropane arbonyl)-4fluoropyrrolidin-3 yl ]-4-fluorobenzamide 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-1(3,3difluorocyclopentane carbonyl )-4fluoropyrrolidin-3 yl]-4-fluorobenzamide 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1C[1,2,4]triazine-7m]-N-[(3R,4S)-1(4,4difluorocyclohexane arbonyl)-4fluoropyrrolidin-3 yl ]-4-fluorobenzamide U V' T Tf \^^F 531.0 559.0 573.1 8.83 - 8.68 (m, 1H), 8.31 (br s, 1H), 8.14 - 8.03 (m, 2H), 7.56 - 7.45 (m, 1H), 7.39 (s, 1H), 5.44-5.14 (m, 1H) , 4.89 - 4.53 (m, 1H), 4.27 - 3.55 (m, 4H), 3.12-2.81 (m, 1H), 2.03 - 1.80(m, 2H) 8.72 (br dd, J=18.9, 6.7 Hz, 1H), 8.30 (brd, >5.2 Hz, 1H), 8.10 (s, 1H), 8.06 (br s, 1H), 7.50 (td, J=9.0, 4.6 Hz, 1H), 7.39 (s, 1H), 5.37-5.11 (m, 1H), 4.81 - 4.51 (m, 1H), 4.09 3.36 (m, 4H), 3.28 - 3.05 (m, 1H), 2.40 - 2.24 (m, 2H), 2.23 - 1.97 (m, 3H), 1.87 - 1.72 (m, 1H) 8.72 (br dd, J=20.0, 6.9 Hz, 1H), 8.30 (brd, J=5.5 Hz, 1H), 8.10 (s, 1H), 8.05 (br s, 1H), 7.49 (td, J=9.0, 4.9 Hz, 1H), 7.38 (s, 1H), 5.41 -5.11 (m, 1H), 4.82 - 4.52 (m, 1H), 4.113.52 (m, 3H), 2.67 - 2.55 (m, 1H), 2.04 (br d, J=9.5 Hz, 2H), 1.95 - 1.70 (m, 4H), 1.58 (brs, 2H); 1 CH pyrrolidine closed due to water suppression 426 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-4-fluoro-Н[(3K,48)-4-fluoro-1[(2R )-3,3,3-trifluoro2-hydroxy-2methylpropanoyl]pyrolidin-3yl]benzamide, TFA ^CF ₃ 'he 567.2 8.71 (br dd, J=17.4, 7.0 Hz, 1H), 8.30 (brd, >6.4Hz, 1H), 8.10 (s, 1H), 8.06 (br s, 1H), 7.49 (brt, J=9.2 Hz, 1H), 7.38 (br d, J=3.7 Hz, 1H), 5.34 - 5.13 (m, 1H), 4.71 - 4.48 (m, 1H), 4.43 - 4.23 (m, 1H), 4.03 - 3.89 (m, 1H ), 3.84 - 3.58 (m, 2H), 1.52 (s, 3H) 427 3-[4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazin-7yl]-4-fluoro-M[(3R,4S)-4-φτop-l-(2hydroxy -2methylpropanoyl)pyrolidin-3yl]benzamide, TFA 513.0 8.73 (br dd, J=18.0, 6.7 Hz, 1H), 8.31 (brd, J=6.4 Hz, 1H), 8.128.02 (m, 2H), 7.50 (br t, J=9.2 Hz, 1H), 7.40 (s, 1H), 5.37-5.11 (m, 1H), 4.69 - 4.50 (m, 1H), 4.42 - 4.26 (m, 1H), 4.03 - 3.50 (m, 3H), 1.35 1.27 (m, 6H)

Connections in the table. 23 was obtained by methods similar to those detailed in example 44. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 23 h ₂ n^/ N \=n

HKI

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 428 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7m]-N-[(3R,4S)-1-[(2,2difluorocyclopropyl)methyl ]-4fluoropyrrolidin-3 -yl] 2-methylpyridine-3 carboxamide V\^ ^F 514.2 9.16 (d, T=2.1Hz, 1H), 8.76 (d, .1=7.6Hz, 1H), 8.37 (d, J=2.1Hz, 1H), 8.20 (s, 1H), 7.70 (s, 1H) , 5.31 - 5.08 (m, 1H), 4.62 4.35 (m, 1H), 3.21 -2.64 (m, 4H), 2.56 (s, 3H), 2.02 - 1.75 (m, 1H), 1.59 (tdd, J=12.1 .7.8, 4.3 Hz, 1H), 1.34 - 1.07 (m, 3H) 429 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7m]-N-[(3R,4S)-1-[(2,2difluorocyclopropyl)methyl ]-4fluoropyrrolidin-3 -yl] 2-methylpyridine-3 carboxamide 514.2 9.47 - 8.98 (m, 1H), 8.89 - 8.63 (m, 1H), 8.48 - 8.28 (m, 1H), 8.26 - 8.05 (m, 1H), 7.84 - 7.60 (m, 1H), 5.34-4.95 (m , 1H), 4.70-4.32 (m, 1H), 3.14-2.54 (m, 7H), 2.00-1.70 (m, 1H), 1.68-1.39 (m, 1H), 1.34-1.01 (m, 3H) 430 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-N-[(ЗR,4S)-4-φτop1-(3,3,3 -trifluoro-2 hydroxypropyl)pyrrolidin-3-yl]-2methylpyride in-3 carboxamide He 536.2 9.16 (d, >2.0Hz, 1H), 8.72 (d, J=7.5Hz, 1H), 8.37 (d, J=2.0Hz, 1H), 8.20 (s, 1H), 7.70 (s, 1H), 6.22 (d, J=6.4 Hz, 1H), 5.32 - 5.06 (m, 1H), 4.62 - 4.40 (m, 1H), 4.17-3.96 (m, 1H), 3.27-3.12 (m, 1H), 3.06 (br t, >8.5Hz, 2H), 2.91 -2.61 (m, 5H), 2.56 (s, 3H) 431 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-N-[(ЗR,4S)-4-φτop1-(3,3,3 -trifluoro-2 hydroxypropyl)pyrrolidin-3-yl]-2methylpyride in-3 carboxamide He 536.2 9.23 - 9.03 (m, 1H), 8.89 - 8.63 (m, 1H), 8.49 - 8.27 (m, 1H), 8.26 - 8.03 (m, 1H), 7.83 - 7.53 (m, 1H), 6.03 (s, 1H ), 5.39 4.90 (m, 1H), 4.66 -4.35 (m, 1H), 4.19-3.93 (m, 1H), 3.222.62 (m, 11H)

Connections in the table. 24 was prepared by the methods detailed in Example 44 or by the methods detailed in Example 1361 below. All compounds are enantiomerically pure fluoropyrrolidine as shown. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 24

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 432 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazin-7nn]-N-[(3R,4S)-4fluoro-G(1phenylethyl)pyrrole idin-3-yl ]-2methoxypyride in-3 carboxamide And 544.2 8.90 (d, J=2.4Hz, 1H), 8.83 (d, J=2.3Hz, 1H), 8.35 (br d, J=7.3Hz, 1H), 8.15 (s, 1H), 7.55 (s, 1H) , 7.39 - 7.28 (m, 4H), 7.28 - 7.10 (m, 1H), 5.34 - 5.03 (m, 1H), 4.62 4.42 (m, 1H), 4.11 - 4.04 (m, 3H), 3.65 - 3.28 (m , 2H), 3.05 - 2.75 (m, 2H), 2.58 -2.55 (m, 1H), 1.33 (d, J=6.6 Hz, ZN) 433 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-G(1phenylethyl)pyrrole idine-3- yl]-2methoxypyride in-3 carboxamide And 544.2 8.90 (d, 1=2.1Hz, 1H), 8.82 (d, J=2.1Hz, 1H), 8.36 (br d, J=7.4Hz, 1H), 8.14 (s, 1H), 7.54 (s, 1H) , 7.34 (d, J=4.3 Hz, 4H), 7.30 - 7.15 (m, 1H), 5.31 - 5.03 (m, 1H), 4.60 - 4.38 (m, 1H), 4.06 (s, 3H), 3.56 3.33 ( m, 1H), 3.22 - 3.06 (m, 1H), 2.87 - 2.77 (m, 1H), 2.77 - 2.63 (m, 1H), 2.58-2.53 (m, 1H), 1.32 (d, J=6.5 Hz, ZN) 434 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1b][1,2,4]triazin-7yl]-N-[(ЗR,4S)-l[1-(3cyanophenyl)ethyl] 4- fluoropyrrolidin3-yl]-2methoxypyride in-3 carboxamide /1 CN 569.2 8.90 (d, J=2.4 Hz, 1H), 8.86 - 8.77 (m, 1H), 8.43 (br d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.80 (s, 1H), 7.72 ( br t, J=6.7 Hz, 2H), 7.59 (s, 1H), 7.58 -7.52 (m, 1H), 5.31 - 5.08 (m, 1H), 4.63 - 4.45 (m, 1H), 4.06 (s, 3H ), 3.58 (q, J=6.4 Hz, 1H), 3.03 2.96 (m, 1H), 2.96 - 2.88 (m, 1H), 2.87-2.69 (m, 1H), 2.51 - 2.47 (m, 1H), 1.32 (d, J=6.7 Hz, ZN)

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435 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine-7nn]-N-[(3R,4S)-l[1-(3cyanophenyl)ethyl] 4 -fluoropyrrolidin3-yl]-2methoxypyride in-3 carboxamide A CN 569.1 8.90 (d, J=2.4 Hz, 1H), 8.86 - 8.76 (m, 1H), 8.44 (br d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.767. 68 (m, 2H), 7.63 - 7.54 (m, 2H), 5.32 - 5.06 (m, 1H), 4.60 - 4.41 (m, 1H), 4.05 (s, 3H), 3.67 - 3.43 (m, 1H), 3.26 - 3.04 (m, 1H), 2.79 (t, J=8.1 Hz, 1H), 2.75 - 2.62 (m, 1H), 2.60 - 2.56 (m, 1H), 1.32 (d, J=6.4 Hz, ZN) 436 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine-7nn]-N-[(3R,4S)-l[1-(2,4difluorophenyl)ethyl ]-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide IN 580.2 8.91 (s, 1H), 8.82 (br s, 1H), 8.40 (br d, J=7.3 Hz, 1H), 8.16 (s, 1H), 7.67 - 7.48 (m, 2H), 7.25 - 7.16 (m, 1H), 7.13 (brt, J=8.3 Hz, 1H), 5.43 -5.08 (m, 1H), 4.74 - 4.47 (m, 1H), 4.07 (s, 4H), 3.37 - 2.65 (br d, J=5.8 Hz, 4H), 1.42 (br d, J=6.3 Hz, ZN) 437 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-l[1-(2,4difluorophenyl)ethyl] -4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide V 580.4 8.91 (s, 1H), 8.83 (s, 1H), 8.39 (br d, J=7.5 Hz, 1H), 8.15 (s, 1H), 7.64 -7.51 (m, 2H), 7.18 (brt, J=9.7 Hz, 1H), 7.11 (brt, J=7.7 Hz, 1H), 5.44 - 5.05 (m, 1H), 4.73 - 4.41 (m, 1H), 4.15-3.98 (m, 4H), 3.722.88 (m, 3H), 2.70 (brd, J=11.0 Hz, 1H), 1.41 (br d, J=6.4 Hz, ZN) 438 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1(pyridin-4yl) ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide, 2 TFA Ho 545.2 8.90 (d, J=2.4 Hz, 1H), 8.82 (d, J=2.1 Hz, 1H), 8.53 (br d, J=4.6 Hz, 2H), 8.49 - 8.38 (m, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.37 (brd, J=5.2 Hz, 2H), 5.40 - 5.04 (m, 1H), 4.65 - 4.37 (m, 1H), 4.05 (s, 3H), 3.51 - 3.47 (m, 1H, partially suppressed), 3.19 - 3.05 (m, 1H), 2.83 (brt, 3=8.4Hz, 1H), 2.77 2.66 (m, 1H), 2.60 - 2.55 (m, 1H), 1.31 (d , J=6.4 Hz, ZN) 439 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1(pyridin-4yl) ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide, 2 TFA Ho 545.2 8.90 (d, А2.1Hz, 1H), 8.82 (d, J=2.1Hz, 1H), 8.53 (br s, 2H), 8.49 - 8.38 (m, 1H), 8.16 (s, 1H), 7.59 (s , 1H), 7.39 (br d, J=4.9 Hz, 2H), 5.33 - 5.09 (m, 1H), 4.70 - 4.39 (m, 1H), 4.06 (s, 3H), 3.57 - 3.47 (m, 1H, partially suppressed), 3.11 2.74 (m, ZN), 2.55 (brt, J=8.7 Hz, 1H), 1.32 (d, J=6.4 Hz, ZN) 440 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1-(5fluoro pyridine -3 yl)ethyl] pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide A F 562.8 8.91 (d, A2.4Hz, 1H), 8.82 (d, J=2.4Hz, 1H), 8.52 - 8.44 (m, 2H), 8.42 (br d, J=7.6Hz, 1H), 8.17 (s, 1H ), 7.70 (br d, J=10.1 Hz, 1H), 7.60 (s, 1H), 5.30 - 5.09 (m, 1H), 4.62 - 4.46 (m, 1H), 4.06 (s, 3H), 3.69 - 3.62 (m, 1H), 3.06 - 2.97 (m, 1H), 2.94 (dd, J=12.1, 4.7 Hz, 1H), 2.91-2.77 (m, 1H), 2.57 - 2.53 (m, 1H), 1.36 (d , J=6.4 Hz, ZN)

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441 5-[4-Amino-5(trifluoromethyl)pyrolo[2,10 [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(5fluoro-pyridine- 3 yl)ethyl] pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide A F 563.4 8.91 (d, J=2.1Hz, 1H), 8.83 (d, J=2.1Hz, 1H), 8.49 (d, J=2.4Hz, 1H), 8.47 - 8.40 (m, 2H), 8.16 (s, 1H ), 7.69 (br d, J=9.8 Hz, 1H), 7.60 (s, 1H), 5.31 -5.12 (m, 1H), 4.61 - 4.43 (m, 1H), 4.05 (s, 3H), 3.65 (brd , J=6.4 Hz, 1H), 3.223.04 (m, 1H), 2.83 (br t, J=8.2 Hz, 1H), 2.77 - 2.64 (m, 1H), 2.60 (br t, J=8.4 Hz, 1H), 1.36 (d, J=6.4 Hz, ZN) 442 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1 -[ 1 -(2-methyl1, 3-thiazol-4yl)ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide chu- 565.2 8.90 (d, >2.1Hz, 1H), 8.83 (d, >2.4Hz, 1H), 8.41 (brd, J=7.3Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.27 ( s, 1H), 5.32 - 5.02 (m, 1H), 4.53 - 4.30 (m, 1H), 4.04 (s, 3H), 3.79 (q, J=6.6 Hz, 1H), 3.26 - 3.08 (m, 1H) , 2.93 (t, J=8.1 Hz, 1H), 2.87-2.71 (m, 1H), 2.64 (s, 3H), 2.59 (brt, J=8.5 Hz, 1H), 1.37 (d, J=6.7 Hz, ZN) 443 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1 -[ 1 -(2-methyl1, 3-thiazol-4yl)ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide Pu- 565.2 8.90 (d, >2.1Hz, 1H), 8.83 (d, J=2.1Hz, 1H), 8.41 (br d, J=7.0Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.28 (s, 1H), 5.28 - 5.03 (m, 1H), 4.53 -4.33 (m, 1H), 4.05 (s, 3H), 3.83 (br d, J=5.5 Hz, 1H), 3.45 (br d, J=15.6 Hz, 1H), 3.23 - 2.81 (m, 2H), 2.64 (s, 3H), 2.61 - 2.57 (m, 1H), 1.37 (brd, >6.7Hz, ZN) 444 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(1,3thiazole- 5yl)ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide 551.2 9.04 (s, 1H), 8.92 (d, J=2.4Hz, 1H), 8.84 (d, J=2.1Hz, 1H), 8.42 (brd, >7.6Hz, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.61 (s, 1H), 5.395.03 (m, 1H), 4.61 - 4.38 (m, 1H), 4.10 - 4.03 (m, 4H), 3.26 - 3.05 (m, 1H), 2.91 (t, J=8.4 Hz, 1H), 2.84 2.69 (m, 1H), 2.62 (brt, J=8.7 Hz, 1H), 1.41 (d, J=6.4 Hz, ZN)

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445 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-[1-(1,3thiazole -5yl)ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide A A 551.2 9.03 (s, IH), 8.92 (d, >2.1 Hz, IH), 8.84 (d, >2.4 Hz, IH), 8.41 (br d, >7.3 Hz, IH), 8.18 (s, IH), 7.82 ( s, IH), 7.61 (s, IH), 5.35 5.07 (m, IH), 4.66 - 4.38 (m, IH), 4.15-4.00 (m, 4H), 3.10 - 2.97 (m, 2H), 2.93 -2.81 (m, IH), 2.592.55 (m, IH), 1.42 (d, J=6.4 Hz, ZN) 446 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(3,3,3trifluoro- 1phenylpropyl)pyrr olidin-3-yl]-2methoxypyride in-3 carboxamide /CF ₃ h 612.1 8.92 (d, >2.4 Hz, IH), 8.85 (s, IH), 8.44 (br d, >7.6 Hz, IH), 8.17 (s, IH), 7.91 (br d, >6.7 Hz, IH), 7.71 (br d, >8.2 Hz, 2H), 7.62 (s, IH), 7.48 (br s, IH), 5.30 5.07 (m, IH), 4.58 (brd, >18.6 Hz, IH), 4.07 (s, 3H ), 3.92 - 3.69 (m, IH), 3.19-2.67 (m, 6H, partially suppressed), 1.33 (br d, >6.1 Hz, ZN) 447 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(3,3,3trifluoro- 1phenylpropyl)pyrr olid in-3 -yl]-2methoxypyride in-3 carboxamide /CF ₃ h 612.1 8.66 (d, >2.4 Hz, IH), 8.57 (d, >2.1 Hz, IH), 8.21 (brd, >7.3 Hz, IH), 7.92 (s, IH), 7.64 (br d, >7.9 Hz, IH ), 7.49 (br t, >7.6 Hz, IH), 7.45 (br d, >7.9 Hz, IH), 7.36 (s, IH), 7.28 - 7.21 (m, IH), 5.08 - 4.88 (m, IH) , 4.37 - 4.20 (m, IH), 3.80 (s, 3H), 3.51 (brs, IH), 3.04 - 2.84 (m, ZN, partially suppressed), 2.58 -2.37 (m, 2H), 2.35 -2.30 (m , IH), 1.07 (brd, >6.1 Hz, ZN) 448 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(2fluorophenyl)ethyl] pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide to 562.3 8.91 (d, >2.1 Hz, IH), 8.84 (d, >2.1 Hz, IH), 8.43 (br d, >7.6 Hz, IH), 8.17 (s, IH), 7.61 (s, IH), 7.52 ( brt, >6.9 Hz, IH), 7.427.27 (m, IH), 7.27 - 7.12 (m, 2H), 5.38 - 5.07 (m, IH), 4.71 - 4.43 (m, IH), 4.07 (s, 3H ), 3.87 (q, >6.7 Hz, IH), 3.18 (d, >5.5 Hz, IH), 3.06 - 2.92 (m, 2H), 2.87 - 2.73 (m, IH), 1.35 (d, >6.7 Hz, ZN)

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449 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1-(2fluorophenyl)ethyl ] pyrrolide in-3 -yl] -2 methoxypyride in-3 carboxamide pho 562.1 8.91 (d, 1=2.4Hz, 1H), 8.83 (d, J=2.1Hz, 1H), 8.43 (br d, J=7.3Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H) , 7.56 - 7.46 (m, 1H), 7.42 - 7.27 (m, 1H), 7.27 - 7.20 (m, 1H), 7.20 7.14 (m, 1H), 5.36 - 4.98 (m, 1H), 4.65 - 4.37 (m , 1H), 4.05 (s, 3H), 3.84 (q, 1=6.6Hz, 1H), 3.18 (d, J=5.2 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.85 (t, J= 8.1Hz, 1H), 2.80 - 2.64 (m, 1H), 1.35 (d, 1=6.4Hz, ZN) 450 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1-(3fluoropyridin-2yl )ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide pho 563.2 8.92 (d, >2.1Hz, 1H), 8.84 (d, J=2.1Hz, 1H), 8.47 (br s, 1H), 8.44 - 8.37 (m, 1H), 8.19 (s, 1H), 7.73 (br s, 1H), 7.63 (s, 1H), 7.44 (br s, 1H), 5.33 - 5.04 (m, 1H), 4.60 4.34 (m, 1H), 4.29 - 4.11 (m, 1H), 4.05 (s, 3H), 3.57 - 2.60 (m, 4H, partially suppressed), 1.45 (br d, J=6.7 Hz, ZN) 451 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1[phenyl(deutero)methyl] pyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 532.2 8.91 (d, 1=2.4Hz, 1H), 8.84 (d, J=2.1Hz, 1H), 8.44 (br d, J=7.6Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H) , 7.37 - 7.32 (m, 4H), 7.32 - 7.18 (m, 1H), 5.33 - 5.05 (m, 1H), 4.64 4.44 (m, 1H), 4.05 (s, 3H), 3.22 - 2.99 (m, 1H), 2.91 (t, J=8.2 Hz, 1H), 2.87 - 2.72 (m, 1H), 2.59 (t, J=8.4 Hz, 1H) 452 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-[1(pyrimidin-4yl) ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide 546.3 9.12 (s, 1H), 8.90 (d, J=2.4Hz, 1H), 8.82 (d, J=2.4Hz, 1H), 8.78 (d, J=5.2Hz, 1H), 8.44 (br d, J= 7.6 Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.57 (d, J=5.2 Hz, 1H), 5.29 - 5.09 (m, 1H), 4.61 - 4.47 (m, 1H), 4.05 (s, 3H), 3.68 (q, 1=6.6Hz, 1H), 3.22 - 3.00 (m, 2H), 2.94 - 2.81 (m, 1H), 2.61 (brt, J=8.5Hz, 1H), 1.35 (d, J=6.7 Hz, ZN)

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453 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazin-7mi]-N-[(3R,4S)-4fluoro-1-[1(pyrimidin-4yl) ethyl] pyrrolide n-3-yl]-2methoxypyride in-3 carboxamide 546.0 9.12 (s, 1H), 8.90 (d, >2.4 Hz, 1H), 8.82 (d, >2.4 Hz, 1H), 8.79 (d, >5.2 Hz, 1H), 8.45 (br d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.57 (d, >5.5 Hz, 1H), 5.34 - 5.12 (m, 1H), 4.59 - 4.43 (m, 1H), 4.05 (s, 3H), 3.67 (q, >6.7 Hz, 1H), 3.24-3.05 (m, 1H), 2.92 (t, J=8.4 Hz, 1H), 2.90 - 2.74 (m, 1H), 2.66 (brt, >8.4 Hz, 1H), 1.35 (d, J=6.7 Hz, ZN) 454 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(3fluoropyridin-4yl )ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide I Fvb 563.2 8.91 (d, >2.4 Hz, 1H), 8.87 - 8.78 (m, 1H), 8.54 (s, 1H), 8.50 - 8.40 (m, 2H), 8.16 (s, 1H), 7.60 (s, 1H), 7.55 (t, >5.5 Hz, 1H), 5.37 - 4.99 (m, 1H), 4.64 - 4.40 (m, 1H), 4.05 (s, 3H), 3.89 (q, >6.5 Hz, 1H), 3.24-3.04 (m, 1H), 2.89 (t, >8.1 Hz, 1H), 2.84 - 2.70 (m, 1H), 2.60 (brt, >8.2 Hz, 1H), 1.36 (d, J=6.7 Hz, VN) 455 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(3fluoropyridin-4yl )ethyl] pyrrolide n-3-yl]-2methoxypyride in-3 carboxamide I F Ύν 563.2 8.91 (d, >2.4 Hz, 1H), 8.83 (d, >2.4 Hz, 1H), 8.53 (s, 1H), 8.49 8.39 (m, 2H), 8.17 (s, 1H), 7.60 (s, 1H) , 7.56 (t, J=5.5 Hz, 1H), 5.36 5.02 (m, 1H), 4.66 - 4.41 (m, 1H), 4.06 (s, 3H), 3.99-3.87 (m, 1H), 3.11 -2.95 ( m, 2H), 2.91 - 2.76 (m, 1H), 2.58 (brt, >8.5 Hz, 1H), 1.36 (d, >6.7 Hz, ZN) 456 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1G][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1(pyridine-3 yl)ethyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide With/ 545.0 8.91 (d, >2.1 Hz, 1H), 8.83 (d, >2.1 Hz, 1H), 8.55 (s, 1H), 8.49 (br d, >3.7 Hz, 1H), 8.46 - 8.32 (m, 1H), 8.21 - 8.13 (m, 1H), 7.77 (brd, >7.6 Hz, 1H), 7.70-7.51 (m, 1H), 7.39 (dd, >7.5, 4.7 Hz, 1H), 5.32 - 5.06 (m, 1H) , 4.56 - 4.43 (m, 1H), 4.08 - 4.03 (m, 3H), 3.55 (brq, >6.7 Hz, 1H), 3.243.07 (m, 1H), 2.80 (t, >8.2 Hz, 1H), 2.75 - 2.62 (m, 1H), 2.59 2.56 (m, 1H), 1.35 (d, >6.7 Hz, ZN) 457 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1(pyridine-3 - d- 545.0 8.91 (d, >2.1 Hz, 1H), 8.88-8.78 (m, 1H), 8.56 (s, 1H), 8.47 (br d, >4.3 Hz, 1H), 8.45 - 8.33 (m, 1H), 8.17 ( s, 1H), 7.77 (br d, >7.6 Hz, 1H), 7.61 (s, 1H), 7.38 (dd, >7.6, 4.9 Hz, 1H), 5.31-5.07 (m, 1H), 4.61 - 4.45 ( m, 1H), 4.06 (s, 3H), 3.57 (q, >6.3 Hz, 1H), 3.03 - 2.95 (m, 1H), 2.95 - 2.78 (m, 2H), 2.50 - 2.46 (m, 1H), 1.35 (d, >6.7 Hz, ZN) 458 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine-7mi]-N-[(3R,4S)-l[1-(3,5difluorophenyl)ethyl ]-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide F 580.2 8.90 (d, >2.4 Hz, 1H), 8.82 (d, >2.4 Hz, 1H), 8.44 (br d, >7.3 Hz, 1H), 8.16 (s, 1H), 7.58 (s, 1H), 7.15- 7.03 (m, 3H), 5.36 - 5.11 (m, 1H), 4.58 - 4.44 (m, 1H), 4.05 (s, 3H), 3.51 (m, 1H, partially suppressed), 3.23 -2.99 (m, 1H) , 2.82 (brt, >8.2 Hz, 1H), 2.77 2.64 (m, 1H), 2.62 - 2.56 (m, 1H), 1.30 (d, >6.7 Hz, ZN)

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459 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7Ni]-N-[(3R,4S)-l[1-(3,5difluorophenyl) ethyl]-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 5 "P 580.2 8.90 (d, 4=2.1Hz, 1H), 8.82 (d, J=2.1Hz, 1H), 8.43 (br d, J=7.6Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H) , 7.08 (br d, J=7.3 Hz, ZN), 5.314.96 (m, 1H), 4.61 - 4.47 (m, 1H), 4.06 (s, 3H), 3.60 - 3.40 (m, 2H, partially suppressed) , 3.05 - 2.90 (m, 2H), 2.88 - 2.68 (m, 1H), 1.31 (br d, J=6.4 Hz, ZN) 460 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1[1-(3,4difluorophenyl)ethyl] -4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide _F 580.2 8.93 - 8.88 (m, 1H), 8.84 - 8.81 (m, 1H), 8.42 (br d, J=7.7 Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.457.32 (m , 2H), 7.20 (br s, 1H), 5.30 - 5.03 (m, 1H), 4.60 - 4.40 (m, 1H), 4.05 (s, 3H), 3.52 - 3.35 (m, 2H, partially suppressed), 3.02 2.89 (m, 2H), 2.84 - 2.73 (m, 1H), 1.29 (d, >6.6Hz, ZN) 461 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1[1-(3,4difluorophenyl)ethyl] -4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide d 580.1 8.90 (d, J=2.2Hz, 1H), 8.83 (d, J=2.2Hz, 1H), 8.43 (br d, J=7.3Hz, 1H), 8.16 (s, 1H), 7.60 (s, 1H) , 7.42 - 7.36 (m, 2H), 7.20 (br s, 1H), 5.42 - 5.05 (m, 1H), 4.59 4.41 (m, 1H), 4.04 (s, 3H), 3.46 3.35 (m, 2H, partially suppressed), 3.18-3.06 (m, 1H, partially suppressed), 2.79 (brt, J=8.3 Hz, 1H), 2.73-2.62 (m, 1H), 2.56 2.52 (m, 2H), 1.29 (d, J= 6.6 Hz, ZN

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462 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1C[1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(4fluorophenyl)ethyl] pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide 562.2 8.91 (d, 3=2.2Hz, 1H), 8.84 (d, 3=1.8Hz, 1H), 8.41 (brd, J=7.3Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.38 (dd, J=8.1, 5.9 Hz, 2Н), 7.15 (t, J=8.6 Hz, 2Н), 5.31 - 5.08 (t, 1Н), 4.58 - 4.39 (m, 1Н), 4.06 (s, ЗН) , 3.53-3.31 (m, 1Н), 3.042.85 (t, 2Н), 2.83 - 2.69 (t, 1Н), 2.47 (br t, J=8.6 Hz, 1Н), 1.30 (d, J=6.2 Hz, ZN) 463 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[1-(4fluorophenyl)ethyl ] pyrrolide in-3 -yl] -2 methoxypyride in-3 carboxamide Αχ 562.2 (600 MHz, DMSO-d6) δ 8.90 (d, J=2.2 Hz, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.42 (br d, J=7.7 Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.37 (dd, J=8.3, 5.7 Hz, 2H), 7.16 (t, J=8.8 Hz, 2H), 5.29 - 5.09 (m, 1H), 4.55 - 4.35 (m , 1H), 4.04 (s, 3H), 3.49 3.35 (m, 1H, partially suppressed), 3.23 - 3.04 (m, 1H), 2.77 (t, J=8.3 Hz, 1H), 2.71 - 2.62 (m, 1H ), 2.55 - 2.52 (m, 1H), 1.30 (d, J=6.6 Hz, ZN) 464 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[(5fluoropyridin-2yl)methyl ] pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide A/ 549.2 8.90 (d, J=2.2 Hz, 1H), 8.83 (d, J=2.2 Hz, 1H), 8.52 - 8.47 (m, 1H), 8.45 (br d, J=7.7 Hz, 1H), 8.16 (s, 1H), 7.71 (td, J=8.6, 2.9 Hz, 1H), 7.60 (s, 1H), 7.52 (dd, J=8.8, 4.8 Hz, 1H), 5.33 - 5.09 (m, 1H), 4.62 - 4.41 (m, 1H), 4.05 (s, 3H), 3.85 3.77 (m, 2H), 3.22 - 3.04 (m, 1H), 2.99 (t, J=8.3 Hz, 1H), 2.94 - 2.78 (m, 1H) , 2.67 (t, J=8.4 Hz, 1H) 465 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-(2hydroxy-2phenylethyl)pyrroleidine -3 -yl]-2methoxypyride in-3 carboxamide O 560.1 8.93 (br d, J=2.6 Hz, 1H), 8.86 8.78 (m, 1H), 8.53 (br s, 1H), 8.18 (s, 1H), 7.62 (br s, 1H), 7.44 - 7.38 (m, 2H), 7.36 (br s, 2H), 7.34 7.26 (m, 1H), 5.48 - 5.16 (m, 1H), 4.99 - 4.39 (m, 2H), 4.05 (s, 3H), 3.66 -2.88 (m, 6H, partially suppressed)

Connections in the table. 25 was prepared by methods similar to those detailed in Example 68.

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Table 25

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 466 7-{5-[(3S)-3-[(4fluorophenyl)methyl]piperidin-1carbonyl]-6methoxypyride in-3yl}-5-{2-oxa-6azaspiro[3.3 ]heptane-6carbonyl}pyrrolo[2, 1-f][1,2,4]triazine4-amine A X ^m 586.4 Not determined due to rotomers 467 4-aMHHO-N-ethyl-7 {5-[(3S)-3-[(4fluorophenyl)methyl]piperidin-1carbonyl]-6methoxypyride in-3yl}pyrrolo[2,1- D][1,2,4]triazine-5carboxamide n x ^N ^ 532.3 Not determined due to rotomers 468 4-Amino-M(cyanomethyl)-7-{5[(3S)-3-[(4fluorophenyl)methyl]piperidin-1carbonyl]-6methoxypyride in-3yl}pyrrolo[2.1D][1,2,4 ]triazine-5carboxamide n CN 543.2 Not determined due to rotomers

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469 4-amino-7-{5-[(38)3-[(4fluorophenyl)methyl]piperidin-1carbonyl]-6methoxypyride in-3yl}-H-(2hydroxyethyl)pyrrolo[2.11][1.2 ,4]triazine-5carboxamide H ^OH 548.3 Not determined due to rotomers 470 4-amino-7-{5-[(38)3-[(4- fluorophenyl)methyl]piperidin-1carbonyl]-6- methoxypyride in-3 yl}-H,Hdimethylpyrrolo[2,1-f] [ 1,2,4]triazine-5carboxamide \ ^xN 532.2 Not determined due to rotomers 471 14-{2-[(4-Amino-7{5-[(3S)-3-[(4fluorophenyl)methyl]piperidin-1carbonyl]-6methoxypyride in-3yl}pyrrolo[2.11][1.2 ,4]triazin-5yl)formamido]ethyl (acetamide I °l ^NH 589.2 Not determined due to rotomers

Connections in the table. 26 was prepared by the methods detailed in Example 68. Table 26

BUT. /=\ o f Vnh gin h ₂ n^^ N \=N ^x A

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 472 5-[4-amino-5(ethylcarbamoyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl]-2methoxypyride in- 3 carboxamide H 524.4 10.44 (br s, 1H), 8.95 (d, J=2.4 Hz, 1H), 8.68 (d, >2.4 Hz, 1H), 8.67 8.63 (m, 1H), 8.54 (brt, J=5.3 Hz, 1H) , 8.20 (br s, 1H), 8.05 (br s, 1H), 7.75 (s, 1H), 7.40 (s, 4H), 5.55 (d, >4.3 Hz, 1H), 4.72 (dt, >7.9, 4.2 Hz, 1H), 4.05 (s, 3H), 3.18 (d, J=5.2 Hz, 1H), 1.97-1.70 (m, 2H), 1.18 (t, >7.2 Hz, ZN) 473 5-{4-amino-5[(cyanomethyl)carbamoyl]pyrrolo[2.1 G][1.2.4]triazine-7nn}-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl] -2methoxypyride in-3 carboxamide n CN 535.1 10.00 (brs, 1H), 9.49 - 9.29 (m, 1H), 8.92 (d, >2.1 Hz, 1H), 8.67 (d, >2.4 Hz, 1H), 8.59 - 8.49 (m, 1H), 8.33 (br s, 1H), 8.07 (s, 1H), 7.72 (s, 1H), 7.48 - 7.05 (m, 4H), 4.72 (br dd, >7.6, 4.6 Hz, 1H), 4.39 (br d, >5.2 Hz , 2H), 4.15 - 3.86 (m, 3H), 1.67 (br d, >8.2 Hz, 2H)

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474 5-{4-amino-5-[(2hydroxyethyl)carbamoyl]pyrrolo[2,1 f] [ 1,2,4]triazine-7 mi}-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl ]-2methoxypyride in-3 carboxamide H ^OH 540.1 10.39 -10.13 (m, 1H), 8.84 (d, J=2.1Hz, 1H), 8.64 (d, J=2.1Hz, 1H), 8.61 (brt, J=5.3Hz, 1H), 8.56 (brt, J =5.3 Hz, 1H), 8.00 (br s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.40 7.29 (m, 4H), 4.82 - 4.38 (m, 1H), 3.98 - 3.92 ( m, 2H), 3.56 (br s, 2H), 3.47 - 3.18 (m, 4H), 2.01 - 1.71 (m, 2H) 475 5-[4-Amino-5(propylcarbamoyl)pyrrolo[2,1f] [1,2,4]triazine-7 wi]-N-[(3S)-3-(4chlorophenyl)-3hydroxypropyl]-2methoxypyride in-3 carboxamide, TFA n 538.2 10.64 (br s, 1H), 8.94 (d, J=1.8 Hz, 1H), 8.71 (brt, J=5.3 Hz, 1H), 8.68 (d, J=2.4 Hz, 1H), 8.55 (brt, J= 5.3 Hz, 1H), 8.37 (br s, 1H), 8.05 (s, 1H), 7.78 (s, 1H), 7.39 (s, 4H), 4.72 (dd, J=7.6, 4.6 Hz, 1H), 4.05 (s, 3H), 3.40 (br d, J=7.0 Hz, 1H), 3.28 (q, 1=6.6Hz, 2H), 1.97 - 1.72 (m, 2H), 1.65 - 1.46 (m, 2H), 0.93 (t, J=7.3 Hz, ZN) 476 477 5-[4-amino-5(dimethylcarbamoyl)pyrrolo[2,1£][1,2,4]triazine-7im]-N-[(3 8)-3-(4chlorophenyl)-3hydroxypropyl]-2methoxypyride in- 3 carboxamide 5-[4-amino-5(methylcarbamoyl)pyrrolo[2,1f] [1,2,4]triazine-7 - im]-N-[(3 8)-3-(4chlorophenyl)-3hydroxypropyl]-2methoxypyride in-3 carboxamide, TFA \ x ^N n 524.2 510.0 8.90 (d, J=2.1 Hz, 1H), 8.77 (d, J=2.4 Hz, 1H), 8.52 (br t, J=5.2 Hz, 2H), 8.08 (br s, 1H), 8.06 (s, 1H ), 7.43 (s, 1H), 7.40 (s, 4H), 5.54 (d, J=4.3 Hz, 1H), 4.72 (dt, J=7.9, 4.3 Hz, 1H), 4.04 (s, 3H), 2.51 (br s, 6H), 1.95 - 1.79 (m, 4H) 10.46 (br s, 1H), 8.90 (d, J=2.1 Hz, 1H), 8.69 (brt, J=4.6 Hz, 1H), 8.67 (d, J=2.4 Hz, 1H), 8.55 (br t, J =5.3 Hz, 1H), 8.20 (br s, 1H), 8.01 (s, 1H), 7.66 (s, 1H), 7.38 (s, 4H), 4.71 (br d, J=3.1 Hz, 1H), 4.04 (s, 3H), 3.55 (br s, 1H), 3.45 - 3.32 (m, 1H), 2.84 (d, J=4.3 Hz, ZH), 1.94 - 1.79 (m, 2H)

Connections in the table. 27 was obtained by the methods detailed in examples 57 and 63. The compounds are a mixture of diastereomers with secondary alcohol.

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Table 27

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 478 5-(4-amino-5-{[(2hydroxyethyl)amino] methyl} pyrrolo[2,1f] [1,2,4]triazine-7 mi)-N-[(3R,4S)-4fluoro-1- (3,3,3trifluoro-2hydroxypropyl)pyrrolide in-3-yl]-2methoxypyride in-3carboxamide, TFA H ^on 557.1 8.68 (br s, 1H), 8.60 - 8.47 (m, 1H), 8.36 (br d, J=7.6 Hz, 1H), 7.76 (s, 1H), 7.03 (s, 1H), 5.27 - 4.98 (m, 1H), 4.70 - 4.50 (m, 1H), 4.34 - 4.26 (m, 2H), 4.25 - 4.09 (m, 1H), 3.80 (s, 3H), 3.53 - 3.34 (m, 1H, partially suppressed), 3.28 - 2.96 (m, 1H), 2.86 (br d, J=1.2 Hz, 2H) 479 5-{4-amino-5[(dimethylamino)methyl]pyrrolo[2,1£][1,2,4]triazine-7mi}-N-[(3R,4S)-4fluoro-1-(3, 3,3trifluoro-2hydroxypropyl)pyrrolide in-3-yl]-2methoxypyridine-3 carboxamide 1 541.2 8.93 (s, 1H), 8.86 (br s, 1H), 8.44 (br d, J=7.6 Hz, 1H), 7.90 (s, 1H), 7.05 (br s, 1H), 5.34 - 5.02 (m, 1H ), 4.68 4.43 (m, 1H), 4.11 (br d, J=5.5 Hz, 1H), 4.04 (s, 3H), 3.78 - 3.34 (m, 1H), 3.26-2.57 (m, 7H, partially suppressed) , 2.27 (br s, 6H, partially suppressed) 480 5-[4-amino-5-({2oxa-6azaspiro[3.3] heptane -6- yl } methyl)pyrrolo [2, 1 -f] [1,2,4]triazin7-yl]-N-[(3R,4S)-4fluoro-1-(3,3,3trifluoro-2hydroxypropyl)pyrrolide in- 3 -yl]-2methoxypyridine-3 carboxamide L 595.2 9.06 - 8.92 (m, 1H), 8.85 - 8.69 (m, 1H), 8.65 - 8.56 (m, 1H), 8.10 - 7.89 (m, 1H), 7.39 - 7.32 (m, 1H), 5.58 5.25 (m, 1H), 4.97 - 4.74 (m, 1H), 4.74.4.56 (m, 2H), 4.56 - 4.34 (m, 1H), 4.11 -4.00 (m, 3H), 4.00-3.80 (m, 3H), 3.75 - 3.21 (m, 3H), 3.21 - 3.10(m, 1H)

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481 5-{4-amino-5[(morpholin-4yl)methyl]pyrrolo[2,1-1][1,2,4]triazine7-nn}-N-[(3R,4S)-4fluoro-1-( 3,3,3trifluoro-2hydroxypropyl)pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide 583.1 8.66 (s, 1H), 8.55 (br d, J=6.4 Hz, 1H), 8.33 (br d, J=7.3 Hz, 1H), 7.73 (brs, 1H), 6.91 (brs, 1H), 5.344.95 (m, 1H), 4.75 - 4.34 (m, 1H), 4.17 (br d, J=5.2 Hz, 1H), 3.79 (s, 3H), 3.49 - 2.87 (m, 16H, partially suppressed) 482 5-{4-amino-5-[(3aminoazetidin-1 yl)methyl]pyrrolo[2 , 1 -f] [ 1,2,4]triazine7-mi}-N-[(3R,4S)-4fluoro-1 -(3,3,3trifluoro-2hydroxypropyl)pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide, TFA 568.2 8.93 (s, 1H), 8.84 - 8.77 (m, 1H), 8.60 (br d, J=7.3 Hz, 1H), 8.03 (s, 1H), 5.59 - 5.26 (m, 1H), 5.05 - 4.72 (m , 1H), 4.65 - 4.40 (m, 1H), 4.05 (s, 3H), 3.95 - 3.13 (m, IN, partially suppressed), 2.25 - 2.50 (m, 2H) 483 5-{4-amino-5- [(azetidin-1yl)methyl]pyrrolo[2,1-1][1,2,4]triazine7-mi}-N-[(3R,4S)-4fluoro-1-(3,3,3trifluoro-2hydroxypropyl) pyrrolide in-3 -yl]-2methoxypyride in-3 carboxamide, TFA 553.2 8.99 - 8.90 (m, 1H), 8.84 - 8.72 (m, 1H), 8.67 - 8.44 (m, 1H), 8.14 - 7.96 (m, 1H), 7.36 - 7.27 (m, 1H), 5.56 5.22 (m, 1H), 4.79 - 4.64 (m, 2H), 4.64 - 4.40 (m, 1H), 4.24 - 4.10 (m, 2H), 4.08 - 3.97 (m, 5H), 2.44 - 2.27 (m, 2H) 484 5-{4-amino-5-[(1,1dioxothiomorpholin-4yl)methyl]pyrrolo[2,1-1][1,2,4]triazine7-nn}-N-[(3R,4S)-4fluoro- 1-(3,3,3trifluoro-2hydroxypropyl)pyrrolide in-3-yl]-2methoxypyride in-3 carboxamide, TFA γ° 631.2 9.05 - 8.87 (m, 1H), 8.86 - 8.69 (m, 1H), 8.69 - 8.50 (m, 1H), 8.05 - 7.86 (m, 1H), 7.16-7.14 (m, 1H), 7.147.12 (m , 1H), 7.05 - 7.01 (m, 1H), 5.61 - 5.17 (m, 1H), 4.99 - 4.67 (m, 1H), 4.67 - 4.37 (m, 1H), 4.09 - 4.00 (m, 3H), 4.02 - 3.89 (m, 2H), 3.31 3.14 (m, 4H), 3.11 -2.94 (m, 4H)

Connections in the table. 28 was obtained by the methods detailed in examples 57 and 63.

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Table 28

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 485 5-{4-amino-5[(dimethylamino)methyl]pyrrolo[2,1 C[1,2,4]triazin-7-yl}N-[(3R,4S)-l-(3,3difluorocyclobutanecarb onyl)-4fluoropyrrolidin-3 -yl] 2-methoxypyridine-3 carboxamide 1V- 547.1 9.68 -9.39 (m, 1H), 9.06-8.83 (m, 1H), 8.86 - 8.66 (m, 1H), 8.60 - 8.43 (m, 1H), 7.96 - 7.84 (m, 1H), 7.81 -7.65 (m , 1H), 7.11-6.94 (m, 1H), 5.46-5.19 (m, 1H), 4.87 -4.57 (m, 1H), 4.09-4.01 (m, 3H), 3.99 - 3.68 (m, 3H), 3.69 -3.59 (m, 2H), 3.30 - 3.23 (m, 1H), 3.22-3.10 (m, 1H), 2.89 - 2.66 (m, 4H), 2.35-2.18 (m, 6H) 486 5-{4-amino-5[(methylamino)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide n 533.1 (600 MHz, DMSO-d6) δ 8.98 8.90 (m, 1H), 8.84 - 8.71 (m, 1H), 8.55 - 8.37 (m, 1H), 7.88 7.81 (m, 1H), 7.08-7.01 (m, 1H ), 5.43 -5.18(m, 1H), 4.90 4.56 (m, 1H), 4.08 - 4.00 (m, 3H), 4.00 -3.22 (m, 6H), 3.223.09 (m, 1H), 2.89 - 2.70 ( m, 4H), 2.35 -2.28 (m, 3H) 487 5-{4-amino-5[(morpholin-4yl)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide, TFA k ^N 4 589.3 8.99 - 8.83 (m, 1H), 8.79 - 8.63 (m, 1H), 8.61 - 8.40 (m, 1H), 8.12-7.90 (m, 1H), 7.12-7.01 (m, 1H), 5.46-5.15 (m , 1H), 4.88 -4.58 (m, 1H), 4.09 - 3.99 (m, 3H), 3.30 -3.23 (m, 1H), 3.97-3.08 (m, 5H), 2.90 - 2.66 (m, 4H)

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488 5-{4-amino-5-[(3hydroxyazetidin-1 yl)methyl]pyrrolo[2.11][1.2.4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide, TFA __/HE A 575.2 9.08 - 8.86 (w, 1H), 8.85-8.67 (w, 1H), 8.66 - 8.39 (m, 1H), 8.15-7.99 (m, 1H), 7.39-7.27 (w, 1H), 5.48 -5.17 (m , 1Н), 5.05–4.15 (t, 6Н), 4.16–4.02 (t, GL), 3.98–3.10 (t, 7Н), 2.96–2.67 (t, 4Н) 489 5-{4-amino-5-[(3,3d iftorazetidin-1 yl)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}N-[(3R,4S)-l -(3,3difluorocyclobutanecarb onyl)-4fluoropyrrolidin-3 -yl] 2-methoxypyridine-3 carboxamide, TFA A 595.2 9.03 - 8.83 (t, 1H), 8.81 -8.65 (t, 1H), 8.65 - 8.43 (t, 1H), 8.14-8.02 (t, 1H), 7.27-7.19 (t, 1H), 5.43 -5.16 (t , 1H), 4.92-4.59 (t, 1H), 4.29 - 4.12 (t, 4H), 4.09-4.01 (t, 3H), 4.01-3.00 (t, 7H), 2.90 - 2.67 (t, 4H) 490 5-{4-amino-5-[(2,6dimethylmorpholin-4yl)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}N-[(3R,4S)-l-( 3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3 -yl] 2-methoxypyridine-3 carboxamide, TFA A 617.2 9.09-8.87 (t, 1H), 8.83-8.65 (t, 1H), 8.63-8.44 (t, 1H), 8.17-7.95 (t, 1H), 7.17-7.09 (t, 1H), 5.45-5.13 (t , 1Н), 5.01-4.45 (t, 1Н), 4.14 - 4.01 (t, GL), 4.01 -3.07 (t, 7Н), 2.92-2.68 (t, 4Н), 1.20-1.07 (t, 6Н) 491 5 - { 4-amino-5 - [(propane2- yloxy)methyl]pyrrolo[2,1-f][1,2,4]triazin-7mi}-N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2- methoxypyr idine-3 carboxamide, TFA /A 562.1 9.06-8.85 (t, 1H), 8.81-8.72 (t, 1H), 8.59-8.46 (t, 1H), 8.00-7.89 (t, 1H), 7.17-7.11 (t, 1H), 5.44-5.16 (t , 1Н), 4.92-4.52 (t, GL), 4.08 - 4.00 (t, GL), 4.00 -3.06 (t, 6Н), 2.89-2.67 (t, 4Н), 1.21-1.13 (t, 6Н)

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492 5-[4-Amino-5(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazine-7mi]-N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidine -3 -yl] 2-methoxypyr idine-3 carboxamide 534.1 9.00 - 8.87 (m, 1H), 8.87 - 8.72 (m, 1H), 8.58 - 8.40 (m, 1H), 8.02-7.86 (m, 1H), 7.18-6.96 (m, 1H), 5.49-5.13 (m , 1H), 5.00-4.49 (br, W), 4.12-4.00 (w, W), 3.99 -3.23 (m, 5H), 3.36 (s, W), 3.23 - 3.07 (m, 2H), 2.88 - 2.68 (m, 4H) 493 methyl H-{[4-amino-7(5-{[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3 yl]carbamoyl}-6methoxypyridin-3 yl)pyrrolo[2,1f] [ 1,2,4]triazin-5yl]methyl } carbamate, TFA H k ^N Y ⁰ ^ O 577.2 8.91 (s, 1Н), 8.74 (dd, >18.0, 2.1 Hz, 1Н), 8.53 (brdd, J=10.4, 7.9 Hz, 1Н), 7.92 (s, 1Н), 7.87 (br s, 1Н), 7.69 - 7.38 (m, 2H), 7.01 (s, 1H), 5.51-5.15 (m, 1H), 4.93 -4.57 (m, 1H), 4.47 (br d, >5.8 Hz, 2H), 4.04 (s, 3H ), 3.99 - 3.60 (br, ZN), 3.57 (s, ZN, partially suppressed), 3.44 - 3.09 (m, 2Н, partially suppressed), 2.99 - 2.66 (m, 4Н) 494 5-[4-amino-5(methanesul fonamide omethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl]- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide, TFA H 0° 597.2 9.00 - 8.86 (t, 1H), 8.84 - 8.70 (t, 1H), 8.63 - 8.41 (t, 1H), 8.10-7.92 (t, 1H), 7.82-7.63 (t, 1H), 7.17-7.14 (t , 1Н), 5.52 - 5.08 (t, 1Н), 4.93 - 4.60 (t, 1Н), 4.56 - 4.42 (t, 2Н), 4.10-4.00 (t, GL), 4.00-3.10 (t, 5Н), 3.09 -2.93 (t, 3N), 2.90 - 2.65 (t, 4N) 495 5-[4-Amino-5(acetamidomethyl)pyrrolo[2,1-f] [1,2,4]triazine7-wi]-N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)- 4fluoropyrrolidin-3 -yl] 2-methoxypyr idine-3 carboxamide, TFA n kV ABOUT 561.2 8.98 - 8.86 (t, 1H), 8.86-8.76 (t, 1H), 8.76 - 8.63 (t, 1H), 8.58 - 8.42 (t, 2H), 8.15-7.90 (t, 1H), 7.13-7.08 (t , 1H), 5.48-5.18 (t, 1H), 5.01-4.57 (t, 1H), 4.57-4.36 (t, 2H), 4.14-4.00 (t, 3H), 4.00-3.02 (t, 5H), 2.91 -2.66 (t, 4N), 1.97 - 1.83 (t, ZN)

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496 5 - [4-amino-5 -( { 2-oxa6-azaspiro[3.3 ]heptan6yl } methyl)pyrrolo[2,1 f][ 1,2,4]triazin-7-yl]- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide /^0 601.2 9.59 (br d, J=6.4 Hz, 1H), 8.90 (s, 1H), 8.84 - 8.69 (m, 1H), 8.53 (br t, J=7.6 Hz, 1H), 7.86 (s, 1H), 7.63 (br d, J=9.2 Hz, 1H), 7.01 (s, 1H), 5.48-5.16 (m, 1H), 4.92 - 4.64 (m, 3H), 4.63 (s, 3H), 4.15 -3.06(m, 13H), 2.95 -2.66 (m, 4H) 497 5-{4-amino-5-[(3aminoazetide in-1 yl)methyl]pyrrolo[2.11][1.2.4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide 574.2 8.99-8.90 (m, 1H), 8.85-8.71 (m, 1H), 8.57-8.48 (m, 1H), 7.98-7.86 (m, 1H), 7.10-7.02 (m, 1H), 5.44-5.10 (m , 1H), 4.88-4.49 (m, 1H), 4.10 - 4.01 (m, 3H), 4.01 - 3.07 (m, 12H), 2.92 - 2.69 (m, 4H) 498 5-{4-amino-5[(azetidin-1yl)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}N-[(3R,4S)-l-(3,3difluorocyclobutanecarb onyl)-4fluoropyrrolidin-3 -yl] 2-methoxypyridine-3 carboxamide νΆ a 559.3 10.12-9.66 (m, 1H), 9.02-8.86 (m, 1H), 8.85 - 8.70 (m, 1H), 8.59-8.47 (m, 1H), 8.01 -7.85 (m, 1H), 7.85 -7.54 (m , 1H), 7.19-6.74 (m, 1H), 5.46-5.15 (m, 1H), 4.95 - 4.44 (m, 1H), 4.12-4.01 (m, 3H), 4.01 -3.57 (m, 5H), 3.41 -3.27 (m, 2H), 3.27-3.11 (m, 4H), 2.89-2.65 (m, 4H), 2.16-1.99 (m, 2H) 499 5-{4-amino-5-[(1,1dioxo-thiomorpholin-4yl)methyl]pyrrolo[2,11][1,2,4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide °o 637.2 9.00-8.85 (m, 1H), 8.84 - 8.65 (m, 1H), 8.58 - 8.41 (m, 1H), 7.97-7.89 (m, 1H), 7.12-7.04 (m, 1H), 5.47-5.17 (m , 1H), 4.94-4.59 (m, 1H), 4.13 -4.00 (m, 3H), 3.99 -3.56 (m, 5H), 3.24-3.11 (m, 4H), 3.08-2.93 (m, 4H), 2.89 - 2.66 (m, 4H) 500 5-(4-Amino-5-{[(2hydroxyethyl)amino]methyl}pyrrolo[2,1f][1,2,4]triazin-7-yl)- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoro-pyrrolidin-3-yl]2-methoxypyridine-3 carboxamide n ^he 563.2 (600 MHz, DMSO-d6) δ 8.98 8.88 (m, 1H), 8.84 - 8.71 (m, 1H), 8.60 - 8.45 (m, 1H), 7.89 7.76 (m, 1H), 7.11-7.03 (m, 1H ), 5.43 -5.17 (m, 1H), 4.88 4.54 (m, 1H), 4.09-4.01 (m, 3H), 3.99 -3.45 (m, 6H), 3.333.24 (m, 2H), 3.23 -3.10 ( m, 1H), 2.88-2.71 (m, 4H), 2.69 2.58 (m, 2H) 501 5-{4-amino-5-[(4methylpiperazin-1 yl)methyl]pyrrolo[2,1C[1,2,4]triazin-7-yl}- N-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide 602.2 (600 MHz, DMSO-d6) δ 9.65 9.38 (m, 1H), 9.00 - 8.85 (m, 1H), 8.85 - 8.69 (m, 1H), 8.61 8.42 (m, 1H), 7.93 - 7.85 (m, 1H ), 7.83 -7.67 (m, 1H), 7.11 6.98 (m, 1H), 5.47-5.17 (m, 1H), 4.90 - 4.57 (m, 1H), 4.09 4.00 (m, 3H), 4.00-3.51 (m , 5H), 3.30 -3.24 (m, 1H), 3.243.10 (m, 1H), 2.89-2.71 (m, 4H), 2.18 (s, 3H)

Connections in the table. 29 was prepared by methods similar to those detailed in Example 1468 below.

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Table 29

R

Ό

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 502 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(2cyanobenzenesulfonyl)4-fluoropyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide CN 605.2 8.91 (d, J=2.1 Hz, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.51 (brd, J=7.3 Hz, 1H), 8.23-8.15 (m, 2H), 8.15-8.08 (m , 1H), 7.98 (t, J=7.6 Hz, 1H), 7.95 - 7.89 (m, 1H), 7.60 (s, 1H), 5.385.18 (m, 1H), 4.82-4.60 (m, 1H), 4.01 (s, 3H), 3.86-3.74 (m, 2H), 3.33 - 3.22 (m, 1H, partially suppressed), 3.18 (d, J=5.2 Hz, 1H, partially suppressed) 503 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4[(ЗR,4S)-4-φτop-l-[(2methyl -1,3-thiazol-5yl)sulfonyl]pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide % 601.2 8.91 (d, J=2.4Hz, 1H), 8.72 (d, J=2.1Hz, 1H), 8.51 (brd, J=7.3Hz, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 5.35 -5.11 (m, 1H), 4.72 - 4.48 (m, 1H), 4.01 (s, 3H), 3.84-3.54 (m, ZN, partially suppressed), 3.25 (t, J= 10.1Hz, 1H), 2.76(s, 3H) 504 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-(3fluorobenzenesulfonyl) pyrrolidin-3 -yl]-2methoxypyride in-3 carboxamide F 598.2 8.90 (d, 1=2.1Hz, 1H), 8.70 (d, J=2.4Hz, 1H), 8.46 (d, J=7.6Hz, 1H), 8.15 (s, 1H), 7.767.68 (m, 4H ), 7.63 - 7.59 (m, 1H), 7.58 (s, 1H), 5.29-5.10 (m, 1H), 4.63 - 4.43 (m, 1H), 3.99 (s, 3H), 3.83 - 3.46 (m, ZH , partially suppressed), 3.23 -3.14(m, 1H) 505 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-X- [(3R,4S)-4-φτop-l-(4fluorobenzenesulfonyl)pyrrolidin-3-yl]-2methoxypyride in-3 carboxamide, TFA ήΠ F 597.9 8.91 (d, J=2.4Hz, 1H), 8.72 (d, J=2.4Hz, 1H), 8.45 (br d, J=7.3Hz, 1H), 8.17 (s, 1H), 7.96 (dd, J= 8.5, 5.2Hz, 2H), 7.60(s, 1H), 7.51(t, 1=8.9Hz, 2H), 5.32 - 5.03(m, 1H), 4.66 -4.38(m, 1H), 4.01(s, 3H ), 3.78 - 3.52 (m, ZN, partially suppressed), 3.20-3.12 (m, 1H)

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506 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]^[(3R,4S)-4^to _P -1(pyridine- 3 sulfonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide Xj 581.0 9.04 (s, 1H), 8.91 (d, 1=2.4Hz, 2H), 8.71 (d, J=2.4Hz, 1H), 8.45 (br d, J=7.3Hz, 1H), 8.30 (brd, J= 8.2 Hz, 1H), 8.17 (s, 1H), 7.71 (dd, J=7.9, 4.9 Hz, 1H), 7.60 (s, 1H), 5.33 - 5.06 (m, 1H), 4.69 - 4.50 (m, 1H ), 4.00 (s, 3H), 3.81-3.65 (m, 3H), 3.21 (t, 1=9.9Hz, 1H, partially suppressed) 507 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1(pyridine- 3 sulfonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide R 580.1 (600 MHz, DMSO-d6) δ 8.98 8.87 (m, 1H), 8.72 (d, J=2.2 Hz, 1H), 8.44 (d, J=7.3 Hz, 1H), 8.17 (s, 1H), 7.87 ( d, J=7.3 Hz, 2H), 7.75 (t, J=7.3 Hz, 1H), 7.70 - 7.64 (m, 2H), 7.60 (s, 1H), 5.30-5.12 (m, 1H), 4.57-4.36 (m, 1H), 3.99 (s, 3H), 3.76 - 3.53 (m, 3H), 3.15 (t, .1=9.9 Hz, 1H)

Connections in the table. 30 was obtained by the methods detailed in examples 4 and 61. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

Table 30

Oh άΑ oh /

F VnH rw

Η,Ν^^Ν \=Ν ^Χ

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 508 5-{4-Amino-6fluoropyrrolo[2,1£][1,2,4]triazine-7nn}-N-[(3R,4S)-l(3,3difluorocyclobutane pbonyl)-4fluoropyrrolidin-3 yl]-2methoxypyridine -3 carboxamide U F 508.4 8.83 (dd, J=6.6, 2.0 Hz, 1H), 8.65 (dd, J=16.6, 2.3 Hz, 1H), 8.53 (brt, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.89 (br s, 2H), 6.91 (s, 1H), 5.43 - 5.19 (m, 1H), 4.87 - 4.55 (m, 1H), 4.05 (d, J=6.1 Hz, ZN), 4.00 - 3.23 (m, 4H) , 3.23 -3.11 (m, 1H), 2.90-2.66 (m, 4H) 509 5-{4-Amino-6fluoropyrrolo[2,11][1,2,4]triazine-7nn}-N-[(3R,4S)-4fluoro-1-(oxane-4carbonyl)pyrrolidi n-3-yl]-2methoxypyridine-3 carboxamide, TFA P?o 502.2 8.84 (brd, J=5.0Hz, 1H), 8.748.63 (m, 1H), 8.45 (br dd, J=18.0, 7.4Hz, 1H), 8.04 (s, 1H), 6.96 (s, 1H), 5.48 - 5.21 (m, 1H), 4.88 4.56 (m, 1H), 4.23 -3.31 (m, 11H), 2.80 - 2.62 (m, 1H), 1.69-1.51 (m, 4H)

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510 5-{4-amino-6fluoropyrrolo[2,1 1][1,2,4]triazine-7mi}-N-[(3R,4S)-l(4,4difluorocyclohexane arbonyl)-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide % 536.3 8.83 (dd, J=8.1, 2.0 Hz, 1H), 8.70 8.61 (m, 1H), 8.54 (dd, J=17.7, 7.6 Hz, 1H), 8.01 (s, 1H), 7.89 (br s, 2H) , 6.91 (s, 1H), 5.45-5.19 (m, 1H), 4.87-4.59 (m, 1H), 4.20-3.15 (m, 7H), 2.15-1.72 (m, 7H), 1.65-1.50 (m, 2H ) 511 5-{4-amino-6fluoropyrrolo[2,1 f] [1,2,4]triazine-7^}-N-[(3R,4S)-l(3,3difluorocyclopentane arbonyl)-4fluoropyrrolidin-3 yl]- 2methoxypyride in-3 carboxamide, TFA F L/ ^F 522.2 8.86 - 8.80 (m, 1H), 8.70 - 8.62 (m, 1H), 8.53 (br dd, J=13.3, 8.1 Hz, 1H), 8.09 - 7.98 (m, 1H), 6.96 (s, 1H), 5.45 - 5.20 (m, 1H), 4.88 4.59 (m, 1H), 4.19 - 3.41 (m, 6H), 3.33 - 2.88 (m, 2H), 2.41 - 2.25 (m, 2H), 2.23 - 1.99 (m, 3H ), 1.881.73 (m, 1H) 512 5-{4-Amino-6fluoropyrrolo[2,11][1,2,4]triazine-7mi}-N-[(3R,4S)-4fluoro-1-(4fluorobenzoyl)pyrrole idin-3-yl]-2methoxypyride in-3 carboxamide ήη X^F 512.0 8.82 (br s, 1H), 8.64 (br s, 1H), 8.60 - 8.47 (m, 1H), 8.01 (br d, J=11.3 Hz, 1H), 7.88 (br s, 2H), 7.71 - 7.59 (m, 2H), 7.34 - 7.24 (m, 2H), 6.91 (br d, J=7.3 Hz, 1H), 5.47 - 5.17 (m, 1H), 4.90-4.59 (m, 1H), 4.11 3.41 (m, 7H) 513 in -3 carboxamide 518.2 8.83 (br d, J=7.3 Hz, 1H), 8.70 8.63 (m, 1H), 8.52 (brdd, J=17.9, 7.5 Hz, 1H), 8.02 (s, 1H), 7.89 (br s, 2H), 6.92 (s, 1H), 5.44 - 5.19 (m, 1H), 4.97 - 4.42 (m, 2H), 4.163.11 (m, 7H), 2.06 (br d, 1=10.1Hz, 1H), 1.94 (br d, J=10.1 Hz, 1H), 1.78 (br s, 1H), 1.70 - 1.35 (m, 6H) 514 5-{4-Amino-6fluoropyrrolo[2,1f] [1,2,4]triazine-7^}-N-[(3R,4S)-l(2,2difluorocyclopropane arbonyl)-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide, TFA A/ F F 494.0 8.87 - 8.79 (m, 1H), 8.72 - 8.50 (m, 2H), 8.04 (s, 1H), 6.95 (s, 1H), 5.48 - 5.22 (m, 1H), 4.93 - 4.63 (m, 1H), 4.37 - 3.23 (m, 7H), 3.12 - 2.85 (m, 1H), 2.03 - 1.81 (m, 2H)

Connections in the table. 31 was obtained by the methods detailed in example 46. When the diastereomers were separated, they were included as separate data.

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Table 31

ABOUT

Ά'Ζ oh,}—

H ₂ N^An \= ⁿ CD ₃ N>

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 515 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7wi]-N-[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl)-4 -fluoropyrrolidine- 3-yl]-2- (deutero)methoxy-bmethylpyride in-3 carboxamide γz. 589.3 8.47 (br dd, J=11.6, 7.6 Hz, 1H), 8.16 (d, >14.6Hz, 1H), 8.07 (s, 1H), 7.31 (s, 1H), 5.455.20 (m, 1H), 4.87 -4.56 (m, 1H), 4.09 -3.10 (m, 5H, absorbed by water), 2.39-2.01 (m, 8H), 1.89 - 1.73 (m, 1H) 516 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7wi]-N-[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl)-4 -fluoropyrrolidin3-yl]-2(deutero)methoxy-bmethylpyride in-3 carboxamide F L/ ^F 589.4 8.43 (br dd, J=14.2, 7.8 Hz, 1H), 8.15 (d, >13.7Hz, 1H), 8.06 (s, 1H), 7.31 (s, 1H), 5.43 5.19 (m, 1H), 4.83 - 4.61 (m, 1H), 4.12-3.16 (m, 5H, absorbed by water), 2.43 - 1.99 (m, 8H), 1.87-1.71 (m, 1H) 517 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-L[(3^48)-4-fluoro-1[(2R)-3 ,3,3-τpiφτop-2hydroxy-2methylpropanoyl]pyrroli din-3-yl]-2(deutero)methoxy-bmethylpyride in-3 carboxamide ?OCF ₃ 'bn 597.2 8.41 - 8.29 (m, 1H), 8.16 (brd, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.26 (s, 1H), 5.39-5.17 (m, 1H), 4.77-4.56 (m, 1H), 4.623.30 (m, 4H, absorbed by water), 2.34 (s, 3H), 1.54 (s, 3H) 518 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-b[(3^48)-4-fluoro-1(sfluorocyclobutanecarbonyl)pyrrolidine-3 -yl]-2(deutero)methoxy-bmethylpyride in-3 carboxamide h 557.0 8.41 (br dd, 7=15.4, 7.5 Hz, 1H), 8.15 (d, 7=10.7 Hz, 1H), 8.07 (s, 1H), 7.31 (s, 1H), 5.405.18 (m, 1H), 5.09-4.88 (m, 1H), 4.85-4.53 (m, 1H), 3.97-3.52 (m, 3H), 3.44-3.16 (m, 1H), 2.86-2.67 (m, 1H), 2.602.48 (m, 2H, absorbed by DMSO), 2.35 (d, 7=2.7 Hz, ZH), 2.31–2.15 (m, 2H).

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519 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7ππ]-Ν-[(3Κ,48)-4-φτορ-1(sfluorocyclobutanecarbonyl)pyrrolidine- 3 -yl] -2(deutero)methoxy-bmethylpyride in-3 carboxamide h F 556.9 8.51 - 8.36 (m, 1Н), 8.15 (brd, J=8.5 Hz, 1Н), 8.10-8.03 (br, 1Н), 7.70 - 7.59 (m, 2Н), 7.34 7.26 (br, ZN), 5.45 -5.15 (t, 1Н), 4.87-4.60 (t, 1Н), 4.073.74 (t, ZN), 3.69-3.50 (t, 1Н), 2.34 (br d, J=5.2 Hz, ZN) 520 (5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7m)-N-((3R,4S)-1-(3,3difluorocyclobutane-1 carbonyl )-4fluoro pyrrolidin-3 -yl)-2(methoxy-d3)-b- methylnicotinamide h 575.1 8.41 (brdd, J=12.1,7.8Hz, IH), 8.16 (d, >14.0Hz, IH), 8.07 (s, IH), 7.32 (s, IH), 7.24 6.98 (m, IH), 5.46 - 5.08 (m, IH), 4.93 - 4.53 (m, IH), 4.07 3.59 (m, 2H), 3.22-3.04 (m, IH), 3.04 -2.87 (m, IH), 2.79 (br dd, J=12.5, 8.2Hz, 4H), 2.56(s, 3H)

Connections in the table. 32 was obtained by methods similar to those detailed in examples 67 and 31. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

Table 32

R

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 521 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-4-chloro-2-fluoroΝ-[(3Κ,48)-4-φτορ1-( 1fluorocyclobutane pbonyl)pyrrolidi n-3-yl]benzamide 561.2 8.88 (br d, J=6.7 Hz, IH), 8.05 (s, IH), 7.81 - 7.68 (m, 2H), 7.31 (d, J=2.1 Hz, IH), 5.36 - 5.12 (m, IH), 4.79 - 4.53 (m, IH), 4.00 - 3.50 (m, 3H, absorbed by water), 3.53 - 3.33 (m, IH), 2.73 - 2.22 (m, 4H absorbed by MeOH), 1.93 - 1.77 (m, IH), 1.59 - 1.47 (m, IH) 522 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-4-chloro-2-fluoroΝ-[(3Κ,48)-4-φτορ1-( 2-fluoro-2methylpropanoyl)p irrolidin-3yl]benzamide 549.2 8.93 - 8.82 (m, IH), 8.05 (s, IH), 7.82 7.71 (m, 2H), 7.31 (s, IH), 5.36 - 5.12 (m, IH), 4.75 - 4.48 (m, IH), 4.16 - 3.16 (m, 4H, absorbed by water), 1.59 - 1.46(m, 6H)

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523 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-4-chloro-M[(3R,4S)-l-(3,3difluorocyclopentancarbonyl) -4fluoropyrrolidin-3 yl]-2fluorobenzamide A-l. F ha 593.2 8.87 (brt, >8.7 Hz, 1H), 8.06 (s, 1H), 7.83 - 7.71 (m, 2H), 7.31 (s, 1H), 5.38 5.14 (m, 1H), 4.83 - 4.49 (m, 1H) , 4.06 - 3.21 (t, 4H, absorbed by water), 3.22 - 3.08 (t, 1H), 2.38 - 2.21 (t, 2H), 2.21 - 1.98 (t, 3H), 1.85 - 1.68 (t, 1H) 524 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazin-7yl]-4-chloro-M[(3R,4S)-l-(3,3difluorocyclobutane carbonyl )-4fluoropyrrolidin-3 yl]-2fluorobenzamide, TFA F 579.2 8.85 (br dd, >15.4, 7.3 Hz, 1H), 8.08 (s, 1H), 7.84 - 7.72 (m, 2H), 7.33 (s, 1H), 5.38 - 5.12 (m, 1H), 4.80 - 4.50 ( m, 1H), 3.95 - 3.23 (m, 4H), 3.20 - 3.07 (m, 1H), 2.88 - 2.66 (m, 4H)

Connections in the table. 33 was obtained by methods similar to those detailed in examples 67 and 31. In the case of tertiary amides, the full amine is designated as the R group. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

Table 33

Example Name R Ion mass observed by HMS Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 525 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7nn]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine -3 -yl] - 7 η G 542.2 8.90 - 8.75 (m, 1H), 8.07 (s, 1H), 7.78 (br d, >7.8 Hz, 1H), 7.30 (s, 1H), 5.45 - 5.13 (m, 1H), 4.88 - 4.52 (m, 1H), 4.23 -3.22 (m, 4H), 3.11 - 2.95 (m, 1H), 2.59 (brd, >6.3 Hz, ZN), 2.33 (s, ZN), 2,6-dimethylpyridine-3 carboxamide 2.00 - 1.76 (m, 2H) 5-[4-amino-5- (trifluoromethyl)pyrrolo 8.85 - 8.74 (m, 1H), 8.07 (s, [2,1-f][1,2,4]triazine-7- F. G\ 1H), 7.77 (d, >2.1 Hz, 1H), mi]-N-[(3R,4S)-l-(3,3- La 7.29(s, 1H), 5.44-5.15(m, 526 difluorocyclopentancar 570.3 1H), 4.79-4.50 (m, 1H), bonyl) -4- With 4.02-3.06 (m, 5H), 2.59 (d, fluoropyrrolidin-3-yl] - F >3.7 Hz, ZN), 2.38- 1.98 2,6-dimethylpyridine-3 - (m, 8H), 1.86-1.69 (m, 1H) carboxamide 527 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7mi]-N-[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidine -3 -yl] - F. h h 570.1 8.79 (br dd, >18.8, 7.2 Hz, 1H), 8.07 (s, 1H), 7.76 (s, 1H), 7.29 (s, 1H), 5.43 - 5.14 (m, 1H), 4.80 - 4.49 (m, 1H), 4.12-3.12 (m, 5H, absorbed by water), 2.59 (d, >4.6 Hz, ZN), 2.40-1.98 2,6-dimethylpyridine-3 carboxamide (m, 8H), 1.83 - 1.71 (m, 1H)

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528 7-[5-(2- benzylmorpholine-4carbonyl) -2,6dimethylpyridin-3 -yl] - 5- (trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4amine, TFA ^l sgo 511.2 8.09 - 8.02 (m, 1H), 7.90 7.76 (m, 1H), 7.38 - 7.20 (t, 5H), 7.19-7.04 (m, 4H), 4.32 (brt, J=12.1 Hz, 1H), 3.97 -3.57 (m, 1H), 3.33 2.59 (m, 4H), 2.48 (br s, W), 2.42 - 2.36 (br, W) 529 7-{5-[(3S)-3-[(4fluorophenyl)methyl]piperidine-1-carbonyl]-2,6dimethylpyridin-3-yl } 5(trifluoromethyl)pyrrolo [2,1-f] [1, 2,4]triazine-4amine, TFA i_ 0 R 527.2 8.04 (d, J=6.1 Hz, 1H), 7.747.51 (m, 1H), 7.38 -6.97 (br, 5H), 4.27 (br d, J=12.2 Hz, 1H), 3.50-2.62 (br, 3H ), 2.57 - 2.48 (m, 2H, absorbed by DMSO), 2.46 2.27 (m, 6H), 1.79 - 1.50 (m, SH), 1.48 - 1.13 (m, 2H) 530 7-{5-[(3R)-3-[(4fluorophenyl)methyl]piperidine-1-carbonyl]-2,6dimethylpyridin-3-yl } 5(trifluoromethyl)pyrrolo [2,1-f] [1, 2,4]triazine-4amine, TFA X y—Z O L 527.4 8.04 (br d, J=7.3 Hz, 1H), 7.36 - 6.97 (m, 6H), 4.44 4.17 (m, 1H), 3.68 -2.95 (m, 3H), 2.91 - 2.62 (m, 2H), 2.47 ( s, 2H), 2.40 (s, 3H), 2.36 (s, 1H), 1.81 - 1.52 (m, 3H), 1.48 - 1.13 (m, 2H) 531 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-N-[(ЗR,4S)-4-φτop1-(3fluorocyclobutanecarbonyl)pyrroleidine -3 -yl] 2,6-dimethylpyridine-3 carboxamide ,O 0% F 538.0 8.77 (br dd, J=17.7, 7.3 Hz, 1H), 8.08 (s, 1H), 7.77 (d, J=2.1 Hz, 1H), 7.30 (s, 1H), 5.38 - 5.01 (m, 2H), 4.77 4.49 (m, 1H), 3.94 -3.52 (m, 3H), 3.45-3.12 (m, 2H), 2.59 (d, J=2.1 Hz, 3H), 2.58 2.35 (m, 4H, absorbed by DMSO), 2.33 (s, 3H) 532 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl]-N-[(ЗR,4S)-4-φτop1-(3fluorocyclobutanecarbonyl)pyrroleidine -3 -yl] 2,6-dimethylpyridine-3 carboxamide F 538.3 8.83 - 8.71 (m, 1H), 8.08 (s, 1H), 7.77 (d, 1=3.4Hz, 1H), 7.30 (s, 1H), 5.40-5.15 (m, 1H), 5.10-4.87 (m, 1H), 4.79-4.49 ( _m , 1H), 3.96 3.54 (m, 3H), 3.45-3.16 (m, 1H), 2.73 (td, J=15.3, 7.6 Hz, 1H), 2.60 (d, J=2.1 Hz, ZN), 2.58 - 2.47 (m, 2H, absorbed by DMSO), 2.33 (s, 3H), 2.30 -2.14 (m, 2H)

Connections in the table. 34 was obtained by methods similar to those detailed in examples 67 and 31. In the case of tertiary amides, the full amine is designated as the R group. When the diastereomers were separated, they were included as separate data. If the stereochemistry was not determined, the compound was isolated as a mixture of diastereomers.

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Table 34

At Name R observed by the Navy Assignment of signals in the NMR spectrum measures weight (500 MHz, DMSO-d6) δ and she 5-[4-amino-5(trifluoromethyl)pyr 8.51-8.41 (m, 1H), 8.02 (s, rollo[2,1- 1H), 7.36 (br d, J=2.7 Hz, 1H), f] [ 1,2,4]triazine-7- N— 4 7.25 (br s, 1H), 7.14 (s, 1H), 533 mi]-N-[(3R,4S)-4- V 535.2 5.38-5.13 (m, 1H), 4.73 -4.47 fluorine-1 - (oxolan-3 - So (m, 1H), 4.05 - 3.38 (m, 9H), carbonyl)pyrrolide 2.41 (br d, J=4.3 Hz, ZN), 2.15- in-3-yl]-2,4dimethylbenzamide 1.87(m, 5H) 5-[4-amino-5- 534 (trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7mi]-N-[(3R,4S)-4fluoro-1-(3fluorocyclobutane pbonyl)pyrrolidi n-3-yl]-2,4- F^ ^N- · F 537.4 8.57 (br dd, J=10.4, 7.6 Hz, 1H), 8.03 (s, 1H), 7.36 (s, 1H), 7.26 (s, 1H), 7.17 (s, 1H), 5.36-5.01 (m, 2H ), 4.72 - 4.46 (m, 1H), 3.87-3.15 (m, 4H), 2.69 - 2.29 (m, 8H, absorbed by DMSO), 2.11 (s, 3H) dimethylbenzamide 5-[4-amino-5- 8.60 (brt, >7.9Hz, 1H), 8.02 (trifluoromethyl)pyr (s, 1H), 7.34 (s, 1H), 7.26 (s, rollo[2,1- With 1H), 7.16(s, 1H), 5.34-5.13 f] [ 1,2,4]triazine-7- (m, 1H), 5.07-4.87 (m, 1H), 535 mi]-N-[(3R,4S)-4- V 537.3 4.72-4.46 (m, 1H), 3.90 - 3.15 fluoro-1-(3- O (m, 4H, absorbed by water), 2.78 fluorocyclobutane - 2.68 (m, 1H), 2.59 - 2.47 (m, 2 pbonyl)pyrrolidi G H, absorbed by DMSO), 2.39 (br n-3-yl]-2,4- d, J=2.1 Hz, ZN), 2.29 - 2.15 (m, dimethylbenzamide 2H), 2.10(s, 3H)

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536 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-l(3,3difluorocyclopenta ncarbonyl)-4fluoropyrrolidine-3 yl]-2,4dimethylbenzamide f < 569.2 8.46 (brt, 1=6.8Hz, 1H), 8.01 (s, 1H), 7.35 (s, 1H), 7.25 (br s, 1H), 7.13 (s, 1H), 5.38-5.13 (m, 1H), 4.74 - 4.47 (m, 1H), 4.00 - 3.24 (m, 4H, absorbed by water), 3.22-3.09 (m, 1H), 2.40 (d, J=4.4 Hz, ZH), 2.35 1.71 (m, 9H) 5-[4-amino-5- 537 (trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazine-7nn]-N-[(3R,4S)-l(3,3difluorocyclobutane carbonyl)-4fluoropyrrolidin-3 yl]-2,4- £ · r ^F F 555.2 8.46 (brt, 1=6.8Hz, 1H), 8.01 (s, 1H), 7.35 (s, 1H), 7.25 (s, 1H), 7.13 (s, 1H), 5.36-5.12 (m, 1H), 4.74 - 4.46 (m, 1H), 3.90 - 3.26 (m, 4H, absorbed by water), 3.16-3.06 (m, 1H), 2.86-2.66 (m, 4H), 2.40 (d, J=3.2 Hz, WN), 2.11(s, 3N) dimethylbenzamide 538 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-(4fluorobenzoyl)pyrrolidine-3 -yl]-2,4dimethylbenzamide f^ ) F 559.2 8.59 - 8.37 (m, 1H), 8.01 (br s, 1H), 7.59 (dd, J=8.2, 5.6 Hz, 2H), 7.43 -7.20 (m, 4H), 7.12 (br s, 1H), 5.42- 5.13 (m, 1H), 4.75 -4.50 (m, 1H), 3.99 - 3.33 (m, 4H, absorbed by water), 2.40 (br d, J=13.0 Hz, ZH), 2.10 (br s, 3H) 5-[4-amino-5(trifluoromethyl)pyr 8.46 (brt, >8.0Hz, 1H), 8.01 rollo[2,1- (s, 1H), 7.35 (d, 1=2.7Hz, 1H), 1][1,2,4]triazine-7- O 7.25 (brd, >3.2Hz, 1H), 7.13 m]-N-[(3R,4S)-1- ^ν Α (s, 1H), 5.38-5.13 (m, 1H), 539 (4,4- \ 583.2 4.74-4.47 (n _5W ), 4.03 -3.46 difluorocyclohexane % A (m, 4H merged with water), carbonyl) -4- F 2.40 (d, 3=5.6Hz, 3H), 2.11 (s, fluoropyrrolidine-3 - 3H), 2.04 (brs, 2H), 1.95 - 1.70 silt]-2,4- (m, 5H), 1.65-1.51 (m, 2H) dimethylbenzamide 540 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- 1][1,2,4]triazine-7m]-N-[(3R,4S)-1(2 2- V C 541 1 8.56 - 8.43 (m, 1H), 8.02 (s, 1H), 7.37 (br d, J=6.8 Hz, 1H), 7.25 (s, 1H), 7.14 (s, 1H), 5.42 5.15 (m, 1H) , 4.80-4.51 (m, difluorocyclopropa ncarbonyl)-4fluoropyrrolidin-3 yl]-2,4- V 1H), 4.24 -3.38 (m, 5H, absorbed by water), 2.42 (br d, 1=5.0Hz, ZN), 2.11 (s, ZN), 2.00 - 1.78 (m, 2H) dimethylbenzamide 7-{5-[(3R)-3-[(4- — 8.01 (brd, >5.8Hz, 1H), 7.25 fluorophenyl)methyl] (br s, 2H), 7.20 - 6.78 (m, 5H), piperidine-1- 4.27 (brd, 1=11.0Hz, 1H), 3.52 carbonyl]-2,4- Λ - 3.28 (m,2H, absorbed 541 dimethyl phenyl } -5 - 526.3 water), 3.18 (d, J=5.2 Hz, 1H), (trifluoromethyl)pyr 3.04-2.89 (m, 1H), 2.27 - 2.01 rollo[2,1- (m, 6H), 1.72 (brs, 2H), 1.62- f] [ 1,2,4]triazine-4- 1.47 (m, 1H), 1.44-1.29 (m, amine 1H), 1.28 - 1.08 (m, 2H)

Example 542: 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Method 1 - 4-amino-7-bromopyrrolo[2,1f][1,2,4]triazine-6-carbonitrile (13.66 mg, 0.057 mmol, prepared according to WO2007/056170, p.

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391, in step 3), N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)-2- methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (29 mg, 0.057 mmol, prepared as in Example 1559A) and dioxane (1 ml). The mixture was cooled in a dry ice/acetone bath until freezing. Five freeze-purge cycles were repeated. To this frozen solid was added PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (3.52 mg, 4.30 µmol) and 2.0 M aqueous potassium triphosphate solution (0.086 ml, 0.172 mmol). The mixture was evacuated and filled with nitrogen. The pressure vessel was then sealed and warmed to room temperature to form a light yellow biphasic mixture. After melting, the mixture was immersed in an oil bath at 101°C for 4 h, and then at 95°C for another 6 h. The crude reaction mixture was diluted with 4 ml of ethyl acetate and 2 ml of water. The organic residues were extracted into a layer of ethyl acetate and the extraction was repeated two more times. The clear organic extracts were combined, concentrated and purified by chromatography. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 9% B, 9-49% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give the compound (9.3 mg, 28% yield).

MS (ERI) m/z 537.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 8.75 (br s, 1H), 8.62-8.46 (m, 2H), 8.31 (br d, J=16.8 Hz, 2H), 8.04 (s, 1H), 7.48 (s, 1H), 7.06 (br d, J=5.8 Hz, 1H), 5.37-5.17 (m, 1H), 4.75-4.58 (m, 1H), 4.53-4.25 (m, 1H), 4.07 (s, 3H), 4.00-3.52 (m, 2H), 1.54 (s, 3H).

Method 2 Step A: 4-amino-7-bromopyrrolo[2,1£][1,2,4]triazine-6-carbonitrile (13.66 mg, 0.057 mmol, prepared according to WO2007/056170) was added to a pressure-closable tube , p. 391 in Step 3), methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (217 mg, 0.739 mmol, prepared as described in example 10A) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (41.2 mg, 0.050 mmol). The dry mixture was cooled in a dry ice bath. Dioxane (2 ml) and 2.0 M aqueous potassium phosphate solution (1.008 ml, 2.016 mmol) were added to this mixture. The solid mixture was evacuated and filled with nitrogen. The pressure vessel was then sealed and warmed to room temperature to form a light yellow biphasic mixture. After melting, it was immersed in an oil bath at 95° C. for 6 hours. LC-MS analysis showed complete conversion to the desired product. The mixture was diluted with 4 ml of ethyl acetate, extracted with 2x2 ml of water to remove inorganic substances. The resulting residue (containing both the organic phase and solids) was triturated with methanol, filtered and concentrated to give the crude desired product (226 mg, xx mmol, 100%). This material was immediately used in the next step.

Step B: Sodium 5-(4-amino-6-cyanopyrrolo[2,1-£][1,2,4]triazin-7-yl)-2-methoxynicotinate: crude material from Step A methyl 5-(4- amino-6-cyanopyrrolo[2,1-L][1,2,4]triazin-7-yl)-2methoxynicotinate (226 mg, 0.697 mmol) was suspended in methanol (2.5 ml) at room temperature. To this cloudy mixture was added water (0.7 ml) and 1.0 N sodium hydroxide. sodium hydroxide solution (0.697 ml, 0.697 mmol). The mixture was stirred at 50° C. overnight to form a more dilute suspension. All volatile solvents were evaporated and the crude sodium carboxylate was dried to constant weight (240 mg, xx mmol, 100%).

MS (ERI) m/z 333.0 (M+Na)+.

1H NMR (400 MHz, DMSO-d6) δ 8.83-8.79 (m, 1H), 8.62-8.58 (m, 1H), 8.47-8.43 (m, 0.5H), 8.34-8.24 (br. s, 2H), 8.18-8.16 (m, 0.5H), 8.03 (s, 1H), 7.47 (s, 1H), 4.04-4.01 (m, 3H).

Step C: tert-butyl (3R,4S)-3-(5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4 -fluoropyrrolidine-1-carboxylate: to the crude dried sodium salt from Step B (0.045 g, 0.136 mmol) and PyBOP (0.106 g, 0.204 mmol) in a pressure vessel was added tert-butyl (3R,4S)-3-amino-4 -fluoropyrrolidine-1-carboxylate (0.028 g, 0.136 mmol) followed by the addition of DMF (4 ml) and N,N-diisopropylethylamine (0.071 ml, 0.408 mmol). The suspension was stirred at room temperature, and after one hour it became clear. The suspension was allowed to stir at 56° C. overnight. All volatile solvents were evaporated under high vacuum. The residue was taken up in ethyl acetate (6 ml), washed with water (3 x 1 ml) to remove most of the water-soluble inorganic substances, and the aqueous layers were combined and back-extracted with ethyl acetate (3 x 1 ml) to obtain as much of the desired product. The organic layers were combined, concentrated to a crude solid and used in the next step without further purification.

MS (ERI) m/z 519.1 (M+Na)+.

1H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.42 (br s, 2H), 8.20 (br s, 1H), 8.03 (s, 1H), 5.38-4.93 (m, 1H), 4.81-4.24 (m, 1H), 4.08 (s, 3H), 3.84-3.70 (m, 1H), 3.67-3.43 (m, 3H), 2.98-2.81 (m, 1H), 1.41 (s, 9H).

Step D: 5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-224 042342 yl)-2-methoxynicotinamide: to a suspension of tert-butyl (3R,4S)-3-(5-(4-amino-6-cyanopyrrolo[2,1f][1,2,4]triazin-7-yl) -2-Methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (110 mg, 0.222 mmol) in DCM (2 mL) was added with TFA (0.4 mL, 5.19 mmol) at room temperature to form a clear solution.

The mixture was stirred at room temperature for 1 hour and the reaction mixture was evaporated to dryness under high vacuum.

Step E: 5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide: 5-(4-amino-6cyanopyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (88 mg, 0.222 mmol) was stirred with (R)-3,3,3-trifluoro- 2-hydroxy-2-methylpropanoic acid (35.1 mg, 0.222 mmol) and PyBOP (116 mg, 0.222 mmol). Then DMF (2 ml) and N,N-diisopropylethylamine (0.116 ml, 0.666 mmol) were added. The suspension was stirred at room temperature, which after a while became soluble. The clear solution was stirred for a total of 4 hours. The solution was evaporated to dryness and the residue taken up in ethyl acetate and filtered through a plug of silica gel. The crude mixture was purified by reverse phase preparative HPLC to give 100 mg of the desired product. Characteristics correspond to the characteristics of the substance obtained by Method 1.

Example 543: 5-(4-amino-6-(1H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S )-4-fluoro1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

To a mixture of benzene (0.7 ml) and 1,4-dioxane (0.4 ml) in a small pressure vessel was added 5-(4amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl )-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (11.6 mg, 0.022 mmol) Tri-n-butyltin azide (100 µl, 0.364 mmol) was added with a pipette. The contents of the tube were quickly purged with a stream of nitrogen, sealed and heated to 120° C. overnight. The reaction mixture was purified by reverse phase HPLC to give the title compound (12.5 mg, 0.022 mmol, 88% yield). MS (ERI) m/z 580.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.57-8.44 (m, 2H), 8.37 (br d, J=9.2 Hz, 1H), 8.26-7.93 (, 1H), 7.90 (s, 1H), 7.49 -7.43 (m, 1H), 7.10 (br d, J=7.0 Hz, 1H), 5.38-5.16 (m, 1H), 4.75-4.58 (m, 1H), 4.53-4.25 (m, 1H), 4.06 ( s, 3H), 4.03–3.52 (m, 2H), 1.54 (s, 3H).

Examples 544 and 545: 5-(4-amino-6-(1-methyl-1H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N ((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxynicotinamide (544) and 5-(4 -amino-6-(2-methyl-2H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)N-((3R,4S)-4- fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxynicotinamide (545)

544: to a suspension of the crude material from Example 543, 5-(4-amino-6-(1H-tetrazol-5yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N- ((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (50 mg, 0.086 mmol) in crushed potassium carbonate (50 mg, 0.362 mmol) and iodomethane (50 µl, 0.800 mmol) were added to acetonitrile (2 ml) at room temperature. Stirring was continued at room temperature for 1 hour. The crude reaction slurry was filtered through a pad of silica gel, washed with ethyl acetate, and concentrated to a gum to give 5-(4-amino-6-(1-methyl-1H-tetrazol-5-yl)pyrrolo[ 2,1f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy- 2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (1.8 mg, 3.03 µmol, 3.51% yield).

MS (ERI) m/z 594.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.55-8.43 (m, 1H), 8.36 (br s, 1H), 8.34-8.28 (m, 1H), 8.28-8.06 (m, 1H), 7.98 (s, 1H), 7.52-7.48 (m, 1H), 5.26 (s, 1H), 4.73-4.57 (m, 1H), 4.52-4.25 (m, 1H), 4.04 (s, 3H), 4.03-3.99 (m, 3H), 3.98-3.75 (m, 1H), 3.75-3.68 (m, 1H), 3.58 (br t, J=11.0 Hz, 1H), 1.54 (s, 3H).

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545: 5-(4-Amino-6-(2-methyl-2H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N(( 3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxynicotinamide (1.58 mg, 2.66 µmol, 3.09% yield ). MS (ERI) m/z 594.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.58-8.45 (m, 2H), 8.41-8.22 (m, 2H), 8.21-7.97 (m, 1H), 7.92-7.88 (m, 1H), 7.61 ( s, 1H), 5.37-5.17 (m, 1H), 4.57 (s, 1H), 4.52-4.27 (m, 1H), 4.34 (s, 3H), 4.07 (s, 3H), 4.00-3.75 (m,

2H), 3.74-3.42 (m, 1H), 1.54 (s, 3H).

Example 546: (S)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3hydroxypropyl )-2-methoxynicotinamide

OME

Example 546 was prepared using (S)-3-(4-chlorophenyl)-3-hydroxypropane-1-aminium chloride according to the method described for Example 542, Method 2, Step 3 to give (S)-5- (4-amino-6cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (6.01 mg, 0.013 mmol, 17% yield).

MS (ERI) m/z 478.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.57 (s, 1H), 8.56-8.49 (m, 1H), 8.36-8.23 (m, 2H), 8.02 (s, 1H), 7.50-7.46 (m, 1H), 7.39 (s, 4H), 5.52 (br s, 1H), 4.71 (br d, J=8.5 Hz, 1H), 4.07 (s, 3H), 3.40-3.30 (m, 1H), 1.96-1.74 (m, 2H).

Example 547: (R)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3hydroxypropyl )-2-methoxynicotinamide

Example 547 was prepared using (R)-3-(4-chlorophenyl)-3-hydroxypropane-1-aminium chloride according to the method described for Example 542, Method 2, Step 3 to give (R)-5- (4-amino-6cyanopyrrolo[2,1-1][1,2,4]triazin-7-yl)-K-(3-(4-chlorophenyl)-3-hydroxypropyl)-2-methoxynicotinamide (6.21 mg, 0.013 mmol, 25% yield). MS (ERI) m/z 478.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.72 (d, J=1.8 Hz, 1H), 8.57 (d, J=2.1 Hz, 1H), 8.56-8.50 (m, 1H), 8.378.23 ( m, 2H), 8.02 (s, 1H), 7.50-7.44 (m, 1H), 7.39 (s, 4H), 5.52 (br d, J=3.7 Hz, 1H), 4.75-4.65 (m, 1H), 4.07 (s, 3H), 3.37 (br d, J=9.5 Hz, 1H), 1.95-1.77 (m, 2H).

Example

548:

(R)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5(trifluoromethoxy)phenyl )ethyl)-2-methoxynicotinamide

Example 548 was prepared using (R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethan-1-amine hydrochloride according to the method described for Example 542, Method 2, Step 3 to give (R )-5-(4amino-6-cyanopyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethyl) -2 methoxynicotinamide (2.33 mg, 4.52 µmol, 6.8% yield).

MS (ERI) m/z 516.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (br d, J=7.6 Hz, 1H), 8.71 (s, 1H), 8.38 (s, 1H), 8.36-8.21 (m, 2H), 8.03- 7.97 (m, 1H), 7.53 (br s, 1H), 7.47 (s, 1H), 7.42-7.29 (m, 1H), 7.27-6.97 (m, 1H), 5.42-5.28 (m, 1H), 4.06 (s, 3H), 1.47 (br d, J=7.0 Hz, 3H).

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Example 549: (R)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5( trifluoromethyl)phenyl)ethyl)-2-methoxynicotinamide

OME

Prepared using (R)-1-(2-fluoro-5-(trifluoromethyl)phenyl)ethane-1-amine hydrochloride according to the method described for Example 542, Method 2, Step 3 to give (R)-5 -(4-amino6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5-(trifluoromethyl)phenyl)ethyl)-2methoxynicotinamide ( 2.21 mg, 4.43 µmol, 7.7% yield).

MS (ERI) m/z 500.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.00-8.93 (m, 1H), 8.74-8.68 (m, 1H), 8.37 (s, 1H), 8.36-8.21 (m, 2H), 8.01 (s, 1H), 7.88 (s, 1H), 7.78-7.69 (m, 1H), 7.52-7.40 (m, 2H), 5.46-5.33 (m, 1H), 4.06 (s, 3H), 1.48 (br d, J =6.7 Hz, 3H).

Example 550 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1-benzyl-1 H-pyrazol-4-yl)- 2 methoxynicotinamide

Suspension of crude 5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinate sodium (obtained according to the method described for example 542, method 2, stage 2) (30 mg, 0.090 mmol), 1-benzyl-1H-pyrazole-4-amine (15.64 mg, 0.090 mmol), BOP (39.9 mg, 0.090 mmol) and DIPEA (0.079 ml, 0.451 mmol) in DMF ( 1 ml) was stirred at room temperature overnight. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (8.5 mg, 20% yield).

MS (ERI) m/z 466.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.73 (s, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.36-8.24 (m, 2H), 8.15 ( s, 1H), 8.02 (s, 1H), 7.62 (s, 1H), 7.48 (s, 1H), 7.38-7.32 (m, 2H), 7.32-7.28 (m, 1H), 7.26 (d, J= 7.0 Hz, 2H), 5.32 (s, 2H), 4.07 (s, 3H).

Connections in the table. 35 was obtained by the method described in example 550. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 35

R

Example Name R Ion mass observed by HMS ¹ H assignment of signals in the NMR spectrum (500 MHz, DMSO-d ₆ ) δ 551 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((3R,4S)-1-(2,2difluorocyclopropane-1 carbonyl)-4fluoropyrrolidine-3 -yl)2-methoxynicotinamide ^F 501.1 8.74 (br s, 1H), 8.65 - 8.52 (m, 2H), 8.33 (br d, 7=17.7 Hz, 2H), 8.04 (s, 1H), 7.48 (s, 1H), 5.45 5.20 (m, 1H ), 4.91 - 4.63 (m, 1H), 4.35-4.11 (m, 1H), 4.09 - 4.04 (m, 3H), 4.03 - 3.58 (m, 3H), 3.21 - 2.84 (m, 1H), 2.01 - 1.80 (m, 2H). 552 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((3R,4S)-l-(3,3difluorocyclobutane-1 carbonyl)-4fluoropyrrolidine- 3-yl)2-methoxynicotinamide F 515.2 8.75 (dd, J=7.9, 2.1 Hz, 1H), 8.57 (br d, J=1.5 Hz, 1H), 8.56-8.52 (m, 1H), 8.33 (brd, J=15.3 Hz, 2H), 8.03 ( s, 1H), 7.48 (s, 1H), 5.42-5.18 (m, 1H), 4.86 - 4.58 (m, 1H), 4.07 (br d, J=6.1 Hz, SA), 4.01-3.57 (m, SA ), 3.24 3.09 (m, 1H), 2.89–2.66 (m, 5H). 553 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((3R,4S)-l-(3,3difluorocyclopentane-1 carbonyl)-4fluoropyrrolidine-3 -yl)2-methoxynicotinamide 1—V ^F A/ ⁴ _F 529.2 8.74 (brd, 7=8.2 Hz, 1H), 8.57 (br s, 1H), 8.54 (br s, 1H), 8.33 (br d, 7=16.8 Hz, 2H), 8.03 (s, 1H), 7.48 ( s, 1H), 5.42-5.19 (m, 1H), 4.84 - 4.59 (m, 1H), 4.07 (br d, 7=6.7 Hz, ZN), 4.13 -4.02 (m, 1H), 4.02-3.81 (m , 2H), 3.79- 3.42 (m, 1H), 3.35 - 3.10 (m, 1H), 2.33 (br dd, 7=17.5, 9.3 Hz, 2H), 2.21 - 1.98 (m, 3H), 1.88 - 1.69 (m, 1H). 554 5-(4-amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((3R,4S)-4-φτop-l-(l(trifluoromethyl)cyclopropane- 1carbonyl)pyrrolidin3-yl)-2methoxynicotinamide f ₃ ^7 533.1 8.74 (br s, 1H), 8.59 (br s, 1H), 8.55 (br s, 1H), 8.33 (br d, J=15.3 Hz, 2H), 8.03 (s, 1H), 7.48 (s, 1H) , 5.31 (d, >53.7Hz, 1H), 4.81 -4.63 (m, 1H), 4.24-4.14 (m, 1H), 4.06 (s, 3H), 4.03 - 3.48 (m, 3H), 1.41 - 1.20 ( m, 4H). 555 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((3R,4S)-1-(4,4d ifluorocyclohexane-1 carbonyl)-4fluoropyrrolidine- 3-yl)2-methoxynicotinamide A: 543.2 8.75 (br d, 7=10.7 Hz, 1H), 8.61 8.50 (m, 2H), 8.42 - 8.30 (m, 2H), 8.05 (s, 1H), 7.49 (s, 1H), 5.45 5.18 (m, 1H ), 4.90 - 4.58 (m, 1H), 4.15 -4.09 (m, 1H), 4.07 (br d, 7=8.2 Hz, SA), 4.02 -3.44 (m, SA), 2.12-1.71 (m, 7H) , 1.651.50 (m, 2H).

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556 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((ZK,48)-4-fluoro-1-(4(trifluoromethyl)cyclohexane- 1carbonyl)pyrrolidin3-yl)-2methoxynicotinamide ^^CF ₃ isomer 1 575.2 8.74 (br d, 7=9.5 Hz, 1H), 8.59 8.50 (m, 2H), 8.41 - 8.30 (m, 2H), 8.04 (s, 1H), 7.48 (s, 1H), 5.40 - 5.17 (m, 1H), 4.85 - 4.59 (m, 1H), 4.12-4.02 (m, 4H), 3.99 - 3.53 (m, 3H), 2.37 - 2.21 (m, 1H), 1.93 - 1.71 (m, 5H ), 1.49–1.30 (m, 4H). 557 5-(4-Amino-6cyanopyrrolo[2,1f] [1,2,4]triazin-7-yl)-Н((3K,48)-4-fluoro-1-(4(trifluoromethyl)cyclohexan-1carbonyl )pyrrolidin3-yl)-2methoxynicotinamide ^^CF ₃ isomer 2 575.2 8.75 (dd, 7=8.1, 2.3 Hz, 1H), 8.61 - 8.48 (m, 2H), 8.33 (br d, 7=16.5 Hz, 2H), 8.03 (s, 1H), 7.48 (s, 1H), 5.39 -5.18 (m, 1H), 4.844.59 (m, 1H), 4.10 - 4.00 (m, 4H), 3.94 -3.43 (m, 3H), 2.39 - 2.21 (m, 1H), 1.93 - 1.68 (m , 5H), 1.69 - 1.47 (m, 4H). 558 5-(4-Amino-6cyanopyrrolo[2,1f] [1,2,4]triazin-7-yl)-Н((ZK,48)-4-fluoro-1-(4hydroxy-4(trifluoromethyl)cyclohexane -1carbonyl)pyrrolidin3-yl)-2methoxynicotinamide *C CF ₃ 591.1 8.75 (dd, 7=8.9, 2.1 Hz, 1H), 8.60 -8.50(m, 2H), 8.36 (br s, 1H), 8.32 (br s, 1H), 8.04 (s, 1H), 7.49 (d, 7=1.2 Hz, 1H), 5.40 - 5.18 (m, 1H), 4.85 - 4.59 (m, 1H), 4.07 (d, 7=7.0 Hz, ZN), 4.06 -3.43 (m, 5H), 2.10- 1.47 (m, 9H). 559 5-(4-Amino-6cyanopyrrolo[2,1f] [1,2,4]triazin-7-yl)-M((ZK,48)-4-fluoro-1-(3hydroxy-3(trifluoromethyl)cyclobutane -1carbonyl)pyrrolidin3-yl)-2methoxynicotinamide _CF3 563.1 8.74 (dd, 7=6.1, 2.1 Hz, 1H), 8.59 -8.50(m, 2H), 8.35 (br s, 1H), 8.31 (br s, 1H), 8.03 (s, 1H), 7.47 (s, 1H), 5.39-5.18 (m, 1H), 4.82 - 4.57 (m, 1H), 4.06 (d, 7=5.2 Hz, ZN), 3.95 - 3.54 (m, ZN), 3.30 3.14 (m, 1H), 3.01 - 2.89 (m, 1H), 2.65 - 2.53 (m, 2H), 2.43 - 2.31 (m, 2H). 560 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-Н((3Κ,48)-4-φτορ-1-(3,3,3trifluoro-2 ,2dimethylpropanoyl)pyrr olidin-3-yl)-2methoxynicotinamide X^Me Me ^CF 3 535.1 8.73 (s, 1H), 8.55 (br s, 2H), 8.33 (br s, 1H), 8.23 (br s, 1H), 8.00 (s, 1H), 7.46 (s, 1H), 5.37-5.17 (m , 1H), 4.80 - 4.57 (m, 1H), 4.05 (s, 3H), 3.97 - 3.40 (m, 4H), 1.46 (s, 3H), 1.43 (s, 3H). 561 5-(4-Amino-6cyanopyrrolo[2,1 f] [1,2,4]triazin-7-yl)-M((ZK,48)-4-fluoro-1-(2fluoro-2methylpropanoyl)pyrrole idin- 3-yl)-2methoxynicotinamide X^Me Me ^F 485.1 8.74 (d, J=2.4Hz, 1H), 8.60 - 8.49 (m, 2H), 8.34 (br s, 1H), 8.31 (br s, 1H), 8.03 (s, 1H), 7.48 (s, 1H), 5.39-5.16 (m, 1H), 4.84 - 4.60 ( m, 1H), 4.26 - 4.07 (m, 1H), 4.06 (s, 3H), 4.05 - 3.52 (m, 3H), 1.58 - 1.54 (m, 3H), 1.53 1.50 (m, 3H).

Example 562: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-N-((3R,4S)- 4fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2-methylbenzamide

F

562A: (3-fluoro-5-(methoxycarbonyl)-4-methylphenyl)boronic acid: degassed solution of methyl 5-bromo-3-fluoro-2-methylbenzoate (430 mg, 1.740 mmol), 4,4,4',4 ',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (575 mg, 2.263 mmol), potassium acetate (273 mg, 2.78 mmol) and PdCl ₂ adduct (dppf )-CH ₂ Cl ₂ (114 mg, 0.139 mmol) in dioxane (10 ml) was heated to 65°C for 16 h. The reaction mixture was used as is.

562B: Methyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-3-fluoro-2methylbenzoate: 7-bromo-5 degassed solution -(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine

- 229 042342 (450 mg, 1.601 mmol), (3-fluoro-5-(methoxycarbonyl)-4-methylphenyl)boronic acid (367 mg, 1.729 mmol), potassium triphosphate (2M in water) (2.402 ml, 4.80 mmol) and adduct 1,1'bis(diphenylphosphino)ferrocene palladium dichloride -CH ₂ Cl ₂ (78 mg, 0.096 mmol) was stirred at 75°C for 2 h. The reaction mixture was purified on a silica gel column with hexanes/EtOAc (from 100/0 to 0/100) to give methyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-3-fluoro-2methylbenzoate (547 mg , 1.334 mmol, 83% yield).

MS (ERI) m/z 369.1 (M+H)+.

¹ H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 8.14-8.07 (m, 2H), 7.44 (s, 1H), 3.96 (s, 3H), 2.52 (d, J=2.3 Hz, 3H ).

562C: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-2-methylbenzoic acid, sodium salt: methyl solution 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-3fluoro-2-methylbenzoate (547 mg, 1.485 mmol) and 1 M solution NaOH (2.2 ml, 2.23 mmol) in MeOH (10 ml) was heated to 100°C for 15 min. The reaction mixture was concentrated to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-3-fluoro-2-methylbenzoic acid, sodium salt ( 619 mg, 1.747 mmol, ~100% yield).

562D: tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3fluoro- 2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-3- fluoro-2-methylbenzoic acid, sodium salt (526 mg, 1.485 mmol), tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1-carboxylate (334 mg, 1.633 mmol) and DIPEA (0.778 ml, 4.45 mmol) in DMF (8 ml) was added BOP (788 mg, 1.782 mmol). The reaction mixture was stirred at 23°C for 2 h. The reaction mixture was diluted with EtOAc (80 ml), then washed with 10% LiCl solution (2x30 ml), brine (30 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,11][1,2,4]triazin-7-yl)-3 -fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (515 mg, 0.953 mmol, 64% yield).

MS (ERI) m/z 541.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD3OD) δ 8.11 (s, 1H), 8.03 (dd, J=11.3, 1.5 Hz, 1H), 7.91 (s, 1H), 7.47 (s, 1H), 5.395.20 (m , 1H), 4.82-4.65 (m, 1H), 3.96-3.41 (m, 4H), 2.38 (d, J=2.0 Hz, 3H), 1.51 (s, 9H).

562E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-N-((3R,4S)-4fluoropyrrolidine -3-yl)-2-methylbenzamide, 1.25 TFA: tert-butyl (3R,4S)-3-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2, 4]triazin-7-yl)-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1carboxylate (515 mg, 0.953 mmol) and TFA (1.835 ml, 23.82 mmol) in CH ₂ Cl ₂ (5 ml) were stirred at 23° C. for 1 hour. The reaction mixture was concentrated and triturated with ether (20 ml). The solid was collected as 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truazin-7-yl)-3-fluoro-N((3R,4S)- 4-Fluoropyrrolidin-3-yl)-2-methylbenzamide, 1.25 TFA (578.5 mg, 0.949 mmol, 100% yield).

MS (ERI) m/z 441.1 (M+H) ⁺ .

¹ H NMR (400 MHz, CD3OD) δ 8.10 (s, 1H), 8.07-8.02 (m, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 5.56-5.38 (m, 1H), 4.98 -4.90 (m, 1H), 3.90-3.60 (m, 4H), 2.38 (d, J=2.0 Hz, 3H).

562: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-ul)-3-fluoro-N-((3R,4S) 4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 1.25 TFA (15 mg, 0.026 mmol), 4,4,4-trifluoro-3-hydroxy-3(trifluoromethyl)butanoic acid (5.8 mg, 0.026 mmol) and DIPEA (0.013 ml, 0.077 mmol) in DMF (1 ml) was added BOP (13.7 mg, 0.031 mmol) and stirred at 23°C for 16 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18 , 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 5-45% B over 20 min, then 3 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (5.2 mg, 7.63 µmol, 30%).

MS (ERI) m/z 649.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 8.92-8.81 (m, 1H), 8.20 (s, 1H), 8.12-8.03 (m, 1H), 7.90 (br d, J=5.2 Hz, 1H), 7.65 (d, J=4.9 Hz, 1H), 5.46-5.20 (m, 1H), 4.86-4.56 (m, 1H), 4.22-3.32 (m, 4H, absorbed by water), 3.202.90 (m, 2H) , 2.29(s, 3H).

Example 563: 5-(4-Amino-5-(trifluoromethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4-difluoro-1-(( R) 3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

563A: tert-Butyl 4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido)-3,3-difluoropyrrolidine -1-carboxylate: to a solution of 5-(4-amino-5

- 230 042342 (trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid (130 mg, 0.368 mmol), tert-butyl 4-amino-3,3 -difluoropyrrolidine-1-carboxylate (82 mg, 0.368 mmol) and DIPEA (0.193 ml, 1.104 mmol) in DMF (2 ml) was added BOP (195 mg, 0.442 mmol). The reaction mixture was stirred at 23°C for 2 hours. The reaction mixture was diluted with EtOAc (80 ml), then washed with 10% LiCl solution (2x30 ml), brine (30 ml) and dried over anhydrous sodium sulfate. Filtration and concentration gave tert-butyl 4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)-2-methoxynicotinamido)-3, 3-difluoropyrrolidine-1-carboxylate (248 mg, 0.439 mmol, ~100% yield).

MS (ERI) m/z 558.1 (M+H)+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.94 (d, J=2.4 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.65 (d, J=8.7 Hz, 1H), 8.18 ( s, 1H), 7.63 (s, 1H), 5.14-4.94 (m, 1H), 4.03 (s, 3H), 3.90-3.47 (m, 4H), 1.43 (s, 9H).

563B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4-difluoropyrrolidin-3 yl)-2 -methoxynicotinamide, TFA: This compound was prepared using the method described for the preparation of 562E. 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4difluoropyrrolidin-3-yl)-2- methoxynicotinamide, TFA (259.5 mg, 0.373 mmol, ~100% yield).

MS (ERI) m/z 458.1 (M+H)+.

1H NMR (400 MHz, CD3OD) δ 9.01 (s, 2H), 8.08 (s, 1H), 7.44 (s, 1H), 5.08-4.95 (m, 1H), 4.20 (s, 3H), 4.05-3.47 ( m, 4H).

563: This compound was prepared using the method described for Example 562, yielding 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) -N-(4,4-difluoro-1-((R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (13.3 mg, 21 µmol, 29% ).

MS (ERI) m/z 598.0 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.86 (d, J=1.5 Hz, 1H), 8.72 (br t, J=8.2 Hz, 1H), 8.63 (br d, J=4.9 Hz, 1H), 8.11 (s, 1H), 7.53 (s, 1H), 5.14-4.87 (m, 1H), 4.46-4.24 (m, 1H), 4.04-3.77 (m, 7H, absorbed by water), 1.53 (br d, J =14.0 Hz, 3H).

Example 564 2-chloro-3-fluoro-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl )-5-(4-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamido)-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine- 7-yl)benzamide

F

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1 -f][1,2,4]triazin-7-yl)-2-chloro-3-fluoro-N((3R,4S )-4-fluoropyrrolidin-3-yl)benzamide, 1.0 TFA (15 mg, 0.026 mmol), (R)-3,3,3-trifluoro-2-hydroxy2-methylpropionic acid (4.13 mg, 0.026 mmol) and DIPEA ( 0.014 ml, 0.078 mmol) BOP (11.54 mg, 0.026 mmol) was added to DMF (1 ml). The reaction mixture was stirred at 23° C. for 2 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 5-45% B over 20 min, then 3 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (4 mg, 5.40 µmol, 21%).

MS (ERI) m/z 741.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.10-8.91 (m, 1H), 8.35 (br d, J=8.5 Hz, 1H), 8.16-8.05 (m, 1H), 7.95 (s, 1H), 7.87-7.63 (m, 1H), 7.29-6.98 (m, 1H), 5.40-5.13 (m, 1H), 4.73-4.52 (m, 1H), 4.46-4.25 (m, 1H), 4.08-3.53 (m , 3H), 1.59–1.42 (m, 6H).

Example 565: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)- 4fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2-methoxybenzamide

This compound was prepared using the method described for the preparation of Example 563, yielding 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4 -fluoro-N-((3R,4S)-4-fluoro-1 -(4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2-methoxybenzamide (9.7 mg, 14 µmol, 54%).

MS (ERI) m/z 665.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.46-8.35 (m, 1H), 8.17 (br dd, J=16.2, 8.5 Hz, 1H), 8.08 (s, 1H), 7.327.19 (m, 2H ), 5.43-5.19 (m, 1H), 4.87-4.59 (m, 1H), 4.21-3.24 (m, 7H, absorbed by water), 3.12-2.87 (m, 2H).

- 231 042342

Example 566: 5-(4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3 ,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-(methylamino)benzamide

566A: methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-5-bromobenzoate: to a solution of methyl 5-bromo-2(methylamino)benzoate (200 mg, 0.819 mmol) and N-methylmorpholine (0.135 ml, 1.229 mmol) in THF (5 mL) at 0°C was added benzyl chloroformate (0.13 mL, 0.901 mmol). The reaction mixture was heated to 23°C and stirred for 16 hours. The reaction mixture was diluted with EtOAc (100 ml), then washed with 10% LiCl solution (2x20 ml), brine (20 ml) and dried over anhydrous sodium sulfate. Filtration and concentration gave methyl 2-(((benzyloxy)carbonyl)(methyl)amino)-5-bromobenzoate (267.6 mg, 0.688 mmol, 84% yield).

MS (ERI) m/z 378.1 (M+H)+.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.02 (d, J=2.5 Hz, 1H), 7.51-7.30 (m, 6H), 6.58 (d, J=9.0 Hz, 1H), 5.42 (s, 2H) , 3.88 (s, 3H), 2.83 (s, 3H).

566B: Sodium 5-bromo-2-(methylamino)benzoate: solution of methyl 2(((benzyloxy)carbonyl)(methyl)amino)-5-bromobenzoate (267.6 mg, 0.708 mmol) and 1 N a solution of NaOH (1.4 ml, 1.415 mmol) in MeOH (3 ml) was heated to 100°C for 15 min and to 110°C for 2 h under the influence of microwaves. The reaction mixture was concentrated to give sodium 5-bromo-2(methylamino)benzoate (246 mg, 0.976 mmol, ~100% yield).

566C: tert-butyl (3R,4S)-3-(5-bromo-2-(methylamino)benzamido)-4-fluoropyrrolidine-1-carboxylate: to sodium 5-bromo-2-(methylamino)benzoate solution (246 mg , 0.976 mmol), tert-butyl (3R,4S)-3-amino-4fluoropyrrolidine-1-carboxylate (130 mg, 0.634 mmol) and DIPEA (0.223 ml, 1.279 mmol) , 0.637 mmol). The reaction mixture was stirred at 23°C for 3 days. The reaction mixture was diluted with EtOAc (100 ml), then washed with 10% LiCl solution (2x20 ml), brine (20 ml) and dried over anhydrous sodium sulfate. Filtration and concentration gave a crude material which was purified by silica gel column with hexanes/EtOAc (100/0 to 0/100) to give t-butyl (3R,4S)-3-(5-bromo-2-(methylamino )benzamido)-4fluoropyrrolidine-1-carboxylate (189 mg, 0.420 mmol, 43% yield).

MS (ERI) m/z 416.1 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ 8.53 (br dd, J=11.8, 6.8 Hz, 1H), 7.79 (br d, J=6.1 Hz, 1H), 7.44 (dd, J=8.9, 2.3 Hz , 1H), 6.96-6.95 (m, 1H), 5.31-5.07 (m, 1H), 4.67-4.42 (m, 1H), 3.78-3.45 (m, 4H), 2.84-2.74 (m, 3H), 1.42 (s, 9H).

566D: tert-butyl (3S,4R)-3-fluoro-4-(2-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-g-ioxaborolan-2yl)benzamido)pyrrolidine -1-carboxylate: degassed solution of tert-butyl (3R,4S)-3-(5-6pom-2(methylamino)benzamido)-4-fluoropyrrolidine-1-carboxylate (189 mg, 0.454 mmol), 4,4,4 ',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (121 mg, 0.477 mmol), potassium acetate (71.3 mg, 0.726 mmol) and adduct PdCl ₂ (dppf)-CH ₂ Cl2 (18.54 mg, 0.023 mmol) in dioxane (5 mL) was heated to 100°C for 16 h. The reaction mixture was used as is.

MS (ERI) m/z 464.1 (M+H) ⁺ .

566E: tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2( methylamino)benzamido)-4-fluoropyrrolidine-1-carboxylate: degassed solution of 7-bromo-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine (130 mg, 0.463 mmol) , tert-butyl (3S,4R)-3-fluoro-4(2-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)pyrrolidine -1-carboxylate (210 mg, 0.453 mmol), potassium triphosphate (2 M in water) (0.694 ml, 1.388 mmol) and adduct 1,1'bis (diphenylphosphino) ferrocene palladium dichloride - CH ₂ Cl ₂ (18.89 mg, 0.023 mmol) was stirred at 100° C. for 4 h. The reaction mixture was purified by silica gel column with hexanes/EtOAc (100/0 to 0/100) to give tert-butyl (3R,4S)-3-(5-( 4-αmino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-(methylamino)benzamido)-4-fluoropyrrolidine-1-carboxylate (54.6 mg, 0.091 mmol , 20% yield).

MS (ERI) m/z 538.1 (M+H) ⁺ .

566F: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-(methylamino)benzamide, TFA (54.8 mg, 0.099 mmol, 98% yield) was prepared using the method described for Example 562E. MS (ERI) m/z 438.1 (M+H) ⁺ .

566: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3, 3-Difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-(methylamino)benzamide was prepared using the method described for the preparation of Example 562. MS (ESI) m/z 556.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.64-8.49 (m, 1H), 8.12-8.08 (m, 2H), 8.05 (br d, J=5.2 Hz, 1H), 7.80-232 042342

7.68 (m, 1H), 7.39 (s, 1H), 6.79 (dd, J=9.2, 1.8 Hz, 1H), 5.43-5.15 (m, 1H), 4.82-4.46 (m, 1H), 4.22-3.37 ( m,

4H, absorbed by water), 3.19–3.16 (m, 1H), 2.91–2.68 (m, 7H).

Example 567: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethyl-3-fluoro-N ((3R, 4S)-4-fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)benzamide

567A: methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate: to a solution of methyl 5-bromo-3-fluoro-2methylbenzoate (500 mg, 2.024 mmol) at 75°C was added NBS (720 mg, 4.05 mmol) with followed by addition of AIBN (83 mg, 0.506 mmol). The reaction mixture was stirred at 75°C for 2.5 h and cooled to room temperature. The reaction mixture was purified by silica gel column with hexanes/EtOAc (100/0 to 50/50) to give methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate (649.6 mg, 1.949 mmol, 96% yield).

1H NMR (400 MHz, CD3OD) δ 7.95 (t, J=1.5 Hz, 1H), 7.66 (dd, J=9.3, 2.0 Hz, 1H), 4.97 (d, J=1.8 Hz, 2H), 3.97 (s , 3H).

567B: methyl 5-bromo-2-ethyl-3-fluorobenzoate: to a solution of copper (I) iodide (466 mg, 2.448 mmol) in Et ₂ O (5 ml) in an atmosphere of N2 at 0°C was added methyllithium, 1.6 M in Et ₂ O (3.1 ml, 4.90 mmol) and then stirred for 30 min. The reaction mixture was cooled to -78°C and methyl 5-bromo2-(bromomethyl)-3-fluorobenzoate (532 mg, 1.632 mmol) in Et ₂ O (5 ml) was added dropwise. The reaction mixture was stirred at -78°C for 1 h. The temperature of the reaction mixture was raised to 0°C, the mixture was stirred for 30 min, and the reaction was stopped with a saturated solution of NH ₄ Cl. The aqueous phase was extracted with Et ₂ O (100 ml). The organic layer was washed with water (50 ml), brine (50 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave a crude material which was purified by silica gel column with hexanes/CH ₂ Cl ₂ (100/0 to 80/20) to give methyl 5-bromo-2-ethyl-3-fluorobenzoate (260 mg, 0.996 mmol, 61% yield).

1H NMR (400 MHz, CD3OD) δ 7.81-7.77 (m, 1H), 7.52 (dd, J=9.4, 2.0 Hz, 1H), 3.92 (s, 3H), 2.94 (qd, J=7.4, 2.1 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).

567C: Sodium 5-bromo-2-ethyl-3-fluorobenzoate was prepared using the method described for the preparation of Example 562C (263 mg, 0.978 mmol, 98% yield).

567D: tert-butyl (3R,4S)-3-(5-bromo-2-ethyl-3-fluorobenzamido)-4-fluoropyrrolidine-1-carboxylate was prepared using the method described for the preparation of example 566C (351 mg, 0.810 mmol , 83% yield).

MS (ERI) m/z 433.1 (M+H)+.

1H NMR (400 MHz, CD3OD) δ 7.41 (dd, J=9.5, 1.9 Hz, 1H), 7.37 (s, 1H), 5.35-5.17 (m, 1H), 4.77-4.59 (m, 1H), 3.86 ( q, J=9.1 Hz, 1H), 3.78-3.57 (m, 2H), 3.33-3.31 (m, 1H, absorbed by MeOH), 2.74 (q, J=7.5 Hz, 2H), 1.50 (s, 9H), 1.20 (t, J=7.5 Hz, 3H).

569E: tert-butyl (3R,4S)-3-(2-ethyl-3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido)-4- fluoropyrrolidine-1-carboxylate was obtained using the method described for the preparation of example 566D.

MS (ERI) m/z 481.1 (M+H) ⁺ .

567F: tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2- ethyl 3-fluorobenzamido)-4-fluoropyrrolidine-1-carboxylate was prepared using the method described for the preparation of Example 566E (403 mg, 0.727 mmol, 90% yield).

MS (ERI) m/z 555.1 (M+H) ⁺ .

567G: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethyl-3-fluoro-N-((3R, 4S)-4fluoropyrrolidin-3-yl)benzamide, TFA, was prepared using the method described for the preparation of Example 562E (395 mg, 0.695 mmol, 96% yield).

MS (ERI) m/z 455.1 (m+H) ⁺ .

567: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethyl-3-fluoro-N-((3R, 4S)-4fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)benzamide was prepared using the method described for Example 562.

MS (ERI) m/z 663.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.98-8.94 (m, 1H), 8.92-8.87 (m, 1H), 8.21 (s, 1H), 8.07 (br dd, J=11.8, 4.8 Hz, 1H ), 7.86 (br d, J=7.8 Hz, 1H), 7.65 (d, J=6.6 Hz, 1H), 5.46-5.22 (m, 1H), 4.82-4.55 (m, 1H), 4.20-3.35 (m , 4H, absorbed by water), 3.13-2.92 (m, 2H), 2.75 (br d, J=5.1 Hz, 2H), 1.18 (br t, J=7.3 Hz, 3H).

- 233 042342

Example 568: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3 ,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide

5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3 difluorocyclobutanecarbonyl )-4-Fluoropyrrolidin-3 -yl]-4-fluoro-2-methoxybenzamide was prepared using the method described for Example 562.

MS (ERI) m/z 575.3 (M+H)+.

LCMS, retention time using method 1 = 1.74 min.

Example 569: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)- 4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide

5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1 -[(2R)

3,3,3-Trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide was prepared using the method described for Example 562.

MS (ERI) m/z 581.3 (M+H) ⁺ .

LCMS, retention time using method 2 = 1.71 min.

Example 570: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)- 4fluoro-1 - [4,4,4-trifluoro-3 -hydroxy-3 - (trifluoromethyl) butanoyl] pyrrolidin-3 -yl] -2- (fluoromethyl) benzamide

570A: Methyl 5-bromo-2-(bromomethyl)-3-fluorobenzoate was prepared using the method described for the preparation of Example 567A (648 mg, 1.962 mmol, 97% yield).

1H NMR (400 MHz, CDCl ₃ ) δ 7.97-7.94 (m, 1H), 7.47 (dd, J=8.9, 2.0 Hz, 1H), 4.96 (d, J=1.9 Hz, 2H), 4.01-3.98 (m , 3H).

570B: methyl 5-bromo-3-fluoro-2-(fluoromethyl)benzoate: tetrabutylammonium fluoride (6.0 ml, 5.96 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was concentrated to give the crude material, which was diluted with EtOAc (100 ml). The organics were washed with water (20 mlx2), brine (20 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave a crude material which was purified by silica gel column with hexanes/EtOAc (100/0 to 50/50) to give methyl 5-bromo-3fluoro-2-(fluoromethyl)benzoate (269 mg, 1.015 mmol, 51% yield).

1H NMR (400 MHz, CDCl3) δ 7.93 (d, J=0.9 Hz, 1H), 7.50 (dt, J=8.9, 1.6 Hz, 1H), 5.84 (d, J=1.9 Hz, 1H), 5.72 (d , J=2.0 Hz, 1H), 3.97 (s, 3H).

570C: sodium 5-bromo-3-fluoro-2-(fluoromethyl)benzoate: solution of methyl 5-bromo-3-fluoro-2(fluoromethyl)benzoate (269mg, 1.015mmol) and 1N. NaOH solution (1.5 mL, 1.522 mmol) in MeOH (9 mL) was heated to 100°C for 15 min under microwave action. The reaction mixture was concentrated to give sodium 5-bromo-3-fluoro-2-(fluoromethyl)benzoate (304 mg, 1.114 mmol, ~100% yield).

570D: tert-butyl (3R,4S)-3-(5-bromo-3-fluoro-2-(fluoromethyl)benzamido)-4-fluoropyrrolidine-1 carboxylate was prepared using the method described for preparing Example 566C. (285 mg, 0.579 mmol, 57% yield).

MS (ERI) m/z 437.1 (M+H) ⁺ .

1H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.45 (br d, J=8.8 Hz, 1H), 6.47 (br d, J=4.3 Hz, 1H), 5.67-5.46 (m, 2H) , 5.30-5.09 (m, 1H), 4.87-4.67 (m, 1H), 4.08-3.97 (m, 1H), 3.91-3.55 (m, 2H), 3.30-3.17 (m, 1H), 1.50 (s, 9H).

570E: tert-Butyl (3S,4R)-3-fluoro-4-(3-fluoro-2-(fluoromethyl)-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl )benzamido)pyrrolidine-1-carboxylate was prepared using the method described for

- 234 042342 receive example 566D.

570F: tert-butyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3- Fluoro2-(fluoromethyl)benzamido)-4-fluoropyrrolidine-1-carboxylate was prepared using the method described for the preparation of Example 566E (368 mg, 0.584 mmol, 90% yield).

MS (ERI) m/z 559.1 (M+H)+.

1H NMR (400 MHz, CD3OD) δ 8.21 (d, J=11.7 Hz, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.58 (s, 1H), 5.70 (s, 1H), 5.58 (s, 1H), 5.38-5.18 (m, 1H), 4.81-4.68 (m, 1H), 3.96-3.85 (m, 1H), 3.80-3.57 (m, 3H), 3.37-3.30 (m, 1H) , 1.22(s, 9H).

570G: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-2-(fluoromethyl)-N((3R ,4S)-4-Fluoropyrrolidin-3-yl)benzamide, TFA, was prepared using the method described for the preparation of Example 562E (309 mg, 0.540 mmol, 82% yield).

MS (ERI) m/z 459.1 (M+H)+.

570: 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4 -fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide was prepared using the method described for Example 562 (5.9 mg , 8.9 µmol, 34% yield).

MS (ERI) m/z 667.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.09-8.97 (m, 1H), 8.93-8.85 (m, 1H), 8.29-8.19 (m, 2H), 8.03 (br d, J=5.8 Hz, 1H ), 7.74 (d, J=4.9 Hz, 1H), 5.70-5.53 (m, 2H), 5.45-5.22 (m, 1H), 4.86-4.55 (m, 1H), 4.22-3.63 (m, 3H), 3.55-2.89 (m, 3H, absorbed by water).

Example 571: 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N[(3R, 4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]πirrolidin-3-yl]benzamide

Method 1: 571A Ethyl 3-bromo-6-(bromomethyl)-2-fluorobenzoate was prepared using the method described for the preparation of Example 567A (298 mg, 0.877 mmol, 92% yield).

1H NMR (400 MHz, CDCl3) δ 7.62 (dd, J=8.2, 6.8 Hz, 1H), 7.18-7.07 (m, 1H), 4.62 (s, 2H), 4.54-4.43 (m, 2H), 1.45 ( t, J=7.2 Hz, 3H).

Method 1: 571B ethyl 3-bromo-6-ethyl-2-fluorobenzoate was prepared using the method described for the preparation of example 567B (105 mg, 0.382 mmol, 44% yield).

1H NMR (400 MHz, CDCl3) δ 7.53 (dd, J=8.1, 7.2 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 4.45-(q, J=7.1 Hz, 2H), 2.69 ( q, J=7.6Hz, 2H), 1.42 (t, J=7.1Hz, 3H), 1.24 (t, J=7.5Hz, 3H)

Method 1: 571C sodium 3-bromo-6-ethyl-2-fluorobenzoate was prepared using the method described for the preparation of example 562C (88 mg, 0.327 mmol, 95% yield).

Method 2: 571D 1-bromo-4-ethyl-2-fluorobenzene: Triethylsilane (2.94 ml, 18.43 mmol). The reaction mixture was heated to 23°C and stirred for 16 h. The reaction mixture was diluted with ether (150 ml) and washed with water (50 ml), 1.5 M Na ₂ HPO ₄ solution (50 ml), water (50 ml) and brine (50 ml). The combined organics were dried over anhydrous sodium sulfate. Filtration and concentration gave the crude material, which was purified using a silica gel column with hexanes. The product was collected as 1-bromo-4-ethyl-2-fluorobenzene (1.35 g, 6.65 mmol, 72% yield).

1H NMR (400 MHz, CD3OD) δ 7.45-(dd, J=6.6, 2.0 Hz, 1H), 7.23-7.17 (m, 1H), 7.14-7.06 (m, 1H), 2.64 (q, J=7.6 Hz , 2H), 1.23 (t, J=7.6 Hz, 3H).

Method 2: 571E 3-bromo-6-ethyl-2-fluorobenzoic acid: to a solution of diisopropylamine (1.137 ml, 7.98 mmol) in THF (14 ml) was added 2.5 M n-butyllithium in hexanes (2.9 ml, 7.31 mmol) dropwise at 20°C in an N2 atmosphere. After stirring for 20 min, the mixture was cooled to -78°C, then 1-bromo-4-ethyl-2-fluorobenzene (1.35 g, 6.65 mmol) in THF (1 ml) was added dropwise. After stirring at 78°C for 45 min, a piece of dry ice, carbon dioxide (2.9 g, 66.5 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight. The reaction was stopped by dropwise addition of a saturated aqueous ammonium chloride solution (1 ml) and concentrated to give the crude material, which was dissolved in EtOAc (20 ml). The organic phase was extracted with 1 N. NaOH solution (3x20 ml). The combined aqueous layers were acidified with concentrated HCl in an ice water bath to pH ~2. The aqueous layer was extracted with EtOAc (80 ml). The organic layer was washed with brine (20 ml) and dried over Na ₂ SO ₄ . Filtration and concentration gave 3-bromo-6-ethyl-2-fluorobenzoic acid (1.10 g, 4.45 mmol, 67% yield).

MS (ERI) m/z 247.1 (M+H)+.

1H NMR (400 MHz, CD3OD) δ 7.74 (dd, J=6.2, 2.2 Hz, 1H), 7.69 (dd, J=6.0, 2.3 Hz, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H).

- 235 042342

571F: tert-Butyl (3R,4S)-3-(3-bromo-6-ethyl-2-fluorobenzamido)-4-fluoropyrrolidine-1-carboxylate was prepared using the method described for Example 566C (121.4 mg, 0.280 mmol , 86% yield).

MS (ERI) m/z 433.1 (M+H)+.

1H NMR (400 MHz, CDCl ₃ ) δ 7.54 (t, J=7.8 Hz, 1H), 6.99 (br d, J=8.1 Hz, 1H), 6.21-6.07 (m, 1H), 5.315.10 (m, 1H), 4.94-4.73 (m, 1H), 4.10-4.00 (m, 1H), 3.91-3.54 (m, 2H), 3.28-3.15 (m, 1H), 2.71 (br d, J=7.2 Hz, 2H ), 1.51 (s, 9H), 1.30–1.20 (m, 3H).

571G: tert-butyl (3R,4S)-3-(6-ethyl-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido)-4- fluoropyrrolidine-1-carboxylate was obtained using the method described for the preparation of example 566D.

571F: tert-butyl (3R,4S)-3-(3-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6- ethyl2-fluorobenzamido)-4-fluoropyrrolidine-1-carboxylate was prepared using the method described for the preparation of example 566E (168.3 mg, 0.276 mmol, 97% yield).

MS (ERI) m/z 555.1 (M+H) ⁺ .

Ή NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.22 (s, 2H), 6.32-6.16 (m, 1H), 5.83 (br s, 2H ), 5.33-5.11 (m, 1H), 4.98-4.75 (m, 1H), 4.10-4.00 (m, 1H), 3.91-3.53 (m, 2H), 3.31-3.14 (m, 1H), 2.892.74 (m, 2H), 1.50 (s, 9H), 1.36-1.29 (m, 3H).

571G: 3-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-ethyl-2-fluoro-N-((3R, 4S)-4fluoropyrrolidin-3-yl)benzamide, TFA, was prepared using the method described for the preparation of Example 562E (146.4 mg, 0.258 mmol, 93% yield).

MS (ERI) m/z 455.1 (M+H) ⁺ .

571: 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R, 4S)-4fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide was prepared using the method described for the preparation of Example 562 (6.4 mg, 9.7 µmol , 46% yield).

MS (ERI) m/z 663.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.19-9.05 (m, 1H), 8.09 (s, 1H), 7.84-7.73 (m, 1H), 7.33-7.23 (m, 2H), 5.45-5.17 ( m, 1H), 4.85-4.53 (m, 1H), 4.19-3.22 (m, 4H, absorbed by water), 3.12-2.87 (m, 2H), 2.66 (q, J=7.7 Hz, 2H), 1.20 (br t, J=6.7 Hz, 3H).

Connections in the table. 36 were prepared by the methods detailed in Example 562. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. Retention time (RT) in LC-MS was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

Table 36

°\

Example Name ^{R1 R2} The ion mass observed in MS RT (Method) 572 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(2fluorobenzoyl)pyrrolidine -3-yl]5-methoxybenzamide H d 561.2 1.67 (2) 573 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-(3,3 ,3trifluoro-2methylpropanoyl)pyrrolide in-3yl] - 5-methoxybenzamide H X^Me F ₃ C 563.0 1.7 (1) 574 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrro lidin-3-yl]-5-methoxybenzamide H h 539.2 1.53 (2)

- 236 042342

575 576 577 578 579 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]H[(ZK,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidine -3 -yl] -5-methoxybenzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]H[(ZK,48)-4-fluoro-1-(1fluorocyclopropanecarbonyl)pyrrolide in-3-yl]-5-methoxybenzamide 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]H[(ЗR,4S)-4-φτop-l-[4,4,4trifluoro-3-hydroxy-3 ( trifluoromethyl)butanoyl]pyrrole idin-3-yl]-5-methoxybenzamide 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]H[(3Κ,48)-4-φτορ-1-[(2Κ)-3,3,3trifluoro-2-hydroxy -2methylpropanoyl] pyrrolidin-3 yl] - 5-methoxybenzamide 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,4S)-4-φτop-1-(4,4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolide in-3 yl]-5-methoxybenzamide H H n n n h CF ₃ X CHON CF ₃ X / CF ₃ * OH Me Y 4OH CF ₃ 539.2 525.1 647.3 579.1 593.3 1.6 (1) 1.6 (2) 1.93 (2) 1.65 (2) 1.63 (2) 580 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,48)-1-(4,4difluorocyclohexanecarbonyl)-4fluoropyrrolidine- 3-yl]-5methoxybenzamide n L J< ^F hhh F 585.3 1.75 (1) 581 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine- 3 -yl]-5 methoxybenzamide n . F X_4f 543.2 1.59 (2) 582 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3K48)-4-fluoro-1-[2-hydroxy-2 (trifluoromethyl)butanoyl]pyrrole idin-3-yl]-5-methoxybenzamide n Me F^ ^H 593.3 1.74 (1) 583 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(ЗR,4S)-4-φτop-1-(4,4 ,4trifluoro-3methylbutanoyl)pyrrolide in-3yl]-5-methoxybenzamide n Me ^^^OFg 577.3 1.83 (1) 584 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidine- 3 -yl]-5 methoxybenzamide n F 557.2 1.65 (2) 585 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(ЗR,4S)-4-φτop-1 -(2-fluoro -2methylpropanoyl)pyrrolidin-3 yl] - 5-methoxybenzamide n X^Me Me ^F 527.3 1.64 (2)

- 237 042342

586 587 588 589 590 591 592 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-K[(3R,4S)-4-φτop-l-[4,4 ,4trifluoro-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-5-methoxybenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 b][1,2,4]triazin-7-yl ]-M[(3R,48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoro pyrrolidin-3-yl]-5 methoxybenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2.1 1][1.2 ,4]triazin-7-yl]-K[(3Sch48)-4-fluoro-1 -(2-hydroxy-2methylpropanoyl)pyrrolide in-3yl] - 5-methoxybenzamide 3-[4-amino-5(trifluoromethyl) pyrrolo[2,1 1][1,2,4]triazin-7-yl]-K[(ZSch48)-4-fluoro-1-(3methylbutanoyl)pyrrolide in-3yl] - 5-methoxybenzamide 3-[4 -amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-(3,3,3trifluoropropanoyl)pyrrolidine3 -yl] -5-methoxybenzamide -1-(4,4,4trifluoro-3methylbutanoyl)pyrrolide in-3yl]-2,3-dimethoxybenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 b][1,2,4]triazine -7-yl]-M[(3R,4S)-4-(j)Top-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylprop anoyl]pyrrolidin-3 yl]-2,3-dimethoxybenzamide H H n n n OME OME CF ₃ ^^^CFs X^Me ' ^OH Me he Me ^'^Ce X^CF ₃ Me pOcf ₃ '' he 631.4 571.3 525.2 523.1 549.2 607.2 609.1 1.92 (1) 1.74 (1) 1.4 (2) 1.68 (1) 1.6 (2) 1.86 (2) 1.67 (2) 593 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-[4,4,4trifluoro -3-hydroxy-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2,3dimethoxybenzamide OME CF ₃ kA?/bz 677.2 2.11(1) 594 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ZA48)-4-fluoro-1-(2fluorobenzoyl)pyrrolidin-3 -yl]2,3-dimethoxybenzamide OME f 591.3 1.75 (2) 595 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-1 -[4,4 ,4trifluoro-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2,3dimethoxybenzamide OME CF ₃ ^^CF, 661.1 2.05 (1)

Connections in the table. 37 was obtained by the methods detailed in examples 569 and 570. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

- 238 042342

Table 37

F

Example Name ^{R1 R2} Observe May in MS the mass of the ion RT (Method) 596 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl]-5-fluoroΝ-[(3^48)-4-φτορ-1-[ (2Κ)3,3,3-trifluoro-2hydroxypropanoyl]pyrrolide and n-3-yl]benzamide H X ^CF 3 he 553.0 1.73(2) 597 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroΝ-[(3^48)-4-φτορ-1-( 3fluorocyclobutanecarbonyl)pyrrolide in-3-yl]benzamide H 527.3 1.64 (2) 598 599 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroΝ-[(3^48)-4-φτορ-1-( 3,3,3trifluoro-2,2dimethylpropanoyl)pyrrolidi n-3-yl]benzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]- 5-fluoroN-[(3R,4S)-4-φτop-l-(2-φτop-2methylpropanoyl)pyrrolidin3-yl]benzamide H H X^Me Me ^CF 3 X^Me Me ^F 565.3 515.4 1.9 (2) 1.75 (2) 600 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroN-[(3R,4S)-4-φτop-l-( 2methylpropanoyl)pyrrolidin3-yl]benzamide H X^Me Me 497.1 1.7 (2) 601 602 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroΝ-[(3^48)-4-φτορ-1-( 3methylbutanoyl)pyrrolidin-3yl]benzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroN-[(3R,4S)-4-φτop-l-( 2hydroxy-2methylpropanoyl)pyrrolidin3-yl]benzamide H H Me X^Me Me^ ^0H 511.3 513.1 1.76 (2) 1.41(1) 603 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 3,3,3trifluoropropanoyl)pyrrolidi n-3-yl]benzamide H X^CF ₃ 537.3 1.69 (2)

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604 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(2,2dimethylpropanoyl)-4fluoropyrrolidine- 3 -yl]-5 fluorobenzamide H X^Me ^Me Me 511.4 1.78 (2) 605 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X- [(3R,4S)-1cyclobutanecarbonyl-4fluoropyrrolidin-3-yl]-5fluorobenzamide n 509.3 1.65 (1) 606 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoro- Ν-[(3^48)-4-φτορ-1-(4fluorobenzoyl)pyrrolidin-3 yl]benzamide n (Q) 549.0 1.87 (2) 607 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoro- Ν-[(3^48)-4-φτορ-1-(2fluorobenzoyl)pyrrolidin-3 yl]benzamide n % 549.3 1.72 (1) 608 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)4-fluoropyrrolide in-3 -yl]-5 fluorobenzamide n F Xy-VF 531.3 1.69 (2) 609 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)4-fluoropyrrolide in-3 -yl]-5 fluorobenzamide n T \f F 573.3 1.8 (2) 610 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3- n Tx 559.1 1.86 (2)

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difluorocyclopentanecarbonyl)4-fluoropyrrolide in-3-yl]-5fluorobenzamide 611 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoroΝ-[(3^48)-4-φτορ-1-( 3fluorocyclobutanecarbonyl)pyrrolide in-3-yl]benzamide H 527.3 1.67 (2) 612 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3^48)-4-φτορ-1-( 1fluorocyclopropanecarbonyl)pyrolide in-3-yl]-2(fluoromethyl)benzamide ch ₂ f / ^V7 545.2 1.67 (3) 613 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 2-φτορ-2methylpropanoyl)pyrrolidin3 -yl]-2-(fluoromethyl)benzamide ch ₂ f X^Me mA 547.2 1.7 (4) 614 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-(fluoromethyl)benzamide ch ₂ f . Fkxf 563.3 1.63 (3) 615 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-(fluoromethyl)benzamide ch ₂ f ^^S^f F 577.3 1.73 (4)

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616 5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl)-3-fluoroΝ-((3^48)-4-φτορ-1-( 3fluorocyclobutane-1 carbonyl)pyrrolidin-3-yl)-2(fluoromethyl)benzamide ch ₂ f 559.1 1.61 (4) 617 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroN-[(3R,4S)-4^ _T op-l-[ (2R)3,3,3 -trifluoro-2-hydroxy-2methylpropanoyl] pyrrolide in3 -yl] -2-(fluoromethyl)benzamide ch ₂ f A/CF ₃ * he 599.3 1.66 (4) 618 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-(fluoromethyl)benzamide ch ₂ f 591.1 1.74 (4) 619 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-(fluoromethyl)benzamide ch ₂ f Xi 605.0 1.73 (4) 620 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3^48)-4-φτορ-1-( 4,4,4trifluoro-3methylbutanoyl)pyrrolidin-3yl]-2-(fluoromethyl)benzamide ch ₂ f Me ^^^CFa 597.1 1.82 (4)

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621 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 4,4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidin-3yl]-2-(fluoromethyl)benzamide ch ₂ f Me Y- ₃ 613.3 1.69 (3) 622 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-[ 4,4,4trifluoro-3(trifluoromethyl)butanoyl]pyrr olidin-3-yl]-2(fluoromethyl)benzamide ch ₂ f CF ₃ ^^CFg 651.0 1.94 (4) 623 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 2hydroxy-2methylpropanoyl)pyrrolidin3 -yl]-2-(fluoromethyl)benzamide ch ₂ f X^Me % ^MeOH 545.1 1.46 (4) 624 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 3,3,3trifluoropropanoyl)pyrrolidi n-3-yl]-2-(fluoromethyl)benzamide ch ₂ f X^CF ₃ 569.2 1.64 (3) 625 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 3methylbutanoyl)pyrrolidin-3yl]-2-(fluoromethyl)benzamide ch ₂ f Me 543.2 1.71 (4)

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626 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 2fluorobenzoyl)pyrrolidin-3yl]-2-(fluoromethyl)benzamide ch ₂ f A 581.2 1.82 (4) 627 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 3,3,3trifluoro-2methylpropanoyl)pyrrolidin3 -yl]-2-(fluoromethyl)benzamide ch ₂ f X^Me F ₃ C 583.1 1.83 (4) 628 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-[ 2hydroxy-2(trifluoromethyl)butanoyl]pyrr olidin-3-yl]-2(fluoromethyl)benzamide ch ₂ f Me Y F ₃ C ^0H 613.1 1.77 (4) 629 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1(4,4,4-trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidin-3yl]benzamide Cl Me / J<OH CF ₃ 615.3 1.86 (4) 630 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1-(2fluoro-2methylpropanoyl)pyrrolidin3-yl]benzamide Cl /yMe Me ^F 549.3 1.85 (4)

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631 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloroN-[(3R,4S)-l-(2,2difluorocyclopropanecarbonyl) 4-fluoropyrrolide in-3 -yl]-3 fluorobenzamide C1 l F ALf 565.1 1.78 (4) 632 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτop-N-[(ЗR,4S)-4-φτop -l[4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide C1 CF ₃ CF ₃ 653.3 2.08 (4) 633 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτop-N-[(ЗR,4S)-4-φτop -l(3,3,3-trifluoro-2methylpropanoyl)pyrrolidin3-yl]benzamide C1 X^Me F ₃ C 585.3 1.88 (4) 634 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτop-N-[(ЗR,4S)-4-φτop -1 (4,4,4-trifluoro-3methylbutanoyl)pyrrolidin-3yl]benzamide C1 Me 599.3 1.54 (3) 635 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloroN-[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl) 4-fluoropyrrolide in-3 -yl]-3 fluorobenzamide C1 Y^F F 579.0 1.85 (4)

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636 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1-(1fluorocyclopropanecarbonyl) pyrrolide in-3 -yl] benzamide C1 547.3 1.32 (3) 637 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1[4,4,4-trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide C1 CF ₃ ion CF ₃ 669.2 2.12(4) 638 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1-(3fluorocyclobutanecarbonyl)pyrr olid in-3 -yl]benzamide C1 561.0 1.72 (4) 639 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1-(2hydroxy-2methylpropanoyl)pyrrolidin3-yl]benzamide C1 YMe 547.1 1.6 (4) 640 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτορ-Ν-[(3Κ,48)-4-φτορ -1(3,3,3trifluoropropanoyl)pyrrolidi n-3-yl]benzamide C1 X^CF ₃ 570.9 1.79 (4)

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641 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτop-N-[(ЗR,4S)-4-φτop -l-(3methylbutanoyl)pyrrolidin-3yl]benzamide C1 Me 545.1 1.81 (3) 642 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3φτop-N-[(ЗR,4S)-4-φτop -l-(2fluorobenzoyl)pyrrolidin-3 yl]benzamide C1 / 583.3 1.81 (3) 643 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloroN-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) 4-fluoropyrrolide in-3 -yl]-3 fluorobenzamide C1 IX ^F F 607.2 1.88 (4) 644 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloroN-[(3R, 48)-1-(3,3difluorocyclopentanecarbonyl) 4-fluoropyrrolide in-3 -yl]-3 fluorobenzamide C1 593.3 1.87 (4) 645 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-ethyl-3 φτop-N-[(ЗR,4S)-4- φτop-l-(2fluorobenzoyl)pyrrolidin-3 yl]benzamide Et ύ 577.2 1.92 (4)

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646 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-ethyl-3 φτop-N-[(ЗR,4S)-4- φτop-l-(3methylbutanoyl)pyrrolidin-3 yl]benzamide Et Me 539.2 1.86 (3) 647 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1-(2hydroxy-2methylpropanoyl)pyrrolidin3-yl]benzamide Et X/Me MeA 541.1 1.65 (4) 648 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1(3,3,3trifluoropropanoyl)pyrrolidi n-3-yl]benzamide Et X^CF ₃ 565.3 1.87 (4) 649 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)4-fluoropyrrolide in-3-yl]-2ethyl-3-fluorobenzamide Et . Fxvf 559.3 1.79 (3) 650 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2 -ethyl-3 φτορ-Ν-[(3^48)-4- φτορ-1[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl] pyrrolide in3-yl] benzamide Et X/ _CF3 *OH 595.3 1.86 (3) 651 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-ethyl-3 φτop-N-[(ЗR,4S)-4- φτop-l-[2hydroxy-2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide Et Me Zh F ₃ C ^0H 609.1 1.88 (3)

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652 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1(4,4,4-trifluoro-3methylbutanoyl)pyrrolidin-3yl]benzamide Et Me 593.2 2.02 (4) 653 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1(4,4,4-trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidin-3yl]benzamide Et Me Cr ₃ 609.2 1.91 (4) 654 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1[4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide Et _CF3 647.0 2.18(4) 655 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1-(3fluorocyclobutanecarbonyl)pyrr olid in-3-yl] benzamide Et 555.3 1.85 (4) 656 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1-(3fluorocyclobutanecarbonyl)pyrr olid in-3-yl] benzamide Et /, 555.1 1.84 (3)

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657 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1-(1fluorocyclopropanecarbonyl)pyrrolide in-3-yl] benzamide Et fS ⁷ 541.3 1.94 (4) 658 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,48)-1-(3,3diφτopcyclopentananκarbonyl)4-fluoropyrrolide in-3-yl]-2ethyl-3-fluorobenzamide Et I—V ^F AA _F 587.1 1.93 (4) 659 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1-(2fluoro-2methylpropanoyl)pyrrolidin3-yl]benzamide Et X^Me m5 543.1 1.86 (3) 660 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)4-fluoropyrrolide in-3-yl]-2ethyl-3-fluorobenzamide Et A 601.1 1.96 (3) 661 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl] -2-ethyl-3 φτορ-Ν-[(3Κ,48)-4- φτορ-1(3,3,3-trifluoro-2methylpropanoyl)pyrrolidin3-yl]benzamide Et X^Me F ₃ C 579.3 1.94 (3)

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662 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 4,4,4trifluoro-3methylbutanoyl)pyrrolidin-3yl]-2-methylbenzamide Me Me 579 1.96 (2) 663 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-K[(3R,4S)-1cyclobutanecarbonyl-4fluoropyrrolidin-3-yl]-3 -fluoro2-methylbenzamide Me 523.4 1.67 (1) 664 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ48)-4-φτορ-1-(3, 3,3trifluoropropanoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me X^CF ₃ 551.3 1.78 (2) 665 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3M8)-4-φτορ-1-(2hydroxy- 2methylpropanoyl)pyrrolidin3-yl]-2-methylbenzamide Me ^MeOH 527.3 1.5 (2) 666 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2dimethylpropanoyl)-4fluoropyrrolidine- 3 -yl] -3 -fluoro2-methylbenzamide Me /Sme ./ Me Me 525.4 1.74 (1)

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667 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 3methylbutanoyl)pyrrolidin-3yl]-2-methylbenzamide Me Me 525.3 1.72 (1) 668 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 2methylpropanoyl)pyrrolidin3-yl]-2-methylbenzamide Me X^/Me Me 511.1 1.64 (2) 669 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 2fluorobenzoyl)pyrrolidin-3yl]-2-methylbenzamide Me D 563.3 1.74 (1) 670 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 4fluorobenzoyl)pyrrolidin-3 yl]-2-methylbenzamide Me 563.3 1.76 (1) 671 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-( 1hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]-2methylbenzamide Me on 539.1 1.54 (2)

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672 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroN-[(3R,4S)-44top-1-[(2R )3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolide and n-3-yl]-2-methylbenzamide Me / ^ACF3OH 567.2 1.61 (1) 673 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroN-[(ЗR,4S)-4-φτop-l-( 2-φτop-2methylpropanoyl)pyrrolidin3-yl]-2-methylbenzamide Me X^Me mZ 529.3 1.71 (1) 674 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-H[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methylbenzamide Me A 587.4 1.77 (1) 675 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methylbenzamide Me ^F ? ^4Vf 545.3 1.65 (1) 676 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ48)-4-φτορ-1-(3, 3,3trifluoro-2,2dimethylpropanoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me X^-Me Me ^CF 3 579.3 1.78 (1)

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677 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,48)-1-(3,3diφτopcylobutanκarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methylbenzamide Me F 559.4 1.71 (1) 678 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3M8)-4-φτορ-1-(3fluorocyclobutanecarbonyl) pyrr olidin-3-yl]-2-methylbenzamide Me 541.3, 541.3 1.66 (2) 679 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M[(3R,48)-1-(3,3diφtorcyclopentananκarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methylbenzamide Me Tx 573.4 1.75 (1) 680 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3M8)-4-φτορ-1-(3methylbutanoyl) pyrrolidin-3 yl]-2-methoxybenzamide OME Me 541.1 1.75 (2) 681 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro- Ν-[(3M8)-4-φτορ-1-(2fluorobenzoyl)pyrrolidin-3 yl]-2-methoxybenzamide OME 579.3 1.84 (1)

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682 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1cyclobutanecarbonyl-4fluoropyrrolidin-3-yl]-3 -fluoro2-methoxybenzamide OME 539.1 1.73 (1) 683 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-3-fluoroΝ-[(3M8)-4-φτορ-1-(4fluorobenzoyl) pyrrolidin-3 yl]-2-methoxybenzamide OME ήη 579.3 1.54 (1) 684 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X[(3R,48)-1-(3,3diφτopcylobytaanκarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methoxybenzamide OME F 575.2 1.52(1) 685 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroN-[(ЗR,4S)-4-φτop-l-( 2-φτop-2methylpropanoyl)pyrrolidin3 -yl]-2-methoxybenzamide OME X^Me Me ^F 545.1 1.65 (2) 686 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroN-[(3R,4S)-4^ _T op-l- [(2R)3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide in3-yl]-2-methoxybenzamide OME ? _OCF3 *OH 597.2 1.65 (2)

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687 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Ρ,48)-4-φτορ-1-( 3fluorocyclobutanecarbonyl)pyrr olidin-3-yl]-2methoxybenzamide OME 557.3 1.82 (4) 688 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Ρ,48)-4-φτορ-1-( 1fluorocyclopropanecarbonyl)pyrolide in-3-yl]-2methoxybenzamide OME 543.3 1.96 (3) 689 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f][1,2,4]τpiazin-7-yl]-N[(ЗR,4S)-l-(4,4diφτopcycloheκcanκarbonyl)4-fluoropyrrolide in-3 -yl]-3 fluoro-2-methoxybenzamide OME Λ 603.1 2.05 (4) 690 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3^48)-4-φτορ-1-[ 4,4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxybenzamide OME SRz 665.3 2.11(3) 691 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroΝ-[(3^48)-4-φτορ-1-[ 4,4,4trifluoro-3(trifluoromethyl)butanoyl]pyrr olidin-3-yl]-2methoxybenzamide OME _CF3 649.0 2.23(4)

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692 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-[2hydroxy -2(trifluoromethyl)butanoyl]pyrr olidin-3 -yl]-2methoxybenzamide OME Me F ₃ C ^0H 611.3 1.87 (3) 693 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(4 ,4,4trifluoro-3methylbutanoyl)pyrrolidin-3yl]-2-methoxybenzamide OME Me ^^^CFs 595.4 1.99 (3) 694 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(3 ,3,3trifluoro-2methylpropanoyl)pyrrolidin3 -yl]-2-methoxybenzamide OME X^Me F ₃ C 581.0 1.9 (3) 695 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(4fluorocyclohexanecarbonyl )pyrrolide in-3-yl]-2methoxybenzamide OME 585.3 1.85 (3) 696 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(4 ,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3yl]-2-methoxybenzamide OME Me K J<OH CF ₃ 611.1 2.01 (4)

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697 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-K[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)4-fluoropyrrolide in-3-yl]-3 fluoro-2-methoxybenzamide OME p F W ^F 561.3 1.94 (4) 698 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-K- [(3R,4S)-l-(3,3- difluorocyclopentanecarbonyl)4-fluoropyrrolide in-3-yl]-3fluoro-2-methoxybenzamide OME I—V ^F ZA _F 589.3 1.92 (4) 699 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoroN-[(3R,4S)-4^Top-l-( 3,3,3trifluoropropanoyl)pyrrolidi n-3-yl]-2-methoxybenzamide OME X^CF ₃ 567.3 1.81 (4) 700 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro- Ν-[(3M8)-4-φτορ-1-(2- hydroxy-2methylpropanoyl)pyrrolidin3 -yl]-2-methoxybenzamide OME X^Me 543.4 1.53 (3)

Connections in the table. 38 was obtained by the methods detailed in example 562. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 38

Me

Example Name R Observe May in MS the mass of the ion RT (Method) 701 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 13[1,2,4]triazin-7-yl]-2-chloro-M[(3R,48)-4-fluoro-1 -(4,4,4-trifluoro- 3 methylbutanoyl)pyrrolide in-3 -yl]-3 methylbenzamide Me^^CEz 595.0 1.96 (4) 702 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-2-chloro-T4[(3R,48)-4-fluoro-1 - [4,4,4-trifluoro-3 hydroxy-3 (trifluoromethyl)butanoyl]pyrrolidin3-yl]-3-methylbenzamide with ^r s X> ° ⁿ 665.2 2.11(4) 703 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-2-chloro-M[(ZK,48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl )butanoyl]pyrrolidin3-yl]-3-methylbenzamide Me Y F ₃ C ^0H 611.3 1.87 (4) 704 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-2-chloro-H[(3R, 48)-1-(2,2difluorocyclopropanecarbonyl )-4fluoropyrrolidin-3 -yl]-3 methylbenzamide ^F Yx 561.0 1.81 (4) 705 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.1 £][1.2.4]triazin-7-yl]-2-chloro-H[(3R,4S)-4-φτop-1 - (2-fluoro-2methylpropanoyl)pyrrolidin-3 -yl]-3 methylbenzamide X^Me Me ^CF 3 545.2 1.85 (4)

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706 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-L1[(3R,48)-1-(3,3difluorocyclobutanecarbonyl) -4fluoropyrrolidin-3 -yl]-3 methylbenzamide F 575.3 1.84 (4) 707 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-2-chloro-L1[(3H48)-4-fluoro-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3 -yl]-3 methylbenzamide mg°n 543.0 1.62 (4) 708 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3R,4S)-4^Top-l-( 2fluorobenzoyl)pyrrolidin-3 -yl]-3 methylbenzamide X 579.0 1.86 (4) 709 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-2-chloro-M[(ZA48)-4-fluoro-1-[4,4,4-trifluoro-3 (trifluoromethyl)butanoyl]pyrrolidin3-yl]-3-methylbenzamide CF ₃ ^^CFs 649.2 2.08 (4) 710 5-[4-amino-5- (trifluoromethyl)pyrrolo[2.1 £][1,2,4]triazin-7-yl]-2-chloro-X[(3R,48)-1-(3,3diφtorcyclopentanκarbonyl)-4fluoropyrrolidin-3-yl] -3 methylbenzamide S^X/F X/ F 589.0 1.89 (4) 711 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-2-chloro-L1[(3N48)-4-fluoro-1-(4,4,4-trifluoro-3hydroxy -3methylbutanoyl)pyrrolide in-3 -yl]-3methylbenzamide Me //OH CF ₃ 611.2 1.75 (3) 712 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3R, 48)-1-(4,4difluorocyclohexanecarbonyl) -4fluoropyrrolidin-3 -yl]-3 methylbenzamide 603.2 1.79 (3)

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713 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3K,48)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin3 -yl]-3-methylbenzamide 557.1 1.63 (3) 714 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3R,4S)-4-φτop-l-[ (2R)-3,3,3-τpiφτop2-hydroxy-2methylpropanoyl]pyrrolidin-3 -yl]-3 methylbenzamide /Acf ₃ 'he 597.2 1.69 (3) 715 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-M[(3^48)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidine -3 -yl] -3-methylbenzamide Sv 543.2 1.72 (3) 716 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3K,48)-4-fluoro-1-( 3methylbutanoyl)pyrrolide in-3-yl]-3methylbenzamide Me 541.1 1.74 (3) 717 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-M[(3Κ,48)-4-φτορ-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3 -yl]-3 methylbenzamide X^CF ₃ 567.3 1.67 (3) 718 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-2-chloro-X[(3R,4 8)-4-fluoro-1-(3,3,3-trifluoro -2 methylpropanoyl)pyrrolidin-3 -yl] -3 methylbenzamide X^Me F ₃ C 581.2 1.77 (3)

Connections in the table. 39 was obtained by the methods detailed in examples 562 and 571. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 39

Example Name ^{R1 R2} Ion mass observed by HMS RT (Method) 719 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-H[(3K,48)-4-fluoro- 1-(3methylbutanoyl)pyrrolidin-3yl]benzamide F Me 529.3 1.65 (4) 720 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-H[(3R,48)-4-fluoro-1-[4,4,4 -trifluoro-3 hydroxy-3 - (trifluoromethyl)butanoyl]pyrrolidi n-3-yl]benzamide F CF ₃ X> ^he Yz 653 1.95 (4) 721 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f][ 1,2,4]triazin-7-yl]-2,6-difluoro-H[(3^4δ)-4-φτορ-1 -(4,4,4 -trifluoro-3 hydroxy-3 methylbutanoyl)pyrrolidin-3 yl]benzamide F Me A/ SPz 599.1 1.67 (4) 722 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-M[(3R,4S)-4-φτop- l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide F pOcf ₃ 'he 585.0 1.52 (4) 723 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-H[(3K,48)-4-fluoro- 1-(3fluorocyclobutanecarbonyl)pyrrolidi n-3-yl]benzamide F 545.1 1.58 (4)

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724 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]τpiazin-7-yl]-2,6-diφτop-N[(ЗR,4S)-4-φτop- l-(3φτopcyclobutanκapbonyl)pyrpolidi n-3-yl]benzamide F h 545.2 1.56 (4) 725 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-X[(3A48)-4-fluoro-1- (2fluorobenzoyl)pyrrolidin-3yl]benzamide F th 567.1 1.67 (4) 726 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f][ 1,2,4]triazin-7-yl]-2,6-difluoro-X[(3R,4 8)-4-fluoro-1-(3,3, 3-trifluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide F X^Me F ₃ C 569.2 1.61 (3) 727 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(ZA48)-1 (3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2,6difluorobenzamide F F 563.2 1.57 (3) 728 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-X[(ZA48)-4-fluoro-1-(4,4,4-trifluoro -3 methylbutanoyl)pyrrolidin-3 yl]benzamide F Me AA \ _C f ₃ 583.2 1.78 (4) 729 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,6-difluoro-X[(ZA48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl )butanoyl]pyrrolidi n-3-yl]benzamide F Me 599.1 1.69 (4) 730 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M-[(ZA48)-1 (2,2-difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-2,6difluorobenzamide F . F YAf 549.2 1.5 (3) 731 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(ZA48)-1 (4,4-difluorocyclohexanecarbonyl)-4fluoropyrrolidin-3-yl]-2,6difluorobenzamide F A: 591.1 1.64 (3)

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732 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]τpiazin-7-yl]-2,6-diφτop-N[(ЗR,4S)-4-φτop- 1 -[4,4,4 -trifluoro-3 (trifluoromethyl)butanoyl]pyrrolidi n-3-yl]benzamide F CF ₃ ^^^CFs 637.2 1.85 (3) 733 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-Ni(3K,48)-1 (3,3-d ifluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl]-2, 6difluorobenzamide F 1—V ^F X/F 577.2 1.67 (4) 734 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoroN-[(3 R,48)-4- fluoro-1-(4,4,4-trifluoro3-hydroxy-3 methylbutanoyl)pyrrolidin-3yl]benzamide Et Me K J< ^OH CF ₃ 609.3 1.81 (4) 735 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoroΝ-[(3Κ,48)-4-φτορ -1-(3,3,3trifluoropropanoyl)pyrrolide in-3yl]benzamide Et Acf ₃ 565.3 1.77 (4) 736 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoroΝ-[(3Κ,48)-4-φτορ-1-[4,4, 4-τρπφτορ- 3- (trifluoromethyl)butanoyl]pyrrolidi n-3-yl]benzamide Et CF ₃ ^^CFs 647.3 2.07 737 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoroΝ-[(3Κ,48)-4-φτορ -1-[(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide Et Acf ₃ 595.3 1.78 (4) 738 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoro- Ν-[(3Κ,48)-4-φτορ-1-(3- methylbutanoyl)pyrrolidin-3 yl]benzamide Et Me 539.3 1.84 (4)

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739 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M-[(3 R,4S)-I (4,4-difluorocyclohexanecarbonyl)-4fluoropyrrolidin-3-yl] - 6-ethyl-2fluorobenzamide Et % 601.1 1.84 (3) 740 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(3K,48)-1 (2,2-difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-6 -ethyl-2fluorobenzamide Et F 559.3 1.76 (4) 741 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(3K,48)-1 (3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-6 -ethyl-2fluorobenzamide Et SA-f F 573.3 1.82 (4) 742 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoro- Ν-[(3Κ,48)-4-φτορ-1-(3fluorocyclobutanecarbonyl)pyrrolidi n-3-yl]benzamide Et 555.3 1.69 (3) 743 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(ZK,48)-1 (3,3-d ifluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl] - 6-ethyl-2fluorobenzamide Et 1—V ^F L/F 587.0 1.86 (4) 744 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-6-ethyl-2-fluoroΝ-[(3Κ,48)-4-φτορ -1-(2fluorobenzoyl)pyrrolidin-3yl]benzamide Et % 577.1 1.8 (3) 745 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl )butanoyl]pyrrolidi n-3-yl]-6-methylbenzamide Me Me Zh F ₃ C ^0H 595.3 1.63 (3) 746 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3R,48)-4-fluoro-1 - (4,4,4-trifluoro-3 hydroxy-3methylbutanoyl)pyrrolide in-3-yl]-6methylbenzamide Me Me 595.0 1.6 (3)

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747 748 749 750 751 752 753 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]τpiazin-7-yl]-2-φτop-N[(ЗR,4S)-4-φτop-l- (lφτopcyclopropanκarbonyl)pyrpolide in-3-yl]-6-methylbenzamide LP [(3^48)-4-fluoro-1-(3methylbutanoyl)pyrrolide in-3-yl]-6methylbenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4 ]triazin-7-yl]-2-fluoro-BP [(3^48)-4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin n-3-yl]-6-methylbenzamide 3-[4-amino-5(trifluoromethyl )pyrrolo[2,1f][1,2,4]triazin-7-yl]-Ni(3^48)-1(3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2-fluoro-6methylbenzamide 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-M[(3R,4 8)-4-fluoro-1 -(3,3,3 -trifluoro-2 methylpropanoyl)pyrrolidin-3 -yl] 6-methylbenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazine-7 -yl]-2-fluoro-M[(3^48)-4-fluoro-1 -(4,4,4-trifluoro-3 methylbutanoyl)pyrrolide in-3 -yl]-6methylbenzamide 3-[4-amino- 5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(ЗR,4S)-4-φτop-l-(2-φτo p-2methylpropanoyl)pyrrolidin-3 -yl]6-methylbenzamide Me Me Me Me Me Me Me xX Me ^^^Me 4- F X^Me F ₃ C Me X^Me Me ^F 527.3 525.3 541.3, 541.3 559.3 565.1 579.3 529.1 1.57 (3) 1.6 (3) 1.53, 1.56 (4) 1.59 (3) 1.65 (4) 1.72 (3) 1.56 (3) 754 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M-[(3 R,4S)-I (2,2-difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl] - 2-fluoro-6methylbenzamide Me jF A_VF 545.2 1.57 (4)

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755 756 757 758 759 760 761 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-M-[(3 R,4S)-I (4,4-difluorocyclohexanecarbonyl)- 4fluoropyrrolidin-3-yl]-2-fluoro-6methylbenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1- f] [1,2,4]triazin-7-yl]-2-fluoro-M[(3K,48)-4-fluoro-1-(2fluorobenzoyl)pyrrolidin-3-yl]-6methylbenzamide 3-[4- amino-5(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazin-7-yl]-2-fluoro-X[(ZK,48)-4-fluoro-1-(2-hydroxy-2methylpropanoyl)pyrrole idin-3-yl] 6- methylbenzamide 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-2-fluoro-X- [(3Κ,48)-4-φτορ-1-[(2Κ)-3,3,3- trifluoro-2-hydroxy-2-methylpropanoyl] pyrrolidin-3 -yl] 6-methylbenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-2- fluoro-X[(ZK,48)-4-fluoro-1-[4,4,4-trifluoro-3hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin n-3-yl]-6-methylbenzamide 3-[4-amino -5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-2-fluoro-X- [(3R,48)-4-fluoro-1-(3,3,3trifluoropropanoyl)pyrrolide in-3yl]-6-methylbenzamide 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1, 2,4]triazin-7-yl]-2-fluoro-X[(ZK,48)-4-fluoro-1-[4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin n-3-yl ]-6-methylbenzamide Me Me Me Me Me Me Me X f X / And /. c 3 ^ω J ¹ O O « ΤΙ I O / \ N N “G W -η -η ω ω and and 587.4 562.9 527.3 581.3 649.2 551.0 633.3 1.74 (3) 1.66 (3) 1.37 (4) 1.63 (3) 1.96 (4) 1.66 (4) 1.86 (3) 762 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-X-[(3K,48)-1 (3,3-d ifluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl]-2 -fluoro-6methylbenzamide Me /A/ X/F 573.3 1.67 (4)

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763 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M-[(3 R,4S)-I cyclobutanecarbonyl-4fluoropyrrolidin-3-yl ]-2fluorobenzamide H 509.0 1.54 (1) 764 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1- (3methylbutanoyl)pyrrolidin-3yl]benzamide H Me 511.2 1.67 (2) 765 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(ZK,48)-1 (2,2-dimethylpropanoyl)- 4fluoropyrrolidin-3-yl]-2fluorobenzamide n X^Me A Me Me 511.1 1.61 (1) 766 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1- (4fluorobenzoyl)pyrrolidin-3yl]benzamide n 549.3 1.7 (2) 767 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1- (2fluorobenzoyl)pyrrolidin-3yl]benzamide n ύ 549.1 1.68 (2) 768 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-M-[(ZK,48)-1 (3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2fluorobenzamide n Ή- F 545.1 1.65 (2) 769 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1- (2-fluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide n X^Me Me ^F 515.3 1.62 (2) 770 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1 - (3,3,3-trifluoro-2,2dimethylpropanoyl)pyrrolidin-3yl]benzamide n X^Me Me ^CF 3 565.3 1.82 (2)

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771 3-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3K,48)-4-fluoro-1- (3fluorocyclobutanecarbonyl)pyrrolidi n-3-yl]benzamide H ^^^F 527.3, 527.3 1.48 (1) 772 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-K-[(ZK,48)-1 (3,3-d ifluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl] - 2fluorobenzamide H —V ^F V/ ⁴ F 559.3 1.62 (1) 773 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X-[(3K,48)-1 (2,2-difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-2fluorobenzamide n . F KXf 531.0 1.59 (1) 774 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-fluoro-X[(3Κ,48)-4-φτορ-1- [(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide n X^cf ₃ *oh 567.3 1.57 (2)

Connections in the table. 40 was obtained by the methods detailed in examples 562 and 568. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 40

Example Name ^{R1 R2} Ion mass observed in MC RT (Method) 775 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4diφτop-N-[(ЗR,4S)-4-φτop-l (3,3,3trifluoropropanoyl)pyrrolidin3-yl]benzamide F ?^CF ₃ 555.3 1.8 (3) 776 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2,4difluoro-H-[(3A48)-4-fluoro-1 -( 2hydroxy-2methylpropanoyl)pyrrolide in-3yl]benzamide F X^Me ΜθθΗ 531.1 1.57 (4) 777 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3A48)-4-fluoro-1 -( 3 methylbutanoyl)pyrrolide in-3 yl]benzamide F me ^?? ^ ^h Me 529.3 1.79 (4) 778 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3A48)-4-fluoro-1 -( 3 fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide F 545.3 1.70 (4) 779 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3A48)-4-fluoro-1 -( 1 fluorocyclopropanecarbonyl)pyrr olid in-3-yl]benzamide F xXz 531.2 1.92 (3) 780 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidine- 3 -yl]-2,4difluorobenzamide F F 563.1 1.79 (4) 781 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4diφτop-N-[(ЗR,4S)-4-φτop-1 -[2hydroxy-2(trifluoromethyl)butanoyl]pyrrole idin-3-yl]benzamide F Me Th F ₃ C ^0H 599.1 1.93 (4)

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782 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4d πφτορ-Ν-[(3^48)-4-fluoro- 1-(2fluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide F X^Me Me 533.1 1.81 (4) 783 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-N-[(3K,48)-4-fluoro-1 [4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]benzamide F CF ₃ CF ₃ 637.2 2.22(4) 784 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3^48)-4-fluoro-1 [4,4,4-trifluoro-3-hydroxy-3 (trifluoromethyl)butanoyl]pyrrole idin-3-yl]benzamide F _CF3A ? _CF3 653.0 2.14(3) 785 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-N-[(3K,48)-4-fluoro-1 (4,4,4-trifluoro-3methylbutanoyl)pyrrolide in-3yl]benzamide F Me 583.0 1.89 (4) 786 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3^48)-4-fluoro-1 (4,4,4-trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolide in-3yl]benzamide F Me X J<OH CF ₃ 599.0 1.78 (4) 787 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-H-[(3^48)-4-fluoro-1 (3,3,3-trifluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide F X^Me F ₃ C 569.3 1.92 (4) 788 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-H[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine- 3 -yl]-2,4difluorobenzamide F kA F Χγ_Α ^ρ 549.2 1.71 (4)

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789 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-H[(3R,48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidine- 3 -yl]-2,4difluorobenzamide F AY A/F 577.2 1.97 (3) 790 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl]-2,4difluoro-M-[(3A48)-4-fluoro-1[( 2R)-3,3,3-trifluoro-2-hydroxy2-methylpropanoyl]pyrrolidin3-yl]benzamide F XAF _3'OH 585.3 1.69 (3) 791 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidin-3-yl]-4-fluoro2-methylbenzamide Me 523.3 1.65 (2) 792 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-R[(3A48)-4-fluoro-1-(4fluorobenzoyl )pyrrolidin-3-yl]2-methylbenzamide Me LL I 563.1 1.86 (2) 793 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-H[(3K48)-4-fluoro-1-(2methylpropanoyl )pyrrolide in-3 yl]-2-methylbenzamide Me X^Me Me 511.1 1.73(2) 794 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3A48)-4-fluoro-1-(3methylbutanoyl )pyrrolide in-3 yl]-2-methylbenzamide Me Me ^3>? ^^ ^h me 525.1 1.84 (2) 795 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,48)-1-(2,2dimethylpropanoyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methylbenzamide Me X^Me Ame Me 525.1 1.85 (2)

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796 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3R,4S)-4-φτop-l- (3,3,3trifluoropropanoyl)pyrrolidin3-yl]-2-methylbenzamide Me X^CF ₃ 551.1 1.73 (1) 797 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl]-X[(3R,4S)-1cyclopentanecarbonyl-4fluoropyrrolidin-3-yl] -4- fluoro-2methylbenzamide Me 537.4 1.75 (2) 798 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3^48)-4-fluoro-1- [1(trifluoromethyl)cyclobutanecarbonyl]pyrrolidin-3-yl]-2methylbenzamide Me Fs^O 591.2 1.81 (1) 799 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-H[(3R,4S)-4-φτop-l- [4,4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2-methylbenzamide Me _CF3 633.3 1.95 (2) 800 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R, 48)-1-(4,4difluorocyclohexanecarbonyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methylbenzamide Me Λ; 587.4 1.76 (2) 801 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-T4[(3R,4S)-4-φτop-1- (4,4,4trifluoro-3methylbutanoyl)pyrrolide in-3yl]-2-methylbenzamide Me Me ^^^SEz 579.3 1.77 (1) 802 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3R,4S)-4-φτop-l- [4,4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2-methylbenzamide Me CF ₃ xA-one CF ₃ 649.3 1.98 (1)

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803 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-p [(3K,48)-4-fluoro-1- (1hydroxycyclopentanecarbonyl)p irrolidin-3-yl]-2methylbenzamide Me 553.4 1.54 (1) 804 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-p [(3R,48)-4-fluoro-1- (1hydroxycyclobutanecarbonyl)pyrrolide in-3-yl]-2methylbenzamide Me NUTZ 539.4 1.52(2) 805 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-p [(3K,48)-4-fluoro-1- (1fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide Me 541.4 1.77 (2) 806 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-p [(ЗR,4S)-4-φτop-l- (3,3,3trifluoro-2,2dimethylpropanoyl)pyrrolidin3-yl]-2-methylbenzamide Me X^Me maz 579.2 1.79 (1) 807 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-X[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methylbenzamide Me F XXF 545.3 1.65 (2) 808 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]H[(3R,4S)-l-(2-chloro-4,5difluorobenzoyl) -4fluoropyrrolidin-3 -yl]-4-fluoro-2methylbenzamide Me & O 615.4 1.85 (4) 809 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]H[(3R,4S)-l-(2-chloro-4fluorobenzoyl)-4fluoropyrrolidine -3 -yl]-4-fluoro-2methylbenzamide Me Ll about 597.2 1.83 (4)

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810 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ZK,48)-1-(2-chloro-3fluorobenzoyl)- 4fluoropyrrolidin-3-yl]-4-fluoro-2methylbenzamide Me O 597.0 1.8 (4) 811 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-X[(ZK,48)-1-(5-cyano-2fluorobenzoyl)- 4fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide Me II N 588.2 1.76 (4) 812 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-H[(3R,48)-4-fluoro-1 - (2-methyl-1,3thiazole-4-carbonyl)pyrrolidin3-yl]-2-methylbenzamide Me 566.1 1.72 (4) 813 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-H[(3R,4S)-4-φτop-1 - (4-methyl-1,3thiazole-2-carbonyl)pyrrolidin3-yl]-2-methylbenzamide Me S' 566.2 1.85 (4) 814 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,4S)-1 -(3,4-difluorobenzoyl)4 -fluoropyrrolidin-3 -yl]-4-fluoro2-methylbenzamide Me (A F F 581.0 1.78 (4) 815 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3R,4S)-44top-1-(2 ,4,5trifluorobenzoyl)pyrrolide in-3yl]-2-methylbenzamide Me v. F 599.2 1.88 (4) 816 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-X[(3R,4S)-1 -(3,5-d iftorobenzoyl )4-fluoropyrrolidin-3 -yl]-4-fluoro2-methylbenzamide Me LL 581.0 1.87 (4)

- 275 042342

817 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3R,48)-4-fluoro-1- (3fluoropyridine-2carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me b 564.3 1.63 (4) 818 5-[4-amino-5(trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]-M[(3R,4S)-1 -(4-chloropyridine-3 carbonyl)-4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me Cl% 580.2 1.58 (4) 819 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]-M[(3R,48)-1-(3,5-difluoropyridine2-carbonyl )-4-fluoro-pyrrolidin3-yl]-4-fluoro-2-methylbenzamide Me F /ίη ν F 582.1 1.64 (4) 820 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3K,48)-4-fluoro-1- (5-Fluoro-2methylpyridine-4carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me 578.3 1.66 (4) 821 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3K,48)-4-fluoro-1- (5fluoropyridine-2carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me N. F 564.1 1.65 (4) 822 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3^48)-4-fluoro-1- (4fluoropyridine-2carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me At 564.2 1.65 (4) 832 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3R,4S)-4-φτop-1- (2,4,6trifluorobenzoyl)pyrrolide in-3yl]-2-methylbenzamide Me FjS 599.2 1.81 (4)

- 276 042342

824 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 ί][1,2,4]τρΗΒ3ΐΐΗ-7-Ηπ]-Ν[(3R,48)-1-(2-chlorobenzoyl)-4fluoropyrrolidin-3-yl]-4-fluoro -2methylbenzamide Me CI b 579.2 1.75 (3) 825 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.1 £][1.2.4]triazin-7-yl]-X[(ZK,48)-1-(2-chloro-6fluorobenzoyl)- 4fluoropyrrolidin-3-yl]-4-fluoro-2methylbenzamide Me CI 597.1 1.86 (4) 826 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro^[(3K,48)-4-fluoro-1-( 3fluorobenzoyl)pyrrolidin-3-yl]2-methylbenzamide Me at F 563.1 1.84 (4) 827 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-M[(ZK,48)-1-(4-chlorobenzoyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methylbenzamide Me V 579.1 1.83 (4) 828 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3R,48)-4-fluoro-1 - (pyridine-2carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me 546.2 1.57 (4) 829 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3R,48)-4-fluoro-1 - (pyridine-4carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me % 546.3 1.31 (3) 830 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-X[(3R,4 S)-1 -(2,5-d iftorobenzoyl )4-fluoropyrrolidin-3 -yl]-4-fluoro2-methylbenzamide Me Λ F 581.2 1.75 (4)

- 277 042342

831 5-[4-amino-5(trifluoromethyl)pyrrolo[2.1 £][1.2.4]triazin-7-yl]-Ch- [(3K,48)-1-(2,6-difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro2-methylbenzamide Me F JM 581.0 1.81 (4) 832 5-[4-amino-5- (trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]-M[(3R,48)-1-(2,4-difluorobenzoyl)4-fluoropyrrolidin-3 -yl] - 4-fluoro2-methylbenzamide Me F (A^^F 581.1 1.79 (4) 833 834 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-4-fluoro-Ch[(3 R,4 8)-4-fluoro-1 -(1,3-thiazole -4carbonyl)pyrrolide in-3 -yl] -2methylbenzamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]-4-fluoro-X[(3>48)-4-fluoro-1-(3fluoropyridine-4carbonyl)pyrrolide in- 3 -yl]-2methylbenzamide Me Me b s 552.2 564.3 1.62 (4) 1.61 (4) 835 5-[4-amino-5(trifluoromethyl)pyrrolo[2.1 G][1.2.4]triazin-7-yl]-M[(3R,4 S)-1-(3,5-difluoropyridine4- carbonyl)-4-fluoropyrrolidin3-yl]-4-fluoro-2-methylbenzamide Me F fan 582.2 1.67 (3) 836 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-X[(3R, 48)-1-(2,3-difluorobenzoyl)4-fluoropyrrolidin-3-yl] -4-fluoro2-methylbenzamide Me A 581.2 1.84 (4) 837 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-4-fluoro-M[(3>48)-4-fluoro-1- (2methylpyridine-4carbonyl)pyrrolide in-3-yl]-2methylbenzamide Me 560.2 1.59 (4)

- 278 042342

838 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,4S)-1 -(3-chloro pyridine-4carbonyl )-4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me CI 580.2 1.56 (3) 839 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-T4[(3A48)-4-fluoro-1-(4methylpyridine -2carbonyl)pyrrolide in-3 -yl]-2methylbenzamide Me O 560.1 1.63 (4) 840 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-M[(3R,4 S)-1 -(2,5-dimethyl- 1,3thiazol-4-carbonyl)-4fluoropyrrolidin-3-yl]-4-fluoro-2methylbenzamide Me 41 580.3 1.7 (4) 841 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-M[(3R,4S)-1 -(3-chloropyridine-2carbonyl)- 4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me Cl b 580.2 1.83 (4) 842 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3A48)-4-fluoro-1-(6methylpyridine -2carbonyl)pyrrolide in-3 -yl]-2methylbenzamide Me 560.3 1.71 (4) 843 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-T4[(3A48)-4-fluoro-1-[5 (trifluoromethoxy)pyridine-2carbonyl]pyrrolide in-3-yl]-2methylbenzamide Me NX OCF ₃ 630.2 1.92 (4) 844 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]-M[(3R,4S)-l-(6-6poMnHpHflHH-2carbonyl)- 4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me / Br 623.9 1.75 (3)

- 279 042342

845 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,4S)-l-(5-6poM-3fluoropyridin-2 -carbonyl)-4fluoropyrrolidin-3 -yl]-4-fluoro-2methylbenzamide Me CD -5 642.2 1.79 (4) 846 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-L1[(3N48)-4-fluoro-1-[3 (trifluoromethyl)pyridine-2carbonyl]pyrrolidin-3-yl]-2methylbenzamide Me _CF3 614.3 1.71 (4) 847 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f][ 1,2,4]triazin-7-yl]-H[(3R,4S)-1-(6-6 _P om-5fluoropyridine -2-carbonyl)-4fluoropyrrolidin-3 -yl]-4-fluoro-2methylbenzamide Me LL 642.2 1.88 (4) 848 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl]-4-fluoro-X [(3R,4S)-44to _P -1-[ 6(trifluoromethyl)pyridine-2carbonyl]pyrrolide in-3-yl]-2methylbenzamide Me ^j1 614.3 1.88 (4) 849 5-[4-Amino-5(trifluoromethyl)pyrrolo[2.1 G][1,2,4]triazin-7-yl]^[(3R,4S)-1 -(4-chloropyridine-2carbonyl)-4 -fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me % O 580.0 1.69 (3) 850 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X [(3R,4S)-4-φτop-l- [3-φτop-5(trifluoromethyl)pyridine-2carbonyl]pyrrolide in-3-yl]-2methylbenzamide Me LL? about U—/H 632.0 1.79 (3) 851 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(ЗR,4S)-l-(5-chloroπpiridine-2carbonyl)- 4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me 580.3 1.79 (4)

- 280 042342

852 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-H[(3R,4S)-1 -(6-chloropyridine-2carbonyl)-4 -fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me CI 580.2 1.78 (4) 853 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-M[(3R,4S)-l-[6-xlop-3(trifluoromethyl )pyridine-2carbonyl]-4-fluoropyrrolidin-3yl]-4-fluoro-2-methylbenzamide Me CF ₃ Cl 648.2 1.87 (4) 854 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-H[(3R,4S)-1-(3-bromopyride in-2carbonyl) -4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me Br b 624.0 1.65 (4) 855 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3^48)-4-fluoro-1- [4(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2methylbenzamide Me A 614.1 1.68 (4) 856 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3R,4S)-4-φτop-1- (4,4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolide in-3yl]-2-methylbenzamide Me Me CF ₃ 594.9 1.77 (2) 857 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3A48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl)butanoyl ]pyrrole idin-3-yl]-2-methylbenzamide Me ?V ^CF 3 /OH Me 595.1 1.85 (2) 858 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3M8)-4-φτορ-1-(3 ,3,3trifluoro-2methylpropanoyl)pyrrolide in-3yl]-2-methylbenzamide Me /yMe F ₃ C 565.3 1.79 (2)

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859 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-X[(3R,48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methylbenzamide Me AA F 573.1 860 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-X[(3R,48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoro pyrrolidine -3 -yl]-4-fluoro-2methylbenzamide Me AA F 573.1 861 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl]-M[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine-3 -yl]-4-fluoro-2methylbenzamide Me . FXAf 545.1 862 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl]-M[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine-3 -yl]-4-fluoro-2methylbenzamide Me l F 545.2 863 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro^[(3R,48)-4-fluoro-1-(2 ,3,3,3tetrafluoro-2methylpropanoyl)pyrrolide in-3yl]-2-methylbenzamide Me X^Me F ₃ CF 583.4 1.96 (4) 864 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11'][1,2,4]triazin-7-yl]-M[(3R,4S)-1-(6-chloropyridazine-3 carbonyl) -4-fluoropyrrolide in-3 yl]-4-fluoro-2-methylbenzamide Me 581.2 1.65 (4) 865 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-b>T[(3K,48)-4-fluoro-1-(pyridazin-3carbonyl)pyrrolide in -3 -yl] -2methylbenzamide Me b 547.1 1.51 (4)

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866 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3A48)-4-fluoro-1-(6methylpyridazine -3 carbonyl)pyrrolide in-3 -yl] -2methylbenzamide Me 561.2 1.46 (3) 867 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3Κ,48)-4-φτορ-1- [(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxybenzamide OME Y/CF3 * HE 597.3 1.7 (2) 868 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3K,48)-4-fluoro-1 - (2-fluoro-2methylpropanoyl)pyrrolide in-3yl]-2-methoxybenzamide OME X^Me Me ^F 545.1 1.9 (2) 869 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M[(3R,48)-1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methoxybenzamide OME . F 561.3 1.68 (1) 870 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3Κ,48)-4-φτορ-1- (3,3,3trifluoro-2,2dimethylpropanoyl)pyrrolidin3-yl]-2-methoxybenzamide OME X^Me Me ^CF 3 595.3 1.96 (2) 871 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 £][1,2,4]triazin-7-yl]-X[(3R, 48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidine- 3 -yl]-4-fluoro-2methoxybenzamide OME Ύ' 589.3 1.78 (1) 872 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3A48)-4-fluoro-1-(3fluorocyclobutanecarbonyl )pyrrolidin-3-yl]-2-methoxybenzamide OME 557.4 1.73 (1)

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873 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-R[(3K,48)-4-fluoro-1- (4fluorobenzoyl)pyrrolidin-3 -yl] 2-methoxybenzamide OME I, 579.0 1.79 (1) 874 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3Κ,48)-4-φτορ-1- (3,3,3trifluoropropanoyl)pyrrolidin3-yl]-2-methoxybenzamide OME 567.3 1.75 (2) 875 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3K,48)-4-fluoro-1-( 4,4,4trifluoro-3methylbutanoyl)pyrrolide in-3yl]-2-methoxybenzamide OME Me 595.1 1.98 (4) 876 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-M[(3K,48)-4-fluoro-1-[ 4,4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2-methoxybenzamide OME CF ₃ ^^CFg 649.0 2.06 (4) 877 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3K,48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl) butanoyl]pyrrole idin-3-yl]-2-methoxybenzamide OME Me Vh F ₃ C ^0H 611.0 1.91 (4) 878 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-X[(3Κ,48)-4-φτορ-1-( 3,3,3trifluoro-2methylpropanoyl)pyrrolide in-3yl]-2-methoxybenzamide OME /yMe F ₃ C 581.2 1.9 (4) 879 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-4-fluoro-R[(3K,48)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolide in-3yl]-2-methoxybenzamide OME Me CF ₃ 611.4 1.82 (4)

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880 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτop-N-[(ЗR,4S)-4-φτop -l-[2hydroxy-2(trifluoromethyl)butanoyl]pyrrole idin-3-yl]benzamide C1 Me A F ₃ C ^0H 614.9 1.79 (2) 881 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτορ-Ν-[(3Κ,48)-4-φτορ -1-(4,4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolide in-3yl]benzamide C1 Me/RON CF ₃ 615.2 1.83 (2) 882 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1] [1,2,4]triazin-7-yl]-2-chloro-4φτορ-Ν-[(3Κ,48)-4-φτορ-1-[4,4, 4trifluoro-3- (trifluoromethyl)butanoyl]pyrrole idin-3-yl]benzamide C1 CF ₃ ^^CFs 653.2 2.05(2) 883 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτop-N-[(ЗR,4S)-4-φτop-l-(4,4, 4trifluoro-3methylbutanoyl)pyrrolidin-3yl]benzamide C1 Me ^^^CFs 599.2 1.97 (2) 884 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτop-N-[(ЗR,4S)-4-φτop -l-(3,3,3trifluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide C1 /yMe F ₃ C 585.1 1.89 (2) 885 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτορ-Ν-[(3Κ,48)-4-φτορ -1-[4,4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrole-idin-3-yl]benzamide C1 CF ₃ Q J<OH CF ₃ 669.3 2.03(2) 886 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-2-chloro-X[(3R, 48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl] -4fluorobenzamide C1 F 593.1 1.71 (3) 887 888 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 L][1,2,4]triazin-7-yl]-2-chloro-LP [(3R, 48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl] -4fluorobenzamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-4φτορ-Ν-[(3^48)-4-φτορ-1-(3fluorocyclobutanecarbonyl)pyrrolidine -3 -yl]benzamide C1 C1 A/ ⁴ _F 4 593.2 561.0 1.71 (3) 1.73 (4) 889 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-4-fluoro^[(3^48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl) butanoyl]pyrrole idin-3-yl]benzamide n Me F^ ^H 581.0 1.74 (2)

Connections in the table. 41 was obtained by the methods detailed in examples 31, 562, 566 and 567. When the diastereomers were separated, they were included as separate data. If the stereochemistry was not determined, the compound was isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

Table 41

Example Name ^{R1 R2} Ion mass observed by HMS RT (Method) 890 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(1fluorocyclopropanecarbonyl) pyrrolidin-3 -yl]-2(trifluoromethyl)benzamide _CF3 563.3 1.82 (4) 891 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(trifluoromethyl)benzamide _CF3 CF ₃ C-oh CF ₃ 685.2 2.07(3) 892 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolide in-3 -yl] 2-(trifluoromethyl)benzamide _CF3 Sa-f F 595.1 1.81 (3) 893 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl) p irrolidin-3 -yl]-2(trifluoromethyl)benzamide _CF3 577.3, 577.3 1.75, 1.77 (4) 894 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(2- fluoro2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethyl)benzamide _CF3 X^Me Me ^F 565.3 1.79 (4) 895 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidin -3-yl]-2(trifluoromethyl)benzamide _CF3 Me 615.3 1.88 (3) 896 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolide in-3 - yl]-2(trifluoromethyl)benzamide _CF3 j F X-Vf 581.3 1.73 (4)

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897 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(2hydroxy- 2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethyl)benzamide _CF3 X^Me m? ^Oh 563.3 1.61 (3) 898 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidine -3-yl]-2(trifluoromethyl)benzamide _CF3 Me L--OH CF ₃ 631.3 1.80 (4) 899 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(trifluoromethyl)benzamide _CF3 Me Uh F ₃ C ^0H 631.3 1.82 (4) 900 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-H[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(trifluoromethyl)benzamide _CF3 I—V ^F AX F 609.3 1.88 (4) 901 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]^[(3Κ,48)-4-φτορ-1-(3,3 ,3trifluoropropanoyl)pyrroli din-3-yl]-2(trifluoromethyl)benzamide _CF3 X^CF ₃ 587.3 1.74 (4) 902 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3R,48)-4-fluoro-1-(3methylbutanoyl) pyrrolidine -3-yl]-2(trifluoromethyl)benzamide _CF3 Me 561.1 1.8 (4)

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903 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(trifluoromethyl)benzamide _CF3 T J < ^F 623.1 1.87 (3) 904 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-4^to _P -1-[( 2R)3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]-2(trifluoromethyl)benzamide _CF3 A/CF ₃ * bn 617.3 1.74 (4) 905 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-[4,4, 4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(trifluoromethyl)benzamide _CF3 CF ₃ ^^CF, 669.2 2.07 (4) 906 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-(2fluorobenzoyl) pyrrolidin-3 yl]-2(trifluoromethyl)benzamide _CF3 τί 599.0 1.81 (4) 907 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-(3,3, 3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethyl)benzamide _CF3 X^Me F ₃ C 601.0 1.82 (4) 908 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(2hydroxy- 2methylpropanoyl)pyrrolidi n-3-yl]-2(fluoromethyl)benzamide CH ₂ F X^Me Xnui Me ^OH 527.3 1.46 (4)

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909 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3K48)-4-fluoro-1-(3methylbutanoyl)pyrrolidine -3-yl]-2(fluoromethyl)benzamide ch ₂ f Me 525.1 1.72 (3) 910 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-4^to _P -1-[( 2R)3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]-2(fluoromethyl)benzamide ch ₂ f X/ _CF3 *OH 581.2 1.67 (4) 911 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3 -yl] 2-(fluoromethyl)benzamide ch ₂ f F 559.3 1.68 (4) 912 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-Ni[(3K,48)-4-fluoro-1-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(fluoromethyl)benzamide ch ₂ f cf ₃ + r ₃ 649.1 2.03 (4) 913 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(2fluorobenzoyl) pyrrolidin-3 yl]-2-(fluoromethyl)benzamide ch ₂ f ύ 563.1 1.75 (3) 914 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolide in-3 yl]-2-(fluoromethyl)benzamide ch ₂ f j F XbF 545.1 1.58 (3)

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915 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-R[(ZA48)-4-fluoro-1-[4,4, 4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(fluoromethyl)benzamide ch ₂ f CF ₃ ^^ Cr3 633.1 1.99 (4) 916 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-T4[(ZA48)-4-fluoro-1-(1fluorocyclopropanecarbonyl)pyrrolidine- 3 -yl]-2(fluoromethyl)benzamide ch ₂ f fSz 527.1 1.66 (4) 917 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidin -3-yl]-2(fluoromethyl)benzamide ch ₂ f Me ^^^CFs 579.3 1.8 (4) 918 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)- 4-fluoropyrrolidin-3 -yl] 2-(fluoromethyl)benzamide ch ₂ f T Yf F 587.3 1.71 (3) 919 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4S)-4^Top-l-(4, 4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidine -3-yl]-2(fluoromethyl)benzamide ch ₂ f Me / L-OH CF ₃ 595.2 1.66 (3) 920 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4[(3R, 48)-1-(3,3difluorocyclopentanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(fluoromethyl)benzamide ch ₂ f A/FA/ ⁴ f 573.2 1.69 (3)

- 290 042342

921 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3Κ,48)-4-φτορ-1-(3, 3,3trifluoropropanoyl)pyrroli din-3-yl]-2(fluoromethyl)benzamide ch ₂ f ?^CF ₃ 551.0 1.65 (3) 922 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(fluoromethyl)benzamide ch ₂ f Me F ₃ C ^0H 595.3 1.76 (3) 923 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-H[(3K,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl) p irrolidin-3 -yl]-2(fluoromethyl)benzamide ch ₂ f 4 541.4 1.64 (3) 924 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3Κ,48)-4-φτορ-1-(3, 3,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2(fluoromethyl)benzamide ch ₂ f X^Me F ₃ C 565.1 1.69 (3) 925 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-N-[(3K,48)-4-fluoro-1( sfluorocyclobutanecarbonyl)p irrolidin-3-yl]benzamide Cl 543.2, 543.3 1.67, 1.70 (2) 926 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-N-[(3K,48)-4-fluoro-1[ 4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide Cl _CF3 635.2 2.02(2)

- 291 042342

927 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloroA[(ZI.,48)-4-fluoro-1[2- hydroxy-2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide C1 Me An F ₃ C ^0Н 597.2 1.8 (2) 928 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-A[(3K,48)-4-fluoro-1(3 ,3,3trifluoropropanoyl)pyrroli din-3-yl]benzamide C1 X^CF ₃ 553.2 1.71(2) 929 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloroA-[(3K,48)-4-fluoro-G(2- hydroxy-2methylpropanoyl)pyrrolidi n-3-yl]benzamide C1 X^Me Me^ ^H 529.0 1.52 (2) 930 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-A[(3K,48)-1-(3,3difluorocyclopentanecarbonyl) )-4-fluoropyrrolidin-3 yl]benzamide C1 1—V ^F A/ ⁴ f 575.2 1.81 (2) 931 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-LC(3K,48)-4-fluoro-1[4, 4,4-trifluoro-3-hydroxy3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide C1 CF ₃ N- 3 651.1 2.07(2) 932 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-A[(3K,48)-4-fluoro-1(2fluorobenzoyl )pyrrolidin-3 yl]benzamide C1 ύ 565.0 1.79 (2)

- 292 042342

933 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2χπορ-Ν-[(3Κ,48)-4-φτορ-1( 2-fluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide C1 X^Me Me ^F 531.0 1.77 (2) 934 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2xlor-N-[(ЗR,4S)-4-φτop-l( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide C1 / ^X7 529.2 1.75 (2) 935 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2χπορ-Ν-[(3^48)-4-φτορ-1[ (2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]benzamide C1 ?</CF ₃ *EN 583.2 1.72 (2) 936 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2xlor-N-[(ЗR,4S)-4-φτop-l( 4,4,4-trifluoro-3-hydroxy3methylbutanoyl)pyrrolidin-3-yl]benzamide C1 Me ΑΛϊ urz 597.2 1.78 (2) 937 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2xlor-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbon yl)-4-fluoropyrrolide in-3 yl]benzamide C1 F Xj/F 547.2 1.71(2) 938 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3P,48)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3 yl]benzamide C1 T Lf 589.2 1.83 (2)

- 293 042342

939 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1( 3methylbutanoyl)pyrrolidin-3-yl]benzamide C1 Me ^^^^Me 527.3 1.79 (2) 940 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1( 3,3,3-trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide C1 X^/Me F ₃ C 567.2 1.8 (2) 941 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1( 4,4,4-trifluoro-3methylbutanoyl)pyrrolidin-3-yl]benzamide C1 Me ^^^CFs 581.2 1.9 (2) 942 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3R,48)-1-(3,3difluorocyclobutanecarbonyl)- 4-fluoropyrrolidin-3 yl]benzamide C1 F 561.2 1.76 (2) 943 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1[ 4-(trifluoromethyl)pyridine2-carbonyl]pyrrolidin-3yl]benzamide C1 ΟP 616.2 1.85 (3) 944 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3R,48)-1-(2,4difluorobenzoyl)- 4fluoropyrrolidin-3 yl]benzamide C1 P 583.1 1.79 (3)

- 294 042342

945 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3K,48)-1-(3,5difluoropyridine-2carbonyl )-4fluoropyrrolidin-3 yl]benzamide C1 F ιίη N F 584.0 1.7 (4) 946 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-X-[(3K,48)-4-fluoro-1( 1,3-thiazole-4carbonyl)pyrrolide in-3yl]benzamide C1 b S 554.2 1.55 (4) 947 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3K, 48)-1-(4chlorobenzoyl)-4fluoropyrrolidine- 3 yl] benzamide C1 % O 580.9 1.84 (4) 948 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(ZK, 48)-1-(3,4difluorobenzoyl)- 4fluoropyrrolidin-3 yl]benzamide C1 (A F 583.3 1.81 (3) 949 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-X-[(3K,48)-4-fluoro-1( 3-fluoropyridine-2carbonyl)pyrrolide in-3yl]benzamide C1 ύ 566.1 1.49 (3) 950 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-X-[(3K,48)-4-fluoro-1( pyridine-4carbonyl)pyrrolide in-3yl]benzamide C1 % 548.1 1.5 (4) 951 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-X-[(3K,48)-4-fluoro-1( sfluorobenzoyl)pyrrolidin-3yl]benzamide C1 '4 F 565.3 1.92 (4)

- 295 042342

952 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-N-[(3R,48)-4-fluoro-1( 4fluorobenzoyl)pyrrolidin-3yl]benzamide C1 565.2 1.73 (4) 953 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-N-[(3R,48)-4-fluoro-1[ 4-(trifluoromethyl)pyridine3-carbonyl]pyrrolidin-3yl]benzamide C1 _CF3 615.9 1.65 (3) 954 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-1-benzoyl-4fluoropyrrolidin-3-yl ]-2chlorobenzamide C1 Ό 547.0 1.75 (4) 955 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3R,48)-1-(3,5difluoropyridine-4carbonyl )-4fluoropyrrolidin-3 yl]benzamide C1 F _f *Yn 584.1 1.62 (4) 956 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1( pyridine-2carbonyl)pyrrolide in-3yl]benzamide C1 I 548.1 1.48 (3) 957 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3R,48)-1-(2,5difluorobenzoyl)- 4fluoropyrrolidin-3 yl]benzamide C1 -i F 583.1 1.79 (3) 958 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-M-[(3K,48)-4-fluoro-1( 5-Fluoropyridine-2carbonyl)pyrrolide in-3yl]benzamide C1 /ΓΥ Ν V. F 565.8 1.78 (4)

- 296 042342

959 960 961 962 963 964 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-Ni(3K,48)-1-(4chloropyridine-3- 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2chloro-T4-[(3K ,48)-4-fluoro-1(2-methylpyridine-4carbonyl)pyrrolide in-3yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine -7-yl]-2chloro-T4-[(ZK,48)-4-fluoro-1(3-fluoropyridine-4carbonyl)pyrrolide in-3yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2 ,1 -f] [1,2,4]triazin-7-yl]-2chloro-Ni(ZK, 48)-1-(4chloropyridine-2-carbonyl)4-fluoropyrrolidin-3 yl]benzamide 5-[4- amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2chloro-Ni(3K, 48)-1-(2chlorobenzoyl)-4fluoropyrrolidin-3yl]benzamide 5 -[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2chloro-Ni(3K,48)-1-(2,6difluorobenzoyl)-4fluoropyrrolidine -3 yl]benzamide C1 C1 C1 C1 C1 C1 Cl VR Cl X F F^X 582.2 562.0 566.2 582.2 580.9 583.2 1.55 (4) 1.57 (4) 1.53 (4) 1.74 (4) 1.77 (4) 1.74 (4) 965 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-T4-[(ZK,48)-4-fluoro-1 ( 2-fluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide Et X^Me mX 525.4 1.71 (3)

- 297 042342

966 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-G4-[(3R,48)-4-fluoro-1 [4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide Et _CF3 629.3 2.00 (3) 967 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2ethyl-N-[(ZK,48)-4-fluoro-1 [ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide Et Me Ah F ₃ C ^0H 591.3 1.84 (4) 968 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3-yl]2-ethylbenzamide Et F 555.3 1.80 (4) 969 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-G4-[(ZK,48)-4-fluoro-1 ( sfluorocyclobutanecarbonyl)p irrolidin-3-yl]benzamide Et 4 537.4, 537.4 1.62, 1.65 (3) 970 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-Н-[(3K,48)-4-fluoro-1 ( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide Et eAz 523.3 1.79 (4) 971 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-G4-[(ZK,48)-4-fluoro-1 ( 4,4,4-trifluoro-3methylbutanoyl)pyrrolidin-3-yl]benzamide Et Me 575.3 1.93 (4) 972 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-H-[(3K,48)-4-fluoro-1[ 4,4,4-trifluoro-3-hydroxy3(trifluoromethyl)butanoyl] pyrrolide in-3-yl] benzamide Et CF ₃ X>° ^H Uh 3 645.2 2.14(4)

- 298 042342

973 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl l)- 4-Fluoropyrrolidin-3-yl]2-ethylbenzamide Et T Lf 583.0 1.83 (3) 974 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-1-(3,3difluorocyclopentanecarbonyl)- 4-fluoro-pyrrolidin-3-yl]2-ethylbenzamide Et F 569.0 1.87 (4) 975 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-N-[(ЗR,4S)-4-φτop-1 ( 4,4,4-trifluoro-3-hydroxy- 3- methylbutanoyl)pyrrolidin-3-yl]benzamide Et Me XA™ UI-3 591.2 1.85 (4) 976 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2ethyl-L-[(3E,48)-4-fluoro-1[ (2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]benzamide Et ? _OCF3'OH 577.0 1.79 (4) 977 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-H-[(3^48)-4-fluoro-1 ( 3,3,3-trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide Et XyMe F ₃ C 561.2 1.80 (4) 978 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-N-[(ЗR,4S)-4-φτop-1 ( 3methylbutanoyl)pyrrolidin-3-yl]benzamide Et Me 521.1 1.84 (4)

- 299 042342

979 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-Fluoropyrrolide in-3 yl]-2-ethylbenzamide Et _? FK/F 541.2 1.75 (4) 980 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-T4-[(ZA48)-4-fluoro-1(2- hydroxy-2methylpropanoyl)pyrrolidi n-3-yl]benzamide Et X^Me 523.0 1.54 (3) 981 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-T4-[(ZA48)-4-fluoro-ΙΟ,3, 3trifluoropropanoyl)pyrroli din-3-yl]benzamide Et X^CF ₃ 547.2 1.76 (4) 982 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethyl-H-[(3A48)-4-fluoro-1(2fluorobenzoyl) pyrrolidin-3 yl]benzamide Et % 559.2 1.81 (3) 983 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K[(3R,4S)-4-φτop-l-(lfluorocyclopropanecarbonyl) pyrrolidin-3-yl]-2methylbenzamide Me 509.3 1.65 (3) 984 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methylbenzamide Me Me % F ₃ C ^0H 576.9 1.73 (4) 985 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-K[(3A48)-4-fluoro-1-(3D3trifluoropropanoyl)pyrrolidine -3-yl]-2-methylbenzamide Me 4/ _CF3 533.3 1.62 (3)

- 300 042342

986 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-1-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3-yl]2-methylbenzamide Me ^F 541.1 1.65 (3) 987 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolidin-3 yl]-2-methylbenzamide Me To? ^F Ar 527.3 1.60 (3) 988 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3K,48)-4-fluoro-1-(2hydroxy- 2methylpropanoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me mA 509.3 1.44 (4) 989 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-Fluoropyrrolidin-3-yl]2-methylbenzamide Me A/ ^4F 554.9 1.68 (3) 990 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)- 4-Fluoropyrrolidin-3-yl]2-methylbenzamide Me t X ^F 568.9 1.70 (3) 991 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(3methylbutanoyl) pyrrolidin -3-yl]-2-methylbenzamide Me Me ^^^^^Me 507.3 1.71 (4) 992 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-Ni[(3R,48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidin -3-yl]-2-methylbenzamide Me Me 561.4 1.79 (3)

- 301 042342

993 994 995 996 997 998 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ηπ]-Ν[(ZK,48)-4-fluoro-1-[(2K )3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin n-3-yl]-2-methylbenzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ηπ]-N[(ZK,48)-4-fluoro-1-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2methylbenzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ππ]-N[(ZK,48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ππ]-N[(ZK,48)-4-fluoro-1-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2methylbenzamide 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ππ]-N[(3K,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl) p irrolidin-3-yl]-2methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3K,48)-4-fluoro-1-(2fluorobenzoyl) pyrrolidin-3 yl]-2-methylbenzamide Me Me Me Me Me Me A/CF3 < OH CF ₃ X i-OH CF ₃ Me X_A° ^H A CF ₃ ^^CF, 4 F b 563.3 631.3 577.3 615.3 523.4, 523.4 545.3 1.63 (3) 1.98 (3) 1.71 (4) 1.95 (4) 1.57, 1.60 (3) 1.69 (3) 999 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-7-ππ]-Ν[(3Κ,48)-4-φτορ-1-(3, 3,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me X^Me F ₃ C 547.0 1.69 (3)

- 302 042342

1000 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]^[(3K,48)-4-fluoro-1-(2-fluoro2methylpropanoyl )pyrrolidi n-3-yl]-2-methylbenzamide Me X^Me m/ 511.3 1.67 (3) 1001 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]^[(3R,48)-4-fluoro-1-[4(trifluoromethyl )pyridine-2carbonyl]pyrrolidin-3yl]-2-methylbenzamide Me X about 596.0 2.01 (4) 1002 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(4fluorobenzoyl) pyrrolidin-3 yl]-2-methylbenzamide Me F 544.9 1.73 (3) 1003 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3fluorobenzoyl) pyrrolidin-3 yl]-2-methylbenzamide Me % F 545.1 1.73 (3) 1004 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]^[(3K,48)-4-fluoro-1-(1,3thiazole -4carbonyl)pyrrolidin-3 yl]-2-methylbenzamide Me hs 534.0 1.52 (4) 1005 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]^[(3R,4S)-l-(3,5difluoropyridine-4carbonyl)- 4fluoropyrrolidin-3-yl]-2methylbenzamide Me F An 564.3 1.69 (4) 1006 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3fluoropyridin- 4carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me An 546.0 1.52 (4)

- 303 042342

1007 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,5difluoropyridine-2carbonyl) -4fluoropyrrolidin-3 -yl]-2methylbenzamide Me F N. F 564.1 1.55 (3) 1008 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-l-(3,4difluorobenzoyl)-4fluoropyrrolidine -3 -yl] -2methylbenzamide Me SA F 563.2 1.78 (4) 1009 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-X[(3^48)-4-fluoro-1-[4( trifluoromethyl)pyridine-3 carbonyl]pyrrolidin-3yl]-2-methylbenzamide Me I 596.0 1.57 (3) 1010 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(3fluoropyridine- 2carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me FvS 546.2 1.46 (3) 1011 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ZK,48)-1-(4-chlorobenzoyl)4- fluoropyrrolidin-3-yl]-2methylbenzamide Me u 561.2 1.83 (4) 1012 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3^48)-4-fluoro-1-(5fluoropyridine- 2carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me N.A. F 546.2 1.59 (3) 1013 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3^48)-1-(4-chloropyridine3-carbonyl) -4fluoropyrrolidin-3 -yl]-2methylbenzamide Me I'm about 562.2 1.55 (4)

- 304 042342

1014 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(2,6difluorobenzoyl)-4fluoropyrrolidine -3 -yl] -2methylbenzamide Me FjS F^W 563.2 1.72 (4) 1015 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[(3R,4S)-l-(4-chloroπpiridine2-carbonyl) -4fluoro-pyrrolidin-3-yl]-2methylbenzamide Me O P 562.1 1.73 (3) 1016 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K- [(3R,4S)-l-(2,5- difluorobenzoyl)-4fluoropyrrolidin-3 -yl]-2methylbenzamide Me F 562.8 1.75 (3) 1017 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-1-benzoyl-4fluoropyrrolidin-3-yl ]-2methylbenzamide Me ήθ 526.9 1.69 (3) 1018 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K- [(3^48)-4-fluoro-1- (pyridine-4carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me at 528.1 1.22 (3) 1019 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M- [(3^48)-4-fluoro-1- (pyridine-2carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me b 528.1 1.45 (3) 1020 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K[(3 R, 4 8)-1-(2-chlorobenzoyl) 4-fluoropyrrolidin-3 -yl]-2methylbenzamide Me Cl b 561.3 1.86 (4)

- 305 042342

1021 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-1-(2methylpyridin- 4carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me (TV 542.0 1.21 (3) 1022 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,4difluorobenzoyl)-4fluoropyrrolidine -3 -yl] -2methylbenzamide Me On 563.1 1.86 (4) 1023 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4- [(3M8)-4-fluoro-1-(4- methylpyridine-2carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me 542.4 1.59 (3) 1024 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(ZA48)-4-fluoro-1-(2,4, 6trifluorobenzoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me -P 581.3 1.85 (4) 1025 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4S)-l-(2-xlor-4, 5difluorobenzoyl)-4fluoropyrrolidin-3 -yl]-2methylbenzamide Me o A 597.1 1.84 (3) 1026 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(ZA48)-4-fluoro-1-(2,4, 5trifluorobenzoyl)pyrrolidi n-3-yl]-2-methylbenzamide Me 580.9 1.79 (3) 1027 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-(2methoxypyride in -3 carbonyl)pyrrolide in-3 yl]-2-methylbenzamide Me ome A 558.3 1.51 (3)

- 306 042342

1028 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4 8)-4-fluoro-1-(1 -methyl1 H-imidazole-4carbonyl) pyrrolide in-3 yl]-2-methylbenzamide Me b N 1 531.3 1.38 (4) 1029 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(3,5- difluorobenzoyl)-4fluoro pyrrolidin-3 -yl]-2methylbenzamide Me V F 563.3 1.80 (3) 1030 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(1-cyclopropyl1H-1, 2,3-triazole-4carbonyl)-4fluoropyrrolidin-3-yl]-2methylbenzamide Me A\ N A 558.2 1.56 (3) 1031 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-[6( trifluoromethyl)pyridine-3 carbonyl]pyrrolidin-3yl]-2-methylbenzamide Me b. ^N CF ₃ 596.1 1.75 (3) 1032 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4 8)-4-fluoro-1-(1 -methyl1H-pyrazole-4carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me h 1 531.1 1.42 (3) 1033 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]N[(3R, 48)-1-(1,3-dimethyl-1Hpyrazole -5-carbonyl)-4fluoropyrrolidin-3 -yl]-2methylbenzamide Me A__ 545.2 1.56 (3) 1034 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]L[(3R,4S)-l-(2-xlor-3fluorobenzoyl)- 4fluoropyrrolidin-3-yl]-2methylbenzamide Me Cl /U 579.3 1.73 (3)

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1035 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-1-(5-cyano-2fluorobenzoyl) -4fluoropyrrolidin-3 -yl]-2methylbenzamide Me II N 570.1 1.66 (3) 1036 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3^48)-4-fluoro-1-(2methanesulfonylbenzoyl) pyrrolidin-3-yl]-2methylbenzamide Me SO ₂ Me 605.0 1.62 (3) 1037 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(4fluoropyridine- 2carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me "P 546.3 1.65 (3) 1038 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4 S)-1-(3-chloropyride in4- carbonyl)-4fluoropyrrolidin-3 -yl]-2methylbenzamide Me Cl A 562.3 1.65 (4) 1039 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-X[(3R, 48)-1-(2,3difluorobenzoyl)-4fluoropyrrolidine -3 -yl] -2methylbenzamide Me 563.1 1.75 (3) 1040 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(2- methyl1,3-oxazole-4carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me b 0^^ 532.2 1.52 (3) 1041 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(2-chloro-6fluorobenzoyl) -4fluoropyrrolidin-3 -yl]-2methylbenzamide Me O 579.1 1.80 (3)

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1042 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(5- fluoro2-methylpyridine-4carbonyl)pyrrolide in-3yl]-2-methylbenzamide Me jY 560.3 1.56 (4) 1043 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(2-chloro-4fluorobenzoyl) -4fluoro-pyrrolidin-3 -yl]-2methylbenzamide Me if about 579.0 1.88 (4) 1044 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(2cyclopentylacetyl)-4fluoropyrrolidin-3-yl]-2methylbenzamide Me λ 533.3 1.66 (4) 1045 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-[2-(3,3e butyl) acetyl] 4-fluoropyrrolidin-3 -yl] -2methylbenzamide Me 555.2 1.70 (4) 1046 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-H[(3R,4S)-4-φτop-l-(2fluorobenzoyl) pyrrolidin-3 yl]-2(trifluoromethoxy)benzamide OCF ₃ •ΰ 615.3 1.92 (4) 1047 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]A[(3^48)-4-fluoro-1-(3methylbutanoyl)pyrrolidine -3-yl]-2(trifluoromethoxy)benzamide OCF ₃ Me 577.0 1.92 (4) 1048 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-(2hydroxy- 2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethoxy)benzamide OCF ₃ X^Me Me ^0H 579.3 1.57 (3)

- 309 042342

1049 1050 1051 1052 1053 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3, 3,3trifluoropropanoyl)pyrroli din-3-yl]-2(trifluoromethoxy)benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]- M[(ZK,48)-4-fluoro-1-(4,4,4trifluoro-3methylbutanoyl)pyrrolidine -3-yl]-2- (trifluoromethoxy)benzamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4[(3K,48)-4-fluoro-1-[2hydroxy-2- (trifluoromethyl)butanoyl] pyrrolide in-3 -yl] -2- (trifluoromethoxy)benzamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2 (trifluoromethoxy)benzamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4[(ZK,48)-4-fluoro-1-(3fluorocyclobutanecarbonyl)p irrolidin-3-yl] - 2(trifluoromethoxy)benzamide OCF ₃ OCF ₃ OCF ₃ OCF ₃ OCF ₃ ?^CF ₃ Me Me Th F ₃ C ^0H 4 603.3 631.2 647.4 579.3 593.3, 593.3 1.82 (3) 1.99 (4) 1.9 (4) 1.86 (3) 1.78, 1.81 (3) 1054 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3 -yl] 2(trifluoromethoxy)benzamide OCF ₃ F 611.3 1.88 (3)

- 310 042342

1055 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2(trifluoromethoxy)benzamide OCF ₃ AVX/F 625.0 1.93 (4) 1056 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(ЗR,4S)-4-φτop-l-(2- φτop2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethoxy)benzamide OCF ₃ X^Me Me ^F 581.0 1.91 (4) 1057 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)- 4-fluoropyrrolidin-3 -yl] - 2(trifluoromethoxy)benzamide OCF ₃ L J< ^F XX^ F 639.0 2.00 (3) 1058 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-4^Top-l-(3, 3,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2(trifluoromethoxy)benzamide OCF ₃ X^Me F ₃ C 617.0 1.86 (3) 1059 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-Fluoropyrrolide in-3 yl]-2(trifluoromethoxy)benzamide OCF ₃ ^F Xy_v ^F 597.3 1.84 (4) 1060 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-N[(3R,4S)-4^Top-l-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(trifluoromethoxy)benzamide OCF ₃ 9 ^F 3 Uh 3 701.0 2.18(4)

- 311 042342

1061 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K[(3K,48)-4-fluoro-1-[(2K )3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]-2(trifluoromethoxy)benzamide OCF ₃ A/CF3 * he 633.3 1.85 (4) 1062 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-K[(3K,48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidin -3-yl]-2(trifluoromethoxy)benzamide OCF ₃ Me Y- ₃ 647.0 1.91 (4) 1063 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K[(3K,48)-4-fluoro-1-(2- fluoro2methylpropanoyl)pyrrolidi n-3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 X^Me Me ^F 595.1 1.83 (4) 1064 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-K[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 _F 639.1 1.85 (4) 1065 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-K[(3K,48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidine -3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 Me 645.3 1.99 (3) 1066 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-[(2K )3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 X/ _CF3 *OH 647.3 1.82 (3)

- 312 042342

1067 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[(3K,48)-4-fluoro-1-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 CF ₃ ^^CF, 699.1 2.05 (4) 1068 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-(4,4, 4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidine -3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 Me L-OH CF ₃ 661.1 1.82 (4) 1069 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-T4[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-Fluoropyrrolide in-3 yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 AF W ^F 611.1 1.75 (4) 1070 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 Me 661.1 1.84 (4) 1071 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-(3fluorocyclobutanecarbonyl) p irrolidin-3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 4 607.3, 607.3 1.84, 1.87 (4) 1072 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3 -yl] 2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 F 625.3 1.77 (3)

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1073 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]А[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)-4 -fluoropyrrolidin-3 -yl] 2-(2,2,2trifluoroethoxy)benzamide _{OCH2CF3 _} T \f F 653.3 1.87 (4) 1074 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]A[(3^48)-4-fluoro-1-(1fluorocyclopropanecarbonyl)pyrrolidine -3-yl]-2-(2,2,2trifluoroethoxy)benzamide OCH2CF3 593.3 1.76 (3) 1075 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,4S)-4-φτop-l-(3methylbutanoyl) pyrrolidin -3-yl]-2-(2,2,2trifluoroethoxy)benzamide _{OCH2CF3 _} Me '’^'^Me 591.4 1.83 (4) 1076 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]A[(3R,4S)-4-φτop-l-(2fluorobenzoyl)pyrrolidine -3 yl]-2-(2,2,2trifluoroethoxy)benzamide och ₂ cf ₃ ύ 629.3 1.83 (4) 1077 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]A[(3^48)-4-fluoro-1-(3,3 ,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2-(2,2,2trifluoroethoxy)benzamide och ₂ cf ₃ X^Me F ₃ C 631.0 1.85 (4) 1078 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]A[(3K,48)-4-fluoro-1-[4,4 ,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2trifluoroethoxy)benzamide och ₂ cf ₃ CF ₃ xA ΟΓ3 715.2 2.13(3)

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1079 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)^[(3Q48)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide OCHF ₂ 561.2 1.69 (3) 1080 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2(difluoromethoxy)^[(3R,4S)-44to _P -1- [(2R)3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]benzamide OCHF ₂ AuSRz * he 615.1 1.71 (4) 1081 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2(difluoromethoxy)^[(3^48)-4-fluoro-1 -[4,4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide OCHF _{2 CF3} 667.1 1.99 (4) 1082 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2- (difluoromethoxy)^[(3^48)-4-fluoro-1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide OCHF ₂ ?^CF ₃ 585.0 1.67 (3) 1083 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)^[(3Q48)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]benzamide OCHF ₂ Me '^^'' 559.0 1.77 (4) 1084 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3^48)-4-fluoro- 1-(4,4,4trifluoro-3methylbutanoyl)pyrrolidin-3-yl]benzamide OCHF ₂ Me ^^^CFs 613.1 1.83 (3)

- 315 042342

1085 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3R,48)-4-fluoro- 1-(2hydroxy-2methylpropanoyl)pyrrolidi n-3-yl]benzamide OCHF ₂ X^Me m?° ⁿ 561.1 1.50 (4) 1086 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolide in-3 - yl]-2(difluoromethoxy)benzamide OCHF ₂ AXf 579.3 1.7 (4) 1087 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3R,4S)-4-φτop- l-(3fluorocyclobutanecarbonyl)p irrolidin-3 -yl]benzamide OCHF ₂ 575.1, 575.1 1.65, 1.68 (4) 1088 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3K48)-4-fluoro-1- [4,4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide OCHF ₂ CF ₃ X-on CF ₃ 683.0 2.05 (4) 1089 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3R,4S)-4-φτop- l-(2fluorobenzoyl)pyrrolidin-3 yl]benzamide OCHF ₂ ύ 597.1 1.72 (3) 1090 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(difluoromethoxy)benzamide OCHF ₂ 621.1 1.8 (4)

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1091 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-X[(3K,48)-4-fluoro- 1-(4,4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidin-3-yl]benzamide OCHF ₂ Me L-OH CF ₃ 629.1 1.72 (3) 1092 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-p[(3K,48)-4-fluoro- 1-(2-fluoro2methylpropanoyl)pyrrolidi n-3-yl]benzamide OCHF ₂ X^Me Me ^F 563.1 1.71 (3) 1093 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-1] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-M[(3Κ,48)-4-φτορ- 1-(3,3,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide OCHF ₂ X^Me F ₃ C 599.0 1.8 (4) 1094 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-fluoropyrrolidin-3 -yl] 2-(difluoromethoxy)benzamide OCHF ₂ i^vf AX _F 607.1 1.75 (3) 1095 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3 -yl] 2-(difluoromethoxy)benzamide OCHF ₂ F 593.1 1.74 (4) 1096 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2(difluoromethoxy)-p[(3R,48)-4-fluoro- 1-[2hydroxy-2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide OCHF ₂ Me Ah F ₃ C ^0H 629.1 1.79 (4)

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1097 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2stokch-N-[(3R,48)-4-fluoro-1 (3,3,3trifluoropropanoyl)pyrroli din-3-yl]benzamide OEt Acf ₃ 563.3 1.76 (3) 1098 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-N-[(3K,48)-4-fluoro-1 ( 4,4,4-trifluoro-3-hydroxy- 3methylbutanoyl)pyrrolidin-3-yl]benzamide OEt Me Λ L-OH CF ₃ 607.2 1.82 (3) 1099 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-N-[(3K,48)-4-fluoro-1 ( 2fluorobenzoyl)pyrrolidin-3yl]benzamide OEt 4 575.3 1.91 (4) 1100 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-N-[(3K,48)-4-fluoro-1 ( 2-hydroxy-2methylpropanoyl)pyrrolidi n-3-yl]benzamide OEt AME MeA 539.4 1.59 (4) 1101 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-N-[(3K,48)-4-fluoro-1 ( 4,4,4-trifluoro-3methylbutanoyl)pyrrolidin-3-yl]benzamide OEt Me 591.3 1.90 (3) 1102 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-18G[(3R, 48)-1-(3,3difluorocyclopentanecarbonyl)- 4-Fluoropyrrolidin-3-yl]2-ethoxybenzamide OEt I—V ^F f 585.2 1.88 (4) 1103 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Н[(3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3-yl]2-ethoxybenzamide OEt F 571.3 1.77 (3)

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1104 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2stokch-N-[(3R,48)-4-fluoro-1 (ifluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide OEt 539.2 1.81 (3) 1105 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-N-[(3K,48)-4-fluoro-1 ( 2-fluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide OEt X^Me Me ^F 541.4 1.86 (4) 1106 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-23τοκοπ-Ν-[(3Κ,4δ)-4-φτορ-1 [ 4,4,4-trifluoro-3-hydroxy3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide OEt CF ₃ XA® 661.2 2.13(3) 1107 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2ethoxy-H-[(3K,48)-4-fluoro-1 [ (2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolide and n-3-yl]benzamide OEt X/CF ₃ * OH 593.3 1.76 (3) 1108 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-I[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl l)- 4-Fluoropyrrolidin-3-yl]2-ethoxybenzamide OEt L J< ^F \X^F 599.4 1.86 (3) 1109 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl]-2ethoxy-H-[(3K,48)-4-fluoro-1 [ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide OEt Me Uh F ₃ C ^0H 607.2 1.80 (3)

- 319 042342

1110 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2stokch-N-[(3 H48)-4-fluoro-1 [4 ,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide OEt CF ₃ ^^OF, 645.1 2.20 (4) 1111 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2ethoxy-X[(3K,48)-4-fluoro-1 (3 ,3,3-trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]benzamide OEt X^Me F ₃ C 576.9 1.92 (3) 1112 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolide in-3 yl]-2-ethoxybenzamide OEt . F/-/ ^F 557.2 1.82 (4) 1113 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2etoκci-N-[(ЗR,4S)-4-φτop-1 ( 3methylbutanoyl)pyrrolidin-3-yl]benzamide OEt Me 537.4 1.80 (3) 1114 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-2etoκci-N-[(ЗR,4S)-4-φτop-1 ( 3fluorocyclobutanecarbonyl)p irrolidin-3-yl]benzamide OEt 553.3 1.71 (3) 1115 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-23tokch-N-[(3N48)-4-fluoro-1(sfluorocyclobutanecarbonyl )p irrolidin-3-yl]benzamide OEt 553.3 1.74 (3) 1116 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-(2hydroxy- 2methylpropanoyl)pyrrolidi n-3-yl]-2-methoxybenzamide ome X^Me Me^ ^0H 525.0 1.46(2)

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1117 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3methylbutanoyl) pyrrolidine -3 -yl]-2-methoxybenzamide OME Me ^jii ^^ ⁴ Me 523.3 1.82 (2) 1118 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidine -3 -yl]-2-methoxybenzamide OME Me 577.3 1.94 (2) 1119 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3K,48)-4-fluoro-1-(2- fluoro2methylpropanoyl)pyrrolidi n-3-yl]-2-methoxybenzamide OME X^Me Me ^F 527.3 1.84 (2) 1120 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-[(2R )3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin n-3-yl]-2-methoxybenzamide OME ?ACF ₃ *OH 579.3 1.78 (2) 1121 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-Ni[(3R,48)-4-fluoro-1-(3, 3,3trifluoropropanoyl)pyrroli din-3-yl]-2methoxybenzamide OME X^CF ₃ 549.2 1.55 (1) 1122 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-Ni[(3K,48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2methoxybenzamide OME Me 593.0 1.86 (2) 1123 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3, 3,3trifluoro-2methylpropanoyl)pyrrolidi n-3-yl]-2-methoxybenzamide OME Χγ^Μβ F ₃ C 563.0 1.86 (2)

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1124 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(2fluorobenzoyl) pyrrolidin-3 yl]-2-methoxybenzamide OME 561.3 1.74 (1) 1125 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-l-(3,3difluorocyclopentanecarbonyl l)- 4-Fluoropyrrolidin-3-yl]2-methoxybenzamide OME AL/ A/F 571.0 1.86 (2) 1126 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-b[(3^48)-4-fluoro-1-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2methoxybenzamide OME cf ₃ Cr ₃ 647.2 2.12(2) 1127 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-b[(3^48)-4-fluoro-1-(1fluorocyclopropanecarbonyl) pyrrolidin-3-yl]-2methoxybenzamide OME fA ⁷ 525.0 1.82 (2) 1128 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-LG[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4 -fluoropyrrolidin-3-yl]2-methoxybenzamide OME F 557.0 1.82 (2) 1129 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl l)- 4-Fluoropyrrolidin-3-yl]2-methoxybenzamide OME T Lf 585.3 1.88 (2) ISO 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide OME Me kA™ SN ₃ 593.3 1.84 (2)

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1131 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-[4,4, 4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2methoxybenzamide OME _CF3 631.3 1.97 (2) 1132 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)- 4-fluoropyrrolide in-3 yl]-2-methoxybenzamide OME . FXyj/F 543.2 1.66 (2) 1133 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3R,4S)-4-φτop-l-(3fluorocyclobutanecarbonyl) p irrolidin-3-yl]-2methoxybenzamide OME 539.05, 539.05 1.73, 1.76(2) 1134 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3A48)-4-fluoro-1-[2hydroxy-2( trifluoromethyl)butanoyl]pyrrolide in-3-yl]benzamide H Me Ah F ₃ C ^0H 563.4 1.69 (1) 1135 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[(3K,48)-4-fluoro-1-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(methylamino)benzamide NHMe CF ₃ ^^CFs 630.0 2.06 (4) 1136 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl]-Ni[(3R,4S)-4ATop-l-[(2R)3 ,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin n-3-yl]-2(methylamino)benzamide NHMe YAY < bn 578.2 1.86 (4) 1137 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-H[(ZA48)-4-fluoro-1-[4,4, 4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2(methylamino)benzamide NHMe CF ₃ L-oh CF _:i 646.1 2.11(4)

Connections in the table. 42 was obtained by the methods detailed in examples 57, 63 and 562. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 42

^R1

Example Name ^{R1 R2} Observe May in MS the mass of the ion RT (Method) 1138 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2chloro-H-[(ZA48)- 4-fluoro-1[4,4,4-trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3yl]benzamide 0' N-/ h CF ₃ ^^CFg 699.9 1.63 (3) 1139 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2chloro-H-[(ZA48)- 4-fluoro-1[4,4,4-trifluoro-3hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3yl]benzamide 0' N—/ h CF ₃ Cr ₃ 716.3 2.15(4)

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1140 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl }-2xaop-N-[(3R,48 )-1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolide in-3yl]benzamide 0' N-/ H F 626.1 1.47 (3) 1141 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl }-2χπορ-Ν-[(3^48 )-4-φτορ-1[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3-yl]benzamide d' N-X H Z/CF ₃ * he 648.4 1.84 (4) 1142 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-4-φτop-l(sfluorocyclobutanecarbonyl)pyrrolidin-3yl]benzamide 0' N-/ H 608.4, 608.4 1.80, 1.83 (4) 1143 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-4-φτop-l(1fluorocyclopropanecarbonyl l)pyrrolidin-3 yl]benzamide su N-/ h fS ⁷ 594.4 1.42(3) 1144 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl }-2χπορ-Ν-[(3^48 )-4-φτορ-1(2-fluoro-2methylpropanoyl)pyrrolidin-3-yl]benzamide d' N-/ H HuMe Me ^F 596.4 1.89 (4)

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1145 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-4-φτop-l(3,3,3trifluoropropanoyl)pyrrolidin-3 -yl]benzamide 0' N-/ h ?^SRz 618.1 1.32 (3) 1146 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-4-φτop-l(3methylbutanoyl)pyrrolidi n-3-yl]benzamide s/ N-/ H Me ^^^^^Me 592.4 1.90 (4) 1147 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-1-(4,4difluorocyclohexanecarbonyl)-4-fluoropyrrolide in-3 yl]benzamide With/ N—/ H T J.F 654.4 1.94 (4) 1148 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7-yl }-2xlor-N-[(3R,4S )-l-(3,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3yl]benzamide With/ N—/ H i—V ^F LX F 640.2 1.87 (4) 1149 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2xlop-N-[( 3R,4S)-4-φτop-l(1fluorocyclopropanecarbonyl l)pyrrolidin-3 yl]benzamide No. /1-/ Sv ⁷ 626.1 1.47 (3)

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1150 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( ZK,48)-4-fluoro-1- (4,4,4-trifluoro-3methylbutanoyl)pyrrolidi n-3-yl]benzamide cf ₃ ^N-% Me 678.3 1.61 (3) 1151 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3K,48)-4-fluoro-1(sfluorocyclobutanecarbonyl)pyrrolidin-3yl]benzamide /CF ₃ 7 /N—/ ^^^F 640.3, 640.3 2.02, 2.04 (3) 1152 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3K,48)-4-fluoro-1(2-fluoro-2methylpropanoyl)pyrrolidin-3-yl]benzamide /CF ₃ 7 /N—/ X^Me Me ^F 628.3 1.50 (3) 1153 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( ZK,48)-4-fluoro-1- (4,4,4-trifluoro-3hydroxy-3methylbutanoyl)pyrrolidi n-3-yl]benzamide £F ₃ /N-/ Me d L-OH CF ₃ 694.1 1.51 (3) 1154 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3K,48)-4-fluoro-1(3methylbutanoyl)pyrrolidi n-3-yl]benzamide /CF ₃ b /N—/ Me ^^^^^Me 624.1 1.49 (3)

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1155 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2xlop-N-[( 3R,4S)-4-φτop-l(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide G /14- ?Acf ₃ 650.1 2.06 (4) 1156 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3K,48)-4-fluoro-1[4,4,4-trifluoro-3hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3yl]benzamide Y _^CF ₃ CF ₃ kA™ 748.3 2.34 (4) 1157 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2xlop-N-[( 3R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolide in-3 yl]benzamide G /14- ^C ^p ₃ YS-f F 658.3 1.49 (3) 1158 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3K,48)-4-fluoro-1(2fluorobenzoyl)pyrrolidin3-yl]benzamide Y _^CF ₃ I 662.3 1.52 (3) 1159 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3^48)-4-fluoro-1[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3-yl]benzamide _^CF ₃ X/SR ₃ 'he 680.3 1.44 (3)

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1160 5-(4-Amino-5-{[4(trifluoromethyl)piperidin -1-yl]methyl } 48)-1-(4,4difluorocyclohexanecarbonyl)-4-fluoropyrrolide in-3yl]benzamide PF ₃ /N—/ LX ^F 686.4 1.56 (3) 1161 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-Ni(3R, 48)-1-(3,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3yl]benzamide PF ₃ N—/ AA F 672.4 1.54 (3) 1162 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3R,48)-4-fluoro-1(3,3,3-trifluoro-2 methylpropanoyl)pyrrolidin-3-yl]benzamide /CF ₃ b N—/ X^Me F ₃ C 664.3 1.52 (3) 1163 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1-yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-2chloro-M-[( 3R,48)-4-fluoro-1[2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3yl]benzamide Me F ₃ C ^0H 694.3 1.53 (3)

Connections in the table. 43 was obtained by the methods detailed in examples 57, 63 and 562. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 43

Xi a Vw Ό ε¥ή ^r

Example Name R Observe May in MS the mass of the ion RT (Method) 1164 3-{4-amino-5-[(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f][1,2,4]triazine-7- m}-N-[(3R,4S)-4^top-1-[(2R)-3,3,3- trifluoro-2- hydroxypropanoyl]pyrrolidin-3 yl]benzamide Ay ^CF 3 OH 572.3 1.73(2) 1165 3 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazine-7 _ΗΛ }-Ν-[(3^48 )-4-φτορ-1-(3methylbutanoyl)pyrrolidin-3yl]benzamide Me ^^^^Me 530.3 1.82 (2) 1166 3 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N- [(3R,4 8 )-4-fluoro-1 -(2-hydroxy-2methylpropanoyl)pyrrolide in-3yl]benzamide X^Me mrn 532.1 1.50 (2) 1167 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl} -N- [(3R,4 8 )-4-fluoro-1 -(2-fluoro-2methylpropanoyl)pyrrolide in-3yl]benzamide X^Me mR 534.3 1.73(2) 1168 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-M-[(3^48) -1-cyclobutanecarbonyl-4fluoropyrrolidin-3 -yl]benzamide 528.3 1.78 (2) 1169 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3R,4S) -4-φτop-1-(3,3,3trifluoropropanoyl)pyrrolide in-3yl]benzamide X^CF ₃ 556.3 1.76 (2) 1170 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7wi}-N-[(3R,48) -1-(2,2dimethylpropanoyl)-4-fluoropyrrolidin-3yl]benzamide X-Me X Me Me 530.1 1.43(1) 1171 3-{4-amino-5-[(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f][1,2,4]triazine-7- roi}-N-[(3R,4S)-44Top-l-(2- fluorobenzoyl)pyrrolidin-3-yl]benzamide X 568.2 1.84 (2) 1172 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazine-7^}-N-[(3R,4S )-4-4)Top-l-(2methylpropanoyl)pyrrolide in-3yl]benzamide HuMe Me 516.1 1.32 (1)

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1173 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7ππ}-Ν-[(3^48) -4-φτορ-1-(4fluorobenzoyl)pyrrolidin-3 -yl]benzamide 568.1 1.76 (2) 1174 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazin-7yl}-Ni(3^48)-4 -fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3yl]benzamide 546.2 1.75 (2) 1175 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazin-7yl}-Ni(3^48)-4 -fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3yl]benzamide h 546.1 1.72 (2) 1176 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl }-N-[(ЗR,4S) -4-φτop-l-(3,3,3-τpiφτop2,2-dimethylppopanoyl)pyrpolidin-3yl]benzamide X^Me Me ^CF 3 584.2 1.94 (2) 1177 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7nn}-N-[(3R,48) -1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3 -yl]benzamide kA F 550.1 1.66 (2) 1178 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7m}-N-[(3R,4S) -1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3 -yl]benzamide CL/ A/ ⁴ f 578.1 1.84 (2) 1179 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7nn}-N-[(3R,48) -1-(4,4difluorocyclohexanecarbonyl)-4fluoropyrrolidin-3 -yl]benzamide T\f 592.1 1.78 (2) 1180 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7wi}-N-[(3R,4S) -4^to _P -1-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide /4cf ₃ 'OH 586.0 1.66 (2) 1181 3 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7m}-N-[(3R,4S) -1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3 -yl]benzamide F 564.3 1.66 (2)

Connections in the table. 44 was obtained by the methods detailed in example 563. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 44

Example Name ^{R1 R2 R3} By observing May in MC the mass of the ion RT (Method) 1182 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]H[(ZK,48)-4-fluoro-1-(1fluorocyclopropanecarbonyl) pyrrolidin-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me xA 524.3 1.36 (4) 1183 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3Κ,4δ)-4-φτορ-1 -(2- fluorine- 2methylpropanoyl)pyrrolidin-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me X^Me Me ^F 526.2 1.37 (4) 1184 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-1-(2,4difluorobenzoyl)-4fluoropyrrolidin-3-yl] 2,6-dimethylpyridine-3 carboxamide Me Me LL 578.3 1.46 (4) 1185 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-H[(3R,4S)-4-φτop-l-[(2R )3,3,3-trifluoro-2-hydroxy2methylpropanoyl]pyrrolidin-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me *OH 578.3 1.35 (4)

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1186 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(2chlorobenzoyl)-4fluoropyrrolidin-3-yl] 2,6-dimethylpyridine-3 carboxamide Me Me CI b 575.9 1.59 (4) 1187 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4[(ЗR,4S)-4-φτop-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidi n-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me Me 576 (4)1.65 1188 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4- [(3R,48)-1-(3,5difluoropyridine-4carbonyl)-4fluoropyrrolidin-3-yl] 2,6-dimethylpyridine-3 carboxamide Me Me FfSn 579.3 1.31 (4) 1189 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-1-benzoyl-4fluoropyrrolidin-3-yl ] 2,6-dimethylpyridine-3 carboxamide Me Me b 541.9 1.53 (4) 1190 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZA48)-4-fluoro-1-(2fluorobenzoyl)pyrrolidin3- yl]-2,6dimethylpyridine-3 carboxamide Me Me ύ 560.2 1.41 (4) 1191 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4[(3R,4S)-4^Top-l-(3fluorobenzoyl) pyrrolidin3-yl]-2,6dimethylpyridine-3 carboxamide Me Me x/ 560 1.57 (4)

- 333 042342

1192 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-p [(3R,48)-4-fluoro-1-(3fluoropyridine- 4carbonyl)pyrrolidin-3yl]-2,6-dimethylpyridine3-carboxamide Me Me ύ 561.1 1.22 (4) 1193 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZK,48)-4-fluoro-1-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me CF ₃ ^^CFs 630.3 1.7 (4) 1194 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3 methylbutanoyl)pyrrolidi n-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me Me χ]<0Η CF ₃ 592.4 1.4 (4) 1195 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(3methylbutanoyl) pyrrolidi n-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me Me 522.2 1.42 (4) 1196 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-M[(3Κ,48)-4-φτορ-1-(3, 3,3trifluoro-2methylpropanoyl)pyrroli din-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me X^Me F ₃ C 562.3 1.45 (4)

- 334 042342

1197 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-T4- [(3R,4S)-l-(2,5- difluorobenzoyl)-4fluoropyrrolidin-3 -yl] 2,6-dimethylpyridine-3 carboxamide Me Me ΛF 578.3 1.46 (4) 1198 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(3,4- difluorobenzoyl)-4fluoropyrrolidin-3 -yl] 2,6-dimethylpyridine-3 carboxamide Me Me (A F 578.2 1.29 (3) 1199 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-X[(3^48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6dimethylpyridine-3 carboxamide Me Me Me Yh F ₃ C ^he 592 1.16 (3) 1200 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-X[(3R,4S)-l-(2,6difluorobenzoyl)-4fluoropyrrolidine -3 -yl] 2,6-dimethylpyridine-3 carboxamide Me Me F F^\A 578.3 1.20 (3) 1201 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ЗR,4S)-4-φτop-l-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6dimethylpyridine-3carboxamide Me Me CF ₃ JUoh CF ₃ 646.3 1.52 (3) 1202 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [ 1,2,4]triazin-7-yl]-M[(3R,4S)-l-[2-(3,3difluorocyclobutyl )acetyl]-4-fluoropyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide H OME 572.1 1.91 (4)

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1203 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-H- [(3R,4S)-l-(2- cyclopentylacetyl)-4fluoropyrrolidin-3 -yl]-2methoxypyridine-3 carboxamide H OME 550.4 2.05 (4) 1204 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4- [(3R,4S)-l-(2- cyclobutylacetyl)-4fluoropyrrolidin-3 -yl]-2methoxypyridine-3 carboxamide H OME G 536.2 1.85 (4) 1205 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4- [(3R,4S)-l-[2-(2,2difluorocyclopropyl)acetyl]-4-fluoropyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide n OME F 558 1.73 (4) 1206 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(2cyclopropylacetyl)-4fluoropyrrolidin-3-yl]-2methoxypyridine-3 carboxamide n OME 1 522 1.69 (4) 1207 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-[2-(1methylcyclopropyl )acetyl] pyrrolidin-3 -yl] -2methoxypyridine-3 carboxamide n OME 536 1.81 (4) 1208 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZAch48)-4-fluoro-1-[2-(1hydroxycyclohexyl )acetyl] pyrrolidin-3 -yl] -2methoxypyridine-3 carboxamide n OME 580.4 1.83 (4)

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1209 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(6methoxypyrazin- 2carbonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide H OME Scn Y Meo 576.32, 576.33 1.71, 1.91 (4) 1210 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1(pyridazine-3carbonyl )pyrrolidin-3 yl]-2-methoxypyr idine-3 carboxamide H OME ίΤΖ N. X N 546.1 1.51 (4) 1211 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZK,48)-4-fluoro-1-(2methoxypyrimidin- 5carbonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide n OME A ο ^λζ (D 576.2 1.61 (4) 1212 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-(6methylpyrazin- 2carbonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide n OME Scn Y Me 560.1 1.63 (4) 1213 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(5methylpyrazin- 2carbonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide n OME SAn N Me 560.1 1.63 (4) 1214 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-(2methylpyrimidin- 5 carbonyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide n OME Φ 559.9 1.49 (3)

- 337 042342

1215 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-M- [(3R,48)-1-(6chloropyridazine-4carbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyridine-3-carboxamide H OME Ά ¹ v- ^N 580.2 1.62 (3) 1216 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-(2cyclohexylacetyl)-4fluoropyrrolidin-3-yl]-2methoxypyridine-3 carboxamide H OME 564.3 2.05 (4) 1217 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M- [(3R,4S)-l-[2-(2,2- difluoroethoxy) -2- methylpropanoyl]-4fluoropyrrolidin-3 -yl]-2methoxypyridine-3 carboxamide n OME ''WITH F 590.1 1.89 (2) 1218 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-1-[2-(tert-butoxy)acetyl ]-4fluoropyrrolidin-3-yl]-2methoxypyr idine-3 carboxamide n OME X 554.2 1.79 (2) 1219 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3K,48)-4-fluoro-1-[(28 )3,3,3-trifluoro-2-methoxy2-phenylpropanoyl]pyrroli-din-3-yl]-2methoxypyridine-3-carboxamide n OME RZSC/ 656.1 2.28(2)

- 338 042342

1220 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3R,48)-4-fluoro-1-[4, 4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3carboxamide H OME CF ₃ χΛΤ UI-3 648.3 2.11(2) 1221 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-H[(ZK,48)-4-fluoro-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidi n-3-yl]-2methoxypyr idine-3 carboxamide H OME Me 578.4 1.86 (1) 1222 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-H[(3R,48)-4-fluoro-1-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3carboxamide n OME CF ₃ ^^CFs 632.3 2.12(2) 1223 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-H[(3R,48)-4-fluoro-1{spiro[2.2 ] pentane-1 carbonyl} pyrrolidin-3 yl] -2-methoxypyridine-3 carboxamide n OME Α^Δ 534.3 1.84 (2) 1224 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-H[(ZK,48)-4-fluoro-1-(4, 4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidi n-3-yl]-2methoxypyr idine-3 carboxamide n OME Me L--OH CF ₃ 594.1 1.83 (2)

- 339 042342

1225 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-H[(3Κ,48)-4-φτορ-1-(3, 3,3trifluoro-2methylpropanoyl)pyrroli din-3-yl]-2methoxypyridine-3 carboxamide H OME X^Me F ₃ C 564.2 1.88 (2) 1226 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-G4[(3K,48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3carboxamide H OME X^CF ₃ (An Me 594.0 1.86 (2) 1227 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-F4[(3R,48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3carboxamide n OME /UCF ₃ (An Me 594.2 1.86 (2) 1228 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-G4[(3K,48)-4-fluoro-1-(2, 2,2trifluoroacetyl)pyrrolidi n-3-yl]-2methoxypyridine-3 carboxamide n OME A 536.2 1.99 (4) 1229 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(ZK,48)-4-fluoro-1-(2, 3,3,3tetrafluoro-2methylpropanoyl)pyrroli din-3-yl]-2methoxypyridine-3 carboxamide n OME A/ ^Mer 582.2 2.03 (4)

- 340 042342

1230 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl]-N[(ЗR,4S)-4-φτop-l-[(2R )3,3,3-trifluoro-2-methoxy2methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3carboxamide H OME X^CF ₃ V 594.1 1231 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-[2hydroxy- 2(trifluoromethyl)butanoyl]pyrrolidin-3 -yl]-2methylpyridine-3 carboxamide H Me X^CFs ^OH Me 578.4 1.30 (1) 1232 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-K[(3R,4S)-4-φτop-1-(4, 4,4trifluoro-3methylbutanoyl)pyrrolidi n-3-yl]-2-methylpyridine3-carboxamide n Me Me 562.3 1.52(2) 1233 5-[4-amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-T4[(ЗR,4S)-4-φτop-l-[4, 4,4trifluoro-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methylpyridine-3 carboxamide n Me CF ₃ ^^OF ₃ 616.3 1.62 (1) 1234 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-K[(3R,4S)-4-φτop-1-(4, 4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidi n-3-yl]-2-methylpyridine3-carboxamide n Me Me x>oh CF ₃ 578.3 1.38 (1) 1235 1236 5-[4-Amino-5(trifluoromethyl)pyrrolo[2, 1-f] [1,2,4]triazin-7-yl]-M[(3^48)-4-fluoro-1-(3, 3,3trifluoro-2methylpropanoyl)pyrrolidin-3-yl]-2methylpyridin-3 carboxamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -M[(3M8)-4-fluoro-1-[4,4,4trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methylpyridine-3 carboxamide n n Me Me X^Me F ₃ C CF ₃ JL-OH CF ₃ 548.3 632.0 1.49 (2) 1.77 (2)

Connections in the table. 45 was obtained by the methods detailed in examples 57, 63 and 563. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

- 341 042342

Table 45

Example Name R Observe May in MC ion mass RT (Method) 1237 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f][1,2,4]triazin-7yl } -N- [(3R,4 8) -4-fluoro-1 -(pyridine-4carbonyl)pyrrolide in-3 -yl] -2methoxypyride in-3-carboxamide A 610.2 1.64 (4) 1238 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-H-[(3^48)- 1-(4-chlorobenzoyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 643 2.07 (4) 1239 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-H-[(3^48)- 4-fluoro-1-(3fluorobenzoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide V F 627.2 2.01 (4) 1240 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-I-[(3 R, 48) -1-(2-chlorobenzoyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide CL / 643 2.00 (4) 1241 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-I-[(3 R, 48) -1-(2,5-difluorobenzoyl)-4fluoropyrrolidin-3 -yl]-2methoxypyride in-3-carboxamide f/f 645.1 1.98 (4) 1242 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-I-[(3 R, 48) -1-(2,6-difluorobenzoyl)-4fluoropyrrolidin-3 -yl]-2methoxypyride in-3-carboxamide F jn F^W 645.1 1.96 (4) 1243 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl }-N-[(3R, 48)- 1-(3,5-difluoropyridine-4carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide F jj 646.1 1.91 (4) 1244 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(3R,4S)- l-(3-chloropiridine-2carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide CL / 644.2 1.90 (4) 1245 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazine-7ra}-N-[(3R,4S)- 4-4) Top-l-(lfluorocyclopropanecarbonyl)pyrrolidin3-yl]-2-methoxypyridine-3-carboxamide 591.2 1.92 (4) 1246 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-H-[(3^48)- 4-fluoro-1-(4,4,4-trifluoro3-hydroxy-3 methylbutanoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide Me X J<OH ^42F ₃ 659.1 1.93 (4) 1247 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7wi}-N-[(3R,4S)- 4^to _P -1-(3methylbutanoyl)pyrrolidin-3 -yl] -2methoxypyride in-3-carboxamide Me 589 2.01 (4)

-342 042342

1248 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7yl }-Ν-[(3Κ,48)- 4-φτορ-1-(2methylpyridine-4-carbonyl)pyrrolidin-3yl]-2-methoxypyridine-3-carboxamide iTY 624.2 1.80 (4) 1249 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7yl}-N-[(ЗR,4S)- 4-φτop-l-[4,4,4-τpiφτop3-(trifluoromethyl)butanoyl]pyrrolidin3-yl]-2-methoxypyridine-3-carboxamide CF ₃ ^^ Cr3 697.1 2.20 (4) 1250 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N- [(3R,4 8) -4-fluoro-1 -(3 -fluoro pyridine4-carbonyl)pyrrolidin-3 -yl] -2methoxypyride in-3-carboxamide 628 1.74 (4) 1251 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(3R,4S)- 4-φτop-l-(2,4,6trifluorobenzoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 1_1_ 663.1 2.01 (4) 1252 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-K-[(ZA48)-1- (4-chloropyridine-3carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide o R 644.1 1.85 (4) 1253 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7wi}-N-[(3R,48)- 1-(2-Chloro-4-fluorobenzoyl)4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide R O 661.2 2.09 (4) 1254 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N- [(3R,4 8) -4-fluoro-1 -(pyridine-2carbonyl)pyrrolide in-3 -yl] -2methoxypyride in-3-carboxamide 610.2 1.41 (3) 1255 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-H-[(ZA48)-4- fluoro-1-[4(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide Yj F ₃ C^ ⁴ ^' 678.4 1.53 (3) 1256 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-K-[(ZA48)-4- fluoro-1-(1,3-thiazole-4carbonyl)pyrrolide in-3-yl]-2methoxypyride in-3-carboxamide b 616.2 1.40 (3)

- 343 042342

1257 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- l-(5-chloropiridine-2carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide O 644.1 1.63 (3) 1258 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7yl}-X[(ZK,48)-4 -fluoro-1-(4,4,4-trifluoro3-methylbutanoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide Me ^^^CFg 642.9 1.65 (3) 1259 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl } -Ν-[(3Κ,4δ)- 4-φτορ-1 -(5-fluoro-2methylpyridine-4-carbonyl)pyrrolidin-3yl]-2-methoxypyridine-3-carboxamide jpK f// 641.9 1.41 (3) 1260 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-T4-[(ZK,48)- 4-fluoro-1-(2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide //Me Me^OH 591.2 1.35 (3) 1261 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7Nΐ}-N-[(3^4δ )-4-φτορ-1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide ?/ _CF3 615.2 1.39 (3) 1262 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- l-(3,4-diφtorbenzoyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide (A ^F F 644.9 1.63 (3) 1263 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7wi}-N-[(3R,48)- 1-(3,5-difluoropyridine-2carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide F /η N % F 645.9 1.48 (3) 1264 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7yl}-N-[(3R,4 δ) -4-φτορ-1 -(5-fluoropyridine2-carbonyl)pyrrolidin-3-yl]-2methoxypyride in-3-carboxamide F 628.3 1.42(3) 1265 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- l-(2-chloro-3-φτopbenzoyl)4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 0 660.9 1.65 (3) 1266 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- 4-φτop-l-(3,3,3-τpiφτop2-methylpropanoyl)pyrrolide in-3-yl]-2methoxypyride in-3-carboxamide X^Me F ₃ C 629.2 1.46 (3) 1267 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl } -N-[(ЗR,4δ)- 1 -(3,5-d ifluorobenzoyl)-4fluoropyrrolidin-3 -yl] -2methoxypyride in-3-carboxamide F 645.1 1.54 (3) 1268 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- l-(3-chloropiridine-4carbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide CI^Cn 644.2 1.32 (3) 1269 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl }-N-[(3R,4 δ) -4-φτορ-1 -(3-fluoro pyridine2-carbonyl)pyrrolidin-3 -yl] -2methoxypyride in-3-carboxamide ύ 628.2 1.44 (3) 1270 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl}-N-[(ЗR,4δ)- l-(2-chloro-6-φτopbenzoyl)4-fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide O 661 2.11(3)

Connections in the table. 46 was obtained by the methods detailed in examples 57, 63 and 563. When

- 344 042342 diastereomers were separated and included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

Table 46 h ₂ n

i-r

Example Name R Observe May in MS the mass of the ion RT (Method) 1271 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrole o[2,1 -f] [1,2,4]triazin-7 yl}-H-[(3^ 48)-4-fluoro-1-(2-fluoro-2methylpropanoyl)pyrrolidin-3-yl]-2(methoxy-03)nicotinamide ABOUT D-me me f 568.1 1.88 (2) 1272 5 - {4-amino-5-[(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f] [1,2,4]triazine-7nn}-N-[(3R,48) -1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 612.4 1.84 (2) 1273 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3R,4 8 )-4-fluoro-1 -(3 fluorocyclobutanecarbonyl)pyrrolidin-3yl ]-2-(MeTOKCH-d3 )nicotinamide b F 580.41, 580.41 1.70, 1.73 (2) 1274 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7™}-N-[(3R,48 )-1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2-(methoxyd3)nicotinamide X F 598.4 1.81 (2) 1275 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3R,4 8 )-4-fluoro-1 -(4fluorobenzoyl)pyrrole idin-3 -yl]-2-(methoxyd3 )nicotinamide F 602.4 1.85 (2) 1276 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl} -N-[(3R, 4 8 )-4-fluoro-1 -(3,3,3-trifluoro-2,2d imethylpropanoyl)pyrrolidin-3 -yl]-2(methoxy-03)nicotinamide About D~Me Me CF ₃ 618.4 1.98 (2) 1277 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl }-N-[(3R, 48) -1-(2,2-dimethylpropanoyl)-4fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 0 D-me me me 564.4 1.85 (2) 1278 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-N-[(ЗR,4S) -4-φτop-l-(2,2,2trifluoroethanesulfonyl)pyrrolidin-3 -yl]-2(MeTOKCH-d3 )nicotinamide 0 F ₃ C 626.3 1.88 (4) 1279 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-K-[(ZK,48) -4-fluoro-1-(3,3,3trifluoropropanesulfonyl)pyrrolidin-3yl]-2-(MeTOKCH-d3 )nicotinamide _0CF3 640.2 1.95 (4) 1280 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3R,4 8 )-4-fluoro-1 -(4fluorobenzenesulfonyl)pyrrolide in-3 -yl]-2(MeTOKCH-d3 )nicotinamide 0 Q F 638.1 1.95 (4)

- 345 042342

1281 1282 1283 1284 1285 1286 1287 1288 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}h-[(ZK,48)- 1-(cyclohexanesulfonyl)4-fluoropyrrolidin-3-yl]-2-(methoxyd3)nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N- [(3R,4 8 )-4-fluoro-1 - {[ 1 -methyl-3 (trifluoromethyl) -1 H-pyrazol-4yl] sulfonyl } pyrrolidin-3 -yl] -2 (MeTOKcn-d3 ) nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazin-7yl}Ch-[(ZK48)-1- (ethanesulfonyl)-4fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-M-[(ZK48)-1 -(cyclopropanesulfonyl)4-fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-H-[(3^48) -4-fluoro-1-(3methylbutanoyl)pyrrolide in-3-yl]-2(methoxyCh3) nicotine id 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(ЗR,4S) -4-φτop-1-(3,3,3trifluoropropanoyl)pyrrolidin-3 -yl]-2(MeTOKcn-d3 )nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7m}-N-[(3R,4S) -1-(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazine-7Nΐ}-N-[(3M8) -4-φτορ-1-[2(trifluoromethoxy)benzenesulfonyl]pyrroli din-3-yl]-2-(methoxy^3)nicotinamide Tso ύ Tso F ₃ C 0 TsO Me 0 Tso Me—( Me F 0 F ₃ CO-/P 626.3 692.2 572.1 584.1 564.5 590.4 584.1 704.1 2.02 (4) 1.89 (4) 1.67 (4) 1.71 (4) 1.47 (1) 1.40 (1) 1.24(1) 1.85 (3) 1289 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-N-[(ЗR,4S) -4-φτop-l-(2methylpropanesulfonyl)pyrrolidin-3-yl]2-(MeTOKcn-d3 )nicotinamide ABOUT Tso Me-Ts Me 600.3 1.56 (3)

- 346 042342

1290 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3R,4S) -1 -[(1,2-d imethyl-1Nimidazol-4-yl)sulfonyl]-4fluoropyrrolidin-3 -yl] -2-(methoxyd3)nicotinamide ABOUT A / 638.3 1.22 (3) 1291 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7Ηπ}-Ν-[(3Κ,48) -4-φτορ-1-(4,4,4trifluorobutanesulfonyl)pyrrolidin-3-yl]2-(MeTOKCH-d3 )nicotinamide 0 As' ⁰ F ₃ C 654.3 1.61 (3) 1292 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1-f] [1,2,4]triazine-7Ni}-N-[(3R, 4S)-l- cyclopropylmethanesulfonyl-4fluoropyrrolidin-3 -yl]-2-(methoxyd3)nicotinamide 0 ro I 598.1 1.41(3) 1293 5 - { 4-amino-5 - [(3,3 -difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -N-[(3Κ,48) -4-φτορ-1 -(2,2,2-trifluoro-1-phenylethanesulfonyl)pyrrolidin-3-yl]-2(methoxy^3)nicotinamide O LcF ₃ O 702.2 1.79 (3) 1294 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-Ni(ZK,48)-4 -fluoro-1methanesulfonylpyrrolidin-3 -yl]-2(methoxy-^3)nicotinamide 0 Me 558.3 1.24 (3) 1295 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-X-[(ZK,48) -4-fluoro-1-(2methoxybenzenesulfonyl)pyrrolidin-3yl]-2-(MeTOKCH-d3 )nicotinamide 0 Ls'-o MeO— 650.3 1.55 (3) 1296 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-Ni(ZK,48)-4 -fluoro-1phenylmethanesulfonylpyrrolide in-3 -yl]-2(methoxy-N3)nicotinamide 0 O 634.1 1.55 (3) 1297 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-X-[(ZK,48) -4-fluoro-1-(2phenylethanesulfonyl)pyrrolidin-3-yl]-2(methoxy^3)nicotinamide Do o 648.2 1.64 (3) 1298 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl} -N-[(ZK,48) -4-fluoro-1-(propane-2sulfonyl)pyrrolidin-3-yl]-2-(methoxyd3)nicotinamide O /s/o /~Me Me 586.4 1.43 (3) 1299 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-X-[(ZK,48) -4-fluoro-1-[(2K)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3-yl]-2(methoxy-^3)nicotinamide Acf ₃ < н 620.0 1.88 (2)

Connections in the table. 47 was obtained by the methods detailed in example 10. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 47\ ^F

Dx a xw

G u% ^{N r}

NOM

Example 1300 1301 1302 1303 1304 Name 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-H-[4-(tert-butylcarbamoyl)-1,3-oxazol-2-yl]-2methoxypyridine-3-carboxamide 5 -[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-M-{4[(cyclopropylmethyl)carbamoyl]-1,3oxazol-2-yl } -2-methoxypyridine-3 carboxamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-2-methoxy-H-{4[(propan-2-yl)carbamoyl]-1,3-oxazol2-yl } pyridine-3-carboxamide 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-H-[4(cyclopentylcarbamoyl)-1,3-oxazol-2yl]-2-methoxypyridine-3-carboxamide 5 -[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1D][1,2,4]triazin-7-yl]-M-{4[(cyclopropylmethyl)(propyl)carbamoyl]-1,3-oxazol-2-yl} - 2-methoxypyride in3-carboxamide R n ⁿ V bA n n Lie Observe May in MS the mass of the ion 519.3 517.3 505 531 559.3 RT (Method) 1.73 (4) 1.78 (4) 1.59 (3) 1.74 (3) 1.97 (3) 1305 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-I-[5-({ [2-fluoro-5(trifluoromethoxy)phenyl]methyl}carbamoyl)-1, 3-thiazol-2-yl]-2-methoxypyride in3-carboxamide F ₃ CO^^. γ'Τ n 671.2 2.15(3)

Connections in the table. 48 was obtained by the methods detailed in examples 57, 63 and 562. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 48

Example Name R Ion mass observed in MC RT (Method) 1306 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -2-chloro-4-fluoro- H-[(3R,4 8)-4-fluoro-1(2-fluoro-2-methylpropanoyl)pyrrolidin3-yl]benzamide X^Me Me ^F 586.3 1.4 (1) 1307 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -2-chloro-4-fluoro- H-[(3R,4 8)-4-fluoro-1 (3,3,3-trifluoro propanoyl) pyrrolide in-3 yl] benzamide ?^CF ₃ 608.0 1.66 (2) 1308 5 - { 4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl] pyrrolo[2,1 -f] [1,2,4]triazin-7yl } -2-chloro-4-fluoro- H-[(3R,4 8)-4-fluoro-1 (3,3,3-trifluoro-2,2- X^Me Me ^CF 3 636.3 1.54 (1) dimethylpropanoyl)pyrrolide in-3yl]benzamide 1309 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-2-chloro-I-[( 3 R, 48)-1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3 -yl]-4-fluorobenzamide F 616.3 1.39 (1) 1310 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1 -f] [1,2,4]triazin-7yl}-2-chloro-I-[( 3 R, 48)-1-(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3 -yl]-4-fluorobenzamide F 630.3 1.81 (2) 1311 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl} -2-chloro-4-fluoro- H-[(3R,4 8)-4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin3-yl]benzamide ^^^F 598.3 1.31 (1) 1312 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7yl} -2-chloro-4-fluoro- H-[(3R,4 8)-4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin3-yl]benzamide 4 598.1 1.68 (2) 1313 5 - {4-amino-5 - [(3,3-difluoroazetidin-1 yl)methyl]pyrrolo[2,1 -f] [1,2,4]triazin-7yl} -2-xloro-4-φτορ -Ν-[(3R,4 8)-4-fluoro-1 [(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3yl]benzamide Pk/CF ₃ 'OH 638.3 1.7 (2)

Connections in the table. 49 was obtained by the methods detailed in examples 562 and 567. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 49

F

Example Name ^{R1 R2} Observe May in MC ion mass RT (Method) 1314 3-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoro-Н[(3Κ,48)-4-φτορ-1- [(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide H ?OCF ₃ <EN 567.2 1.66 (1) 1315 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7-yl]-H-[(ZA48)-1 (3,3-d ifluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-5fluorobenzamide H F 545.3 1.70 (1) 1316 3-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-5-fluoro-Н[(ЗR,4S)-4-φτop-1 -[2-hydroxy-2(trifluoromethyl )butanoyl]pyrrolidine-3-yl]benzamide H Me F^ ^H 581.4 1.78 (1) 1317 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro-Н[(3R,4 8)-4-fluoro-1 - {spiro[2.2]pentane1-carbonyl} pyrrolidin-3-yl]-2methylbenzamide Me 535.1 1.79 (1) 1318 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro-H[(ZA48)-4-fluoro-1-(4,4,4-trifluoro-3hydroxy -3methylbutanoyl)pyrrolidin-3 -yl]-2methylbenzamide Me Me Or ₃ 595.1 1.77 (1) 1319 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro-H[(3A48)-4-fluoro-1-(3,3,3-trifluoro-2methylpropanoyl )pyrrolidin-3-yl]-2methylbenzamide Me X^Me F ₃ C 565.1 1.83 (2) 1320 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 1][1,2,4]triazin-7-yl]-3-fluoro-H[(ZA48)-4-fluoro-1-[4,4,4-trifluoro-3 (trifluoromethyl)butanoyl]pyrrolidine -3 -yl] -2-methylbenzamide Me CF ₃ ^^^CFs 633.3 2.03(2)

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1321 1322 1323 1324 1325 1326 1327 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoro-X[(3 C48)-4-fluoro-1 -[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl ]-3-fluoro-X[(3R,4 8)-4-fluoro-1 -(pyridine-3 carbonyl)pyrrolide in-3-yl]-2methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2 ,1 C[1,2,4]triazin-7-yl]-3-fluoro-X[(3^48)-4-fluoro-1-(3-fluoropyridine-4carbonyl)pyrrolide in-3-yl] - 2methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 C[1,2,4]triazin-7-yl]-3-fluoro-X[(3^48)-4-fluoro-1- (5-fluoropyridine-3carbonyl)pyrrolide in-3-yl]-2methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-X- [(ZK48)-1 (3,5-d iffluoropyridine-4-carbonyl)-4fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl]-2-chloro-3-fluoroX-[(3^48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidine -3- yl] benzamide 4^to _P - 1 -[(2R)-3,3,3 trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]benzamide Me Me Me Me Me Cl Cl A ^cf ' 1 he 4 y F F jS fA ⁿ OH ?OCF ₃ < OH 595.2 546.0 564.3 564.3 582.3 615.2 601.2 1.70 (1) 1.53 (2) 1.68 (2) 1.64 (1) 1.75 (2) 1.91(2) 1.76 (1) 1328 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl]-2-chloro-3-fluoroN-[(3R,4 8)-4-fluoro-1-(3,3 ,3-trifluoro-2methylpropanoyl)pyrrolidin-3yl]benzamide Cl X^Me F ₃ C 585.3 1.80 (3)

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1329 1330 1331 1332 1333 1334 1335 1336 1337 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-2-chloro-3-fluoroΝ-[(3Κ,48)-4-φτορ -1-(3,3,3-τρπφτορ-2methylpropanoyl)pyrrolidin-3yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - 1] [ 1,2,4]triazin-7-yl]-2-chloro-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(4,4,4-τρπφτορ-3methylbutanoyl)pyrrolide in -3 yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - f] [ 1,2,4]triazin-7-yl]-2-chloro-3-fluoroΝ-[(3Κ,48)-4-φτορ-1-(4,4,4-τρπφτορ-3methylbutanoyl)pyrrolide in -3 yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - £][1,2,4]triazin-7-yl]-2,3-difluoro-X[(3Κ,48)-4-φτορ-1-[(2Κ)-3,3,3trifluoro-2-hydroxy -2methylpropanoyl]pyrrolidin-3yl]benzamide 1 (3,3-difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl]-2,3 difluorobenzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - (][1,2,4]triazin-7-yl]-2,3-difluoro-P[(ZK,48)-4-fluoro-1-(4,4,4-trifluoro-3hydroxy-3methylbutanoyl)pyrrolide in-3 yl]benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - f] [ 1,2,4]triazin-7-yl] -2,3 -d iffluoro-N[(3Κ,4δ)-4-φτορ-1 -(3,3,3 -trifluoro-2methylpropanoyl)pyrrolidine- 3 yl] benzamide 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1 - f] [1,2,4]triazin-7-yl]-H[(ZK,48)-1 (3,3-d ifluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2,3 difluorobenzamide 5-[4- amino-5(trifluoromethyl)pyrrolo[2,1 - D][1,2,4]triazin-7-yl]-2,3-difluoro-H[(3R,48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidine -3 -yl]benzamide C1 C1 C1 F F F F F F X^Me F ₃ C Me Me ^^^ CFs X/CF ₃ 'OH γλχ V/ ⁴ F Me XJ/OH CF ₃ X^Me F ₃ C ^X/Xf F A-CF3 1 he 585.1 599.1 599.1 585.1 577.1 599.1 569.1 563.3 599.0 1.80 (3) 1.72 (4) 1.88 (4) 1.78 (4) 1.75 (3) 1.76 (4) 1.88 (4) 1338 5-[4-amino-5- (trifluoromethyl)pyrrolo[2,1 f] [1,2,4]triazin-7-yl]-H-[(3H,48)-1 (3,3-d ifluorocyclobutanecarbonyl)-4fluoropyrrole idin-3-yl] -2-ethyl-3 fluorobenzamide Et ^^XXf F 573.0 1.84 (4)

NMR data for selected examples from the table. 36-49

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Table 49

Example NMR data 572 1HNMR (500 MHz, DMSO-d6) δ 8.84 - 8.60 (m, 1H), 8.17 (d, J=11.0 Hz, 1H), 8.12 - 7.95 (m, 1H), 7.86 (br d, J=18.9 Hz, 1H), 7.68 - 7.29 (m, 6H), 5.48 - 5.12 (m, 1H), 4.91 - 4.54 (m, 1H), 4.05 - 3.40 (m, 7H), 2 exchangeable protons 593 1HNMR (500 MHz, DMSO-d6) δ 8.70 (dd, J=13.8, 7.4 Hz, 1H), 8.14 (s, 1H), 7.98 - 7.87 (m, 1H), 7.75 (s, 1H), 7.56 (s , 2H), 5.45 - 5.19 (m, 1H), 4.85 - 4.56 (m, 1H), 4.20 - 3.94 (m, 2H), 3.92 (d, J=1.9 Hz, ZN), 3.84 (d, J=6.4 Hz, ZN), 3.79 - 3.74 (m, 1H), 3.57 - 3.22 (m, 1H), 2 exchangeable protons 596 1HNMR (500 MHz, DMSO-d6) δ 9.42 - 9.14 (m, 1H), 9.03 - 8.86 (m, 1H), 8.23 8.15 (m, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.11 (d, J=4.7 Hz, 1H), 5.44 - 5.18 (m, 1H), 4.88 - 4.48 (m, 1H), 4.44 - 4.22 (m, 1H) , 4.18 - 3.86 (m, 2H), 3.75 (br s, 1H), 3.00 (s, 1H), 2.96 - 2.76 (m, 1H), 2 exchangeable protons 598 1HNMR (500 MHz, DMSO-d6) δ 8.81 (br s, 1H), 8.37 (s, 1H), 8.25 - 8.19 (m, 2H), 7.72 (br d, J=8.9 Hz, 1H), 7.69 (s , 1H), 5.41 - 5.15 (m, 1H), 4.82 - 4.57 (m, 1H), 4.32 - 3.36 (m, 4H), 1.52 - 1.41 (m, 6H), 2 exchangeable protons 599 1HNMR (500 MHz, DMSO-d6) δ 8.71 (br s, 1H), 8.35 (s, 1H), 8.23 - 8.17 (m, 2H), 7.71 (br d, J=9.1 Hz, 1H), 7.67 - 7.60 (m, 1H), 5.42 - 5.07 (m, 1H), 4.85 4.51 (m, 1H), 4.33 - 3.41 (m, 4H), 1.63 - 1.47 (m, 6H), 2 exchangeable protons 629 1Н NMR (500 MHz, DMSO-d6) δ 9.11 - 9.00 (m, 1H), 8.33 (brd, >10.7Hz, 1H), 8.23 (s, 1H), 8.08 (br s, 1H), 7.77 (br s , 1H), 5.48 - 5.07 (m, 1H), 4.83 - 4.50 (m, 1H), 4.18 - 3.26 (m, overlap with water peak, 4H), 2.84 - 2.68 (m, 1H), 2.48 - 2.32 (m , 1H), 1.41 (br s, 3H), 3 exchangeable protons 630 1HNMR (500 MHz, DMSO-d6) δ 9.01 (br dd, J=14.0, 7.0 Hz, 1H), 8.32 (br d, J=10.7 Hz, 1H), 8.22 (s, 1H), 8.08 (br s, 1H), 7.77 (br d, J=3.7 Hz, 2H), 5.43 5.11 (m, 1H), 4.99 - 4.48 (m, 1H), 4.25 - 3.27 (m, 4H), 1.65 - 1.42 (m, 6H) , 2 exchangeable protons 631 1HNMR (500 MHz, DMSO-d6) δ 9.17 - 8.92 (m, 1H), 8.33 (br d, J=10.7 Hz, 1H), 8.23 (s, 1H), 8.09 (br s, 1H), 7.78 (br s, 1H), 5.44 - 5.16 (m, 1H), 4.89 - 4.50 (m, 1H), 4.33 - 3.91 (m, 1H), 3.88 - 3.56 (m, 2H), 3.51 - 2.83 (m, 2H), 2.03 - 1.78 (m, 2H), 2 exchangeable protons

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632 1HNMR (500 MHz, DMSO-d6) δ 9.13 - 8.95 (m, 1H), 8.47 - 8.28 (m, 1H), 8.28 8.20 (m, 1H), 8.10 (br s, 1H), 7.78 (br d, J =4.6 Hz, 1H), 5.45 - 5.16 (m, 1H), 4.90 - 4.52 (m, 1H), 4.34 (br s, 1H), 4.19 - 3.99 (m, 1H), 3.99 - 3.83 (m, 1H) , 3.81 3.59 (m, 1H), 3.53-3.19 (m, 1H), 3.11 - 2.94 (m, 1H), 2.94 - 2.75 (m, 1H), 2 exchangeable protons 645 1HNMR (500 MHz, DMSO-d6) δ 8.95 - 8.74 (m, 1H), 8.18 (d, J=15.9 Hz, 1H), 8.05 (brt, J=12.8 Hz, 1H), 7.90 - 7.75 (m, 1H ), 7.70 - 7.57 (m, 1H), 7.56 - 7.51 (m, 1H), 7.51 - 7.41 (m, 1H), 7.39 - 7.25 (m, 2H), 5.50 - 5.16 (m, 1H), 4.92 - 4.53 (m, 1H), 4.02 - 3.14 (m, overlap with water peak, 4H), 2.79-2.63 (m, 2H), 1.20 - 1.09 (m, 3H), 2 exchangeable protons 646 1HNMR (500 MHz, DMSO-d6) δ 8.84 (br dd, J=17.5, 6.9 Hz, 1H), 8.20 (s, 1H), 8.06 (br d, J=12.2 Hz, 1H), 7.85 (br d, J=5.8 Hz, 2H), 7.64 (d, J=6.7 Hz, 2H), 5.42 - 5.16 (m, 1H), 4.78 - 4.45 (m, 1H), 4.02 - 3.41 (m, 3H), 3.34 - 3.14 (m, 1H), 2.78 - 2.68 (m, 2H), 2.23 - 2.07 (m, 2H), 2.06 - 1.95 (m, 1H), 1.17 (brt, J=7.2 Hz, ZN), 0.96 - 0.79 (m , 6H), 2 exchangeable protons 647 1HNMR (500 MHz, DMSO-d6) δ 8.88 - 8.77 (m, 1H), 8.20 (s, 1H), 8.17 - 8.02 (m, 1H), 7.86 (s, 1H), 7.65 (s, 1H), 5.38 - 5.12 (m, 1H), 4.69 - 4.45 (m, 1H), 4.43 - 4.26 (m, 1H), 4.04 - 3.45 (m, 2H), 3.35 - 3.16 (m, 1H), 2.78-2.69 (m, 2H), 1.34 - 1.27 (m, 6H), 1.17 (brt, J=7.2 Hz, ZN), 3 exchangeable protons 662 1H NMR (500 MHz, DMSO-d6) δ 8.81 -8.68 (m, 1H), 8.17 (s, 1H), 8.03 (brd, J=11.3 Hz, 1H), 7.86 (br s, 1H), 7.58 (br s, 1H), 5.47 - 5.13 (m, 1H), 4.86 - 4.43 (m, 1H), 4.05 - 3.56 (m, 4H), 2.85 (br d, J=4.2 Hz, 1H), 2.73 - 2.54 (m , 1H), 2.46 - 2.31 (m, 1H), 2.29 (br s, 3H), 1.17 - 1.01 (m, 3H), 2 exchangeable protons 663 1HNMR (500 MHz, DMSO-d6) δ 8.82 (br dd, J=12.8, 7.0 Hz, 1H), 8.19 (s, 1H), 8.05 (brd, J=11.3 Hz, 1H), 7.87 (br s, 1H ), 7.63 (d, J=4.3 Hz, 1H), 5.43 - 5.16 (m, 1H), 4.79 - 4.48 (m, 1H), 3.96 - 3.62 (m, 3H), 3.43 - 3.13 (m, 2H), 2.28 (br s, 3H), 2.22-2.01 (m, 4H), 1.98 - 1.82 (m, 1H), 1.74 (brd, >11.0Hz, 1H), 2 exchangeable protons 664 1HNMR (500 MHz, DMSO-d6) δ 8.95 - 8.75 (m, 1H), 8.25 - 8.19 (m, 1H), 8.08 (br dd, J=10.8, 5.0 Hz, 1H), 7.92 (br d, J= 4.3 Hz, 1H), 7.67 (d, J=4.3 Hz, 1H), 5.49 - 5.18 (m, 1H), 4.84 - 4.43 (m, 1H), 4.09 - 3.79 (m, 2H), 3.76 - 3.58 (m , 2H), 3.57 - 3.27 (m, 2H), 2.30 (s, 3H), 2 exchangeable protons 667 1HNMR (400 MHz, DMSO-d6) δ 8.87 - 8.73 (m, 1H), 8.22 (s, 1H), 8.09 (d, J=11.6 Hz, 1H), 7.93 (s, 1H), 7.69 (d, J =3.4 Hz, 1H), 7.09 - 7.00 (m, 1H), 5.42 5.16 (m, 1H), 4.69 - 4.53 (m, 1H), 4.43 - 3.36 (m, 4H, absorbed by water), 2.29 (s, WN ), 1.53 (s, ZN) 668 1HNMR (400 MHz, DMSO-d6) δ 8.88 - 8.74 (m, 1H), 8.21 (s, 1H), 8.09 (br d, J=11.4 Hz, 1H), 7.92 (s, 1H), 7.68 (d, J=5.2 Hz, 1H), 5.45 - 5.17 (m, 1H), 4.83 4.52 (m, 1H), 4.11 - 3.18(m, 4H), 2.78 - 2.59 (m, 1H), 2.29 (s, 3H), 1.09-0.94(m, 6H) 670 1HNMR (400 MHz, DMSO-d6) δ 8.89 - 8.73 (m, 1H), 8.21 (d, J=9.3 Hz, 1H), 8.08 (brt, 1=11.6Hz, 1H), 7.97 - 7.85 (m, 1H ), 7.72 - 7.58 (m, 3H), 7.30 (t, J=8.9 Hz, 2H), 5.48 -5.17 (m, 1H), 4.88 - 4.50 (m, 1H), 4.11 -3.51 (m, 4H), 2.28 (br d, J=16.5 Hz, ZN) 677 1HNMR (400 MHz, DMSO-d6) δ 8.89 - 8.76 (m, 1H), 8.22 (s, 1H), 8.09 (ddd, J=11.3, 4.5, 1.7 Hz, 1H), 7.92 (dd, J=4.2, 1.6 Hz, 1H), 7.68 (d, J=6.1 Hz, 1H), 5.46 - 5.15 (m, 1H), 4.83 - 4.53 (m, 1H), 3.96 - 3.57 (m, ZN, absorbed by water), 3.48 - 3.26 (m, 1H), 3.23 - 3.09 (m, 1H), 2.88 - 2.71 (m, 4H), 2.30 (s, 3H)

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680 1HNMR (500 MHz, DMSO-d6) δ 8.66 (br dd, >14.2, 7.5 Hz, 1H), 8.20 (s, 1H), 8.17 (brd, >13.1 Hz, 1H), 8.10 (br d, >11.9 Hz , 1H); overlap m, 4H), 2.23 - 2.07 (m, 2H), 2.07 - 1.95 (m, 1H), 0.92 (dt, >6.6, 3.4 Hz, 6H), 2 exchangeable protons 681 1HNMR (500 MHz, DMSO-d6) δ 8.83 - 8.60 (m, 1H), 8.24 - 8.11 (m, 2H), 8.11 7.99 (m, 1H), 7.67 - 7.58 (m, 1H), 7.53 (br s, 1H), 7.51 - 7.44 (m, 1H), 7.33 7.33 (m, 1H), 5.53 - 5.12 (m, 1H), 4.86 - 4.61 (m, 1H), 3.98 - 3.90 (m, 3H overlap) 4.07 - 3.41 (overlap m, partially suppressed, 4H), 2 exchangeable protons 682 1HNMR (500 MHz, DMSO-d6) δ 8.65 (br dd, 1=13.3, 7.5 Hz, 1H), 8.19 (s, 1H), 8.16 (brd, >13.4 Hz, 1H), 8.08 (br d, >9.2 Hz, 1H), 7.62 (br d, >3.4 Hz, 1H), 5.39 - 5.12 (m, 1H), 4.87 - 4.49 (m, 1H), 3.95 (br d, J=3.7 Hz, ZN), 3.91 - 3.10 (m, 5H), 2.26 - 2.03 (m, 4H), 1.96 - 1.85 (m, 1H), 1.76 (br s, 1H), 2 exchangeable protons 686 1HNMR (400 MHz, DMSO-d6) δ 8.75 - 8.61 (m, 1H), 8.24 - 8.15 (m, 2H), 8.10 (dd, >11.0, 1.0 Hz, 1H), 7.65 (d, >3.1 Hz, 1H ), 7.07 (brd, >5.9 Hz, 1H), 5.39 5.15 (m, 1H), 4.77 - 4.55 (m, 1H), 4.49 - 4.25 (m, 1H), 4.11 -3.31 (m, 6H), 1.53 ( s, 3H) 687 1HNMR (500 MHz, DMSO-d6) δ 8.66 (br dd, >14.8, 7.5 Hz, 1H), 8.19 (s, 1H), 8.17 (brd, >13.4 Hz, 1H), 8.09 (brd, J=9.5 Hz , 1H), 7.63 (brd, >4.0 Hz, 1H), 5.39-5.19 (m, 1H), 5.19 - 4.89 (m, 1H), 4.88 - 4.53 (m, 1H), 3.95 (br d, J=4.3 Hz, 3H), 3.92 - 3.16 (m, 4H), 2.78 - 2.46 (m, 3H), 2.43 - 2.36 (m, 1H), 2.31 - 2.12 (m, 1H), 2 exchangeable protons 688 1HNMR (500 MHz, DMSO-d6) δ 8.70 (br dd, >19.5, 7.0 Hz, 1H), 8.18 (s, 1H), 8.14(brs, 1H), 8.06 (br s, 1H), 7.61 (s, 1H), 5.45 - 5.16 (m, 1H), 4.90 - 4.54 (m, 1H), 4.32 - 3.97 (m, 1H), 3.94 (s, 3H), 3.91 - 3.57 (m, 1H), 3.44 (br s , 2H), 1.50 0.91 (m, 4H), 2 exchangeable protons 689 1HNMR (500 MHz, DMSO-d6) δ 8.67 (br dd, >16.6, 7.8 Hz, 1H), 8.17 (s, 1H), 8.15 (brd, >13.1 Hz, 1H), 8.11 -8.03 (m, 1H) , 7.60 (brd, >4.3 Hz, 1H), 5.465.14 (m, 1H), 4.85 - 4.54 (m, 1H), 4.10 - 3.78 (overlap m, 1H), 3.94 (br d, >9.5 Hz, ZN ), 3.75 - 3.18 (m, 3H), 2.69 - 2.55 (m, 1H), 2.04 (br d, >8.9 Hz, 2H), 1.96 - 1.69 (m, 4H), 1.65 - 1.45 (m, 2H), 2 exchangeable protons 690 1HNMR (400 MHz, DMSO-d6) δ 8.94 (d, >16.3 Hz, 1H), 8.73 (dd, >14.0, 7.6 Hz, 1H), 8.24 - 8.14 (m, 2H), 8.10 (br d, >8.0 Hz, 1H), 7.64 (d, >3.3 Hz, 1H), 5.48 - 5.20 (m, 1H), 4.91 - 4.55 (m, 1H), 4.24 - 2.91 (m, 9H, absorbed by water) 701 1HNMR (500 MHz, DMSO-d6) δ 8.98 - 8.83 (m, 1H), 8.20 (s, 1H), 8.15 (br s, 1H), 8.03 (s, 1H), 7.63 (d, >3.4 Hz, 1H ), 5.41 - 5.14 (m, 1H), 4.90 - 4.46 (m, 1H), 4.11 - 3.50 (m, 3H), 3.47 - 3.17 (m, 1H), 2.92 - 2.78 (m, 1H), 2.75 - 2.57 (m, 1H), 2.45 (s, 3H), 2.42 - 2.16 (m, 1H), 1.15 - 1.07 (m, 3H), 2 exchangeable protons 702 1HNMR (500 MHz, DMSO-d6) δ 9.02 - 8.90 (m, 1H), 8.18 (s, 1H), 8.15 - 8.10 (m, 1H), 8.00 (br s, 2H), 7.60 (d, >2.4 Hz , 2H), 5.44 - 5.13 (m, 1H), 4.87 - 4.51 (m, 1H), 4.23 - 3.84 (m, 2H), 3.82 - 3.56 (m, 1H), 3.39 - 2.87 (m, 3H), 2.44 (s, 3H), 2 exchangeable protons 709 1HNMR (400 MHz, DMSO-d6) δ 8.97 - 8.85 (m, 1H), 8.21 (s, 1H), 8.15 (dd, >3.6, 2.0 Hz, 1H), 8.04 (t, >2.0 Hz, 1H), 7.63 (d, >2.6 Hz, 1H), 5.44 - 5.15 (m, 1H), 4.83 - 4.52 (m, 1H), 4.42 - 4.26 (m, 1H), 4.16 - 3.59 (m, ZH, absorbed by water), 3.50 - 3.24 (m, 1H), 3.10 - 2.76 (m, 2H), 2.45 (s, 3H)

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711 1HNMR (500 MHz, DMSO-d6) δ 9.00 - 8.85 (m, 1H), 8.19 (s, 1H), 8.17-8.11 (m, 1H), 8.02 (br s, 1H), 7.62 (s, 1H), 5.43 - 5.14 (m, 1H), 4.83 - 4.47 (m, 1H), 4.16 - 3.56 (m, 4H), 3.35 - 2.66 (m, 2H), 1.42 (s, 3H), 2 exchangeable protons 719 1HNMR (500 MHz, DMSO-d6) δ 9.31 - 9.21 (m, 1H), 8.12 (s, 1H), 7.94 (q, J=7.3 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.34 (s , 1H), 5.39 - 5.06 (m, 1H), 4.81 - 4.53 (m, 1H), 4.01 - 3.75 (m, 2H), 3.74 - 3.49 (m, 1H), 3.44 - 3.11 (m, 1H), 2.24 - 2.07 (m, 2H), 2.06 - 1.96 (m, 1H), 0.94 -0.88 (m, 6H), 2 exchangeable protons 720 1HNMR (400 MHz, DMSO-d6) δ 9.38 - 9.24 (m, 1H), 8.89 (d, J=12.7 Hz, 1H), 8.16 - 8.07 (m, 1H), 8.00 - 7.88 (m, 1H), 7.41 - 7.28 (m, 2H), 5.45 - 5.15 (m, 1H), 4.90 - 4.52 (m, 1H), 4.24 - 3.83 (m, 2H), 3.76 (s, 1H), 3.14 - 2.89 (m, 2H) . 1 proton under the water peak. 721 1H NMR (500 MHz, DMSO-d6) δ 9.41 -9.14(m, 1H), 8.11 (s, 1H), 8.02-7.87 (m, 1H), 7.41 - 7.26 (m, 2H), 5.44 - 4.94 (m , 1H), 4.84 - 4.48 (m, 1H), 4.24 - 3.79 (m, 2H), 3.77 - 3.12 (m, 2H), 2.94 - 2.66 (m, 1H), 2.48 - 2.29 (m, 1H), 1.41 (s, 3H), 3 exchangeable protons 722 1HNMR (500 MHz, DMSO-d6) δ 9.39 - 9.17 (m, 1H), 8.11 (s, 1H), 7.98 - 7.86 (m, 1H), 7.38 - 7.34 (m, 1H), 7.34 (s, 1H) , 7.22 - 7.06 (m, 1H), 5.35 - 5.14 (m, 1H), 4.74 - 4.53 (m, 1H), 4.46 - 3.26 (m, 4H), 1.52 (s, 3H), 2 exchangeable protons 734 1HNMR (500 MHz, DMSO-d6) δ 9.20 - 8.95 (m, 1H), 8.11 (s, 1H), 7.80 (br t, J=7.5 Hz, 1H), 7.28 (br s, 2H), 6.45 - 6.31 (m, 1H), 5.51 - 5.13 (m, 1H), 4.76 - 4.45 (m, 1H), 4.20 - 3.43 (m, 3H), 3.33 - 3.14 (m, 1H), 2.84 - 2.72 (m, 1H), 2.68 (q, J=7.4 Hz, 2H), 2.49 - 2.30 (m, 1H), 1.41 (br s, 3H), 1.22 (br t, J=7.3 Hz, 3H), 2 exchangeable protons 735 1HNMR (500 MHz, DMSO-d6) δ 9.22 - 8.95 (m, 1H), 8.10 (s, 1H), 7.79 (br t, J=6.1 Hz, 1H), 7.32 - 7.24 (m, 2H), 5.45 - 5.15 (m, 1H), 4.86 - 4.42 (m, 1H), 4.09 - 3.09 (m, 6H), 2.74 - 2.61 (m, 2H), 1.22 (br t, J=7.5 Hz, ZN), 2 capable of proton exchange 736 1HNMR (500 MHz, DMSO-d6) δ 9.14 - 9.01 (m, 1H), 8.10 (s, 1H), 7.84 - 7.74 (m, 1H), 7.31 - 7.23 (m, 2H), 5.46 - 5.12 (m, 1H), 4.89 - 4.50 (m, 1H), 4.42 - 4.21 (m, 1H), 4.18-3.47 (m, 3H), 3.34 - 3.15 (m, 1H), 3.09 - 2.93 (m, 1H), 2.91 - 2.72 (m, 1H), 2.72 - 2.62 (m, 2H), 1.21 (td, J=7.5, 2.4 Hz, ZN), 2 capable of proton exchange 745 1HNMR (500 MHz, DMSO-d6) δ 9.14 - 8.95 (m, 1H), 8.08 (s, 1H), 7.73 (br t, J=7.6 Hz, 1H), 7.27 (s, 1H), 7.23 (br d , J=7.6 Hz, 1H), 5.39 - 5.08 (m, 1H), 4.76 4.46 (m, 1H), 4.46 - 4.20 (m, 1H), 4.11-3.62 (m, 2H), 3.54 - 3.26 (m, 1H), 2.33 (s, 3H), 2.22 - 1.99 (m, 1H), 1.84 - 1.59 (m, 1H), 0.97 - 0.78 (m, 3H), 3 exchangeable protons 746 1HNMR (500 MHz, DMSO-d6) δ 9.18 - 8.85 (m, 1H), 8.10 (s, 1H), 7.75 (br t, J=7.8 Hz, 1H), 7.27 (s, 1H), 7.24 (br d , J=7.6 Hz, 1H), 5.52 - 5.09 (m, 1H), 4.88 4.47 (m, 1H), 4.18-3.44 (m, 3H), 3.32-3.12 (m, 1H), 2.84 - 2.65 (m, 1H), 2.48 2.40 (m, 1H), 2.34 (s, 3H), 1.41 (s, 3H), 3 exchangeable protons 747 1HNMR (500 MHz, DMSO-d6) δ 9.08 (br dd, J=18.9, 7.3 Hz, 1H), 8.10 (s, 1H), 7.84 - 7.62 (m, 1H), 7.28 (s, 1H), 7.25 ( br d, J=7.9 Hz, 1H), 5.52 - 5.06 (m, 1H), 4.94 - 4.56 (m, 1H), 4.31 - 3.50 (m, 3H), 3.53 - 3.10 (m, partly below the water peak, 1H ), 2.35 (s, 3H), 1.48 - 1.05 (m, 4H), 3 exchangeable protons

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748 1HNMR (500 MHz, DMSO-d6) δ 9.15 - 8.92 (m, IH), 8.15 - 8.04 (m, IH), 7.83 7.68 (m, IH), 7.28 (s, IH), 7.27 - 7.14 (m, IH ), 5.41 - 5.06 (m, IH), 4.80 - 4.51 (m, IH), 3.96 - 3.17 (m, 4H), 2.35 (s, 3H), 2.22 - 2.05 (m, 2H), 2.05 - 1.94 (m, IH), 0.91 (dt, >6.5, 4.3 Hz, 6H), 2 exchangeable protons 759 1HNMR (400 MHz, DMSO-d6) δ 8.97 - 8.85 (m, IH), 8.21 (s, IH), 8.15 (dd, >3.6, 2.0 Hz, IH), 8.04 (t, >2.0 Hz, IH), 7.63 (d, J=2.6 Hz, IH), 5.44 - 5.15 (m, IH), 4.83 - 4.52 (m, IH), 4.42 - 4.26 (m, IH), 4.16 - 3.59 (m, WN, absorbed by water) , 3.50 - 3.24 (m, IH), 3.10 - 2.76 (m, 2H), 2.45 (s, 3H) 763 1HNMR (500 MHz, DMSO-d6) δ 8.79 (br d, J=6.7 Hz, IH), 8.10 (s, IH), 7.91 (br s, IH), 7.66 (br s, IH), 7.42 (br t , J=7.3 Hz, IH), 7.35 (s, IH), 5.44 - 5.04 (m, IH), 4.85 - 4.49 (m, IH), 3.91 - 3.63 (m, partially suppressed, 4H), 3.55 - 3.31 ( m, IH), 3.30 - 3.20 (m, IH), 2.23 - 2.01 (m, 4H), 1.99 - 1.83 (m, IH), 1.74 (br d, >9.5 Hz, IH), 2 exchangeable protons 764 1HNMR (500 MHz, DMSO-d6) δ 8.84 (br d, J=7.0 Hz, IH), 8.06 (s, IH), 7.89 (brs, IH), 7.66 (br s, IH), 7.47-7.37 (m , IH), 7.33 (s, IH), 5.36 - 5.11 (m, IH), 4.91 - 4.46 (m, IH), 3.98 - 3.13 (m, overlap with water peak, 4H), 2.22 2.05 (m, 2H) , 2.03 - 1.89 (m, IH), 0.94 - 0.77 (m, 6H), 2 exchangeable protons 771 1HNMR (500 MHz, DMSO-d6) δ 8.65 (br d, J=6.3 Hz, IH), 8.08 (s, IH), 7.92 (br s, IH), 7.68 (br s, IH), 7.42 (br t , J=7.7 Hz, IH), 7.32 (s, IH), 5.40 - 5.18 (m, IH), 5.17 - 4.84 (m, IH), 4.77 - 4.42 (m, IH), 3.93 - 3.22 (m, overlap with water peak, 4H), 3.02 - 2.65 (m, IH), 2.48 - 2.32 (m, 2H), 2.32 - 2.14 (m, IH), 2 exchangeable protons 773 1HNMR (500 MHz, DMSO-d6) δ 8.90 - 8.73 (m, IH), 8.11 (s, IH), 7.93 (br s, IH), 7.67 (br s, IH), 7.47 - 7.38 (m, IH) , 7.35 (s, IH), 5.46 - 5.11 (m, IH), 4.90 4.54 (m, IH), 4.32 - 3.60 (m, 3H), 3.50 - 3.24 (m, IH), 3.12 - 2.74 (m, IH ), 2.03 1.77 (m, 2H), 2 exchangeable protons 774 1HNMR (500 MHz, DMSO-d6) d 8.80 (br t, J=7.6 Hz, IH), 8.09 (s, IH), 7.91 (br t, >6.9 Hz, IH), 7.67 (q, >6.1 Hz, IH), 7.42 (br t, J=7.6 Hz, IH), 7.35 (s, IH), 7.21 (brd, >3.7 Hz, IH), 5.35-5.13 (m, IH), 4.69 - 4.51 (m, IH ), 4.46 - 4.25 (m, IH), 4.04 - 3.12 (m, 3H), 1.52 (s, 3H) 775 1HNMR (500 MHz, DMSO-d6) δ 8.85 - 8.71 (m, IH), 8.17 - 8.09 (m, IH), 8.05 (brt, >7.5 Hz, IH), 7.58 (brt, >10.1 Hz, IH), 7.38 (s, 2H), 5.45 - 5.10 (m, IH), 4.84 - 4.49 (m, IH), 4.08 - 3.15 (m, 6H), 2 exchangeable protons 776 1HNMR (500 MHz, DMSO-d6) δ 8.79 - 8.65 (m, IH), 8.12 (s, IH), 8.10 - 8.02 (m, IH), 7.58 (brt, >10.1 Hz, IH), 7.38 (s, IH), 5.39 - 5.08 (m, IH), 4.71 - 4.46 (m, IH), 4.43 - 4.22 (m, IH), 4.06 - 3.54 (m, 2H), 1.32 - 1.26 (m, 6H), 3 capable to proton exchange 777 1HNMR (500 MHz, DMSO-d6) δ 8.84 - 8.69 (m, IH), 8.11 (s, IH), 8.08 - 8.00 (m, IH), 7.57 (brt, >9.0 Hz, 2H), 7.37 (s, 2H), 5.39 - 5.12 (m, IH), 4.81 -4.46 (m, IH), 4.01 - 3.12 (m, 4H), 2.27 - 1.89 (m, 3H), 0.90 (s, 6H), 2 exchangeable proton 778 1HNMR(500 MHz, DMSO-d6) δ 8.72 (br dd, >15.6, 7.0 Hz, IH), 8.11 (s, IH), 8.08 - 7.99 (m, IH), 7.57 (brt, >10.1 Hz, IH) , 7.37 (s, IH), 5.40 - 4.83 (m, 2H), 4.77 - 4.47 (m, IH), 3.98 - 3.40 (m, 3H), 3.38 - 2.65 (m, partially suppressed, SA), 2.44 - 2.32 (m, 2H), 2.31 - 2.16 (m, IH), 2 exchangeable protons 783 1HNMR (400 MHz, DMSO-d6) δ 8.76 (dd, >13.2, 7.5 Hz, IH), 8.13 (s, IH), 8.06 (t, >8.0 Hz, IH), 7.65 - 7.56 (m, IH), 7.39 (s, IH), 5.46 - 5.16 (m, IH), 4.84 - 4.51 (m, IH), 4.43 - 4.24 (m, IH), 4.16-3.42 (m, 4H), 3.10 - 2.75 (m, 2H ).

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784 1HNMR (400 MHz, DMSO-d6) δ 8.97 - 8.86 (m, 1Η), 8.79 (dd, J=18.4, 7.4 Hz, 1H), 8.13 (s, 1H), 8.06 (td, J=8.0, 1.9 Hz , 1H), 7.61 (t, J=10.2 Hz, 1H), 7.39 (s, 1H), 5.47 - 5.15 (m, 1H), 4.86 - 4.51 (m, 1H), 4.22 - 3.85 (m, 2H), 3.82 - 3.45 (m, 2H), 3.19-2.88 (m, 2H) 790 1HNMR(500 MHz, DMSO-d6) δ 8.73 (br dd, J=19.1, 6.9 Hz, 1H), 8.12 (s, 1H), 8.05 (brd, 1=6.7Hz, 1H), 7.57 (brt, J= 10.1 Hz, 1H), 7.37 (s, 1H), 7.08 (brd, J=4.9 Hz, 1H), 5.36 - 5.13 (m, 1H), 4.72 - 4.51 (m, 1H), 4.45 - 4.23 (m, 1H ), 4.06 - 3.56 (m, 2H), 3.40 - 3.11 (m, 1H), 1.52 (s, 3H) 791 1HNMR (500 MHz, DMSO-d6) δ 8.54 (br dd, J=11.2, 7.4 Hz, 1H), 8.09 (s, 1H), 7.79 (brd, 1=7.0Hz, 1H), 7.39-7.19 (m, 2H), 5.41-5.07 (m, 1H), 4.79 - 4.31 (m, 1H), 3.90 - 3.07 (m, overlap with water peak, 4H), 2.45 (s, 3H), 2.25 2.02 (m, 4H), 1.99 - 1.85 (m, 1H), 1.78 (br dd, J=8.3, 5.0 Hz, 1H), 2 exchangeable protons 792 1Н NMR (500 MHz, DMSO-d6) δ 8.87 - 8.60 (m, 1H), 8.08 (br d, J=11.6 Hz, 1H), 7.81 - 7.66 (m, 1H), 7.66 - 7.50 (m, 2H) , 7.38 - 7.20 (m, 4H), 5.44 - 5.08 (m, 1H), 4.85 - 4.47 (m, 1H), 4.07 - 3.44 (m, overlap with water peak, 4H), 2.47 - 2.33 (m, WN) , 2 exchangeable protons 793 1HNMR(500 MHz, DMSO-d6) δ 8.67 (br dd, J=18.8, 7.2 Hz, 1H), 8.11 (s, 1H), 7.78 (d, J=7.3 Hz, 1H), 7.36 - 7.29 (m, 2H), 5.41 - 5.10 (m, 1H), 4.82 - 4.39 (m, 1H), 4.04 - 3.40 (m, 3H), 3.32-3.14 (m, 1H), 2.76 - 2.59 (m, 1H), 2.44 ( d, J=3.7 Hz, ZN), 1.06 - 0.96 (m, 6H), 2 exchangeable protons 794 1HNMR(500 MHz, DMSO-d6) δ 8.67 (br dd, J=15.4, 7.2 Hz, 1H), 8.11 (s, 1H), 7.78 (br d, J=7.0 Hz, 1H), 7.37 - 7.29 (m , 2H), 5.41 - 5.02 (m, 1H), 4.84 - 4.44 (m, 1H), 4.00 - 3.40 (m, 3H), 3.37 - 3.13 (m, 1H), 2.44 (d, J=2.7 Hz, ZN ), 2.23 2.05 (m, 2H), 2.05 - 1.93 (m, 1H), 0.96 - 0.83 (m, 6H), 2 exchangeable protons 799 1HNMR (400 MHz, DMSO-d6) δ 8.77 - 8.64 (m, 1H), 8.11 (s, 1H), 7.78 (dd, J=7.4, 2.8 Hz, 1H), 7.33 (t, J=5.6 Hz, 2H ), 5.46 - 5.15 (m, 1H), 4.79 - 4.49 (m, 1H), 4.43 - 3.59 (m, 4H, absorbed by water), 3.50 - 3.24 (m, 1H), 3.09 - 2.96 (m, 1H), 2.92 - 2.76 (m, 1H), 2.44 (d, J=1.3 Hz, ZN) 802 1HNMR (400 MHz, DMSO-d6) δ 8.99 - 8.87 (m, 1H), 8.80 - 8.63 (m, 1H), 8.11 (s, 1H), 7.78 (dd, J=7.4, 3.9 Hz, 1H), 7.33 (t, J=5.6 Hz, 2H), 5.47 - 5.16 (m, 1H), 4.82-4.51 (m, 1H), 4.17-2.87 (m, 6H), 2.44 (s, 3H) 807 1HNMR (500 MHz, DMSO-d6) δ 8.72 - 8.56 (m, 1H), 8.09 (s, 1H), 7.80 (br d, J=7.2 Hz, 1H), 7.38 - 7.21 (m, 3H), 5.44 - 5.15 (m, 1H), 4.96 - 4.47 (m, 1H), 4.26 - 3.45 (m, 4H), 3.08 - 2.78 (m, 1H), 2.45 (br d, J=4.1 Hz, ZN), 1.94 (dt , J=12.9, 6.2 Hz, 1H), 1.89 - 1.77 (m, 1H), 2 exchangeable protons 838 1HNMR (500 MHz, DMSO-d6) δ 9.07 - 8.92 (m, 1H), 8.29 - 8.20 (m, 2H), 8.04 (br s, 2H), 7.76 (s, 3H), 5.71 - 5.51 (m, 2H ), 5.46 - 5.18 (m, 1H), 4.84 - 4.56 (m, 1H), 4.29 - 3.59 (m, 4H), 4.32 - 3.39 (m, 2H), 1.54 - 0.96 (m, 4H), 2 capable of proton exchange 842 1HNMR (500 MHz, DMSO-d6) δ 8.90 - 8.70 (m, 1H), 8.03 (d, J=10.7 Hz, 1H), 7.79 (td, J=7.4, 3.8 Hz, 1H), 7.75 - 7.64 (m , 1H), 7.53 - 7.48 (m, 1H), 7.43 - 7.16 (m, 3H), 5.39 - 5.13 (m, 1H), 4.78 - 4.43 (m, 1H), 4.12 - 3.92 (m, 2H), 3.78 - 3.44 (m, 2H), 2.49 - 2.42 (m, 3H), 2.42 - 2.34 (m, 3H), 2 exchangeable protons 856 1HNMR (500 MHz, DMSO-d6) δ 8.64 - 8.53 (m, 1H), 8.09 (s, 1H), 7.80 (br d, J=7.2 Hz, 1H), 7.34 - 7.24 (m, 2H), 5.42 - 5.17 (m, 1H), 4.74 - 4.49 (m, 1H), 4.15 - 3.40 (m, 4H), 3.36 - 3.30 (m, 2H, absorbed by water), 2.84 - 2.67 (m, 1H), 2.45 (s, 3H), 1.42(s, 3H)

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857 1HNMR (500 MHz, DMSO-d6) δ 8.75 - 8.60 (m, 1H), 8.11 (s, 1H), 7.79 (br d, J=7.3 Hz, 1H), 7.37 - 7.28 (m, 2H), 5.40 - 5.12 (m, 1H), 4.72 - 4.46 (m, 1H), 4.43 - 4.22 (m, 1H), 4.10 - 3.59 (m, 3H), 2.44 (s, 3H), 2.23 - 1.99 (m, 1H), 1.86 - 1.67 (m, 1H), 0.98 - 0.78 (m, 3H) 858 1HNMR (500 MHz, DMSO-d6) δ 8.10 (s, 1H), 7.81 (br d, J=7.3 Hz, 1H), 7.36 7.26 (m, 2H), 5.44 - 5.16 (m, 1H), 4.81-4.56 (m, 1H), 4.21-3.21 (m, 5H), 2.46 (d, J=2.5 Hz, VN), 1.28 (td, J=6.8, 2.4 Hz, VN) 859 1HNMR (500 MHz, CD ₃ OD) δ 8.03 (s, 1H), 8.00 (dd, J=7.3, 1.3 Hz, 1H), 7.28 (s, 1H), 7.23 (dd, J=11.4, 4.2 Hz, 1H ), 5.43 - 5.23 (m, 1H), 4.84 - 4.69 (m, 1H), 4.22 - 3.20 (m, 5H, absorbed by MeOH), 2.52 (d, J=4.2 Hz, ZH), 2.46 - 1.85 (m, 6H). 860 1HNMR (500 MHz, CD ₃ OD) δ 8.03 (s, 1H), 8.00 (dd, J=7.3, 1.3 Hz, 1H), 7.28 (s, 1H), 7.23 (dd, J=11.4, 4.2 Hz, 1H ), 5.43 - 5.23 (m, 1H), 4.84 - 4.69 (m, 1H), 4.22 - 3.20 (m, 5H, absorbed by MeOH), 2.52 (d, J=4.2 Hz, ZH), 2.46 - 1.85 (m, 6H). 861 1HNMR (400 MHz, DMSO-d6) δ 8.78 - 8.61 (m, 1H), 8.11 (s, 1H), 7.79 (dd, J=7.1, 5.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 5.45 - 5.15 (m, 1H), 4.87 - 4.53 (m, 1H), 4.27 - 4.08 (m, 1H), 3.99 - 3.27 (m, SA, absorbed by water), 3.14 - 2.96 (m, 1H), 2.45 (d , J=4.8 Hz, ZN), 1.99 - 1.79 (m, 2H). 862 1HNMR (400 MHz, DMSO-d6) δ 8.78 - 8.61 (m, 1H), 8.11 (s, 1H), 7.79 (dd, J=7.1, 5.7 Hz, 1H), 7.37 - 7.27 (m, 2H), 5.45 - 5.15 (m, 1H), 4.87 - 4.53 (m, 1H), 4.27 - 4.08 (m, 1H), 3.99 - 3.27 (m, SA, absorbed by water), 3.14 - 2.96 (m, 1H), 2.45 (d , J=4.8 Hz, ZN), 1.99 - 1.79 (m, 2H). 863 1HNMR (500 MHz, DMSO-d6) δ 8.77 - 8.64 (m, 1H), 8.09 (s, 1H), 7.77 (br d, J=6.7 Hz, 1H), 7.38 - 7.27 (m, 2H), 5.41 - 5.17 (m, 1H), 4.81 - 4.47 (m, 1H), 4.34 - 3.29 (m, 4H), 2.43 (br s, 3H), 1.88 - 1.70 (m, 3H) 864 1HNMR (500 MHz, DMSO-d6) δ 8.80 - 8.67 (m, 1H), 8.15 - 8.07 (m, 3H), 7.87 7.74 (m, 1H), 7.39 - 7.27 (m, 2H), 5.45 - 5.23 (m , 1H), 4.84 - 4.54 (m, 1H), 4.30 3.20 (m, 4H), 2.45 (br d, J=15.3 Hz, ZN) 865 1HNMR (500 MHz, DMSO-d6) δ 9.34 (brt, J=4.1 Hz, 1H), 8.82 - 8.68 (m, 1H), 8.10 (brd, 1=10.4Hz, 1H), 8.01 (brd, 1=8.8 Hz, 1H), 7.91 - 7.83 (m, 1H), 7.82 7.73 (m, 1H), 7.36 - 7.25 (m, 2H), 5.47 - 5.22 (m, 1H), 4.86 - 4.57 (m, 1H), 4.25 3.40 (m, 4H, absorbed by water), 2.44 (br d, J=16.5 Hz, SA) 866 1HNMR (500 MHz, DMSO-d6) δ 8.81 - 8.70 (m, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.91 (dd, J=8.6, 1.9 Hz, 1H), 7.84 - 7.70 (m , 2H), 7.37 - 7.26 (m, 2H), 5.44 - 5.22 (m, 1H), 4.84 - 4.58 (m, 1H), 4.26 - 3.40 (m, 4H, absorbed by water), 2.69 (d, J=5.5 Hz, ZN), 2.44 (d, J=15.4 Hz, ZN) 867 1HNMR (400 MHz, DMSO-d6) δ 8.45 - 8.29 (m, 1H), 8.19 (dd, J=9.8, 8.8 Hz, 1H), 8.11 (d, J=0.7 Hz, 1H), 7.35 - 7.24 (m , 2H), 7.05 (d, J=4.0 Hz, 1H), 5.38 5.12 (m, 1H), 4.77 - 4.55 (m, 1H), 4.52 - 4.24 (m, 1H), 4.09 - 3.34 (m, 6H) , 1.53(s, 3H) 868 1HNMR (500 MHz, DMSO-d6) δ 8.47 - 8.32 (m, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 7.27 (brd, 1 =12.2Hz, 1H), 5.38 - 5.13 (m, 1H), 4.84 4.55 (m, 1H), 4.26 - 4.00 (m, 1H), 3.97 (s, 3H), 3.95 - 3.61 (m, 2H), 3.48 - 3.28 (m, 1H), 1.58 - 1.48 (m, 6H), 2 exchangeable protons 873 1HNMR (500 MHz, DMSO-d6) δ 8.48 - 8.32 (m, 1H), 8.18 (br d, J=8.5 Hz, 1H), 8.08 (brd, 1=12.2 Hz, 1H), 7.69 - 7.54 (m, 2H), 7.37 - 7.20 (m, 4H), 5.47 - 5.10 (m, 1H), 4.93 - 4.50 (m, 1H), 3.97 (br s, 3H), 3.90 - 3.44 (m, 4H), 2 capable of proton exchange

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875 1HNMR (500 MHz, DMSO-d6) δ 8.36 (br t, J=8.1 Hz, 1H), 8.26 - 8.16 (m, 1H), 8.10 (s, 1H), 7.33 -7.23 (m, 2H), 5.42 - 5.16 (m, 1H), 4.87 - 4.53 (m, 1H), 4.09 3.14 (m, 7H), 2.94 - 2.78 (m, 1H), 2.74 - 2.20 (m, 2H, absorbed by DMSO), 1.15 1.05 (m, 3H) 876 1HNMR (500 MHz, DMSO-d6) δ 8.37 (br t, J=7.0 Hz, 1H), 8.26 - 8.16 (m, 1H), 8.09 (s, 1H), 7.36 - 7.25 (m, 2H), 5.46 - 5.17 (m, 1H), 4.87 - 4.56 (m, 1H), 4.41 4.23 (m, 1H), 4.17-2.68 (m, 9H) 877 1HNMR (500 MHz, DMSO-d6) δ 8.46 - 8.30 (m, 1H), 8.17 (br d, J=7.9 Hz, 1H), 8.09 (s, 1H), 7.36 - 7.19 (m, 2H), 5.42 - 5.12 (m, 1H), 4.78 - 4.53 (m, 1H), 4.51 4.23 (m, 1H), 4.10-3.30 (m, 6H, absorbed by water), 2.23 - 1.99 (m, 1H), 1.83 1.66 (m, 1H), 0.97 - 0.79 (m, 3H) 878 1HNMR (500 MHz, DMSO-d6) δ 8.46 - 8.35 (m, 1H), 8.26 - 8.14 (m, 1H), 8.08 (s, 1H), 7.33 - 7.21 (m, 2H), 5.41 - 5.17 (m, 1H), 4.87 - 4.59 (m, 1H), 4.23 - 3.25 (m, 8H, absorbed by water), 1.26 (br d, J=5.8 Hz, WN) 879 1HNMR (500 MHz, DMSO-d6) δ 8.43 - 8.33 (m, 1H), 8.25 - 8.14 (m, 1H), 8.10 (s, 1H), 7.35 - 7.24 (m, 2H), 5.41 - 5.18 (m, 1H), 4.83 - 4.51 (m, 1H), 4.25 - 3.12 (m, 7H), 2.84 - 2.68 (m, 1H), 2.53 - 2.32 (m, 1H, absorbed by DMSO), 1.41 (br s, 3H) 880 1HNMR (500 MHz, DMSO-d6) δ 9.01 - 8.86 (m, 1H), 8.12 (s, 1H), 7.92 (br d, J=7.3 Hz, 1H), 7.71 (br d, J=9.8 Hz, 1H ), 7.38 (s, 1H), 5.39 - 5.08 (m, 1H), 4.70 4.47 (m, 1H), 4.45 - 4.21 (m, 1H), 4.08 - 3.32 (m, W, absorbed by water), 2.22 1.97 ( m, 1H), 1.74 (tt, J=13.7, 6.6 Hz, 1H), 0.97 - 0.81 (m, 3H) 881 1HNMR (500 MHz, DMSO-d6) δ 9.03 - 8.87 (m, 1H), 8.13 (s, 1H), 7.97 - 7.89 (m, 1H), 7.73 (brd, J=10.1 Hz, 1H), 7.38 (s , 1H), 5.39-5.13 (m, 1H), 4.75-4.46 (m, 1H), 4.17-3.14 (m, 4H), 2.86-2.66 (m, 1H), 2.50-2.31 (m, 1H, absorbed by DMSO ), 1.40 (br s, 3H) 882 1HNMR (500 MHz, DMSO-d6) δ 8.94 (br dd, J=19.5, 7.3 Hz, 1H), 8.13 (s, 1H), 7.93 (brdd, J=7.3, 3.1 Hz, 1H), 7.73 (brd, 1=9.8Hz, 1H), 7.39 (s, 1H), 5.39 5.14 (m, 1H), 4.77 - 4.47 (m, 1H), 4.06-3.53 (m, 3H), 3.47 - 3.14 (m, 1H, absorbed water), 2.83 (br s, 1H), 2.72 - 2.23 (m, 2H, taken up in DMSO) 883 1HNMR (500 MHz, DMSO-d6) δ 8.94 (br dd, J=19.5, 7.3 Hz, 1H), 8.13 (s, 1H), 7.93 (brdd, J=7.3, 3.1 Hz, 1H), 7.73 (brd, 1=9.8Hz, 1H), 7.39 (s, 1H), 5.39 5.14 (m, 1H), 4.77 - 4.48 (m, 1H), 4.06-3.53 (m, 3H), 3.46 - 3.14 (m, 1H, absorbed water), 2.83 (br s, 1H), 2.72 - 2.19 (m, 2H, absorbed by DMSO), 1.10 (q, J=6.8 Hz, SA) 884 1HNMR (500 MHz, DMSO-d6) δ 9.03 - 8.89 (m, 1H), 8.13 (s, 1H), 7.93 (br t, J=6.9 Hz, 1H), 7.73 (br d, J=9.8 Hz, 1H ), 7.39 (s, 1H), 5.41 - 5.15 (m, 1H), 4.82 4.55 (m, 1H), 4.21 - 3.15 (m, 5H, absorbed by water), 1.30 - 1.20 (m, WN) 885 1HNMR (500 MHz, DMSO-d6) δ 9.05 - 8.83 (m, 2H), 8.13 (s, 1H), 7.93 (t, J=6.9 Hz, 1H), 7.73 (d, J=9.8 Hz, 1H), 7.38 (s, 1H), 5.43 - 5.15 (m, 1H), 4.82 - 4.52 (m, 1H), 4.20 - 3.61 (m, 3H), 3.50 - 2.88 (m, SA, absorbed by water) 886 1HNMR (500 MHz, DMSO-d6) δ 8.95 (br dd, J=18.5, 7.5 Hz, 1H), 8.12 (s, 1H), 7.92 (brdd, J=7.3, 3.1 Hz, 1H), 7.71 (brd, J=9.5 Hz, 1H), 7.38 (s, 1H), 5.39 5.12 (m, 1H), 4.79 - 4.51 (m, 1H), 4.10 - 3.09 (m, 5H, absorbed by water), 2.41 2.23 (m, 2H ), 2.21 - 1.95 (m, 3H), 1.85 - 1.65 (m, 1H)

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887 1HNMR (500 MHz, DMSO-d6) δ 9.01 - 8.89 (m, 1H), 8.15 - 8.09 (m, 1H), 7.91 (br dd, J=7.3, 3.7 Hz, 1H), 7.76 - 7.67 (m, 1H ), 7.38 (br s, 1H), 5.42 - 5.14 (m, 1H), 4.81 - 4.44 (m, 1H), 4.07 - 3.34 (m, SA, absorbed by water), 3.28 - 3.02 (m, 2H), 2.36 - 2.21 (m, 2H), 2.20 - 1.97 (m, 3H), 1.89 - 1.67 (m, 1H) 888 1HNMR (500 MHz, DMSO-d6) δ 9.02 - 8.91 (m, 1H), 8.17 - 8.09 (m, 1H), 7.99 7.87 (m, 1H), 7.80 - 7.70 (m, 1H), 7.40 (s, 1H ), 5.39 - 5.01 (m, 2H), 4.78 - 4.51 (m, 1H), 3.88 - 3.16 (m, 5H, absorbed by water), 2.55 - 2.28 (m, 4H, absorbed by DMSO) 889 1HNMR (500 MHz, DMSO-d6) δ 8.67 - 8.55 (m, 1H), 8.34 (br d, J=6.5 Hz, 1H), 8.15 - 8.03 (m, 2H), 7.48 (t, J=9.3 Hz, 1H), 7.37 (s, 1H), 5.37 - 5.11 (m, 1H), 4.73 - 4.52 (m, 1H), 4.48 - 4.27 (m, 1H), 4.11 - 3.51 (m, 3H), 2.24 - 2.03 ( m, 1H), 1.87 - 1.69 (m, 1H), 0.99 - 0.85 (m, 3H) 894 1HNMR (500 MHz, DMSO-d6) δ 8.96 (br dd, J=15.1, 7.2 Hz, 1H), 8.41 (br d, J=7.3 Hz, 1H), 8.22 (br d, J=5.8 Hz, 2H) , 7.91 (br d, J=8.5 Hz, 1H), 7.75 (br d, J=4.3 Hz, 1H), 5.37 - 5.09 (m, 1H), 4.87 - 4.49 (m, 1H), 4.22 - 3.96 (m , 1H), 3.95 - 3.47 (m, 2H), 3.47 - 3.29 (m, 1H), 1.63 - 1.45 (m, 6H), 2 exchangeable protons 899 1HNMR (500 MHz, DMSO-d6) δ 9.01 - 8.91 (m, 1H), 8.41 (br d, J=7.9 Hz, 1H), 8.22 (br s, 2H), 7.90 (br d, J=8.2 Hz, 1H), 7.78 - 7.72 (m, 1H), 5.41 - 5.04 (m, 1H), 4.77 - 4.49 (m, 1H), 4.48-4.19 (m, 1H), 4.11 -3.54(m, 3H), 2.23 - 1.94 (m, 1H), 1.79 - 1.66 (m, 1H), 0.98 - 0.77 (m, 3H), 3 exchangeable protons 905 1HNMR (500 MHz, DMSO-d6) δ 9.12 - 8.90 (m, 1H), 8.41 (br t, J=7.8 Hz, 1H), 8.27 - 8.19 (m, 2H), 7.91 (br d, J=8.2 Hz , 1H), 7.74 (br d, J=7.3 Hz, 1H), 5.43 5.08 (m, 1H), 4.85 - 4.47 (m, 1H), 4.32 (br s, 1H), 4.16 - 3.56 (m, 3H) , 3.49 3.23 (m, 1H), 3.11 - 2.71 (m, 2H), 2 exchangeable protons 906 1HNMR (500 MHz, DMSO-d6) δ 9.07 - 8.88 (m, 1H), 8.46 - 8.35 (m, 1H), 8.27 8.13 (m, 2H), 7.89 (br dd, J=19.2, 8.2 Hz, 1H) , 7.80 - 7.67 (m, 1H), 7.59 - 7.50 (m, 1H), 7.50 - 7.40 (m, 1H), 7.36 - 7.27 (m, 2H), 5.43 - 5.05 (m, 1H), 4.93 - 4.42 ( m, 1H), 4.04 - 3.65 (m, 2H), 3.62 - 3.29 (m, 2H), 2 exchangeable protons 910 1HNMR (400 MHz, DMSO-d6) δ 8.88 - 8.72 (m, 1H), 8.35 - 8.26 (m, 1H), 8.19 (d, J=8.1 Hz, 2H), 7.72 - 7.66 (m, 1H), 7.64 (d, J=2.8 Hz, 1H), 7.08 (br d, J=5.0 Hz, 1H), 5.74 (d, J=2.0 Hz, 1H), 5.62 (d, J=2.0 Hz, 1H), 5.37 - 5.11 (m, 1H), 4.73 - 4.51 (m, 1H), 4.45 - 4.25 (m, 1H), 4.07 - 3.41 (m, 3H), 1.57-1.51 (m, 3H). MS (ERI) 581.3 (M+H) ⁺ 912 1HNMR (400 MHz, DMSO-d6) δ 8.99 - 8.78 (m, 2H), 8.34 - 8.26 (m, 1H), 8.23 8.12 (m, 2H), 7.68 (d, J=8.5 Hz, 1H), 7.62 ( d, J=3.3 Hz, 1H), 5.74 (s, 1H), 5.62 (s, 1H), 5.49 - 5.14 (m, 1H), 4.90 - 4.50 (m, 1H), 4.23 - 3.35 (m, 4H) , 3.18 - 2.88 (m, 2H). MS (ERI) 649.3 (M+H) ⁺ 916 1HNMR (500 MHz, DMSO-d6) δ 8.89 (br dd, J=14.8, 7.5 Hz, 1H), 8.42 - 8.21 (m, J=8.2 Hz, 1H), 8.19 - 8.13 (m, 1H), 7.67 ( d, J=8.2 Hz, 1H), 7.59 (s, 1H), 5.75 - 5.54 (m, 2H), 5.41 - 5.14 (m, 1H), 4.80 - 4.57 (m, 1H), 4.27 - 3.38 (m, 4H), 1.47 - 1.11 (m, 4H), 2 exchangeable protons 922 1HNMR (500 MHz, DMSO-d6) δ 8.87 - 8.78 (m, 1H), 8.26 (br d, J=7.3 Hz, 1H), 8.17 (s, 1H), 8.14 (s, 1H), 7.66 (br d , 3=8.2Hz, 1H), 7.60 (s, 1H), 5.73 - 5.56 (m, 2H), 5.39 - 5.13 (m, 1H), 4.74 - 4.50 (m, 1H), 4.47 - 4.25 (m, 1H ), 4.08 - 3.35 (m, 3H), 2.24 - 1.96 (m, 1H), 1.84 - 1.63 (m, 1H), 0.94 - 0.82 (m, 3H), 3 exchangeable protons

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923 1HNMR (500 MHz, DMSO-d6) δ 8.88 - 8.73 (m, 1H), 8.28 (br d, J=8.2 Hz, 1H), 8.19 (s, 1H), 8.16 (brd, 3=4.6Hz, 1H) , 7.72 - 7.65 (m, 1H), 7.65 - 7.57 (m, 1H), 5.76 - 5.57 (m, 2H), 5.43 - 5.19 (m, 1H), 5.18 - 4.87 (m, 1H), 4.78 - 4.44 ( m, 1H), 4.01 - 3.50 (m, 3H), 3.38 - 3.19 (m, partially suppressed, 2H), 2.98 - 2.60 (m, 1H), 2.47 - 2.34 (m, 2H), 2.32 - 2.11 (m, 1H), 2 exchangeable protons 924 1HNMR (500 MHz, DMSO-d6) δ 8.95 - 8.77 (m, 1H), 8.28 (br d, J=7.3 Hz, 1H), 8.18 (s, 1H), 8.16 (br s, 1H), 7.68 (br d, J=7.0 Hz, 1H), 7.61 (d, J=4.6 Hz, 1H), 5.77 - 5.55 (m, 2H), 5.42 - 5.16 (m, 1H), 4.87 - 4.54 (m, 1H), 4.25 - 3.50 (m, 4H), 3.49 - 3.28 (m, partially suppressed, 2H), 1.29 - 1.22 (m, 3H), 2 exchangeable protons 926 1HNMR (400 MHz, DMSO-d6) δ 9.03 - 8.88 (m, 1H), 8.27 - 8.13 (m, 3H), 7.71 7.57 (m, 2H), 5.45 - 5.17 (m, 1H), 4.85 - 4.49 (m , 1H), 4.45 - 4.24 (m, 1H), 4.17 3.83 (m, 3H), 3.79-3.61 (m, 1H), 3.53-3.21 (m, 1H), 3.11 -2.98 (m, 1H), 2.93 2.75 (m, 1H) 927 1HNMR (500 MHz, DMSO-d6) δ 9.03 - 8.83 (m, 1H), 8.22 - 8.10 (m, 3H), 7.69 7.57 (m, 2H), 5.41 - 5.01 (m, 1H), 4.75 - 4.49 (m , 1H), 3.60 (s, overlap with water peak, 4H), 2.32 - 1.94 (m, 1H), 1.76 (td, J=14.3, 7.0 Hz, 1H), 1.00 - 0.78 (m, 3H), 3 capable to proton exchange 931 1HNMR (400 MHz, DMSO-d6) δ 9.04 - 8.87 (m, 2H), 8.25 - 8.13 (m, 3H), 7.68 7.62 (m, 2H), 5.45 - 5.18 (m, 1H), 4.86 - 4.56 (m , 1H), 4.20 - 3.86 (m, 2H), 3.80 - 3.62 (m, 1H), 3.55 - 3.27 (m, 1H), 3.19 - 2.87 (m, 2H) 934 1HNMR (500 MHz, DMSO-d6) δ 8.96 (br dd, J=17.9, 7.2 Hz, 1H), 8.23 - 8.10 (m, 3H), 7.66 - 7.59 (m, 2H), 5.45 - 5.10 (m, 1H ), 4.69 (br s, 1H), 4.27 - 3.56 (m, 4H), 1.48 - 1.20 (m, 3H), 1.14 (br s, 1H), 2 exchangeable protons 941 1HNMR (500 MHz, DMSO-d6) δ 8.81 (br dd, J=16.7, 7.4 Hz, 1H), 8.22 - 8.13 (m, 3H), 7.69 - 7.55 (m, 2H), 5.47 - 5.16 (m, 1H ), 4.90 - 4.51 (m, 1H), 4.05 - 3.34 (m, 4H), 2.86 (br s, 1H), 2.74 - 2.53 (m, 1H), 2.48 - 2.23 (m, 1H), 1.19-1.05 ( m, 3H), 2 exchangeable protons 965 1HNMR (500 MHz, DMSO-d6) δ 8.72 (dd, 1=12.4, 6.9 Hz, 1H), 8.16 (s, 1H), 8.06 (br d, J=7.9 Hz, 1H), 7.94 (br s, 1H ), 7.51 (d, J=4.3 Hz, 2H), 7.43 (d, J=8.2 Hz, 1H), 5.45 - 5.09 (m, 1H), 4.82 - 4.49 (m, 1H), 4.24 - 3.31 (m, partially suppressed, 6H), 2.85 - 2.67 (m, 2H), 1.59 - 1.48 (m, 6H), 1.19 (t, J=7.6 Hz, ZN), 2 exchangeable protons 972 1HNMR (400 MHz, DMSO-d6) δ 8.99 - 8.88 (m, 1H), 8.84 - 8.71 (m, 1H), 8.17 (s, 1H), 8.07 (dt, J=8.1, 2.1 Hz, 1H), 7.95 (dd, J=6.0, 1.8 Hz, 1H), 7.52 (d, J=4.1 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 5.47 - 5.20 (m, 1H), 4.82 - 4.56 ( m, 1H), 4.19 2.71 (m, 8H), 1.19 (td, J=7.5, 1.0 Hz, ZN) 981 1HNMR (500 MHz, DMSO-d6) δ 8.88 - 8.68 (m, 1H), 8.20 - 8.10 (m, 1H), 8.09 8.00 (m, 1H), 7.92 (br d, J=2.0 Hz, 1H), 7.50 (br d, J=2.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 5.47 - 5.09 (m, 1H), 4.81 - 4.47 (m, 1H), 4.06 - 3.75 (m, 3H) , 3.65 - 3.59 (m, 2H) 3.53 - 3.22 (m, 1H), 2.85 - 2.64 (m, 2H), 1.26 - 1.11 (m, 3H), 2 exchangeable protons 985 1HNMR (500 MHz, DMSO-d6) δ 8.82 - 8.61 (m, 1H), 8.15 (s, 1H), 8.04 (br d, J=7.9 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.52 ( br s, 1H), 7.39 (br d, J=8.2 Hz, 1H), 5.45 - 5.16 (m, 1H), 4.86 - 4.46 (m, 1H), 4.12 - 3.23 (m, 6H), 2.39 (s, 3H), 2 exchangeable protons

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986 1HNMR (500 MHz, DMSO-d6) δ 8.82 - 8.64 (m, 1H), 8.16 (s, 1H), 8.04 (br d, J=7.9 Hz, 1H), 8.01 - 7.94 (m, 1H), 7.52 ( br d, J=4.6 Hz, 1H), 7.39 (br d, J=7.6 Hz, 2H), 5.42 - 5.08 (m, 1H), 4.89 - 4.50 (m, 1H), 4.00 - 3.54 (m, 3H) , 3.48 - 3.07 (m, 2H), 2.94 - 2.66 (m, 4H), 2.39 (br s, 3H), 2 exchangeable protons 990 1Н NMR (500 MHz, DMSO-d6) δ 8.81 -8.63 (m, 1H), 8.16 (s, 1H), 8.05 (brd, J=7.9 Hz, 1H), 8.01 - 7.95 (m, 1H), 7.52 ( br d, J=5.2 Hz, 2H), 7.44 - 7.36 (m, 2H), 5.49 - 5.07 (m, 1H), 4.91 - 4.52 (m, 1H), 4.11 - 3.25 (m, 4H), 2.68 - 2.56 (m, 2H), 2.40 (br d, J=5.2 Hz, ZH), 2.05 (br s, 2H), 1.97 - 1.70 (m, 4H), 1.66 - 1.50 (m, 2H), 2 exchangeable protons 993 1Н NMR (500 MHz, DMSO-d6) δ 8.81 - 8.57 (m, 1H), 8.17 (s, 1H), 8.05 (brd, J=8.2 Hz, 1H), 8.02 - 7.88 (m, 1H), 7.54 ( br d, J=3.4 Hz, 1H), 7.42 - 7.34 (m, 1H), 5.39 - 5.13 (m, 1H), 4.81 - 4.52 (m, 1H), 4.44 - 4.23 (m, 1H), 4.10 - 3.39 (m, 3H), 2.40 (s, 3H), 1.53 (br s, 3H), 3 exchangeable protons 997 1HNMR (500 MHz, DMSO-d6) δ 8.68 (br dd, J=16.8, 7.0 Hz, 1H), 8.15 (s, 1H), 8.03 (brd, >7.9Hz, 1H), 7.99 - 7.95 (m, 1H ), 7.51 (brd, J=3.1 Hz, 1H), 7.38 (br d, J=7.9 Hz, 1H), 5.39 - 5.17 (m, 1H), 5.17 - 4.84 (m, 1H), 4.79 - 4.46 (m , 1H), 3.95 - 3.49 (m, 3H), 3.35 - 2.64 (m, 2H), 2.56 - 2.52 (m, 3H), 2.38 (br s, 3H), 2.31 - 2.13 (m, 1H), 2 capable to proton exchange 1000 1HNMR (500 MHz, DMSO-d6) δ 8.66 (br dd, J=13.9, 6.9 Hz, 1H), 8.15 (s, 1H), 8.04 (br s, 1H), 8.02 - 7.94 (m, 1H), 7.52 (br d, J=3.4 Hz, 1H), 7.38 (br d, J=8.2 Hz, 2H), 5.40 - 5.16 (m, 1H), 4.82 - 4.47 (m, 1H), 4.21 - 3.54 (m, 3H ), 3.45 - 3.28 (m, 2H), 1.59 - 1.47 (m, 6H), 2 exchangeable protons. 1023 1HNMR (500 MHz, DMSO-d6) δ 8.81 - 8.66 (m, 1H), 8.51 - 8.46 (m, 1H), 8.24 8.12 (m, 1H), 8.09 - 7.90 (m, 2H), 7.64 (br s, 1H), 7.58 - 7.46 (m, 1H), 7.42 - 7.35 (m, 2H), 5.43 - 5.15 (m, 1H), 4.92 - 4.54 (m, 1H), 4.22 - 3.70 (m, 2H), 3.60 3.42 ( m, partly under water peak, 2H), 2.43 - 2.35 (m, 6H), 2 exchangeable protons 1024 1H NMR (500 MHz, DMSO-d6) δ 8.86 - 8.63 (m, 1H), 8.14 (brd, >13.4Hz, 1H), 8.08 - 8.01 (m, 1H), 8.01 - 7.86 (m, 1H), 7.57 - 7.45 (m, 1H), 7.39 (dd, J=14.8, 8.3 Hz, 1H), 7.34 (br s, 2H), 5.48 - 5.16 (m, 1H), 4.92 - 4.53 (m, 1H), 4.08 - 3.33 (m, partly below the water peak, 4H), a2.47 - 2.21 (w, 3H), 2 exchangeable protons 1037 1HNMR (500 MHz, DMSO-d6) δ 8.80 - 8.66 (m, 2H), 8.26 - 8.11 (m, 1H), 8.10 7.88 (m, 2H), 7.69 (br d, J=9.1 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.46 - 7.32 (m, 1H), 5.50 - 5.09 (m, 1H), 4.90 - 4.52 (m, 1H), 4.25 - 3.74 (m, 2H), 3.52 - 3.40 (m, 2H), 2.40 (br d, J=13.3 Hz, ZN), 2 exchangeable protons 1044 1HNMR (500 MHz, DMSO-d6) δ 8.68 (dd, J=20.0, 7.1 Hz, 1H), 8.17 (d, J=1.0 Hz, 1H), 8.05 (br d, J=8.1 Hz, 1H), 8.02 - 7.97 (m, 1H), 7.54 (d, J=4.3Hz, 1H), 7.40 (d, >8.2Hz, 1H), 5.41 -5.15(m, 1H), 4.80 - 4.49 (m, 1H), 3.98 - 3.15 (m, 4H, absorbed by water), 2.40 (d, J=2.6 Hz, SA), 2.37 - 2.11 (m, SA), 1.83 - 1.71 (m, 2H), 1.65 - 1.44 (m, 4H), 1.21 - 1.03 (m, 2H) 1045 1HNMR (500 MHz, DMSO-d6) δ 8.76 - 8.62 (m, 1H), 8.16 (s, 1H), 8.04 (br d, J=8.2 Hz, 1H), 7.99 (s, 1H), 7.52 (s, 1H), 7.39 (dd, J=8.1, 2.3 Hz, 1H), 5.43 - 5.14 (m, 1H), 4.78 - 4.48 (m, 1H), 4.02 - 3.14 (m, 4H, absorbed by water), 2.77 - 2.58 (m, ZN), 2.57 - 2.47 (m, 1H, absorbed by DMSO), 2.40 (d, J=3.4 Hz, 4H), 2.35 2.19 (m, 2H) 1046 1HNMR (500 MHz, DMSO-d6) δ 9.00 - 8.74 (m, 1H), 8.38 - 8.10 (m, 3H), 7.72 7.51 (m, 3H), 7.47 (q, J=7.7 Hz, 1H), 7.38 - 7.27 (m, 2H), 5.41 - 5.07 (m, 1H), 4.90 - 4.59 (m, 1H), 4.07 - 3.66 (m, 2H), 3.64 - 3.19 (m, 2H), 2 exchangeable protons

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1047 1HNMR (500 MHz, DMSO-d6) δ 8.88 (br dd, J=18.6, 7.3 Hz, 1H), 8.29 (br d, J=8.5 Hz, 1H), 8.27 - 8.23 (m, 1H), 8.22 - 8.17 (m, 1H), 7.65 (d, J=4.9 Hz, 1H), 7.62 - 7.55 (m, 1H), 5.38 - 5.05 (m, 1H), 4.82 - 4.52 (m, 1H), 4.05 - 3.48 (m , 3H), 3.39 - 3.18 (m, 1H), 2.25 - 2.07 (m, 2H), 2.06 - 1.92 (m, 1H), 0.94 - 0.88 (m, 6H), 2 exchangeable protons 1048 1HNMR (500 MHz, DMSO-d6) δ 8.88 (br dd, J=19.2, 7.9 Hz, 1H), 8.26 (br d, J=8.2 Hz, 1H), 8.23 (s, 1H), 8.17 (s, 1H ), 7.61 (s, 1H), 7.57 (br d, J=8.2 Hz, 1H), 5.31 - 5.02 (m, 1H), 4.76 - 4.49 (m, 1H), 4.45 - 3.65 (m, partially suppressed, ZN ), 3.45 - 3.26 (m, partially suppressed, 1H), 1.33 - 1.25 (m, 6H), 3 exchangeable protons 1049 1HNMR (500 MHz, DMSO-d6) δ 9.05 - 8.88 (m, 1H), 8.41 - 8.26 (m, 1H), 8.26 8.22 (m, 1H), 8.21 - 8.18 (m, 1H), 7.64 (br s, 1H), 7.62 - 7.56 (m, 1H), 5.40 - 5.10 (m, 1H), 4.86 - 4.52 (m, 1H), 4.12 - 3.62 (m, partially suppressed, 5H), 3.49 - 3.21 (m, partially suppressed, 1H), 2 exchangeable protons 1071 1HNMR (500 MHz, DMSO-d6) δ 8.46 - 8.38 (m, 1H), 8.34 (br dd, J=13.6, 7.8 Hz, 1H), 8.23 - 8.08 (m, 2H), 7.54 (s, 1H), 7.42 - 7.33 (m, 1H), 5.37 - 5.00 (m, 2H), 4.98 - 4.88 (m, 2H), 4.86 - 4.55 (m, 1H), 4.01 - 3.10 (m, partly below the water peak, 5H), 2.79 - 2.72 (m, 1H), 2.47 - 2.14 (m, 4H), 2 exchangeable protons 1072 1HNMR (500 MHz, DMSO-d6) δ 8.41 (dd, J=10.9, 2.2 Hz, 1H), 8.39 - 8.32 (m, 1H), 8.20 - 8.16 (m, 2H), 7.56 (d, J=3 3 Hz, 1H), 7.38 (dd, J=8.9, 3.9 Hz, 1H), 5.42 - 5.10 (m, 1H), 5.04 - 4.89 (m, 2H), 4.86 - 4.54 (m, 1H), 4.06 - 3.50 ( m, partially suppressed, 3H), 3.46 - 3.09 (m, partially suppressed, 2H), 2.93 - 2.65 (m, 4H), 2 exchangeable protons 1074 1HNMR (500 MHz, DMSO-d6) δ 8.45 - 8.33 (m, 2H), 8.21 - 8.14 (m, 2H), 7.55 (s, 1H), 7.37 (d, J=8.7 Hz, 1H), 5.43 - 5.08 (m, 1H), 5.04 - 4.88 (m, 2H), 4.77 (br s, 1H), 4.39 - 3.33 (m, 4H), 2.53 - 2.46 (m, 4H), 2 exchangeable protons 1075 1HNMR (500 MHz, DMSO-d6) δ 8.45 - 8.30 (m, 2H), 8.21 - 8.10 (m, 2H), 7.51 (s, 1H), 7.39 - 7.30 (m, 1H), 5.42 - 5.10 (m, 1H), 5.02 - 4.86 (m, 2H), 4.86 - 4.45 (m, 1H), 4.04 - 3.57 (m, 3H), 3.39 - 3.06 (m, 1H), 2.23 - 2.06 (m, 2H), 2.01 ( dt, J=13.2, 6.7 Hz, 1H), 0.97 - 0.77 (m, 6H), 2 exchangeable protons 1079 1HNMR (500 MHz, DMSO-d6) δ 8.72 (br dd, J=19.7, 7.5 Hz, 1H), 8.27 - 8.16 (m, 3H), 7.60 (s, 1H), 7.42 - 7.34 (m, 1H), 5.47 - 5.05 (m, 1H), 4.88 - 4.48 (m, 1H), 4.27 - 3.54 (m, 3H), 3.03 - 2.82 (m, 1H), 1.50 - 1.06 (m, 6H), 2 exchangeable protons 1091 1HNMR (500 MHz, DMSO-d6) δ 8.79 - 8.62 (m, 1H), 8.24 - 8.12 (m, 3H), 7.56 (s, 1H), 7.37 (d, J=8.5 Hz, 1H), 5.40 - 5.11 (m, 1H), 4.84 - 4.49 (m, 1H), 4.21 3.66 (m, partially suppressed, SA), 3.62 - 3.19 (m, partially suppressed, 2H), 2.83 - 2.66 (m, 1H), 2.48 - 2.30 (m, 1Н), 1.40 (br s, ЗН), 3 exchangeable protons 1093 1HNMR (500 MHz, DMSO-d6) δ 8.81 - 8.62 (m, 1H), 8.28 - 8.12 (m, 3H), 7.58 (brd, >4.6Hz, 1H), 7.43 -7.32 (m, 1H), 5.41 - 5.10(m, 1H), 4.88 - 4.60 (m, 1H), 4.27 - 3.59 (m, 4H), 3.55 - 3.13 (m, 2H), 1.27 (br d, J=7.0 Hz, ZN), 3 capable of proton exchange

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1101 1HNMR (500 MHz, DMSO-d6) δ 8.66 - 8.43 (m, 2H), 8.15 (s, 1H), 8.13 (br d, J=9.2 Hz, 1H), 7.46 (s, 1H), 7.30 (t, J=7.6 Hz, 1H), 5.50 - 5.03 (m, 1H), 4.93 4.53 (m, 1H), 4.25 (quin, J=6.9 Hz, 2H), 4.15 - 3.53 (m, 3H), 3.51 - 3.09 ( m, partially below the water peak, 1H), 2.86 (br s, 1H), 2.76 - 2.53 (m, 1H), 2.49 - 2.28 (m, 1H), 1.43 (q, J=6.7 Hz, WN), 1.16 - 1.06 (m, 3N), 2 exchangeable protons 1103 1HNMR (500 MHz, DMSO-d6) δ 8.68 - 8.43 (m, 2H), 8.16 (s, 1H), 8.14 (dd, J=9.0, 2.3 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H ), 7.30 (t, J=8.2 Hz, 1H), 5.50 - 5.17 (m, 1H), 4.96 - 4.53 (m, 1H), 4.26 (quin, J=7.2 Hz, 2H), 4.06 - 3.56 (m, 3H), 3.48 3.09 (m, 2H), 2.93 - 2.66 (m, 4H), 1.43 (q, J=7.2 Hz, ZH), 2 exchangeable protons 1107 1HNMR (500 MHz, DMSO-d6) δ 8.68 - 8.43 (m, 2H), 8.20 - 8.09 (m, 2H), 7.50 7.45 (m, 1H), 7.30 (dd, J=8.7, 5.6 Hz, 1H), 5.43 - 5.17 (m, 1H), 4.86 - 4.60 (m, 1H), 4.59 - 4.29 (m, 1H), 4.29 - 4.18 (m, 2H), 4.12 - 3.61 (m, partially suppressed, SA), 3.55 - 3.20 (m, 1H), 1.54 (s, 3H), 1.43 (q, J=6.4 Hz, ZN), 2 exchangeable protons 1113 1HNMR (500 MHz, DMSO-d6) δ 8.67 - 8.43 (m, 2H), 8.15 (s, 1H), 8.13 (dd, J=8.5, 1.8 Hz, 1H), 7.46 (s, 1H), 7.30 (dd , J=8.4, 6.0 Hz, 1H), 5.43 - 5.13 (m, 1H), 4.98 - 4.56 (m, 1H), 4.25 (quin, J=6.6 Hz, 2H), 4.12 - 3.47 (m, 3H), 3.39 3.05 (m, 1H), 2.28 - 1.93 (m, 3H), 1.48 - 1.36 (m, 3H), 0.97 - 0.82 (m, 6H), 2 exchangeable protons 1118 1HNMR (500 MHz, DMSO-d6) δ 8.57 - 8.35 (m, 2H), 8.19-8.11 (m, 2H), 7.47 (s, 1H), 7.31 (br t, J=8.2 Hz, 1H), 5.45 - 5.16 (m, 1H), 4.89 - 4.61 (m, 1H), 3.96 (overlap br d, J=7.0 Hz, ZN), 4.13 - 3.19 (overlap m, 4H), 2.95 2.78 (m, 1H), 2.75 - 2.55 (m, 1H), 2.48 - 2.24 (m, 1H), 1.16 - 0.95 (m, 3H), 2 exchangeable protons 1121 1HNMR (500 MHz, DMSO-d6) δ 8.53 - 8.33 (m, 2H), 8.18 - 8.11 (m, 2H), 7.46 (s, 1H), 7.30 (br t, J=8.5 Hz, 1H), 5.45 - 5.14 (m, 1H), 4.98 - 4.45 (m, 1H), 3.96 (br d overlap, J=6.7 Hz, 3H), 4.13 - 3.21 (m overlap, partially suppressed, 4H), 2 exchangeable protons 1126 1Н NMR (400 MHz, DMSO-d6) δ 8.96 (br d, J=11.0 Hz, 1H), 8.56 - 8.37 (m, 2H), 8.19 - 8.09 (m, 2H), 7.48 (s, 1H), 7.31 (dd, J=8.8, 6.7 Hz, 1H), 5.46 - 5.22 (m, 1H), 4.91 - 4.59 (m, 1H), 4.25 - 2.90 (m, 9H) 1127 1HNMR (500 MHz, DMSO-d6) δ 8.59 - 8.43 (m, 1H), 8.42 (br s, 1H), 8.22 8.08 (m, 2H), 7.47 (s, 1H), 7.30 (br d, J=8.5 Hz, 1H), 5.51 - 5.14 (m, 1H), 5.02 4.52 (m, 1H), 4.33 - 3.26 (overlap m, partially suppressed, 4H), 3.96 (overlap br d, 3H), 1.45 - 1.20 (m, ZN), 1.15 (br d, J=2.4 Hz, 1H), 2 exchangeable protons 1131 1HNMR (500 MHz, DMSO-d6) δ 8.51 - 8.41 (m, 2H), 8.19 - 8.12 (m, 2H), 7.47 (s, 1H), 7.31 (br t, J=9.3 Hz, 1H), 5.50 - 5.16 (m, 1H), 5.03 - 4.53 (m, 1H), 4.44 4.24 (m, 1H), 3.97 (overlap br d, J=9.2 Hz, ZN), 4.19 - 3.24 (overlap m, 4H), 3.10 - 2.71 (m, 2H), 2 exchangeable protons 1134 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.64 (m, 1H), 8.46 (s, 1H), 8.26 (br d, J=6.7 Hz, 1H), 8.18 (s, 1H), 7.92 (br d , J=7.6 Hz, 1H), 7.66 - 7.55 (m, 2H), 5.38 5.13 (m, 1H), 4.75 - 4.53 (m, 1H), 4.49 - 4.30 (m, 1H), 4.09 - 3.57 (m, 3H), 2.24 2.02 (m, 1H), 1.83 - 1.66 (m, 1H), 0.97 - 0.83 (m, 3H) 1135 1HNMR (500 MHz, DMSO-d6) δ 8.62 - 8.51 (m, 1H), 8.14 - 8.09 (m, 2H), 8.08 8.04 (m, 1H), 7.75 (br d, J=4.9 Hz, 1H), 7.40 (s, 1H), 6.80 (dd, J=8.9, 2.7 Hz, 1H), 5.42 - 5.18 (m, 1H), 4.85 - 4.52 (m, 1H), 4.42 - 4.27 (m, 1H), 4.20 - 2.98 (m, 6H, absorbed by water), 2.87 (d, J=4.6 Hz, ZN)

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1136 1HNMR (500 MHz, DMSO-d6) δ 8.62 - 8.45 (m, 1H), 8.15 - 8.05 (m, 3H), 7.41 (s, 1H), 6.79 (d, >8.8 Hz, 1H), 5.38 - 5.14 ( m, 1H), 4.73 - 4.49 (m, 1H), 4.44 4.29 (m, 1H), 4.08 - 3.40 (m, 3H), 2.91 - 2.86 (m, 3H), 1.55 (s, 3H) 1137 1HNMR (500 MHz, DMSO-d6) δ 8.98 - 8.86 (m, 1H), 8.66 - 8.51 (m, 1H), 8.12 8.07 (m, 2H), 8.05 (dd, >6.1, 1.8 Hz, 1H), 7.79 - 7.68 (m, 1H), 7.38 (s, 1H), 6.79 (dd, >8.9, 1.2 Hz, 1H), 5.45 - 5.18 (m, 1H), 4.81 - 4.54 (m, 1H), 4.21 - 3.60 ( m, 4H), 3.20 - 2.92 (m, 2H), 2.86 (d, >4.9 Hz, ZN) 1141 1HNMR (500 MHz, DMSO-d6) δ 9.08 - 8.67 (m, 1H), 8.26 - 7.98 (m, 3H), 7.73 7.58 (m, 1H), 7.40 - 7.22 (m, 1H), 5.41 - 5.11 (m , 1H), 4.82 - 4.50 (m, 1H), 4.47 4.24 (m, 1H), 4.08 - 3.64 (m, 2H), 3.48 - 3.32 (m, W 2.38 - 1.85 (m, 4H), , 3H). 1146 1HNMR (500 MHz, DMSO-d6) δ 9.34 - 9.05 (m, 1H), 8.96 - 8.75 (m, 1H), 8.23 - 8.16 (m, 1H), 8.16 - 8.06 (m, 1H), 7.99 - 7.88 (m, 1H), 7.76 - 7.51 (m, 2H), 7.15 - 6.93 (m, 1H), 5.43 - 5.07 (m, 1H), 4.83 - 4.41 (m, 1H), 4.11 -3.13 (m, 6H), 2.74 - 2.61 (m, 4H), 2.27 - 2.08 (m, 2H), 2.08 - 1.96 (m, 5H), 1.00 - 0.81 (m, 6H). 1149 1HNMR (500 MHz, DMSO-d6) δ 8.94 (br dd, >17.4, 7.3 Hz, 1H), 8.15 (br d, >8.2 Hz, 1H), 8.10 (br s, 1H), 7.89 (br s, 1H ), 7.58 (br d, >8.2 Hz, 1H), 7.07 (br s, 1H), 5.46 - 5.11 (m, 1H), 4.88 - 4.49 (m, 1H), 4.26 - 2.93 (m, overlap with water peak , 9H), 2.43 - 2.22 (m, 1H), 2.19 - 1.76 (m, 3H), 1.58 - 1.04 (m, 6H), 2 exchangeable protons 1151 1HNMR (500 MHz, DMSO-d6) δ 9.59 - 9.25 (m, 1H), 8.90 (br dd, >18.3, 7.3 Hz, 1H), 8.17 (br dd, >4.0, 2.1 Hz, 1H), 8.11 (s , 1H), 7.90 (s, 1H), 7.80 - 7.63 (m, 1H), 7.58 (d, >8.2 Hz, 1H), 7.08 (d, >4.0 Hz, 1H), 5.41 - 5.16 (m, 1H) , 5.12 - 4.86 (m, 1H), 4.79 - 4.45 (m, 1H), 3.97 - 3.15 (m, 7H), 3.04 (br d, >11.3 Hz, 2H), 2.90 (s, 1H), 2.79 - 2.69 (m, 1H), 2.46 - 2.16 (m, 3H), 2.09 (brt, >11.3 Hz, 2H), 1.90 - 1.79 (m, 2H), 1.55-1.31 (m, 2H) 1157 1HNMR (500 MHz, DMSO-d6) δ 8.95 (dd, >15.9, 7.4 Hz, 1H), 8.20 - 8.13 (m, 1H), 8.11 (d, >1.3 Hz, 1H), 7.89 (br s, 1H) , 7.58 (br d, >8.5 Hz, 1H), 7.07 (br s, 1H), 5.43 - 5.12 (m, 1H), 4.91 - 4.42 (m, 1H), 3.99 - 3.59 (m, overlap with water peak, 6H), 3.45 - 2.94 (m, 3H), 2.87 - 2.65 (m, 4H), 2.46 - 2.23 (m, 1H), 2.17-2.03 (m, 2H), 1.86 (brd, >11.8 Hz, 2H), 1.57- 1.34 (m, 2H), 2 exchangeable protons 1158 1HNMR (500 MHz, DMSO-d6) δ 9.03 - 8.79 (m, 1H), 8.24 - 7.99 (m, 2H), 7.89 (brd, >15.6 Hz, 1H), 7.66 - 7.42 (m, 3H), 7.37 - 7.27 (m, 2H), 7.15 - 6.98 (m, 1H), 5.50 - 4.94 (m, 1H), 4.87 - 4.44 (m, 1H), 4.07 - 2.93 (m, overlap with water peak, 9H), 2.45 - 2.24 (m, 1H), 2.17 - 1.99 (m, 1H), 1.97 - 1.76 (m, 2H), 1.44 (br dd, >5.0, 2.3 Hz, 2H), 2 exchangeable protons 1161 1HNMR (500 MHz, DMSO-d6) δ 9.59 - 9.32 (m, 1H), 9.00 - 8.84 (m, 1H), 8.23 8.13 (m, 1H), 8.11 (s, 1H), 7.89 (s, 1H), 7.79 - 7.64 (m, 1H), 7.57 (brd, >8.5 Hz, 1H), 7.07 (d, >4.6 Hz, 1H), 5.41 - 5.13 (m, 1H), 4.84 - 4.46 (m, 1H), 4.12 - 3.49 (m, 5H), 3.35 - 2.96 (m, 4H), 2.43 - 2.22 (m, 3H), 2.21 - 1.98 (m, 5H), 1.90 - 1.66 (m, 3H), 1.55 - 1.33 (m, 2H) 1170 1HNMR (500 MHz, DMSO-d6) δ 8.74 (br s, 1H), 8.41 (s, 1H), 8.22 (br d, >7.9 Hz, 1H), 7.86 (s, 1H), 7.81 (br d, > 7.6 Hz, 1H), 7.57 (t, >7.8 Hz, 1H), 7.07 (s, 1H), 5.42 - 5.00 (m, 1H), 4.81 - 4.44 (m, 1H), 4.00 (s, 2H), 3.85 - 3.59 (m, 8H), 1.18 (s, 9H), 2 exchangeable protons

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1172 1HNMR (500 MHz, DMSO-d6) δ 8.76 (br dd, J=16.2, 7.0 Hz, 1H), 8.42 (s, 1H), 8.23 (br d, J=7.9 Hz, 1H), 7.88 (s, 1H ), 7.81 (br d, J=7.9 Hz, 1H), 7.59 - 7.55 (m, 1H), 7.07 (s, 1H), 5.47 - 5.15 (m, 1H), 4.48 (s, 1H), 4.03 - 3.98 (m, 2H), 3.96 3.68 (m, 3H), 3.60 - 3.36 (m, 1H), 2.79 - 2.60 (m, 1H), 1.05 - 0.99 (m, 6H), 2 exchangeable protons 1174 1HNMR (500 MHz, DMSO-d6) δ 8.85 - 8.66 (m, 1H), 8.47 - 8.33 (m, 1H), 8.27 - 8.13 (m, 1H), 7.90 - 7.83 (m, 1H), 7.83 - 7.67 (m, 1H), 7.63 - 7.46 (m, 1H), 7.11 - 6.91 (m, 1H), 5.45 - 5.12 (m, 1H), 5.12 - 4.84 (m, 1H), 4.84 - 4.47 (m, 1H), 4.10 - 3.96 (m, 1H), 3.93 - 3.35 (m, 7H), 2.84 - 2.67 (m, 1H), 2.37 - 2.07 (m, 2H). 1175 1HNMR (500 MHz, DMSO-d6) δ 8.85 - 8.66 (m, 1H), 8.47 - 8.33 (m, 1H), 8.27 - 8.13 (m, 1H), 7.90 - 7.83 (m, 1H), 7.83 - 7.67 (m, 1H), 7.63 - 7.46 (m, 1H), 7.11 - 6.91 (m, 1H), 5.45 - 5.12 (m, 1H), 5.12 - 4.84 (m, 1H), 4.84 - 4.47 (m, 1H), 4.10 - 3.96 (m, 1H), 3.93 - 3.35 (m, 7H), 2.84 - 2.67 (m, 1H), 2.37 - 2.07 (m, 2H). 1176 1HNMR (500 MHz, DMSO-d6) δ 8.64 (br d, J=6.8 Hz, 1H), 8.41 (br s, 1H), 8.19 (br d, J=7.0 Hz, 1H), 7.99 (s, 1H) , 7.87 (br d, J=7.7 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.15 (s, 1H), 5.37 - 5.12 (m, 1H), 4.75 - 4.49 (m, 1H) , 4.13 (s, 2H), 3.83 (br t, J=12.3 Hz, 4H), 3.71 - 3.41 (m, 4H), 1.47 (br d, J=11.9 Hz, 6H), 2 exchangeable protons 1180 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.64 (m, 1H), 8.44 (s, 1H), 8.28 (br t, J=7.6 Hz, 1H), 7.93 - 7.88 (m, 1H), 7.84 ( br d, J=7.6 Hz, 1H), 7.57 (br t, J=7.8 Hz, 1H), 7.09 (s, 1H), 5.36 - 5.17 (m, 1H), 4.74 - 4.53 (m, 1H), 4.46 - 4.28 (m, 1H), 4.03 (br s, 2H), 3.98 - 3.57 (m, 7H, absorbed by water), 1.55 (br s, 3H) 1181 1HNMR (500 MHz, DMSO-d6) δ 8.80 - 8.72 (m, 1H), 8.43 (s, 1H), 8.23 (br d, J=7.6 Hz, 1H), 8.00 (s, 1H), 7.87 (br d , J=7.6 Hz, 1H), 7.60 (br t, J=7.5 Hz, 1H), 5.44 - 5.15 (m, 1H), 4.89 - 4.49 (m, 1H), 4.12 (br s, 2H), 3.97 - 3.42 (m, 8H), 3.26-3.11 (m, 1H), 2.87-2.71 (m, 4H) 1182 1HNMR (500 MHz, DMSO-d6) δ 8.79 (br dd, J=14.8, 7.2 Hz, 1H), 8.07 (s, 1H), 7.79 (br s, 1H), 7.30 (s, 1H), 5.49 - 5.03 (m, 1H), 4.87 - 4.48 (m, 1H), 4.35 - 3.29 (m, 4H), 2.60 (s, 3H), 2.33 (s, 3H), 1.45 - 1.03 (m, 4H), 2 capable of proton exchange 1185 1HNMR (500 MHz, DMSO-d6) δ 8.91 - 8.57 (m, 1H), 8.07 (s, 1H), 7.78 (d, J=3.4 Hz, 1H), 7.29 (s, 1H), 5.39 - 5.09 (m , 1H), 4.72 - 4.48 (m, 1H), 4.42 - 4.21 (m, 1H), 4.05 - 3.27 (m, 3H), 2.59 (s, 3H), 2.32 (s, 3H), 1.52 (br d, J=3.1 Hz, ZN), 2 exchangeable protons 1196 1HNMR (500 MHz, DMSO-d6) δ 8.97 - 8.64 (m, 1H), 8.06 (s, 1H), 7.76 (br s, 1H), 7.28 (s, 1H), 5.46 - 5.06 (m, 1H), 4.88 - 4.42 (m, 1H), 4.26 - 3.42 (m, 5H), 2.58 (d, J=2.1 Hz, ZN), 2.32 (d, J=1.2 Hz, ZN), 3 exchangeable protons 1198 1HNMR (500 MHz, DMSO-d6) δ 8.90 - 8.66 (m, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.84 - 7.74 (m, 1H), 7.69 - 7.49 (m, 2H), 7.42 (br s, 1H), 5.44 - 5.14 (m, 1H), 4.89 - 4.47 (m, 1H), 4.09 - 3.36 (m, partially suppressed, 4H), 2.59 (br d, J=18.3 Hz, ZN), 2.33 (br d, J=10.4 Hz, ZN), 3 exchangeable protons 1217 1HNMR (500 MHz, DMSO-d6) δ 8.91 (br s, 1H), 8.77 (br d, J=18.3 Hz, 1H), 8.52 (brd, >4.9 Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 6.33 - 6.01 (m, 1H), 5.37 5.18 (m, 1H), 4.81 -4.60 (m, 1H), 4.43-4.19 (m, 1H), 4.04 (br d, 1=3.1Hz , 3H), 3.97 - 3.16 (m, 5H, absorbed by water), 1.42 - 1.33 (m, 6H) 1218 1HNMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.78 (br d, J=4.9 Hz, 1H), 8.61 8.48 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H ), 5.44 - 5.19 (m, 1H), 4.84 - 4.53 (m, 1H), 4.13 - 3.14 (m, 9H), 1.18 (d, J=3.1 Hz, 9H)

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1219 1HNMR (500 MHz, DMSO-d6) δ 8.93 - 8.88 (m, IH), 8.76 - 8.64 (m, IH), 8.37 (brt, J=6.4 Hz, IH), 8.15 (d, J=6.6 Hz, IH ), 7.55 (br d, J=7.4 Hz, IH), 7.52 - 7.47 (m, 5H), 5.35 - 5.01 (m, IH), 4.82 - 4.25 (m, IH), 4.03 (d, J=6.0 Hz , SA), 3.98 3.81 (m, IH), 3.64 (br d, J=14.7 Hz, SA), 3.55 - 2.96 (m, SA, absorbed by water) 1220 1HNMR (400 MHz, DMSO-d6) δ 8.99 - 8.90 (m, 2H), 8.79 (dd, J=8.9, 2.5 Hz, IH), 8.55 (dd, J=10.5, 7.8 Hz, IH), 8.18 (s , IH), 7.62 (s, IH), 5.48 - 5.23 (m, IH), 4.92 - 4.62 (m, IH), 4.25 - 3.87 (m, 5H), 3.86 - 3.61 (m, IH), 3.58 - 3.33 (m, IH), 3.15-2.87 (m, 2H) 1221 1HNMR (500 MHz, DMSO-d6) δ 8.85 (s, IH), 8.70 (br d, J=11.9 Hz, IH), 8.63 (brt, >7.6 Hz, IH), 8.10 (s, IH), 7.52 ( s, IH), 5.40 - 5.20 (m, IH), 4.76 - 4.55 (m, IH), 4.20 - 3.21 (m, 7H, absorbed by water), 2.65 - 2.36 (m, 3H, absorbed by DMSO), 1.07 (br d, J=6.1 Hz, ZN) 1222 1HNMR (500 MHz, DMSO-d6) δ 8.89 (s, IH), 8.76 (br d, J=17.0 Hz, IH), 8.49 (brt, >6.4 Hz, IH), 8.13 (s, IH), 7.53 ( s, IH), 5.45 - 5.22 (m, IH), 4.88 - 4.58 (m, IH), 4.33 - 4.18 (m, IH), 4.15 - 3.26 (m, 7H, absorbed by water), 3.05 - 2.75 (m, 2H) 1223 1HNMR (500 MHz, DMSO-d6) δ 8.90 (br s, IH), 8.75 (br s, IH), 8.55 - 8.39 (m, IH), 8.14 (d, J=1.8 Hz, IH), 7.54 (s , IH), 5.43 - 5.17 (m, IH), 4.89 - 4.54 (m, IH), 4.22 - 3.16 (m, 7H, absorbed by water), 2.23 -2.09 (m, IH), 1.40 (br s, IH) , 1.30 - 1.22 (m, IH), 0.98 - 0.63 (m, 4H) 1224 1HNMR (500 MHz, DMSO-d6) δ 8.92 (br s, IH), 8.81 - 8.75 (m, IH), 8.62 8.50 (m, IH), 8.17 (s, IH), 7.61 (s, IH), 5.43 - 5.20 (m, IH), 4.85 - 4.58 (m, IH), 4.23 - 3.22 (m, 7H), 2.55 (s, 2H), 1.42 (br s, 3H) 1225 1HNMR (500 MHz, DMSO-d6) δ 8.93 (br s, IH), 8.85 - 8.76 (m, IH), 8.53 8.43 (m, IH), 8.17 (s, IH), 7.57 (s, IH), 5.46 - 5.23 (m, IH), 4.90 - 4.64 (m, IH), 4.29 - 3.40 (m, 8H), 1.35 - 1.24 (m, 3H) 1226 1HNMR (500 MHz, DMSO-d6) δ 8.92 (s, IH), 8.78 (s, IH), 8.52 - 8.39 (m, IH), 8.16 (s, IH), 7.57 (s, IH), 5.42 - 5.18 (m, IH), 4.80 - 4.58 (m, IH), 4.57 - 4.31 (m, IH), 4.07 (s, 3H), 4.02 - 3.28 (m, 3H), 2.18 - 2.03 (m, IH), 1.79 (br dd, J=14.1, 7.4 Hz, IH), 0.94 (br d, J=6.5 Hz, ZN) 1227 1HNMR (500 MHz, DMSO-d6) δ 8.92 (s, IH), 8.78 (br s, IH), 8.51 - 8.39 (m, IH), 8.16 (s, IH), 7.57 (s, IH), 5.39 - 5.17 (m, IH), 4.78 - 4.58 (m, IH), 4.55 4.26 (m, IH), 4.06 (s, 3H), 4.04 - 3.39 (m, 3H), 2.15 (br d, J=4.9 Hz, IH), 1.85 1.68 (m, IH), 0.90 (br d, J=6.0 Hz, ZN) 1228 1HNMR (500 MHz, DMSO-d6) δ 8.91 (s, IH), 8.76 (br d, J=3.7 Hz, IH), 8.58 (brt, >9.0 Hz, IH), 8.16 (s, IH), 7.60 ( s, IH), 5.49 - 5.24 (m, IH), 5.02 - 4.68 (m, IH), 4.24-3.13 (m, 7H) 1229 1HNMR (500 MHz, DMSO-d6) δ 8.92 (br s, IH), 8.77 (br d, J=11.6 Hz, IH), 8.57 (br dd, J=15.6, 7.0 Hz, IH), 8.16 (br s , IH), 7.60 (br s, IH), 5.49 - 5.20 (m, IH), 4.91 - 4.61 (m, IH), 4.31 - 3.41 (m, 7H, absorbed by water), 1.89 - 1.69 (m, WN) 1230 1HNMR (500 MHz, CD ₃ OD) δ 9.03 - 8.90 (m, 2H), 8.71 (br dd, J=15.7, 7.6 Hz, IH), 8.12 (s, IH), 7.46 (s, IH), 5.42 - 5.21 (m, IH), 4.95 - 4.72 (m, IH, absorbed by water), 4.70 - 4.41 (m, IH), 4.22 - 3.86 (m, 5H), 3.64 - 3.42 (m, 4H), 1.67 (s, 3H). 1231 1HNMR (500 MHz, DMSO-d6) δ 9.19 (s, IH), 8.96 - 8.82 (m, IH), 8.40 (br s, IH), 8.20 (s, IH), 7.70 (s, IH), 5.41 - 5.16 (m, IH), 4.76 - 4.51 (m, IH), 4.48 4.31 (m, IH), 4.09 - 3.61 (m, 3H), 2.58 (s, 3H), 2.07 (td, J=14.2, 7.3 Hz , IH), 1.84 - 1.65 (m, IH), 0.99 - 0.85 (m, 3H)

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1232 1HNMR (500 MHz, DMSO-d6) δ 9.18 (br s, 1H), 8.96 - 8.85 (m, 1H), 8.40 (br d, J=2.4 Hz, 1H), 8.20 (s, 1H), 7.69 (d , J=3.4 Hz, 1H), 5.48 - 5.19 (m, 1H), 4.82 4.50 (m, 1H), 4.11 - 3.18 (m, 4H), 2.84 (br s, 1H), 274 - 2.27 (m, 5H , absorbed by DMSO), 1.17–1.04 (m, 3H) 1233 1HNMR (500 MHz, DMSO-d6) δ 9.18 (br s, 1H), 9.00 - 8.83 (m, 1H), 8.39 (br d, J=3.7 Hz, 1H), 8.20 (s, 1H), 7.69 (d , J=2.4 Hz, 1H), 5.49 - 5.15 (m, 1H), 4.87 4.55 (m, 1H), 4.32 (br d, J=8.9 Hz, 1H), 4.16 - 3.25 (m, 3H), 3.10 - 2.73 (m, 1H), 2.58 (Br, 2H), 2.54 (s, 3H) 1234 1HNMR (500 MHz, DMSO-d6) δ 9.19 (br s, 1H), 8.98 - 8.85 (m, 1H), 8.40 (br s, 1H), 8.20 (s, 1H), 7.69 (d, J=1.8 Hz , 1H), 5.43 - 5.20 (m, 1H), 4.77 - 4.51 (m, 1H), 4.20 - 3.16 (m, 4H), 2.93 - 2.68 (m, 1H), 2.58 (s, 3H), 2.50 - 2.33 (m, 1H, absorbed by DMSO), 1.42 (br s, 3H) 1235 1HNMR (500 MHz, DMSO-d6) δ 9.18 (br s, 1H), 8.90 - 8.74 (m, 1H), 8.38 (br s, 1H), 8.19 (s, 1H), 7.65 (d, SW.OGz, 1H), 5.47 - 5.22 (m, 1H), 4.87 - 4.59 (m, 1H), 4.27 - 3.23 (m, 5H), 2.60 (d, J=1.8 Hz, SA), 1.34 - 1.23 (m, SA) 1236 1HNMR (500 MHz, DMSO-d6) δ 9.18 (br s, 1H), 8.91 - 8.77 (m, 1H), 8.39 (br d, J=5.3 Hz, 1H), 8.19 (s, 1H), 7.64 (br s, 1H), 5.50 - 5.22 (m, 1H), 4.90 - 4.59 (m, 1H), 4.20 - 3.30 (m, 4H), 3.13 - 2.90 (m, 2H), 2.61 (s, 3H) 1237 1HNMR (500 MHz, DMSO-d6) δ 9.41 - 9.04 (m, 1H), 8.90 (dd, J=11.0, 2.4 Hz, 1H), 8.75 (dd, J=10.1, 2.4 Hz, 1H), 8.73 - 8.65 (m, 2H), 8.62 - 8.41 (m, 1H), 7.87 (d, >13.7Hz, 1H), 7.62 - 7.42 (m, 3H), 7.03 (d, >16.2Hz, 1H), 5.49 - 5.11 ( m, 1H), 4.92 - 4.60 (m, 1H), 4.11 - 3.33 (m, overlap with d at 4.02 and water peak, 6H), 4.02 (d overlap, J=8.9 Hz, WA), 2.62 (br s, 4H ), 2.08 - 1.93 (w, 4H) 1247 1HNMR (500 MHz, DMSO-d6) δ 8.92 (br s, 1H), 8.76 (br d, J=16.2 Hz, 1H), 8.62 - 8.44 (m, 1H), 7.97 (br s, 1H), 7.12 ( br s, 1H), 5.42 - 5.14 (m, 1H), 4.91 4.52 (m, 1H), 4.03 (d, J=4.8 Hz, ZH), 4.02 - 3.19 (m, overlap with water peak, JH), 2.26 - 1.95 (m, 7H), 1.03 - 0.71 (m, 6H), 2 exchangeable protons 1254 1HNMR (500 MHz, DMSO-d6) δ 8.89 (dd, J=8.5, 2.4 Hz, 1H), 8.74 (dd, J=13.6, 2.3 Hz, 1H), 8.63 - 8.54 (m, 2H), 7.96 (brt , J=7.6 Hz, 1H), 7.86 (d, J=9.8 Hz, 1H), 7.79 (br d, J=7.9 Hz, 1H), 7.59 - 7.45 (m, 1H), 7.03 (d, J=10.7 Hz, 1H), 5.46 - 5.14 (m, 1H), 4.87 - 4.60 (m, 1H), 4.22 - 4.04 (m, 2H), 4.01 (d, J=7.6 Hz, ZN), 3.96 - 3.47 (m, overlap with water peak, 5H), 2.62 (br s, WN), 2.00 (br s, 4H) 1256 1HNMR (500 MHz, DMSO-d6) δ 9.38 - 9.21 (m, 1H), 9.20 - 9.10 (m, 1H), 8.90 (br d, J=2.4 Hz, 1H), 8.75 (s, 1H), 8.57 ( br d, J=6.7 Hz, 1H), 8.34 (s, 1H), 7.88 (d, J=4.9 Hz, 1H), 7.70 - 7.27 (m, 1H), 7.04 (br d, J=4.6 Hz, 1H ), 5.48 - 5.12 (m, 1H), 4.95 - 4.63 (m, 1H), 4.45 - 4.04 (m, 1H), 4.02 (s, 3H), 3.96 - 3.55 (m, 6H), 2.62 (br s, 3H), 2.10-1.92 (m, 4H) 1262 1HNMR (500 MHz, DMSO-d6) δ 8.93 - 8.84 (m, 1H), 8.71 (d, J=2.1 Hz, 1H), 8.62 - 8.43 (m, 1H), 8.04 (br d, J=12.5 Hz, 1H), 7.72 - 7.57 (m, 1H), 7.57 - 7.47 (m, 1H), 7.46 - 7.37 (m, 1H), 7.21 - 7.15 (m, 1H), 5.48 - 5.08 (m, 1H), 4.93 - 4.52 (m, 1H), 4.03 (br d, J=2.7 Hz, 3H), 3.99 - 3.44 (m, overlap with water peak, 9H), 3.11 - 2.91 (m, 1H), 2.15 (br s, 4H) , 2 exchangeable protons

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1275 1HNMR (400 MHz, DMSO-d6) δ 8.96 - 8.89 (m, 1H), 8.76 (d, J=2.4 Hz, 1H), 8.59 - 8.44 (m, 1H), 7.96 - 7.87 (m, 1H), 7.66 (br dd, J=5.6, 1.8 Hz, 2H), 7.30 (br s, 2H), 7.07 (s, 1H), 5.48 - 5.15 (m, 1H), 4.90 - 4.58 (m, 1H), 4.01 (br d, J=3.8 Hz, ZN), 3.82 (br d, J=5.3 Hz, 1H), 3.71 (br s, 4H), 3.65 - 3.49 (m, 1H), 3.18 (d, J=2.9 Hz, 1H ). 1278 1HNMR (500 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.77 (d, J=2.1 Hz, 1H), 8.51 (br d, J=7.6 Hz, 1H), 7.92 - 7.87 (m, 1H) , 7.08 (s, 1H), 5.41 - 5.26 (m, 1H), 4.83 - 4.71 (m, 1H), 4.70 - 4.59 (m, 2H), 4.07 - 3.97 (m, 2H), 3.92 - 3.66 (m, 8H), 3.42 - 3.39 (m, 1H). 1285 1HNMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.82 - 8.74 (m, 1H), 8.55 - 8.44 (m, 1H), 7.91 (s, 1H), 7.09 (s, 1H), 5.41 - 5.16 (m, 1H), 4.87 - 4.52 (m, 1H), 4.07 - 3.52 (m, 9H), 3.48 - 3.19 (m, 1H), 2.24 - 1.96 (m, 3H), 0.92 (dt, J= 6.5, 2.7Hz, 6H) 1290 1HNMR (500 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.72 (d, J=1.2 Hz, 1H), 8.45 (br d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.81 (s, 1H), 7.07 (s, 1H), 5.38 - 5.12 (m, 1H), 4.56 4.30 (m, 1H), 4.01 (br s, 2H), 3.80 - 3.67 (m, partially suppressed, 7H), 3.63 (s, 3H), 3.60 - 3.55 (m, 1H), 2.33 (s, 3H), 2 exchangeable protons 1295 1HNMR (500 MHz, DMSO-d6) δ 8.91 (d, J=2.1 Hz, 1H), 8.73 (d, J=2.1 Hz, 1H), 8.48 (br d, J=7.6 Hz, 1H), 7.89 (s , 1H), 7.80 (br d, J=7.6 Hz, 1H), 7.69 - 7.61 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.13 (t, J=7.5 Hz, 1H), 7.07 (s, 1H), 5.40 - 5.15 (m, 1H), 4.71 - 4.37 (m, 1H), 4.00 (s, 2H), 3.96 (s, 3H), 3.84 (t, J=9.0 Hz, 1H) , 3.75 3.56 (m, 3H), 3.46 (br s, 3H), 3.29 - 3.14 (m, 1H), 2 exchangeable protons 1298 1HNMR (500 MHz, DMSO-d6) δ 8.90 (d, J=2.1 Hz, 1H), 8.75 (d, J=2.1 Hz, 1H), 8.54 (br d, J=7.0 Hz, 1H), 7.88 (s , 1H), 7.06 (s, 1H), 5.42 - 5.20 (m, 1H), 4.86 4.64 (m, 1H), 4.02 - 3.97 (m, 2H), 3.79 (br t, J=9.0 Hz, 1H), 3.74 - 3.66 (m, 1H), 3.64 - 3.52 (m, 3H), 3.44 (dt, J=13.5, 6.8 Hz, 1H), 3.32 (br t, J=9.8 Hz, 1H), 1.26 (d, J =6.7 Hz, 6H), 2 exchangeable protons 1299 1HNMR (500 MHz, DMSO-d6) δ 8.91 (br s, 1H), 8.77 (br d, J=7.8 Hz, 1H), 8.53 - 8.38 (m, 1H), 7.87 (s, 1H), 7.05 (s , 1H), 5.41 - 5.19 (m, 1H), 4.74 - 4.58 (m, 1H), 4.56 - 4.29 (m, 1H), 4.10 - 3.78 (m, 4H), 3.71 (br t, J=12.4 Hz, 4H), 3.63 3.40 (m, 1H, absorbed by water), 1.54 (s, 3H). 1300 1HNMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.71 (br s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.64 (s, 1H), 7.09 (br s , 1H), 4.01 (s, 3H), 1.37 (s, 9H), 2 exchangeable protons 1303 1HNMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.73 (s, 1H), 8.41 (s, 1H), 8.18 (s, 1H), 7.94 (br s, 1H), 7.65 (s, 1H), 4.19 (br d, J=6.4 Hz, 1H), 4.03 (s, 3H), 1.92 1.82 (m, 2H), 1.74 -1.63 (m, 2H), 1.58 - 1.47 (m, 4H), 2 capable of proton exchange 1304 1HNMR (500 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.70 (s, 1H), 8.31 (br s, 1H), 8.17 (s, 1H), 7.64 (s, 1H), 3.99 (s, 3H), 3.43 - 3.26 (m, 4H), 1.63 - 1.50 (m, 2H), 1.09 - 0.94 (m, 1H), 0.92 - 0.68 (m, 3H), 0.49 - 0.37 (m, 2H), 0.32 - 0.12 (m, 2H), 3 exchangeable protons 1306 1HNMR (500 MHz, DMSO-d6) δ 8.93 (br dd, J=10.8, 7.5 Hz, 1H), 8.03 (br d, J=7.6 Hz, 1H), 7.84 (s, 1H), 7.65 (d, J =10.4 Hz, 1H), 6.93 (s, 1H), 5.40 - 5.12 (m, 1H), 4.78 - 4.44 (m, 1H), 4.20 - 3.11 (m, JH, absorbed by water), 1.62 - 1.44 (m, 6H)

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1307 1HNMR (500 MHz, DMSO-d6) δ 8.90 - 8.77 (m, 1H), 8.06 (br d, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.61 (d, J=10.3 Hz, 1H) , 6.93 (s, 1H), 5.43 - 5.17 (m, 1H), 4.80 4.49 (m, 1H), 4.02 (s, 2H), 3.50 - 3.30 (m, JUN, absorbed by water) 1308 1HNMR (500 MHz, DMSO-d6) δ 8.90 (br s, 1H), 8.05 (br d, J=7.9 Hz, 1H), 7.86 (s, 1H), 7.66 (d, J=10.4 Hz, 1H), 6.93 (s, 1H), 5.39 - 5.10 (m, 1H), 4.80 - 4.47 (m, 1H), 4.25 - 3.62 (m, JH, absorbed by water), 1.45 (br d, J=15.0 Hz, 6H) 1309 1HNMR (500 MHz, DMSO-d6) δ 8.98 - 8.83 (m, 1H), 8.10 - 7.99 (m, 1H), 7.86 (s, 1H), 7.67 (d, J=10.4 Hz, 1H), 6.93 (s , 1H), 5.43 - 5.14 (m, 1H), 4.80 - 4.49 (m, 1H), 4.02 (s, 2H), 3.94 - 3.10 (m, 9H, absorbed by water), 2.91 - 2.65 (m, 4H) 1310 1HNMR (500 MHz, DMSO-d6) δ 8.98 - 8.87 (m, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.86 (s, 1H), 7.66 (brd, J=10.1 Hz, 1H), 6.93 (s, 1H), 5.39 - 5.14 (m, 1H), 4.82 4.51 (m, 1H), 4.09 - 3.38 (m, 9H, absorbed by water), 3.32 - 3.06 (m, 2H), 2.42 1.98 (m 5H), 1.90 - 1.68 (m, 1H) 1311 1HNMR (500 MHz, DMSO-d6) δ 8.79 (br dd, J=11.0, 7.5 Hz, 1H), 8.04 (br d, J=7.7 Hz, 1H), 7.83 (s, 1H), 7.59 (br d, J=10.3 Hz, 1H), 6.92 (s, 1H), 5.40 - 5.15 (m, 1H), 5.09 - 4.87 (m, 1H), 4.75 - 4.48 (m, 1H), 4.02 (s, 2H), 3.90 - 3.16 (m, 8H, absorbed by water), 2.81 - 2.65 (m, 1H), 2.55 - 2.46 (m, 2H, absorbed by DMSO), 2.35-2.14 (m, 2H) 1312 1HNMR (500 MHz, DMSO-d6) δ 8.79 (br t, J=8.2 Hz, 1H), 8.04 (br d, J=7.6 Hz, 1H), 7.83 (s, 1H), 7.59 (br d, J= 10.2 Hz, 1H), 6.92 (s, 1H), 5.36 - 5.01 (m, 2H), 4.77.4.48 (m, 1H), 4.01 (s, 2H), 3.87 - 3.14 (m, 8H), 2.55 - 2.28 (m, 5H) 1313 1HNMR (500 MHz, DMSO-d6) δ 8.88 - 8.76 (m, 1H), 8.05 (br d, J=7.5 Hz, 1H), 7.83 (s, 1H), 7.59 (brd, J=10.4 Hz, 1H) , 6.92 (s, 1H), 5.38 - 5.14 (m, 1H), 4.674.50 (m, 1H), 4.46 - 4.24 (m, 1H), 4.01 (s, 2H), 3.92 - 3.40 (m, 7H) , 1.53(s, 3H) 1314 1HNMR (500 MHz, DMSO-d6) δ 8.76 - 8.64 (m, 1H), 8.36 (s, 1H), 8.21 (s, 2H), 7.72 (brd, 1=8.8Hz, 1H), 7.66 (s, 1H ), 6.98 (br d, 1=9.9Hz, 1H), 5.39-5.16 (m, 1H), 4.72-4.54 (m, 1H), 4.51 - 4.30 (m, 1H), 4.11 -3.53 (m, 3H) , 1.56 (s, 3H). 1315 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.65 (m, 1H), 8.36 (s, 1H), 8.25 - 8.15 (m, 2H), 7.71 (br d, J=8.9 Hz, 1H), 7.66 ( s, 1H), 5.41 - 5.17 (m, 1H), 4.83 - 4.56 (m, 1H), 4.02 - 3.09 (m, 5H, absorbed by water), 2.90 - 2.70 (m, 4H). 1316 1HNMR (500 MHz, DMSO-d6) δ 8.70 (br d, J=17.6 Hz, 1H), 8.37 (s, 1H), 8.26 8.17 (m, 2H), 7.73 (br d, J=8.4 Hz, 1H) , 7.67 (s, 1H), 6.74 (s, 1H), 5.39 - 5.13 (m, 1H), 4.77 - 4.57 (m, 1H), 4.52 - 4.29 (m, 1H), 4.14 - 3.12 (m, 3H) , 2.25 - 2.04 (m, 1H), 1.87 - 1.70 (m, 1H), 0.99 - 0.82 (m, 3H) 1317 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.67 (m, 1H), 8.15 (s, 1H), 8.00 (br d, J=11.4 Hz, 1H), 7.83 (br s, 1H), 7.56 (br s, 1H), 5.41 - 5.17 (m, 1H), 4.78 - 4.50 (m, 1H), 4.15 - 3.16 (m, 4H, absorbed by water), 2.28 (br s, 3H), 2.20 - 2.08 (m, 1H ), 1.43 - 1.32 (m, 1H), 1.25 (br s, 1H), 0.99 - 0.61 (m, 4H) 1318 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.66 (m, 1H), 8.20 (s, 1H), 8.06 (br d, J=11.4 Hz, 1H), 7.90 (br s, 1H), 7.63 (br s, 1H), 5.44 - 5.22 (m, 1H), 4.77 - 4.51 (m, 1H), 4.21 - 3.19 (m, 5H), 2.85 - 2.69 (m, 1H), 2.31 (s, 3H), 1.43 ( s, 3H) 1319 1HNMR (500 MHz, DMSO-d6) δ 8.80 - 8.64 (m, 1H), 8.20 (s, 1H), 8.07 (br d, J=11.5 Hz, 1H), 7.90 (br s, 1H), 7.62 (d , J=6.6 Hz, 1H), 5.47 - 5.20 (m, 1H), 4.87 - 4.56 (m, 1H), 4.23 - 3.21 (m, 5H), 2.31 (br s, 3H), 1.34 - 1.25 (m, 3H)

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1320 1HNMR (500 MHz, DMSO-d6) δ 8.78 - 8.66 (m, 1H), 8.20 (s, 1H), 8.06 (br d, J=10.7 Hz, 1H), 7.90 (br d, J=1.7 Hz, 1H ), 7.62 (d, J=5.3 Hz, 1H), 5.47 - 5.22 (m, 1H), 4.82 - 4.54 (m, 1H), 4.30 (ddd, J=14.1, 8.8, 5.6 Hz, 1H), 4.17 - 2.76 (m, 6H), 2.31 (brs, 3H) 1321 1HNMR (500 MHz, DMSO-d6) δ 8.87 - 8.74 (m, 2H), 8.20 (s, 1H), 8.08 (br d, J=11.6 Hz, 1H), 7.90 (s, 1H), 7.66 (s, 1H), 5.40 - 5.16 (m, 1H), 4.72 - 4.49 (m, 1H), 4.46 - 4.23 (m, 1H), 4.11-3.62 (m, 3H), 2.29 (s, 3H), 2.22 - 1.99 ( m, 1H), 1.83 - 1.66 (m, 1H), 0.98 - 0.82 (m, 3H) 1322 1HNMR (500 MHz, DMSO-d6) δ 8.92 - 8.76 (m, 1H), 8.74 (s, 1H), 8.68 (br s, 1H), 8.19 (d, J=12.8 Hz, 1H), 8.07 (brdd, J=15.1, 12.1 Hz, 1H), 7.97 (brd, J=7.6 Hz, 1H), 7.94 - 7.83 (m, 1H), 7.70 - 7.60 (m, 1H), 7.51 (dd, J=7.5, 5.0 Hz , 1H), 5.49 - 5.20 (m, 1H), 4.85 - 4.56 (m, 1H), 4.12 - 3.15 (m, 4H, absorbed by water), 2.33 - 2.21 (m, WN) 1323 1HNMR (500 MHz, DMSO-d6) δ 8.92 - 8.75 (m, 1H), 8.72 (s, 1H), 8.56 (br d, >4.0Hz, 1H), 8.18 (d, >15.0Hz, 1H), 8.06 (br dd, J=16.8, 11.3 Hz, 1H), 7.95 7.80 (m, 1H), 7.68 - 7.59 (m, 1H), 7.55 (dt, J=10.3, 5.1 Hz, 1H), 5.47 - 5.18 (m , 1H), 4.87 - 4.62 (m, 1H), 4.11 - 3.15 (m, 4H, absorbed by water), 2.33 - 2.21 (m, 3H) 1324 1HNMR (500 MHz, DMSO-d6) δ 8.92 - 8.75 (m, 1H), 8.70 (br s, 1H), 8.62 (s, 1H), 8.19 (brd, J=12.2 Hz, 1H), 8.06 (brdd, J=16.0, 11.7 Hz, 1H), 7.98 - 7.83 (m, 2H), 7.69 - 7.56 (m, 1H), 5.48 - 5.20 (m, 1H), 4.85 - 4.52 (m, 1H), 4.13 - 3.15 ( m, 4H, absorbed by water), 2.32 - 2.21 (m, SA) 1325 1HNMR (500 MHz, DMSO-d6) δ 8.94 - 8.75 (m, 1H), 8.69 (br d, J=2.7 Hz, 2H), 8.18 (d, J=15.0 Hz, 1H), 8.06 (br dd, J =18.2, 11.4 Hz, 1H), 7.95 - 7.79 (m, 1H), 7.68 - 7.57 (m, 1H), 5.48 - 5.20 (m, 1H), 4.93 - 4.66 (m, 1H), 4.13 - 3.15 (m , 4H, absorbed by water), 2.32 - 2.20 (m, W) 1326 1H NMR (500 MHz, DMSO-d6) δ 9.12 - 8.92 (m, 1H), 8.34 (br d, J=11.0 Hz, 1H), 8.24 (s, 1H), 8.09 (br s, 1H), 7.79 ( br s, 1H), 5.40 - 5.12 (m, 1H), 4.78 - 4.51 (m, 1H), 4.49 - 4.23 (m, 1H), 4.09 - 3.13 (m, 3H), 2.22 - 2.00 (m, 1H) , 1.84 - 1.65 (m, 1H), 0.97-0.81 (m, 3H) 1327 1HNMR (500 MHz, DMSO-d6) δ 9.11 - 8.92 (m, 1H), 8.34 (brd, >10.4Hz, 1H), 8.23 (s, 1H), 8.09 (br s, 1H), 7.79 (br d, J=3.7 Hz, 1H), 5.36 - 5.14 (m, 1H), 4.74.4.53 (n ₅ Sh), 4.45 - 4.24 (m, 1H), 4.08 - 3.12 (m, 3H), 1.53 (s, 3H) 1328 1HNMR (500 MHz, DMSO-d6) δ 9.14 - 8.97 (m, 1H), 8.39 - 8.28 (m, 1H), 8.23 (s, 1H), 8.09 (br s, 1H), 7.78 (br d, J= 6.4 Hz, 1H), 5.45 - 5.15 (m, 1H), 4.88 - 4.60 (m, 1H), 4.27 - 3.15 (m, 5H), 1.27 (br t, J=7.9 Hz, ZN) 1329 1HNMR (500 MHz, DMSO-d6) δ 9.14 - 9.00 (m, 1H), 8.41 - 8.30 (m, 1H), 8.24 (br s, 1H), 8.10 (br s, 1H), 7.84 - 7.73 (m, 1H), 5.43 - 5.19 (m, 1H), 4.85 - 4.62 (m, 1H), 4.23 - 3.20 (m, 5H, absorbed by water), 1.41 - 1.20 (m, WN) 1330 1HNMR (400 MHz, DMSO-d6) δ 9.11 - 8.98 (m, 1H), 8.40 - 8.30 (m, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.80 (d, J=3.8 Hz , 1H), 5.42 - 5.17 (m, 1H), 4.83 - 4.52 (m, 1H), 4.04 - 3.23 (m, 4H, absorbed by water), 2.96 - 2.76 (m, 1H), 2.58 - 2.26 (m, 2H , absorbed by DMSO), 1.10 (dd, J=6.8, 2.5 Hz, ZN). 1331 1HNMR (400 MHz, DMSO-d6) δ 9.11 - 8.98 (m, 1H), 8.40 - 8.30 (m, 1H), 8.24 (s, 1H), 8.10 (s, 1H), 7.80 (d, J=3.8 Hz , 1H), 5.42 - 5.17 (m, 1H), 4.83 - 4.52 (m, 1H), 4.04 - 3.23 (m, 4H, absorbed by water), 2.96 - 2.76 (m, 1H), 2.58 - 2.26 (m, 2H , absorbed by DMSO), 1.10 (dd, J=6.8, 2.5 Hz, ZN).

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1332 1HNMR (500 MHz, DMSO-d6) δ 8.78 (br dd, J=19.0, 7.0 Hz, 1H), 8.33 (br dd, J=10.3, 7.8 Hz, 1H), 8.21 (s, 1H), 8.13 (br s, 1H), 7.67 (s, 1H), 6.95 (br d, J=7.9 Hz, 1H), 5.41 -5.17(m, 1H), 4.76-4.56 (m, 1H), 4.51 -4.28 (m, 1H ), 4.12-3.18 (m, 3H), 1.56 (s, 3H) 1333 1HNMR (500 MHz, DMSO-d6) δ 9.00 - 8.87 (m, 1H), 8.34 (br s, 1H), 8.21 (s, 1H), 8.12 (br s, 1H), 7.69 (br s, 1H), 5.42 - 5.15 (m, 1H), 4.84 - 4.54 (m, 1H), 4.15 - 3.06 (m, 4H), 2.41 - 1.96 (m, 6H), 1.78 (br d, J=6.4 Hz, 1H) 1334 1HNMR (500 MHz, DMSO-d6) δ 9.06 - 8.87 (m, 1H), 8.37 (br d, J=9.2 Hz, 1H), 8.23 (s, 1H), 8.14 (br s, 1H), 7.72 (s , 1H), 5.44 - 5.20 (m, 1H), 4.84 - 4.51 (m, 1H), 4.23 - 3.06 (m, 5H), 2.90 - 2.70 (m, 1H), 1.43 (br s, 3H) 1335 1HNMR (500 MHz, DMSO-d6) δ 8.90 - 8.75 (m, 1H), 8.38 - 8.29 (m, 1H), 8.21 (s, 1H), 8.12 (br s, 1H), 7.66 (d, J=3.5 Hz, 1H), 5.46 - 5.21 (m, 1H), 4.86 - 4.61 (m, 1H), 4.26 - 3.24 (m, 5H), 1.36 - 1.22 (m, 3H) 1336 1HNMR (500 MHz, DMSO-d6) δ 8.80 (br dd, J=13.8, 7.3 Hz, 1H), 8.36 - 8.28 (m, 1H), 8.20 (s, 1H), 8.11 (br d, J=3.8 Hz , 1H), 7.65 (d, J=3.7 Hz, 1H), 5.45 5.19 (m, 1H), 4.88 - 4.53 (m, 1H), 4.02 - 3.07 (m, 5H), 2.90 - 2.67 (m, 4H) 1337 1HNMR (500 MHz, DMSO-d6) δ 8.86 - 8.72 (m, 1H), 8.33 (br dd, J=11.7, 7.2 Hz, 1H), 8.21 (s, 1H), 8.13 (br s, 1H), 7.67 (s, 1H), 5.42 - 5.12 (m, 1H), 4.78 - 4.54 (m, 1H), 4.53 - 4.25 (m, 1H), 4.18 - 3.13 (m, 3H), 2.24 - 2.01 (m, 1H), 1.79 (br d, J=8.3 Hz, 1H), 1.00 - 0.82 (m, 3H) 1338 1HNMR (500 MHz, DMSO-d6) δ 8.94 - 8.84 (m, 1H), 8.20 (s, 1H), 8.05 (br dd, J=11.5, 2.9 Hz, 1H), 7.85 (br d, J=6.6 Hz , 1H), 7.64 (br d, J=8.0 Hz, 1H), 5.43 5.18 (m, 1H), 4.79 - 4.52 (m, 1H), 3.99 - 3.07 (m, 5H, absorbed by water), 2.90 2.66 (m , 6H), 1.22-1.10 (m, 3H)

Example 1339: N-[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-5-[4acetamido-5-(trifluoromethyl)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl]-2-methoxypyridine-3-carboxamide

Obtained according to the methods described in example 564.

MS (ERI) m/z 600.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.07-8.48 (m, 3H), 8.20-7.90 (m, 1H), 7.64-7.35 (m, 1H), 5.44-5.18 (m, 1H), 4.89- 4.59 (m, 1H), 4.05 (br t, J 7.0 Hz, 3H), 4.00–3.09 (m, 5H), 2.91–2.68 (m, 4H), 2.55 (s, 3H).

Example 1340: 5-[4-acetamido-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4fluoro-1- [4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide

Obtained according to the methods described in example 564.

MS (ERI) m/z 690.3 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.04-7.31 (m, 6H), 5.46-5.23 (m, 1H), 4.90-4.62 (m, 1H), 4.22-3.27 (m, 7H), 3.06 -2.84 (m, 2H), 2.55 (s, 3H).

Example 1341: 5-[4-acetamido-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4fluoro-1 - [(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3 carboxamide

Obtained according to the methods described in example 564.

MS (ERI) m/z 622.1 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 9.10-7.13 (m, 6H), 5.41-5.19 (m, 1H), 4.79-4.56 (m, 1H), 4.55-4.27 (m, 1H), 4.09-2.86 (m, 6H), 2.55 (s, 3H, absorbed in DMSO), 1.54 (s, 3H).

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Example 1342: N-[(3R,4S)-1-[(1 R)-3,3-difluorocyclopentanecarbonyl]-4-fluoropyrrolidin-3-yl]-5-[4acetamido-5-(trifluoromethyl)pyrrolo[2, 1-1][1,2,4]triazin-7-yl]-2-methoxypyridine-3-carboxamide

Obtained according to the methods described in example 564. MS (ESI) m/z 617.1 (M+H)+

1H NMR (500 MHz, DMSO-d6) δ 9.11-7.34 (m, 5H), 5.45-5.19 (m, 1H), 4.92-4.58 (m, 1H), 4.15-3.15 (m, 4H), 2.55 (s , 3H, absorbed by DMSO), 2.41–1.69 (m, 7H).

Example 1343: N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin3-yl]-5-[4-( 2-fluoro-2-methylpropanamido)-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-2methoxypyridine-3-carboxamide

Obtained according to the methods described in example 564.

MS (ERI) m/z 668.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.09-7.02 (m, 6H), 5.43-5.18 (m, 1H), 4.81-4.57 (m, 1H), 4.54-4.26 (m, 1H), 4.10- 3.15 (m, 6H), 1.72-1.50 (m, 9H).

Example 1344: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1H1,2,4- triazol-3-yl)-2-methoxypyridine-3-carboxamide

Obtained according to the methods described in example 10.

MS (ERI) m/z 510.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.55 (br s, 1H), 8.92 (br s, 1H), 8.78-8.47 (m, 2H), 8.16 (br s, 1H), 7.62 (s, 1H) , 7.46-7.24 (m, 5H), 5.36 (br s, 2H), 4.00 (br s, 3H).

Example 1345: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3,3difluorocyclobutanecarbonyl)-4, 4-difluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

Obtained according to the methods described in example 563.

MS (ERI) m/z 576.5 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.92 (s, 1H), 8.77-8.63 (m, 2H), 8.17 (s, 1H), 7.61 (s, 1H), 5.19-4.95 (m, 1H), 4.11-3.81 (m, 6H), 3.59-3.39 (m, 1H, absorbed by water), 3.23-3.11 (m, 1H), 2.89-2.68 (m, 4H).

Example 1346: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 ((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxy-N-methylnicotinamide

1346A: 5-bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA: to tert-butyl (3R,4S)-3-(5-bromo-2-methoxynicotinamido) solution -4-Fluoropyrrolidine-1-carboxylate (110 mg, 0.263 mmol) (please refer to synthesis 1549A) in CH ₂ Cl ₂ (2 ml) was added TFA (0.405 ml, 5.26 mmol) and stirred at 23°C for 1 h. The reaction mixture was concentrated and triturated in 10 ml Et ₂ O. The solid was collected as 5-bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA (109.5 mg, 0.253 mmol, 96% yield).

MS (ERI) m/z 318.1 (M+H).

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1346B: 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin3-yl)-2-methoxy -N-methylnicotinamide

OH F ^F

1346C: 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)pyrrolidin-3yl)-2-methoxy -N-methylnicotinamide

To a solution of 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2 -methoxynicotinamide (109.6 mg, 0.239 mmol) in THF (3 ml) was added NaH (33.5 mg, 0.837 mmol) and stirred at 23°C for 10 min. Methyl iodide (0.037 ml, 0.598 mmol) was added to the reaction mixture and stirred for 3 h. The reaction mixture was diluted with 50 ml of EtOAc, then washed with 10x2 ml of 10% LiCl solution, 10 ml of brine and dried over Na ₂ SO ₄ . Filtration and concentration gave the crude material. The crude product was purified by preparative HPLC to give 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidine-3 -yl)-2-methoxy-N-methylnicotinamide (27.2 mg, 0.058 mmol, 24% yield), MS (ERI) m/z 472.1 (M+H); and 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-methoxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxy- N-methylnicotinamideα (13.3 mg, 0.027 mmol, 11% yield), MS (ERI) m/z 486.1 (M+H).

1346D: N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxy-N-methyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide: degassed solution of 5-bromo-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxy-N-methylnicotinamide (23 mg, 0.049 mmol), 4,4,4',4', 5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (12.99 mg, 0.051 mmol), potassium acetate (7.65 mg, 0.078 mmol) and PdCl ₂ (dppf)CH adduct ₂ Cl ₂ (1.989 mg, 2.435 µmol) in 1,4-dioxane (1 ml) was heated to 90°C for 2 h. The reaction mixture was used as is.

1346: degassed solution of 7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (13.5 mg, 0.048 mmol), N-((3R,4S)- 4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)-2-methoxy-N-methyl-5-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (24.95 mg, 0.048 mmol), potassium triphosphate (2 M in water) (0.072 ml, 0.144 mmol) and 1,1'bis(diphenylphosphino)ferrocene adduct palladium dichloride-CH ₂ Cl ₂ (1.961 mg, 2.402 µmol) was stirred at 90°C for 16 h. The reaction mixture was concentrated and the crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 19x200 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 5-45% B over 20 min, then 3 min hold at 100% B; flow rate: 20 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (7.1 mg, 12 μmol, 25%).

MS (ERI) m/z 594.2 (M+H).

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (br d, J=1.5 Hz, 1H), 8.46-8.32 (m, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.33 -7.08 (m, 1H), 5.53-5.05 (m, 1H), 4.46-4.13 (m, 1H), 4.02-3.50 (m, 7H, absorbed by water), 3.12-2.83 (m, 3H), 1.55 (br d, J=6.9 Hz, 3H).

Example 1347: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 ((R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxy-N-methylnicotinamide

1347A: N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-methoxy-2-methylpropαnoyl)pyrrolidin-3-yl)-2methoxy-N-methyl -5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide: degassed solution of 5-bromo-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxy-N-methylnicotinamide (1346С, 13.3 mg, 0.027 mmol), 4,4,4',4 ',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (7.29 mg, 0.029 mmol), potassium acetate (4.29 mg, 0.044 mmol) and PdCl ₂ adduct (dppf )-CH ₂ Cl ₂ (1.117 mg, 1.368 µmol) in dioxane (1 ml) was heated to 100°C for 4 h. LC-MS showed that the reaction was complete. The reaction mixture was used as is.

1347: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -((R)- 375 042342

3,3,3-trifluoro-2-methoxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxy-N-methylnicotinamide was prepared using the method described for 1346 (2.9 mg, 4.6 µmol, 13% yield) .

MS (ERI) m/z 608.3 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.95 (br d, J=7.1 Hz, 1H), 8.48-8.34 (m, 1H), 8.18 (s, 1H), 7.63 (br s, 1H), 5.57- 5.32 (m, 1H), 5.27-4.96 (m, 1H), 4.41-3.38 (m, 10H, absorbed by water), 3.12-2.86 (m, 3H), 1.63-1.46 (m, 3H).

Example 1348: (2R)-1-{5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-yl} -2-[2-fluoro-5-(trifluoromethoxy)phenyl]propan-1-one

1348A: 7-iodo-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine: 5-iodo-N,N-bis(4methoxybenzyl)-7-(trifluoromethyl) solution )pyrrolo[2,1-1][1,2,4]triazine-4-amine (0.50 g, 0.880 mmol) in TFA (4.6 mL, 59.7 mmol) was heated at 135°C under microwave for 25 min. The TFA was removed in vacuo and co-evaporated once with ether. The crude product was dissolved in a minimum amount of dichloromethane and purified by silica gel flash chromatography (Teledyne-Isco RediSep Rf, 40 g column), eluting each time with 200 ml of hexanes, 95:5, 90:10, 80:20, 85:15 , 300 ml 80:20, and 300 ml 70:30 hexanes:EtOAc to give 7-iodo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4amine (179.9 mg, 0.548 mmol, 62% yield) as a light tan solid. MS (ERI) m/z 329.0 (M+H) ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.06 (s, 1H), 7.86 (d, J=2.9 Hz, 1H), 7.10 (d, J=2.9 Hz, 1H).

1348B: tert-butyl 5-bromo-2-methoxynicotinate: DMAP (0.074 g, 0.603 mmol) was added to a portion of a solution of 5-bromo-2-methoxynicotinic acid (2.0 g, 8.62 mmol), tert-butanol (3.30 ml, 34.5 mmol ) and DCC (2.67 g, 12.93 mmol) in dichloromethane (8.62 ml) at room temperature under N ₂ atmosphere. The reaction flask was placed in a sonicator for 1 min. Stirring was continued for 16 hours. The reaction was diluted with dichloromethane (10 ml) and filtered through a pad of celite. The filtrate was concentrated to dryness in vacuo and the remaining oil was diluted with ether (20 ml). The suspension was sonicated for 2 min. The suspension was filtered through celite and the filtrate was concentrated in vacuo to give a yellow oil. The oil was dissolved in ether (20 ml) and filtered through a 25 mm syringe filter with a 0.45 μm nylon membrane. The filtrate was concentrated in vacuo to give a yellow oil. The crude product was completely dissolved in hexanes (20 ml) and sonicated for 2 minutes. A small amount of precipitate was removed by filtration through a syringe filter with a 0.45 μm nylon membrane. The crude material was purified by silica gel flash chromatography (Teledyne-Isco RediSep Rf, 80 g column) eluting with 0-30% EtOAc in hexanes to give tert-butyl 5-bromo-2-methoxynicotinate (1.6055 g, 5.57 mmol, 65%) as a colorless oil.

MS (ERI) m/z 288.0/290.0 (M+H) ⁺ .

1H NMR (400 MHz, DMSO-d6) δ 8.47 (d, J=2.6 Hz, 1H), 8.18 (d, J=2.6 Hz, 1H), 3.90 (s, 3H), 1.52 (s, 9H).

1348C: tert-butyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate: mixture of tert-butyl 5-bromo-2-methoxynicotinate (1.59 g , 5.52 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2dioxaborolane) (1.68 g, 6.63 mmol) and potassium acetate (0.81 g, 8.29 mmol) in dioxane (27 ml) was degassed with nitrogen. Continuing degassing, 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (0.451 g, 0.552 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours After cooling to room temperature, the reaction mixture was diluted with EtOAc (25 ml) and filtered through celite, washing with EtOAc. The combined filtrate was washed with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give a brown oil. The crude product was dissolved in dichloromethane and purified by silica gel flash chromatography (Teledyne-Isco RediSep Rf, 80 g column) eluting with 0-30% EtOAc in hexanes to give t-butyl 2-methoxy-5(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (1.6681 g, 4.98 mmol, 90% yield) as a light off-white solid.

MS (ERI) m/z 254.1 (M+H-82 tetramethylethylene).

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.52 (d, J=2.0 Hz, 1H), 8.37-7.84 (m, 1H), 3.95 (s, 3H), 1.53 (s, 9H), 1.31 (s , 12H).

1348D: tert-Butyl 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinate: mixture of 5-iodo-7-(trifluoromethyl )pyrrolo[2,1-1][1,2,4]triazine-4-amine (71.5 mg, 0.218 mmol) and tert-butyl 2-methoxy-5-(4,4,5,5-tetramethyl-1 ,3,2-Dioxaborolan-2-yl)nicotinate (94.8 mg, 0.283 mmol) in potassium triphosphate (2.0 M aqueous solution) (330 μL, 0.654 mmol) was degassed with N ₂ . A complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (17.8 mg, 0.022 mmol) was added, followed by N2 degassing. The reaction mixture was heated at 105°C for 2.5 h. After cooling to room temperature, EtOAc and water were added. The layers were separated, the EtOAc layer

- 376 042342 washed with brine, dried over Na ₂ SO ₄ , filtered through celite and concentrated under vacuum to obtain a light tan solid. The crude product was dissolved in dichloromethane and purified by silica gel flash chromatography (Teledyne-Isco RediSep Rf, 12 g column) eluting with 0-40% EtOAc in hexanes to give tert-butyl 5-(4-amino-5-( trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methoxynicotinate (46.5 mg, 0.114 mmol, 52% yield) as an off-white solid.

MS (ERI) m/z 410.3/411.3 (M+H)+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.95 (d, J=2.4 Hz, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 3.99 (s, 3H), 1.55 (s, 9H).

1348E: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, TFA: tert-butyl 5-( 4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinate (42.2 mg, 0.103 mmol) in TFA (1985 µl, 25.8 mmol) was stirred at room temperature for 75 min. Excess TFA was removed in vacuo followed by co-evaporation twice with ether to give, after drying in vacuo, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazine-7- yl)-2-methoxynicotinic acid, TFA (44.0 mg, 0.078 mmol, 75% yield) as a light tan solid.

MS (ERI) m/z 354.1/355.2 (M+H)+.

1H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=2.4 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.28-7.99 (m, 1H), 7.63 (s, 1H) , 3.99(s, 3H).

1348: solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinic acid, TFA (15.0 mg, 0.042 mmol), ( K)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)ethan1-amine, HCl (12.13 mg, 0.047 mmol), BOP (22.54 mg, 0.051 mmol) and triethylamine (20.71 µl, 0.149 mmol) in DMF ( 425 µl) was stirred at room temperature for 80 min. The reaction was diluted with methanol and filtered through a syringe filter with a 0.45 μm nylon membrane. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 46% B, 46-86% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain (2R)-1-{5-[4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7- yl]-2-methoxypyridin-3-yl}-2-[2-fluoro-5(trifluoromethoxy)phenyl]propan-1-one (10 mg, 0.017 mmol, 41% yield).

MS (ERI) m/z 559.3/560.4 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (br s, 1H), 8.77 (br d, J=7.2 Hz, 1H), 8.59 (br s, 1H), 8.11 (s, 1H), 7.52 ( s, 1H), 7.49 (br s, 1H), 7.40-7.18 (m, 2H), 5.43-5.26 (m, 1H), 4.04 (s, 3H), 1.48 (br d, J=6.9 Hz, 3H) .

Example 1349: 5-[4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[(3R, 4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide

F

I

1349A: 4-amino-7-bromopyrrolo[2,1-1][1,2,4]triazine-5-carboxylic acid, sodium salt: ethyl 4-amino-7-bromopyrrolo[2,1-C[1] suspension ,2,4]triazine-5-carboxylate (0.50 g, 1.754 mmol) in THF (5.3 ml), ethanol (5.3 ml), and 1 N sodium hydroxide (5.3 ml, 5.26 mmol) was stirred at 50°C for 16 h. The solvent was removed under vacuum to give 4-amino-7-bromopyrrolo[2,1-C[1,2,4]triazine-5carboxylic acid, sodium salt (0.4461 g, 1.73 mmol, 99%) as a white solid.

MS (ERI) m/z 257.0 (M+H)+.

1349B: (4-Amino-7-bromopyrrolo[2,1-1][1,2,4]triazin-5-yl)(3,3-difluoroazetidin-1-yl)methanone: to a stirred suspension of 4-amino- 7-bromopyrrolo[2,1-1][1,2,4]triazine-5-carboxylic acid, sodium salt (0.15 g, 0.584 mmol), 3,3-difluoroazetidine, HCl (0.060 g, 0.642 mmol) and BOP (0.208 g, 0.700 mmol) triethylamine (0.33 ml, 2.33 mmol) was added to DMF at room temperature. Stirring was continued for 2 h at room temperature, then the reaction mixture was heated to 45°C for 135 min. After cooling to room temperature, EtOAc and 10% LiCl aqueous solution were added. The layers were separated and the EtOAc layer was washed with 10% aqueous LiCl (2x), saturated aqueous NaHCO ₃ (2x), brine dried over Na ₂ SO ₄ and evaporated in vacuo to give (4amino-7-bromopyrrolo[2.1-1 ][1,2,4]triazin-5-yl)(3,3-difluoroazetidin-1-yl)methanone (0.1689 g, 0.509 mmol, 87% yield) as a light orange-reddish solid. MS (ERI) m/z 333.9 (M+H)+.

- 377 042342 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.55 (br s, 1H), 8.37 (br s, 1H), 8.09 (s, 1H), 7.27 (s, 1H), 5.23-4.95 ( m,

2H), 4.71-4.37 (m, 2H).

1349C: tert-butyl (3R,4S)-3-(5-(4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1f][1,2,4]triazine-7 -yl)-2-methoxynicotinamido)-4-fluoropyrrolidin-1-carboxylate: vial filled with (4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)(3 ,3-difluoroazetidin-1-yl)methanone (90.0 mg, 0.271 mmol) and tert-butyl (3S,4R)-3-fluoro-4-(2-methoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2yl)nicotinamido)pyrrolidine-1-carboxylate (164 mg, 0.3523 mmol) in potassium triphosphate (2.0 M aqueous solution) (406 µL, 0.813 mmol) and dioxane (2.7 mL), degassed with N2 . The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (22.1 mg, 0.027 mmol) was added and degassing with nitrogen was continued again. The vial was sealed and stirred at 105°C for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and water. The layers were separated and the EtOAc layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to give a light brown solid. The crude material was dissolved in dichloromethane and purified by silica gel flash chromatography (Teledyne-Isco RediSep Rf, 24 g column), eluting with 50 ml hexanes and 80:20 hexanes:EtOAc, followed by 200 ml 1:1 hexanes:EtOAc, 200 ml 98:2 CH ₂ Cl ₂ :CH ₃ OH and 100 ml 95:5 CH ₂ Cl ₂ :CH ₃ OH to give a sticky tan solid. Chromatography material was suspended in ether, sonicated for 2 min, then stirred rapidly for 1 h. The solid was collected by filtration, washed with ether and dried under vacuum to give t-butyl (3R,4S)3-(5- (4-Amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (98.1 mg, 0.166 mmol, 61% yield) as a tan solid.

MS (ERI) m/z 591.3/592.3 (M+H)+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (br s, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.79 (br s, 1H), 8.49 (br d, J=7.3 Hz, 1H), 8.31 (br d, J=1.6 Hz, 1H), 8.09 (s, 1H), 7.49 (s, 1H), 5.37-5.19 (m, 1H), 5.15 -4.89 (m, 1H), 4.85- 4.40 (m, 3H), 4.05 (s, 1H), 4.03-3.99 (m, 1H), 3.83-3.71 (m, 1H), 3.64-3.50 (m, 1H), 3.27-3.12 (m, 1H), 1.43(s, 9H).

1349D: 5-(4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R,4S )-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA salt: tert-butyl (3R,4S)-3-(5-(4amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo) solution [2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4fluoropyrrolidine-1-carboxylate (95.3 mg, 0.161 mmol) in TFA (1614 µl) was stirred at room temperature for 55 min. Excess TFA was removed in vacuo followed by co-evaporation twice with ether. The crude product was suspended in ether, sonicated for 2 min, collected by filtration, washed with ether and dried in vacuo to give 5-(4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl)N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA salts (127.6 mg, 0.211 mmol, ~100 % yield) as a reddish solid.

MS (ERI) m/z 491.2/492.2 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.65 (br s, 1H), 9.52-9.28 (m, 1H), 9.13-9.01 (m, 1H), 8.96 (d, J=2.2 Hz, 1H) , 8.79 (d, J=2.2 Hz, 1H), 8.60 (br d, J=7.6 Hz, 1H), 8.36 (br s, 1H), 8.10 (s, 1H), 7.62-7.35 (m, 1H), 5.51-5.30 (m, 1H), 5.23-4.97 (m, 2H), 4.91-4.76 (m, 1H), 4.68-4.39 (m, 2H), 4.05 (s, 3H), 3.80-3.47 (m, 3H ), 3.34-3.06 (m, 1H).

1349: 5-(4-Amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R, 4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, TFA salts (15.0 mg, 0.025 mmol), (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoic acid (4.3 mg, 0.027 mmol ), BOP (13.17 mg, 0.030 mmol) and triethylamine (13.8 μl, 0.099 mmol) in DMF (248 μl) were stirred at room temperature for 2.5 h. The reaction mixture was diluted with methanol and filtered through a 25 mm syringe filter with a 0.45 μm nylon membrane . The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 19% B, 19-59% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-[4-amino-5-(3,3-difluoroazetidine-1carbonyl)pyrrolo[2,1-f][1,2,4]triazine-7 -yl]-N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridin-3 -carboxamide (8.8 mg, 11.8 µmol, 47%).

MS (ERI) m/z 631.2/633.3 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.59 (br s, 1H), 8.95 (br s, 1H), 8.81 (br d, J=2.9 Hz, 1H), 8.56-8.37 (m, 1H), 8.17 (br s, 1H), 8.08 (s, 1H), 7.53-7.40 (m, 1H), 5.42-5.16 (m, 1H), 5.02-4.80 (m, 2H), 4.75-4.59 (m, 2H) , 4.52 (br t, J=9.1 Hz, 1H), 4.41-4.28 (m, 1H), 4.07 (s, 3H), 4.00 -3.90 (m, 1H), 3.85-3.72 (m, 1H), 3.66- 3.54 (m, 1H), 3.47-3.32 (m, 1H), 1.56 (s, 3H).

Example 1350: 5-[4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N- 378 042342

[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

F

A solution of 5-(4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N ((3R,4S) -4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, salts of TFA (15.0 mg, 0.025 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (3.72 mg, 0.027 mmol), BOP (13.17 mg, 0.030 mmol) and triethylamine (13.84 µl, 0.099 mmol) in DMF (248 µl) was stirred at room temperature for 2.5 h. The reaction mixture was diluted with methanol and filtered through a 25 mm syringe filter with a 0.45 µm nylon membrane. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 21% B, 21-61% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-[4-amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1f][1,2,4]triazine-7 -yl]-N-[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyridine-3-carboxamide (9.3 mg, 12.9 µmol, 52% yield).

MS (ERI) m/z 609.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.59 (br s, 1H), 8.94 (d, J=2.3 Hz, 1H), 8.81 (dd, J=19.9, 2.3 Hz, 1H), 8.45 (br t, J=8.6 Hz, 1H), 8.16 (br s, 1H), 8.08 (s, 1H), 7.52-7.39 (m, 1H), 5.52-5.19 (m, 1H), 5.03-4.53 (m, 3H ), 4.07/4.08 (s, 3H together), 4.00-3.94 (m, 1H), 3.90-3.85 (m, 1H), 3.80 (br s, 1H), 3.75-3.69 (m, 1H), 3.47-3.38 (m, 1H), 3.32-3.22 (m, 1H), 3.20-3.10 (m, 1H), 3.00-2.69 (m, 4H).

Example 1351: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(1R)-1-[2-fluoro -5(trifluoromethyl)phenyl]ethyl]-2-methoxypyridine-3-carboxamide

Prepared as detailed in Example 31.

MS (ERI) m/z 543.4 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.98-8.88 (m, 2H), 8.61 (s, 1H), 8.15 (s, 1H), 7.94 (br d, J=5.8 Hz, 1H), 7.73 ( br s, 1H), 7.61 (s, 1H), 7.46 (br t, J=9.3 Hz, 1H), 5.41 (quin, J=7.2 Hz, 1H), 4.03 (s, 3H), 1.48 (br d, J=7.0 Hz, 3H).

Example 1352: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(2phenoxyphenyl)methyl]pyridine -3-carboxamide

Prepared as detailed in Example 31.

MS (ERI) m/z 535.5 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.87 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 8.68 (br t, J=5.7 Hz, 1H), 8.13 ( s, 1H), 7.53 (s, 1H), 7.46 (br d, J=7.4 Hz, 1H), 7.36 (br t, J=7.9 Hz, 2H), 7.29 (br t, J=7.2 Hz, 1H) , 7.17 (br t, J=7.4 Hz, 1H), 7.09 (br t, J=7.3 Hz, 1H), 6.98 (br d, J=7.9 Hz, 2H), 6.89 (br d, J=8.0 Hz, 1H), 4.55 (br d, J=5.9 Hz, 2H), 3.99 (s, 3H).

Example 1353: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 (3-methyl-2,3-dihydro-1H-inden-1-yl)pyrrolidin-3-yl)-2-methoxynicotinamide

5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N- 379 042342 ((3R,4S)- 4-Fluoronirrolidin-3-yl)-2-methoxynicotinamide (20 mg, 0.046 mmol) with 3-methylindan-1-one (16.64 mg, 0.114 mmol, 2.5 equiv.) in a mixture of MeOH (0.300 ml) and AcOH (0.075 ml ). Borane-2picoline complex (19.48 mg, 0.182 mmol, 4 eq.) was added to the mixture. The mixture was heated to 50°C and stirred overnight. The crude mixture was filtered and purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; gradient = 39-79% B over 25 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation to give the target compound (12.7 mg, 49% yield) as a mixture of two diastereomers.

MS (ERI) m/z 570.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 8.80 (br s, 1H), 8.74 (br d, J=6.4 Hz, 1H), 8.68 (br s, 1H), 8.04 (s, 1H), 7.50- 7.40 (m, 2H), 7.40-7.26 (m, 3H), 5.43 (br s, 0.5H), 5.36-5.30 (m, 0.5H), 5.05-4.93 (m, 1H), 4.87-4.67 (m, 1H), 4.43-4.34 (m, 1H), 3.99 (br s, 3H), 3.77-3.57 (m, 2H), 3.48-3.31 (m, 1H), 3.17-3.09 (m, 1H), 2.72 (m , 1H), 1.65-1.53 (m, 1H), 1.34-1.27 (m, 3H).

Connections in the table. 50 was prepared in a manner similar to those detailed in Example 1353. In some cases where low or incomplete conversion to the desired product was observed on the analytical LC-MS of the crude reaction mixture, additional starting ketone or aldehyde (2.5 additional equivalents) was added to the crude mixture and/ or additional borane-2picoline complex (4 additional equivalents) along with additional heating of the resulting mixture to 55° C. overnight to improve the reaction result. In most cases, a mixture of two or more diastereomers was obtained as end products. When the diastereomers were separated, they were included as separate data, which may refer either to a single diastereomer or to a mixture of two or more diastereomers, depending on the stereochemistry of the starting aldehyde or ketone and according to preparative HPLC. Compounds in this table containing a secondary free alcohol moiety on the carbon atom adjacent to the fluorinated carbon atom were the result of additional reduction of the ketone moiety to a secondary alcohol during the reaction. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 1-6 are as described in the Preparation Methods section.

Table 50

Example Name R Observe in MS the mass of the M ⁺ ion (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or LC-MS, retention time 1354 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1 -(2,3-dihydro1 H-ind e -1 -yl)4fluoropyrrolidine- 3-yl]-2- methoxypyridine3-carboxamide Mixture of 2 isomers 556.2(1) LC-MS Method 1 retention time = 1.48 min LC-MS Method 2 retention time = 2.24 min

- 380 042342

1355 5-[4-Amino-5(trifluoromethyl)p irrolo[2,1G][1,2,4]triazine7-nn]-N-[(3R,4S)4-fluoro-1-(4-fluoro2,3 -dihydro-1Ninden-1yl)pyrrolide in-3yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 574.2(2) 8.94 - 8.90 (m, 1H), 8.85 - 8.82 (t, 1H), 8.41 (br d, J=T6 Hz, 1H), 8.17 (d, 7=2.1 Hz, 1H), 7.61 (d, 7=2.7 Hz, 1H), 7.297.22 (m, 1H), 7.21 -7.17 (m, 1H), 7.04 (t, 7=8.6 Hz, 1H), 5.28 - 5.24 (m, 0.5H), 5.17- 5.13 (m, 0.5H), 4.55-4.43 (m, 1H), 4.42-4.38 (m, 1H), 4.074.03 (m, 3H), 3.01-2.78 (m, 4H), 2.70-2.63 (m, 1H), 2.23 2.14 (m, 1H), 2.13–2.03 (m, 1H). 1356 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-nn]-N-[(3R,4S)4-fluoro-1 -(5-fluoro2,3 -dihydro-1Ninden-1yl)pyrrolide in-3yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 574.2(2) 8.94-8.87 (m, 1H), 8.86 - 8.82 (m, 1H), 8.41 (br d, 7=7.6 Hz, 1H), 8.19-8.15 (m, 1H), 7.61 (s, 1H), 7.34 (t , 7=6.4 Hz, 1H), 7.08 (br d, 7=9.3 Hz, 1H), 7.03 -6.97 (m, 1H), 5.26 (t, 7=4.7 Hz, 0.5H), 5.15 (t, 7= 4.8 Hz, 0.5H), 4.54 - 4.43 (m, 1H), 4.28 (brt, 7=6.1 Hz, 1H), 4.07 -4.02 (m, 3H), 3.29 -3.07 (m, 1H), 3.03-2.91 ( m, 2H), 2.892.75 (m, 2H), 2.67 - 2.62 (m, 1H), 2.20 - 2.00 (m, 2H). 1357 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-nn]-N-[(3R,4S)4-fluoro-1-{6,7,8 ,9tetrahydro-5Hbenzo[7]annulen5yl}pyrrolidin3-yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 584.2(2) 8.91 (dd, 7=4.3, 2.4Hz, 1H), 8.86 (d, 7=2.4Hz, 0.45H), 8.83 (d, 7=2.4Hz, 0.55H), 8.41 (br d, 7=7.8Hz, 1H), 8.17 (d, 7=3.2 Hz, 1H), 7.61 (d, 7=3.5 Hz, 1H), 7.21 - 7.06 (m, 4H), 5.30 - 5.25 (m, 0.5H), 5.185.15 ( m, 0.5H), 4.62-4.47 (m, 1H), 4.07 (s, 1.4H), 4.05 (s, 1.6H), 3.40 - 3.33 (m, 2H), 3.16-3.05 (m, 1H), 2.92 -2.81 (m, 1H), 2.74 - 2.62 (m, 1H), 2.62 - 2.52 (m, 2H), 2.32 - 2.25 (m, 1H), 2.09 - 1.97 (m, 2H), 1.95 - 1.85 (m, 1H), 1.75 - 1.66 (m, 1H), 1.62 - 1.49 (m, 1H), 1.32 - 1.20 (m, 1H).

- 381 042342

1358 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-(4methyl-1,2 ,3,4tetrahydronaphthal en-1yl)pyrrolide in-3yl]-2methoxypyridine3-carboxamide /0) Mixture of 2 isomers 584.2(2) 8.91 (brs, 1H), 8.84 (br s, 1H), 8.44 (m, 1H), 8.16 (s, 1H), 7.61 (s, 1H), 7.48 - 7.36 (m, 1H), 7.33-7.11 (m , 3H), 5.31 5.24 (m, 0.5H), 5.19-5.13 (m, 0.5H), 4.56 - 4.43 (m, 1H), 4.09-4.02 (m, 3H), 3.75 (br d, 7=18.9 Hz , 0.6H), 3.42 (br d, 7=5.8 Hz, 0.4H), 3.17 (br d, 7=4.0 Hz, 0.4H), 3.03-2.83 (m, 1.6H), 2.80-2.68 (m, 1H ), 1.86 (brd,7=6.4Hz, 2H), 1.76 (brd, 7=9.2Hz, 2H), 1.291.19 (m, 5H). 1359 5-[4-amino-5(trifluoromethyl)p irrolo[2, ΙΟ [1,2,4]triazine7-mi]-N-[(3R,4S)1-(5-bromo-1,2,3, 4tetrahydronaphthal en-1-yl)-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide 'O/ Mixture of 2 isomers 648.1(2) 8.93 - 8.88 (m, 1H), 8.87-8.81 (m, 1H), 8.43 (br d, 7=7.0 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.53 -7.44 (m , 2H), 7.17–7.08 (m, 1H), 5.27 (brs, 0.5H), 5.16 (brs, 0.5H), 4.57–4.42 (m, 1H), 4.09–4.01 (m, 3H), 3.76 ( br s, 1H), 2.95 - 2.81 (m, 1H), 2.79 - 2.67 (m, 3H), 2.07 (br d, 7=5.5 Hz, 1H), 1.87 - 1.65 (m, 3H), 1.22 (br s , 2H). 1360 5-[4-amino-5(trifluoromethyl)p irrolo[2,10[1,2,4]triazine7-mi]-N-[(3R,4S)1-(7-chloro-2,3dihydro-1Nindene- 1-yl)-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide AF Mixture of 2 isomers 590.2(1) 8.92-8.87 (m, 1H), 8.85-8.82 (m, 1H), 8.43 - 8.35 (m, 1H), 8.20 - 8.08 (m, 1H), 7.64 - 7.58 (m, 1H), 7.30 - 7.21 (m , 3H), 5.28-5.21 (m, 0.5H), 5.175.11 (m, 0.5H), 4.52-4.42 (m, 1H), 4.42-4.35 (m, 1H), 4.084.01 (m, 3H) , 3.91 (s, 1H), 3.19-3.04 (m, 2H), 3.00-2.94 (m, 1H), 2.90 - 2.73 (m, 2H), 2.69-2.58 (m, 1H), 2.22 - 2.12 (m, 1H), 2.10-1.99 (m, 1H).

- 382 042342

1361 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-(1,2,3 ,4tetrahydronaphthal en-1yl)pyrrolidin-3 yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 570.2(1) 8.94 - 8.88 (m, 1H), 8.84 (s, 1H), 8.43 (br d, 7=7.3 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.47 -7.35 (m, 1H ), 7.13 (br s, 2H), 7.08 (brd, 7=6.1 Hz, 1H), 5.27 (br s, 0.5H), 5.16 (brs, 0.5H), 4.56-4.43 (m, 1H), 4.09 - 4.01 (m, 3H), 3.76 (br s, 1H), 3.43 3.35 (m, 1H), 2.94 - 2.66 (m, 4H), 2.07 - 1.91 (m, 1H), 1.80 (brd, 7=5.2 Hz, 2H), 1.701.61 (m, 1H), 1.24-1.20 (m, 1H). 1362 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[2(2,2 ,2-trifluoro-1hydroxyethyl)cyclopentyl]pyrrole idin-3-yl]-2methoxypyridine3-carboxamide ^Vf NSU\ F 1-5 isomers 606.2(2) 8.92 (s, 1H), 8.85 (br s, 1H), 8.52 - 8.38 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.30 - 6.22 (m, 1H), 5.26 (br s, 0.5H), 5.14 (br s, 0.5H), 4.50 (m, 1H), 4.05 (m, 4H), 3.38 - 3.33 (m, 1H), 3.18-3.09 (m, 1H), 3.02-2.93 (m, 1H), 2.90 - 2.79 (m, 1H), 2.69 - 2.60 (m, 1H), 2.04 - 1.94 (m, 1H), 1.76 - 1.67 (m, 1H), 1.66 - 1.49 (m, 5H) . 1363 5-[4-Amino-5(trifluoromethyl)p pyrrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-(2methylcyclopentyl)pyrrolidine- 3 yl]-2methoxypyridine3-carboxamide 1-3 isomers 522.2(2) 8.91 (s, 1H), 8.86 (s, 1H), 8.44 (br s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.25 (br s, 0.5H), 5.14 (br d, 7=5.2Hz, 0.5H), 4.60 - 4.42(m, 1H), 4.05(s, 3H), 3.37(br d, 7=7.6Hz, 1H), 3.17(d, 7=4.9Hz, 1H), 1.97 - 1.64 (m, 3H), 1.55 (br s, 3H), 1.20 - 1.11 (m, 1H), 0.99 (brd, 7=5.5 Hz, ZN).

- 383 042342

1364 5-[4-Amino-5(trifluoromethyl)p yrrolo[2,1L][1,2,4]triazine7-mi]-N-[(3R,4S)1-{5H,6H,7H cycle openta[b ]pyridin-5-yl}-4fluoropyrrolidin3-yl]-2methoxypyride in3-carboxamide vYYn Λ Λ Mixture of 2 isomers 557.2 (1) 8.90 (br d, 7=2.4 Hz, 1H), 8.83 (d, 7=4.8 Hz, 1H), 8.82 (s, 1H), 8.47-8.36 (m, 2H), 8.17 (s, 1H), 7.72 ( br t, 7=6.9 Hz, 1H), 7.61 (br s, 1H), 7.19 (br d, 7=3.7 Hz, 1H), 5.27 (br s, 0.5H), 5.15 (br s, 0.5H), 4.554.44 (m, 1H), 4.36 (br s, 1H), 4.06-4.01 (m, 1H), 3.40-3.34 (m, 1H), 3.22-3.09 (m, 1H), 3.05-2.95 (m, 2H), 2.94 - 2.79 (m, 2H), 2.71 -2.63 (m, 1H), 2.23 -2.14 (m, 1H), 2.06 (br d, 7=5.2 Hz, 1H). 1365 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-(2,2dimethylcyclopentyl)-4fluoropyrrolidin3-yl ]-2methoxypyride in3-carboxamide 1 isomer 536.2(2) Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.87 (s, 1H), 8.44 (br d, 7=7.9 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.23 (br s, 0.5H), 5.11 (br s, 0.5H), 4.54 4.44 (m, 1H), 4.06 (s, 3H), 3.08 -2.97 (m, 2H), 2.92 - 2.82 (m , 1H), 2.31-2.18 (m, 2H), 1.89-1.82 (m, 1H), 1.61-1.52 (m, 2H), 1.52-1.37 (m, 4H), 1.08 (s, 3H), 0.89 (s , 3H), 0.87 - 0.84 (m, 1H). 1366 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[2-(2,2-difluoro1hydroxyethyl) cyclopentyl]-4fluoropyrrolidine- 3-yl]-2- methoxypyride in3-carboxamide A.F H<7\ F 1-5 isomers 588.2 (1) 8.91 (s, 1H), 8.85 (br s, 1H), 8.43 (br s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.88 (t, 7=55.8 Hz, 1H), 5.25 (br s, 0.5H), 5.17 -5.11 (m, 0.5H), 4.56-4.41 (m, 1H), 4.05 (s, 3H), 3.71 (br d, 7=3.4 Hz, 1H), 2.01 - 1.84 (m, 1H), 1.69 - 1.43 (m, 7H).

- 384 042342

1367 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-(2methyl-2,3dihydro -1Ninden-1yl)pyrrolidin-3 yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 570.2(1) 8.90 (d, 7=9.2 Hz, 1H), 8.83 (dd, 7=12.4, 2.0 Hz, 1H), 8.43 - 8.26 (t, 1H), 8.17 (brd, 7=3.1 Hz, 1H), 7.61 (d , 7=5.8 Hz, 1H), 7.36 (dd, 7=15.6, 7.0 Hz, 1H), 7.28-7.16 (br, 3H), 5.19 (br s, 0.5H), 5.08 (br s, 0.5H), 4.47-4.31 (m, 1H), 4.19-4.07 (m, 1H), 4.06 - 3.99 (m, 3H), 3.39 (br d, 7=9.8 Hz, 1H), 3.27-3.06 (m, 1H), 3.05 2.79 (m, 3H), 2.65-2.53 (m, 2H), 2.47-2.40 (m, 1H), 1.201.08 (m, 3H). 1368 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1 -(6-fluoro2,3 -dihydro-1Ninden-1yl)pyrrolidine-3 - silt]-2- methoxypyridine3-carboxamide F Blend 2 isomers 574.1(2) 8.90 (d, 7=2.4 Hz, 1H), 8.848.81 (m, 1H), 8.43 (brd, 7=7.3 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.29 -7.23 (m, 1H), 7.11 (br d, 7=9.2 Hz, 1H), 7.03 (br t, 7=8.7 Hz, 1H), 5.26 (br s, 0.5H), 5.15 (br s, 0.5H), 4.554.43 (m, 1H), 4.37 - 4.32 (m, 1H), 4.07-4.01 (m, 3H), 3.39 (brd, 7=9.5 Hz, 1H), 3.292.62 (m, 6H), 2.22- 2.12 (m, 1H), 2.09 - 2.00 (m, 1H). 1369 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[1-(2methoxyphenyl )ethyl]pyrrolidin-3yl]-2methoxypyridine3-carboxamide 1 1 isomer 574.2(2) 8.90 (s, 1H), 8.82 (s, 1H), 8.44 (br s, 1H), 8.16 (s, 1H), 7.60 (s, 1H), 7.42 (br d, 7=7.3 Hz, 1H), 7.23 (br s, 1H), 7.07 - 6.94 (m, 2H), 5.26 (br s, 0.5H), 5.15 (br s, 0.5H), 4.55 - 4.44 (m, 1H), 4.04 (s, 3H), 4.01 -3.87 (m, 1H), 3.83 - 3.75 (m, 3H), 3.42 3.36 (m, 1H), 2.83 (br s, 1H), 2.78 (s, 1H), 2.71 (br s, 1H), 1.28 (brs, 3H). LC-MS Method 1 retention time = 1.52 min LC-MS Method 2 retention time = 2.19 min

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1370 5-[4-amino-5(trifluoromethyl)p irrolo[2,10[1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[1-(2methoxyphenyl) ethyl]pyrrolidin-3 yl]-2methoxypyridine3-carboxamide 1 1 isomer 574.2(2) LC-MS Method 1 retention time =1.52 min LC-MS Method 2 retention time = 2.22 min 1371 methyl 2-[(3R,4S)3-{5-[4-amino-5(trifluoromethyl)p irrolo[2,10[1,2,4]triazin7-yl]-2- methoxypyridine 3-amido } -4fluoropyrrolidin1yl ] cyclopentane 1-carboxylate 1-3 isomers 566.2(2) 8.94 - 8.86 (m, 2H), 8.49 - 8.34 (br, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.23 (br s, 0.5H), 5.12 (br s, 0.5H), 4.52 - 4.42 (m, 1H), 4.06 (s, 3H), 3.59 (s, 2H), 3.53 (s, 1H), 3.38 - 3.32 (m, 1H), 3.18 (brs, 1H), 3.08 -2.98 ( m, 1H), 2.95 (br s, 1H), 2.91 2.81 (m, 1H), 2.81-2.70 (m, 1H), 2.60-2.53 (m, 1H), 1.91 1.77 (m, 4H), 1.76-1.63 (m, 1H), 1.63 - 1.53 (m, 1H). 1372 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[2-(2,2-difluoro1hydroxyethyl) cyclopentyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide nsg\ F 1-5 isomers 588.2 (1) 8.91 (s, 1H), 8.85 (s, 1H), 8.46 - 8.36 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.10-5.84 (m, 1H), 5.24 (br s , 0.5H), 5.13 (br s, 0.5H), 4.55 - 4.44 (m, 1H), 4.05 (s, 3H), 3.60-3.52 (m, 1H), 3.39 - 3.33 (m, 1H), 3.17 ( brd,/=4.9 Hz, 1H), 3.092.96 (m, 1H), 2.92 (brs, 1H), 2.64 (brs, 1H), 1.99 (brs, 1H), 1.69 (brs, 1H), 1.59 (br s, 4H), 1.42 (brd, /=5.2 Hz, 1H).

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1373 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[2-(2,2-difluoro1hydroxyethyl) cyclopentyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide NSG \ F 1-5 isomers 588.2(1) 8.94 - 8.85 (m, 2H), 8.49 - 8.41 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.03 - 5.77 (m, 1H), 5.27 (br s, 0.5H), 5.15 (brs, 0.5H), 4.53 (br dd,/=14.3, 7.9 Hz, 1H), 4.06 (s, 3H), 3.99-3.89 (m, 1H), 3.41-3.33 (m, 1H), 3.03 ( brd,/=8.5 Hz, 1H), 2.95 (br s, 1H), 2.92 - 2.79 (m, 1H), 2.65 (br d, /=7.9 Hz, 1H), 2.61 -2.54(m, 1H), 2.07 (brs, 1H), 1.85 (brs, 1H), 1.70 (brs, 3H), 1.63 (brd,/=10.4 Hz, 1H), 1.51 (brs, 1H). 1374 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[2-(2,2-difluoro1hydroxyethyl) cyclopentyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide T/F F 1-5 isomers 588.2 (1) 8.92 (brs, 1H), 8.86 (brs, 1H), 8.43 (brs, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.01 - 5.74 (m, 1H), 5.31 -5.23 (m , 0.5H), 5.19-5.12 (m, 0.5H), 4.60 4.47 (m, 1H), 4.11 (s, 1H), 4.06 (s, 3H), 3.95 (br s, 1H), 3.40 - 3.35 (m , 1H), 3.17 (s, 1H), 2.97–2.91 (m, 1H), 2.822.71 (m, 1H), 2.68–2.61 (m, 1H), 2.07 (br s, 1H), 1.87 (br s , 1H), 1.70 (brs, 2H), 1.661.56 (m, 1H), 1.52 (brs, 1H). 1375 5-[4-Amino-5(trifluoromethyl)p irrolo[2.11][1.2.4]triazin7-yl]-N-[(3R,4S)4-fluoro-1-[2(2.2 ,2-trifluoro-1hydroxyethyl)cyclopentyl]pyrrole idin-3-yl]-2methoxypyridine3-carboxamide jYf H(J\ F 1-5 isomers 606.2(1) 8.91 (s, 1H), 8.85 (s, 1H), 8.42 (brd, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.26 (br d, /=6.4 Hz, 1H), 5.26 (br s, 0.5H), 5.14 (br s, 0.5H), 4.554.44 (m, 1H), 4.05 (s, 4H), 3.36 (brs, 1H), 3.18–3.07 (m, 1H), 3.07 -2.97 (m, 1H), 2.89 (br d, /=11.3 Hz, 1H), 2.82 (br d, /=11.6 Hz, 1H), 2.64 (brt, /=8.2 Hz, 1H), 1.97 (brd, /=8.2 Hz, 1H), 1.75 - 1.65 (m, 1H), 1.65 - 1.49 (m, 5H).

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1376 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[2(2,2 ,2-trifluoro-1hydroxyethyl)cyclopentyl]pyrrole idin-3-yl]-2methoxypyridine3-carboxamide ns>\F 1-5 isomers 606.2(2) 8.92 (brs, 1H), 8.88 (brs, 1H), 8.45 (brd, 7=5.5 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.28 (brs, 0.5H), 5.17 (br s, 0.5H), 4.61 4.49 (m, 1H), 4.40 - 4.32 (m, 1H), 4.06 (s, 3H), 3.37-3.33 (m, 1H), 3.10-2.91 (m, 2H), 2.90-2.76 (m, 1H), 2.66 - 2.57 (m, 1H), 2.21 (brs, 1H), 1.981.90 (m, 1H), 1.74-1.58 (m, 4H), 1.56 - 1.46 (m, 1H ). 1377 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[2(2,2 ,2-trifluoro-1hydroxyethyl)cyclopentyl]pyrrole idin-3-yl]-2methoxypyridine3-carboxamide nsg\ F 1-5 isomers 606.2(2) 8.92 (brs, 1H), 8.85 (br s, 1H), 8.43 (br d, 7=6.7 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.27 (brs, 0.5H), 5.16 (br s, 0.5H), 4.594.48 (m, 1H), 4.35 (br s, 1H), 4.05 (s, 3H), 3.38 - 3.33 (m, 1H), 3.18-3.06 (m, 1H) , 2.97 (br s, 1H), 2.84-2.71 (m, 1H), 2.67-2.58 (m, 1H), 2.20 (br s, 1H), 1.99-1.91 (m, 1H), 1.75 1.62 (m, 4H ), 1.60 (brs, 1H), 1.51 (brs, 1H). 1378 5-[4-Amino-5(trifluoromethyl)p pyrrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-(2methylcyclopentyl)pyrrolidine- 3 yl]-2methoxypyridine3-carboxamide 1-3 isomers 522.2(2) 8.92 (brs, 1H), 8.86 (br s, 1H), 8.57 - 8.37 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.34 - 5.21 (m, 0.5H), 5.21 - 5.12 (m, 0.5H), 4.64 - 4.45 (m, 1H), 4.05 (s, 3H), 3.39 (br d, 7=12.2 Hz, 1H), 3.17 (br s, 1H), 2.242.02 (m , 1H), 1.71 (br s, 3H), 1.60–1.42 (m, 3H), 1.41–1.29 (m, 1H), 0.82 (br s, 3H).

- 388 042342

1379 5-[4-amino-5(trifluoromethyl)p irrolo[2,1C[1,2,4]triazin7-mi]-N-[(3R,4S)1-(2,2dimethylcyclopentyl)-4fluoropyrrolidin3-yl] -2methoxypyridine3-carboxamide 1 isomer 536.2(2) 8.91 (s, 1H), 8.87 (s, 1H), 8.41 (brd, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.22 (br s, 0.5H), 5.10 (br s, 0.5H), 4.53 4.43 (m, 1H), 4.05 (s, 3H), 3.21-3.09 (m, 1H), 2.91 (brt, 7=8.1 Hz, 1H), 2.82 - 2.70 (m, 1H), 2.65 (brt, 7=8.1Hz, 1H), 2.25 - 2.17 (m, 1H), 1.88 - 1.80 (m, 1H), 1.65 - 1.55 (m, 2H), 1.51 - 1.38 (m, 3H) , 1.06 (s, 3H), 0.90–0.84 (m, 4H). 1380 5-[4-amino-5(trifluoromethyl)p irrolo[2,1C[1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-[(6oxo-1,6dihydropyridin2yl )methyl]pyrrole idin-3-yl]-2methoxypyridine3-carboxamide " But 1 isomer 547.1 (6) 8.92 (s, 1H), 8.87-8.82 (m, 1H), 8.44 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.43 - 7.35 (m, 1H), 6.22 (brd, 7=9.2 Hz, 1H), 6.18 -6.11 (m, 1H), 5.28 (br s, 0.5H), 5.17 (br s, 0.5H), 4.62-4.51 (m, 1H), 4.06 (s, 3H), 3.59-3.49 (m, 1H), 3.18-3.06 (m, 1H), 3.022.97 (m, 1H), 2.92-2.81 (m, 1H), 2.67 (brt, 7=8.4Hz, 1H). 1381 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-(5,5,5trifluoro -4hydroxypentan2-yl)pyrrolidin- 3-yl]-2- methoxypyridine3-carboxamide 1 he + ^F 1-3 isomers 580.1(5) 8.92 (d, 7=2.1 Hz, 1H), 8.86 (s, 1H), 8.42 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.25 (br s , 0.5H), 5.14 (br s, 0.5H), 4.55 -4.45 (m, 1H), 4.06 (s, 4H), 3.19-2.99 (m, 1H), 2.942.78 (m, 1H), 2.69 - 2.62 (m, 1H), 1.73 (brt, 7=9.5 Hz, 1H), 1.57-1.48 (m, 1H), 1.06 (brt, 7=6.0 Hz, ZN). LC-MS Method 5 retention time =1.34 min LC-MS, Method 6 retention time = 2.10 min

- 389 042342

1382 5-[4-Amino-5(trifluoromethyl)p irrolo[2.1G][1.2.4]triazin7-yl]-N-[(3R,4S)1-[1-(3,3difluorocyclopentyl)ethyl ]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide VA-x F G U-F 1-3 isomers 572.2 (5) 8.92 (brs, 1Н), 8.86 (br s, 1Н), 8.44-8.35 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.24 (br s, 0.5H), 5.12 (br s, 0.5H), 4.56 4.42 (m, 1H), 4.06 (s, 3H), 3.02–2.93 (m, 1H), 2.91–2.79 (m, 1H), 2.71–2.55 (m, 1H), 2.24– 2.11 (m, 2H), 2.10-1.93 (m, 2H), 1.90 (brs, 1H), 1.871.75 (m, 1H), 1.62-1.54 (m, 1H), 1.33 - 1.21 (m, 1H), 0.93 (brs, 2H). 1383 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-(5,5,5trifluoro -4hydroxy-4phenylpentan-2yl)pyrrolide in-3yl]-2methoxypyridine3-carboxamide / NO _SRz 4 isomers 656.1(5) 8.92 (brd,/=2.1Hz, 1H), 8.85 -8.81(m, 1H), 8.48 - 8.38 (m, 1H), 8.18 (s, 1H), 7.69-7.55 (m, 3H), 7.47 - 7.32 ( m, 3H), 5.24 (br d,/=13.1 Hz, 0.5H), 5.16-5.10 (m, 0.5H), 4.594.42 (m, 1H), 4.09 - 4.04 (m, 3H), 3.22-3.08 (m, 1H), 3.07 2.87 (m, 2H), 2.76–2.54 (m, 2H), 2.27–1.96 (m, 2H), 1.05 0.91 (m, 3H). 1384 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-^]-N-[(3R,4S)4-fluoro-1-[5,5,5trifluoro -4hydroxy-4(trifluoromethyl)pentan-2yl] pyrrolidine-3 - silt]-2- methoxypyridine3-carboxamide MJ. cf ₃ 4 isomers 648.1(6) 8.94 - 8.91 (m, 1H), 8.82 (dd, /=6.6, 2.3 Hz, 1H), 8.51 - 8.45 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.29 (br s , 0.5H), 5.18 (br s, 0.5H), 4.66 - 4.54 (m, 1H), 4.05 (d,/=2.4 Hz, ZH), 3.48 3.41 (m, 1H), 3.23 -3.09 (m, 1H ), 3.07-2.96 (m, 1H), 2.822.74 (m, 1H), 2.12-1.98 (m, 1H), 1.89 (brd,/=14.6 Hz, 1H), 1.12-1.06 (m, 3H).

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1385 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-roi]-N-[(3R,4S)41-(3,3difluorocyclopentyl)ethyl]-4fluoropyrrolidine3 -il]-2- V\r-^\ ^F G U-F 1-3 isomers 572.2 (6) 8.92 (brs, 1Н), 8.86 (br s, 1Н), 8.38 (br s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.23 (brs, 0.5H), 5.12 (br s, 0.5H), 4.56-4.42 (m, 1H), 4.06 (s, 3H), 3.022.93 (m, 1H), 2.92 - 2.77 (m, 1H), 2.68 -2.55 (m, 1H), 2.27 2.10 ( m, 3H), 2.10-1.90 (m, 2H), 1.83 (br d, 7=7.3 Hz, 1H), 1.49-1.38 (m, 1H), 1.02-0.82 methoxypyridine3-carboxamide 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine- — (m, 3H). LC-MS Method 5 7-mi]-N-[(3R,4S)- 1 he retention time = 1.35 Λ/ΤΤ/ΓΜ 4-fluoro-1-(5,5,5- YxA.f 580.1 IVlrlil 1J OO trifluoro-4- F ^F 1-3 isomers (6) LC-MS Method 6 1 idrixisn 1 aH2-yl)pyrrolidin3-yl]-2- retention time = 2.18 min methoxypyridine- 3-carboxamide 1387 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazin7-mi]-N-[(3R,4S)1-[1-(2,3difluoropyridin4-yl) ethyl]-4fluoropyrrolidin3-yl]-2- A' Mixture of 2 isomers 581.2(1) 8.92 - 8.89 (m, 1H), 8.83 (s, 1H), 8.44 (brt, 7=6.7 Hz, 1H), 8.16 (s, 1H), 8.04 (t, 7=6.1 Hz, 1H), 7.60 (s , 1Н), 7.52 - 7.47 (w, 1Н), 5.29 - 5.24 (m, 0.5Н), 5.18-5.13 (m, 0.5Н), 4.60 4.48 (m, 1Н), 4.05 (d, 7=4.3 Hz, ZH), 4.02 - 3.90 (m, 1H), 3.42-3.36 (m, 1H), 3.18-3.05 (t, 1H), 3.01 (brt, 7=8.2 Hz, 1H), 2.91 -2.73 (t, 2H) , 2.64- methoxypyridine3-carboxamide 2.56 (t, 1H), 1.37 (brd, 7=6.7 Hz, ZN).

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1388 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazin7-mi]-N-[(3R,4S)1-[1-(2,6difluoropyridin4-yl) ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide H F Mixture of 2 isomers 581.1(1) 8.91 (brs, 1H), 8.87-8.81 (t, 1H), 8.44 (br d, 7=5.2 Hz, 1H), 8.17 (brs, 1H), 7.61 (br s, 1H), 7.21-7.12 (m, 2H), 5.26 (br d, 7=10.7 Hz, 0.5H), 5.18-5.12 (m, 0.5H), 4.61-4.49 (m, 1H), 4.05 (br d, 7=3.7 Hz, ZN), 3.72 -3.64 (m, 1H), 3.32 -3.22 (m, 1H), 3.21 -3.04(m, 1H), 3.00 (brd, 7=8.2Hz, 1H), 2.93 2.69 (m, 1H), 2.64-2.57 ( m, 1H), 1.35 - 1.30 (m, 3H). 1389 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-[1(pyrimidin-5yl )ethyl]pyrrolide in-3-yl]-2methoxypyridine3-carboxamide bh 1 isomer 546.2(1) 9.12 (s, 1H), 8.91 (s, 1H), 8.83 (br s, 1H), 8.80 (s, 2H), 8.43 (br d, 7=7.6 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.27 (br s, 0.5H), 5.16 (br s, 0.5H), 4.564.46 (m, 1H), 4.04 (s, 3H), 3.66-3.61 (m, 1H), 3.39 -3.34 (m, 1H), 3.20 -3.09 (m, 1H), 2.83 (brt, 7=8.2Hz, 1H), 2.77 -2.68 (m, 1H), 2.60 (brt, 7=8.5Hz, 1H) , 1.39 (brd, 7=6.4 Hz, ZN). 1390 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)- 4-fluoro-1-[1- (2,4,6trifluorophenyl)ethyl] pyrrolidine-3 - yl]-2methoxypyridine3-carboxamide 1 F AS fXX _f Mixture of 2 isomers 598.1(1) 8.91 (br s, 1H), 8.84 (br d, 7=8.5 Hz, 1H), 8.42 (br dd, 7=11.3, 8.9 Hz, 1H), 8.17 (br s, 1H), 7.61 (br s, 1H ), 7.19 (brt, 7=9.3 Hz, 2H), 5.24 (br s, 0.5H), 5.13 (br s, 0.5H), 4.554.42 (m, 1H), 4.07-3.96 (m, 4H), 3.37 (br d, 7=6.4 Hz, 1H), 3.20-3.09 (m, 1H), 3.02-2.91 (m, 1H), 2.85 - 2.75 (m, 1H), 2.73 -2.59 (m, 1H), 2.55 (brd, 7=7.6 Hz, 1H), 1.52 - 1.40 (m, 3H).

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1391 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-{1-[4( trifluoromethyl)phenyl]ethyl } pyrrolidin-3 -yl]-2methoxypyridine3-carboxamide ^^SEz Mix 2 isomers 612.1(2) 8.91 (brs, 1H), 8.83 (br s, 1H), 8.44 (br d, 7=7.0 Hz, 1H), 8.16 (s, 1H), 7.74 - 7.68 (m, 2H), 7.63 - 7.56 (m, 3H), 5.26(br d, 7=14.3 Hz, 0.5H), 5.15 (br d, 7=14.3 Hz, 0.5H), 4.59 - 4.44 (m, 1H), 4.05 (brd, 7=6.1Hz, ZN ), 3.59 (br d, 7=5.8 Hz, 1H), 3.37 (brd, 7=6.4 Hz, 1H), 3.03-2.89 (m, 1H), 2.87-2.71 (m, 1H), 2.60-2.54 (m , 1H), 1.35 1.30 (m, 3H). 1392 5-[4-amino-5(trifluoromethyl)p irrolo[2,1G][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-[1-(2hydroxyphenyl) ethyl]pyrrolidin3-yl]-2- methoxypyridine3-carboxamide Mixture of 2 isomers 560.2(2) 8.93 - 8.89 (m, 1H), 8.83-8.80 (m, 1H), 8.52 - 8.44 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.18 -7.05 (m, 2H), 6.81 -6.73 (m, 2H), 5.29 (br s, 0.5H), 5.18 (br s, 0.5H), 4.65 - 4.52 (m, 1H), 4.10-4.02 (m, 3H), 3.78 (br s, 1H), 3.41-3.36 (m, 1H), 3.202.58 (m, 3H), 1.34-1.28 (m, 3H). 1393 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[1-(3,5-difluoro2hydroxyphenyl) ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide Ya F Mixture of 2 isomers 596.2(2) 8.91 (d, 7=2.1Hz, 1H), 8.81 (s, 1H), 8.53 - 8.46 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.10 (brt, 7=8.5Hz , 1H), 6.91 (brd, 7=8.2 Hz, 1H), 5.30 (br s, 0.5H), 5.19 (br s, 0.5H), 4.664.54 (m, 1H), 4.07 - 4.03 (m, 3H ), 3.88 (br s, 1H), 3.19- 2.62 (m, 3H), 1.32 (brd, 7=5.8 Hz, ZN). 1394 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)4-fluoro-1-{1-[3( trifluoromethoxy)phenyl]ethyl}pyrrolide in-3-yl]-2methoxypyridine3-carboxamide Mixture of 2 isomers 628.2(1) 8.91 (brs, 1H), 8.83 (brs, 1H), 8.44 (brs, 1H), 8.16 (s, 1H), 7.68 - 7.59 (m, 1H), 7.54 - 7.43 (m, 1H), 7.43 - 7.29 (m, 2H), 7.25 (brs, 1H), 5.26 (brs, 0.5H), 5.15 (brs, 0.5H), 4.594.45 (m, 1H), 4.09 - 4.02 (m, 3H), 3.40 (br d, 7=10.7 Hz, 1H), 3.04 -2.54 (m, 1H), 1.32 (br s, 3H). 1395 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)- 4-fluoro-1-[1(pyrimidin-5yl)ethyl]pyrrolide in-3-yl]-2methoxypyridine3-carboxamide That 1 isomer 546.2(2) 9.11 (s, 1H), 8.91 (s, 1H), 8.83 - 8.78 (m, 3H), 8.43 (br d, 7=7.6 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.25 (brs, 0.5H), 5.14 (br s, 0.5H), 4.59-4.49 (m, 1H), 4.05 (s, 3H), 3.64 (br d, 7=6.4 Hz, 1H), 3.37 (brd, 7=7.3 Hz, 1H), 3.04-2.91 (m, 2H), 2.90 - 2.79 (m, 1H), 2.56 2.53 (m, 1H), 1.39 (brd, 7=6.4 Hz, ZN). 1396 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[1-(2,4dimethylpyrimide in-5 -yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide [WITH 1 isomer 574.2 (1) 8.91 (s, 1H), 8.83 (d, 7=2.1 Hz, 1H), 8.57 (s, 1H), 8.44 (br d, 7=7.3 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.26 (brs, 0.5H), 5.15 (br s, 0.5H), 4.61-4.50 (m, 1H), 4.06 (s, 3H), 3.72 (br d, 7=6.4 Hz, 1H), 3.37 (brd, 7=7.3 Hz, 1H), 3.03 -2.91 (m, 2H), 2.90 - 2.78 (m, 1H), 2.53 (s, 3H), 1.32 (brd, 7=6.4 Hz, ZN).

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1397 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-Ni]-N-[(3R,4S)1-[1-(2-chloro-4methyl -1,3-thiazol5-yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide JL X ^CI /N Mixture of 2 isomers 599.1(2) 8.91 (brs, 1Н), 8.84 (br s, 1Н), 8.47-8.39 (m, 1H), 8.17 (s, 1H), 7.62 (s, 1H), 5.26 (br s, 0.5H), 5.15 (br s, 0.5H), 4.594.47 (m, 1H), 4.06 (br d, 7=3.4 Hz, ZN), 3.92 - 3.85 (m, 1H), 3.37 - 3.33 (m, 1H), 3.17 (brd, 7=5.2 Hz, 1H), 3.12-2.99 (m, 1H), 2.96-2.83 (m, 1H), 2.662.59 (m, 1H), 2.30 (s, 3H), 1.33 (br d, 7=6.1 Hz, ZN). 1398 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1 -[1-(2,5-dibromo1, 3-thiazol-4yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide Al Mixture of 2 isomers 706.9(1) 8.91 (brs, 1H), 8.85 - 8.82 (m, 1H), 8.44 (br dd, 7=17.5, 7.5 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.26 (br d, 7=4.3 Hz, 0.5H), 5.15 (br d, 7=4.3 Hz, 0.5H), 4.60 - 4.48 (m, 1H), 4.05 (br d, 7=4.9 Hz, ZN), 3.95 -3.88(m , 1H), 3.39 (brd, 7=9.2 Hz, 1H), 3.18-2.96 (m, 2H), 2.94 - 2.84 (m, 1H), 2.68 (q, 7=7.8 Hz, 1H), 1.36 (brd, 7=6.4 Hz, ZN). 1399 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[1-(4-chloro-1, 3thiazol-2yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide ArL zL ^s1 Mixture of 2 isomers 585.1(1) 8.91 (brs, 1H), 8.83 (br s, 1H), 8.42 (brt, 7=6.4 Hz, 1H), 8.17 (s, 1H), 7.66 - 7.57 (m, 2H), 5.25 (br s, 0.5H ), 5.14 (br s, 0.5H), 4.56 - 4.45 (m, 1H), 4.05 (s, 3H), 4.04-3.99 (m, 1H), 3.35 (br d, 7=11.9 Hz, 1H), 3.18-3.07 (m, 1H), 3.07 3.00 (m, 1H), 2.98 - 2.78 (m, 1H), 2.68 -2.53 (m, 1H), 1.39 (br d, 7=5.5 Hz, ZN) .

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1400 5-[4-Amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-Ni]-N-[(3R,4S)4-fluoro-1-[1-(2methyl -1,3-thiazol5yl)ethyl]pyrrolide in-3-yl]-2methoxypyride in3-carboxamide Mixture of 2 isomers 565.2(2) 8.91 (br s, 1Н), 8.84 (br s, IH), 8.48 - 8.36 (m, IH), 8.17 (s, IH), 7.61 (s, IH), 7.49 (br s, IH), 5.24 (br s, 0.5H), 5.13 (br s, 0.5H), 4.54 - 4.42 (m, IH), 4.05 (br d, 7=2.4 Hz, ZN), 3.99 -3.89(m, IH), 3.36 (brd, 7=6.4 Hz, IH), 3.20 -2.96 (m, IH), 2.93 - 2.67 (m, IH), 2.61 (br s, 3H), 2.56 (br d, 7=8.9 Hz, IH), 1.40 - 1.34 (m, 3H), 1.32 (brs, IH). 1401 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[1-(3,5dimethyl-1, 2oxazol-4yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyride in3-carboxamide h 1 isomer 563.2(1) 8.91 (br s, IH), 8.85 (br s, IH), 8.43 (br d, 7=7.0 Hz, IH), 8.17 (s, IH), 7.61 (s, IH), 5.27 (brs, 0.5H) , 5.16 (br s, 0.5H), 4.58 4.47 (m, IH), 4.05 (s, 3H), 3.36 (br d, 7=5.8 Hz, IH), 3.12 -2.99 (m, IH), 2.75 (brt , 7=7.9 Hz, IH), 2.71 - 2.57 (m, 2H), 2.37 (s, 3H), 2.24 (s, 3H), 1.28 (br d, 7=6.1 Hz, ZN). 1402 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-nn]-N-[(3R,4S)4-fluoro-1-[1-(1, 3thiazol-4yl)ethyl]pyrrolide in-3-yl]-2methoxypyride in3-carboxamide X Mixture of 2 isomers 551.1(2) 9.07 (br s, IH), 8.90 (br s, IH), 8.83 (s, IH), 8.41 (brd,7=7.0 Hz, IH), 8.17 (s, IH), 7.61 (s, IH), 7.55 (br s, IH), 5.22 (br s, 0.5H), 5.11 (br s, 0.5H), 4.43 (brdd, 7=14.2, 8.7 Hz, IH), 4.04 (s, 3H), 3.97 (brs, IH), 3.37 (br d, 7=7.9 Hz, IH), 3.18 -3.04 (m, IH), 3.00 -2.76 (m, IH), 2.65 -2.54 (m, IH), 1.41 (br d, 7=5.8 Hz, ZN). 1403 1404 5-[4-amino-5(trifluoromethyl)p irrolo[2,11][1,2,4]triazine7-mi]-N-[(3R,4S)1-[1-(3,5dimethyl-1, 2oxazol-4yl)ethyl]-4fluoropyrrolidin3-yl]-2methoxypyridine3-carboxamide ,4S)1-[1-(2,4dimethyl-1,3thiazol-5yl)ethyl]-4fluoropyrrolidine- 3-yl]-2- methoxypyridine3-carboxamide h 1 isomer N 1 isomer 563.2(2) 579.2(2) 8.91 (brs, IH), 8.85 (br s, IH), 8.43 (br d, 7=7.0 Hz, IH), 8.17 (s, IH), 7.62 (s, IH), 5.26 (brs, 0.5H), 5.15 (br s, 0.5H), 4.54 (brdd, 7=15.0, 7.0Hz, IH), 4.05 (s, 3H), 3.35 (br s, IH), 2.94 (brd, 7=6.1Hz, IH), 2.85 (br s, IH), 2.82 - 2.75 (m, IH), 2.48 - 2.42 (m, IH), 2.37 (s, 3H), 2.24 (s, 3H), 1.30 (brd, 7=6.1 Hz, ZN ). 8.91 (s, IH), 8.85 (br s, IH), 8.41 (br d, 7=7.0 Hz, IH), 8.17 (s, IH), 7.62 (s, IH), 5.25 (brs, 0.5H), 5.13 (br s, 0.5H), 4.564.45 (m, IH), 4.06 (s, 3H), 3.85 (brd, 7=6.1 Hz, IH), 3.38 -3.30(m, IH), 3.05 -2.94 ( m, 2H), 2.92-2.80 (m, IH), 2.582.53 (m, 4H), 2.28 (s, 3H), 1.31 (brd,7=6.1 Hz, ZN).

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Example 1405: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(3-hydroxy-2,3-dimethylbutan-2-yl)pyrrolidin-3-yl)-2-methoxynicotinamide

5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S )-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide (10 mg, 0.023 mmol) and 2,2,3,3-tetramethyloxirane (0.25 ml, 1.949 mmol), then distilled water (150 µl) was added. The mixture was heated to 175°C for 3.5 h in a microwave reactor. The mixture was left to cool to room temperature and concentrated in a stream of nitrogen. The residue was dissolved in 2 ml DMF. The crude material was filtered and purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; gradient = 28-68% B over 20 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (1.3 mg, 10% yield).

MS (ERI) m/z 540.2 (M+H)+.

Ή NMR (500 MHz, DMSO-d6) δ 8.91 (d, J=2.1 Hz, 1H), 8.87 (d, J=2.1 Hz, 1H), 8.42-8.35 (m, 1H), 8.17 (s, 1H) , 7.62 (s, 1H), 5.16 (br s, 0.5H), 5.05 (br s, 0.5H), 4.44-4.33 (m, 1H), 4.05 (s, 3H), 3.40 (br d, J=12.5 Hz, 1H), 3.27-3.02 (m, 2H), 2.73 (br t, J=8.5 Hz, 1H), 1.14 (s, 6H), 1.00 (br s, 3H), 0.98 (br s, 3H).

Connections in the table. 51 was prepared in a manner similar to those detailed in Example 1405. In most cases, reactions took 30 minutes or less to complete at 170-175°C. When the diastereomers were separated, they were included as separate data, which may refer either to a single diastereomer or to a mixture of two or more diastereomers, depending on the stereochemistry of the starting epoxy compound and on preparative HPLC data. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 16 are as described in the Preparation Methods section.

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Table 51

Example Name R Observe in MS the mass of the M ⁺ ion (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or LC-MS retention time 1406 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2hydroxycyclopentyl)pyrrolide 3- yl]-2methoxypyride in-3 carboxamide 4 isomers 524.2(1) 8.92 (d, 7=2.4 Hz, 1H), 8.86 (d, 7=2.3 Hz, 1H), 8.52 - 8.37 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.23 (br s, 0.5H), 5.12 (br s, 0.5H), 4.61 (br s, 1H), 4.55 - 4.42 (m, 1H), 4.06 (s, 3H), 3.96 - 3.84 (m, 1H), 3.293. 25 (m, 1H), 3.24 - 3.08 (m, 1H), 3.07 - 2.96 (m, 1H), 2.95 - 2.81 (m, 1H), 1.86 - 1.77 (m, 2H), 1.661.51 (m, 2H ), 1.51-1.35 (m, 3H). 1407 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(3hydroxy-3methylbutan-2yl) pyrrolide in-3 yl]-2methoxypyride in-3 carboxamide aan 1 isomer 526.2(2) LC-MS, Method 1 retention time = 1.29 min LC-MS Method 2 retention time =1.83 min 1408 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(2hydroxy-2methylcyclopentyl)pyrrolidine- 3 -yl] 2-methoxypyridine 3-carboxamide ^he 1-3 isomers 538.2(1) LC-MS Method 1 retention time =1.26 min LC-MS Method 2 retention time =1.71 min 1409 In -3 yl]-2methoxypyride in-3 carboxamide HuON 1 isomer 512.2(1) LC-MS Method 1 retention time =1.23 min LC-MS Method 2 retention time =1.61 min

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1410 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2hydroxy-2methylcyclohexyl)pyrrolidine- 3 -yl] 2-methoxypyridine 3-carboxamide 1-3 isomers 552.2(1) LC-MS Method 1 retention time =1.35 min LC-MS Method 2 retention time =1.92 min 1411 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(3hydroxybutan-2yl)pyrrolide -3 - yl]-2methoxypyride in-3 carboxamide 1 isomer 512.2(2) LC-MS Method 1 retention time =1.24 min LC-MS Method 2 retention time =1.64 min 1412 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2hydroxy-2methylcyclopentyl)pyrrolidine- 3 -yl] 2-methoxypyridine 3-carboxamide ^ _he 1-3 isomers 538.2(1) 8.92 (s, 1H), 8.88 (s, 1H), 8.39 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.22 (br s, 0.5H), 5.135.08 (m, 0.5H), 4.53 - 4.40 (m, 2H), 4.12 - 4.03 (m, ZN), 3.20 - 3.05 (m, 1H), 3.00 -2.80 (m, 2H), 2.77 2.67 (m , 1H), 2.48 - 2.34 (m, 1H), 1.89 - 1.77 (m, 1H), 1.74 - 1.63 (m, 1H), 1.60 - 1.39 (m, 4H), 1.10 (s, 3H). LC-MS Method 1 retention time = 1.27 min LC-MS Method 2 retention time =1.74 min

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1413 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(3hydroxybutan-2yl)pyrr o ly din-3 yl]-2methoxypyride in-3 carboxamide 2 isomers 512.2(2) LC-MS Method 1 retention time = 1.26 min LC-MS Method 2 retention time =1.70 min 1414 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(2hydroxy-2methylcyclohexyl)pyrrolidine- 3-yl]2-methoxypyridine3-carboxamide 1-3 isomers 552.2(1) LC-MS, Method 1 retention time = 1.37 min LC-MS Method 2 retention time =1.96 min 1415 5-[4-amino-5(trifluoromethyl) pyrrolo[2,1- f] [ 1,2,4]triazin-7nn]-N-[(3R,4S)-4fluoro-1-(3hydroxy-3methylbutan-2yl)pyrrolidinin-3yl]-2methoxypyride in-3carboxamide 1 isomer 526.2(1) LC-MS Method 1 retention time =1.31 min LC-MS Method 2 retention time =1.85 min

Example 1416: methyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)- 4-fluoropyrrolidine-1-carboxylate

In a 1 dram vial, 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R,4S)-4-fluoropyrrolidine -3-yl)-2-methoxynicotinamide (15 mg, 0.034 mmol) with DIPEA (0.018 ml, 0.102 mmol) in DMF (0.3 ml). The mixture was treated with methyl chloroformate (3.17 μl, 3.87 mg, 0.041 mmol) and stirred at room temperature overnight. The crude mixture was filtered and purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; gradient = 21-61% B over 20 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation to give the target compound (9.4 mg, 55% yield).

MS (ERI) m/z 498.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (s, 1H), 8.77 (s, 1H), 8.52 (br d, J=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36-5.17 (m, 1H), 4.77-4.63 (m, 1H), 4.04 (s, 3H), 3.84-3.72 (m, 2H), 3.70-3.64 (m, 1H), 3.61 (s, 3H), 3.39-3.23 (m, 1H).

Example 1417: 2,2,3,3-tetrafluorocyclobutyl (3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7- yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate

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In a 1 dram vial, Ν,Ν'-disuccinimidyl carbonate (87 mg, 0.341 mmol), 2,2,3,3tetrafluorocyclobutanol (0.049 mL, 0.478 mmol) and DIPEA (0.179 mL, 1.024 mmol) were combined in a mixture of acetonitrile (0.15 mL) and DCM (0.15 ml). The mixture was stirred at room temperature overnight. The mixture was then treated with 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3- yl)-2-methoxynicotinamide (30 mg, 0.068 mmol) and stirred at room temperature overnight. The mixture was concentrated under a stream of nitrogen to a residue, redissolved in 2 ml DMF and filtered. The crude material was purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B = 95:5 acetonitrile: water with 0.1% trifluoroacetic acid; gradient = 33-73% B over 20 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified with chiral SFC under the following conditions: Instrument = Waters 100 Prep SFC; column = Chiral AS, 250 mm x 30 mm, 5 µm particles; mobile phase = 80% CO ₂ / 20% MeOH with 0.1% DEA; flow rate = 100 ml/min. Fractions containing the target product were combined and dried by centrifugal evaporation to give the target compound (1.8 mg, 3.0 mmol, 4% yield).

MS (ERI) m/z 610.1 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.93 (d, J=2.1 Hz, 1H), 8.84-8.72 (m, 1H), 8.54 (br dd, J=6.9, 2.6 Hz, 1H), 8.18 (s , 1H), 7.62 (s, 1H), 5.44-5.24 (m, 2H), 4.90-4.68 (m, 1H), 4.05 (s, 3H), 3.95-3.64 (m, 3H), 3.40-3.14 (m , 1H), 2.96–2.76 (m, 1H).

Example 1418: (R)-1-hydroxy-4-methylpentan-2-yl-(3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1 ,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-carboxylate

In a 1 dram vial, Ν,Ν'-disuccinimidyl carbonate (43.7 mg, 0.171 mmol), (R)-1-((tert-butyldimethylsilyl)oxy)-4-methylpentan-2-ol (55.5 mg, 0.239 mmol) and DIPEA ( 0.060 ml, 0.341 mmol) in a mixture of acetonitrile (0.15 ml) and DCM (0.15 ml). The mixture was stirred at room temperature overnight. The reaction mixture was then treated with 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3 -yl)-2-methoxynicotinamide (15 mg, 0.034 mmol) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated to a residue under nitrogen flow and the residue was treated with TBAF, 1.0 M in THF (0.341 ml, 0.341 mmol). The mixture was stirred overnight. The mixture was diluted with MeOH and filtered. The crude material was purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; gradient = 30-70% B over 20 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation to give the target compound (4.5 mg, 23% yield).

MS (ERI) m/z 610.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (s, 1H), 8.79 (br s, 1H), 8.50 (d, J=7.4 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.76-4.62 (m, 3H), 4.05 (s, 3H), 3.84-3.57 (m, 3H), 3.42 (br t , J=5.2 Hz, 2H), 1.69-1.54 (m, 1H), 1.52-1.42 (m, 1H), 1.41-1.34 (m, 1H), 0.96-0.84 (m, 7H).

Connections in the table. 52 was prepared in a manner similar to those detailed in Example 1416 or Example 1418 or Example 1418. Some Examples were prepared from a neutral starting amine while others used the TFA salt starting amine. The amount of DIPEA used in each reaction was adjusted accordingly. In some cases, LC-MS showed that an unwanted by-product was formed during the reaction with the mass ion moiety, indicating the presence of two newly formed carbamate moieties in the unwanted by-product molecule. In these cases, the crude reaction mixtures were concentrated under nitrogen flow to a residue, redissolved in methanol (1 ml), and the resulting mixture was then treated with excess potassium carbonate (approximately 100-200 mg) and heated with stirring to 45°C overnight . This workup effectively destroyed the unwanted by-product and the title compounds were obtained after aqueous workup and preparative purification by HPLC. Examples in Table. containing a free aliphatic hydroxyl group were prepared in a similar manner as detailed in Example 1428. Examples in Table. are single diastereomers unless otherwise noted. When the diastereomers were separated either by reverse phase preparative HPLC or additionally by chiral SFC, similar to that described in

- 400 042342 example 1427, they are included as separate data. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 1-6 are as described in the Preparation Methods section.

Table 52

O Fy^lV^R o / Vnh F ₃ C. .___/

H ₂ N^/^N \=n ^x

Example Name R Observe in MS the mass of the M ⁺ ion (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or LC/MS retention time 1419 1420 2-methoxyethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate propyl (3R,4S)-3{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate 542.1(2) 526.2(1) 8.93 (s, 1H), 8.77 (s, 1H), 8.52 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.37 - 5.16 (m, 1H), 4.77-4.64 (m, 1H), 4.19-4.10 (t, SH), 4.04 (s, SH), 3.85-3.72 (m, 2H), 3.70-3.60 (m, 2H), 3.56-3.51 (m, 2H ), 3.38-3.25 (m, 2H). 8.93 (d, 7=2.4Hz, 1H), 8.78 (d, 7=2.4Hz, 1H), 8.50 (d, 7=7.5Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s, 0.5H), 5.22 (br s, 0.5H), 4.78 - 4.63 (m, 1H), 4.04 (s, 3H), 4.01 - 3.94 (m, 2H), 3.85 - 3.77 (m, 1H) , 3.75 - 3.60 (m, 2H), 3.29 -3.22 (m, 1H), 1.60 (sxt, 7=7.0 Hz, 2H), 0.91 (t, 7=7.4 Hz, ZN).

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1421 phenyl (3R,4S)-3{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate b 560.1(2) 8.93 (s, 1H), 8.81-8.76 (m, 1H), 8.62-8.51 (m, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 7.41 (brt, /=7.6 Hz, 2H) , 7.24 (brt, /=7.3 Hz, 1H), 7.17 (br d, /=5.8 Hz, 2H), 5.445.19 (m, 1H), 4.89 - 4.71 (m, 1H), 4.11-4.01 (m, 4H), 4.01 -3.67 (w, 2H). 1422 ethyl (3R,4S)-3-{5[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 512.2(1) 8.93 (d, /=2.4 Hz, 1H), 8.78 (d, /=2.3 Hz, 1H), 8.50 (d, /=7.5 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33-5.31 (m, 0.5H), 5.23 - 5.20 (br, 0.5H), 4.77-4.63 (m, 1H), 4.10 - 4.05 (m, 2H), 4.04 (s, W), 3.85 - 3.75 (m , 1Н), 3.74-3.60 (m, 2Н), 3.29-3.25 (m, 1Н), 1.210,/=7.1 Hz, ZN). 1423 butyl (3R,4S)-3-{5[4-amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2- methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 540.2(1) 8.93 (f/=2.6Hz, 1H), 8.77 (d, /=2.3Hz, 1H), 8.50 (d, /=7.5Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.34 - 5.30 (m, 0.5H), 5.23 - 5.20 (m, 0.5H), 4.78 - 4.63 (m, 1H), 4.10-3.97 (m, 5H), 3.84-3.76 (br, 1H), 3.74 - 3.59 ( m, 2Н), 3.49 -3.34(br, 1Н), 3.30-3.17 (br, 1Н), 1.60 - 1.53 (m, 2Н), 1.36 (sxt, /=7.4 Hz, 2Н), 0.91 (t, /= 7.4 Hz, ZN). 1424 butan-2-yl (3R,4S)3-{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate Mixture of 2 isomers 540.2(2) 8.93 (d, /=2.4 Hz, 1H), 8.78 (s, 1H), 8.49 (br d, /=7.5 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s , 0.5H), 5.21 (br s, 0.5H), 4.774.60 (m, 2H), 4.04 (s, 3H), 3.84 3.75 (m, 1H), 3.73–3.59 (m, 2H), 3.29–3.22 (m, 1H), 1.59-1.49 (m, 2H), 1.20-1.15 (m, 3H), 0.91-0.83 (m, 3H).

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1425 2-methylpropyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 540.2(2) LC-MS Method 1 retention time =1.99 min LC-MS Method 2 retention time = 2.07 min 1426 prop-2-en-1-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 2,2-dimethylpropyl 524.1(1) 8.92 (s, 1H), 8.77 (s, 1H), 8.53 (br d, J=T6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.95 (qd, /=10.7, 4.9 Hz, 1H), 5.33 (br s, 1H), 5.29 (br s, 0.5H), 5.22 (br s, 1H), 5.20 (s, 0.5H), 4.79–4.65 (m, 1H), 4.56 (br d, /=4.0 Hz, 2H), 4.04 (s, 3H), 3.89 -3.77 (m, 1H), 3.69 (br t, /=12.5 Hz, 1H), 3.63 (br s, 1H), 3.40 -3.26 (m, 1H). (3R,4S)-3-{5-[4- amino-5- 8.93 (d,/=2.4 Hz, 1H), 8.79- (trifluoromethyl)pyr 8.77 (m, 1H), 8.51 (br t,/=6.9 Hz, rollo[2,1- 554 9 1H), 8.18 (s, 1H), 7.62 (s, 1H), 1427 f] [ 1,2,4]triazine-7- 5.35-5.31(m, 0.5H), 5.23(m, silt]-2- BUT 0.5H), 4.81 - 4.65 (m, 1H), 4.08 - methoxypyridine-3 - 3.98 (s, 3H), 3.88-3.61 (m, 5H), amido}-4- 3.37 - 3.26 (m, 1H), 0.93 (s, 9H). fluoropyrrolidine-1 - carboxylate 1428 3-methylbutan-2-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrolo[2,1f] [1,2,4]triazin-7yl]-2- Mixture 554.2(2) 8.93 (d,/=2.4 Hz, 1H), 8.808.76 (m, 1H), 8.54 - 8.47 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.35 5.29 (m, 0.5 H), 5.23 - 5.19 (m, 0.5H), 4.79 - 4.64 (m, 1H), 4.57 4.49 (m, 1H), 4.04 (s, 3H), 3.85 3.71 (m, 1H), 3.69 - 3.59 (m , 2H), methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate 2 isomers 3.30-3.24 (m, 1H), 1.77 (dq, /=13.0, 6.4 Hz, 1H), 1.16-1.10 (m, 3H), 0.91 - 0.84 (m, 6H).

- 403 042342

1429 1-methoxypropan2-yl (3R,4S)-3-{5[4-amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2- methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate V^°\ Mixture of 2 isomers 556.2(1) 8.81 (s, 1Н), 8.66 (s, 1Н), 8.63 (br d, 7=7.3 Hz, 1Н), 8.07 (s, 1Н), 7.48 (s, 1Н), 5.29 (br s, 0.5Н), 5.19 (br s, 0.5H), 4.83 - 4.77 (m, 1H), 4.69 - 4.56 (m, 1H), 4.19 (br s, 3H), 3.87 - 3.75 (m, 1H), 3.703.53 (m, 2H), 3.42-3.33 (m, 2H), 3.26-3.20 (m, 4H), 1.12 (brd, 7=5.8 Hz, ZN). 1430 2,2-difluoroethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2- methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate F 548.1(2) 8.92 (s, 1H), 8.77 (d, 7=1.8 Hz, 1H), 8.54 (br d, 7=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.26 (t, 7=54.6 Hz, 1H), 5.34 (br s, 0.5H), 5.23 (br s, 0.5H), 4.80 - 4.66 (m, 1H), 4.34 (br t, 7=14.5 Hz, 2H), 4.04 (s, 3H), 3.89 -3.62 (m, 3H), 3.41 -3.29 (m, 1H). 1431 cyclobutylmethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 552.2(2) 8.94 - 8.91 (m, 1H), 8.77 (s, 1H), 8.52 (brd, 7=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s, 0.5H) , 5.21 (br s, 0.5H), 4.784.63 (m, 1H), 4.04 (s, 3H), 4.00 (br d, 7=6.1 Hz, 2H), 3.84 - 3.60 (m, 3H), 3.41 - 3.35 (m, 1H), 3.29 (q, 7=10.9 Hz, 1H), 2.62-2.55 (m, 1H), 2.04 - 1.95 (m, 2H), 1.90 - 1.79 (m, 2H), 1.79-1.71 ( m, 2H). 1432 2-ethoxyethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine- 1 carboxylate 556.2(2) 8.93 (d, 7=2.4Hz, 1H), 8.77 (d, 7=2.4Hz, 1H), 8.51 (br d, 7=7.3Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 5.33 (t, 7=2.9 Hz, 0.5H), 5.22 (br s, 0.5H), 4.78 - 4.65 (m, 1H), 4.17 - 4.10 (m, 2H), 4.04 (s, 3H), 3.85 - 3.76 (m, 1H), 3.75 3.59 (m, 2H), 3.57 (t, 7=4.8 Hz, 2H), 3.47 (q, 7=6.9 Hz, 2H), 3.29 - 3.22 (m, 1H), 1.11 ( t, 7=7.0 Hz, ZN).

- 404 042342

1433 [Ι,Γbi(cyclopropane)] l-yl (3R,4S)-3-{5[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 564.2(2) 8.92 (s, 1H), 8.77 (br s, 1H), 8.54 -8.47 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.30 (br s, 0.5H), 5.20 (br s, 0.5H), 4.75 - 4.62 (m, 1H), 4.04 (s, 3H), 3.81-3.72 (m, 1H), 3.71 3.55 (m, 2H), 3.40-3.33 (m, 1H), 3.29- 3.21 (m, 1H), 1.68-1.61 (m, 1H), 0.79 - 0.68 (m, 2H), 0.62 - 0.53 (m, 2H), 0.45 (br d, 7=7.9 Hz, 2H), 0.25-0.18 (m, 2H). 1434 cyclopentyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2- methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 552.1(1) 8.92 (s, 1H), 8.77 (br s, 1H), 8.51 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.31 (br s, 0.5H) , 5.20 (br s, 0.5H), 5.00 (br s, 1H), 4.76 - 4.62 (m, 1H), 4.04 (s, 3H), 3.78 (brt, 7=9.5 Hz, 1H), 3.723.56 ( m, 2H), 3.42 - 3.35 (m, 1H), 3.25 (brt, 7=10.1 Hz, 1H), 1.841.74 (m, 2H), 1.65 (br s, 4H), 1.60 - 1.49 (m, 2H ). 1435 prop-2-yn-1-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 522.1(2) 8.92 (s, 1H), 8.78 - 8.75 (m, 1H), 8.53 (brd, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H) , 5.22 (br s, 0.5H), 4.774.65 (m, 3H), 4.04 (s, 3H), 3.89 3.59 (m, 2H), 3.54(brs, 1H), 3.43–3.23 (m, 2H).

- 405 042342

1436 1- methylcyclopropyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate And 538.2(2) 8.92 (s, 1Н), 8.76 (s, 1H), 8.49 (br s, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.29 (br s, 0.5H), 5.19 (br s, 0.5H), 4.74-4.61 (m, 1H), 4.03 (s, 3H), 3.75 (dt, 7=18.4, 9.3 Hz, 1H), 3.69 - 3.53 (m, 1H), 3.40 (br d, 7=9.2 Hz, 1H), 3.23 (q, 7=10.5 Hz, 1H), 1.49 (s, 3H), 0.86 - 0.75 (m, 2H), 0.62 (brs, 2H). 1437 2,2,2-trifluoroethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido} -4fluoropyrrolidine-1 carboxylate And 566.1(1) 8.94-8.91 (m, 1H), 8.78-8.75 (m, 1H), 8.55 (brd, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.35 (br s, 0.5 H), 5.24 (br s, 0.5H), 4.81–4.68 (m, 3H), 4.04 (s, 3H), 3.91–3.64 (m, 3H), 3.46–3.32 (m, 1H). 1438 but-2-yn-1-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 536.1(1) 8.94 - 8.91 (m, 1H), 8.76 (s, 1H), 8.53 (brd, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s, 0.5H) , 5.22 (br s, 0.5H), 4.764.68 (m, 1H), 4.66 (br s, 2H), 4.04 (s, 3H), 3.84 - 3.61 (m, 3H), 3.41 3.25 (m, 1H) , 1.83 (br s, 3H). 1439 cyclopropylmethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 538.2(1) 8.93 (d, 7=1.8 Hz, 1H), 8.77 (s, 1H), 8.51 (brd, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.77 4.62 (m, 1H), 4.05 (s, 3H), 3.87 (d, 7=7.0 Hz, 2H), 3.85 - 3.74 (m, 1H), 3.72 -3.60 (m, 2H), 3.32 3.25 (m, 1H), 1.15-1.07 (m, 1H), 0.54 - 0.48 (m, 2H), 0.30 - 0.26 (m, 2H).

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1440 but-3-en-2-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate Mixture of 2 isomers 538.1(1) 8.93 (s, 1H), 8.77 (s, 1H), 8.50 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.95 - 5.87 (m, 1H), 5.35-5.16 (m, 3H), 5.13 (brd, 7=10.4 Hz, 1H), 4.77 - 4.65 (m, 1H), 4.05 (s, 3H), 3.89 - 3.74 (m, 1H), 3.74-3.60 ( m, 2H), 3.33 3.25 (m, 1H), 1.28 (brd, 7=6.4 Hz, ZN). 1441 4,4,4trifluorobutan-2-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 1F JLf Mixture of 2 isomers 594.1(1) 8.93 (s, 1H), 8.79 - 8.74 (m, 1H), 8.55 - 8.48 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H), 5.22 ( br s, 0.5H), 5.05 -4.97 (m, 1H), 4.77 - 4.65 (m, 1H), 4.04 (s, 3H), 3.86 - 3.75 (m, 1H), 3.73 3.60 (m, 2H), 3.31 - 3.21 (m, 1H), 2.68 -2.58 (m, 2H), 1.29 (brd, 7=6.4 Hz, ZN). 1442 cyclohexyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate 566.2(2) 8.92 (s, 1H), 8.77 (s, 1H), 8.50 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.32 (br s, 0.5H), 5.21 (br s, 0.5H), 4.78 - 4.62 (m, 1H), 4.58 (br s, 1H), 4.04 (s, 3H), 3.85 - 3.75 (m, 1H), 3.73-3.60 (m, 2H) , 3.38 - 3.24 (m, 1H), 1.79 (br s, 2H), 1.66 (br s, 2H), 1.521.26 (m, 6H). 1443 propan-2-yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine -1 carboxylate 526.1(1) 8.92 (d, 7=2.1 Hz, 1H), 8.77 (s, 1H), 8.50 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.32 (br s , 0.5H), 5.21 (br s, 0.5H), 4.79 (dt, 7=12.2, 6.1 Hz, 1H), 4.75 4.62 (m, 1H), 4.04 (s, 3H), 3.80 (q, 7=9.2 Hz, 1H), 3.74 -3.57 (m, 2H), 3.28 (brs, 1H), 1.21 (brd, 7=6.1 Hz, 6H).

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1444 3,3,3trifluoropropyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}-4fluoropyrrolidine- 1 carboxylate F H. >F * 580.1(1) 8.94-8.91 (m, 1H), 8.77 (br s, 1H), 8.55 - 8.49 (m, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.36 - 5.30 (m, 0.5H), 5.25 - 5.19 (m, 0.5H), 4.78 - 4.66 (m, 1H), 4.30 - 4.19 (m, 2H), 4.04 (s, 3H), 3.85 - 3.79 (m, 1H), 3.76 - 3.58 (m, 2H), 3.33 3.22 (m, 2H), 2.71–2.62 (m, 2H). 1445 3-fluoropropyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridin-3 amido}-4fluoropyrrolidine-1 - 544.1(1) 8.93 (d, 7=2.1 Hz, 1H), 8.77 (s, 1H), 8.50 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.33 (br s , 0.5H), 5.22 (br s, 0.5H), 4.78 4.63 (m, 1H), 4.59 (t, 7=6.0 Hz, 1H), 4.50 (t, 7=6.0 Hz, 1H), 4.14 4.09 (m , 2H), 4.04 (s, 3H), 3.87 3.74 (m, 1H), 3.73 - 3.61 (m, 2H), 3.33 - 3.25 (m, 1H), 2.03 - 1.93 (m, 2H). carboxylate 1,1,1- trifluoropropane-2- 1446 yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2- 4: Mixture of 2 isomers 580.1(2) 8.93 (s, 1H), 8.79 - 8.75 (m, 1H), 8.58 - 8.49 (m, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.37 - 5.22 (m, 2H), 4.82- 4.67 (m, 1H), 4.07 - 4.01 (m, 3H), 3.90 - 3.79 (m, 1H), 3.77 - 3.64 (m, 2H), 3.34 - 3.30 (m, methoxypyridine-3 amido}-4fluoropyrrolidine-1 - 1H), 1.38 (brd, 7=6.4 Hz, ZN). carboxylate cyclopropyl (3R,4S)-3-{5-[4- 8.92(s, 1H), 8.76(d, 7=2.1Hz, amino-5- 1H), 8.53 - 8.45 (m, 1H), 8.19- (trifluoromethyl)pyr 8.15 (m, 1H), 7.63 - 7.58 (m, 1H), rollo[2,1- 574 1 5.34 - 5.28 (m, 0.5H), 5.23 - 5.17 1447 f] [ 1,2,4]triazine-7- L λ (m, 0.5H), 4.76-4.59 (m, 1H), silt]-2- 4.06-3.99 (m, 4H), 3.85-3.71 methoxypyride in-3 - (m, 1H), 3.71 - 3.50 (m, 3H), 3.34 amido}-4- -3.17(m, 1H), 0.68 -0.60(m, fluoropyrrolidine-1 - 4H). carboxylate 1448 cyclobutyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazin-7yl]-2- 538.2(1) 8.92 (d, 7=2.4 Hz, 1H), 8.77 (br s, 1H), 8.50 (d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.32 (brs, 0.5H), 5.21(brs, 0.5H), 4.90- 4.83 (m, 1H), 4.74 - 4.63 (m, 1H), 4.04 (s, 3H), 3.87 - 3.57 (m, 4H), 3.35-3.21 (m, 1H), 2.29 - 2.22 methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate (m, 2H), 2.05 - 1.96 (m, 2H), 1.76 - 1.69 (m, 1H), 1.60-1.51 (m, 1H). (2S)-1- hydroxypropane-2- 1449 yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1- £][1,2,4]triazin-7yl]-2- 542.2 (1) 8.94 - 8.92 (m, 1H), 8.78 (s, 1H), 8.50 (brd, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s, 0.5H) , 5.21 (br s, 0.5H), 4.854.63 (m, 3H), 4.05 (s, 3H), 3.83 3.58 (m, 3H), 3.42 (br s, 2H), 1.14 methoxypyride in-3 amido}-4fluoropyrrolidine-1 - (d, 7=6.1 Hz, ZN). carboxylate

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1450 (2R)-1hydroxypropan-2yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}- 4fluoropyrrolidine-1 carboxylate A 542.1(2) 8.93 (d, 7=2.4 Hz, 1H), 8.77 (s, 1H), 8.50 (br d, 7=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (br s , 0.5H), 5.21 (br s, 0.5H), 4.80 (t, 7=6.0 Hz, 1H), 4.75 - 4.62 (m, 2H), 4.05 (s, 3H), 3.82 - 3.57 (m, 3H) , 3.45 - 3.39 (m, 2H), 1.14 (d, 7=6.4 Hz, ZN). 1451 (2S)-2hydroxypropyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridin-3 amido}-4fluoropyrrolidine- 1 carboxylate 542.2(2) 8.93 (s, 1H), 8.78 (s, 1H), 8.51 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.81 (br s, 1H), 4.76 - 4.65 (m, 1H), 4.05 (s, 3H), 3.92-3.78 (m, 4H), 3.78 - 3.61 (m, 2H), 3.31-3.25 (m, 1H), 3.19 -3.14(m, 1H), 1.61 - 1.52 (m, 1H), 1.35 - 1.28 (m, 1H), 1.07 (br d, 7=5.8 Hz, ZN). 1452 (2R)-1cyclopropyl-3 hydroxypropan-2yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine- 3 amido}-4fluoropyrrolidine-1 carboxylate 582.2(1) 8.93 (s, 1H), 8.78 (br s, 1H), 8.50 (br d, 7=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H) , 5.22 (br s, 0.5H), 4.77-4.61 (m, 3H), 4.05 (s, 3H), 3.88 - 3.75 (m, 1H), 3.73 - 3.59 (m, 2H), 3.53 3.48 (m, 2H ), 3.19 - 3.14 (m, 1H), 1.61 - 1.54 (m, 1H), 1.53 - 1.38 (m, 2H), 0.74 - 0.66 (m, 1H), 0.41 (br d, 7=6.1 Hz, 2H) , 0.10 - 0.00 (m, 2H).

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1453 2-hydroxyethyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate 7 528.1(1) 8.93 (s, 1H), 8.78 (s, 1H), 8.51 (d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.82–4.77 (m, 1H), 4.77–4.61 (m, 1H), 4.05 (s, 5H), 3.92–3.55 (m, 6H). 1454 3,3difluorocyclobutyl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate F 574.1(2) 8.93 (s, 1H), 8.78 (br s, 1H), 8.51 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.34 (br s, 0.5H) , 5.23 (br s, 0.5H), 4.89-4.81 (m, 1H), 4.78 - 4.66 (m, 1H), 4.05 (s, 3H), 3.91-3.85 (m, 1H), 3.83 - 3.76 (m, 1H), 3.75 - 3.59 (m, 2H), 3.31-3.25 (m, 1H), 3.10-3.01 (m, 2H), 2.75 - 2.64 (m, 2H). 1455 1,1,1,3,3,3hexafluoropropan2-yl (3R,4S)-3-{5[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7yl] -2methoxypyridine-3 amido}-4fluoropyrrolidine-1 carboxylate X ^F 634.1(1) 8.93 (s, 1H), 8.80 - 8.75 (m, 1H), 8.58 - 8.53 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.64 - 6.55 (m, 1H), 5.38 ( br s, 0.5H), 5.29 - 5.25 (m, 0.5H), 4.88 - 4.76 (m, 1H), 4.06 4.02 (m, 3H), 3.95 - 3.87 (m, 1H), 3.86-3.67 (m, 2H ), 3.47-3.39(m, 2H), 3.21-3.14(m, 1H).

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1456 3,3,4,4,4pentafluorobutan-2yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride -3 amido}-4fluoropyrrolidine-1 carboxylate I F 630.2(1) 8.94 - 8.89 (m, 1H), 8.75 (dd, 7=14.9, 2.2 Hz, 1H), 8.55 (d, 7=7.4 Hz, 1H), 8.17 (d, 7=1.9 Hz, 1H), 7.61 (d, 7=2.8 Hz, 1H), 5.50 - 5.37 ( m, 1H), 5.35 (brs, 0.5H), 5.26 - 5.21 (m, 0.5H), 4.82 - 4.66 (m, 1H), 4.04 (d, 7=5.0 Hz, ZN), 3.88 (s, 1H) , 3.72 (br d, 7=6.3 Hz, 1H), 3.67 (br d, 7=3.9 Hz, 1H), 3.32 - 3.23 (m, 1H), 1.42 (brd, 7=6.1 Hz, ZN). 1457 (2,2difluorocyclopropyl)methyl (3R,4S)-3{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7- yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate /X, Cf 574.2(2) 8.90 (d, 7=2.5Hz, 1H), 8.74 (d, 7=2.2Hz, 1H), 8.54 (d, 7=7.4Hz, 1H), 8.15 (s, 1H), 7.58 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.77 - 4.61 (m, 1H), 4.28 4.16 (m, 1H), 4.03 (s, 3H), 4.00 3.91 (m, 1H), 3.88 - 3.79 (m, 2H), 3.34 - 3.24 (m, 1H), 2.16 - 2.01 (m, 1H), 1.71 - 1.59 (m, 1H), 1.48 - 1.36 (m, 1H). 1458 3,3,4,4,4pentafluorobutan-2yl (3R,4S)-3-{5-[4amino-5(trifluoromethyl)pyrolo[2,1f] [1,2,4]triazin-7yl]-2methoxypyride -3 amido}-4fluoropyrrolidine-1 carboxylate 1 F Vx/c ^F r ^F 630.2(1) 8.89 (d, 7=1.4 Hz, 1H), 8.74 (dd, 7=4.7, 2.2 Hz, 1H), 8.54 (br d, 7=7.7 Hz, 1H), 8.15 (s, 1H), 7.57 (s, 1H), 5.48 - 5.36 (m, 1H), 5.36 - 5.31 (m, 0.5H), 5.26 - 5.19 (m, 0.5H), 4.81 -4.63 (m, 1H), 4.03 (s, 3H), 3.86 - 3.74 (m, 2H), 3.38 - 3.29 (m, 1H), 1.40 (brd, 7=6.3 Hz, ZN). 1459 (2,2difluorocyclopropyl)methyl (3R,4S)-3{5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7- yl]-2methoxypyride in-3 amido}-4fluoropyrrolidine-1 carboxylate . _ F -X-/-F 574.2(1) 8.93 (d, 7=2.5Hz, 1H), 8.77 (d, 7=1.9Hz, 1H), 8.52 (br d, 7=6.9Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H) , 5.33 (br s, 0.5H), 5.23 (br s, 0.5H), 4.79 - 4.63 (m, 1H), 4.27 4.18 (m, 1H), 4.04 (s, 3H), 4.01 3.95 (m, 1H) , 3.88 - 3.60 (m, 2H), 3.31 (brd, 7=11.8 Hz, 1H), 2.172.04 (m, 1H), 1.73 - 1.62 (m, 1H), 1.45 (br d, 7=6.9 Hz, 1H).

Example 1460: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-X-((3K,48)-4-fluoro- 1(isopropylsulfonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-X-((3K,48)-4fluoropyrrolidin-3-yl) mixture -2-methoxynicotinamide (15 mg, 0.034 mmol) and Hunig's base (0.018 ml, 0.102 mmol) in DMF (0.5 ml) were treated with isopropylsulfonyl chloride (5.75 μl, 0.051 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered. The crude material was purified by preparative LC-MS under the following conditions: column = XBridge Cl8, 200 mm x 19 mm, particles 5 μm; mobile phase A = 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B=95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient = 18-58% B over 25 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation to give the target compound (11.5 mg, 43% yield). MS (ERI) m/z 546.1 (M+H) ⁺ .

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1H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (d, J=2.4 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.53 (d, J=7.3 Hz, 1H),

8.18 (s, 1H), 7.61 (s, 1H), 5.36 (br s, 0.5H), 5.26 (br s, 0.5H), 4.82-4.69 (m, 1H), 4.05 (s, 3H), 3.83- 3.63(m, 3H),

3.50-3.38 (m, 2H), 1.27 (d, J=6.7 Hz, 6H).

Connections in the table. 53 was prepared in a manner similar to those detailed in Example 1460. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 1-6 are as described in the Preparation Methods section.

Table 53

Example Name R Mass of М ⁺ ion observed in MS (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or LC/MS retention time 1461 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7m]-N-[(3R,4S)-1(cyclopropanesulfonyl)-4fluoropyrrolidin-3yl] -2methoxypyride in-3 carboxamide 544.1(2) 8.93 (d, /=2.4 Hz, 1H), 8.79 (d, /=2.4 Hz, 1H), 8.53 (br d, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 5.38 (br d, /=3.1 Hz, 0.5H), 5.28 - 5.26 (m, 0.5H), 4.80 - 4.69 (m, 1H), 4.05 (s, 3H), 3.83 - 3.70 (m, 2H), 3.66 (t, /=12.5 Hz, 1H), 3.40 - 3.35 (m, 1H), 2.78 (quin, /=6.3 Hz, 1H), 1.04 0.96 (m, 4H).

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1462 5-[4-amino-5(trifluoromethyl)pyrrolo[2, ΙΟ [1,2,4]triazine-7wi]-N-[(3R,4S)-l(cyclohexanesulfonyl)-4fluoropyrrolidin-3yl]- 2methoxypyride in-3 carboxamide 586.1(2) 8.93 (d, /=2.4 Hz, 1H), 8.77 (d, /=2.4 Hz, 1H), 8.52 (br d, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 5.36 (br d, /=2.7 Hz, 0.5H), 5.25 (br s, 0.5H), 4.81 - 4.69 (m, 1H), 4.05 (s, 3H), 3.83 - 3.62 (m, 3H), 3.30 - 3.21 (m, 1H), 2.03 (br d, /=7.3 Hz, 2H), 1.79 (br d, /=12.8 Hz, 2H), 1.66 1.60 (m, 1H), 1.47 - 1.37 (m, 2H) , 1.34 - 1.25 (m, 2H), 1.20-1.10 (m, 1H). 1463 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1(cyclopentanesulfonyl)-4fluoropyrrolidin-3yl] -2methoxypyride in-3 carboxamide 572.1(1) 8.93 (d, /=2.1Hz, 1H), 8.78 (d, /=2.4Hz, 1H), 8.52 (br d, /=7.9Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 5.37 5.34 (m, 0.5H), 5.25 (br s, 0.5H), 4.79 - 4.67 (m, 1H), 4.05 (s, 3H), 3.82 - 3.62 (m, 4H), 2.01 - 1.94 (m, 2H), 1.89 - 1.81 (m, 2H), 1.73 - 1.65 (m, 2H), 1.63 - 1.54 (m, 2H). 1464 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,10 [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(3methylbutan-2sulfonyl)pyrrole idin- 3-yl]-2methoxypyride in-3 carboxamide 574.2(2) 8.93 (s, 1H), 8.78 (dd, /=8.9, 2.4 Hz, 1H), 8.53 (t, /=6.2 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36 (br d, /=2.7 Hz, 0.5H), 5.25 (br s, 0.5H), 4.80 4.68 (m, 1H), 4.05 (d, /=2.1 Hz, SA), 3.83 - 3.62 (m, SA), 3.29 - 3.26 (m, 1H), 2.36 - 2.27 (m, 1H), 1.20 (dd, /=7.0, 2.4 Hz, 3H), 0.97 (dd, /=15.7, 6.9 Hz, 6H). 1465 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(4methylpentan-2sulfonyl)pyrrole idine -3-yl]-2methoxypyride in-3 carboxamide 588.2(2) 8.93 (s, 1H), 8.78 (dd, /=6.7, 2.4 Hz, 1H), 8.53 (brd, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36 (brs , 0.5H), 5.26 (br d, /=2.1 Hz, 0.5H), 4.80 - 4.69 (m, 1H), 4.05 (d, /=2.1 Hz, SA), 3.84 - 3.63 (m, SA), 3.38 3.34 (m, 1H), 1.73 - 1.58 (m, 2H), 1.44 - 1.37 (m, 1H), 1.25 (br d, /=5.5 Hz, ZH), 0.95 - 0.85 (m, 6H).

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1466 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4- fluoro-1-(1,1,1trifluoropropane-2sulfonyl)pyrrole idin-3-yl]-2methoxypyride in-3 carboxamide 600.0 (1) 8.93 (d, /=2.4 Hz, 1H), 8.77 (s, 1H), 8.55 (br d, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.39 (brd, /=3.1 Hz, 0.5H), 5.28 (br d, /=2.4 Hz, 0.5H), 4.85 - 4.72 (m, 2H), 4.05 (s, ZN), 3.92 - 3.72 (t, ZN), 3.42 - 3.35 (w, 1H), 1.50 (d, /=7.0 Hz, ZH). 1467 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-(2,2,2trifluoroethanesulfonyl) )pyrrolidin-3 yl]-2methoxypyride in-3 carboxamide G 586.0 (1) 8.93 (d, /=2.1 Hz, 1H), 8.78 (d, /=2.4 Hz, 1H), 8.53 (br d, /=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 5.38 (br s, 0.5H), 5.27 (br s, 0.5H), 4.83 - 4.61 (m, ZN), 4.05 (s, ZN), 3.92 - 3.69 (m, 3H), 3.41 - 3.36 (m, 1H), 2.48 - 2.46 (m, 1H). 1468 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7nn]-N-[(3R,4S)-4φτορ-1-[(Ζ)-2fluoroethenesulfonyl ]pyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 548.1(1) 8.93 (d, /=2.1 Hz, 1H), 8.78 (dd, /=8.4, 2.3 Hz, 1H), 8.61 - 8.53 (m, 1H), 8.18 (s, 1H), 7.91 - 7.79 (m, 1H) , 7.62 (s, 1H), 5.48 - 5.23 (m, 2H), 5.00 - 4.70 (m, 1H), 4.16 - 3.95 (m, 5H), 3.74 - 3.68 (m, 1H), 3.65 3.53 (m, 1H ), 3.29-3.15 (m, 1H). 1469 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-l(3,4dimethylbenzenesulfonyl)-4fluoropyrrolidine-3 yl]-2methoxypyride in-3 carboxamide 608.0 (1) 8.91 (d, /=2.4Hz, 1H), 8.72 (d, /=2.4Hz, 1H), 8.43 (d, /=7.6Hz, 1H), 8.17 (s, 1H), 7.63 (s, 1H), 7.61 7.56 (m, 2H), 7.42 (d, /=7.9 Hz, 1H), 5.27-5.25 (m, 0.5H), 5.15 (br s, 0.5H), 4.52-4.41 (m, 1H), 4.00 ( s, 3H), 3.72 - 3.53 (m, 4H), 3.19 - 3.12 (m, 1H), 2.33 (d, /=6.7 Hz, 6H). 1470 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1(2,5dimethoxybenzenesulphonyl)-4fluoropyrrolidine-3 yl]-2methoxypyride in-3 carboxamide OSN ₃ V H ₃ CO 640.1(2) 8.92 (d, /=2.4Hz, 1H), 8.75 (d, /=2.4Hz, 1H), 8.48 (d, /=7.3Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.30 (s, 1H), 7.25 (s, 2H), 5.34 (brs, 0.5H), 5.23 (br d, /=3.4 Hz, 0.5H), 4.63 - 4.51 (m, 1H), 4.02 (s, 3H ), 3.90 (s, 3H), 3.85 (t, /=8.9 Hz, 1H), 3.78 (s, 3H), 3.74 - 3.60 (m, 2H), 3.25 (t, /=9.9 Hz, 1H). 1471 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7nn]-N-[(3R,4S)-4fluoro-1-(naphthalene- 1sulfonyl)pyrrole idin-3-yl]-2methoxypyride in-3 carboxamide xO 630.1(1) 8.90 (d, /=2.4Hz, 1H), 8.72 - 8.68 (m, 2H), 8.47 (d, /=7.3Hz, 1H), 8.31 (d, /=8.2Hz, 1H), 8.20 (d, / =7.3 Hz, 1H), 8.16 (s, 1H), 8.13 (d, /=7.9 Hz, 1H), 7.77 (t, /=7.8 Hz, 1H), 7.70 (q, /=8.2 Hz, 2H), 7.59 (s, 1H), 5.34 5.31 (m, 0.5H), 5.22 (br d,/=3.1 Hz, 0.5H), 4.73 - 4.61 (m, 1H), 3.99 (s, 3H), 3.84 - 3.70 ( m, 3H), 3.31 - 3.25 (m, 1H).

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1472 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1phenylmethanesulfonylpyrrolidine-3 - yl]-2methoxypyride in-3 carboxamide 594.0 (2) 8.94 - 8.91 (m, 1H), 8.78 (d, 7=2.4 Hz, 1H), 8.49 (d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.47 - 7.37 (t, 5H), 5.37 - 5.18 (w, 1H), 4.74 - 4.63 (w, 1H), 4.58 - 4.51 (m, 2H), 4.05 (s, W), 3.72 - 3.58 (w, W), 3.28 - 3.20 (w, 1H). 1473 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-[(3methylphenyl)methanes ulfonyl ] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide 2 608.0 (1) 17.99 (s, 1H), 8.93 (d, 7=2.4 Hz, 1H), 8.78 (d, 7=2.4 Hz, 1H), 8.48 (d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.30 - 7.22 (t, 3H), 7.19 (br d, 7=7.6 Hz, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.75 - 4.63 (m, 1H), 4.53 - 4.45 (m, 2H), 4.05 (s, 3H), 3.71 - 3.54 (m, 3H), 3.26 - 3.19 (m, 1H), 2.34 (s, 3H). 1474 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2methoxybenzenesulfonyl)pyrrolidine -3-yl]-2methoxypyride in-3 carboxamide OSN ₃ d 610.0 (1) 8.92 (d, 7=2.4Hz, 1H), 8.75 (d, 7=2.4Hz, 1H), 8.48 (d, 7=7.6Hz, 1H), 8.17 (s, 1H), 7.81 (d, 7=7.7 Hz, 1H), 7.66 (t, 7=7.7 Hz, 1H), 7.61 (s, 1H), 7.30 (d, 7=8.5 Hz, 1H), 7.13 (t, 7=7.6 Hz, 1H), 5.33 ( br s, 0.5H), 5.24 - 5.21 (m, 0.5H), 4.63 - 4.51 (m, 1H), 4.02 (s, 3H), 3.96 (s, 3H), 3.84 (t, 7=9.0 Hz, 1H ), 3.74 - 3.59 (m, 2H), 3.24(1.7=10.1 Hz, 1H). 1475 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2-methoxy5methylbenzenesulfonyl)pyrrolidine -3 yl]-2methoxypyride in-3 carboxamide DOS ₃ 624.1(2) 8.92 (d, 7=2.4Hz, 1H), 8.75 (d, 7=2.1Hz, 1H), 8.48 (d, 7=7.3Hz, 1H), 8.17 (s, 1H), 7.61 (s, 2H), 7.46 (dd, 7=8.4, 1.7Hz, 1H), 7.19 (d, 7=8.5Hz, 1H), 5.34 - 5.32 (m, 0.5H), 5.22 (t, 7=2.7Hz, 0.5H), 4.62 - 4.50 (m, 1H), 4.02 (s, 3H), 3.92 (s, 3H), 3.83 (t, 7=9.0 Hz, 1H), 3.73-3.58 (m, 2H), 3.26-3.21 (m, 1H ), 2.31 (s, 3H), 1.29–1.21 (m, 1H). 1476 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(2methylbenzenesulfonyl)pyrrolidine-3 yl]-2methoxypyride in-3 carboxamide ^*0 594.1(2) LC-MS Method 1 retention time = 1.98 min LC-MS Method 2 retention time = 2.19 min 1477 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(3methylbenzenesulfonyl)pyrrolidine-3 yl]-2methoxypyride in-3 carboxamide 594.1(1) 8.91 (d, 7=2.4 Hz, 1H), 8.72 (d, 7=2.4 Hz, 1H), 8.44 (d, 7=7.6 Hz, 1H), 8.17 (s, 1H), 7.69 - 7.64 (br, 2H ), 7.60 (s, 1H), 7.55 (d, 7=4.6 Hz, 2H), 5.27 - 5.25 (m, 0.5H), 5.15 (br s, 0.5H), 4.54 - 4.43 (m, 1H), 4.00 (s, ZN), 3.75 - 3.54 (m, ZN), 3.16 (t, 7=9.9 Hz, 1H), 2.43 (s, 3H), 1.26 1.22 (m, 1H), 0.87 - 0.80 (m, 1H) .

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1478 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(4methylbenzenesulfonyl)pyrrolidine-3 - yl]-2methoxypyride in-3 carboxamide 594.1(2) 8.91 (d, 7=2.1 Hz, 1H), 8.72 (d, 7=2.4 Hz, 1H), 8.43 (d, 7=7.3 Hz, 1H), 8.17 (s, 1H), 7.76 - 7.73 (m, 7 =7.9 Hz, 2H), 7.60 (s, 1H), 7.48 7.45 (m, 7=7.9 Hz, 2H), 5.26 - 5.24 (m, 0.5H), 5.14 (br s, 0.5H), 4.51 4.41 (m , 1H), 4.00 (s, 3H), 3.73 3.51 (m, 3H), 3.14 (t, 7=9.9 Hz, 1H), 2.42 (s, 3H). 1479 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(oxolane-3sulfonyl)pyrrole idin-3-yl]-2methoxypyride in-3 carboxamide b 574.1(2) 8.93 (d, 7=2.4 Hz, 1H), 8.78 (s, 1H), 8.53 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36 (br s , 0.5H), 5.26 (br s, 0.5H), 4.81 - 4.71 (m, 1H), 4.20 - 4.14 (m, 1H), 4.05 (s, 3H), 3.99 - 3.90 (m, 2H), 3.88 - 3.78 (m, 3H), 3.75 - 3.66 (m, 3H), 2.29 - 2.22 (m, 1H), 2.20-2.13 (m, 1H). 1480 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-1{bicyclo[2.2.1]heptan- 2-sulfonyl} 4-fluoropyrrolidine- 3-yl]-2methoxypyride in-3 carboxamide 598.1(1) 8.93 (s, 1H), 8.78 (dt, 7=5.4, 2.6 Hz, 1H), 8.55 - 8.49 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36 (br d, 7 =2.4 Hz, 0.5H), 5.25 (br d, 7=1.8 Hz, 0.5H), 4.78 - 4.66 (m, 1H), 4.05 (s, 3H), 3.83 - 3.60 (m, 4H), 3.31 - 3.26 (m, 1H), 2.62 - 2.56 (m, 1H), 2.34 (br s, 1H), 2.05 - 1.79 (m, 1H), 1.701.63 (m, 1H), 1.58 - 1.46 (m, 2H), 1.43 - 1.23 (m, 3H), 1.20-1.13 (m, 1H). 1481 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1[(1,1dioxidotetrahydr othiophen-3yl)sulfonyl ]-4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 622.0 (2) 8.93 (d, 7=2.4Hz, 1H), 8.77 (t, 7=2.1Hz, 1H), 8.53 (d, 7=7.6Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.36 (brd, 7=3.4Hz, 0.5H), 5.26 (brd, 7=3.4Hz, 0.5H), 4.89 - 4.78 (m, 1H), 4.45 4.37 (m, 1H), 4.05 (s, 3H) , 3.86 3.59 (m, 4H), 3.42 - 3.36 (m, 2H), 3.28 - 3.15 (m, 2H), 2.59 - 2.53 (m, 1H), 2.35 - 2.26 (m, 1H). 1482 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-l(butane-1sulfonyl)-4fluoropyrrolidin-3yl ]-2methoxypyride in-3 carboxamide λ 560.1(1) 8.93 (d, 7=2.4Hz, 1H), 8.78 (d, 7=2.4Hz, 1H), 8.52 (d, 7=7.3Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.35 (t, 7=2.7 Hz, 0.5H), 5.24 (br d, 7=2.7 Hz, 0.5H), 4.79 - 4.68 (m, 1H), 4.05 (s, 3H), 3.80 - 3.59 (m, 3H ), 3.33 3.27 (m, 1H), 3.20-3.12 (m, 2H), 1.68 (quin, 7=7.6 Hz, 2H), 1.42 (sxt, 7=7.4 Hz, 2H), 0.92 (t, 7=7.3 Hz, ZN). 1483 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7wi]-N-[(3R,4S)-4- fluoro-1-[(2- hydroxycyclohexyl)sulfonyl]pyrr olidin-3-yl]-2methoxypyride in-3 carboxamide 602.1(2) 8.95 - 8.89 (m, 1H), 8.80 - 8.74 (m, 1H), 8.55 - 8.45 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.37-5.19 (m, 1H), 4.78 - 4.63 (m, 1H), 4.26 - 4.20 (m, 1H), 4.08 - 4.03 (m, 3H), 4.01 3.50 (m, 3H), 3.34 - 3.22 (m, 2H), 2.24 - 1.99 (m, 1H), 1.96 - 1.78 (m, 1H), 1.77 - 1.70 (m, 2H), 1.69 - 1.54 (m, 1H), 1.52-1.13 (m, 4H).

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1484 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-(3,3,3trifluoropropanesulfonyl) )pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide H 600.0 (1) 8.93 (d, 7=2.4Hz, 1H), 8.77 (d, 7=2.4Hz, 1H), 8.52 (d, 7=7.6Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.37 5.34 (m, 0.5H), 5.26 - 5.23 (m, 0.5H), 4.88 - 4.76 (m, 1H), 4.05 (s, 3H), 3.88 - 3.68 (t, 3H), 3.53 - 3.44 (t, 2H), 3.41 - 3.35 (m, 1H), 2.80 - 2.69 (t, 2H). 1485 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(oxane-4sulfonyl)pyrrole idine -3-yl]-2methoxypyride in-3 carboxamide 588.1(2) 8.93 (d, 7=2.1 Hz, 1H), 8.78 (d, 7=2.4 Hz, 1H), 8.53 (d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.37 (br s, 0.5H), 5.26 (br s, 0.5H), 4.83 4.72 (m, 1H), 4.05 (s, 3H), 3.95 (br dd, 7=11.4, 3.8 Hz, 2H), 3.85- 3.65 (m, 3H), 3.58 (tt, 7=11.9, 4.0 Hz, 1H), 3.38 - 3.35 (m, 2H), 1.89 (brt, 7=11.0 Hz, 2H), 1.74 - 1.64 (m, 2H) . 1486 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-1(cyclohex-1-ene-1sulfonyl) -4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide G) 584.1(2) 8.93 (d, 7=2.4Hz, 1H), 8.75 (d, 7=2.4Hz, 1H), 8.54 (d, 7=7.0Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 6.68 (s, 1H), 5.39 - 5.20 (m, 1H), 4.80 4.64 (m, 1H), 4.04 (s, 3H), 3.73 3.50 (m, 4H), 3.24 (s, 1H), 2.31 2.22 (m , 4H), 1.70-1.61 (m, 2H), 1.58 (br d, 7=4.3 Hz, 2H). 1487 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-[(2nitrophenyl)methanes ulfonyl ] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide sch about 639.1(2) 8.95 - 8.92 (m, 1H), 8.78 (d, 7=2.1 Hz, 1H), 8.53 (br d, 7=7.6 Hz, 1H), 8.19 (s, 1H), 8.08 (br d, 7=7.6 Hz , 1H), 7.83 - 7.77 (m, 1H), 7.77 - 7.73 (m, 1H), 7.74 - 7.67 (m, 1H), 7.62 (s, 1H), 5.37 (br s, 0.5H), 5.26 (br s, 0.5H), 5.02 (q, 7=13.7 Hz, 2H), 4.83 - 4.71 (m, 1H), 4.05 (s, 3H), 3.73 3.56 (m, 3H), 3.30 - 3.23 (m, 1H) .

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1488 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-4fluoro-1-[(4fluorophenyl)methanes ulfonyl ] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide ^7F 612.0 (2) 8.93 (d, 7=2.1 Hz, 1H), 8.78 (d, 7=2.1 Hz, 1H), 8.49 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 7.50 (t, 7=6.2 Hz, 2H), 7.24 (br t, 7=8.9 Hz, 2H), 5.34 (br s, 0.5H), 5.23 (br s, 0.5H), 4.75 - 4.64 (m, 1H), 4.59 4.52 (m, 2H), 4.05 (s, 3H), 3.74 3.57 (m, 3H), 3.25 (brt, 7=9.8 Hz, 1H). 1489 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7mi]-N-[(3R,4S)-l[(2,5difluorophenyl)methanesulfonyl]- 4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide X Y 630.1(2) 8.93 (d, 7=2.1Hz, 1H), 8.78 (d, 7=2.1Hz, 1H), 8.53 (br d, 7=7.6Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 7.39 7.28 (m, 3H), 5.37 (br s, 0.5H), 5.26 (br s, 0.5H), 4.81 - 4.70 (m, 1H), 4.60 (q, 7=13.9 Hz, 2H), 4.05 ( s, 3H), 3.81 - 3.59 (m, 3H), 3.33 - 3.27 (m, 1H). 1490 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7wi]-N-[(3R,4S)-4- fluoro-1-[(3fluorophenyl)methanes ulfonyl] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide Π 612.1(2) 8.92 (s, 1H), 8.78 (s, 1H), 8.50 (d, 7=7.5 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.48 - 7.43 (m, 1H), 7.32 - 7.20 (m, 3H), 5.35 (br s, 0.5H), 5.24 (br s, 0.5H), 4.76 - 4.56 (m, 3H), 4.05 (s, 3H), 3.77 - 3.58 (m, 3H) , 3.26 (brt, 7=9.8 Hz, 1H). 1491 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-7ra]-N-[(3R,4S)-l[(chlorophenyl)methanesulphonyl]-4fluoropyrrolidine- 3 yl]-2methoxypyride in-3 carboxamide O 628.1(2) 8.93 (s, 1H), 8.79 - 8.77 (m, 1H), 8.50 (br d, 7=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.47 7.41 (m, 3H), 5.36 (br s, 0.5H), 5.25 (br s, 0.5H), 4.76 - 4.66 (m, 1H), 4.62 - 4.56 (m, 2H), 4.05 (s, 3H) , 3.78 3.59 (m, 3H), 3.34 - 3.32 (m, 1H), 3.26 (brt, 7=9.8 Hz, 1H). 1492 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7wi]-N-[(3R,4S)-l[(2,6dichlorophenyl)methanesulfonyl]- 4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide 662.0 (2) 8.94 (d, 7=2.1Hz, 1H), 8.78 (d, 7=2.1Hz, 1H), 8.56 (br d, 7=7.3Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H) , 7.57 (d, 7=8.2 Hz, 2H), 7.45 (t, 7=8.1 Hz, 1H), 5.39 (br s, 0.5H), 5.28 (br s, 0.5H), 4.87 - 4.76 (m, 3H ), 4.05 (s, 3H), 3.83 - 3.64 (m, 3H), 3.42 - 3.35 (m, 1H). 1493 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1£][1,2,4]triazine-7^]-N-[(3R,4S)-l[(2chlorophenyl)methanesulfonyl]- 4fluoropyrrolidin-3 yl]-2methoxypyride in-3 carboxamide O 628.0 (2) 8.94 (d, 7=2.1 Hz, 1H), 8.78 (d, 7=2.4 Hz, 1H), 8.53 (br d, 7=7.3 Hz, 1H), 8.18 (s, 1H), 7.63 - 7.52 (m, 3H), 7.44 - 7.39 (m, 2H), 5.37 (br s, 0.5H), 5.26 (br s, 0.5H), 4.83 - 4.74 (m, 1H), 4.68 (q, 7=13.9 Hz, 2H) , 4.05 (s, 3H), 3.78–3.59 (m, 3H).

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1494 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-[(pyridin2yl)methanesulfonyl] pyrrolidine -3 -yl] 2-methoxypyridine 3-carboxamide 595.0 (1) 8.93 (s, 1H), 8.80 - 8.77 (m, 1H), 8.61 (br d, /=4.3 Hz, 1H), 8.50 (br d, /=7.3 Hz, 1H), 8.19 (s, 1H), 7.87 (br t, /=7.6 Hz, 1H), 7.62 (s, 1H), 7.56 (br d, /=7.9 Hz, 1H), 7.42 (t, /=6.2 Hz, 1H), 5.36 (br s, 0.5 H), 5.27 - 5.24 (m, 0.5H), 4.87 - 4.69 (m, 3H), 4.05 (s, 3H), 3.67 - 3.52 (m, 3H), 3.30 - 3.24 (m, 1H). 1495 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7mi]-N-[(3R,4S)-4fluoro-1-[(3nitrophenyl)methanes ulfonyl ] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide about ₂ mA^ 639.1(2) 8.93 (d, /=2.1 Hz, 1H), 8.78 (d, /=2.1 Hz, 1H), 8.50 (br d, /=7.6 Hz, 1H), 8.37 (s, 1H), 8.26 (br d, / =8.5 Hz, 1H), 8.18 (s, 1H), 7.91 (brd, /=7.6 Hz, 1H), 7.73 (t, /=7.9 Hz, 1H), 7.61 (s, 1H), 5.36 (br s, 0.5H), 5.25 (br s, 0.5H), 4.81–4.68 (m, 3H), 4.05 (s, 3H), 3.80–3.60 (m, 3H), 3.31–3.25 (m, 1H). 1496 5-[4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-{[2(trifluoromethyl)phene yl] methanesulfonyl } pyrrolidin-3 yl]-2methoxypyride in-3 carboxamide about ω 662.0 (2) 8.93 (d, /=2.1 Hz, 1H), 8.78 (d, /=2.1 Hz, 1H), 8.55 (br d, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.81 (d, /= 7.6 Hz, 1H), 7.74 (d, /=4.0 Hz, 2H), 7.62 (s, 1H), 7.62 (d, /=5.7 Hz, 2H), 5.39 (br s, 0.5H), 5.28 (br s , 0.5H), 4.89 - 4.77 (m, 1H), 4.72 - 4.64 (m, 2H), 4.05 (s, 3H), 3.83 - 3.62 (m, 3H). 1497 5-[4-amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-[(2fluorophenyl)methanes ulfonyl ] pyrrolydin-3-yl]-2methoxypyride in-3 carboxamide 612.1(1) 8.93 (s, 1H), 8.78 (s, 1H), 8.52 (br d, /=7.3 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.53 (br t, /=7.6 Hz , 1H), 7.48 7.42 (m, 1H), 7.30 - 7.23 (m, 2H), 5.36 (br s, 0.5H), 5.25 (br s, 0.5H), 4.80 - 4.68 (m, 1H), 4.63 - 4.53 (m, 2H), 4.05 (s, 3H), 3.77 - 3.57 (m, 3H), 3.37 - 3.24 (m, 1H). 1498 5-[4-amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m]-N-[(3R,4S)-4fluoro-1-(2,2,2tr iffluoro -1phenylethanesulfone yl)pyrrolidin-3 yl]-2methoxypyride in-3 carboxamide X^CF ₃ and 662.0 (1) 8.92 (s, 1H), 8.75 (dd, /=7.0, 2.1 Hz, 1H), 8.49 - 8.39 (m, 1H), 8.20 - 8.16 (m, 1H), 7.66 (br d, /=6.3 Hz, 2H ), 7.61 (s, 1H), 7.56 - 7.49 (m, 3H), 6.21 - 6.09 (m, 1H), 5.33 - 5.11 (m, 1H), 4.61 - 4.40 (m, 1H), 4.06 - 4.01 (m , 3H), 3.79 (s, 2H), 3.30–3.23 (m, 1H).

Connections in the table. 54 was prepared in a manner similar to those detailed in Example 1416 or 1417, except that 5-(4-amino-5-((4,4-difluoropiperidin-1yl)methyl)pyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide, 4 TFA, instead of 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-N((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide. These reactions used additional DIPEA to compensate for 4 equivalents of TFA in the starting material. In some cases, LC-MS showed that an unwanted by-product was formed during the reaction with the mass ion moiety, indicating the presence of two newly formed carbamate moieties in the unwanted by-product molecule. In these cases, the crude reaction mixtures were concentrated under a stream of nitrogen to a residue, redissolved in methanol (1 ml), and then the resulting mixture was treated with excess potassium carbonate (approximately 100-200 mg) and heated with stirring to 45°C overnight . This treatment effectively destroyed the unwanted by-product

- 419 042342 product and after work-up with water and purification by preparative HPLC, the title compounds were obtained. Examples in table. are single diastereomers unless otherwise noted. If diastereomers were separated either by reverse phase preparative HPLC or by additional chiral SFC as described in Example 1417, they are included as separate data. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 1-6 are as described in the Preparation Methods section.

Table 54

O F^nA/ ^R o ' Anh / ^-0 ν ' ^{:N x} n/ ⁿ

Example Name R Mass of М ⁺ ion observed in MS (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or HPLC retention time 1499 in- 3 amido)-4fluoropyrrolidine-1 carboxylate F 613.2(2) 9.29-9.12 (m, 1H), 8.94 (d, 7=2.1 Hz, 1H), 8.77 (d, 7=2.1 Hz, 1H), 8.50 (br d, 7=7.0 Hz, 1H), 7.91 (s, 1H), 7.71 - 7.55 (m, 1H), 7.06 (s, 1H), 6.39 - 6.13 (m, 1H), 5.35 (br s, 0.5H), 5.24 (br s, 0.5H), 4.80 - 4.68 ( m, IH), 4.38 - 4.29 (m, 2H), 4.03 (s, 3H), 3.90 - 3.64 (m, 5H), 3.41 - 3.35 (m, IH), 2.65 (br s, 4H), 2.02 (br s, 4H). 1500 ethyl (3R,4S)-3-(5{4-amino-5-[(4,4difluoropiperidine- 1- yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 577.2(1) 9.28 - 9.14 (m, IH), 8.94 - 8.92 (m, IH), 8.77 (s, IH), 8.48 (br d, 7=7.3 Hz, IH), 7.91 (s, IH), 7.71 - 7.57 (m , IH), 7.06 (s, IH), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.76 - 4.64 (m, IH), 4.07 (q, 7=7.0 Hz, 2H), 4.04 (s, 3H), 3.86 - 3.78 (m, 3H), 3.76 - 3.60 (m, 2H), 3.29 - 3.24 (m, IH), 2.65 (br s, 4H), 2.07 - 1.96 (m, 4H) , 1.21 (t, 7=7.0 Hz, ZN). 1501 cyclopropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,11][1,2,4]triazin-7yl}-2methoxypyride in-3 amido)- 4fluoropyrrolidine-1 carboxylate γ-Δ 589.2(1) 9.28-9.13 (m, IH), 8.93 (s, IH), 8.77 (d, 7=2.1 Hz, IH), 8.47 (brt, 7=7.2 Hz, IH), 7.91 (s, IH), 7.70 7.56 ( m, IH), 7.06 (s, IH), 5.31 (br s, 0.5H), 5.20 (br d, 7=2.7 Hz, 0.5H), 4.75 - 4.63 (m, IH), 4.03 (s, 4H) , 3.86 - 3.73 (m, 3H), 3.71 - 3.52 (m, 2H), 3.29 - 3.20 (m, IH), 2.65 (br s, 4H), 2.02 (br s, 4H), 0.68 - 0.62 (m, 4H).

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1502 propan-2-yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in- 3 amido)-4fluoropyrrolidine-1 carboxylate 591.2 (1) 9.31 -9.16(m, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.48 (br d, ./7.3 Hz, 1H), 7.94 - 7.89 (m, 1H), 7.74 - 7.58 (m , 1H), 7.07 (br s, 1H), 5.32 (br s, 0.5H), 5.21 (br s, 0.5H), 4.83 - 4.77 (m, 1H), 4.75 - 4.64 (m, 1H), 4.04 ( s, 3H), 3.89 - 3.76 (m, 3H), 3.75 - 3.58 (m, 2H), 3.29 - 3.23 (m, 1H), 2.65 (br s, 4H), 2.02 (br s, 4H), 1.21 ( br d, /=6.1 Hz, 6H). 1503 1504 1505 3,3,3trifluoropropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl}-2methoxypyride in- 3 amido)-4fluoropyrrolidine-1 carboxylate 1,1,1trifluoropropan-2yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine- 1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 4,4,4trifluorobutan-2-yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine- 1yl)methyl]pyrrolo} 2,1f] [ 1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F h. Lf Yxa^f yaa A 1F* 645.2(1) 645.2(1) 659.4(1) 9.32 - 9.20 (m, 1H), 8.93 (s, 1H), 8.76 (br s, 1H), 8.50 (br t, /=6.4 Hz, 1H), 7.94 - 7.90 (m, 1H), 7.73 - 7.59 ( m, 1H), 7.07 (br s, 1H), 5.33 (br s, 0.5H), 5.23 (br s, 0.5H), 4.77 - 4.66 (m, 1H), 4.30 - 4.20 (m, 2H), 4.03 (s, 3H), 3.85 - 3.78 (m, 3H), 3.76 - 3.59 (m, 2H), 3.29 - 3.26 (m, 1H), 2.75 2.59 (m, 5H), 2.02 (br s, 4H). 8.95 - 8.89 (m, 1H), 8.78 - 8.72 (m, 1H), 8.58 - 8.49 (m, 1H), 7.91 (br s, 1H), 7.76 - 7.55 (m, 1H), 7.03 (s, 1H) , 5.41 - 5.20 (m, 2H), 4.83 - 4.66 (m, 1H), 4.07 - 3.99 (m, 3H), 3.92 3.65 (m, 6H), 3.36 - 3.29 (m, 1H), 2.77 - 2.56 (m , 4H), 2.10 - 1.95 (m, 4H), 1.38 (br d, /=6.5 Hz, ZN). 9.36-9.15 (m, 1H), 8.95 - 8.88 (m, 1H), 8.79 - 8.72 (m, 1H), 8.57 - 8.49 (m, 1H), 7.90 (s, 1H), 7.72 - 7.54 (m, 1H ), 7.08 - 7.02 (m, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 5.06 (s, 1H), 4.78 - 4.61 (m, 1H), 4.02 (d, / =3.6 Hz, 2H), 4.05 - 3.99 (m, 1H), 3.84 3.81 (m, 1H), 3.87 - 3.78 (m, 1H), 3.71 - 3.57 (m, 4H), 3.30 - 3.19 (m, 1H) , 2.64 (br s, 5H), 2.02 (brt, /=13.4 Hz, 4H), 1.29 (d, /=6.3 Hz, ZH).

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1506 4,4,4trifluorobutan-2-yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,11][1,2,4]triazin-7yl} -2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 1F J U V 659.4(1) 9.34 - 9.14 (m, 1H), 8.95 - 8.89 (m, 1H), 8.80 - 8.73 (m, 1H), 8.57 - 8.48 (m, 1H), 7.87 (s, 1H), 7.53 (s, 1H), 7.09 - 7.02 (m, 1H), 5.29 (br dd, 7=4.7, 1.8 Hz, 0.5H), 5.21 (br d, 7=2.4 Hz, 0.5H), 5.06 - 4.95 (m, 1H), 4.79 - 4.63 (m, 1H), 4.02 (s, 2H), 3.98 (s, 1H), 3.84 - 3.77 (m, 2H), 3.85 - 3.76 (m, 1H), 3.70 (br s, 1H), 3.33 - 3.24 (m, 1H), 2.70 - 2.57 (m, 6H), 2.07 - 1.95 (m, 4H), 1.29 (d, 7=6.4 Hz, ZN). 1D,1- trifluoropropan-2yl (3R,4S)-3-(5-{4- amino-5-[(4,4- 8.92 - 8.87 (m, 1H), 8.77 - 8.72 (m, difluoropiperidine- 1H), 8.58 - 8.52 (m, 1H), 7.90 - 7.85 1- (m, 1H), 7.05 - 7.00 (m, 1H), 5.36 - 1507 yl)methyl]pyrrolo[ Al 645.4 5.20 (m, 2H), 4.80 - 4.66 (m, 1H), 2.1- If (1) 4.03 - 4.00 (m, 3H), 3.88 - 3.77 (m, 1][1,2,4]triazine-7- F 6H), 3.37 - 3.29 (m, 1H), 2.62 (br s, il}-2- 4H), 2.07 - 1.95 (m, 4H), 1.37 (d, methoxypyride in-3 - 7=6.6 Hz, ZN). amido)-4- fluoropyrrolidine-1 - carboxylate 3,3,3-trifluoro-2,2- — dimethylpropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1 _ 9.33 - 9.20 (m, 1H), 8.94 - 8.89 (m, 1H), 8.76 (br d, 7=2.3 Hz, 1H), 8.57 - 8.49 (m, 1H), 7.89 (s, 1H), 7.67 - 1508 1 " yl)methyl]pyrrolo[ 2,11][1,2,4]triazin-7yl}-2- F * 673.5 (1) 7.53 (m, 1H), 7.05 (s, 1H), 5.37 5.19 (m, 2H), 4.81 - 4.64 (m, 2H), 4.12 - 3.98 (m, 3H), 3.89 - 3.78 (m, 2H), 3.77 - 3.62 (m, 2H), 3.46 - 3.25 (m, 3H), 2.71 - 2.58 (m, 3H), 2.07 - methoxypyride in-3 amido)-4fluoropyrrolidine-1 - 1.95 (m, 3H), 1.15 (brs, 3H). carboxylate

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1509 cyclobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)- 4fluoropyrrolidine-1 carboxylate ^77 603.1(2) 9.29 - 9.17 (m, 1H), 8.93 (d, 7=2.4Hz, 1H), 8.77 (dd, 7=5.9, 2.1Hz, 1H), 8.50 (d, 7=7.6Hz, 1H), 7.91 (s , 1H), 7.72 - 7.57 (m, 1H), 7.06 (s, 1H), 5.26 (s, 1H), 4.91 - 4.82 (m, 1H), 4.77 - 4.61 (m, 1H), 4.03 (s, 3H ), 3.87 - 3.72 (m, 2H), 3.65 (br dd, 7=10.6, 4.5 Hz, 1H), 3.33 - 3.29 (m, 1H), 3.37 - 3.21 (m, 1H), 2.65 (br s, 2H ), 2.31 - 2.21 (m, 2H), 2.08 - 1.94 (m, 6H), 1.72 (q, 7=10.3 Hz, 1H), 1.63-1.51 (m, 1H). 1510 [1(trifluoromethyl)cyclopropyl]methyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl} -2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 671.3(2) 9.36-9.15 (m, 1H), 8.92 (d, 7=2.4 Hz, 1H), 8.76 (d, 7=2.4 Hz, 1H), 8.53 (br t, 7=8.2 Hz, 1H), 7.95 - 7.87 ( m, 1H), 7.74 - 7.52 (m, 1H), 7.11 - 7.02 (m, 1H), 5.37 - 5.20 (m, 1H), 4.81 4.61 (m, 1H), 4.25 - 4.12 (m, 2H), 4.06 - 4.01 (m, 3H), 3.87 - 3.78 (m, 3H), 3.76 - 3.59 (m, 2H), 3.30 (td, 7=10.3, 4.2 Hz, 1H), 2.72 - 2.57 (m, 3H), 2.02 (brt, 7=13.0 Hz, 4H), 1.09 - 0.92 (m, 4H). 1511 1(trifluoromethyl)cyclobutyl (3R,4S)-3(5-{4-amino-5[(4,4difluoropiperidine- 1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 671.4(1) LC-MS Method 1 retention time = 1.84 min LC-MS Method 2 retention time = 2.33 min

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1512 (ls,3s)-3fluorocyclobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate TO 621.5(1) 9.36 - 9.19 (m, 1H), 8.95 - 8.89 (br, 1H), 8.79 - 8.72 (m, 1H), 8.56 - 8.48 (m, 1H), 7.92 - 7.87 (m, 1H), 7.67 7.53 (m, 1Н), 7.08 - 7.02 (m, 1Н), 5.36 - 5.19 (m, 1Н), 4.92 - 4.60 (br, 2Н), 4.55 - 4.44 (m, 1Н), 4.06 - 3.99 (br, ZN), 3.90 - 3.64 (m, 5H), 3.35 3.21 (m, 1H), 2.91 - 2.79 (m, 2H), 2.71 - 2.57 (m, 4H), 2.30 - 2.14 (br, 2H), 2.09 - 1.95 (m, 4H) . 1513 1-cyclopropylethyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido )-4fluoropyrrolidine-1 carboxylate Mixture of 2 isomers 617.3(1) 9.28-9.16 (m, 1H), 8.92 (d, 7=1.7 Hz, 1H), 8.77 (br s, 1H), 8.49 (br d, 7=6.9 Hz, 1H), 7.89 (s, 1H), 7.69 7.54 (m, 1H), 7.05 (s, 1H), 5.32 (br s, 0.5H), 5.22 - 5.20 (m, 0.5H), 4.76 4.63 (m, 1H), 4.20 (br d, 7=5.8 Hz , 1H), 4.06 - 3.98 (m, 3H), 3.88 - 3.57 (m, 5H), 3.31-3.23 (m, 1H), 2.70 (br s, 1H), 2.64 (br s, 2H), 2.48 - 2.46 (m, 1H), 2.01 (br t, 7=13.8 Hz, 4H), 1.25 (brd, 7=6.1 Hz, ZN), 1.00 (br dd, 7=7.7, 2.8 Hz, 1H), 0.52 - 0.41 ( m, 2H), 0.37 - 0.22 (m, 2H). 1514 in- 3 amido)-4fluoropyrrolidine-1 carboxylate 619.5(1) 9.33 - 9.22 (m, 1H), 8.89 (s, 1H), 8.79 - 8.73 (m, 1H), 8.58 - 8.50 (m, 1H), 7.92 - 7.85 (m, 1H), 7.64 - 7.55 (m, 1H ), 7.08 - 7.02 (m, 1H), 5.37 5.30 (m, 0.5H), 5.25 - 5.19 (m, 0.5H), 4.80 - 4.62 (m, 2H), 4.02 (s, 2H), 3.90 - 3.68 ( m, 7H), 3.36 - 3.23 (m, 2H), 2.72 - 2.57 (m, 4H), 2.09 - 1.94 (m, 4H), 0.91 (s, 6H).

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(1R)-1cyclopropylethyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1- 9.39 - 9.19 (m, 1H), 8.95 - 8.88 (m, 1H), 8.80 - 8.73 (m, 1H), 8.56 - 8.47 (m, 1H), 7.94 - 7.86 (m, 1H), 7.72 7.52 (m, 1H), 7.10 - 7.02 (m, 1H), 5.35 - 5.30 (m, 0.5H), 5.24 - 5.19 (m, ISIS yl)methyl]pyrrolo[ 617.4 0.5H), 4.77 - 4.61 (m, 1H), 4.24 - 2.1- (1) 4.13 (m, 1H), 4.02 (s, 3H), 3.88 - f] [ 1,2,4]triazine-7- 3.65 (m, 5H), 3.34 - 3.21 (m, 1H), il}-2- 2.76 - 2.56 (m, 4H), 2.02 (br s, 1H), methoxypyridine-3 - 2.10-1.94 (m, 1H), 1.25 (brd, 7=3.3 amido)-4- Hz, ZN), 1.07 - 0.94 (m, 1H), 0.53 - fluoropyrrolidine-1 - 0.40 (m, 2H), 0.37 - 0.20 (m, 2H). 3-fluoropropyl carboxylate — (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1 9.28 - 9.15 (m, 1H), 8.95 - 8.89 (m, 1H), 8.79 - 8.74 (m, 1H), 8.52 - 8.44 (m, 1H), 7.90 (s, 1H), 7.87 (br d, 1516 1 - yl)methyl]pyrrolo[ 2.1- f] [ 1,2,4]triazin-7yl}-2- 609.0 (5) 7=1.4 Hz, 1H), 7.68 - 7.56 (m, 1H), 7.08 - 7.02 (m, 1H), 5.36 - 5.30 (m, 0.5H), 5.24 - 5.19 (m, 0.5H), 4.79 4.62 (m , 2H), 4.62 - 4.45 (m, 2H), 4.18 - 4.06 (m, 2H), 4.03 (s, 3H), methoxypyride in-3 amido)-4fluoropyrrolidine-1 - 3.83 (s, 2H), 3.33 - 3.23 (m, 2H), 2.64 (br s, 3H), 2.09 - 1.90 (m, 6H). carboxylate cyclopropylmethyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1 9.33-9.13 (m, 1H), 8.92 (d, 7=1.9 Hz, 1H), 8.77 (br s, 1H), 8.50 (br d, 7=7.7 Hz, 1H), 7.90 (s, 1H), 7.72 - 1517 1 - yl)methyl]pyrrolo[ 2.1- f] [ 1,2,4]triazin-7yl}-2- 603.2 7.51 (m, 1H), 7.05 (s, 1H), 5.33 (br s, 0.5H), 5.22 (br s, 0.5H), 4.78 - 4.60 (5) (m, 1H), 4.03 (s, 3H), 3.91 - 3.60 (m, 8H), 3.34 - 3.24 (m, 1H), 2.64 (br s, 3H), 2.07 - 1.93 (m, 4H), 1.16- 1.07 methoxypyride in-3 amido)-4fluoropyrrolidine-1 - (m, 1H), 0.55 - 0.48 (m, 2H), 0.28 (br d, 7=4.7 Hz, 2H). carboxylate

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1518 2,2-difluoropropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl}-2methoxypyride 3 amido)-4fluoropyrrolidine-1 carboxylate 627.4(1) 9.31 - 9.21 (m, 1H), 8.95 - 8.90 (t, 1H), 8.79 - 8.74 (t, 1H), 8.57 - 8.50 (t, 1H), 7.89 (s, 1H), 7.65 - 7.55 (t, 1H ), 7.08 - 7.02 (t, 1H), 5.38 - 5.32 (t, 0.5H), 5.26 - 5.22 (t, 0.5H), 4.82 - 4.65 (t, 2H), 4.37 - 4.26 (t, 1H), 4.40 - 4.24 (t, 1H), 4.02 (s, 3H), 3.92 - 3.64 (t, 4H), 3.40 - 3.27 (t, 2H), 2.64 (br s, 2H), 2.09 - 1.95 (t, 4H), 1.67(1.7=19.2 Hz, ZN). 1519 1- methylcyclopropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)- 4fluoropyrrolidine-1 carboxylate 603.5(1) 9.35 - 9.19 (t, 1H), 8.94 - 8.88 (t, 1H), 8.79 - 8.73 (t, 1H), 8.54 - 8.45 (t, 1H), 7.91 - 7.86 (t, 1H), 7.67 7.52 (t, 1Н), 7.08 - 7.01 (t, 1Н), 5.33 - 5.27 (t, 0.5Н), 5.22 - 5.16 (t, 0.5Н), 4.75 - 4.58 (t, 1Н), 4.05 3.99 (t, GL), 3.91 - 3.67 (t, GL), 3.27 - 3.16 (t, 1Н), 2.71 - 2.57 (t, 4Н), 2.08 - 1.94 (t, 4Н), 1.48 (s, ЗН), 0.87 - 0.74 (t, 2Н) , 0.68 - 0.56 (t, 2H). 1520 2,2,3,3tetrafluoropropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F 663.5 (5) 9.31 -9.13 (t, 1H), 8.93 (s, 1H), 8.77 (br s, 1H), 8.52 (br d, 7=7.2 Hz, 1H), 7.90 (s, 1H), 7.73-7.51 (t, 1Н), 7.09 - 7.04 (t, 1Н), 6.77 - 6.51 (t, 1Н), 5.38 - 5.32 (t, 0.5Н), 5.24 (br d, 7=1.4 Hz, 0.5Н), 4.83 - 4.66 (t , 1H), 4.65–4.53 (t, 2H), 4.03 (s, 3H), 3.95–3.64 (t, 6H), 2.64 (br s, 4H), 2.10–1.93 (t, 4H).

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1521 [Ι,Γbi(cyclopropane)] l-yl (3R,4S)-3-(5{4-amino-5-[(4,4difluoropiperidine- 1yl)methyl]pyrrolo[2,11][1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4- 0 629.2(1) 9.32 - 9.16 (m, 1H), 8.91 (br s, 1H), 8.78 - 8.72 (m, 1H), 8.52 - 8.44 (m, 1H), 7.93 - 7.86 (m, 1H), 7.70 - 7.55 (m, 1H), 7.09 - 7.00 (m, 1H), 5.33 5.26 (m, 0.5H), 5.21 - 5.15 (m, 0.5H), 4.75 - 4.59 (m, 1H), 4.01 (s, 3H), 3.83 - 3.60 (m, 5H), 3.24 (br d, 0=10.0 Hz, 2H), 2.72 - 2.55 (m, 4H), 2.08 - 1.93 (m, 3H), 1.67 - 1.58 (m, 1H), 0.79 - 0.64 ( m, 2H), 0.61 - 0.52 (m, 2H), 0.50 - 0.40 (m, 2H), 0.21 (br fluoropyrrolidine-1 - s, 2H). carboxylate 2,2,3,3,3- pentafluoropropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1 9.40 - 9.16 (m, 1H), 8.95 - 8.88 (m, 1H), 8.79 - 8.72 (m, 1H), 8.60 - 8.50 (m, 1H), 7.93 - 7.87 (m, 1H), 7.72 - 1522 1 - yl)methyl]pyrrolo[ 2,11][1,2,4]triazin-7yl}-2- F 681.4(1) 7.46 (m, 1H), 7.10 - 7.03 (m, 1H), 5.38 - 5.33 (m, 0.5H), 5.27 - 5.22 (m, 0.5H), 4.91 - 4.68 (m, 3H), 4.06 3.99 (m, 3H), 3.87 - 3.64 (m, 5H), 3.38 - 3.30 (m, 1H), 2.70 - 2.58 (m, methoxypyride in-3 amido)-4fluoropyrrolidine-1 - 4H), 2.09 - 1.94 (m, 4H). carboxylate 2,2,3,3,4,4,4- — heptafluorobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine1 _ 9.37 - 9.18 (m, 1H), 8.95 - 8.90 (m, 1H), 8.79 - 8.72 (m, 1H), 8.59 - 8.50 (m, 1H), 7.94 - 7.88 (m, 1H), 7.72 - 1523 1 " yl)methyl]pyrrolo[ 2,11][1,2,4]triazin-7yl}-2- F and and 731.1(1) 7.53 (m, 1H), 7.09 - 7.02 (m, 1H), 5.38 - 5.32 (m, 0.5H), 5.27 - 5.22 (m, 0.5H), 4.95 - 4.66 (m, 3H), 4.02 (d, 0 =2.0 Hz, ZN), 3.89 - 3.60 (m, 5H), 3.35 (td, 0=10.2, 2.8 Hz, 1H), 2.65 methoxypyride in-3 amido)-4fluoropyrrolidine-1 - (br s, 4H), 2.02 (br s, 4H). carboxylate

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1524 3,3difluorocyclobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido )-4fluoropyrrolidine-1 carboxylate F 639.4(2) 9.38 - 9.21 (m, 1H), 8.94 - 8.88 (br, 1H), 8.78 - 8.73 (m, 1H), 8.57 - 8.50 (m, 1H), 7.91 - 7.86 (m, 1H), 7.66 7.46 (m, 1Н), 7.07 - 7.00 (m, 1Н), 5.37 - 5.30 (m, 0.5Н), 5.25 - 5.20 (br, 0.5Н), 4.90 - 4.79 (m, 1Н), 4.78 4.61 (m, 1Н), 4.05 - 3.99 (w, W), 3.92 - 3.74 (m, 4H), 3.35 - 3.22 (w, 1H), 3.11 - 2.97 (m, 2H), 2.77 - 2.57 (m, 6H), 2.10 - 1.93 (m, 4H). 1525 (2,2difluorocyclopropyl)methyl (3R,4S)-3(5-{4-amino-5- [(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate ₅ _ F V\Af Mixture of 2 isomers 639.1(1) 9.35 - 9.23 (m, 1Н), 8.95 - 8.87 (br, 1Н), 8.75 (br s, 1Н), 8.57 - 8.48 (br, 1Н), 7.92 - 7.86 (m, 1Н), 7.65 - 7.54 (m, 1Н), 7.08 - 7.01 (m, 1Н), 5.36 5.30 (m, 0.5Н), 5.25 - 5.19 (m, 0.5Н), 4.80 - 4.62 (m, 1Н), 4.31 - 4.16 (br, 1Н), 4.07 - 3.93 (m, 4H), 3.89 - 3.75 (m, 2H), 3.35 - 3.22 (t, 2H), 2.73 2.58 (t, 4H), 2.15-1.94 (t, 5H), 1.73 - 1.61 (t, 2H ), 1.50 - 1.37 (t, 2H). 1526 1,1,1,3,3,3hexafluoropropan2-yl (3R,4S)-3-(5{4-amino-5-[(4,4difluoropiperidine- 1yl)methyl]pyrrolo} 2.1- f] [ 1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate th F ^G 699.3(5) LC-MS Method 5 retention time =1.79 min LC-MS Method 6 retention time = 2.28 min

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1527 1,1,1-trifluoro-3 methylbutan-2-yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidine- 1- yl)methyl]pyrrolo} 2,1- f] [ 1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate A Mixture of 2 isomers 673.5 (1) LC-MS Method 1 retention time =1.89 min LC-MS Method 2 retention time = 2.40 min 1528 2,2,3,4,4,4hexafluorobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazine- 7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F VaY^f Mixture of 2 isomers 713.1(1) 9.33 - 9.22 (m, 1H), 8.93 - 8.88 (t, 1H), 8.80 - 8.73 (m, 1H), 8.57 - 8.50 (t, 1H), 7.91 - 7.85 (m, 1H), 7.64 7.47 (m, 1Н), 7.08 - 7.01 (m, 1Н), 6.19 - 6.00 (m, 1Н), 5.39 - 5.31 (t, 0.5Н), 5.27 - 5.20 (m, 0.5Н), 4.84 - 4.50 (m, 2H), 4.02 (s, 3H), 3.97 3.72 (m, 5H), 3.33 (br d, /=10.2 Hz, 2H), 2.71 - 2.56 (m, 4H), 2.07 - 1.92 (t, 4H). 1529 1-cyclopropyl2,2,2-trifluoroethyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,11][1,2,4]triazin-7yl} -2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate Υγζ 671.1(1) 9.33 - 9.11 (m, 1H), 8.96 - 8.89 (t, 1H), 8.79 - 8.73 (m, 1H), 8.56 - 8.47 (t, 1H), 7.93 - 7.86 (br, 1H), 7.73 7.46 (m, 1Н), 7.08 - 7.01 (m, 1Н), 5.39 - 5.19 (m, 1Н), 4.85 - 4.67 (t, 2Н), 4.03 (s, ЗН), 3.88 - 3.80 (t, ЗН), 3.79 - 3.54 ( m, 1H), 3.37 - 3.32 (m, 1H), 2.64 (br s, 4H), 2.08 - 1.94 (t, 4H), 1.22-1.13 (br, 1H), 0.73 0.65 (m, 1H), 0.64 - 0.55 (t, 2H), 0.49–0.42 (t, 1H).

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1530 1,1,1-trifluoro-3,3dimethylbutan-2-yl (3R,4S)-3-(5-{4- amino-5-[(4,4difluoropiperidine- 1- yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate Sy 687.4(2) LC-MS Method 1 retention time =1.91 min LC-MS, Method 2 retention time = 2.47 min 1531 3,3,4,4,4pentafluorobutan-2yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,1f] [1,2,4]triazine- 7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 1 F A R F ^F 695.4(2) 9.39 - 9.17 (m, 1H), 8.99 - 8.86 (t, 1H), 8.75 (dd, /=14.2, 1.8 Hz, 1H), 8.63 - 8.50 (m, 1H), 7.96 - 7.83 (t, 1H), 7.70 - 7.48 (m, 1H), 7.05 (s, 1H), 5.52 - 5.37 (m, 1H), 5.35 (br s, 0.5H), 5.24 (br s, 0.5H), 4.80 - 4.67 (m, 1H ), 4.02 (d, /=4.7 Hz, SA), 3.90 - 3.80 (m, SA), 3.77 - 3.64 (m, SA), 3.36 - 3.23 (m, 1H), 2.64 (br s, 4H), 2.09 -1.91 (m, 4H), 1.41 (brd,/=6.1 Hz, ZN). 1532 2,2,3,3tetrafluorocyclobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[ 2,10[1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F Vv ^f F 675.4(2) 9.30 - 9.18 (m, 1H), 8.95 - 8.87 (m, 1H), 8.79 - 8.73 (m, 1H), 8.56 - 8.50 (m, 1H), 7.91 - 7.86 (m, 1H), 7.62 7.54 (m, 1H), 7.07 - 7.02 (m, 1H), 5.38 - 5.22 (m, 2H), 4.82 - 4.66 (m, 1H), 4.02 (s, 3H), 3.95 - 3.65 (m, 5H), 3.27-3.14 ( m, 2H), 2.92 - 2.75 (m, 2H), 2.73 - 2.57 (m, 4H), 2.10 1.93 (m, 4H).

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1533 3,3,3-trifluoro-2methylpropyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1C[1,2,4]triazin-7yl}- 2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F * [G Mixture of 2 isomers 659.1(2) 9.32 - 9.21 (m, 1H), 8.90 (s, 1H), 8.75 (s, 1H), 8.52 (brt, 7=6.3 Hz, 1H), 7.88 (s, 1H), 7.62-7.51 (m, 1H) , 7.03 (s, 1H), 5.36 - 5.29 (m, 0.5H), 5.24 - 5.18 (m, 0.5H), 4.79 4.61 (m, 1H), 4.22 - 4.06 (m, 3H), 4.01 (s, 3H ), 3.81 (br s, 5H), 3.27 (br t, 7=10.3 Hz, 1H), 2.79 (br s, 2H), 2.63 (br s, 4H), 2.01 (br s, 4H), 1.12 (br d, 7=6.6 Hz, ZN). 1534 1,1,1trifluorobutan-2-yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl} -2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate ί 659.1(1) 9.37 - 9.17 (m, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.57-8.51 (m, 1H), 7.94 - 7.88 (m, 1H), 7.73 - 7.58 (m, 1H), 7.07 (br s, 1H), 5.39 - 5.31 (m, 1H), 5.28 - 5.17 (m, 2H), 4.85 - 4.69 (m, 2H), 4.03 (s, 3H), 3.89 - 3.59 (m, 4H) , 2.72 - 2.58 (m, 4H), 2.02 (br s, 2H), 1.91 - 1.78 (m, 2H), 1.71 (td, 7=15.3, 7.2 Hz, 2H), 0.99 - 0.90 (m, 3H). 1535 propyl (3R,4S)-3(5-{4-amino-5[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)- 4fluoropyrrolidine-1 carboxylate — 591.2 (1) 9.25-9.13 (m, 1H), 8.93 (s, 1H), 8.77 (s, 1H), 8.48 (br d, 7=7.3 Hz, 1H), 7.90 (s, 1H), 7.68 - 7.54 (m, 1H ), 7.06 (s, 1H), 5.36-5.18 (m, 1H), 4.76 - 4.65 (m, 1H), 4.03 (d, 7=1.5 Hz, ZH), 4.01 - 3.94 (m, 2H), 3.83 ( s, 3H), 3.73 - 3.59 (m, 2H), 3.31-3.24 (m, 1H), 2.65 (br s, 4H), 2.06 - 1.96 (m, 4H), 1.64 - 1.56 (m, 2H), 0.91 (brt, 7=7.5 Hz, ZN).

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1536 3,3,4,4,4pentafluorobutan-2yl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,1f] [1,2,4]triazine- 7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate /F A j^F 695.4(2) 9.37 - 9.11 (m, 1H), 8.95 - 8.87 (m, 1H), 8.79 - 8.73 (m, 1H), 8.55 - 8.45 (m, 1H), 7.91 (s, 1H), 7.69 - 7.47 (m, 1H ), 7.08 - 6.99 (m, 1H), 5.49 - 5.37 (m, 1H), 5.36 - 5.30 (m, 0.5H), 5.26 5.19 (m, 0.5H), 4.82 - 4.65 (m, 1H), 4.02 ( s, 3H), 3.88 - 3.63 (m, 6H), 3.38 - 3.31 (m, 1H), 2.73 - 2.55 (m, 4H), 2.08 - 1.91 (m, 4H), 1.46 - 1.35 (m, 3H). 1537 2,2,3,3tetrafluorocyclobutyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,11][1,2,4]triazin-7yl}- 2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate F ad-f F 675.4(2) LC-MS Method 1 retention time = 1.71 min LC-MS Method 2 retention time = 2.18 min 1538 1539 1540 1-cyclopropyl2,2,2-trifluoroethyl (3R,4S)-3-(5-{4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,1f][1,2,4]triazin-7yl} -2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate ]pyrrolo[2,1f][1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 1,1,1trifluorobutan-2-yl (3R,4S)-3-(5- {4amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,1f] [1,2,4]triazin-7yl}-2methoxypyride in-3 amido)-4fluoropyrrolidine-1 carboxylate 671.0 (1) 687.1(1) 659.4(2) LC-MS Method 1 retention time =1.77 min LC-MS Method 2 retention time = 2.31 min 9.21 (br s, 1Н), 8.92 (br s, 1Н), 8.76 (br d, 7=3.6 Hz, 1H), 8.52 (br dd, 7=15.0, 7.6 Hz, 1H), 7.89 (s, 1H) , 7.60 (br s, 1H), 7.05 (br s, 1H), 5.24 (br s, 1H), 5.01 (br d, 7=8.0 Hz, 1H), 4.79 (br s, 1H), 4.02 (s, 3H), 3.99 3.66 (m, 6H), 2.64 (br s, 4H), 2.01 (br s, 4H), 1.04 (br d, 7=5.2 Hz, 9H). 9.34 - 9.17 (m, 1H), 8.95 - 8.90 (m, 1H), 8.79 - 8.73 (m, 1H), 8.58 - 8.49 (m, 1H), 7.94 - 7.87 (m, 1H), 7.71 7.58 (m, 1H), 7.08 - 7.03 (m, 1H), 5.25 - 5.22 (m, 1H), 5.38 - 5.17 (m, 1H), 4.86 - 4.69 (m, 1H), 4.03 (s, 3H), 3.96 - 3.62 ( m, 5H), 3.39 - 3.32 (m, 1H), 2.74 - 2.62 (m, 2H), 2.10 1.93 (m, 4H), 1.88 (br d, 7=2.2 Hz, 1H), 1.77 - 1.65 (m, 1H), 1.01 - 0.89 (m, 3H).

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Connections in the table. 55 was prepared in a manner similar to those detailed in Example 1460, except that 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2 ,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 4 TFA, instead of 5-(4amino-5-(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide. These reactions used additional DIPEA to compensate for 4 equivalents of TFA in the starting material. Examples in table. are single diastereomers unless otherwise noted. If diastereomers were separated either by reverse phase preparative HPLC or by additional chiral SFC as described in Example 1417, they are included as separate data. For each example, two of the following analytical LC-MS injections were used with appropriate stationary phase columns to determine final purity. The method(s) used are indicated in each case. Methods 1-6 are as described in the Preparation Methods section.

Table 55

Example Name R Mass of М ⁺ ion observed in MS (Method) Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or HPLC retention time 1541 1542 5-{4-Amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[2,11][1,2,4]triazine-7mi}-N-[(3R,4S)-4fluoro-1-(3 ,3,3trifluoropropanesul phonyl)pyrrolidi n-3-yl]-2methoxypyride in-3 carboxamide 5-{4-amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo[ 2,11][1,2,4]triazine-7mi}-N-[(3R,4S)-4fluoro-1-(2,2,2trifluoroethanesulfonyl)pyrrolidin-3yl]-2methoxypyride in-3 carboxamide 665.1(1) 651.1(1) 9.32 - 9.16 (m, 1H), 8.92 (d, 7=2.4 Hz, 1H), 8.76 (d, 7=2.1 Hz, 1H), 8.52 (br d, 7=7.3 Hz, 1H), 7.89 (s, 1Н), 7.65-7.51 (m, 1Н), 7.05 (s, 1Н), 5.35 (br d, 7=2.7 Hz, 0.5Н), 5.24 (br s, 0.5Н), 4.85 - 4.74 (m, 1H) , 4.03 (s, 3H), 3.85 - 3.66 (m, 6H), 3.40 - 3.33 (m, 2H), 2.79 - 2.69 (m, 2H), 2.64 (br s, 4H), 2.06 - 1.96 (m, 4H ). 9.37 - 9.21 (m, 1H), 8.93 - 8.90 (m, 1H), 8.76 (s, 1H), 8.53 (br d, 7=7.6 Hz, 1H), 7.90 (s, 1H), 7.67 - 7.54 (m , 1H), 7.28 - 6.99 (m, 1H), 5.38 (br s, 0.5H), 5.27 (br s, 0.5H), 4.82 - 4.69 (m, 1H), 4.66 - 4.57 (m, 2H), 4.03 (s, 3H), 3.90 - 3.70 (m, 6H), 2.65 (br s, 4H), 2.02 (br s, 4H).

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1543 5-{4-amino-5-[(4,4difluoropiperidine1- yl)methyl]pyrrolo} 2,1- f]} 1,2,4]triazin-7nn}-N-[(3R,4S)-4fluoro-1 -(1,1,1 trifluoropropane-2sulfonyl)pyrrole idin-3-yl]-2methoxypyridine-3 carboxamide 665.3(1) 9.34 - 9.14 (m, 1H), 8.95 - 8.89 (m, 1H), 8.78 - 8.74 (m, 1H), 8.58 - 8.50 (m, 1H), 7.92 - 7.86 (m, 1H), 7.67 7.49 (m, 1H), 7.07 - 7.02 (m, 1H), 5.41 - 5.36 (m, 0.5H), 5.31 - 5.25 (m, 0.5H), 4.83 - 4.66 (m, 2H), 4.02 (s, 3H), 3.89 ( t, 7=8.7 Hz, 1H), 3.85 3.71 (m, 4H), 3.40 - 3.35 (m, 1H), 2.64 (br s, 4H), 2.01 (br s, 4H), 1.50 (d, 7=7.2 Hz, ZN). 1544 5-{4-amino-5-[(4,4difluoropiperidin1yl)methyl]pyrrolo} 2,1- f]} 1,2,4]triazin-7nn}-N-[(3R,4S)-4fluoro-1 -(1,1,1 trifluoropropane-2sulfonyl)pyrrole idin-3-yl]-2methoxypyridine-3 carboxamide A 665.1(1) 9.40 - 9.20 (m, 1H), 8.90 (d, 7=2.5Hz, 1H), 8.75 (d, 7=2.2Hz, 1H), 8.60 - 8.54 (m, 1H), 7.87 (s, 1H), 7.63 7.43 (m, 1H), 7.03 (s, 1H), 5.41 5.35 (m, 0.5H), 5.30 - 5.24 (m, 0.5H), 4.82 - 4.64 (m, 2H), 4.01 (s, 3H), 3.92 - 3.78 (m, 6H), 3.41 - 3.35 (m, 1H), 2.73 - 2.72 (m, 1H), 2.62 (br s, 2H), 2.00 (br t, 7=13.8 Hz, 4H), 1.49 (d , 7=7.2 Hz, ZN).

Examples 1545 and 1546: N-((3R,4S)-1-(2-amino-2-(trifluoromethyl)pentanoyl)-4-fluoropyrrolidin-3yl)-5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamide, isomer 1 and isomer 2

A mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3- yl)-2-methoxynicotinamide (40 mg, 0.091 mmol), 2-amino-2-(trifluoromethyl)pentanoic acid (20.23 mg, 0.109 mmol), BOP (50.3 mg, 0.114 mmol) and Hunig's base (47.7 µl, 0.273 mmol ) in DMF (910 μL) was stirred at room temperature for 36 h. The mixture was additionally treated with 2-amino-2-(trifluoromethyl)pentanoic acid (40.5 mg, 0.220 mmol), BOP (100 mg, 0.227 mmol), and Hunig's base ( 100 µl, 0.550 mmol) and stirred at room temperature for 3 h. The crude mixture was purified by reverse phase preparative HPLC (Waters Sunfire C18, 30x150 mm, 5 µm, solvent A = 95% H2O, 5% acetonitrile, 10 mM ammonium acetate, solvent B = 95% acetonitrile, 5% H2O, 10 mM ammonium acetate, 50 ml/min, gradient 0-100% B over 20 min, hold at 100% B for 4 min). The product fractions were combined and concentrated in vacuo to give a white powder (35.4 mg, 64% yield) as a mixture of isomers. Separate isomers were separated using chiral SFC (method description: column = Chiralpak IA, preparative column, 30x250 mm, particle size 5 µm; mobile phase = 40% (0.1% DEA) MeOH in CO2, 150 bar; column temperature = 35°C ; flow rate = 70.0 ml/min for 30 min; UV detection @ 254 nm; injection = 0.5 ml, ~17 mg/ml in 2:1 MeOH:CHCl ₃ (~35 mg purified by serial injection)).

Example 1545: An off-white solid was isolated as the isomer eluted first (9.1 mg, 16% yield).

MS (ERI) m/z 607.3 (M+H)+.

1H NMR (500 MHz, DMSO-06) δ 8.93 (s, 1H), 8.79 (br d, J=13.4 Hz, 1H), 8.59-8.47 (m, 1H), 8.18 (s, 1H), 7.63 (s , 1H), 5.37-5.17 (m, 1H), 4.75-4.36 (m, 2H), 4.18-4.00 (m, 4H), 3.91-3.59 (m, 2H), 3.48-3.34 (m, 1H), 3.34 -3.28 (m, 3H), 1.93-1.84 (m, 1H), 1.65-(td, J=13.1, 4.6 Hz, 1H), 1.51-1.39 (m, 1H), 1.35-1.26 (m, 1H), 0.940.86 (m, 3H).

Example 1546: An off-white solid was isolated as the second eluted isomer (15.2 mg, 27% yield).

MS (ERI) m/z 607.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (d, J=2.3 Hz, 1H), 8.79 (br s, 1H), 8.58-8.46 (m, 1H), 8.18 (s, 1H), 7.63 ( s, 1H), 5.36-5.17 (m, 1H), 4.85-4.54 (m, 2H), 4.05 (s, 3H), 4.02-3.66 (m, 2H), 3.58-3.37 (m, 2H), 2.962. 89 (m, 1H), 2.06-1.89 (m, 1H), 1.68-1.55 (m, 1H), 1.46-1.32 (m, 1H), 1.24 (br s, 1H), 0.93-0.84 (m, 3H) .

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Example 1547: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 (3-hydroxy-3-(trifluoromethyl)cyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

The title compound was prepared in a manner analogous to that described in Example 27. This compound was isolated as a mixture of diastereomers (14.2 mg, 69% yield).

MS (ERI) m/z 606.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (d, J=2.4 Hz, 1H), 8.79 (dd, J=18.0, 2.4 Hz, 1H), 8.50 (d, J=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 6.60 (s, 1H), 5.38-5.32 (m, 0.5H), 5.27-5.21 (m, 0.5H), 4.81-4.60 (m, 1H), 4.05 (d, J=5.2 Hz, 3H), 3.96-3.88 (m, 1H), 3.85-3.66 (m, 2H), 3.42-3.34 (m, 1H), 3.30-3.24 (m, 1H), 3.00- 2.88 (m, 1H), 2.65-2.55 (m, 2H), 2.43-2.34 (m, 2H).

Example 1548: 2,2,2-trifluoroethyl (3R,4S)-3-(5-(4-amino-5-((3,3-difluorocyclobutyl)methyl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-2-(methoxy-d ₃ )nicotinamido)-4-fluoropyrrolidine-1 carboxylate

A mixture of 5-(4-amino-5-((3,3-difluorocyclobutyl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) 4-fluoropyrrolidin-3-yl)-2-(methoxy-d ₃ )nicotinamide, 4 TFA (0.030 g, 0.032 mmol) and Hunig's base (0.039 ml, 0.225 mmol) in DMF (0.5 ml) were treated 2,2,2 -trifluoroethyl chloroformate (7.82 mg, 0.048 mmol). The mixture was stirred at room temperature overnight. The mixture was filtered and purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B=95:5 acetonitrile:water with 10 mM ammonium acetate; gradient = 31-71% B over 20 minutes followed by a 4-minute hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column = XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A = 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B = 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient = 30-70% B over 15 min, then 5 min hold at 100% B; flow rate = 20 ml/min; column temperature = 25°C. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (8.8 mg, 28% yield).

MS (ERI) m/z 606.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.71 (s, 1H), 8.52 (br d, J=7.3 Hz, 1H), 8.09 (s, 1H), 7.23 (br s , 1H), 5.37-5.22 (m, 1H), 4.81-4.68 (m, 3H), 4.26-4.16 (m, 2H), 4.06-3.67 (m, 6H), 3.40-3.31 (m, 2H).

Intermediate 1: 7-bromo-5-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4amine

A mixture of N-((4-amino-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl)methyl)-N,N-diethylethanamine (100 mg, 0.306 mmol), pyrrolidine ( 43.5 mg, 0.611 mmol) and Hunig's base (0.107 ml, 0.611 mmol) in acetonitrile (3 ml) were heated at 100°C for 16 h.

A clear yellow solution formed. The reaction mixture was diluted with EtOAc.

The organic layer was washed with water and dried over MgSO ₄ . The mixture was filtered and concentrated to give 7-bromo-5-(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (65 mg, 0.219 mmol, 72% yield) as a reddish solid.

MS (ERI) m/z 296.1 (M+H)+.

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Intermediate 2: 1-(4-amino-7-bromopyrrolo[2,1-G][1,2,4]triazin-5-yl)ethan-1-one.

A. 1-(4-Aminopyrrolo[2,1-E][1,2,4]triazin-5-yl)ethan-1-one: to a mixture of 4-amino-M-methoxy-Mmethylpyrrolo[2,1- l][1,2,4]triazine-5-carboxamide (100 mg, 0.452 mmol) in tetrahydrofuran (3 ml) was added methylmagnesium bromide (0.226 ml, 0.678 mmol) and the mixture was stirred at room temperature for 16 h and diluted EtOAc. The organic layer was washed with water and dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-40% EtOAc/hexanes to give 1-(4-aminopyrrolo[2,1-H1,2,4]triazin-5-yl)ethan-1-one (42 mg , 0.238 mmol, 53% yield) as a yellow solid.

MS (ERI) m/z 177.3 (M+H)+.

¹ H NMR (400 MHz, CDCI3) δ 8.08-7.94 (m, 1H), 7.57-7.48 (m, 1H), 7.18-7.12 (m, 1H), 2.62 (s, 3H).

B. To a mixture of 1-(4-aminopyrrolo[2,1-L][1,2,4]triazin-5-yl)ethan-1-one (800 mg, 4.54 mmol) in DCM (50 mL) was added NBS (970 mg, 5.45 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc. The organic layer was washed with saturated NaHCO ₃ solution and water, dried over MgSO 4 , filtered and concentrated to give 1-(4-amino-7-bromopyrrolo[2,1£][1,2,4]triazin-5-yl)ethan- 1-one (900 mg, 3.53 mmol, 78% yield) as a white solid.

MS (ERI) m/z 256.8 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.19-8.07 (m, 1H), 7.24-7.19 (m, 1H), 2.63 (s, 3H).

Intermediate 3: 7-bromo-5-(difluoromethyl)pyrrolo[2,1-D][1,2,4]triazine-4-amine

NH ₂ y ^f h-h

Br

A. 4-Amino-7-bromopyrrolo[2,1-G][1,2,4]triazine-5-carbaldehyde: (4-amino-7-bromopyrrolo[2,1-L][1,2,4] triazin-5-yl)methanol (400 mg, 1.646 mmol), Dess-Martin periodinane (838 mg, 1.975 mmol) in CH ₂ Cl ₂ (10 mL) was stirred at room temperature for 2 h. The mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO ₃ , 30% NaS ₂ O ₃ and water. The organics were dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-40% EtOAc/hexanes to give 4-amino-7-bromopyrrolo[2,1-H1,2,4]triazine-5-carbaldehyde (350 mg, 1.452 mmol, 88% yield ) as an off-white solid.

1H NMR (400 MHz, CDCl ₃ ) δ 9.75 (s, 1H), 8.21 (s, 1H), 7.26 (s, 1H).

B. A mixture of 4-amino-7-bromopyrrolo[2,1-£][1,2,4]triazine-5-carbaldehyde (50 mg, 0.207 mmol) and DAST (0.137 ml, 1.037 mmol) in CH ₂ Cl ₂ (2 ml) was stirred at room temperature for 3 days. The mixture was concentrated and diluted with EtOAc. The organic layer was washed with NaHCO ₃ and water. The organics were dried over MgSO ₄ and purified by silica gel chromatography eluting with 40% EtOAc/hexanes to give 7-bromo-5-(difluoromethyl)pyrrolo[2,1-t][1,2,4]triazine-4 -amine (21 mg, 0.080 mmol, 39% yield) as a white solid.

MS (ERI) m/z 264.9 (M+H) ⁺ .

¹ H NMR (400 MHz, CDCl ,) δ 8.19-8.12 (m, 1H), 7.07-6.71 (m, 2H).

Intermediate 4: 7-bromo-5-(difluoromethoxy)pyrrolo[2,1-f][1,2,4]triazine-4-amine

F nh ₂ o-4 _f f ,nV

N D

Br

A. 4-Chloropyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate: a mixture of 4-hydroxypyrrolo[2,1-f][1,2,4]triazin-5- yl 4-methylbenzenesulfonate (2.5 g, 8.19 mmol) (WO 2006007468), POCl ₃ (1.145 ml, 12.28 mmol) and Hunig's base (1.716 ml, 9.83 mmol) in PhCH ₃ (20 ml) was heated at the boil under reflux for 16 hours The reaction mixture was concentrated, cooled to 0°C and diluted with EtOAc. The organic layer was washed with NaHCO ₃ , water and dried over MgSO ₄ . Filtration and concentration gave 4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (2.3 g, 7.10 mmol, 87% yield) as a yellow solid.

1H NMR (400 MHz, CDCI3) δ 8.23-8.09 (m, 1H), 7.85-7.76 (m, 2H), 7.75-7.62 (m, 1H), 7.38-7.31 (m, 2H), 6.86-6.66 (m , 1H), 2.52–2.44 (m, 3H).

B. 7-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate: 4-

- 436 042342 chloropyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (2.2 g, 6.80 mmol), NBS (1.451 g, 8.15 mmol) and TFA (0.052 ml, 0.680 mmol ) in THF was stirred at room temperature for 16 h. The mixture was diluted with EtOAc. The organic layer was washed with saturated NaHCO ₃ solution and water. The organics were dried over MgSO ₄ , filtered and concentrated to give a yellow oil which was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give 7-bromo-4-chloropyrrolo[2,1-f][1,2 ,4]triazin-5-yl 4-methylbenzenesulfonate (2.1 g, 5.22 mmol, 77% yield) as a white solid.

MS (ERI) m/z 403.7 (M+H)+.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30-8.28 (m, 1H), 7.83-7.74 (m, 2H), 7.41-7.35 (m, 2H), 6.93-6.89 (m, 1H), 2.51-2.48 (m, 3H).

C. 4-(Bis(4-methoxybenzyl)amino)-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate: bis(4-methoxybenzyl)amine mixture (153 mg, 0.596 mmol) in tetrahydrofuran (2 ml) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give 4-(bis(4-methoxybenzyl)amino)-7bromopyrrolo [2,1-D][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (100 mg, 0.160 mmol, 32% yield) as a white solid.

MS (ERI) m/z 625.0 (M+H) ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.06-8.04 (m, 1H), 7.71-7.63 (m, 2H), 7.33-7.27 (m, 2H), 7.11-6.97 (m, 4H), 6.87-6.74 ( m, 4H), 6.35-6.30 (m, 1H), 4.77-4.74 (m, 4H), 3.83 (s, 6H), 2.52-2.45 (m, 3H).

D. 4-(Bis(4-methoxybenzyl)amino)-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-ol: mixture of 4-(bis(4methoxybenzyl)amino)-7- bromopyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (250 mg, 0.401 mmol) and 0.5 M sodium methoxide (3.21 ml, 1.604 mmol) in THF (2 ml) were stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give 4-(bis(4-methoxybenzyl)amino)7-bromopyrrolo[2,1-f][1,2,4]triazine-5 -ol (150 mg, 0.320 mmol, 80% yield) as a light yellow solid.

MS (ERI) m/z 468.9 (M+H) ⁺ .

1H NMR (400 MHz, CDCl ₃ ) δ 8.02-7.89 (m, 1H), 7.20-7.12 (m, 4H), 6.96-6.82 (m, 4H), 6.35-6.17 (m, 1H), 4.97-4.81 ( m, 4H), 3.89-3.75 (m, 6H).

E. 7-Bromo-5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine: 4-(bis(4 -methoxybenzyl)amino)-7-bromopyrrolo[2,1-f][1,2,4]triazin-5-ol (130 mg, 0.277 mmol), ethyl 2bromo-2,2-difluoroacetate (141 mg, 0.692 mmol ) and DBU (0.104 mL, 0.692 mmol) in DMF (1 mL) were heated at 70°C for 16 h. The reaction mixture was diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated to give an oil which was purified by silica gel chromatography eluting with 20% EtOAc/hexanes to give 7-bromo-5(difluoromethoxy)-N,N-bis(4 -methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (120 mg, 0.231 mmol, 83% yield) as an off-white solid.

MS (ERI) m/z 520.9 (M+H) ⁺ .

F. 7-Bromo-5-(difluoromethoxy)-N,N-bis(4-methoxybenzyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine mixture (140 mg, 0.270 mmol) in TFA (2 ml) was heated at the boil under reflux for 16 hours the Reaction mixture was concentrated. 5 ml NaHCO ₃ was added to the residue, and the aqueous layer was extracted with EtOAc. The organic layer was washed with water and dried over MgSO ₄ , filtered and concentrated to give 7-bromo-5-(difluoromethoxy)pyrrolo[2,1-f][1,2,4]triazine-4-amine (70 mg, 0.251 mmol , 93% yield) as an off-white solid.

MS (ERI) m/z 278.6 (M+H) ⁺ .

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97-7.81 (m, 1H), 7.32-6.91 (m, 1H), 6.83-6.57 (m, 1H). Intermediate 5: 4-amino-7-bromopyrrolo[2,1-1][1,2,4]triazin-5-yl 4-methylbenzenesulfonate o nh ₂ ο-s"

N A< O h-h

Vg

A mixture of 7-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (140 mg, 0.348 mmol) and ammonium hydroxide (0.135 ml, 3.48 mmol) in dioxane ( 3 ml) was stirred at room temperature for 16 h. The mixture was concentrated to give 4-amino-7-bromopyrrolo[2,11][1,2,4]triazin-5-yl 4-methylbenzenesulfonate (130 mg, 0.339 mmol, 98% yield) as a white solid.

MS (ERI) m/z 382.7 (M+H) ⁺ .

- 437 042342

Example 1549: 5-{4-Amino-5-[(pyrrolidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[(3R,4S )-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1549A: tert-butyl (3R,4S)-3-(5-bromo-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate: mixture of tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1 -carboxylate (220 mg, 1.077 mmol), 5-bromo-2methoxynicotinic acid (250 mg, 1.077 mmol), Hunig's base (0.565 ml, 3.23 mmol) and BOP (572 mg, 1.293 mmol) in DMF (5 ml) was stirred at room temperature for 5 hours. The mixture was diluted with EtOAc. The organic layer was washed with dilute HCl, saturated NaHCO ₃ solution and water. The organic layer was dried over MgSO ₄ , filtered and concentrated to give an oil which was then purified with 50% EtOAc/hexanes to give t-butyl (3R,4S)-3-(5-6pom2-methoxynicotinamido)-4-fluoropyrrolidine-1 -carboxylate (0.39 g, 0.932 mmol, 87% yield) as a solid.

MS (ERI) m/z 440.0, 442.0 (M+Na).

1549B: 5-bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 2 TFA salt: tert-butyl (3R,4S)-3-(5-bromo-2-methoxynicotinamido) mixture )-4-fluoropyrrolidine-1-carboxylate (0.39 g, 0.932 mmol) and TFA (0.718 ml, 9.32 mmol) in CH ₂ Cl ₂ (5 ml) were stirred at room temperature for 2 h. The reaction mixture was concentrated to obtain 5- bromine-N-((3R,4S)-4-fluoropyrrolidin-3-yl)2-methoxynicotinamide, 2 TFA salt (0.39 g, 0.902 mmol, 97% yield) as gray oil.

MS (ERI) m/z 317.9, 319.9 (M+H) ⁺ .

1549S. 5-bromo-N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide: to a mixture of 5-bromo-N-((3R, 4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 2 TFA (2.5 g, 5.78 mmol) in DMF (10 ml) was added 3,3-difluorocyclobutane-1-carboxylic acid (0.945 g, 6.94 mmol), BOP (3.07 g, 6.94 mmol) and Hunig's base (3.03 ml, 17.35 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 20 ml of saturated aqueous NaHCO ₃ . The resulting white precipitate was filtered off and washed with water, dilute HCl and water. The white solid was dried to give 5-bromo-N-((3R,4S)-1-(3,3-difluorocyclobutane-1carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (2.3 g, 5.27 mmol, 91% yield) as a white solid.

MS (ERI) m/z 437.8 (M+H) ⁺ .

1549: mixture of 5-bromo-N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide (25 mg, 0.057 mmol), 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (17.46 mg, 0.069 mmol) and potassium acetate (16.87 mg, 0.172 mmol) in dioxane (2 ml) was degassed and again filled with N ₂ . 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (4.68 mg, 5.73 µmol) was added and the reaction was degassed and refilled with N2. The reaction mixture was heated at 100°C for 6 h. After cooling to room temperature, tribasic potassium phosphate (0.086 ml, 0.172 mmol), 7-bromo-5-(pyrrolidin-1-ylmethyl)pyrrolo[2.1-1] was added [1,2,4]triazine-4amine (16.97 mg, 0.057 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) complex dichloromethane dichloride (4.68 mg, 5.73 µmol), and the reaction was degassed and refilled _N2 . The mixture was then heated for another 6 hours. The reaction was cooled to room temperature, filtered and purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 7% B, 7-47% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-(pyrrolidin-1ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide (20.3 mg, 0.034 mmol, 60% yield) as a white solid.

MS (ERI) m/z 573.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.06-8.84 (m, 1H), 8.84-8.67 (m, 1H), 8.63-8.46 (m, 1H), 8.12-7.96 (m, 1H), 7.36- 7.28 (m, 1H), 5.45-5.13 (m, 1H), 4.97-4.52 (m, 3H), 4.12-4.01 (m, 3H), 3.99-3.04 (m, 9H), 2.89-2.65 (m, 4H ), 2.13-1.95 (m, 2H), 1.95-1.76 (m, 2H).

- 438 042342

Example 1550: 5-[4-Amino-5-({2-azaspiro[3.3]heptan-2-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]N -[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide

1550A. 5-Bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin3-yl)-2-methoxynicotinamide: mixture 5-bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 2 TFA (1 g, 2.314 mmol), (R)-3,3,3-trifluoro-2- hydroxy-2-methylpropanoic acid (0.439 g, 2.78 mmol), Hunig's base (1.212 ml, 6.94 mmol) and BOP (1.228 g, 2.78 mmol) in DMF (10 ml) were stirred at room temperature for 2 h. Water was added to reaction mixture, and the resulting white precipitate was filtered and washed with water. The solid was dried to give 5-bromo-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-ul )2-methoxynicotinamide (0.9 g, 1.964 mmol, 85% yield) as a white solid.

MS (ERI) m/z 459.7 (M+H)+.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 8.62-8.49 (m, 1H), 8.49-8.44 (m, 1H), 8.23-8.16 (m, 1H), 7.17-7.00 (m, 1H), 5.36- 5.12 (m, 1H), 4.72-4.54 (m, 1H), 4.49-4.26 (m, 1H), 4.09-3.66 (m, 5H), 3.62-3.52 (m, 1H), 1.62-1.50 (m, 3H ).

1550B. 5-[4-Amino-5-({2-azaspiro[3.3]heptan-2-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N[( 3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide: prepared by methods described in detail in example 1549.

MS (ERI) (m/z) 621.2 (M+H) ⁺ .

Ή NMR (500 MHz, DMSO-d6) δ 9.03-8.88 (m, 1H), 8.78-8.66 (m, 1H), 8.64-8.43 (m, 1H), 8.12-8.00 (m, 1H), 7.35-7.28 (m, 1H), 5.38-5.16 (m, 1H), 4.76-4.56 (m, 3H), 4.55-4.26 (m, 1H), 4.20-4.09 (m, 2H), 4.09-3.32 (m, 8H) , 2.27-2.08 (m, 4H), 1.84-1.69 (m, 2H), 1.59-1.45 (m, 3H).

Example 1551: 5-(4-amino-5-{[3-(trifluoromethyl)pyrrolidin-1-yl]methyl}pyrrolo[2,1 f][1,2,4]triazin-7-yl)-N- [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1551A. N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrroludin-3-yl)-2methoxy-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide: mixture -trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (440 mg, 0.960 mmol) and 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (293 mg, 1.152 mmol) in dioxane (10 ml) was degassed and refilled with N ₂ . 1,1'Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex was added to the mixture, and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated to give N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl )pyrrolidin-3-yl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (450 mg, 0.891 mmol, 93% yield) in as a brown solid.

MS (ERI) m/z 423.8 (M+H) ⁺ .

1551. A mixture of N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3yl)-2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (25 mg, 0.049 mmol), tribasic potassium phosphate (0.074 ml, 0.148 mmol) and 7-bromo-5-( (3-(trifluoromethyl)pyrrolidin-1yl)methyl)pyrrolo[2,1-1][1,2,4]triazine-4-amine (18.02 mg, 0.049 mmol) in dioxane (2 ml) was degassed and filled again with N ₂ . The complex 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (4.04 mg, 4.95 µmol) was added to the mixture, and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100°C for 16 h, then cooled to room temperature. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 25% B, 25-65% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature:

- 439 042342

25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((3(trifluoromethyl)pyrrolidin-1-yl)methyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -((R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl) -2-methoxynicotinamide (8.9 mg, 0.013 mmol, 27% yield) as a white solid.

MS (ERI) m/z 663.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 8.95-8.83 (m, 1H), 8.80-8.71 (m, 1H), 8.59-8.48 (m, 1H), 7.90-7.82 (m, 1H), 7.26- 7.15 (m, 1H), 7.10-6.93 (m, 1H), 5.38-5.16 (m, 1H), 4.77-4.57 (m, 1H), 4.54-4.26 (m, 1H), 4.07-3.98 (m, 3H ), 3.97-3.01 (m, 6H), 2.87-2.75 (m, 2H), 2.75-2.65 (m, 1H), 2.49-2.40 (m, 1H), 2.17-2.01 (m, 1H), 1.891.73 (m, 1H), 1.61-1.44 (m, 3H).

Example 1552: 5-(4-amino-5-{[3-(trifluoromethyl)azetidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin7-yl)-N-[ (3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoro-pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1552A. N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy-5(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)nicotinamide: 5-6pom-N-((3R,4S)-1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide mixture (1 g, 2.292 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.699 g, 2.75 mmol) and potassium acetate (0.675 g, 6.88 mmol) in dioxane (15 mL) were degassed and refilled with N2. Added adduct PdCl ₂ (dppf) - dichloromethane (0.187 g, 0.229 mmol), and the reaction was degassed and again filled with N ₂ . The mixture was heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc followed by 10% MeOH/EtOAc to give N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl )-2-methoxy-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (0.7 g, 1.448 mmol, 63% yield) as light brown solid.

MS (ERI) m/z 401.9 (M+H) ⁺ .

1552: mixture of N-((3R,4S)-1-(3,3-difluorocyclobutane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)nicotinamide (25 mg, 0.052 mmol), 7-bromo-5-((3(trifluoromethyl)azetidin-1-yl)methyl)pyrrolo[2,1-f][ 1,2,4]triazine-4-amine (21.73 mg, 0.062 mmol) and tribasic potassium phosphate (0.078 mL, 0.155 mmol) in dioxane (2 mL) were degassed with nitrogen flow. 1,1'-Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (4.22 mg, 5.17 µmol) was added and the reaction was degassed and refilled with N2. The mixture was then heated at 100°C for 16 h and cooled to room temperature. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 23% B, 23-63% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((3-(trifluoromethyl)azetidin-1yl)methyl)pyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-N-((3R,4S)-1 -(3,3-difluorocyclobutan-1-carbonyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide (8.5 mg, 0.014 mmol, 26% yield) as a white solid.

MS (ERI) m/z 627.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.98-8.87 (m, 1H), 8.83-8.71 (m, 1H), 8.59-8.38 (m, 1H), 7.94-7.85 (m, 1H), 7.14 -7.03 (m, 1H), 5.47-5.17 (m, 1H), 4.94-4.55 (m, 1H), 4.09-4.00 (m, 3H), 4.01-3.02 (m, 12H), 2.90-2.66 (m, 4H).

- 440 042342

Example 1553: 2,2,2-trifluoroethyl (3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1 ,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate

U' \

A YW

Όlx°/

N OMe/V

F F

1553A. 2,2,2-Trifluoroethyl (3R,4S)-3-(5-bromo-2-methoxynicotinamido)-4-fluoropyrrolidine-1carboxylate: 5-bromo-N-((3R,4S)-4-fluoropyrrolidine-3 mixture -yl)-2-methoxynicotinamide, 2 TFA (250 mg, 0.46 mmol), 2,2,2-trifluoroethyl carbonochloridate (113 mg, 0.694 mmol), Hunig's base (0.101 ml, 0.578 mmol) in DMF (5 ml) were stirred at room temperature for 24 hours. The mixture was then diluted with water. The resulting precipitate was filtered and washed with water. The mixture was then dried to give a solid which was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give 2,2,2-trifluoroethyl (3R,4S)-3-(5-6pom-2methoxynicotinamido)- 4-Fluoropyrrolidine-1-carboxylate (250 mg, 0.563 mmol, 97% yield) as an off-white solid.

MS (ERI) m/z 443.8 (M+H)+.

1553b. 2,2,2-Trifluoroethyl (3S,4R)-3-fluoro-4-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)nicotinamido)pyrrolidine -1-carboxylate: 2,2,2-trifluoroethyl (3R,4S)-3-(5-6pom-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate mixture (250 mg, 0.563 mmol), 4,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (172 mg, 0.675 mmol) and potassium acetate (166 mg, 1.689 mmol) in dioxane ( 5 ml) was degassed and refilled with N ₂ . PdCl ₂ adduct (dppf-dichloromethane (46.0 mg, 0.056 mmol)) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100°C for 16 h. The mixture was cooled to room temperature, diluted with EtOAc and washed with water. dried over MgSO ₄ , filtered and concentrated The residue was purified by silica gel chromatography eluting with EtOAc to 10% MeOH/EtOAc to give 2,2,2-trifluoroethyl (3S,4R)-3fluoro-4-(2-methoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamido)pyrrolidine-1-carboxylate as light brown solid (200 mg, 0.407 mmol, 73% yield).

MS (ERI) m/z 409.9 (M+H) ⁺ .

1553: mixture of 2,2,2-trifluoroethyl (3S,4R)-3-fluoro-4-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) nicotinamido)pyrrolidin-1-carboxylate (30 mg, 0.061 mmol), 7-bromo-5-((4,4difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin 4-amine (21.14 mg, 0.061 mmol) and tribasic potassium phosphate (0.092 mL, 0.183 mmol) in dioxane (2 mL) were degassed and refilled with N ₂ . 1,1'-Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (4.99 mg, 6.11 µmol) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100° C. for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 22% B, 22-52% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 2,2,2-trifluoroethyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidin-1yl)methyl )pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1 carboxylate as an off-white solid (17.2 mg, 0.0272 mmol, 45% exit).

MS (ERI) m/z 631.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.06-8.86 (m, 1H), 8.78-8.66 (m, 1H), 8.60-8.42 (m, 1H), 8.19-8.04 (m, 1H), 7.33- 7.23 (m, 1H), 5.48-5.13 (m, 1H), 4.87-4.64 (m, 3H), 4.15-4.01 (m, 3H), 3.99-3.19 (m, 10H), 2.35-1.98 (m, 4H ).

Example 1554: 5-{4-Amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R, 4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide

1554A: tert-butyl (3R,4S)-3-(5-bromo-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate: mixture of tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine-1 -carboxylate (220 mg, 1.077 mmol), 5-bromo-2-methoxynicotinic acid (250 mg, 1.077 mmol), Hunig's base (0.565 ml, 3.23 mmol) and BOP (572 mg, 1.293 mmol) in DMF (5 ml) was stirred at room temperature for 5 hours. The reaction mixture was diluted with EtOAc. The organic layer was washed with dilute HCl, saturated NaHCO ₃ solution and water. The mixture was then dried over MgSO ₄ , filtered and concentrated to give an oil which was purified with 50% EtOAc/hexanes to give t-butyl (3R,4S)-3-(5-6pom-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate ( 0.39 g, 0.932 mmol, 87% yield) as a solid.

MS (ERI) m/z 440.0, 442.0 (M+Na).

1554B: tert-butyl (3R,4S)-3-(5-(4-amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate: mixture of tert-butyl (3R,4S)-3-(5-6pom-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (150 mg, 0.359 mmol), 4 ,4,4',4',5,5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (109 mg, 0.430 mmol) and potassium acetate (106 mg, 1.076 mmol) in dioxane (5 ml) was degassed and refilled with N ₂ . 1,1'Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (29.3 mg, 0.036 mmol) was added and the reaction was degassed and refilled with N2. The mixture was heated at 100°C for 6 h. After cooling to room temperature, tribasic potassium phosphate (0.538 ml, 1.076 mmol), 5-(azetidin-1ylmethyl)-7-bromopyrrolo[2,1-£][1,2 ,4]triazine-4-amine (101 mg, 0.359 mmol) and 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (29.3 mg, 0.036 mmol), and the reaction was degassed and refilled with N2. The mixture was heated for 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ , filtered and concentrated to give a brown solid which was purified by silica gel chromatography eluting with 50% EtOAc in hexanes to give t-butyl (3R,4S)-3-(5-(4- amino-5-(azetidin-1-ylmethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (150 mg, 0.277 mmol, 77% yield) as a white solid.

MS (ERI) m/z 541.1 (M+H).

1554C: 5-(4-Amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidine -3-yl)-2-methoxynicotinamide, 3 TFA salt: mixture of tert-butyl (3R,4S)-3-(5-(4-amino-5(azetidin-1-ylmethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1 carboxylate (150 mg, 0.277 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 1 h. The reaction mixture was concentrated to give 5-(4-amino-5-(azetidin-1ylmethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)- 4-Fluoropyrrolidin-3-yl)-2methoxynicotinamide, 3 TFA (150 mg, 0.192 mmol, 69% yield) as a brown solid.

MS (ERI) m/z 441.0 (M+H) ⁺ .

1554: mixture of 5-(4-amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)- 4fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 3 TFA (25 mg, 0.037 mmol), (R)-3,3,3-trifluoro-2hydroxy-2-methylpropanoic acid (8.55 mg, 0.054 mmol), Hunig's bases ( 0.024 ml, 0.135 mmol) and BOP (23.93 mg, 0.054 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mmx19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 19% B, 19-59% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-N-((3R,4S)-4-fluoro-1 ((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (8.4 mg , 0.014 mmol, 32% yield) as a white solid.

MS (ERI) m/z 581.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.03-8.87 (m, 1H), 8.83-8.64 (m, 1H), 8.61-8.43 (m, 1H), 8.00-7.84 (m, 1H), 7.30- 6.89 (m, 2H), 5.45-5.10 (m, 1H), 4.81-4.57 (m, 1H), 4.55-4.26 (m, 1H), 4.09-3.47 (m, 6H), 3.47-3.01 (m, 6H ), 2.19-1.95 (m, 2H), 1.66-1.45 (m, 3H).

Example 1555: 2,2,2-trifluoroethyl (3R,4S)-3-(5-{4-amino-5-[(azetidin-1-yl)methyl]πirrolo[2,1f] [ 1,2,4 ]triazin-7-yl} -2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate

A mixture of 5-(4-amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin- 3-yl)-2-methoxynicotinamide, 3 TFA salt (25 mg, 0.032 mmol), 2,2,2-trifluoroethyl car

- 442 042342 bonochloridate (11.07 mg, 0.068 mmol) and Hunig's base (9.91 µl, 0.057 mmol) in DMF (0.5 ml) were stirred at room temperature for 24 h. The mixture was concentrated. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 26% B, 26-66% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 2,2,2-trifluoroethyl (3R,4S)-3-(5-(4amino-5-(azetidin-1-ylmethyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4fluoropyrrolidine-1-carboxylate (3.3 mg, 5.32 µmol, 9% yield) as a white solid.

MS (ERI) m/z 567.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.04-8.82 (m, 1H), 8.82-8.70 (m, 1H), 8.60-8.35 (m, 1H), 7.92-7.83 (m, 1H), 7.08- 6.86 (m, 1H), 5.46-5.12 (m, 1H), 4.92-4.54 (m, 3H), 4.10-3.97 (m, 3H), 3.96-3.53 (m, 6H), 3.28-3.04 (m, 4H ), 2.13–2.00 (m, 2H).

Example 1556: 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide

1556A: tert-Butyl (3S,4R)-3-fluoro-4-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)nicotinamido)pyrrolidine-1 -carboxylate: tert-butyl (3R,4S)-3-(5-6pom-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate mixture (350 mg, 0.837 mmol), 4,4,4',4',5, 5,5',5'octamethyl-2,2'-bi(1,3,2-dioxaborolane) (255 mg, 1.004 mmol) and potassium acetate (246 mg, 2.51 mmol) in dioxane (15 ml) were degassed and again filled with N ₂ . 1,1'Bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride complex (68.3 mg, 0.084 mmol) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water and dried over MgSO ₄ , filtered and concentrated to give tert-butyl (3S,4R)-3-fluoro-4-(2-methoxy-5(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)nicotinamido)pyrrolidine-1-carboxylate (320 mg, 0.688 mmol, 82% yield) as a brown solid.

MS (ERI) m/z 327.7 (M+H)+ (boronic acid ester was hydrolyzed during LCMS).

1556B: tert-butyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1 f] [ 1,2,4 ]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate: a mixture of 7-bromo-5-((4,4difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine (238 mg, 0.688 mmol), tert-butyl (3S,4R)-3-fluoro-4-(2-methoxy-5-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)nicotinamido)pyrrolidine1-carboxylate (320 mg, 0.688 mmol) and tribasic potassium phosphate (1.032 mL, 2.063 mmol) in dioxane (10 mL) were degassed and refilled with N ₂ . 1,1'-Bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (56.2 mg, 0.069 mmol) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100° C. for 16 hours. The mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 50% to 100% EtOAc/hexanes to give t-butyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidine- 1yl)methyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1carboxylate (140 mg, 0.232 mmol, 34% yield) as off-white solid.

MS (ERI) m/z 605.2 (M+H) ⁺ .

1556C: 5 - (4-amino-5 - ((4,4-difluoropiperidin-1 -yl) methyl) pyrrolo [2,1-f] [1,2,4] triazin-7-yl) -N (( 3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 3 TFA salt: tert-butyl mixture (3R,4S)-3-(5-(4amino-5-((4,4-difluoropiperidine- 1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate (140 mg, 0.232 mmol) and TFA (178 µl , 2.315 mmol) was stirred at room temperature for 1 h. The mixture was then concentrated to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-N-((3R,4S)4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 3 TFA salt (170 mg, 0.201 mmol, 87% yield) as brown solid.

MS (ERI) m/z 505.0 (M+H) ⁺ .

1556: mixture of 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N( (3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide, 3 TFA (25 mg, 0.030 mmol), 3.3

- 443 042342 bis(trifluoromethyl)-3-hydroxypropionic acid (6.68 mg, 0.030 mmol), Hunig base (0.015 ml, 0.089 mmol) and BOP (15.67 mg, 0.035 mmol) in DMF (1 ml) was stirred at room temperature for 2 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 minute hold at 16% B, 16-56% B over 23 minutes, then 6 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4] triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(4,4,4-trifluoro-3-hydroxy-3(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2- methoxynicotinamide (14.5 mg, 0.020 mmol, 69% yield) as a white solid.

MS (ERI) m/z 713.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.98-8.87 (m, 2H), 8.82-8.69 (m, 1H), 8.65-8.49 (m, 1H), 8.05-7.94 (m, 1H), 7.27 -7.22 (m, 2H), 5.51-5.20 (m, 1H), 5.02-4.61 (m, 1H), 4.27-3.26 (m, 17H), 3.09 -3.05 (m, 2H).

Example 1557: 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[ (3R,4S)-1-[(1 S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3 carboxamide

5-(4-Amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1(2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (18.5 mg, 0.032 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral AD, 250 mm x 30 mm, particles 5 µm; mobile phase 60% CO2, 40% IPA with 0.1% DEA; flow rate: 100 ml/min. Fraction collection was triggered by MC and UV signals. Peaks eluted first were combined and dried to give 5-(4-amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1f][1,2,4]triazin-7- yl)-N-((3R,4S)-1-((S)-2,2-difluorocyclopropane-1-carbonyl)-4-fluoro-pyrrolidin-3-yl)-2methoxynicotinamide (5.6 mg, 29.1%) as white solid.

MS (ERI) m/z 581.4 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 8.99-8.80 (m, 2H), 8.79-8.69 (m, 1H), 8.62-8.44 (m, 1H), 7.93-7.83 (m, 1H), 7.15- 6.99 (m, 1H), 5.50-5.12 (m, 1H), 4.94-4.59 (m, 1H) 4.35-3.14 (m, 12H), 3.12-2.93 (m, 1H), 2.08-1.70 (m, 2H ).

Example 1558: 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[ (3R,4S)-1-[(1R)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3carboxamide

5-(4-Amino-5-((3,3-difluoroazetidin-1-yl)methyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1(2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (18.5 mg, 0.032 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral AD, 250 mm x 30 mm, particles 5 µm; mobile phase 60% CO2, 40% IPA with 0.1% DEA; flow rate: 100 ml/min. Fraction collection was triggered by MC and UV signals. The peaks eluted second were combined and dried to give 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1f][1,2,4]triazin-7- yl}-N-[(3R,4S)-1-[(1R)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2methoxypyridine-3-carboxamide (5.9 mg, 31.2%) as white solid. The absolute stereochemistry with cyclopropane is unknown.

MS (ERI) m/z 581.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.02-8.86 (m, 1H), 8.85-8.70 (m, 1H), 8.63-8.43 (m, 1H), 7.96-7.85 (m, 1H), 7.15 -6.95 (m, 1H), 5.49-5.23 (m, 1H), 4.96-4.60 (m, 1H), 4.23-3.56 (m, 11H), 3.55-3.40 (m, 1H), 3.39-3.25 (m, 1H), 3.06-2.82 (m, 1H), 2.05-1.77 (m, 2H).

- 444 042342

Example 1559: 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-1-[(1S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyrudin-3carboxamide

5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1 (2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (27.5 mmol, 0.045 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral AJ, 250 mm x 30 mm, particles 5 µm; mobile phase 80% CO ₂ , 20% MeOH with 0.1% DEA; flow rate: 100 ml/min. Fraction collection was initiated by MS and UV signals. Peaks eluted first were combined and dried to give 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]truazine-7- yl}-N-[(3R,4S)-1-[(1 S)-2,2-difluorocyclopropanecarbonyl]-4fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide (9.2 mg, 32.2%) as white solid.

MS (ERI) m/z 609.3 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 9.38-9.10 (m, 1H), 8.95-8.86 (m, 1H), 8.79-8.70 (m, 1H), 8.62-8.46 (m, 1H), 7.94-7.81 (m, 1H), 7.72-7.40 (m, 1H), 7.09-6.97 (m, 1H), 5.45-5.18 (m, 1H), 4.94-4.62 (m, 1H), 4.33-4.10 (m, 1H) , 4.07-3.98 (m, 3H), 3.98-3.89 (m, 1H), 3.89-3.55 (m, 3H), 3.32-3.12 (m, 1H), 3.11-2.95 (m, 1H), 2.732.55 ( m, 4H), 2.10-1.75 (m, 6H).

Example 1560: 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-1-[(1 R)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3 carboxamide

5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1 (2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide (27.5 mmol, 0.045 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral AJ, 250 mm x 30 mm, particles 5 µm; mobile phase 80% CO2, 20% MeOH with 0.1% DEA; flow rate: 100 ml/min. Fraction collection was initiated by MS and UV signals. The peaks eluted second were combined and dried to give 5-{4-amino-5-[(4,4-difluoropiperidin-1ul)methyl]nirrolo[2,1-f][1,2,4]truazine-7- yl}-N-[(3R,4S)-1-[(1R)-2,2-difluorocyclopropanecarbonyl]-4fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide (9.2 mg, 33.1%) as white solid.

MS (ERI) m/z 609.4 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.42-9.06 (m, 1H), 8.97-8.88 (m, 1H), 8.85-8.72 (m, 1H), 8.62-8.47 (m, 1H), 7.94- 7.85 (m, 1H), 7.79-7.46 (m, 1H), 7.12-6.97 (m, 1H), 5.45-5.22 (m, 1H), 4.90-4.64 (m, 1H), 4.14-3.99 (m, 4H ), 3.94-3.84 (m, 1H), 3.84-3.78 (m, 2H), 3.78-3.59 (m, 1H), 3.06-2.84 (m, 1H), 3.30-3.16 (m, 1H), 2.722.60 (m, 4H), 2.09-1.82 (m, 6H).

Example 1561: tert-butyl (3R,4S)-3-(5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2.1P][1,2,4 ]triazin-7-yl}-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate

1561A: tert-butyl (3R,4S)-3-(5-bromo-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: tert-butyl (3R,4S)-3-amino-4 mixture -fluoropyrrolidine-1-carboxylate (324 mg, 1.588 mmol), 5-bromo-3-445 042342 fluoro-2-methylbenzoic acid (370 mg, 1.588 mmol), Hunig's base (832 µl, 4.76 mmol) and BOP (843 mg , 1.905 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The mixture was then diluted with EtOAc. The organic layer was washed with dilute HCl, saturated NaHCO ₃ solution and water, dried over MgSO ₄ , filtered and concentrated to give an oil. The mixture was then purified by silica gel chromatography eluting with 0-30% EtOAc/hexanes to give tert-butyl (3R,4S)-3-(5-bromo-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1 -carboxylate (530 mg, 1.264 mmol, 80% yield) as a white solid.

MS (ERI) m/z 442.9 (M+H)+.

1H NMR (400 MHz, chloroform-d) δ 7.38-7.29 (m, 2H), 6.27-5.94 (m, 1H), 5.29-5.05 (m, 1H), 4.89-4.56 (m, 1H), 4.10-3.93 (m, 1H), 3.89-3.52 (m, 2H), 3.28-3.13 (m, 1H), 2.34-2.26 (m, 3H), 1.50 (s, 9H).

1561: mixture of tert-butyl (3R,4S)-3-(5-bromo-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (100 mg, 0.239 mmol), potassium acetate (70.2 mg, 0.716 mmol) , 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi(1,3,2-dioxaborolane) (72.7 mg, 0.286 mmol) in dioxane (3 ml) degassed and again filled with N ₂ . 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (19.05 mg, 0.024 mmol) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100°C for 16 h. The reaction mixture was cooled to room temperature, and tribasic potassium phosphate (0.358 mL, 0.716 mmol), 7-bromo-5-((3,3-difluoroazetidin-1-yl)methyl )pyrrolo[2,1-1][1,2,4]triazine-4-amine (76 mg, 0.239 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) complex dichloromethane dichloride (19.05 mg , 0.024 mmol). The reaction mixture was degassed and again filled with N ₂ . After heating to reflux for 16 h, the reaction mixture was cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to give t-butyl (3R,4S)-3-(5-(4-amino-5-((3,3-difluoroazetidin-1yl) methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1 carboxylate (55 mg, 0.095 mmol, 40% yield) as a brown solid.

MS (ERI) m/z 578.2 (M+H) ⁺ .

mg of the material obtained above was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 33% B, 33-73% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give tert-butyl (3R,4S)-3-(5-(4-amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo [2,11][1,2,4]triazin-7-yl)-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (9.4 mg, 93% yield) as a white solid.

MS (ERI) m/z 578.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.84-8.68 (m, 1H), 8.13-8.04 (m, 1H), 7.98-7.89 (m, 1H), 7.87-7.72 (m, 1H), 7.19- 7.03 (m, 1H), 5.36-5.15 (m, 1H), 4.71-4.43 (m, 1H), 4.06-3.96 (m, 2H), 3.78-3.13 (m, 8H), 2.31-2.23 (m, 3H ), 1.49-1.39 (m, 9H).

Example 1562: 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[ (3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide

1562A: 5-(4-Amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro -N((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA salt: mixture of tert-butyl (3R,4S)-3-(5-(4-amino5-((3, 3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-3-fluoro-2-methylbenzamido)-4fluoropyrrolidine-1-carboxylate (45 mg, 0.078 mmol) and TFA (0.1 ml, 1.298 mmol) in CH ₂ Cl ₂ (2 ml) were stirred at room temperature for 1 h. The mixture was concentrated to give 5-(4-amino5-((3,3-difluoroazetidine-1 -yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-N-((3R,4S)-4fluoropyrrolidin-3-yl)-2-methylbenzamide , 2 TFA (45 mg, 0.064 mmol, 82% yield) as a brown solid.

MS (ERI) m/z 478.1 (M+H) ⁺ .

1562: mixture of 5-(4-amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3 fluorine -N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA (15 mg, 0.021 mmol), 2,2difluorocyclobutane-1-carboxylic acid (2.89 mg, 0.021 mmol), bases Hunig (0.013 ml, 0.076 mmol) and BOP (13.46 mg, 0.030 mmol) in DMF (0.5 ml) were stirred at room temperature for

- 446 042342 2 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 20% B, 20-60% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-N((3R,4S)-1-(3,3-difluorocyclobutαn-1-carbonyl)-4-fluoropyrrolidin-3-yl)-3-fluoro-2-methylbenzamide (10.2 mg , 0.017 mmol, 81% yield) as a white solid.

MS (ERI) m/z 596.2 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.89-8.72 (m, 1H), 8.13-8.03 (m, 1H), 8.01-7.90 (m, 1H), 7.90-7.80 (m, 1H), 7.18-7.08 (m, 1H), 5.43-5.19 (m, 1H), 4.82-4.46 (m, 1H), 4.13-3.98 (m, 2H), 3.96-3.05 (m, 9H), 2.94-2.67 (m, 4H) , 2.33-2.22 (m, 3H).

Example 1563: 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-3fluoro- N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide

This compound was prepared by the methods detailed in Example 1562.

MS (ERI) m/z 618.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 8.85-8.69 (m, 1H), 8.14-8.05 (m, 1H), 8.00-7.90 (m, 1H), 7.89-7.79 (m, 1H), 7.20- 7.12 (m, 1H), 7.10-7.02 (m, 1H), 5.39-5.17 (m, 1H), 4.70-4.52 (m, 1H), 4.46-4.22 (m, 1H), 4.11-3.98 (m, 2H ), 3.98-3.27 (m, 6H), 3.20-3.11 (m, 1H), 2.33-2.24 (m, 3H), 1.60-1.48 (m, 3H).

Example 1564: 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[ (3R,4S)-1-(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide

^H2N v/1 <4 kJ

F

This compound was prepared by the methods detailed in Example 1562.

MS (ERI) m/z 582.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.95-8.72 (m, 1H), 8.14-8.03 (m, 1H), 8.00-7.91 (m, 1H), 7.90-7.80 (m, 1H), 7.24 -7.08 (m, 1H), 5.49-5.17 (m, 1H), 4.88-4.51 (m, 1H), 4.36-4.07 (m, 1H), 4.07-3.97 (m, 2H), 3.97-3.24 (m, 7H), 3.14-2.85 (m, 1H), 2.33-2.23 (m, 3H), 2.05-1.76 (m, 2H).

Example 1565: 5-{4-amino-5-[(1Z)-1-(methoxyimino)ethyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N[(3R ,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide

Meo

A mixture of 5-(5-acetyl-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R )-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (15 mg, 0.027 mmol) and O-methylhydroxylamine (6.38 mg, 0.136 mmol) in MeOH (0.32 ml) stirred at room temperature for 16 h. The mixture was then concentrated. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 21% B, 21-61% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was triggered by MC and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((Z)-1-447 042342 (methoxyimino)ethyl)pyrrolo[2,1-f][1,2 4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)- 2-methoxynicotinamide (7 mg, 0.012 mmol, 44% yield) as a white solid.

MS (ERI) m/z 583.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.63-9.48 (m, 1H), 9.03-8.91 (m, 1H), 8.82-8.66 (m, 1H), 8.58-8.44 (m, 1H), 8.18 -8.06 (m, 1H), 8.04-7.92 (m, 1H), 7.62-7.48 (m, 1H), 5.40-5.11 (m, 1H), 4.80-4.57 (m, 1H), 4.55-4.20 (m, 1H), 4.10-4.00 (m, 3H), 3.99-3.92 (m, 3H), 3.92-3.12 (m, 3H), 2.42-2.31 (m, 3H), 1.62-1.48 (m, 3H).

Example 1566: 5-{4-Amino-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1566A: 5-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(3,3-difluorocyclobutane1 -carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide: a mixture of 5-(4-aminopyrrolo[2,1-

f] [ 1,2,4]triazin-7 -yl)-N-((3R,4S)-1 -(3,3-difluorocyclobutane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide ( 50 mg, 0.102 mmol) and NBS (21.82 mg, 0.123 mmol) in DCM (2 mL) were stirred at room temperature for 2 h. The mixture was then diluted with water and the aqueous layer was extracted with EtOAc. The organic layer was washed with NaHCO3 and water, dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography eluting with 100% EtOAc to 10% MeOH/EtOAc to give 5-(4-amino-5-bromopyrrolo[2, 1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2- methoxynicotinamide (20 mg, 0.035 mmol, 34% yield) as the target compound.

MS (ERI) m/z 570.0 (M+H) ⁺ .

1566: mixture of cyclopropylboronic acid (18.14 mg, 0.211 mmol), 5-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) -1-(3,3-difluorocyclobutan-1-carbonyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide (20 mg, 0.035 mmol) and tribasic potassium phosphate (0.070 ml, 0.141 mmol) in dioxane (2 ml) were degassed and filled N2 again. To this mixture was added a complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (5.75 mg, 7.04 µmol), and the reaction was degassed and refilled with N2. The mixture was heated at 100° C. for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 24% B, 24-64% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S )-1-(3,3-Difluorocyclobutan-1-carbonyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide (2.2 mg, 3.63 µmol, 10% yield) as a white solid.

MS (ERI) m/z 530.1 (M+H) ⁺ .

Ή NMR (500 MHz, DMSO-d6) δ 8.98-8.89 (m, 1H), 8.84-8.67 (m, 1H), 8.53-8.41 (m, 1H), 7.92-7.79 (m, 1H), 6.93-6.73 (m, 1H), 5.54-5.14 (m, 1H), 4.93-4.52 (m, 1H), 4.08-3.99 (m, 3H), 3.99-2.97 (m, 5H), 2.90-2.71 (m, 4H) , 2.34-2.21 (m, 1H), 1.03-0.92 (m, 2H), 0.78-0.63 (m, 2H).

Example 1567: 5-{4-amino-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1 [( 2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1567A: 5-(4-Amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(( R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide: 5-(4aminopyrrolo[2,1-f][1,2,4]triazine-7 mixture -yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (230 mg, 0.450 mmol) and NBS (96 mg, 0.540 mmol) in tetrahydrofuran (10 mL) were stirred at room temperature for 2 h. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with NaHCO ₃ , water and dried over MgSO ₄ . After filtration, the filtrate was concentrated and purified by silica gel chromatography eluting with 100% EtOAc to 10% MeOH/EtOAc to give 5-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine- 7-yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide ( 200 mg, 0.339 mmol, 75% yield) as

- 448 042342 target compound.

MS (ERI) m/z 591.9 (M+H)+.

1567: mixture of tricyclohexylphosphine (1.188 mg, 4.23 µmol), cyclopropylboronic acid (18.19 mg, 0.212 mmol) and 5-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazine-7- yl)-N-((3R,4S)-4-fluoro-1-((R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (25 mg, 0.042 mmol) in dioxane (2 mL) was degassed and refilled with N2. Pd(OAc)2 (0.475 mg, 2.117 µmol) was added and the reaction was degassed and refilled with N2. The mixture was heated at 100° C. for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 11% B, 11-51% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was triggered by MC and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-4-fluoro-1-((R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (13.4 mg, 0.023 mmol, 54% yield ) as a white solid.

MS (ERI) m/z 552.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 8.95-8.89 (m, 1H), 8.80-8.68 (m, 1H), 8.58-8.45 (m, 1H), 7.97-7.89 (m, 1H), 6.96- 6.89 (m, 1H), 5.38-5.17 (m, 1H), 4.78-4.58 (m, 1H), 4.46 (br s, 1H), 4.09-3.98 (m, 3H), 3.98-3.28 (m, 3H) , 2.32-2.17 (m, 1H), 1.57-1.45 (m, 3H), 1.03-0.95 (m, 2H), 0.81-0.63 (m, 2H).

Example 1568: 5-[4-amino-5-(5-cyanopyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S )-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide

A mixture of (5-cyanopyridin-3-yl)boronic acid (6.26 mg, 0.042 mmol), 5-(4-amino-5-bromopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N -((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (25 mg, 0.042 mmol) and Na ₂ CO ₃ (0.064 mL, 0.127 mmol) in dioxane (2 mL) were degassed and refilled with N2. Tetrakis(triphenylphosphine)palladium (0) (4.89 mg, 4.23 µmol) was added and the reaction was degassed and refilled with N ₂ . The mixture was heated at 100° C. for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 15% B, 15-55% B over 25 min, then 7 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was triggered by UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-(5-cyanopyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-7yl )-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxynicotinamide (5.1 mg, 8.19 µmol, 19% yield) as a white solid.

MS (ERI) m/z 614.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.05-8.93 (m, 3H), 8.90-8.80 (m, 1H), 8.63-8.48 (m, 1H), 8.44-8.37 (m, 1H), 8.18- 8.08 (m, 1H), 7.51-7.40 (m, 1H), 7.13-7.01 (m, 1H), 5.43-5.14 (m, 1H), 4.83-4.55 (m, 1H), 4.55-4.23 (m, 1H ), 4.13-4.02 (m, 3H), 4.02-3.11 (m, 3H), 1.61-1.50 (m, 3H).

Example 1569: 5-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[ (2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide

1569A: 5-(4-Amino-5-iodopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -(( R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide: 5-(4aminopyrrolo[2,1-f][1,2,4]triazine-7 mixture -yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (70 mg, 0.137 mmol) and NIS (30.8 mg, 0.137 mmol) in tetrahydrofuran (1 mL) were stirred at room temperature for 2 h. The mixture was then diluted with water and extracted with EtOAc. The organic layer was washed with NaHCO ₃ , water and dried over MgSO ₄ . The filtrate was concentrated and purified by silica gel chromatography eluting with 100% EtOAc to 10% MeOH/EtOAc to give 5-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazine- 7- 449 042342 yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)- 2 methoxynicotinamide (75 mg, 0.118 mmol, 86% yield) as the title compound.

MS (ERI) m/z 638.0 (M+H)+.

1569: mixture of 5-(4-amino-5-iodopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -( (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (30 mg, 0.047 mmol) and dicyanozinc (11.05 mg, 0.094 mmol) in N,N-dimethylformamide (1 ml) was well degassed with vacuum and nitrogen (3x). Tris(dibenzylideneacetone)dipalladium (0) (4.31 mg, 4.71 µmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (6.89 mg, 9.41 µmol) and zinc (0.923 mg, 0.014 mmol) were added to the mixture. . The yellow heterogeneous solution was degassed (3x), immersed in an oil bath at 150° C. and stirred for 5 hours. The reaction mixture was concentrated. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 14% B, 14-54% B over 22 minutes, then 6 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-cyanopyrrolo[2,1f][1,2,4]triazin-7-yl)-N-((3R,4S )-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (3.8 mg, 6.43 µmol, 14% yield) as white solid.

MS (ERI) m/z 537.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.92-8.86 (m, 1H), 8.77-8.71 (m, 1H), 8.61-8.46 (m, 1H), 8.25-8.14 (m, 1H), 7.78-7.70 (m, 1H), 5.39-5.19 (m, 1H), 4.79-4.59 (m, 1H), 4.55-4.25 (m, 1H), 4.15-4.02 (m, 3H), 4.01-3.31 (m, 3H) , 3.22-3.13 (m, 1H), 1.63-1.48 (m, 3H).

Example 1570: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)4-fluoro -N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxybenzamide

1570A: tert-butyl (3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)-4-fluoropyrrolidine-1-carboxylate: 5-bromo-4-fluoro-2-methoxybenzoic acid mixture (1 g, 4.02 mmol), tert-butyl (3R,4S)-3amino-4-fluoropyrrolidine-1-carboxylate (0.820 g, 4.02 mmol), Hunig's base (2.104 ml, 12.05 mmol) and BOP (2.131 g, 4.82 mmol) in DMF (10 ml) was stirred at room temperature for 2 hours. Water was added and the resulting white precipitate was filtered and washed with water. The solid was dried to give tert-butyl (3R,4S)-3-(5-bromo-4-fluoro-2-methoxybenzamido)-4fluoropyrrolidine-1-carboxylate (1 g, 2.297 mmol, 57% yield) as a white solid substances.

MS (ERI) m/z 459.7(M+H) ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.44-8.24 (m, 1H), 8.10-7.82 (m, 1H), 7.43-7.28 (m, 1H), 5.36-5.09 (m, 1H), 4.78- 4.43 (m, 1H), 4.03-3.87 (m, 3H), 3.79-3.07 (m, 4H), 1.51-1.35 (m, 9H).

1570B: tert-butyl (3S,4R)-3-fluoro-4-(4-fluoro-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzamido )pyrrolidine-1-carboxylate: a mixture of tert-butyl (3R,4S)-3-(5-bromo-4-fluoro-2methoxybenzamido)-4-fluoropyrrolidine-1-carboxylate (800 mg, 1.838 mmol), potassium acetate (541 mg, 5.51 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (607 mg, 2.389 mmol) in dioxane (20 ml) was degassed and refilled with N2. The adduct PdCl ₂ (dppf)-dichloromethane (150 mg, 0.184 mmol) was added and the mixture was degassed and refilled with N2. The reaction mixture was heated at 100° C. for 16 hours. The mixture was then cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to give t-butyl (3S,4R)-3-fluoro-4-(4-fluoro-2methoxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)pyrrolidine-1-carboxylate (600 mg, 1.244 mmol, 68% yield) as an off-white solid.

MS (ERI) m/z 446.0 (M+H) ⁺ .

1570C: tert-butyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1 f] [ 1,2,4 ]triazin-7-yl)-4-fluoro-2-methoxybenzamido)-4-fluoropyrrolidine-1-carboxylate: a mixture of tert-butyl (3S,4R)-3-fluoro-4-(4-fluoro-2-methoxy- 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido)pyrrolidine-1-carboxylate (200 mg, 0.352 mmol), 7-bromo-5-((4,4- difluoropiperidin-1yl)methyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (122 mg, 0.352 mmol) and tribasic potassium phosphate (0.529 ml, 1.057 mmol) in dioxane (10 ml) degassed and again filled with N ₂ . Added adduct

- 450 042342

PdCl ₂ (dppf) - dichloromethane (28.8 mg, 0.035 mmol) and the mixture was degassed and refilled with N2. The reaction mixture was heated at 100° C. for 16 hours. The mixture was then diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give t-butyl (3R4,S)-3-(5-(4-amino-5((4,4-difluoropiperidin-1-yl )methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methoxybenzamido)-4fluoropyrrolidine-1-carboxylate (150 mg, 0.241 mmol, 69% yield) as an off-white solid.

MS (ERI) m/z 622.3 (M+H)+.

1570D: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoroN -((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxybenzamide, 2 TFA: tert-butyl mixture (3R,4S)-3-(5-(4-amino5-((4,4- difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-4-fluoro-2-methoxybenzamido)-4fluoropyrrolidine-1-carboxylate (150 mg, 0.241 mmol ) in TFA (2 mL) was stirred at room temperature for 1 h. The mixture was then concentrated to give 5-(4-amino-5-((4,4difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)-4-fluoropyrrolidin3-yl)-2-methoxybenzamide, 2 TFA (150 mg, 0.200 mmol, 83% yield ) as a brown solid.

MS (ERI) m/z 555.1 (M+H) ⁺ .

1570: mixture of 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4fluoro- N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methoxybenzamide, 2 TFA (23 mg, 0.031 mmol), (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoic acid (4.85 mg, 0.031 mmol), BOP (13.57 mg, 0.031 mmol) and Hunig's base (0.021 ml, 0.123 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 minute hold at 25% B, 25-65% B over 20 minutes, then 4 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-4fluoro-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxyu-2-methylpropanoyl)nirroludin-3 -ul)-2methoxybenzamide (8.8 mg, 0.013 mmol, 43% yield) as a white solid.

MS (ERI) m/z 662.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.43-9.05 (m, 1H), 8.51-8.22 (m, 2H), 7.88-7.77 (m, 1H), 7.73-7.35 (m, 1H), 7.32-7.18 (m, 1H), 6.84-6.76 (m, 1H), 5.36-5.16 (m, 1H), 4.81-4.54 (m, 1H), 4.54-4.24 (m, 1H), 4.15-3.50 (m, 9H) , 2.73-2.56 (m, 4H), 2.14-1.94 (m, 4H), 1.61-1.44 (m, 3H).

Example 1571: 5-{4-amino-5-[(4,4-dufluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide

1571 A: tert-butyl (3R,4S)-3-(5-bromo-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: mixture of tert-butyl (3R,4S)-3-amino-4-fluoropyrrolidine- 1-carboxylate (1 g, 4.90 mmol), 5-bromo-2-methylbenzoic acid (1.053 g, 4.90 mmol), Hunig's base (2.57 ml, 14.69 mmol) and BOP (2.60 g, 5.88 mmol) in DMF (10 ml) were stirred at room temperature for 2 hours. Water was added to the reaction mixture. The resulting precipitate was filtered and washed with water. The precipitate was dried to give tert-butyl (3R,4S)-3-(5-bromo-2-methylbenzamido)-4-fluoro-pyrrolidine-1-carboxylate (1.8 g, 4.49 mmol, 92% yield) as a white solid.

MS (ERI) m/z 424.8 (M+Na).

1571B: tert-butyl (3S,4R)-3-fluoro-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido)pyrrolidine-1 -carboxylate: mixture of tert-butyl (3R,4S)-3-(5-bromo-2-methylbenzamido)-4fluoropyrrolidine-1-carboxylate (0.5 g, 1.246 mmol), potassium acetate (0.367 g, 3.74 mmol) and 4, 4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.411 g, 1.620 mmol) in dioxane (10 mL) was degassed and again filled N2. Added adduct PdCl ₂ (dppf) - dichloromethane (0.102 g, 0.125 mmol), and the reaction mixture was degassed and again filled with N ₂ . The reaction mixture was heated at 100° C. for 16 hours. The mixture was then diluted with EtOAc and washed with water. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by silica gel chromatography eluting with 0-50% EtOAc/hexanes to give t-butyl (3S,4R)-3-fluoro-4-(2-methyl-5-(4,4,5,5- tetramethyl 1,3,2-451 042342 dioxaborolan-2-yl)-benzamido)-pyrrolidine-1-carboxylate (500 mg, 1.115 mmol, 90% yield) as an off-white solid.

MS (ERI) m/z 471.1(M+H)+.

1571C: tert-butyl (3R,4S)-3 -(5 -(4-amino-5 -((4,4-difluoropiperidin-1 -yl)methyl)pyrrolo [2,1f][1,2,4] triazin-7-yl)-2-methylbenzamido)-4-fluoro-pyrrolidine-1-carboxylate: mixture of tert-butyl (3S,4R)-3fluoro-4-(2-methyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamido)pyrrolidin-1-carboxylate (200 mg, 0.446 mmol), 7-bromo-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo [2,1-f][1,2,4]triazine-4-amine (154 mg, 0.446 mmol) and tribasic potassium phosphate (0.669 mL, 1.338 mmol) in dioxane (10 mL) were degassed and refilled with N2. The PdCl ₂ adduct (dppf-dichloromethane (36.4 mg, 0.045 mmol)) was added and the reaction mixture was degassed and refilled with N ₂ . The reaction mixture was heated at 100°C for 16 h. The mixture was then diluted with EtOAc. MgSO ₄ and concentrated The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give t-butyl (3R,4S)-3-(5-(4-amino-5-((4,4 -difluoropiperidin-1yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylbenzamido)-4-fluoropyrrolidin-1-carboxylate (140 mg, 0.238 mmol, 53% yield) as an off-white solid.

MS (ERI) m/z 588.3 (M+H) ⁺ .

1571D: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N (( 3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA: tert-butyl (3R,4S)-3-(5-(4-amino-5((4,4-difluoropiperidine- 1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylbenzamido)-4fluoropyrrolidine-1-carboxylate (140 mg, 0.238 mmol) in TFA (1 ml ) was stirred at room temperature for 2 hours. The mixture was then concentrated to give 5-(4-amino-5-((4,4difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2methylbenzamide, 2 TFA (150 mg, 0.210 mmol, 88% yield) as brown oil.

MS (ERI) m/z 488.1 (M+H) ⁺ .

1571: mixture of 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N ( (3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA (20 mg, 0.028 mmol), (R)-3,3,3-trifluoro-2hydroxy-2-methylpropanoic acid (4.42 mg , 0.028 mmol), BOP (14.83 mg, 0.034 mmol) and Hunig's base (0.020 ml, 0.112 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. A few drops of ammonium hydroxide were added and stirring was continued at room temperature within 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 32% B, 32-72% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4] triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydrokCi-2-methylpropanoyl)pyrrolidin-3-yl)- 2-methylbenzamide (10.6 mg, 0.017 mmol, 59% yield).

MS (ERI) m/z 628.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.47-8.99 (m, 1H), 8.84-8.52 (m, 1H), 8.16-8.04 (m, 1H), 8.02-7.94 (m, 1H), 7.94 -7.84 (m, 1H), 7.76-7.42 (m, 1H), 7.43-7.25 (m, 1H), 7.14-6.82 (m, 2H), 5.45-5.09 (m, 1H), 4.74-4.45 (m, 1H), 4.46-4.18 (m, 1H), 4.10-3.15 (m, 5H), 2.70-2.58 (m, 4H), 2.44-2.26 (m, 3H), 2.15-1.93 (m, 4H), 1.651. 41 (m, 3H).

Example 1572: 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-1-[(1S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methylbenzamide

5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1(2,2-Difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide (9 mg, 0.015 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral IC, 250 mm x 21 mm, 5 µm particles; mobile phase 60% CO2, 40% IPA-ACN, 50-50 with 0.1% DEA; flow rate: 60 ml/min. Fraction collection was initiated by MS and UV signals. Peaks eluted first were combined and dried to give 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f][1,2,4]triazin-7- yl}-N-[(3R,4S)-1-[(1S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2methylbenzamide (2.7 mg, 29% yield) as a white solid.

MS (ERI) m/z 592.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.47-9.04 (m, 1H), 8.81-8.51 (m, 1H), 8.09-8.00 (m, 1H), 8.00-7.92 (m,

- 452 042342

1H), 7.92-7.73 (m, 1H), 7.70-7.39 (m, 1H), 7.39-7.26 (m, 1H), 7.09-6.87 (m, 1H), 5.52-5.08 (m, 1H), 4.92- 4.50 (m, 1H), 4.35-4.06 (m, 1H), 4.02-3.56 (m, 6H), 3.13-2.98 (m, 1H), 2.74-2.58 (m, 4H), 2.45-2.31 (m, 3H ), 2.111.72 (m, 6H).

Example 1573: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)N-( (3R,4S)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide

N—' ^H2N vX1 I ⁿ ^n IX ^H ΐχζ

5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1(2,2-Difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide (9 mg, 0.015 mmol) was separated using preparative SFC under the following conditions: Waters 100 instrument, column : Chiral IC, 250 mm x 21 mm, 5 µm particles; mobile phase 60% CO ₂ , 40% IPA-ACN, 50-50 with 0.1% DEA; flow rate: 60 ml/min. Fraction collection was initiated by MS and UV signals. The peaks eluted second were combined and dried to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4]triazin-7- yl)-N-((3R,4S)-1-((R)-2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2methylbenzamide (3 mg, 33% yield) as white solid.

MS (ERI) m/z 592.2 (M+H)+.

Ή NMR (500 MHz, DMSO-d ₆ ) δ 9.47-9.04 (m, 1H), 8.81-8.51 (m, 1H), 8.09-8.00 (m, 1H), 8.00-7.92 (m, 1H), 7.92- 7.73 (m, 1H), 7.70-7.39 (m, 1H), 7.39-7.26 (m, 1H), 7.09-6.87 (m, 1H), 5.52-5.08 (m, 1H), 4.92-4.50 (m, 1H ), 4.35-4.06 (m, 1H), 4.02-3.56 (m, 6H), 3.13-2.98 (m, 1H), 2.74-2.58 (m, 4H), 2.45-2.31 (m, 3H), 2.111.72 (m, 6H).

Example 1574: 2,2,2-trifluoroethyl (3R,4S)-3-[5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1yl]methyl}pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-2-methylbenzamido]-4-fluoropyrrolidine-1-carboxylate

1574A: 5-bromo-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, TFA salt: t-butyl mixture (3R,4S)-3-(5-bromo-2- methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (300 mg, 0.748 mmol) and TFA (288 μl, 3.74 mmol) were stirred at room temperature for 2 h. The mixture was then concentrated to give 5-bromo-N-((3R, 4S)-4-Fluoropyrrolidin-3-yl)-2-methylbenzamide, TFA salt (300 mg, 0.723 mmol, 97% yield) as a brown solid.

MS (ERI) m/z 300.8 (M+H)+.

1574B: 2,2,2-trifluoroethyl (3R,4S)-3-(5-bromo-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: 5-bromo-N-((3R,4S)-4 mixture -fluoropyrrolidin-3-yl)-2-methylbenzamide, TFA (300 mg, 0.723 mmol), 2,2,2 trifluoroethyl carbonochloridate (141 mg, 0.867 mmol) and Hunig's base (0.252 ml, 1.445 mmol) in DMF (5 ml) stirred at room temperature for 24 h. The mixture was then diluted with water. The resulting precipitate was filtered off and washed with water. It was then dried to give a solid which was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give 2,2,2-trifluoroethyl (3R,4S)-3-(5-bromo-2-methylbenzamido )-4fluoropyrrolidine-1-carboxylate (250 mg, 0.585 mmol, 81% yield) as an off-white solid.

MS (ERI) m/z 428.8 (M+H)+.

1574C: 2,2,2-trifluoroethyl (3S,4R)-3-fluoro-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido )pyrrolidine-1-carboxylate: a mixture of 2,2,2-trifluoroethyl (3R,4S)-3-(5-6pom-2methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (100 mg, 0.234 mmol), potassium acetate (68.9 mg, 0.702 mmol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (77 mg, 0.304 mmol) in dioxane (2 ml) was degassed and again filled with N ₂ . Added adduct PdCl ₂ (dppf) - dichloromethane (19.12 mg, 0.023 mmol), and the reaction mixture was degassed and again filled with N ₂ . The mixture was heated at 100° C. for 16 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was dried and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give 2,2,2-trifluoroethyl (3S,4R)-3-fluoro-4-(2-methyl-5-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzamido)pyrrolidine-1-carboxylate (80 mg, 0.169 mmol, 72% yield) as an off-white solid.

MS (ERI) m/z 475.1 (M+H)+.

- 453 042342

1574: mixture of 2,2,2-trifluoroethyl (3S,4R)-3-fluoro-4-(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) benzamido)pyrrolidin-1-carboxylate (25 mg, 0.053 mmol), 7-bromo-5-((4(trifluoromethyl)piperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4] triazine-4-amine (19.94 mg, 0.053 mmol) and tribasic potassium phosphate (0.079 mL, 0.158 mmol) in dioxane (2 mL) were degassed and refilled with N ₂ . Added adduct PdCl ₂ (dppf) - dichloromethane (4.30 mg, 5.27 μmol), and the reaction mixture was degassed and again filled with N ₂ . The mixture was heated at 100° C. for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 34% B, 34-74% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 2,2,2-trifluoroethyl (3R,4S)-3(5-(4-amino-5-((4-(trifluoromethyl)piperidin-1-yl )methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (9.2 mg, 0.013 mmol, 25% yield) as not quite white solid.

MS (ERI) m/z 646.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 9.58-9.18 (m, 1H), 8.70-8.60 (m, 1H), 8.12-8.04 (m, 1H), 8.01-7.92 (m, 1H), 7.92- 7.81 (m, 1H), 7.78-7.46 (m, 1H), 7.40-7.27 (m, 1H), 7.04-6.91 (m, 1H), 5.48-5.17 (m, 1H), 4.83-4.50 (m, 4H ), 4.01-3.58 (m, 6H), 3.16-2.94 (m, 2H), 2.46-2.33 (m, 4H), 2.19-2.02 (m, 2H), 1.96-1.80 (m, 2H), 1.541.37 (m, 2H).

Example 1575: 2,2,2-trifluoroethyl (3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1 ,2,4]triazin-7-yl}-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate 0' \ ^F 4 ^H2N U1 a Yw Cr and

F F

This compound was prepared by the methods detailed in Example 1574.

MS (ERI) m/z 614.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.79-8.60 (m, 1H), 8.17-8.05 (m, 1H), 8.05-7.89 (m, 2H), 7.42-7.34 (m, 1H), 7.28-7.16 (m, 1H), 5.42-5.14 (m, 1H), 4.86-4.50 (m, 3H), 4.07-3.24 (m, 3H), 2.44-2.35 (m, 3H), 2.32-1.94 (m, 4H) .

Example 1576: 2,2,2-trifluoroethyl (3R,4S)-3-(5-(4-amino-5-((1,1dioxidothiomorpholino)methyl)pyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-2-methylbenzamido)-4fluoropyrrolidine-1-carboxylate

This compound was prepared by the methods detailed in Example 1574.

MS (ERI) m/z 628.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.78-8.58 (m, 1H), 8.20-7.86 (m, 3H), 7.44-7.33 (m, 1H), 7.16-7.11 (m, 1H), 5.50 -5.18 (m, 1H), 4.90-4.57 (m, 3H), 4.10-3.93 (m, 2H), 3.88-3.55 (m, 3H), 3.48-3.33 (m, 1H), 3.28-3.18 (m, 4H) , 3.13-3.00 (m, 4H), 2.42-2.32 (m, 3H).

Example 1577: 2,2,2-trifluoroethyl (3R,4S)-3-(5-{4-amino-5-[(morpholin-4-yl)methyl]pyrrolo[2,1f] [ 1,2,4 ]triazin-7-yl} -2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate

This compound was prepared by the methods detailed in Example 1574.

MS (ERI) m/z 580.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.78-8.56 (m, 1H), 8.12-7.98 (m, 2H), 7.98-7.85 (m, 1H), 7.43-7.34 (m,

- 454 042342

1H), 7.22-7.16 (m, 1H), 5.45-5.14 (m, 1H), 4.96-4.55 (m, 3H), 4.11-3.55 (m, 6H), 3.54-3.24 (m, 4H), 2.44- 2.33 (m, 3H), 1.13-0.99 (m, 4H).

Example 1578: 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}N-[ (3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide

1578A: methyl 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)4-fluoro -2-methylbenzoate: a mixture of methyl 4-fluoro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzoate (127 mg, 0.433 mmol), 7-bromo -5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4]triazine-4-amine (150 mg, 0.433 mmol) and tribasic potassium phosphate (0.650 ml, 1.300 mmol) in dioxane (4 ml) was degassed and refilled with N ₂ . The complex 1,1'bis(diphenylphosphino)ferrocene-palladium (II) dichloromethane dichloride (35.4 mg, 0.043 mmol) was added and the reaction was degassed and refilled with N2. The mixture was heated at 100°C for 16 h, then cooled to room temperature and diluted with EtOAc. The organic layer was washed with water, dried over MgSO ₄ , filtered and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc/hexanes to give methyl 5-(4-amino-5-((4,4-difluoropiperidin-1yl)methyl)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoate (130 mg, 0.300 mmol, 69% yield) as an off-white solid.

MS (ERI) m/z 434.1 (M+H)+.

1578B: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro2 -methylbenzoic acid: methyl mixture -fluoro-2-methylbenzoate (130 mg, 0.300 mmol) and NaOH (1.500 ml, 1.500 mmol) in MeOH (5 ml) were heated at reflux for 3 h. The reaction mixture was cooled to room temperature and brought to pH= 5 using 1 n. HCl. The resulting white precipitate was filtered off and washed with water. The mixture was then dried to give 5(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4 -fluoro-2-methylbenzoic acid (118 mg, 0.281 mmol, 94% yield) as a white solid.

MS (ERI) m/z 420.0 (M+H) ⁺ .

1578C: tert-butyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4] triazin-7-yl)-4-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate: mixture of 5-(4-amino-5((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2 ,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzoic acid (118 mg, 0.281 mmol), tert-butyl (3R,4S)-3-amino-4- fluoropyrrolidine-1-carboxylate (57.4 mg, 0.281 mmol), Hunig's base (0.147 ml, 0.844 mmol) and BOP (149 mg, 0.338 mmol) in DMF (10 ml) were stirred at room temperature for 2 h. Water was added to the reaction mixtures. The resulting precipitate was filtered and washed with water. The mixture was then dried to give tert-butyl (3R,4S)-3-(5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1 ,2,4]triazin-7-yl)-4-fluoro-2methylbenzamido)-4-fluoropyrrolidine-1-carboxylate (150 mg, 0.248 mmol, 88% yield) as a white solid.

MS (ERI) m/z 606.4 (M+H) ⁺ .

1578D: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoroN -((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA: tert-butyl mixture (3R,4S)-3-(5-(4-amino-5((4,4 -difluoropiperidin-1 -yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-2-methylbenzamido)-4fluoropyrrolidine-1-carboxylate (150 mg, 0.248 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 1 h. The mixture was then concentrated to give 5-(4-amino-5-((4,4difluoropiperidin-1-yl)methyl)pyrrolo[2 1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)-4-fluoropyrrolidin3-yl)-2-methylbenzamide, 2 TFA (180 mg, 0.245 mmol , 99% yield) as a brown solid.

MS (ERI) m/z 506.3 (M+H) ⁺ .

1578: a mixture of 5-(4-amino-5-((4,4-difluoropiperidin-1 -yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4fluoro- N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide, 2 TFA salt (20 mg, 0.027 mmol), 3,3-difluorocyclobutane-1-carboxylic acid (3.71 mg, 0.027 mmol), BOP (14.47 mg, 0.033 mmol) and Hunig's base (0.019 ml, 0.109 mmol) in DMF (1 ml) were stirred at room temperature for 2 h. A few drops of ammonium hydroxide were added and stirring was continued at room temperature for 16 h. Crude material purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 25% B, 25-65% B over 20 min, then 4 min hold at

- 455 042342

100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1f][1,2,4] triazin-7-yl)-N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-4fluoro-2-methylbenzamide (9.6 mg, 0.015 mmol , 54% yield) as a white solid.

MS (ERI) m/z 624.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.41-9.00 (m, 1H), 8.73-8.56 (m, 1H), 7.93-7.80 (m, 2H), 7.74-7.38 (m, 1H), 7.34- 7.17 (m, 1H), 6.90-6.76 (m, 1H), 5.45-5.15 (m, 1H), 4.80-4.43 (m, 1H), 4.10-3.48 (m, 7H), 3.23-3.06 (m, 1H ), 2.90-2.70 (m, 4H), 2.70-2.59 (m, 3H), 2.45-2.37 (m, 3H), 2.13-1.96 (m, 4H).

Example 1579: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2,2difluorocyclopropanecarbonyl)-4- fluoropiperidin-3-yl]-2-methoxypyridine-3-carboxamide

F

1579 A: tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4-fluoropiperidin- 1-carboxylate: mixture of tert-butyl 3-amino-4-fluoropiperidine-1-carboxylate (61.8 mg, 0.283 mmol), 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-2methoxynicotinic acid (100 mg, 0.283 mmol), Hunig's base (0.148 ml, 0.849 mmol) and BOP (150 mg, 0.340 mmol) in DMF (2 ml) were stirred at room temperature for 2 hours Added water to the reaction mixture. The white precipitate was filtered off and washed with water. The mixture was then dried to give tert-butyl 3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2methoxynicotinamido)-4- fluoropiperidine-1-carboxylate (140 mg, 0.253 mmol, 89% yield) as a white solid.

MS (ERI) m/z 559.3 (M+2Na).

1579B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluoropiperidin-3-yl)2-methoxynicotinamide , 2 TFA: tert-butyl mixture fluoropiperidine-1-carboxylate (140 mg, 0.253 mmol), TFA (0.5 ml, 6.49 mmol) was stirred at room temperature for 1 h. The mixture was then concentrated to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2 ,1-f][1,2,4]triazin-7-yl)-N-(4fluoropiperidin-3-yl)-2-methoxynicotinamide, 2 TFA salt (140 mg, 0.205 mmol, 81% yield) as brown solid.

MS (ERI) m/z 454.2 (M+H)+.

1579: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluoropiperidin-3yl)-2-methoxynicotinamide mixture , 2 TFA (20 mg, 0.029 mmol), 2,2-difluorocyclopropane-1-carboxylic acid (3.58 mg, 0.029 mmol), BOP (15.58 mg, 0.035 mmol) and Hunig's base (0.021 ml, 0.117 mmol) in DMF ( 1 ml) was stirred at room temperature for 2 hours. A few drops of ammonium hydroxide were added and stirred at room temperature for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 23% B, 23-63% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1-(2,2-difluorocyclopropan-1-carbonyl)-4fluoropiperidin-3-yl)-2-methoxynicotinamide (7.9 mg, 0.013 mmol, 46% yield). The compound was isolated as a mixture of diastereomers.

MS (ERI) m/z 558.1 (M+H)+.

LCMS, retention time using method 2 = 1.78 min.

Example 1580: 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4R)-4-fluoro- 1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperidin-3-yl]-2-methoxypyridine-3-carboxamide

5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4-fluoropiperidin-3-yl)2-methoxynicotinamide mixture, 2 TFA (20 mg, 0.029 mmol), (R)-3,3,3-trifluoro-2-hydroxy-2

- 456 042342 methylpropanoic acid (4.64 mg, 0.029 mmol), BOP (15.58 mg, 0.035 mmol) and Hunig's base (0.021 ml, 0.117 mmol) in DMF (1 ml) was stirred at room temperature for 2 h. A few drops of hydroxide were added ammonium and the mixture was stirred at room temperature for 16 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 23% B, 23-63% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N- ((3S,4R)-4fluoro-1-((K)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)piperidin-3-yl)-2-methoxynicotinamide (2.5 mg, 4.15 µmol, 14 % exit). The absolute stereochemistry of piperidine is arbitrarily labeled.

MS (ERI) m/z 594.1 (M+H)+.

LCMS, retention time using method 1 = 2.48 min.

Intermediates in the table. 56 was prepared by the methods detailed for 7-bromo-5(pyrrolidin-1-ylmethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine.

Table 56

R h ₂ n

Br

intermediate connection Name R Ion mass observed in MS 6 7-bromo-5-((3,3-difluoro-pyrrolidin-1 yl)methyl)pyrrolo[2,1 f][1,2,4]triazine-4-amine δ 333.8 7 7-bromo-5-((3-fluoroazetidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine ___ F χ ^N 299.8 8 5-(azetidin-1-ylmethyl)-7 bromopyrrolo[2,1-f] [ 1,2,4]triazine-4amine χ ^Ν ° 281.7, 283.7 9 7-bromo-5-((3- (trifluoromethyl)azetidin-1 yl)methyl)pyrrolo[2,1 1P[1,2,4]triazine-4-amine / _CF3 351.7

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10 7-bromo-5-((3,3-difluoroazetidin-1 yl)methyl)pyrrolo[2,1f][1,2,4]triazine-4-amine F __L-F X ^N 319.8 And 5-((2-azaspiro[3.3]heptan-2yl)methyl)-7-bromopyrrolo[2,1f] [1,2,4]triazine-4-amine 323.8, 325.1 12 7-bromo-5-(piperidin-1ylmethyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine χθ 311.8 13 7-bromo-5-((3,3-dimethylazetidin-1 yl)methyl)pyrrolo[2,1 f] [1,2,4]triazine-4-amine χΆ 309.9 14 7-bromo-5-((3- (trifluoromethyl)pyrrolidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine δ N - ⁷ 365.8 15 (8)-7-bromo-5-((2- (trifluoromethyl)pyrrolidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine N- ⁷ 363.7 16 7-bromo-5-((4,4-d iftor piperidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine 347.7 17 7-bromo-5-((3- (trifluoromethyl)piperidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine b 377.8 18 7-bromo-5-((4- (trifluoromethyl)piperidin-1 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine X 377.8, 379.8 19 7-bromo-5-((3,4-dihydroisoquinolin2(1 H)-yl)methyl)pyrrolo[2,1 f] [1,2,4]triazin-4-amine 347.7 20 7-bromo-5-((6,6-difluoro-3azabicyclo[3.1.0]hexan-3 yl)methyl)pyrrolo[2,1 f] [1,2,4]triazine-4-amine 343.7, 345.7 21 7-bromo-5-(((1C,58)-3,3-difluoro-8az abicyclo o [3.2.1] octan- 8 yl)methyl)pyrrolo[2,1 f] [ 1,2,4]triazine -4-amine Η Η 371.7, 373.7 22 7-bromo-5-((4,4-dimethylpiperidin-1 yl)methyl)pyrrolo[2,1 f][1,2,4]triazine-4-amine 337.7, 339.7 23 7-bromo-5-((4,4-dimethylpiperidin-1 yl)methyl)pyrrolo[2,1 f] [1,2,4]triazine-4-amine Ν/ f ) ^{4 F} 371.8, 373.8 24 4-((4-amino-7-bromopyrrolo[2,11][1,2,4]triazin-5yl)methyl)thiomorpholine 1,1-dioxide Λ ο 360.0, 362.0 25 7-bromo-5(morpholinomethyl)pyrrolo[2,1 f] [ 1,2,4]triazine-4-amine 312.0, 314.0

Connections in the table. 57 was obtained by the methods detailed in examples 1549, 1550, 1551, 1562 and 1563. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 57

Example Name ^{R1 R2 R3} Ion mass observed in MS 1581 1582 1583 1584 1585 1586 5-{4-amino-5-[(3,3difluoropyrrolidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-M[(3R,4S)-l -(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 5-{4-amino-5-[(3-fluoroaz etidin1-yl)methyl]pyrrolo[2.1 1][1, 2,4]triazin-7-yl}-H[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 5 - {4-amino-5 -[ (piperidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-H[(3R,4S)-4-φτop-l-[(2R)-3, 3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide 5-{4-amino-5-[(3,3dimethylazetidin-1 yl)methyl]pyrrolo[2,1 1] [1,2,4]triazin-7-yl}-H[(3R,4S)-4-φτop-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl] -2-methoxypyridine-3 carboxamide 5-(4-amino-5-{[(28)-2(trifluoromethyl)pyrrolidin-1 yl] methyl } 7-yl)-N-[(3R,4S)4-fluoro-1-[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide 5 -{4-amino-5-[(4,4difluoropiperidin-1 yl )methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-M[(ЗR,4S)-4-φτop-l-[(2R)-3,3,3trifluoro-2 -hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Xvf Ana CF ₃ X O, F Η Η Η Η Η Η α F Αα \-Α F K/CF3 *ΟΗ ACFg * He AF3 * He gosrz *bn 609.2 577.2 609.2 609.2 663.2 645.2

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1587 5-(4-amino-5-{[3(trifluoromethyl)piperidin-1 yl]methyl } pyrrolo[2,1 1][1,2,4]triazin-7-yl)-H-[(3^48 )4-fluoro-1 -[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Η ?OCF ₃ *en 677.2 1588 5-{4-Amino-5-[(pyrrolidin-1yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(3R,4S)-4-i _T op-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide 'te Η ?OCF ₃ *en 595.2 1589 5-{4-amino-5-[(3,3difluoropyrrolidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(ЗR,4S)-4 -φτop-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide NN Η ?OCF ₃ * he 631.2 1590 5-(4-amino-5-{[3(trifluoromethyl)azetidin-1 yl]methyl }pyrrolo[2,1f] [1,2,4]τpiazin-7-yl)-N-[(ЗR,4S )4-fluoro-1 -[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Arn Η ?C/CF ₃ *EN 649.2 1591 5 - { 4-amino-5 - [ 1 - (piperidin-1 yl) ethyl] pyrrolo [2,1f] [ 1,2,4] triazin-7-yl } -N [(3M8) -4-φτορ- 1-[(28)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Η Z/CF ₃ * OH 623.2

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1592 5 - { 5 -acetyl-4-aminopyrrolo[2,1 f] [ 1,2,4]triazin-7-yl }-N[(3Κ,4δ)-4-φτορ-1-[(2Κ)-3 ,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Η ?Ο+ ₃ < he 554.1. 1593 1594 1595 1596 5 - {4-amino-5-methylpyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(ЗR,4S)-4-φτop-l-[(2R)-3 ,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide 5 - {4-amino-5-chloropyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(ЗR,4S)-4-φτop-l-[(2R)-3 ,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide 5 - { 4-aminopyrrolo[2,1 f] [1,2,4]triazin-7-yl } - N[(3Κ,4δ)-4-φτορ-1-[(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide 5-{4-amino -5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(3R,4S)-l-(3,3difluorocyclobutanecarbonyl) -4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide No. n F Η Η Η Η Z/CF ₃ * he ?OCF ₃ * OH ?OCF ₃ * OH AD-F F 526.1 546.1 512.2 623.2 1597 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1 yl]methyl }pyrrolo[2,1f][l,2,4]TpHa3HH-7-Hn)-N-[(3R,4S )1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide X^CF ₃ Η Αχ F 655.2

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1598 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1 yl]methyl }pyrrolo[2,1 1][1,2,4]triazin-7-yl)-X-[(3^48 )4-fluoro-1 -[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Η ?ocf ₃ 'he 677.2 1599 5-[4-amino-5-(4aminophenyl)pyrrolo[2,1f] [1,2,4]τpiazin-7-yl]-N-[(ЗR,4S)1-(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidine -3 -yl] -2methoxypyride in-3-carboxamide nh ₂ ο Η F 581.2 1600 5-{4-amino-5-[(1,2,3,4tetrahydroisoquinolin-2yl)methyl]pyrrolo[2,1f][1,2,4]triazin-7-yl }-N[(ЗR,4S )-4-φτop-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide Η Z/CF ₃ 'he 657.2 1601 [ 1,2,4]triazin5-yl 4-methylbenzene-1-sulfonate Η A bh-f F 660.1 1602 5-[4-amino-5(difluoromethyl)pyrrolo[2,1 f][l,2,4]TpHa3HH-7-Hn]-N-[(3R,4S)4-fluoro-1 -[(2R) -3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide F Η Z/CF ₃ 'OH 562.1

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1603 5-{4-amino-6-fluoropyrrolo[2,1 1][1,2,4]triazin-7-yl}-X[(3R,4S)-4-4>Top-l-[(2R) -3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide H F /ACF ₃ 'bn 530.1 1604 5-{4-amino-5methoxypyrrolo[2.1 1][1.2.4]triazin-7-yl}-X[(3R,4S)-4-φτop-l-[(2R)-3.3 ,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide H ?C/CE ₃ < bn 542.1 1605 5-{4-amino-5-fluoropyrrolo[2,11][1,2,4]triazin-7-yl}-X[(3R,4S)-4-φτop-l-[(2R)-3, 3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide ^4F H ?OCF ₃ < 0N 530.0 1606 5-[4-Amino-5(difluoromethoxy)pyrrolo[2,1 f][l,2,4]τpiazin-7-yl]-N-[(3R,4S)4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide A H A/C ^r z 'on 578.1 1607 5 - [4-amino-5 - ( { 6,6-difluoro-3 azabicyclo [3.1.0] hexan-3yl } methyl) pyrrolo [2,1 f] [ 1,2,4] triazin-7-yl] -X-[(ZA48)4-fluoro-1-[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide F H ?OCF ₃ < en 643.1

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LC/MS RT

1 8 min

Methodi Fluoropyrrolidin-3-yl]-25-(4-amino-5-(lR,5S)-3,3difluoro-8azabicyclo[3.2.1]octan-8yl]methyl 1 pyrroloG2,1 1] 1,2,4 ] triazyn-7-yl)-N-Γ(ЗR,4S)5-(4-amino-5-(lR,5S)-3,3difluoro-8azabicyclo[3.2.1]octan-8yl]methyl} pyrroloG2,1 1] 1,2,4 ]triaz in-7-yl)-N-Γ(3R,4S)hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide

5-14-amino-5-G(4,4dimethylpiperidin-1 yl)methyl]pyrroloG2,1 1]G1,2,4]triazin-7-yl} -N(3R,4S)-4-φτop-l- Γ(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide

5-[4-Amino-5-({1,1-difluoro-6azaspiro12.5]octan-6yl 1 methyl)pyrroloG2,1hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3 carboxamide

5-D4-amino-5-({1,1-difluoro-6azaspiro12.5]octan-6yl}methyl)pyrrolo[2,1fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide

[4-amino-5-(]1,1-difluoro-6azaspiro[2.5]octan-6yl 1 methyl)pyrrolo12,1 fΊ G1,2,4]triazin-7-yl]-2methoxypyridin-3-amido1-42, 2,2-trifluoroethyl (3R,4S)-3-[5(4-amino-5-{[4(trifluoromethyl)piperidin-1 yl]methyl }pyrrolo[2,1 1]G1,2,4]triazine- 7-yl)-2methoxypyride in-3-amido]-44-fluoro-1-[(2R)-3,3,3-trifluoro-2LG1,2,4]triazin-7-yl]-X-G(ZK48 )

4-fluoro-1 -[(2R)-3,3,3-trifluoro-2LG1,2,4]triazin-7-yl]-X-G(ZK48) difluorocyclobutanecarbonyl)-4 methoxypyride in-3-carboxamide difluorocyclobutanecarbonyl) -42,2,2-trifluoroethyl (3R,4S)-3-{5 fluoropyrrolidine-1-carboxylate fluoropyrrolidine-1-carboxylate

Connections in the table. 58 was obtained by the methods detailed in examples 1554 and 1556. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 58

1615 5-{4-amino-5-[(azetidin-1yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(ZK,48)-4-fluoro- 1-(2fluorobenzoyl)pyrrolidin-3 -yl] 2-methoxypyridine-3 carboxamide A ύ 563.2 1616 5-{4-amino-5-[(3,3difluoroazetidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(3Κ,48)- 4-φτορ-1-[(2Κ)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxypyridine-3carboxamide >V ^f F ACF ₃ < н 617.2 1617 5-{4-amino-5-[(3,3difluoroazetidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(3R,4S)-1 -(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide ί-Ά F XX f 581.2 1618 5-{4-amino-5-[(3,3difluoroazetidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(3K,48)-4 -fluoro-1 -(3,3,3 -trifluoro2,2dimethylpropanoyl)pyrrolidin3 -yl] -2-methoxypyridine-3 carboxamide ν-Ά F X^CF ₃ 615.2 1619 5-{4-amino-5-[(3,3difluoroazetidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(3R,4S)-1 -(2,2dimethylpropanoyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide Vn-λ Av ^f F HuMe me me 561.2

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1620 5-{4-amino-5-[(3,3difluoroazetidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl }-N[(3R,4S)-l -(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide F %; 609.2 1621 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(3R,4S)-1 -(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide νγ VA^ ^f F e FXAf 609.2 1622 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(ZK,48)-4 -fluoro-1 -(3,3,3 -trifluoro2,2dimethylpropanoyl)pyrrolidin3 -yl] -2-methoxypyridine-3 carboxamide νγ VAa F ^CF ₃ 643.2 1623 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl} -N[(3R,4S)-l -(3,3difluorocyclopentanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide F Ύ 637.2 1624 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N[(ЗR,4S)-4 -φτop-1 -(2-fluoro-2methylpropanoyl)pyrrolidin-3 yl]-2-methoxypyridine-3 carboxamide F F 593.2 1625 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(ZK,48)-4 -fluoro-1 -[2-hydroxy-2(trifluoromethyl)butanoyl]pyrrole idin-3 -yl]-2-methoxypyr idine-3 carboxamide YA F YCF ₃ I OH 659.2 LC-MS, RT 1.54 min (Method 2)

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1626 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N- [(ЗR,4S)-4-φτop-l-(2fluorobenzoyl)pyrrolidin-3-yl] 2-methoxypyridine-3 carboxamide F A 627.2 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 1627 1][1,2,4]triazin-7-yl)-X-[(ZSch48)- j FW ^F 641.1 1-(2,2- OF ₃ difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-2methoxypyride in-3-carboxamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 1628 1][1,2,4]triazin-7-yl)-X-[(ZSch48)- ΑΊχΑ X^Me 625.1 4-fluoro-1 -(2-fluoro-2- OF ₃ Yar Me ^r methylpropanoyl)pyrrolidine-3 - yl] -2-methoxypyr idin-3 - carboxamide 5-(4-amino-5-{[4- — (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - Me 691.2 1629 1][1,2,4]triazin-7-yl)-X-[(ZSch48)- LC/MS RT 4-fluoro-1-[2-hydroxy-2- xf ₃ 2.3 min (trifluoromethyl)butanoyl] pyrrole idin-3 -yl] -2-methoxypyr idin-3 - F ₃ C ⁰ (Method 2) carboxamide 5-(4-amino-5-{[4- — (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 1630 1][1,2,4]triazin-7-yl)-X-[(ZSch48)- X^N^ X^Me 675.2 4-fluoro-1-(3,3,3-trifluoro-2,2dimethylpropanoyl)pyrrolidine- _TF3 Me^ ^F 3 3 -yl] -2-methoxypyr idin-3 - carboxamide 5-(4-amino-5-{[4- — (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 745 7 1][1,2,4]triazin-7-yl)-X-[(ZSch48)- _CF3 LC-MS RT 1631 4-fluoro-1 -[4,4,4-trifluoro-3 hydroxy-3- (trifluoromethyl)butanoyl] pyrrole idin-3 -yl] -2-methoxypyr idin-3 - OF ₃ Uh 3 2.52 min (Method 1) carboxamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - F 1632 £][1,2,4]triazin-7-yl)-X-[(ZAch48)4-fluoro-1-(2- OF ₃ v 659.2 fluorobenzoyl)pyrrolidin-3 -yl] - 2-methoxypyr idine-3 - carboxamide

Connections in the table. 59 was prepared by the methods detailed in Example 1570. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 59

Example Name ^{R1 R2} Ion mass observed in MC 1633 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl }-N[(3R,4S)-l -(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-4-fluoro-2methoxybenzamide F SiAf F 640.2 1634 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N[(3R,4S)-1 -(2,2difluorocyclopropanecarbonyl)-4fluoropyrrolidin-3-yl]-4-fluoro-2methoxybenzamide F . F 626.2 LC-MS RT 1.55 min (Method 2) 635 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-4-fluoro-X[(3^ 48)-4-fluoro-1 -[4,4,4-trifluoro3-hydroxy-3(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2-methoxybenzamide LA" ^f F CF ₃ CF ₃ 730.1

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1636 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-4-fluoro-X[(ZA48) -4-fluoro-1 -(2-fluoro-2methylpropanoyl)pyrrolide in-3yl]-2-methoxybenzamide J^F F /yMe Me ^F 610.2 1637 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-4-fluoro-X[(3^ 48)-4-fluoro-1-[2-hydroxy-2(trifluoromethyl)butanoyl]pyrrole idin-3-yl]-2-methoxybenzamide D-F F Me /n F ₃ C ^0H 676.2 1638 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 1][1,2,4]triazin-7-yl}-4-fluoro-M[(3R, 4 S )-4-fluoro-1-(3,3,3-trifluoro2,2dimethylpropanoyl)pyrrolidin3-yl]-2-methoxybenzamide D-F F X^Me Me ^CF 3 660.2 1639 5-(4-amino-5-{[4(trifluoromethyl)piperidin-1 yl] methyl } pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl)-4-fluoro-M[( 3R,4S)-4-φτop-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methoxybenzamide // ^CF ₃ X/F ₃ <OH 694.2 1640 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1 yl]methyl }pyrrolo[2,1 1][1,2,4]triazin-7-yl)-X-[(ZA48)1 -(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-4-fluoro-2methoxybenzamide // _TF3 ^''X^F F 672.2

Connections in the table. 60 was obtained by the methods detailed in example 1571. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LCMS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 60

Example Name ^{R1 R2} Ion mass observed in MS 1641 5-{4-Amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2.1 G][1,2,4]triazin-7-yl}-H-[(ZK,48)1 -(3,3difluorocyclobutanecarbonyl)-4fluoropyrrolidin-3-yl]-2methylbenzamide F F 606.2 1642 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N-[(3R,4S)4 -fluoro-1 -[4,4,4-trifluoro-3 hydroxy-3 (trifluoromethyl)butanoyl] pyrrolide in-3 -yl] -2-methylbenzamide F CF ₃ CF ₃ 696.2 1643 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N-[(3R,4S)4 -fluoro-1 -(2-fluoro-2methylpropanoyl)pyrrole id in-3yl]-2-methylbenzamide ΧΥΛ F X^Me Me ^F 576.2 1644 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f][l,2,4]τpiazin-7-yl}-N-[(ЗR,4S)4 -fluoro-1 - [2-hydroxy-2 (trifluoromethyl) butanoyl] pyrrolide in-3 -yl] -2-methylbenzamide AA" ^f F Me % F ₃ C ^0H 642.2 LC-MS, RT 1.51 min (Method 2) 1645 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazin-7-yl } -N-[(3R,4S)4 -fluoro-1-(3,3,3-trifluoro-2,2dimethylpropanoyl)pyrrolidin-3yl]-2-methylbenzamide AA" ^f F X^Me Me ^CF 3 626.2 1646 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2,1 f] [1,2,4]triazin-7-yl } -N-[(ЗR,4S)4 -φτop-l-(2φτopbenzoyl)pyrpolidin-3-yl]-2methylbenzamide AAv ^f F ύ 610.2

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1647 5-(4-Amino-5-{[4(trifluoromethyl)piperidin-1 yl]methyl }pyrrolo[2,1f][1,2,4]triazin-7-yl)-X-[(ZA48)4 -fluoro-1-[(2R)-3,3,3-trifluoro-2hydroxy-2methylpropanoyl]pyrrolidin-3yl]-2-methylbenzamide AG ^X CF ₃ Z/CF ₃ 'OH 660.2 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 1648 f] [ 1,2,4]triazin-7-yl)-X-[(ZA48)1-(3,3- OF ₃ ^? *'o _v f 638.2 difluorocyclobutanecarbonyl) -4- F fluoropyrrolidin-3-yl]-2- methylbenzamide 5-(4-amino-5-{[4- — (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 1649 f] [ 1,2,4]triazin-7-yl)-Sch(ZK,48)- jF 624.2 1-(2,2- OF ₃ difluorocyclopropanecarbonyl) -4- fluoropyrrolidin-3-yl]-2- methylbenzamide 5-(4-amino-5-{[4- — (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - 728.2 1650 f] [ 1,2,4]triazin-7-yl)-X-[(3A48)- AG x Jtoh LC-MS, RT 4-fluoro-1 - [4,4,4-trifluoro-3 - OF ₃ 2.44 min hydroxy-3- (Method 1) (trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2-methylbenzamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl } pyrrolo[2,1 - AG X/Me 1651 f] [ 1,2,4]τpiazin-7-yl)-N-[(ЗR,4S)- ^F 608.2 4-fluoro-1 -(2-fluoro-2- Me ^F methylpropanoyl) pyrrolide in-3 - yl]-2-methylbenzamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - yl] methyl} pyrrolo[2,1 - AG AME 1652 f] [ 1,2,4]triazin-7-yl)-Sch(ZK,48)- ^CF 658.2 4-fluoro-1-(3,3,3-trifluoro-2,2dimethylpropanoyl)pyrrolide in-3 - ^CF ₃ Me ^UV 3 yl]-2-methylbenzamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - Me 7 F ₃ C ^0H yl] methyl } pyrrolo[2,1 - AG LC-MS, RT 1653 f] [ 1,2,4]triazin-7-yl)-M-[(3A48)- ^CF ₃ 1.46 min 4-fluoro-1-[2-hydroxy-2- (Method 1) (trifluoromethyl)butanoyl]pyrrolide in-3-yl]-2-methylbenzamide 5-(4-amino-5-{[4- (trifluoromethyl)piper idine-1 - F yl] methyl } pyrrolo[2,1 - ΑΓ 1654 f] [ 1,2,4]triazin-7-yl)-M-[(3A48)- member 642.2 4-fluoro-1-(2- ^F ₃ And fluorobenzoyl)pyrrolidin-3 -yl] -2- methylbenzamide

Connections in the table. 61 was obtained by the methods detailed in example 1578. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

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Table 61

Example Name R Ion mass observed in MS 1655 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl] pyrrolo[2,1-f] [1,2,4]triazin-7-yl} - N-[(3R,48)-1-(2,2- difluorocyclopropanecarbonyl)-4fluoropyrrole idin-3-yl]-4-fluoro-2methylbenzamide F Ar-XF 610.2 LC-MS, RT 2.03 min (Method 1) 1656 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl] pyrrolo[2,1-f] [1,2,4]triazin-7-yl } 4-fluoro-X-[( 3Sch48)-4-fluoro-1-[4,4,4-trifluoro3-hydroxy-3(trifluoromethyl)butanoyl]pyrrolidin-3-yl]2-methylbenzamide CF ₃ GF ₃ 714.2 1657 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7-yl } 4-φτορ-Ν-[( 3^48)-4-φτορ-1-(3,3,3-trifluoro2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2methylbenzamide X^Me Me ^CF 3 644.2 1658 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} 4-φτop-N-[( 3R,4S)-4-φτop-l-[(2R)-3,3,3trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide ?OCF ₃ Tone 646.2 1659 5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f] [1,2,4]triazin-7-yl } 4-φτορ-Ν-[( 3^48)-4-φτορ-1-(3methylbutanoyl)pyrrolide in-3-yl]-2methylbenzamide Me 590.3 1660 5-{4-Amino-5-[(4,4-difluoropiperidin-1yl)methyl] pyrrolo[2,1-ί] [1,2,4]triazin-7-yl } 4-fluoro-X-[( 3Sch48)-4-fluoro-1-(2-fluoro-2methylpropanoyl)pyrrolidin-3-yl]-2methylbenzamide X^Me Me ^F 594.2

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Table 62

NMR data for selected examples from the table. 57-61

Example Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ 1581 9.04 - 8.82 (m, 1H), 8.80 - 8.63 (m, 1H), 8.63 - 8.24 (m, 1H), 8.17 - 7.89 (m, 1H), 7.32-7.15 (m, 1H), 5.45 - 5.12 (m , 1H), 4.88 - 4.58 (m, 1H), 4.22 - 3.07 (m, 14H), 2.88 - 2.61 (m, 4H), 2.46 - 2.24 (m, 2H) 1582 9.01 - 8.93 (m, 1H), 8.80 - 8.68 (m, 1H), 8.61 - 8.43 (m, 1H), 8.11 - 7.99 (m, 1H), 7.43 - 7.27 (m, 1H), 5.60 - 5.18 (m, 2H), 4.88 - 4.60 (m, 2H), 4.10 - 4.00 (m, 3H), 4.00 - 3.23 (m, 6H), 3.22 - 3.06 (m, 4H), 2.92 - 2.68 (m, 4H) 1583 9.00 - 8.85 (m, 1H), 8.85 - 8.67 (m, 1H), 8.62 - 8.40 (m, 1H), 7.95 - 7.79 (m, 1H), 7.28 - 7.17 (m, 1H), 7.07 - 6.89 (m, 1H), 5.39 - 5.17 (m, 1H), 4.82 - 4.20 (m, 2H), 4.10 - 3.98 (m, 3H), 3.97 - 3.25 (m, 7H), 2.48 - 2.36 (m, 2H), 1.60 - 1.36 (m, 7H), 1.25 - 1.16 (m, 2H) 1584 9.02 - 8.81 (m, 1H), 8.78 - 8.64 (m, 1H), 8.64 - 8.42 (m, 1H), 8.11 - 7.88 (m, 1H), 7.38 - 7.30 (m, 1H), 5.43 - 5.14 (m, 1H), 4.84 - 4.56 (m, 3H), 4.55 - 4.25 (m, 1H), 4.10 - 3.99 (m, 3H), 3.99 - 3.55 (m, 4H), 3.44 - 3.29 (m, 4H), 1.61 - 1.46 (m, 3H), 1.32- 1.23 (m, 6H) 1585 8.96 - 8.84 (m, 1H), 8.81 - 8.73 (m, 1H), 8.59 - 8.48 (m, 1H), 7.92 - 7.78 (m, 2H), 7.31 - 7.15 (m, 1H), 7.13 - 6.91 (m, 1H), 5.40 - 5.10 (m, 1H), 4.78 - 4.57 (m, 1H), 4.56 - 4.30 (m, 1H), 4.30 - 4.22 (m, 1H), 4.07 - 3.98 (m, 5H), 3.95 - 3.11 (m, 3H), 2.92 - 2.74 (m, 1H), 2.47 - 2.39 (m, 1H), 2.24 - 2.06 (m, 1H), 2.01 - 1.77 (m, 2H), 1.77 - 1.61 (m, 1H), 1.59 - 1.43 (m, 3H) 1586 8.97 - 8.80 (m, 1H), 8.78 - 8.66 (m, 1H), 8.65 - 8.50 (m, 1H), 8.14 - 8.02 (m, 1H), 7.25 - 7.20 (m, 1H), 5.41 - 5.13 (m , 1H), 4.76 - 4.56 (m, 1H), 4.53 - 4.26 (m, 1H), 4.06 - 3.99 (m, 3H), 3.94 - 3.26 (m, 10H), 2.25 - 2.07 (m, 4H), 1.58 - 1.46 (m, 3H) 1587 9.34 - 9.10 (m, 1H), 9.00 - 8.91 (m, 1H), 8.86 - 8.71 (m, 1H), 8.60 - 8.42 (m, 1H), 7.96 - 7.78 (m, 1H), 7.70 - 7.49 (m , 1H), 7.21 - 7.11 (m, 1H), 7.10 - 6.98 (m, 1H), 5.39 - 5.18 (m, 1H), 4.77 - 4.58 (m, 1H), 4.53 - 4.25 (m, 1H), 4.08 - 3.98 (m, 3H), 3.99 - 3.26 (m, 6H), 3.12 - 3.01 (m, 1H), 2.94 - 2.77 (m, 1H), 2.16 - 2.00 (m, 2H), 1.96 - 1.83 (m, 1H), 1.83 - 1.68 (m, 1H), 1.59 - 1.42 (m, 4H), 1.42 - 1.28 (m, 1H) 1588 9.00 - 8.88 (m, 1H), 8.81 - 8.67 (m, 1H), 8.62 - 8.49 (m, 1H), 8.13 - 7.97 (m, 1H), 7.38 - 7.28 (m, 1H), 5.42 - 5.13 (m, 1H), 4.84 - 4.56 (m, 3H), 4.54 - 4.22 (m, 1H), 4.13 - 3.99 (m, 3H), 3.99 - 3.03 (m, 8H), 2.14 - 1.97 (m, 2H), 1.96 - 1.80 (m, 2H), 1.61 - 1.44 (m, 3H) 1589 8.99 - 8.85 (m, 1H), 8.80 - 8.68 (m, 1H), 8.64 - 8.44 (m, 1H), 8.13 - 8.00 (m, 1H), 7.22 - 7.16 (m, 1H), 5.40 - 5.16 (m , 1H), 4.75 - 4.57 (m, 1H), 4.51 - 4.26 (m, 1H), 4.15 - 2.74 (m, 13H), 2.45 - 2.31 (m, 2H), 1.61 - 1.47 (m, 3H) 1590 9.10 - 8.88 (m, 1H), 8.82 - 8.65 (m, 1H), 8.64 - 8.43 (m, 1H), 8.12 - 7.93 (m, 1H), 7.44.7.29 (m, 1H), 5.48 - 5.11 (m , 1H), 4.82 - 4.59 (m, 1H), 4.54 - 4.22 (m, 1H), 4.09-4.01 (m, 3H), 4.01 - 3.30 (m, 11H), 1.59-1.46 (m, 3H) 1591 10.19 - 9.95 (m, 1H), 9.09 - 8.85 (m, 1H), 8.85 - 8.71 (m, 1H), 8.61 - 8.41 (m, 1H), 7.92 - 7.82 (m, 1H), 7.82 - 7.61 (m, 1H), 7.19 - 6.93 (m, 2H), 5.42 - 5.08 (m, 1H), 4.82 - 4.55 (m, 1H), 4.55 - 4.19 (m, 1H), 4.09 - 4.00 (m, 3H), 4.00 - 2.98 (m, 4H), 2.75 - 2.51 (m, 4H), 1.61 - 1.41 (m, 9H), 1.39 - 1.30 (m, 3H) 1592 9.80 - 9.41 (m, 1H), 9.09 - 8.86 (m, 1H), 8.86 - 8.69 (m, 1H), 8.68 - 8.48 (m, 1H), 8.48 - 8.33 (m, 1H), 8.23 - 8.01 (m, 1H), 8.00 - 7.72 (m, 1H), 7.19 - 6.91 (m, 1H), 5.48 - 5.12 (m, 1H), 4.77 - 4.57 (m, 1H), 4.54 - 4.26 (m, 1H), 4.08 - 4.01 (m, 3H), 4.01 - 2.92 (m, 3H), 2.71 - 2.56 (m, 3H), 1.63 - 1.46 (m, 3H) 1593 8.99 - 8.86 (m, 1H), 8.84 - 8.72 (m, 1H), 8.56 - 8.38 (m, 1H), 7.95 - 7.78 (m, 1H), 7.11 - 7.02 (m, 1H), 7.02 - 6.87 (m, 1H), 5.41 - 5.13 (m, 1H), 4.81 - 4.58 (m, 1H), 4.56 - 4.22 (m, 1H), 4.08 - 4.01 (m, 3H), 4.01 - 3.25 (m, 3H), 3.20 - 3.13 (m, 3H), 1.62- 1.47 (m, 3H) 1594 8.96 - 8.90 (m, 1H), 8.84 - 8.77 (m, 1H), 8.60 - 8.46 (m, 1H), 8.01 - 7.94 (m, 1H), 7.33 - 7.24 (m, 1H), 7.13 - 7.03 (m , 1H), 5.41 - 5.15 (m, 1H), 4.76 - 4.55 (m, 1H), 4.55 - 4.27 (m, 1H), 4.10 - 4.01 (m, 3H), 4.01 - 3.03 (m, 3H), 1.63 - 1.46 (m, 3H)

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1595 9.00 - 8.89 (m, 1H), 8.85 - 8.70 (m, 1H), 8.59 - 8.45 (m, 1H), 8.05 - 7.99 (m, 1H), 7.21 - 7.09 (m, 2H), 5.40 - 5.18 (m , 1H), 4.80 - 4.57 (m, 1H), 4.54 - 4.26 (m, 1H), 4.11-4.01 (m, 3H), 4.01 -3.13 (m, 3H), 1.62-1.49 (m, 3H) 1596 9.00 - 8.91 (m, 1H), 8.80 - 8.69 (m, 1H), 8.55 - 8.46 (m, 1H), 8.13 - 8.05 (m, 1H), 7.24 - 7.17 (m, 1H), 5.44 - 5.21 (m , 1H), 4.89 - 4.55 (m, 1H), 4.11 - 4.00 (m, 3H), 4.00 - 3.02 (m, 11H), 2.88 - 2.67 (m, 4H), 2.33 - 2.03 (m, 4H) 1597 9.55 - 9.21 (m, 1H), 9.02 - 8.90 (m, 1H), 8.86 - 8.70 (m, 1H), 8.58 - 8.37 (m, 1H), 7.97 - 7.83 (m, 1H), 7.83 - 7.60 (m, 1H), 7.13 - 6.95 (m, 1H), 5.48 - 5.16 (m, 1H), 4.90 - 4.57 (m, 1H), 4.12 - 4.01 (m, 3H), 4.01 - 3.13 (m, 7H), 3.13 - 3.01 (m, 2H), 2.94 - 2.65 (m, 4H), 2.47 - 2.32 (m, 1H), 2.16 - 2.00 (m, 2H), 1.92 - 1.80 (m, 2H), 1.56 - 1.37 (m, 2H) 1598 9.57 - 9.17 (m, 1H), 9.02 - 8.86 (m, 1H), 8.82 - 8.70 (m, 1H), 8.57 - 8.38 (m, 1H), 7.97 - 7.85 (m, 1H), 7.81 - 7.48 (m, 1H), 7.13 - 7.00 (m, 2H), 5.38 - 5.16 (m, 1H), 4.77 - 4.56 (m, 1H), 4.54 - 4.23 (m, 1H), 4.11 - 3.24 (m, 9H), 3.14 - 2.96 (m, 2H), 2.46-2.31 (m, 1H), 218-1.98 (m, 2H), 1.92-1.83 (m, 2H), 1.58-1.51 (m, 2H), 1.52- 1.36 (m, 2H) 1599 9.09 - 8.92 (m, 1H), 8.92 - 8.75 (m, 1H), 8.63 - 8.43 (m, 1H), 8.02 - 7.88 (m, 1H), 7.24 - 7.14 (m, 2H), 7.14 - 7.06 (m , 1H), 6.78 - 6.64 (m, 2H), 5.46 - 5.14 (m, 1H), 4.96 - 4.44 (m, 1H), 4.11 - 4.01 (m, 3H), 4.02 - 3.07 (m, 5H), 2.91 - 2.66 (m, 4H) 1600 9.62 - 9.31 (m, 1H), 9.04 - 8.89 (m, 1H), 8.88 - 8.74 (m, 1H), 8.58 - 8.42 (m, 1H), 8.00 - 7.83 (m, 1H), 7.73 - 7.50 (m, 1H), 7.22 - 7.02 (m, 4H), 5.38 - 5.14 (m, 1H), 4.81 - 4.57 (m, 1H), 4.56 - 4.24 (m, 1H), 4.10 - 4.01 (m, 3H), 4.01 - 3.09 (m, 7H), 2.94 - 2.76 (m, 4H), 1.60 - 1.47 (m, 3H) 1601 8.92 - 8.80 (m, 1H), 8.75 - 8.61 (m, 1H), 8.60 - 8.47 (m, 1H), 7.93 - 7.82 (m, 3H), 7.54 - 7.41 (m, 2H), 6.98 - 6.92 (m , 1H), 5.42 - 5.14 (m, 1H), 4.88 - 4.58 (m, 1H), 4.08 - 4.01 (m, 3H), 4.01 - 3.08 (m, 5H), 2.91 - 2.65 (m, 4H), 2.45 - 2.39 (m, 3H) 1602 9.01 - 8.91 (m, 1H), 8.85 - 8.74 (m, 1H), 8.58 - 8.42 (m, 1H), 8.14 - 8.04 (m, 1H), 7.73 - 7.46 (m, 1H), 7.45 - 7.39 (m, 1H), 7.10 - 7.01 (m, 1H), 5.39 - 5.18 (m, 1H), 4.82 - 4.58 (m, 1H), 4.57 - 4.26 (m, 1H), 4.14 - 3.99 (m, 3H), 4.00 - 3.10 (m, 4H), 1.59- 1.48 (m, 3H) 1603 9.06 - 8.75 (m, 1H), 8.75 - 8.58 (m, 1H), 8.58 - 8.44 (m, 1H), 8.13 - 7.98 (m, 1H), 7.98 - 7.71 (m, 2H), 6.99 - 6.63 (m , 1H), 5.39 - 5.13 (m, 1H), 4.87 - 4.56 (m, 1H), 4.57.4.24 (m, 1H), 4.15 - 4.01 (m, 3H), 4.01 - 3.29 (m, 4H), 1.63 - 1.48 (m, 3H) 1604 9.09 - 8.88 (m, 1H), 8.85 - 8.69 (m, 1H), 8.63 - 8.50 (m, 1H), 7.96 - 7.64 (m, 2H), 7.14 - 7.02 (m, 1H), 7.02 - 6.83 (m, 1H), 6.69 - 6.37 (m, 1H), 5.41 - 5.14 (m, 1H), 4.80 - 4.53 (m, 1H), 4.53 - 4.23 (m, 1H), 4.11 - 4.00 (m, 3H), 4.00 - 3.22 (m, 6H), 1.61 - 1.42 (m, 3H) 1605 8.98 - 8.83 (m, 1H), 8.85 - 8.73 (m, 1H), 8.60 - 8.46 (m, 1H), 7.94 - 7.84 (m, 1H), 7.17 - 7.04 (m, 2H), 5.41 - 5.16 (m, 1H), 4.87 - 4.58 (m, 1H), 4.57 - 4.25 (m, 1H), 4.10 - 4.00 (m, 3H), 4.00 - 3.18 (m, 3H), 1.59 - 1.49 (m, 3H) 1606 9.02 - 8.84 (m, 1H), 8.83 - 8.72 (m, 1H), 8.61 - 8.47 (m, 1H), 7.95 - 7.88 (m, 1H), 7.37 - 6.99 (m, 3H), 5.39 - 5.16 (m, 1H), 4.81 - 4.59 (m, 1H), 4.53 - 4.27 (m, 1H), 4.09 - 4.00 (m, 3H), 4.00 - 3.06 (m, 3H), 1.60 - 1.44 (m, 3H) 1607 8.97 - 8.85 (m, 1H), 8.76 - 8.67 (m, 1H), 8.61 - 8.44 (m, 1H), 8.11 - 8.04 (m, 1H), 7.26 - 7.23 (m, 1H), 5.38 - 5.15 (m, 1H), 4.77 - 4.58 (m, 1H), 4.53 - 4.27 (m, 1H), 4.09 - 4.02 (m, 3H), 3.98 - 3.35 (m, 10H), 2.94 - 2.86 (m, 1H), 2.75 - 2.69 (m, 1H), 1.60- 1.49 (m, 3H)

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1608 9.61 - 9.33 (m, 1H), 9.00 - 8.87 (m, 1H), 8.83 - 8.71 (m, 1H), 8.56 - 8.41 (m, 1H), 7.95 - 7.87 (m, 1H), 7.87 - 7.61 (m , 1H), 7.18 - 7.00 (m, 2H), 5.46 - 5.16 (m, 1H), 4.81 - 4.59 (m, 1H), 4.54 - 4.24 (m, 1H), 4.08 - 4.01 (m, 3H), 3.87 - 3.82 (m, 2H), 3.99 - 3.11 (m, 5H), 2.22 - 1.97 (m, 6H), 1.88 - 1.75 (m, 2H), 1.59 - 1.44 (m, 3H) 1609 10.01 - 9.74 (m, 1H), 8.97 - 8.87 (m, 1H), 8.84 - 8.73 (m, 1H), 8.58 - 8.40 (m, 1H), 7.94 - 7.82 (m, 1H), 7.75 - 7.56 (m, 1H), 7.19 - 6.94 (m, 2H), 5.38 - 5.18 (m, 1H), 4.82 - 4.59 (m, 1H), 4.56 - 4.27 (m, 1H), 4.11 - 4.02 (m, 3H), 3.77 - 3.73 (m, 2H), 3.99 - 3.26 (m, 7H), 1.60 - 1.51 (m, 3H), 1.44 - 1.28 (m, 4H), 1.01 - 0.84 (m, 6H) 1611 9.83 - 9.36 (m, 1H), 9.06 - 8.88 (m, 1H), 8.88 - 8.66 (m, 1H), 8.59 - 8.42 (m, 1H), 8.00 - 7.81 (m, 1H), 7.84 - 7.35 (m, 1H), 7.15 - 6.91 (m, 1H), 5.48 - 5.16 (m, 1H), 4.93 - 4.57 (m, 1H), 4.13 - 4.02 (m, 3H), 4.02 - 3.53 (m, 6H), 3.53 - 3.10 (m, 4H), 2.89 - 2.68 (m, 5H), 1.82 - 1.48 (m, 4H), 1.38 - 1.24 (m, 2H) 1612 9.76 - 9.43 (m, 1H), 9.01 - 8.86 (m, 1H), 8.86 - 8.66 (m, 1H), 8.60 - 8.46 (m, 1H), 7.95 - 7.84 (m, 1H), 7.82 - 7.47 (m , 1H), 7.09 (s, 1H), 5.47 - 5.16 (m, 1H), 4.97 - 4.49 (m, 1H), 4.14 - 3.99 (m, 3H), 3.99 - 3.48 (m, 6H), 3.47 - 3.34 ( m, 2H), 3.32 3.02 (m, 2H), 2.91 - 2.66 (m, 4H), 2.24 - 1.96 (m, 7H), 1.86 - 1.71 (m, 2H) 1613 9.66-9.49 (bs, 1H), 9.01 - 8.86 (m, 1H), 8.86 - 8.69 (m, 1H), 8.61 - 8.41 (m, 1H), 8.04 - 7.85 (m, 1H), 7.77-7.68 (bs , 1 H), 7.14 - 6.89 (m, 1H), 5.45 - 5.14 (m, 1H), 4.97-4.57 (m, 3H), 4.17 - 3.95 (m, 3H), 3.92 - 3.58 (m, 6H), 1.85 - 1.45 (m, 4H), 1.36- 1.19 (m, 2H) 1614 9.75 - 9.30 (m, 1H), 9.06 - 8.86 (m, 1H), 8.82 - 8.74 (m, 1H), 8.59 - 8.49 (m, 1H), 7.95 - 7.80 (m, 1H), 7.80 - 7.44 (m, 1H), 7.12 - 6.97 (m, 1H), 5.46 - 5.19 (m, 1H), 4.85 - 4.58 (m, 3H), 4.10 - 3.93 (m, 3H), 3.97 - 3.26 (m, 6H), 3.12 - 2.96 (m, 2H), 2.46 - 2.29 (m, 1H), 2.18 - 2.03 (m, 2H), 1.92 - 1.77 (m, 2H), 1.56 - 1.38 (m, 2H) 1615 9.00 - 8.84 (m, 1H), 8.84 - 8.66 (m, 1H), 8.63 - 8.37 (m, 1H), 7.94 - 7.82 (m, 1H), 7.61 - 7.43 (m, 2H), 7.43 - 7.24 (m , 2H), 7.09 - 6.88 (m, 1H), 5.54 - 5.14 (m, 1H), 4.92 - 4.53 (m, 1H), 4.09 - 3.96 (m, 3H), 3.96 - 3.32 (m, 6H), 3.30 - 3.09 (m, 4H), 2.16- 2.00 (m, 2H) 1616 8.88 - 8.60 (m, 3H), 7.77 (s, 1H), 7.13 - 6.89 (m, 1H), 5.44 - 5.09 (m, 1H), 4.76 - 4.19 (m, 2H), 4.06 - 3.24 (m, 12H), 1.59 - 1.42 (m, 3H) 1617 8.83 - 8.56 (m, 3H), 7.87 - 7.71 (m, 1H), 7.04 - 6.90 (m, 1H), 5.44 - 5.20 (m, 1H), 4.82-4.59 (m, 1H), 4.03 - 3.90 (m , 5H), 3.76 - 3.65 (m, 4H), 4.15 - 3.22 (m, 4H), 2.98 - 2.75 (m, 1H), 1.99 - 1.77 (m, 2H) 1618 8.96 - 8.86 (m, 1H), 8.82 - 8.63 (m, 1H), 8.63 - 8.47 (m, 1H), 7.96 - 7.80 (m, 1H), 7.20 - 6.95 (m, 1H), 5.39 - 5.15 (m , 1H), 4.87 - 4.59 (m, 1H), 4.52 - 2.90 (m, 6H), 4.11 - 3.95 (m, 3H), 3.82 - 3.59 (m, 4H), 1.53 - 1.36 (m, 6H) 1619 8.84 - 8.55 (m, 4H), 8.02 - 7.71 (m, 1H), 7.15 - 7.10 (m, 1H), 5.38 - 5.02 (m, 1H), 4.76 - 4.50 (m, 1H), 4.18 - 4.04 (m , 2H), 4.04 - 3.94 (m, 3H), 3.94 - 3.81 (m, 4H), 3.81 - 3.19 (m, 4H), 1.22 - 1.05 (m, 9H) 1620 8.84 - 8.75 (m, 1H), 8.74 - 8.56 (m, 2H), 7.99 - 7.79 (m, 1H), 7.19 - 7.12 (m, 1H), 5.38 - 5.12 (m, 1H), 4.82 - 4.52 (m, 1H), 4.21 - 4.12 (m, 2H), 4.02 - 3.97 (m, 3H), 3.94 - 3.84 (m, 4H), 4.07 - 3.02 (m, 4H), 2.36 - 2.19 (m, 2H), 2.19 - 1.98 (m, 4H), 1.83 - 1.63 (m, 1H) 1621 9.35 - 9.07 (m, 1H), 8.98 - 8.90 (m, 1H), 8.81 - 8.73 (m, 1H), 8.64 - 8.47 (m, 1H), 7.93 - 7.84 (m, 1H), 7.80 - 7.47 (m, 1H), 7.08 - 7.01 (m, 1H), 5.50 - 5.20 (m, 1H), 4.98 - 4.62 (m, 1H), 4.36 - 4.08 (m, 1H), 4.08 - 4.00 (m, 3H), 4.00 - 2.84 (m, 6H), 2.73 - 2.59 (m, 4H), 2.13 - 1.82 (m, 6H)

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1622 9.00 - 8.89 (m, IH), 8.85 - 8.71 (m, IH), 8.65 - 8.41 (m, IH), 8.00 - 7.84 (m, IH), 7.13 - 6.99 (m, IH), 5.40 - 5.19 (m, IH), 4.97 - 4.52 (m, IH), 4.13 - 4.02 (m, 3H), 3.89 - 3.75 (m, 2H), 4.38 - 3.26 (m, 4H), 2.75 - 2.58 (m, 4H), 2.10 - 1.89 (m, 4H), 1.56 - 1.47 (m, 3H), 1.47 - 1.38 (m, 3H) 1623 9.41 - 9.05 (m, IH), 8.95 - 8.87 (m, IH), 8.84 - 8.68 (m, IH), 8.56 - 8.42 (m, IH), 7.94 - 7.78 (m, IH), 7.70 - 7.43 (m, IH), 7.08 - 7.01 (m, IH), 5.45 - 5.17 (m, IH), 4.91 - 4.48 (m, IH), 4.06 - 4.00 (m, 3H), 3.84-3.78 (m, 2H), 4.22 - 3.03 (m, 5H), 2.74 - 2.58 (m, 4H), 2.44 - 2.25 (m, 2H), 2.23 - 2.12 (m, IH), 2.12 - 1.95 (m, 6H), 1.89- 1.72 (m, IH) 1624 8.98 - 8.85 (m, IH), 8.84 - 8.68 (m, IH), 8.62 - 8.39 (m, IH), 7.98 - 7.86 (m, IH), 7.13 - 7.04 (m, IH), 5.40 - 5.17 (m, IH), 4.86 - 4.56 (m, IH), 4.31 - 4.06 (m, IH), 4.06 - 4.00 (m, 3H), 4.00 - 3.45 (m, 5H), 2.71 - 2.59 (m, 4H), 2.14 - 1.93 (m, 4H), 1.62- 1.49 (m, 6H) 1626 9.50 - 9.03 (m, IH), 9.00 - 8.84 (m, IH), 8.84 - 8.66 (m, IH), 8.66 - 8.29 (m, IH), 7.95 - 7.84 (m, IH), 7.78 - 7.41 (m , 3H), 7.40 - 7.25 (m, 2H), 7.13 - 6.97 (m, IH), 5.57 - 5.15 (m, IH), 5.00 - 4.62 (m, IH), 4.19 - 3.25 (m, 9H), 2.74 - 2.56 (m, 4H), 2.16-1.91 (m, 4H) 1627 9.59 - 9.28 (m, IH), 9.09 - 8.90 (m, IH), 8.80 - 8.72 (m, IH), 8.65 - 8.32 (m, IH), 7.97-7.87 (m, IH), 7.83-7.54 (m, IH), 7.12-7.03 (m, IH), 5.55-5.17 (m, IH), 5.03 - 4.65 (m, IH), 4.44 - 3.45 (m, 8H), 3.15 - 3.03 (m, 2H), 3.03 - 2.80 (m, IH), 2.47 - 2.29 (m, IH), 2.17 - 2.02 (m, 2H), 2.02 - 1.77 (m, 5H), 1.60 - 1.32 (m, 2H) 1628 9.55 - 9.31 (m, IH), 9.00 - 8.86 (m, IH), 8.82 - 8.72 (m, IH), 8.58 - 8.41 (m, IH), 7.96-7.84 (m, IH), 7.82 - 7.59 (m, IH), 7.13 - 7.00 (m, IH), 5.48 - 5.17 (m, IH), 4.88 - 4.53 (m, IH), 4.32 - 3.51 (m, 9H), 3.13 - 2.98 (m, 2H), 2.47 - 2.30 (m, IH), 2.19 - 2.04 (m, 2H), 1.94 - 1.79 (m, 2H), 1.65 - 1.36 (m, 8H) 1630 9.56 - 9.27 (m, IH), 9.01 - 8.89 (m, IH), 8.85 - 8.69 (m, IH), 8.58 - 8.35 (m, IH), 7.98 - 7.85 (m, IH), 7.86 - 7.52 (m, IH), 7.13 - 6.93 (m, IH), 5.46 - 5.18 (m, IH), 4.88 - 4.55 (m, IH), 4.43 - 3.60 (m, 9H), 3.15 - 2.98 (m, 2H), 2.46 - 2.29 (m, IH), 2.17 - 1.99 (m, 2H), 1.96 - 1.79 (m, 2H), 1.54 - 1.38 (m, 8H) 1631 9.59 - 9.16 (m, IH), 9.03 - 8.87 (m, IH), 8.85 - 8.66 (m, IH), 8.60 - 8.37 (m, IH), 7.99 - 7.82 (m, IH), 7.82 - 7.61 (m, IH), 7.61 - 7.40 (m, 2H), 7.40 - 7.20 (m, 2H), 7.12 - 6.85 (m, IH), 5.59 - 5.14 (m, IH), 4.97 - 4.60 (m, IH), 4.18 - 3.45 (m, 8H), 3.18-2.92 (m, 2H), 2.47 - 2.27 (m, IH), 2.18-1.98 (m, 2H), 1.95 - 1.78 (m, 3H), 1.55 - 1.35 (m, 2H) 1633 9.41 - 9.02 (m, IH), 8.39 - 8.22 (m, 2H), 7.95 - 7.79 (m, IH), 7.73 - 7.38 (m, IH), 7.30 - 7.14 (m, IH), 6.85 - 6.72 (m , IH), 5.44 - 5.15 (m, IH), 4.89 - 4.53 (m, IH), 4.11 -3.04 (m, 10H), 2.89-2.72 (m, 4H), 2.72 - 2.57 (m, 4H), 2.11 - 1.94 (m, 4H) 1635 9.40 - 8.92 (m, IH), 8.56 - 8.18 (m, 2H), 7.90 - 7.73 (m, IH), 7.52 (br s, IH), 7.31 - 7.07 (m, IH), 6.89 - 6.62 (m, IH), 5.49 - 5.16 (m, IH), 4.91 - 4.60 (m, IH), 4.33 - 3.47 (m, 9H), 3.19 - 2.89 (m, 3H), 2.77 - 2.57 (m, 4H), 2.13 - 1.94(m, 4H) 1636 9.42 - 8.94 (m, IH), 8.47 - 8.25 (m, 2H), 7.88 - 7.78 (m, IH), 7.73 - 7.35 (m, IH), 7.30 - 7.20 (m, IH), 6.87 - 6.75 (m , IH), 5.40 - 5.11 (m, IH), 4.84 - 4.55 (m, IH), 4.30 - 3.26 (m, 9H), 2.75 - 2.59 (m, 4H), 2.15 - 1.94 (m, 4H), 1.64 - 1.43 (m, 6H) 1637 9.46 - 9.09 (m, IH), 8.43 - 8.28 (m, 2H), 7.91 - 7.77 (m, IH), 7.75 - 7.43 (m, IH), 7.35 - 7.15 (m, IH), 6.95 - 6.70 (m, 2H), 5.41 - 5.06 (m, IH), 4.83 - 4.54 (m, IH), 4.54.4.24 (m, IH), 4.16 - 3.32 (m, 8H), 2.75 - 2.57 (m, 4H), 2.28 - 1.93 (m, 5H), 1.86 - 1.61 (m, IH), 1.02 - 0.80 (m, 3H)

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1638 8.63 - 8.24 (m, 2H), 7.96 - 7.77 (m, 1H), 7.37 - 7.05 (m, 1H), 6.96 - 6.63 (m, 1H), 5.51-5.11 (m, 1H), 4.89 - 4.51 (m , 1H), 4.29 - 3.59 (m, 9H), 2.77 - 2.58 (m, 4H), 2.17 - 1.95 (m, 4H), 1.61 - 1.38 (m, 6H) 1639 9.98 - 9.17 (m, 1H), 8.58 - 8.20 (m, 2H), 7.93 - 7.75 (m, 1H), 7.76 - 7.32 (m, 1H), 7.32 - 7.15 (m, 1H), 7.16 - 7.08 (m , _1H ); - 2.96 (m, 1H), 2.43 - 2.24 (m, 2H), 2.18 - 2.00 (m, 2H), 1.91 - 1.73 (m, 2H), 1.63 - 1.50 (m, 3H), 1.50 - 1.30 (m, 2H) 1640 9.73 - 9.21 (m, 1H), 8.46 - 8.17 (m, 2H), 7.87 - 7.77 (m, 1H), 7.77 - 7.53 (m, 1H), 7.32 - 7.05 (m, 1H), 6.88 - 6.64 (m , 1H), 5.53 - 5.12 (m, 1H), 4.88 - 4.50 (m, 1H), 4.07-3.11 (m, 10H), 3.10-2.96 (m, 2H), 2.90 - 2.64 (m, 4H), 2.45 - 2.29 (m, 1H), 2.18-1.97 (m, 2H), 1.91 - 1.76 (m, 2H), 1.54 - 1.33 (m, 2H) 1641 9.42 - 8.96 (m, 1H), 8.79 - 8.52 (m, 1H), 8.12 - 8.02 (m, 1H), 8.02 - 7.92 (m, 1H), 7.92 - 7.82 (m, 1H), 7.72 - 7.43 (m, 1H), 7.39 - 7.23 (m, 1H), 7.09 - 6.87 (m, 1H), 5.53 - 5.12 (m, 1H), 4.82 - 4.46 (m, 1H), 4.19 - 3.46 (m, 5H), 2.87 - 2.71 (m, 4H), 2.69 - 2.57 (m, 4H), 2.41 - 2.33 (m, 3H), 2.13 - 1.96 (m, 4H), 1.94 - 1.84 (m, 2H) 1642 9.42 - 8.91 (m, 1H), 8.80 - 8.54 (m, 1H), 8.15 - 8.00 (m, 1H), 8.01 - 7.93 (m, 1H), 7.93 - 7.78 (m, 1H), 7.72 - 7.42 (m, 1H), 7.40 - 7.18 (m, 1H), 7.06 - 6.88 (m, 1H), 5.52 - 5.17 (m, 1H), 4.94 - 4.43 (m, 1H), 4.23 - 3.45 (m, 7H), 3.24 - 2.82 (m, 2H), 2.70 - 2.56 (m, 4H), 2.41 - 2.28 (m, 3H), 2.11-1.92 (m, 4H) 1643 9.39 - 8.98 (m, 1H), 8.73 - 8.55 (m, 1H), 8.11 - 8.02 (m, 1H), 8.02 - 7.93 (m, 1H), 7.93 - 7.81 (m, 1H), 7.69 - 7.42 (m, 1H), 7.42 - 7.19 (m, 1H), 7.05 - 6.86 (m, 1H), 5.49 - 5.14 (m, 1H), 4.80 - 4.43 (m, 1H), 4.28 - 3.55 (m, 6H), 2.70 - 2.56 (m, 4H), 2.44 - 2.32 (m, 3H), 2.12 - 1.95 (m, 4H), 1.64 - 1.43 (m, 6H) 1645 8.75 - 8.50 (m, 1H), 8.14 - 8.02 (m, 1H), 8.02 - 7.92 (m, 1H), 7.92 - 7.84 (m, 1H), 7.40 - 7.21 (m, 1H), 7.13 - 6.88 (m, 1H), 5.56 - 5.16 (m, 1H), 4.80 - 4.49 (m, 1H), 3.95 - 3.73 (m, 6H), 2.70 - 2.57 (m, 4H), 2.43 - 2.32 (m, 3H), 2.08 - 1.95 (m, 4H), 1.55 - 1.36 (m, 6H) 1646 8.79 - 8.46 (m, 1H), 8.17 - 7.76 (m, 3H), 7.61 - 7.39 (m, 3H), 7.39 - 7.21 (m, 3H), 7.06 - 6.89 (m, 1H), 5.53 - 5.10 (m , 1H), 4.90 - 4.52 (m, 1H), 4.12 - 3.33 (m, 5H), 2.74 - 2.57 (m, 3H), 2.45 - 2.29 (m, 4H), 2.12 - 1.94 (m, 4H) 1647 9.63 - 9.08 (m, 1H), 8.77 - 8.46 (m, 1H), 8.11 - 8.04 (m, 1H), 8.04 - 7.92 (m, 1H), 7.92 - 7.80 (m, 1H), 7.80 - 7.53 (m, 1H), 7.45 - 7.24 (m, 1H), 7.08 - 6.75 (m, 1H), 5.43 - 5.10 (m, 1H), 4.81 - 4.46 (m, 1H), 4.46 - 4.22 (m, 1H), 4.09 - 3.57 (m, 4H), 3.15 - 2.87 (m, 2H), 2.47 - 2.28 (m, 3H), 2.19 - 2.04 (m, 2H), 1.95 - 1.80 (m, 5H), 1.62 - 1.52 (m, 3H), 1.52-1.31 (m, 2H) 1648 9.55 - 9.16 (m, 1H), 8.74 - 8.58 (m, 1H), 8.10 - 8.02 (m, 1H), 8.02 - 7.91 (m, 1H), 7.91 - 7.81 (m, 1H), 7.81 - 7.49 (m, 1H), 7.43 - 7.27 (m, 1H), 7.05 - 6.91 (m, 1H), 5.49 - 5.13 (m, 1H), 4.89 - 4.44 (m, 1H), 4.09 - 3.52 (m, 6H), 3.29 - 3.10 (m, 1H), 3.10 - 2.96 (m, 2H), 2.96 - 2.65 (m, 4H), 2.46 - 2.28 (m, 4H), 2.20 - 2.01 (m, 2H), 2.01 - 1.76 (m, 2H), 1.59 - 1.27 (m, 2H) 1649 9.58 - 9.18 (m, 1H), 8.81 - 8.54 (m, 1H), 8.12 - 7.99 (m, 1H), 8.03 - 7.93 (m, 1H), 7.92 - 7.81 (m, 1H), 7.78 - 7.48 (m, 1H), 7.42 - 7.25 (m, 1H), 7.08 - 6.89 (m, 1H), 5.59 - 5.15 (m, 1H), 4.92 - 4.52 (m, 1H), 4.36 - 3.44 (m, 6H), 3.12 - 2.79 (m, 3H), 2.45 - 2.32 (m, 4H), 2.20 - 2.02 (m, 2H), 2.02 - 1.76 (m, 4H), 1.59 - 1.26 (m, 2H)

- 477 042342

1651 9.52-9.11 (m, 1H), 8.79 - 8.39 (m, 1H), 8.19-8.03 (m, 1H), 8.03 -7.92 (m, 1H), 7.92 - 7.77 (m, 1H), 7.77 - 7.50 (m, 1H), 7.41 - 7.24 (m, 1H), 7.08 - 6.86 (m, 1H), 5.50 - 5.09 (m, 1H), 4.80 - 4.40 (m, 1H), 4.23 - 3.53 (m, 5H), 3.10 - 2.97 (m, 2H), 2.45 - 2.29 (m, 4H), 2.15 - 1.99 (m, 2H), 1.99 - 1.83 (m, 2H), 1.62 - 1.33 (m, 8H) 1652 9.54 - 9.17 (w, 1H), 8.78 - 8.48 (m, 1H), 8.13 - 8.02 (m, 1H), 8.02 - 7.93 (m, 1H), 7.93 - 7.82 (m, 1H), 7.82 - 7.49 (m, 1H), 7.43 - 7.21 (m, 1H), 7.07 - 6.91 (m, 1H), 5.48 - 5.10 (m, 1H), 4.89 - 4.44 (m, 1H), 4.44 - 3.52 (m, 6H), 3.14 - 2.94 (m, 2H), 2.47 - 2.31 (m, 4H), 2.16 - 2.00 (m, 2H), 1.97 - 1.80 (m, 2H), 1.54 - 1.34 (m, 8H) 1654 9.51 - 9.16 (m, 1Н), 8.93 - 8.46 (m, 1Н), 8.15 - 7.79 (t, ZN), 7.79 - 7.60 (m, 1Н), 7.58 - 7.43 (m, 2Н), 7.39 - 7.26 (t, ZN), 7.04 - 6.83 (m, 1Н), 5.49 - 5.12 (m, 1Н), 4.95 - 4.51 (m, 1H), 4.13 - 3.24 (m, 6H), 3.14 - 2.95 (m, 2H), 2.46 - 2.27 (m, 4H), 2.16 - 2.00 (m, 2H), 1.93 - 1.77 (m, 2H), 1.55 - 1.30 (m, 2H) 1656 9.43 - 8.95 (w, 1H), 8.79 - 8.60 (m, 1H), 7.94 - 7.75 (m, 2H), 7.76 - 7.38 (m, 1H), 7.34 - 7.22 (m, 1H), 6.88 - 6.73 (m, 1H), 5.50 - 5.14 (m, 1H), 4.92 - 4.50 (m, 1H), 4.27 - 3.41 (m, 7H), 3.20 - 2.85 (t, 2H), 2.72 - 2.58 (t, 4H), 2.48 - 2.37 (t, 3H), 2.14-1.93 (t, 4H) 1657 9.43 - 9.01 (t, 1H), 8.73 - 8.51 (t, 1H), 7.92 - 7.86 (t, 1H), 7.86 - 7.76 (t, 1H), 7.74 - 7.36 (t, 1H), 7.31 - 7.09 (t, 1H), 6.89 - 6.77 (t, 1H), 5.45 - 5.13 (t, 1H), 4.82 - 4.47 (t, 1H), 4.34 - 3.52 (t, 6H), 2.76 - 2.57 (t, 3H), 2.46 - 2.34 (t, 4H), 2.09 - 1.96 (t, 4H), 1.54 - 1.38 (t, 6H) 1658 9.52 - 8.98 (t, 1H), 8.79 - 8.56 (t, 1H), 7.92 - 7.74 (t, 1H), 7.75 - 7.34 (t, 1H), 7.33 - 7.17 (t, 1H), 6.90 - 6.70 (t , 1Н), 5.44 - 5.12 (t, 1Н), 4.70 - 4.45 (t, 1Н), 4.42-4.24 (t, 1Н), 4.16 - 3.30 (t, YuN), 2.54 - 2.46 (t, 4Н), 2.13 - 1.96 (t, 4N), 1.60- 1.44 (t, ZN) 1659 9.40 - 9.11 (t, 1H), 8.78 - 8.46 (t, 1H), 7.93 - 7.76 (t, 2H), 7.72 - 7.44 (t, 1H), 7.34-7.11 (t, 1H), 6.89-6.73 (t, 1H), 5.46-5.10 (t, 1H), 4.84-4.40 (t, 1H), 4.14 - 3.09 (t, 6H), 2.71 - 2.58 (t, GL), 2.45 - 2.32 (t, 4H), 2.19 - 2.08 (t, 2H), 2.08 - 1.96 (t, 5N), 1.00 - 0.80 (t, 6N) 1660 9.49 - 9.06 (t, 1H), 8.78 - 8.53 (t, 1H), 7.97 - 7.84 (t, 1H), 7.84 - 7.76 (t, 1H), 7.75 -7.45 (t, 1H), 7.36-7.11 (t, 1H), 6.97-6.61 (t, 1H), 5.49-5.11 (t, 1H), 4.82 - 4.47 (t, 1H), 4.32 - 3.27 (t, 6H), 2.74 - 2.60 (t, 4H), 2.46 - 2.37 (t, 3N), 2.12 - 1.94 (t, 4H), 1.63 - 1.39 (t, 6H)

Connections in the table. 63 was obtained by the methods detailed in example 1579. Compounds were isolated as a mixture of diastereomers.

- 478 042342

Table 63 h ₂ n

O

1661 5-[4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7ππ]-Ν-{4-φτορ-1[4,4,4-trifluoro-3hydroxy-3 (trifluoromethyl)butane oil]piperidin-3yl}-2methoxypyride in-3 carboxamide No. CF ₃ CF ₃ 662.1 2.11(2) 1662 5-{4-amino-5-[(4,4d iftorpiperidin-1 yl)methyl]pyrrolo[2, 1-f] [1,2,4]triazin-7yl}-X-[1-(3,3difluorocyclobutane pbonyl)-4fluoropiper idin-3 yl]-2methoxypyride in-3 carboxamide F ^SD-f F 637.2 2.16(1) 1663 5-{4-amino-5-[(4,4d iftorpiperidin-1 yl)methyl]pyrrolo[2, 1-f] [ 1,2,4]triazine-7ππ}-Ν-{4-φτορ-1[ (2R)-3,3,3-trifluoro2-hydroxy-2methylpropanoyl] piper idin-3 -yl } -2methoxypyride in-3 carboxamide HhA AAh F Z/CF _3'oh 659.2 1.53(2) 1664 5-{4-amino-5-[(4,4d iftorpiperidin-1 yl)methyl]pyrrolo[2, 1-f] [ 1,2,4]triazine-7ππ}-Ν-[4-φτορ-1- (2fluorobenzoyl)piperidin-3-yl]-2methoxypyride in-3 carboxamide F ύ 641.2 2.18(1) 1665 5-{4-amino-5-[(4,4difluoropiperidin-1 yl)methyl]pyrrolo[2, 1-f][ 1,2,4]triazine-7ππ}-Ν-{4-φτορ-1[4 ,4,4-trifluoro-3hydroxy-3(trifluoromethyl)butane oil]piperidin-3yl}-2methoxypyride in-3carboxamide F _{CF3XXOHCF3 _} 727.2 1.81 (2)

Example 1666: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(thiazole-5-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

A mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoropyrro- 479 042342 lidin-3-yl)-2-methoxynicotinamide (10 mg, 0.023 mmol), thiazole-5-carboxylic acid (4.41 mg, 0.034 mmol), HATU (12.98 mg, 0.034 mmol) and Hunig's base (15.90 µl, 0.091 mmol) in DMF (228 μl) was stirred at room temperature for 12 h. The crude reaction mixture was purified by preparative HPLC to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [1,2,4] triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(thiazole-5-carbonyl)pyrrolidin-3-yl)-2methoxynicotinamide (5.7 mg, 0.011 mmol, 46% yield) as white solid.

MS (ERI) m/z 551.15-(M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.92 (s, 1H), 8.84-8.72 (m, 1H), 8.60 (br t, J=7.6 Hz, 1H), 8.41 ( br d, J=14.3 Hz, 1H), 8.17 (br s, 1H), 7.61 (br s, 1H), 5.51-5.17 (m, 1H), 4.97-4.68 (m, 1H), 4.25 (br t, J=9.5 Hz, 1H), 4.05 (br d, J=9.8 Hz, 4H), 3.97-3.82 (m, 1H).

Connections in the table. 64 was obtained by the methods detailed in example 1666. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers. LC-MS, retention time (RT) was determined in minutes using method 1, 2, 3 or 4 as indicated. The methods are described in the Getting Methods section.

Table 64

I

Example Name R Ion mass observed in MC Assignment of signals in the NMR spectrum (500 MHz, DMSO-d6) δ or LC-MS RT (Method) 1667 5-(4-Amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-nn)-N-((3R,4S)-l-(2chlorothiazole-5carbonyl)-4fluoropyrrolidine -3 - silt) -2- methoxynicotinamide Cl 585.15 (M+H) ⁺ 8.92 (s, 1H), 8.83 (s, 1H), 8.76 (s, 1H), 8.59 (brt, /=8.9 Hz, 1H), 8.24-8.14 (m, 2H), 7.61 (s, 1H), 5.57 -5.22 (m, 1Н), 5.02-4.67 (br, 1Н), 4.37-4.12 (br, 1Н), 4.05 (br d, /=12.8 Hz, ZN), 3.95 - 3.73 (m, 1Н), 3.53 - 3.40 (m, 1H). 1668 N-((3R,4S)-l-(2-aMHHO2(trifluoromethyl)pentan oil)-4fluoropyrrolidin-3 yl)-5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [ 1 ,2,4]triazin7-yl)-2- methoxynicotinamide X, ^C F ₃ Η ₂ Ν 607.25 (M+H) ⁺ 8.90 (br s, 1H), 8.84 - 8.72 (br, 1H), 8.64 - 8.43 (br, 1H), 8.15 (s, 1H), 7.59 (s, 1H), 5.38 - 5.08 (m, 1H), 4.81 (br s, 1Н), 4.73 -4.50 (br, 1Н), 4.03 (br s, 2Н), 3.72 -3.60 (m, 1Н) 1669 tert-butyl (1-((3R,4S)3-(5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazin7-yl)-2- methoxynicotinamido)-4-fluoropyrrolidin1 -yl)-2-methyl-1 oxopropan-2yl)(methyl)carbamate BocN^C \ 637.36 (M-N) ⁺ 8.91 (br s, 1Н), 8.76 (br s, 1Н), 8.64 - 8.50 (m, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 5.46-5.14 (m, 1H), 4.80 4.46 (m, 1H), 4.02 (br s, 3H), 3.93 - 3.85 (m, 1H), 3.59-3.51 (m, 1H), 3.30 (br s, 1H), 3.14 (brt, /=12.2 Hz, 1H ), 2.89- 2.76(m, 3H) 1670 5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-^)-N-((3R,4S)-4fluoro-1-(3,3, 3-trifluoro2,2dihydroxypropanoyl) pyrrolidin-3 -yl)-2methoxynicotinamide jcF, HO OH 582.05 (M+H) ⁺ 8.93 (s, 1H), 8.77 (br s, 1H), 8.66 - 8.45 (m, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.45 -5.17 (m, 1H), 4.77 4.59 ( m, 1H), 4.54 - 4.43 (m, 1H), 4.40 - 4.28 (m, 1H), 4.04 (s, 3H), 3.973.87 (m, 1H), 3.84-3.67 (m, 1H), 3.61- 3.48 (m, 1H), 3.17 (d, /=5.2 Hz, 1H).

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1671 5-(4-Amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-im)-N-((3R,4S)-4fluoro-1-(1(trifluoromethyl) cyclopropane-1carbonyl)pyrrolidin3-yl)-2methoxynicotinamide 576.05 (M+H) ⁺ LC-MS RT = 1.86 min (Method 2) 1672 5-(4-Amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7- _Hn )-N-((3R,4S)-l(but-2-inoyl)- 4fluoropyrrolidin-3 yl)-2-methoxynicotinamide h 504.3 (M+H) ⁺ 8.93 (br s, 1H), 8.77 (br d, 7=17.7 Hz, 1H), 8.56 (brt, 7=6.9 Hz, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.36 (br s, 1Н), 5.26 (brs, 1Н), 4.85 -4.54 (m, 1Н), 4.194.10 (m, 1Н), 4.04 (br d, 7=6.7 Hz, ZN), 3.99-3.83 (m, 1Н), 3.76-3.51 (t, 1Н), 3.42 - 3.33 (m, 1H), 3.17 (d, 7=4.9 Hz, 1H), 2.04 (s, ZN) 1673 N-((3R,4S)-l-(2-aMHHO3,3,3trifluoropropanoyl)-4fluoropyrrolidin-3 yl)-5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1, 2,4]triazin7-yl)-2methoxynicotinamide C ^CF 3 h ₂ n 565.10 (M+H) ⁺ 9.01 - 8.90 (m, 1H), 8.86 8.74 (m, 1H), 8.63 - 8.46 (m, 1H), 8.18 (s, 1H), 7.63 (s, 1H), 5.50-5.17 (t, 1H), 4.92 - 4.68 (m, 1Н), 4.50 -4.24 (t, 1Н), 4.13 4.01 (t, GL), 3.96-3.88 (t, 1Н), 3.84 - 3.65 (t, 1Н), 3.47-3.30 (t, 1Н ) 1674 5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7- _Hn )-N-((3R,4S)-4fluoro-1-(2-methyl- 2-(4(trifluoromethyl)-1nimidazol-1yl)propanoyl)pyrroli din-3-yl)-2methoxynicotinamide A' ρ 644.10 (M+H) ⁺ 8.91 (brs, 1H), 8.73 (brd, 7=18.6 Hz, 1H), 8.528.33 (t, 1H), 8.17 (br s, 1H), 8.12-7.92 (t, 2H), 7.61 (br s, 1Н), 5.35-4.97 (m, 1H), 4.84 - 4.54 (m, 1H), 4.01 (br d, 7=15.9 Hz, ZN), 3.51 -3.37 (m, 1H), 1.87 - 1.55 (m, 6H )

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1675 5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7- _H n)-N-((3R,4S)-l-(laminocyclopentane-1 carbonyl) -4fluoropyrrolidin-3 yl)-2- methoxynicotinamide / _v nh ₂ O 551.20 (M+H) ⁺ 8.93 (s, 1H), 8.86 - 8.76 (m, 1H), 8.54 (brd, 7=7.0 Hz, 1H), 8.18 (br s, 4H), 7.62 (s, 1H), 7.26 (s, 2H), 7.16 (s, 2Н), 7.05 (s, 2Н), 5.44-5.19 (m, 1Н), 4.183.99 (m, 4Н), 2.42 - 2.24 (m, 2Н), 1.90 (br s, 6Н). 1676 5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-mi)-N-((3R,4S)-4fluoro-1-(3-hydroxy2, 2dimethylpropanoyl)pyrrolidin-3-yl)-2methoxynicotinamide ^he 540.15 (M+H) ⁺ 8.93 (s, 1H), 8.80 (br s, 1H), 8.50 (br d, 7=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.32 (brs, 1H), 5.21 (br s, 1H), 4.78 -4.59 (m, 1H), 4.05 (s, 3H), 3.563.40 (m, 1H), 1.16 (s, 3H), 1.14 (s, 3H). 1677 N-((3R,4S)-l-(2-aMHHO4-methyl-2(trifluoromethyl)pentan oil)-4fluoropyrrolidin-3 yl)-5-(4-amino-5(trifluoromethyl)pyrrole o[2,1 - f] [ 1,2,4]triazin7-yl)-2methoxynicotinamide Xcf _3i 621.1 (M+H) ⁺ 8.93 (br s, 1H), 8.86 - 8.70 (m, 1H), 8.59 - 8.43 (m, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 5.43 - 5.08 (m, 1H), 4.77 - 4.42 (m, 2H), 4.05 (br s, 3H), 3.87 - 3.58 (m, 1H), 2.05 - 1.76 (m, 2H), 1.60 (brd, 7=8.5 Hz, 1H), 1.02-0.71 ( m, 6H). 1678 tert-butyl 3-((3R,4S)3-(5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazin7-yl)-2- methoxynicotinamido)-4-fluoropyrrolidine1-carbonyl)-3(trifluoromethyl)pyrrole idine-1-carboxylate X Vos 703.2 (M-N) 8.93 (br s, 1H), 8.88 - 8.73 (m, 1H), 8.62 - 8.36 (m, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.45-5.21 (m, 1H), 4.91 -4.65 (m, 1H), 4.164.01 (m, 4H), 3.95-3.75 (m, 3H), 1.41 (br s, 9H). 1679 tert-butyl (3-((3R,4S)3-(5-(4-amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazin7-yl)-2- methoxynicotinamido)-4-fluoropyrrolidin1-yl)-2,2-dimethyl-3oxopropyl)carbamate /g/ ⁴ NHBoc 637.3 (M-N) 8.93 (s, 1H), 8.80 (br s, 1H), 8.49 (brs, 1H), 8.19 (br s, 1H), 7.62 (s, 1H), 6.57 (br s, 1H), 5.46-5.20 (m , 1H), 4.87 - 4.62 (m, 1H), 4.05 (s, 4H), 1.38 (s, 10H), 1.14 (brs, 6H). 1680 5-(4-Amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-mi)-N-((3R,4S)-4fluoro-1-(3(trifluoromethyl) pyrrole idine-3 carbonyl) pyrrolidin3-yl) -2- methoxynicotinamide X '-~NH 605.1 (M+H) ⁺ 8.99-8.91 (m, 1H), 8.868.74 (m, 1H), 8.52 (br s, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.35 (brs, 1H), 5.24 (br s, 1H), 4.85 -4.62 (m, 1H), 4.12-3.72 (m, 6H), 3.63 -3.43 (m, 1H), 2.922.72 (m, 1H), 2.20 (br d, 7=17.1 Hz , 2H). 1681 5-(4-Amino-5(trifluoromethyl)pyrrole o[2,1-f] [1,2,4]triazine7-mi)-N-((3R,4S)-4fluoro-1-(2,2, 5trimethyl-1,3-dioxane5carbonyl)pyrrolidin3-yl)-2- methoxynicotinamide °x° 596.15 (M+H) ⁺ 8.93 (s, 1H), 8.80 (br s, 1H), 8.49 (br d, 7=6.7 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.45 -5.12 (m, 1H) , 4.87–4.57 (m, 1H), 4.21–4.02 (m, 6H), 3.73–3.56 (m, 2H), 1.36–1.12 (m, 12H).

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Example 1682: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(2-methyl-3-oxobutan-2-yl)pyrrolidin-3-yl)-2-methoxynicotinamide

A mixture of 3-bromo-3-methylbutan-2-one (16.90 mg, 0.102 mmol), 5-(4-amino-5(trifluoromethyl)nurrolo[2,1-f][1,2,4]triazine-7- yl)-N-((3R,4S)-4-fluoropyrroludin-3-yl)-2methoxynicotinamide (15 mg, 0.034 mmol) and potassium carbonate (9.44 mg, 0.068 mmol) in DMF (341 μL) was heated at 80°C within 12 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 7% B, 7-47% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (2.0 mg, 2.7 mmol, 8% yield).

MS (ERI) m/z 524.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.00-8.87 (m, 1H), 8.82 (br d, J=9.5 Hz, 1H), 8.64-8.45 (m, 1H), 8.17 (s, 1H), 8.16-8.11 (m, 1H), 7.80 (br s, 1H), 7.68-7.59 (m, 1H), 7.24 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 5.49-5.24 (m, 1H), 4.82-4.53 (m, 1H), 4.15-3.95 (m, 3H).

Example 1683: (E)-5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-X-(3(ethoxyimino)cyclopentyl) -2-methoxynicotinamide

1683A: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinic acid mixture (120 mg, 0.340 mmol), 3-aminocyclopentane -1-one, TFA salt (94 mg, 0.442 mmol), Hunig's bases (237 μl, 1.359 mmol) and BOP (188 mg, 0.425 mmol) in DMF (1132 μl) were stirred at room temperature for 12 h. Crude product purified by reverse phase preparative HPLC on a C18 Luna column (10 μM, 30x100 mm) eluting with 0-100% B (A: 95% water/5% acetonitrile/10 mM ammonium acetate, B: 5% water/95% acetonitrile/10 mM ammonium acetate) in 12 min to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-4][1,2,4]triazin-7-yl)-2-methoxy -X-(3oxocyclopentyl)nicotinamide (100 mg, 0.230 mmol, 68% yield) as a white solid.

MS (ERI) m/z 435.2 (M+H) ⁺ .

1683B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3oxocyclopentyl)nicotinamide mixture (8 mg , 0.018 mmol) and O-ethylhydroxylamine hydrochloride (8.98 mg, 0.092 mmol) in methanol (61.4 μl) were heated at 75°C for 1 h. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mmx19 mm, particles 5 microns; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 24% B, 24-64% B over 25 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.3 mg, 0.69 µmol, 37% yield).

MS (ERI) m/z 478.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.66 (s, 1H), 8.34 (br d, J=6.7 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H ), 4.34 (br d, J=6.7 Hz, 1H), 4.13-3.96 (m, 5H), 3.32 (br s, 1H), 2.69 (br dd, J=16.3, 6.9 Hz, 1H), 2.45-2.33 (m, 2H), 2.19-1.98 (m, 1H), 1.79 (br dd, J=12.4, 7.5 Hz, 1H), 1.20-1.11 (m, 3H).

Example 1684: (E)-5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3((benzyloxy)imino )cyclopentyl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1683 to give the title compound (5.0 mg, 9.2 µmol, 52% yield).

ERI (m/z) 540.1 (M+H) ⁺ .

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1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.66 (s, 1H), 8.34 (br d, J=6.7 Hz, 1H), 8.17 (s, 1H), 7.61 (s,

1H), 7.42-7.25 (m, 5H), 5.03 (s, 2H), 4.43-4.30 (m, 1H), 4.00 (s, 3H), 2.67 (br d, J=6.1 Hz, 2H), 2.47- 2.39(m,

2H), 2.14-1.98 (m, 1H), 1.88-1.67 (m, 1H).

Example 1685: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(5-benzyl-1,3,4oxadiazol- 2-yl)-2-methoxynicotinamide

5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinic acid mixture (10 mg, 0.028 mmol), BOP (15.65 mg, 0.035 mmol), 5-benzyl-1,3,4-oxadiazol-2-amine (5.95 mg, 0.034 mmol) and Hunig's base (14.83 µl, 0.085 mmol) in DMF (283 µl) were stirred at room temperature for 12 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 27% B, 27-67% B over 20 min, then 5 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (4 mg, 16.19 µmol, 22% yield).

MS (ERI) m/z 511.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.06-8.96 (m, 1H), 8.71 (s, 1H), 8.24-8.07 (m, 1H), 7.68-7.58 (m, 1H), 7.43-7.24 ( m, 5H), 4.27 (s, 2H), 4.10–3.92 (m, 4H).

Example 1686: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(5-benzylthiazol-2yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (6.0 mg, 11.4 µmol, 41% yield).

MS (ERI) m/z 526.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 1H), 8.74 (s, 1H), 8.18 (s, 1H), 7.65 (s, 1H), 7.41-7.15 (m, 7H), 4.14 ( s, 2H), 4.04 (s, 3H).

Example 1687: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((1SR,3RS)-3-(4bromophenyl )cyclopentyl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (15 mg, 26.1 µmol, 62% yield).

MS (ERI) m/z 575.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.66 (d, J=2.1 Hz, 1H), 8.36 (br d, J=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.49 (br d, J=8.5 Hz, 2H), 7.26 (br d, J=8.2 Hz, 2H), 4.46 (br d, J=3.7 Hz, 1H), 4.03 (s, 3H), 2.30-1.90 (m, 4H), 1.78-1.42 (m, 2H).

Example 1688: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylcyclopentyl)nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (18 mg, 36.3 µmol, 86% yield).

MS (ERI) m/z 497.15-(M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.68 (dd, J=9.0, 2.0 Hz, 1H), 8.43-8.30 (m, 1H), 8.18 (s, 1H), 7.62 ( s, 1H), 7.39-7.27 (m, 4H), 7.20 (br d, J=6.1 Hz, 1H), 4.40 (br s, 1H), 4.03 (d, J=4.6 Hz, 3H), 3.27-3.18 (m, 1H), 2.46-2.39 (m, 1H), 2.23 (br dd, J=8.7, 3.5 Hz, 1H), 2.18-1.95 (m, 2H), 1.80-1.60 (m, 3H).

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Example 1689: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylcyclohexyl)nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (5.2 mg, 10.2 µmol, 36% yield).

MS (ERI) m/z 511.15-(M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.00-8.85 (m, 1H), 8.78-8.64 (m, 1H), 8.40 (br d, J=7.3 Hz, 1H), 8.228.13 (m, 2H), 7.69-7.60 (m, 1H), 7.38-7.24 (m, 4H), 7.22-7.13 (m, 1H), 4.29 (br s, 1H), 4.09 (s, 1H), 4.01 (s, 2H ), 3.97-3.90 (m, 1H), 2.88 (br s, 1H), 2.69 (br t, J=11.6 Hz, 1H), 2.09-1.67 (m, 5H), 1.57-1.32 (m, 3H).

Example 1690: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxy-3phenylcyclopentyl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (11 mg, 21.5 µmol, 51% yield).

MS (ERI) m/z 511.05-(M-H)-.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.97 (br d, J=8.5 Hz, 1H), 8.93-8.85 (m, 2H), 8.15 (s, 1H), 7.57 (s, 1H), 7.51 (br d, J=7.6 Hz, 2H), 7.34 (br t, J=7.5 Hz, 2H), 7.27-7.16 (m, 1H), 5.46 (s, 1H), 4.66 (br d, J=2.7 Hz , 1H), 4.08 (s, 3H), 3.58 (br s, 2H), 2.31 (br dd, J=13.7, 8.2 Hz, 2H), 2.15-1.80 (m, 4H).

Example 1691: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylcycloheptyl)nicotinamide.

Prepared in a manner similar to that described in Example 1685 to give the title compound (13 mg, 24.8 µmol, 59% yield).

MS (ERI) m/z 525.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (br d, J=4.6 Hz, 1H), 8.66 (dd, J=6.3, 2.3 Hz, 1H), 8.29 (br d, J=7.6 Hz, 1H), 8.20 (br d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.59 (d, J=5.2 Hz, 1H), 7.34-7.22 (m, 4H), 7.20-7.12 (m, 1H), 4.29 (br s, 1H), 2.96 (br t, J=10.5 Hz, 1H), 2.87-2.74 (m, 1H), 2.20-1.43 (m, 11H).

Example 1692: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N((1RS,3RS)-3 -phenylcyclohexyl)nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (10 mg, 19.6 µmol, 47% yield).

MS (ERI) m/z 509.2 (M-H)-.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.38 (br d, J=7.0 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 7.36-7.24 (m, 4H), 7.22-7.11 (m, 1H), 4.30 (br d, J=3.1 Hz, 1H), 4.10 (s, 3H) , 2.88 (br t, J=11.7 Hz, 1H), 2.05-1.47 (m, 9H).

Example 1693: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N((1SR,3RS)-3 -phenylcyclohexyl)nicotinamide

Produced in a manner similar to that described in Example 1685 to give the title

- 485 042342 compounds (8 mg, 15.7 µmol, 37% yield).

MS (ERI) m/z 511.10 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=2.1 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H), 8.24-8.08 (m, 2H), 7.60 (s, 1H) , 7.35-7.25 (m, 4H), 7.23-7.14 (m, 1H), 4.02 (s, 3H), 2.69 (br t, J=12.2 Hz, 1H), 2.12-1.76 (m, 4H), 1.621. 27(m, 4H).

Example 1694: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1phenylpiperidin-3-yl) nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (7 mg, 13.7 µmol, 33% yield).

MS (ERI) m/z 512.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.34 (br d, J=7.6 Hz, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.23 (t, J=7.8 Hz, 2H), 6.99 (br d, J=8.2 Hz, 2H), 6.78 (t, J=7.2 Hz, 1H), 4.09 (br d, J=3.7 Hz, 1H), 4.01 (s, 3H), 3.57 (br d, J=12.2 Hz, 1H), 3.06-2.91 (m, 2H), 1.99-1.75 (m, 2H) , 1.66 (br t, J=8.7 Hz, 2H).

Example 1695: 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)2-methoxy -N-((1SR,3RS)-3-phenylcyclohexyl)nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (6 mg, 10.4 µmol, 43% yield).

MS (ERI) m/z 576.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.87 (s, 1H), 8.65 (s, 1H), 8.16 (br d, J=7.6 Hz, 1H), 7.87 (br s, 1H), 7.36-7.12 (m, 5H), 7.02 (s, 1H), 4.04-3.93 (m, 3H), 3.81 (s, 2H), 3.51 (br d, J=4.6 Hz, 3H), 2.79-2.60 (m, 5H) , 2.10-1.74 (m, 8H), 1.60-1.32 (m, 4H).

Example 1696: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((1SR,3RS)-3-(4fluorophenyl )cyclohexyl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (15 mg, 28.4 µmol, 68% yield).

MS (ERI) m/z 529.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.88 (d, J=1.8 Hz, 1H), 8.67 (d, J=1.8 Hz, 1H), 8.23-8.12 (m, 2H), 7.59 (s, 1H) , 7.37-7.23 (m, 2H), 7.12 (br t, J=8.7 Hz, 2H), 4.01 (s, 3H), 3.97-3.87 (m, 1H), 2.77-2.66 (m, 1H), 2.091. 93 (m, 2H), 1.87 (br d, J=12.5 Hz, 1H), 1.77 (br d, J=12.5 Hz, 1H), 1.58-1.29 (m, 4H).

Example 1697: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N((1 SR,2RS)- 2-phenylcyclopropyl)nicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (15 mg, 32 µmol, 76% yield).

MS (ERI) m/z 469.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (s, 1H), 8.69 (s, 1H), 8.52 (br d, J=4.0 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.35-7.26 (m, 2H), 7.23-7.13 (m, 3H), 4.03 (s, 3H), 3.06 (br d, J=3.7 Hz, 1H), 2.12 (br s, 1H), 1.41 -1.33 (m, 1H), 1.31-1.20 (m, 1H).

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Example 1698: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(( 1 SR,3RS)-3-( 4chlorophenyl)cyclohexyl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1685 to give the title compound (9 mg, 16.5 µmol, 39% yield).

MS (ERI) m/z 545.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.64 (s, 1H), 8.20 (br d, J=8.2 Hz, 1H), 8.14 (s, 1H), 7.56 (s , 1H), 7.37-7.32 (m, 2H), 7.31-7.25 (m, 2H), 3.93 (br d, J=9.2 Hz, 1H), 3.67-3.50 (m, 16H), 2.75-2.63 (m, 2H), 2.07-1.71 (m, 4H), 1.56-1.30 (m, 4H).

Example 1699: tert-butyl (2SR,4SR)-4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)-2-methoxynicotinamido )-2-(methoxymethyl)pyrrolidine-1-carboxylate

Prepared in a manner similar to that described in Example 1685 to give the title compound (4.8 mg, 8.5 µmol, 39% yield).

MS (ERI) m/z 566.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.97-8.83 (m, 1H), 8.71 (br s, 1H), 8.48 (br d, J=6.1 Hz, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 4.39 (br d, J=6.1 Hz, 1H), 4.03 (s, 3H), 3.90 (br s, 1H), 3.76 (br dd, J=10.4, 7.0 Hz, 1H), 3.53 (br s, 1H), 3.44 (br d, J=8.2 Hz, 1H), 3.29 (s, 2H), 3.11 (br d, J=6.7 Hz, 1H), 2.38 (br d, J=5.8 Hz, 1H), 2.00-1.87 (m, 1H), 1.41 (s, 9H).

Example 1700: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3SR,5SR)-1-(3 ,3difluorocyclobutane-1-carbonyl)-5-(methoxymethyl)pyrrolidin-3-yl)-2-methoxynicotinamide

A mixture of 3,3-difluorocyclobutane-1-carboxylic acid (5.47 mg, 0.040 mmol) (prepared from tert-butyl (2S,4S)-4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-2-(methoxymethyl)pyrrolidine-1-carboxylate by treatment with TFA), 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((3S,5S)-5(methoxymethyl)pyrrolidin-3-yl)nicotinamide (17 mg, 0.037 mmol ), BOP (20.19 mg, 0.046 mmol) and Hunig's base (51.0 μl, 0.292 mmol) in DMF (243 μl) were stirred at room temperature for 1 h, and the crude product was purified by HPLC to give 5-(4-amino -5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,5S)-1-(3,3-difluorocyclobutan-1-carbonyl)- 5(methoxymethyl)pyrrolidin-3-yl)-2-methoxynicotinamide (10 mg, 0.017 mmol, 46% yield) as a white solid.

MS (ERI) m/z 584.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.89 (br s, 1H), 8.73 (br s, 1H), 8.68 (br s, 1H), 8.56-8.45 (m, 1H), 8.16 (s, 1H ), 7.59 (s, 1H), 4.49 (br d, J=6.4 Hz, 1H), 4.39 (br d, J=4.9 Hz, 1H), 4.24 (br s, 1H), 4.14 (br d, J= 3.7 Hz, 1H), 4.09-3.99 (m, 3H), 3.93-3.80 (m, 1H), 3.58 (br d, J=3.7 Hz, 1H), 3.50-3.40 (m, 1H), 3.35-3.23 ( m, 3H), 3.22-3.10 (m, 1H), 2.75 (br d, J=17.7 Hz, 4H), 2.43-2.32 (m, 1H), 2.04-1.84 (m, 1H).

Example 1701: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,5S)-5((benzyloxy )methyl)-1-(3,3-difluorocyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described for compounds (13 mg, 19.7 µmol, 48% yield).

MS (ERI) m/z 660.1 (M+H)+.

example 1700 getting header

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1H NMR (500 MHz, DMSO-d ₆ ) δ 9.00-8.82 (m, 1H), 8.75-8.60 (m, 1H), 8.54-8.40 (m, 1H), 8.16 (s, 1H),

7.59 (s, 1H), 7.34-7.14 (m, 5H), 4.56-4.45 (m, 3H), 4.38 (br s, 1H), 4.29 (br s, 1H), 4.22-4.06 (m, 1H), 4.02-3.93 (m, 3H), 3.88 (br dd, J=16.8, 6.4 Hz, 1H), 3.73-3.65 (m, 1H), 3.57 (br d, J=6.1 Hz, 1H), 3.43-3.28 ( m, 1H), 3.243.12 (m, 1H), 2.90-2.60 (m, 4H), 2.45-2.33 (m, 1H), 2.10-1.98 (m, 1H), 1.92 (br d, J=8.5 Hz , 1H).

Example 1702: 5-(4-amino-2-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

A mixture of N-((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxy-5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinamide (17.50 mg, 0.035 mmol), 7-bromo2-fluoropyrrolo[2,1-1][1,2,4]triazine -4-amine (8 mg, 0.035 mmol), K3PO4 (2 M solution, 51.9 μl, 0.104 mmol) in 1,4-dioxane (2 ml) were degassed and refilled with nitrogen. Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (2.83 mg, 3.46 µmol) was added and the reaction mixture was heated at 100°C for 16 h. The crude product was purified by HPLC to give 5-(4-amino-2- fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro1 -((R)-3,3,3-trifluoro-2- hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (4 mg, 7.6 mmol, 22% yield) as an off-white solid.

MS (ERI) m/z 530.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (br s, 1H), 8.73 (br d, J=5.2 Hz, 1H), 8.54 (br d, J=7.0 Hz, 1H), 8.49 (br d , J=5.2 Hz, 1H), 8.39 (br s, 1H), 7.68-7.54 (m, 1H), 7.19-7.04 (m, 2H), 5.34 (br d, J=9.8 Hz, 1H), 5.23 ( br d, J=11.0 Hz, 1H), 4.79-4.59 (m, 1H), 4.49 (br t, J=9.6 Hz, 1H), 4.41-4.27 (m, 1H), 4.04 (br s, 3H), 3.99-3.70 (m, 2H), 3.59 (br t, J=10.5 Hz, 1H), 3.34 (br d, J=7.0 Hz, 1H), 1.54 (s, 3H).

Example 1703: 5-(5-((1H-imidazol-1-yl)methyl)-4-aminopyrrolo [2,1-f][1,2,4]triazin-7-ul)-N ((3R ,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

1703 A: mixture of N-((4-amino-7-bromopyrrolo[2,1-f][1,2,4]Ίriazin-5-yl)methyl)-N,N-diethylethanamine bromide, bromide salt (150 mg , 0.368 mmol), imidazole (75 mg, 1.105 mmol), and Hunig's base (129 μl, 0.737 mmol) in acetonitrile (2456 μl) were heated to reflux for 24 h. After filtration, the filtrate was evaporated under vacuum. The crude material was purified by reverse phase preparative HPLC on a C18 Luna column (10 μM, 30x100 mm), eluting with 0-100% B (A: 95% water/5% acetonitrile/10 mM ammonium acetate, B: 5% water/ 95% acetonitrile/10 mM ammonium acetate) in 12 min to give 5-((1H-imidazol-1-yl)methyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine4-amine ( 8 mg, 0.027 mmol, 7% yield) as a white solid.

MS (ERI) (m/z) 293.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 7.90 (s, 1H), 7.71 (s, 1H), 7.48 (br d, J=2.4 Hz, 2H), 7.12 (s, 1H), 6.88 (s, 1H), 6.70 (s, 1H), 5.50 (s, 2H).

1703: mixture of 5-((1H-imidazol-1-yl)methyl)-7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (7 mg, 0.024 mmol), N- ((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxy-5-(4,4,5,5tetramethyl-1,3,2 -dioxaborolan-2-yl)nicotinamide (11.54 mg, 0.024 mmol), K ₃ PO ₄ (2 M, 35.8 µl, 0.072 mmol) in 1,4-dioxane (2 ml) was degassed and filled up with N2 again. Pd(dppf)Cl ₂ -CH ₂ Cl ₂ (1.950 mg, 2.388 µmol) was added and the reaction mixture was heated at 100°C for 16 h. The reaction mixture was purified by HPLC to give 5-(5-((W- imidazol-1-yl)methyl)-4-aminopyrrolo[2,1f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3,3-difluorocyclobutan-1 -carbonyl)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide (11 mg, 13.8 mmol, 58% yield).

MS (ERI) m/z 570.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.04-8.98 (m, 1H), 8.94 (br s, 1H), 8.80-8.71 (m, 1H), 8.51 (br t, J=8.5 Hz, 1H) , 8.02 (s, 1H), 7.73-7.59 (m, 3H), 7.27 (br s, 1H), 7.21 (s, 1H), 7.17 (br s, 1H), 7.07 (br s, 1H), 5.80 ( s, 2H), 5.44-5.18 (m, 1H), 4.89-4.57 (m, 1H), 4.04 (d, J=6.1 Hz, 3H), 3.99-3.84 (m, 2H), 3.82-3.68 (m, 1H), 3.213.11 (m, 1H), 2.86-2.74 (m, 4H).

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Example 1704: 5-(4-Amino-5-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (1.3 mg, 2.2 µmol, 9% yield).

MS (ERI) m/z 584.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.94-8.84 (m, 1H), 8.66 (br d, J=16.5 Hz, 1H), 8.56-8.44 (m, 1H), 7.96 (s, 1H) , 7.04 (s, 1H), 6.76 (s, 1H), 6.67 (br d, J=4.3 Hz, 1H), 5.50 (s, 2H), 5.41-5.18 (m, 1H), 4.88-4.63 (m, 1H),

4.03 (br d, J=5.8 Hz, 3H), 3.96-3.67 (m, 3H), 2.93-2.65 (m, 5H), 2.33 (s, 3H).

Example 1705: 5-(4-Amino-5-((4-methyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.3 mg, 7.4 µmol, 28% yield).

MS (ERI) m/z 584.2 (M+H) ⁺ .

LCMS, retention time using method 3 = 1.23 min.

Example 1706: 5-(4-amino-5-((4-chloro-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) -N((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (1.8 mg, 3.0 µmol, 12% yield).

MS (ERI) m/z 604.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.65 (br d, J=17.1 Hz, 1H), 8.55-8.44 (m, 1H), 7.97 (s, 1H), 7.85 ( br s, 1H), 7.60 (br s, 1H), 7.04 (s, 1H), 6.72 (d, J=3.4 Hz, 1H), 5.61 (s, 2H), 5.42-5.18 (m, 1H), 4.85 -4.56 (m, 1H), 4.03 (d, J=6.1 Hz, 3H), 3.99-3.66 (m, 3H), 3.29-3.12 (m, 1H), 2.89-2.71 (m, 4H).

Example 1707: 5-(5-((1H-1,2,4-triazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -N((3R,4S)-1-(3,3-difluorocyclobutan-1-αcarbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (5.5 mg, 8.0 µmol, 33% yield).

MS (ERI) m/z 571.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.73 (s, 1H), 8.69 (s, 1H), 8.66 (s, 1H), 8.55-8.47 (m, 1H), 8.03 (s, 1H), 7.98 (s, 1H), 7.75 (br s, 1H), 7.12 (s, 1H), 5.78 (s, 2H), 5.45-5.20 (m, 1H), 4.88-4.52 (m, 1H), 4.04 (br d, J=6.1 Hz, 3H), 4.00-3.61 (m, 3H), 3.32-3.11 (m, 1H), 2.90-2.69 (m, 4H).

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Example 1708: 5-(5-((1H-benzo[d]imidazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)N- ((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (6.0 mg, 9.7 µmol, 37% yield).

MS (ERI) m/z 620.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.70-8.61 (m, 1H), 8.48 (br t, J=8.7 Hz, 1H), 8.34 (br s, 1H), 7.97 (s, 1H), 7.64 (br s, 4H), 7.30-7.17 (m, 2H), 6.95 (br d, J=6.4 Hz, 1H), 5.88 (s, 2H), 5.42-5.16 (m, 1H), 4.854.54 (m, 1H), 4.01 (d, J=5.8 Hz, 3H), 3.97-3.66 (m, 3H), 3.30-3.11 (m, 1H), 2.91-2.69 (m, 4H) .

Example 1709: 5-(5-((1H-pyrazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (5.0 mg, 8.8 µmol, 28% yield).

MS (ERI) m/z 570.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (s, 1H), 8.71 (br d, J=18.9 Hz, 1H), 8.51 (br t, J=8.7 Hz, 1H), 8.077.86 (m , 3H), 7.52 (s, 1H), 7.17 (s, 1H), 6.30 (s, 1H), 5.64 (s, 2H), 5.45-5.21 (m, 1H), 4.93-4.60 (m, 1H), 4.04 (br d, J=6.1 Hz, 3H), 4.00-3.68 (m, 3H), 3.32-3.12 (m, 1H), 2.93-2.69 (m, 4H).

Example 1710: 5-(5-((1H-tetrazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R ,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (2.6 mg, 4.5 µmol, 17% yield).

MS (ERI) m/z 572.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.49-9.35 (m, 1H), 8.91 (s, 1H), 8.73 (br d, J=18.6 Hz, 1H), 8.56-8.41 (m, 1H), 8.00 (s, 1H), 7.64 (br d, J=3.7 Hz, 2H), 7.15 (s, 1H), 6.10 (s, 2H), 5.49-5.11 (m, 1H), 4.94-4.54 (m, 1H ), 4.04 (br d, J=6.1 Hz, 3H), 4.00-3.67 (m, 3H), 3.24-3.11 (m, 1H), 2.91-2.70 (m, 4H).

Example 1711: 5-(5-((2H-tetrazol-2-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R, 4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 7.0 µmol, 26% yield).

MS (ERI) m/z 572.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.01-8.96 (m, 1H), 8.90 (s, 1H), 8.73 (br d, J=17.7 Hz, 1H), 8.50 (br dd, J=11.4, 7.8Hz, 1H), 8.01 (s, 1H), 7.81-7.60 (m, 1H), 7.18 (s, 1H), 6.34 (s, 2H), 5.44-5.19 (m, 1H), 4.88-4.60 (m , 1H), 4.03 (d, J=5.8 Hz, 3H), 4.00-3.68 (m, 3H), 3.31-3.11 (m, 1H), 2.91-2.66 (m, 4H).

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Example 1712: 5-(4-Amino-5-((4-phenyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) N-((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 6.2 µmol, 28% yield).

MS (ERI) m/z 646.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.84-8.77 (m, 1H), 8.60 (br d, J=18.3 Hz, 1H), 8.49 (br t, J=8.7 Hz, 1H), 8.06 ( br d, J=5.5 Hz, 1H), 7.94 (s, 1H), 7.57-7.36 (m, 6H), 7.28 (br s, 1H), 6.49 (br d, J=5.2 Hz, 1H), 5.70 ( s, 2H), 5.43-5.16 (m, 1H), 4.86-4.60 (m, 1H), 4.02 (br d, J=5.8 Hz, 3H), 3.99-3.88 (m, 1H), 3.86 (s, 1H ), 3.82-3.68 (m, 1H), 3.63 (br s, 1H), 3.32-3.12 (m, 1H), 2.89-2.69 (m, 4H).

Example 1713: 5-(4-Amino-5-((5-phenyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl) N-((3R,4S)-1-(3,3-difluorocyclobutane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 6.2 µmol, 28% yield).

MS (ERI) m/z 646.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.75 (br d, J=16.2 Hz, 1H), 8.50 (br t, J=8.9 Hz, 1H), 8.08 (br s, 1H ), 7.99 (s, 1H), 7.80-7.70 (m, 3H), 7.58 (br s, 1H), 7.36 (br t, J=7.5 Hz, 2H), 7.27-7.20 (m, 1H), 7.15 ( d, J=5.2 Hz, 1H), 5.66 (s, 2H), 5.44-5.19 (m, 1H), 4.88-4.56 (m, 1H), 4.04 (d, J=5.8 Hz, 3H), 4.00-3.89 (m, 1H), 3.85 (s, 1H), 3.82-3.67 (m, 1H), 3.63 (br s, 1H), 3.26 (br t, J=10.7 Hz, 1H), 3.22-3.11 (m, 1H ), 2.89-2.66 (m, 4H).

Example 1714: 5-(4-Amino-5-((methoxyamino)methyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 (3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Meq

NH

Prepared in a manner similar to that described in Example 1703 to give the title compound (6.8 mg, 12.4 µmol, 34% yield).

MS (ERI) m/z 549.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.97-8.89 (m, 1H), 8.81 (br d, J=18.9 Hz, 1H), 8.51 (br dd, J=11.6, 7.9 Hz, 1H), 7.92 ( s, 1H), 7.42-7.28 (m, 1H), 7.10 (s, 1H), 5.45-5.20 (m, 1H), 4.89-4.61 (m, 1H), 4.19 (br s, 2H), 4.04 (br d, J=5.8 Hz, 3H), 4.01-3.69 (m, 3H), 3.44 (s, 1H), 3.25-3.12 (m, 1H), 2.91-2.68 (m, 4H).

Example 1715: 5-(4-Amino-5-((3-oxotetrahydropyridazin-1(2H)-yl)methyl)pyrrolo[2,1 f][1,2,4]triazin-7-yl)-N- ((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (5.0 mg, 8.3 µmol, 55% yield).

- 491 042342

MS (ERI) m/z 602.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.86-8.70 (m, 1H), 8.51 (br dd, J=11.3, 8.2 Hz, 1H), 7.93 (s,

2H), 7.12 (s, 1H), 5.43-5.17 (m, 1H), 4.90-4.58 (m, 1H), 4.17 (s, 2H), 4.04 (br d, J=6.1 Hz, 3H), 4.01- 3.68(m,

3H), 3.49-3.34 (m, 4H), 3.31-3.23 (m, 1H), 3.23-3.13 (m, 1H), 2.93 (br s, 2H), 2.88-2.70 (m, 4H), 2.35 (br t,

J=6.6Hz, 1H).

Example 1716: 5-(4-amino-5-((tetrahydropyridazin-1(2H)-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)-N-((3R ,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (5.0 mg, 8.5 µmol, 18% yield).

MS (ERI) m/z 588.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.00-8.89 (m, 1H), 8.86-8.74 (m, 1H), 8.51 (br t, J=8.2 Hz, 1H), 7.967.80 (m, 1H ), 7.11 (br s, 1H), 7.00 (s, 1H), 6.82 (br s, 1H), 5.44-5.16 (m, 1H), 4.88-4.59 (m, 1H), 4.33 (br s, 1H) , 4.04 (br d, J=3.4 Hz, 3H), 4.01-3.68 (m, 4H), 3.24-3.12 (m, 1H), 2.93-2.69 (m, 6H), 2.08 (br s, 1H), 1.95 -1.81 (m, 4H), 1.65 (brs, 1H).

Example 1717: 2,2,2-trifluoroethyl (3R,4S)-3-(5-(4-amino-5-(morpholinomethyl)pyrrolo[2,11][1,2,4]triazin-7-yl) -2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 6.7 µmol, 23% yield).

MS (ERI) m/z 596.9 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.53 (br d, J=7.0 Hz, 1H), 7.86 ( s, 1H), 7.03 (s, 1H), 5.40-5.16 (m, 1H), 4.87-4.63 (m, 3H), 4.01 (s, 3H), 3.94-3.61 (m, 3H), 3.56 (s, 4H), 3.33 (br d, J=10.7 Hz, 1H).

Example 1718: 5-(4-amino-5-(morpholinomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoro-1 - ((3,3,3-trifluoropropyl)sulfonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 6.3 µmol, 22% yield).

MS (ERI) m/z 631.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.65-9.37 (m, 1H), 8.89 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.53 (br d, J=7.3 Hz, 1H), 7.85 (s, 1H), 7.75-7.55 (m, 1H), 7.02 (s, 1H), 5.34 (br s, 1H), 5.23 (br s, 1H), 4.88-4.70 (m, 1H), 4.01 (s, 4H), 3.86-3.78 (m, 2H), 3.74 (br s, 1H), 3.63-3.54 (m, 7H), 3.50-3.42 (m, 2H), 3.35 ( br t, J=9.8 Hz, 1H), 2.71 (td, J=10.5, 6.1 Hz, 3H).

Example 1719: 5-(4-amino-5-(morpholinomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoro-1- ((2,2,2-trifluoroethyl)sulfonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Prepared in a manner similar to that described in Example 1703 to give the title compound (4.0 mg, 6.5 µmol, 22% yield).

- 492 042342

MS (ERI) m/z 617.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.00-8.88 (m, 1H), 8.74 (d, J=2.4 Hz, 1H), 8.56 (br d, J=7.4 Hz, 1H), 8.01 (s, 1H ), 7.25-7.14 (m, 1H), 5.38 (br d, J=3.0 Hz, 1H), 5.27 (br s, 1H), 4.86-4.69 (m, 1H), 4.67-4.52 (m, 2H), 4.04 (s, 2H), 3.87 (br t, J=9.1 Hz, 1H).

Example 1720: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(2-(2phenylmorpholino)ethyl )nicotinamide

1720A: 2-(2-Phenylmorpholino)acetonitrile: To a 100 mL round bottom flask was added 2phenylmorpholine (569 mg, 3.49 mmol) and K ₂ CO ₃ (530 mg, 3.83 mmol) in CH3CN (10 mL) to give a white suspension. 2-Bromoacetonitrile (0.235 ml, 3.49 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as a colorless thick oil (706 mg, 3.49 mmol, 100% yield).

MS (ERI) m/z 203.0 (M+H) ⁺ .

1720B: 2-(2-Phenylmorpholino)ethan-1-amine: To a 50 ml round bottom flask was added 2-(2phenylmorpholino)acetonitrile (706 mg, 3.49 mmol) in THF (10 ml) to give a tan solution. LiAlH ₄ (10.47 ml, 10.47 mmol) was added dropwise. The mixture was stirred at room temperature overnight. Anhydrous Na ₂ SO ₄ was added to the reaction mixture, and the reaction was slowly stopped by dropwise addition of water (gas and heat evolved!) until no more bubbling was observed. The mixture was diluted with EtOAc and filtered. The organic solution was concentrated to give the title compound (611 mg, 2.96 mmol, 85% yield) as a light yellow oil which was used as is.

1720: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinic acid mixture (33.7 mg, 0.1 mmol), BOP (66.3 mg, 0.150 mmol), 2-(2-phenylmorpholino)ethane-1-amine (20.63 mg, 0.100 mmol) and Hunig's base (0.087 ml, 0.500 mmol) in DMF (0.5 ml) was stirred at room temperature overnight . The crude reaction mixture was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 23% B, 23-63% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methyl- N-(2-(2-phenylmorpholino)ethyl)nicotinamide (11.5 mg, 0.021 mmol, 21% yield).

MS (ERI) m/z 526.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.15 (d, J=2.3 Hz, 1H), 8.48 (t, J=5.6 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.17 ( s, 1H), 7.68 (s, 1H), 7.33 (d, J=6.8 Hz, 4H), 7.26 (t, J=6.5 Hz, 1H), 4.47 (d, J=9.9 Hz, 1H), 4.01- 3.90 (m, 1H), 3.68 (dd, J=12.3, 9.9 Hz, 1H), 3.01 (d, J=11.4 Hz, 1H), 2.85 (d, J=11.4 Hz, 1H), 2.60 (s, 3H ), 2.23 (s, 1H), 2.01 (t, J=10.8 Hz, 1H).

Example 1721: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(2-(3phenylmorpholino)ethyl )nicotinamide

Prepared according to the methods described in Example 1720 using 2-(3-phenylmorpholino)ethan-1amine and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine- 7-yl)-2-methylnicotinic acid to give the title compound (22.6 mg, 0.041 mmol, 41% yield).

MS (ERI) m/z 526.3 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 9.11 (s, 1H), 8.40 (t, J=5.8 Hz, 1H), 8.30 (s, 1H), 8.14 (s, 1H), 7.64 (s, 1H ), 7.41-7.17 (m, 5H), 3.86 (d, J=11.3 Hz, 1H), 3.63 (d, J=25.7 Hz, 5H), 3.42-3.08 (m, 5H), 2.61 (dt, J= 15.0, 8.0 Hz, 1H), 2.31 (dt, J=13.2, 6.6 Hz, 1H), 2.07 (dt, J=11.4, 4.9 Hz, 1H).

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Example 1722: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(2-(3phenylpiperidin-1 -yl)ethyl)nicotinamide

Prepared according to the methods described in Example 1720 using 2-(3-phenylpiperidin-1-yl)ethan1-amine hydrochloride and 5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-2methoxynicotinic acid to give the title compound (25.0 mg, 0.046, 59% yield).

MS (ERI) m/z 540.3 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (d, J=2.4 Hz, 1H), 8.83 (d, J=2.6 Hz, 1H), 8.48 (s, 1H), 8.14 (s, 1H), 7.57 (s, 1H), 7.27 (p, J=7.1, 6.5 Hz, 4H), 7.19 (d, J=6.9 Hz, 1H), 4.06 (s, 3H), 3.60-3.56 (m, 1H), 3.45 -(dd, J=10.3, 4.4 Hz, 1H), 3.01-2.90 (m, 2H), 2.76 (t, J=14.8 Hz, 1H), 2.10 (td, J=19.2, 18.2, 7.3 Hz, 2H) , 1.84 (d, J=12.7 Hz, 1H), 1.76 (d, J=13.3 Hz, 1H), 1.63 (q, J=12.4, 10.9 Hz, 1H), 1.52-1.41 (m, 1H).

Example 1723: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-Chimidazol-4-yl) -2-methoxynicotinamide

1723A: 1-Benzyl-1H-imidazole-4-amine: To a 50 ml round bottom flask was added 1-benzyl-4-nitro1H-imidazole (450 mg, 2.215 mmol) and Pd-C (236 mg, 0.221 mmol) in MeOH ( 12 ml) to give a black suspension. The reaction mixture was treated with balloon hydrogen for 18 hours. The mixture was filtered and washed with EtOAc/MeOH. The organic solution was concentrated to the compound (382 mg, 2.22 mmol, 100% yield) as a tan oil.

MS (ERI) m/z 174.0 (M+H)+.

1723: prepared according to the methods described in example 1685 using 1-benzyl-1H-imidazole-4amine and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine -7-yl)-2-methoxynicotinic acid to give the title compound (5.9 mg, 0.011 mmol, 11% yield).

MS (ERI) m/z 509.1 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.89 (d, J=2.5 Hz, 1H), 8.81 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.35 (dd, J=28.8, 8.0 Hz, 7H), 5.19 (s, 2H).

Example 1724: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1Himidazol-4-yl) -2-methylnicotinamide

Prepared according to the methods described in Example 1723 using 1-benzyl-1H-imidazol-4-amine (1723A) and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-2-methylnicotinic acid to give the title compound (26.0 mg, 0.053 mmol, 53% yield).

MS (ERI) m/z 493.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.21 (s, 1H), 8.51 (s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.53-7.28 (m, 6H), 5.22 (s, 2H), 2.59 (s, 3H).

Example 1725: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1Hpyrazol-3-yl) -2-methoxynicotinamide

Prepared according to the methods described in Example 1723 using 1-benzyl-1H-pyrazole-3-amine and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine -7-yl)-2-methoxynicotinic acid to give the title compound (1.2 mg, 0.0024 mmol, 2% yield).

MS (ERI) m/z 509.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.93 (d, J=2.5 Hz, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.18 (s, 1H) , 7.82 (d, J=2.4 Hz, 1H), 7.63 (s, 1H), 7.41-7.21 (m, 6H), 6.68 (d, J=2.3 Hz, 1H), 5.27 (s, 2H), 4.04 ( s, 3H).

Example 1726: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H- 494 042342 example 1723 using 1-benzyl-1H-pyrazol-3-amine and pyrazol-3-yl)-2-methylnicotinamide

V

Obtained according to the methods described

5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinic acid (16.6 mg, 0.032 mmol, 32% yield).

MS (ERI) m/z 493.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.88 (s, 1H), 9.22 (s, 1H), 8.49 (d, J=2.3 Hz, 1H), 8.19 (s, 1H), 7.79 (s, 1H ), 7.69 (s, 1H), 7.40-7.17 (m, 6H), 6.68 (s, 1H), 5.26 (s, 2H), 2.62 (s, 3H).

Example 1727: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)2-hydroxy -2-methylpropyl)-2-methylnicotinamide

1727A: tert-Butyl (3-(4-fluorophenyl)-2-hydroxy-2-methylpropyl)carbamate: To a 50 ml round bottom flask was added tert-butyl (2-oxopropyl)carbamate (0.173 g, 1 mmol) in THF (1.5 ml) to give a colorless solution. (4-Fluorobenzyl)magnesium chloride (4.00 ml, 1.0 mmol) was added dropwise. The resulting clear mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated NH4Cl solution and the mixture was diluted with EtOAc. The layers were separated. The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The remainder was immediately used in the next deprotection step.

1727B: 1-amino-3-(4-fluorophenyl)-2-methylpropan-2-ol 2,2,2-trifluoroacetate, TFA: tert-butyl (3-(4-fluorophenyl)-2 -hydroxy-2-methylpropyl)carbamate (0.283 g, 1 mmol) in CH2Cl2 (2 ml) to give a colorless suspension. TFA (1 ml, 12.98 mmol) was added. The resulting tan-yellow solution was stirred at room temperature for 30 minutes. The volatiles were removed to give the title compound as a tan oil.

MS (ERI) m/z 166.0 (M-H2O) ^- .

1727: prepared according to the methods described in example 1685 using 1-amino-3-(4-fluorophenyl)2-methylpropan-2-ol 2,2,2-trifluoroacetate and 5-(4-amino-5-(trifluoromethyl) pyrrolo[2,1-f][1,2,4]triazin-7yl)-2-methylnicotinic acid to give the title compound (3.6 mg, 0.0072 mmol, 7% yield).

MS (ERI) m/z 503.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.11 (d, J=2.2 Hz, 1H), 8.36 (d, J=2.2 Hz, 1H), 8.27 (t, J=6.0 Hz, 1H), 8.13 ( s, 1H), 7.60 (s, 1H), 7.29 (dd, J=8.3, 5.6 Hz, 2H), 7.05 (t, J=8.7 Hz, 2H), 3.44-3.15 (m, 2H), 2.82-2.67 (m, 2H), 2.58 (s, 3H), 1.04 (s, 3H).

Examples 1728 and 1729: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl) (3-((4-fluorophenyl)(hydroxy)methyl)piperidin-1-yl)methanone

1728/9A: tert-butyl

3-((4-Fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate: To a 50 ml oven-dried round bottom flask was added tert-butyl 3-formylpiperidine-1-carboxylate (457 mg, 2.143 mmol) in THF (4 ml ) to give a colorless solution. (4fluorophenyl)magnesium bromide (2.250 ml, 2.250 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude compound as a colorless thick oil (766 mg, xx mmol, 100% yield).

MS (ERI) m/z 332.2 (M+Na)+.

1728/9B: (4-fluorophenyl)(piperidin-3-yl)methanol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-((4-fluorophenyl)(hydroxy)methyl)piperidine was added to a 50 ml round bottom flask -1-carboxylate (254 mg, 0.706 mmol) in CH ₂ Cl ₂ (2 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 30 minutes. LC-MS showed two diastereomers. The volatiles were removed to give the title compound as a tan oil, which was used as is.

MS (ERI) (m/z) 210.0 (M+H)+.

- 495 042342

1728 and 1729: prepared according to the methods described in example 1685 using 1-amino-3-(4fluorophenyl)-2-methylpropan-2-ol 2,2,2-trifluoroacetate, TFA and 5-(4-amino-5- (trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methylnicotinic acid, and separation by preparative LCMS to give the title compounds (1728: 7.0 mg, 0.012 mmol, 13% yield); 1729: 15.5 mg, 0.029 mmol, 29% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 529.2 (M+H)+ for both compounds.

LCMS, retention time using method 3 = 1.13 min.

LCMS, retention time using method 4 = 1.16 min.

Example 1730: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)2-hydroxy -2-methylpropyl)-2-methoxynicotinamide

Prepared according to the methods described in Example 1727 using 1-amino-3-(4-fluorophenyl)-2methylpropan-2-ol 2,2,2-trifluoroacetate (1727B) and 5-(4-amino-5-(trifluoromethyl) pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid to give the title compound (9.4 mg, 0.018 mmol, 18% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 519.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (d, J=2.5 Hz, 1H), 8.81 (d, J=2.4 Hz, 1H), 8.27 (t, J= 5.5 Hz, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 7.28 (dd, J=8.3, 5.6 Hz, 2H), 7.06 (t, J=8.7 Hz, 2H), 4.07 (s, 3H), 3.33 (qd, J=13.3, 5.7 Hz, 1H), 2.75 (s, 2H), 1.05 (s, 3H).

Examples 1731 and 1732: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl) (3-((4-fluorophenyl)(hydroxy)methyl)piperidin-1yl)methanone

Prepared according to the methods described in example 1729/1730 using 1-amino-3-(4-fluorophenyl)2-methylpropan-2-ol 2,2,2-trifluoroacetate (1728B) and 5-(4-amino-5- (trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, and by separation by preparative LC-MS to give the title compounds (1731: 7.7 mg, 0.014 mmol, 15% yield; 1732: 11.3 mg, 0.021 mmol, 22% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 529.2 (M+H)+ for both compounds.

LCMS, retention time using method 2 = 1.79 min.

LCMS, retention time using method 1 = 1.88 min.

Example 1733 and 1734: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl) (3-(1-(4-fluorophenyl)-1-hydroxyethyl)piperidin-1yl)methanone

F ₃ CF ₃ C \ OH ^H2N \^AJ ίϊ \ ^0H

Г and 1.7 " ιΓί ΐ ttA \^n kA kJ k A \^n k A k J kA

1733/4A: tert-butyl 3-(1-(4-fluorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate: To a 50 ml oven-dried round bottom flask was added tert-butyl 3-acetylpiperidine-1-carboxylate (480 mg , 2.112 mmol) in THF (4 ml) to give a colorless solution. (4fluorophenyl)magnesium bromide (2.53 ml, 2.53 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude material as a colorless thick oil (784.2 mg, 100% yield).

MS (ERI) m/z 346.2 (M+Na)+.

1733/4B: 1-(4-fluorophenyl)-1-(piperidin-3-yl)ethan-1-ol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-(1- (4-fluorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (244.2 mg, 0.657 mmol) in CH ₂ Cl ₂ (1.5 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 30 minutes. The volatiles were removed to give the title compound as a reddish

- 496 042342 oil, which was immediately used in the next reaction.

MS (ERI) m/z 224.0 (M+H)+.

1733 and 1734: Prepared according to the methods described in Example 1685 using 11-(4-fluorophenyl)1-(piperidin-3-yl)ethan-1-ol 2,2,2-trifluoroacetate and lithium 5-(4-amino -5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxynicotinate, and by separation by preparative LC-MS to give the title compounds (1733: 1.8 mg , 0.0028 mmol, 3% yield; 1734: 1.4 mg, 0.0024 mmol, 3% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 559.3 (M+H)+ for both compounds.

LCMS, retention time using method 2 = 1.64 min for both compounds.

Examples 1735 and 1736: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl) (3-(1-(4-fluorophenyl)-1-hydroxyethyl)piperidin-1yl)methanone

1735 and 1736: Prepared according to the methods described in Example 1729/1729 using 11-(4fluorophenyl)-1-(piperidin-3-yl)ethan-1-ol 2,2,2-trifluoroacetate (1733B) and 5-( 4-Amino-5(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methylnicotinic acid, and by separation by preparative LC-MS to give the title compounds (1735: 2.4 mg, 0.0038 mmol, 4% yield; 1736: 1.0 mg, 0.0018 mmol, 2% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 543.3 (M+H) for both compounds.

1735: LC-MS, retention time using method 2 = 1.60 min.

1736: LC-MS, retention time using method 2 = 1.58 min.

Examples 1737 and 1738: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl) (3-((4-fluorophenyl)(hydroxy)methyl)-3-methylpiperidin-1yl)methanone

1737/8A: tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate: tert-butyl 3-formyl-piperidine-1-carboxylate (0.640 g, 3 mmol) and methyl iodide (0.563 ml, 9.00 mmol) in CH ₂ Cl ₂ (15 ml) under nitrogen to give a colorless solution. After cooling to 0°C, potassium tert-butoxide (0.438 g, 3.90 mmol) was added. After 30 minutes, the cooling bath was removed. The reaction mixture was stirred at room temperature for 5 h, and the reaction was stopped with brine. The layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to a colorless oil (~930 mg). Part of the crude material was immediately used in the next step.

1737/8B: tert-butyl 3-((4-fluorophenyl)(hydroxy)methyl)-3-methylpiperidine-1-carboxylate: tert-butyl 3-formyl-3-methylpiperidine-1-carboxylate was added to a 50 ml oven-dried round bottom flask (682 mg, 3 mmol) (azeotropically distilled with dry benzene) in THF (8 ml) to give a colorless solution. (4-Fluorophenyl)magnesium bromide (3.60 mL, 3.60 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude material as a colorless thick oil (995 mg, 3.0 mmol, 100% yield).

MS (ERI) m/z 346.1 (M+H) ⁺ .

1737/8C: (4-fluorophenyl)(3-methylpiperidin-3-yl)methanol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-((4-fluorophenyl)(hydroxy)methyl was added to a 50 ml round bottom flask )-3-methylpiperidine-1carboxylate (320 mg, 0.989 mmol) in CH ₂ Cl ₂ (2 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 60 minutes. The volatiles were removed to give the title compound (crude 328 mg) as a tan oil, which was immediately used in the next reaction.

MS (ERI) m/z 224.2 (M+H) ⁺ .

1737 and 1738: Prepared according to the methods described in Example 1685 using (4-fluorophenyl)(3methylpiperidin-3-yl)methanol 2,2,2-trifluoroacetate and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,11][1,2,4]triazin-7-yl)-2-methoxynicotinate, and by separation by preparative LC-MS to give the title compounds (1737: 7.3 mg, 0.012 mmol, 12% yield; 1738: 7.1 mg, 0.012

- 497 042342 mmol, 12% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 559.2 (M+H)+ for both compounds.

1737: LC-MS, retention time using method 1 = 1.83 min.

1738: LC-MS, retention time using method 1 = 1.94 min.

Examples 1739 and 1740: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl) (3-((4-fluorophenyl)(hydroxy)methyl)-3-methylpiperidin-1yl)methanone

Prepared according to the methods described in example 1737/1738 using (4-fluorophenyl)(3methylpiperidin-3-yl)methanol 2,2,2-trifluoroacetate (1737C) and lithium 5-(4-amino-5(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinate, and by separation by preparative LC-MS to give the title compounds (1739: 2.3 mg, 0.0042 mmol, 4% yield, 1740: 8.0 mg, 0.014 mmol, 14% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 543.3 (M+H) ⁺ for both compounds.

1739: LC-MS, retention time using method 1 = 1.94 min.

1740: LC-MS, retention time using method 1 = 1.73 min.

Example 1741: (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxypyridin3-yl)(3-(4- fluorobenzyl)-3-hydroxypiperidin-1-yl)methanone

1741A: tert-butyl 3-(4-fluorobenzyl)-3-hydroxypiperidine-1-carboxylate: tert-butyl 3-oxo-piperidine-1-carboxylate (227 mg, 1.139 mmol) in THF ( 2 ml) to give a colorless solution. (4-Fluorobenzyl)magnesium chloride (4.78 ml, 1.196 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 3 hours. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to a crude colorless thick oil (317 mg, 1.02 mmol, 90% crude) which was used as is.

1741B: 3-(4-fluorobenzyl)piperidin-3-ol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-(4-fluorobenzyl)-3-hydroxypiperidine-1-carboxylate (317 mg, 1.025 mmol) in CH ₂ Cl ₂ (2 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 60 minutes. The volatiles were removed to give the title compound (crude, 375 mg) as a dark oil which was used immediately as is.

MS (ERI) m/z 210.2 (M+H) ⁺ .

1741: prepared according to the methods described in example 1685 using 3-(4fluorobenzyl)piperidin-3-ol 2,2,2-trifluoroacetate and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][ 1,2,4]triazin-7-yl)-2-methoxynicotinate, and by separation using preparative LC-MS. The NMR characteristics were difficult to determine due to the presence of a diastereomeric mixture.

MS (ERI) m/z 545.2 (M+H) ⁺ .

LCMS, retention time using method 2 = 1.86 min.

Example 1741: (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylpyridin-3yl)(3-(4- fluorobenzyl)-3-hydroxypiperidin-1-yl)methanone

Prepared according to the methods described in Example 1741 using 3-(4-fluorobenzyl)piperidin-3ol 2,2,2-trifluoroacetate (1741B) and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f ][1,2,4]triazin-7-yl)-2methylnicotinic acid to give the title compound (9.1 mg, 0.017 mmol, 17% yield).

MS (ERI) m/z 529.2 (M+H) ⁺ .

LC-MS, retention time using method 2 = 1.69 min.

- 498 042342

Example 1743: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)2,3 -dihydroxy-2-methylpropyl)-2-methoxynicotinamide

1743A: 1-(4-fluorophenyl)-2-methylprop-2-en-1-ol: 4-fluorobenzaldehyde (1.24 g, 9.99 mmol) in THF (20 ml) was added to a 250 ml oven dried round bottom flask to give a colorless solution. Prop-1-en-2-ylmagnesium bromide (22 mL, 10.99 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 30 minutes. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude material as a slightly tan oil (crude, 2.12 g). Half was saved and half (1.06 g) was used in the next reaction.

1743B: (4-fluorophenyl)(2-methyloxiran-2-yl)methanol: 1-(4-fluorophenyl)-2-methylprop-2-en-1-ol (831 mg, 5 mmol) in CH ₂ Cl ₂ (20 ml) to give a colorless solution. mCPBA (863 mg, 5.00 mmol) was added over 16 hours. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a light yellow oil (836 mg, 4.59 mmol, crude, 92% yield from two steps).

1743C: 3-amino-1-(4-fluorophenyl)-2-methylpropan-1,2-diol: (4-fluorophenyl)(2-methyloxiran-2-yl)methanol (274 mg, 1.504 mmol) and added 7 n. ammonia in MeOH (2 ml, 14.00 mmol). The mixture was stirred at room temperature overnight and then heated at 65° C. for 5 h. Volatiles were removed under vacuum to give the crude title compound as a slightly tan thick oil (200 mg, 1.0 mmol, 67% yield).

MS (ERI) m/z 200.1 (M+H)+.

1743: prepared according to the methods described in example 1685 using 3-amino-1-(4-fluorophenyl)2-methylpropan-1,2-diol and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl)-2methoxynicotinate to give the title compound (20.0 mg, 0.036 mmol, 36% yield).

MS (ERI) m/z 535.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 9.01-8.77 (m, 3H), 8.46 (d, J=33.5 Hz, 1H), 8.19-8.14 (m, 1H), 7.62-7.53 (m, 2H) , 7.45-(ddd, J=8.5, 5.5, 2.6 Hz, 2H), 7.11 (dtd, J=9.0, 7.1, 6.1, 3.4 Hz, 2H), 5.58 (d, J=5.2 Hz, 1H), 4.714. 51 (m, 2H), 4.09 (dd, J=10.7, 1.8 Hz, 3H), 1.12-0.90 (m, 3H) (mixture of two diastereomers).

Examples 1744 and 1745: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4fluorophenyl)-2, 3-dihydroxy-2-methylpropyl)-2-methylnicotinamide

Prepared according to the methods described in example 1743 using 3-amino-1-(4-fluorophenyl)-2methylpropane-1,2-diol (1743C) and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1 -1][1,2,4]triazin-7-yl)-2methylnicotinic acid, and by separation by preparative LC-MS to give the title compounds (1744: 12.8 mg, 0.025 mmol, 25% yield; 1745: 9.8 mg, 0.018 mmol, 18% yield).

MS (ERI) m/z 519.3 (M+H)+ for both compounds.

1744: 1H NMR (500 MHz, DMSOY) δ 9.17 (d, J=2.3 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.35 (t, J=6.0 Hz, 1H), 8.18 (s , 1H), 7.68 (s, 1H), 7.43 (dd, J=8.6, 5.8 Hz, 2H), 7.11 (t, J=8.8 Hz, 2H), 5.52 (d, J=4.5 Hz, 1H), 4.55 (s, 1H), 4.52 (d, J=4.6 Hz, 1H), 0.93 (s, 3H).

1745: 1H NMR (500 MHz, DMSOA) δ 9.16 (d, J=2.3 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.21-8.13 (m, 2H), 7.65 (s, 1H) , 7.49-7.43 (m, 2H), 7.14-7.09 (m, 2H), 5.38 (d, J=4.9 Hz, 1H), 4.51 (d, J=4.7 Hz, 1H), 4.43 (d, J=1.6 Hz, 1H), 2.60 (s, 3H), 1.05 (s, 3H).

Example 1746: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(2-hydroxy-2,4,4trimethylpentyl) -2-methylnicotinamide

1746A: 2-methyl-2-neopentyloxirane: To a 500 ml round bottom flask was added 2,4,4-trimethylpent1-ene (2.93 g, 26.1 mmol) in CH ₂ Cl ₂ (80 ml) to give a colorless solution. mCPBA (5.85 g,

- 499 042342

26.1 mmol) followed by the addition of sodium bicarbonate (2.193 g, 26.1 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and water.

The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a colorless oil (3.39 g, 26.1 mmol, crude, 100% yield).

1755: 1-Amino-2,4,4-trimethylpentan-2-ol: 2-methyl-2-neopentyloxirane (1.07 g, 8.35 mmol) was charged into a 75 ml pressure vessel and 7 N hydrochloric acid was added. ammonia in methanol (15 ml, 105 mmol). The mixture was stirred at 62° C. for 18 hours. The volatiles were removed in vacuo to give the title compound as a slightly tan oil (620 mg, 51%) which was used without further purification.

1755: prepared according to the methods described in example 1685 using 1-amino-2,4,4trimethylpentan-2-ol and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2 ,4]triazin-7-yl)-2methylnicotinic acid to give the title compound (13.3 mg, 0.029 mmol, 29% yield).

MS (ERI) m/z 465.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ δ 9.15 (d, J=2.2 Hz, 1H), 8.39 (d, J=2.2 Hz, 1H), 8.31 (t, J=6.1 Hz, 1H), 8.17 (s, 1H), 7.67 (s, 1H), 3.40-3.11 (m, 2H), 2.57 (s, 3H), 1.56-1.37 (m, 2H), 1.21 (s, 3H), 1.01 (s, 9H).

Example 1747: (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxypyridin3-yl)(3-((4 -fluorophenyl)(hydroxy)methyl)-3-hydroxypiperidin-1-yl)methanone

1747A: tert-Butyl 3-(4-fluorobenzoyl)piperidine-1-carboxylate: To a 50 ml round bottom flask was added tert-butyl 3-((4-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1728A) (577 mg, 1.604 mmol) in CH ₂ Cl ₂ (6 ml) to give a colorless solution. DessaMartin periodinan (1701 mg, 4.01 mmol) was added in portions. The mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with NaHCO ₃ solution (mixed with some sodium bisulfite). The layers were separated. The aqueous layer was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography with 50% EtOAc/hexanes to give the title compound (336.4 mg, 1.09 mmol, 68% over two steps) as a white solid.

¹ H NMR (500 MHz, CDCl ₃ ) δ 8.08-7.98 (m, 2H), 7.21-7.12 (m, 2H), 4.22 (d, J=11.1 Hz, 1H), 4.14 (q, J=7.1 Hz, 1H), 3.38 (s, 1H), 2.95 (s, 1H), 2.78 (t, J=12.7 Hz, 1H), 2.08-1.99 (m, 1H), 1.85-1.66 (m, 2H), 1.49 (s , 9H), one exchangeable proton was not observed.

1747B: tert-butyl 3-(4-fluorobenzoyl)-3-hydroxypiperidine-1-carboxylate: tert-butyl 3-(4-fluorobenzoyl)piperidine-1-carboxylate (151 mg, 0.491 mmol) was added to a 50 ml round bottom flask, Cs ₂ CO ₃ (160 mg, 0.491 mmol) and triethyl phosphite (0.172 ml, 0.983 mmol) in DMSO (2 ml) to give a white suspension. The mixture was stirred under a pressure of 1 atm. oxygen (balloon) for 3.5 days (80 hours). The mixture was diluted with water and EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to 50% EtOAc/hexanes to give the title compound (123 mg, 0.38 mmol, 77% yield) as a white solid.

MS (ERI) m/z 346.1 (M+Na) ⁺ .

1H NMR (500 MHz, CDCl ₃ ) δ 8.30-8.19 (m, 2H), 7.14-7.03 (m, 2H), 4.23-3.91 (m, 2H), 3.38 (br, 1H), 2.87 (ddd, J= 13.7, 11.4, 3.2 Hz, 1H), 2.10-1.83 (m, 3H), 1.58 (d, J= 31.4 Hz, 1H), 1.43 (s, 9H), 1.37-1.27 (m, 1H).

1747C: tert-butyl 3-((4-fluorophenyl)(hydroxy)methyl)-3-hydroxypiperidine-1-carboxylate: tert-butyl 3-(4-fluorobenzoyl)-3-hydroxypiperidine-1- was added to a 20 ml round bottom flask carboxylate (100 mg, 0.309 mmol) in MeOH (1 ml) to give a yellow solution. NaBH ₄ (46.8 mg, 1.237 mmol) was added. The mixture was stirred for 60 minutes. Volatile substances were removed. The residue was partitioned between water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4 and concentrated to a white solid (101 mg, 0.31 mmol, 100% yield).

MS (ERI) m/z 348.1 (M+Na) ⁺ .

1747D: 3-((4-fluorophenyl)(hydroxy)methyl)piperidin-3-ol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-((4-fluorophenyl)(hydroxy) was added to a 50 ml round bottom flask methyl)-3-hydroxypiperidine-1carboxylate (101 mg, 0.310 mmol) in CH ₂ Cl ₂ (2 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 60 minutes. The volatiles were removed to give the title compound (crude, 120 mg) as a tan oil which was used immediately as is.

MS (ERI) m/z 226.0 (M+H) ⁺ .

- 500 042342

1747: prepared according to the methods described in example 1685 using 3-((4fluorophenyl)(hydroxy)methyl)piperidin-3-ol 2,2,2-trifluoroacetate and lithium 5-(4-amino-5(trifluoromethyl)pyrrolo[ 2,1-D][1,2,4]triazin-7-yl)-2-methoxynicotinate, and by separation by preparative LC-MS to give the title compound (16.7 mg, 0.028 mmol, 37% yield) .

MS (ERI) m/z 561.1 (M+H)+.

LCMS, retention time using method 1 = 1.1 min.

Examples 1748 and 1749: (unspecified diastereomers) (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl) (3-((4-fluorophenyl)(hydroxy)methyl)-3-hydroxypiperidin-1yl)methanone

Prepared according to the methods described in Example 1747 using 3-((4fluorophenyl)(hydroxy)methyl)piperidin-3-ol 2,2,2-trifluoroacetate (1747D) and 5-(4-amino-5(trifluoromethyl)pyrrolo[ 2,1-D][1,2,4]triazin-7-yl)-2-methylnicotinic acid, and by separation by preparative LC-MS to give the title compounds (1748: 15.0 mg, 0.027 mmol, 34 % yield, 1749: 8.2 mg, 0.014 mmol, 18% yield). The NMR characteristics were difficult to determine due to the presence of diastereomeric mixtures.

MS (ERI) m/z 545.1 (M+H) ⁺ for both compounds.

1748: LC-MS, retention time using method 2 = 1.51 min.

1749: LC-MS, retention time using method 1 = 1.54 min.

Example 1750: (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylpyridin-3yl)(3-(4- fluorobenzyl)-3,5-dihydroxypiperidin-1-yl)methanone

He

1750A: tert-butyl 3-(4-fluorobenzyl)-3-hydroxy-5-oxo-piperidine-1-carboxylate: To an oven-dried 50 ml round bottom flask was added tert-butyl 3,5-diox-piperidine-1-carboxylate (580 mg, 2.72 mmol) in THF (5 ml) to give a yellow suspension. NaH (163 mg, 4.08 mmol) was added under nitrogen atmosphere. The mixture was stirred under nitrogen for 30 minutes. (4Fluorobenzyl)magnesium chloride (16.32 ml, 4.08 mmol) was added. The mixture was stirred at room temperature for 1 h and then at 60°C for 3 h, the Reaction was slowly stopped with a saturated solution of NH ₄ Cl, and the mixture was diluted with EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to 60% EtOAc/hexanes to give the title compound (220 mg, 0.68 mmol, 25%) as a slightly tan thick oil.

1H NMR (500 MHz, CDCl ₃ ) δ 7.24-7.18 (m, 2H), 7.09-7.01 (m, 2H), 4.14 (td, J=11.2, 9.3, 6.5 Hz, 1H), 4.01-3.70 (m, 2H), 3.53-3.34 (m, 1H), 2.91-2.82 (m, 2H), 2.56-2.45 (m, 2H), 2.18-1.88 (br, 1H), 1.46 (s, 9H).

1750B: tert-butyl 3-(4-fluorobenzyl)-3,5-dihydroxypiperidine-1-carboxylate: tert-butyl 3-(4-fluorobenzyl)-3-hydroxy-5-oxo-piperidine-1- was added to a 20 ml round bottom flask carboxylate (88.9 mg, 0.275 mmol) in MeOH (1 ml) to give a yellow solution. NaBH ₄ (41.6 mg, 1.100 mmol) was added. The mixture was stirred for 60 minutes. Volatile substances were removed. The residue was partitioned between water and EtOAc. The layers were separated. The aqueous layer was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated to a tan oil (85 mg, 0.026 mmol, 95%) which was used as is.

MS (ERI) m/z 348.1 (M+Na) ⁺ .

1750C: 3-(4-fluorobenzyl)piperidine-3,5-diol 2,2,2-trifluoroacetate, TFA: tert-butyl 3-(4-fluorobenzyl)-3,5-dihydroxypiperidine-1 was added to a 50 ml round bottom flask -carboxylate (83 mg, 0.255 mmol) in CH ₂ Cl ₂ (2 ml) to give a colorless solution. TFA (1 ml, 12.98 mmol) was added. The resulting tan solution was stirred at room temperature for 60 minutes. The volatiles were removed to give the title compound (crude, 100 mg) as a tan oil which was used immediately as is.

MS (ERI) m/z 226.0 (M+H) ⁺ .

1750: Prepared according to the methods described in Example 1685 using 3-(4fluorobenzyl)piperidine-3,5-diol 2,2,2-trifluoroacetate and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11] [1,2,4]triazin-7-yl)-2-methylnicotinic acid to give the title compound (9.8 mg, 0.017 mmol, 27% yield).

- 501 042342

MS (ERI) m/z 544.9 (M+H)+.

LCMS, retention time using method 2 = 0.88 min.

Example 1751: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(5,5,5trifluoro- 2,4-dihydroxy-4-(trifluoromethyl)pentyl)nicotinamide

1751A: 1,1,1,3,3,3-hexafluoro-2-(oxiran-2-ylmethyl)propan-2-ol: 1,1,1-trifluoro-2-(trifluoromethyl) was added to a 250 ml round bottom flask pent-4-en-2-ol (1.37 g, 6.58 mmol) in CH ₂ Cl ₂ (20 ml) to give a colorless solution. mCPBA (1.475 g, 6.58 mmol) was added followed by sodium bicarbonate (0.553 g, 6.58 mmol). The mixture was stirred at room temperature overnight for 16 hours. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude as a colorless oil (1 g, crude, 68%, compound may be very volatile or water soluble). The crude material was immediately used in the next step.

1751B: 5-amino-1,1,1-trifluoro-2-(trifluoromethyl)pentane-2,4-diol: 1,1,1,3,3,3-hexafluoro-2- (oxiran-2-ylmethyl)propan-2-ol (1 g, 4.46 mmol) and 7N was added. ammonia in MeOH (15 ml, 105 mmol). The mixture was stirred at 62° C. overnight for 18 h. The volatiles were removed in vacuo to give the title compound as a slightly tan solid (470 mg, 1.95 mmol 44% yield) which was used without further purification.

1751: Prepared according to the methods described in Example 1685 using 5-amino-1,1,1-trifluoro-2(trifluoromethyl)pentan-2,4-diol and 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-1][1,2,4]triazin-7-yl)-2methylnicotinic acid to give the title compound (13.0 mg, 0.023 mmol, 23% yield).

MS (ERI) m/z 561.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.63 (t, J=5.9 Hz, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 7.64 (s, 1H) , 4.13 (s, 1H), 3.45-3.24 (m, 2H), 2.56 (s, 3H), 2.19 (d, J=15.2 Hz, 1H), 2.06-1.95 (m, 1H).

Example 1752: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1n24]triazin-7-yl)-N-(3-(4-fluorophenyl)2-hydroxy-3 -methoxy-2-methylpropyl)-2-methylnicotinamide

1752A: 2-((4-fluorophenyl)(methoxy)methyl)-2-methyloxirane: (4-fluorophenyl)(2-methyloxiran-2-yl)methanol (1743B) (342 mg , 1.877 mmol) in THF (4 ml) to give a colorless solution. NaH (225 mg, 5.63 mmol) was added. The mixture was stirred at room temperature for 5 min, and MeI (0.352 mL, 5.63 mmol) was added. The mixture was stirred at room temperature overnight for 16 hours. The reaction was slowly quenched with saturated NH ₄ Cl solution (gas evolved!). The reaction mixture was diluted with EtOAc and water. The layers were separated. The organic layer was washed with brine. The organic solution was then dried and concentrated to the crude material as a light yellow oil (440 mg, 1.88 mmol, crude, >100% wt).

1752B: 3-amino-1-(4-fluorophenyl)-1-methoxy-2-methylpropan-2-ol: 2-((4-fluorophenyl)(methoxy)methyl)-2-methyloxirane was added under pressure to a 20 ml vial (0.184 g, 0.939 mmol) and 7 n. ammonia in MeOH (2 ml, 14.00 mmol). The mixture was stirred at 65° C. overnight for 18 h. Volatiles were removed under vacuum to give the crude title compound as a slightly reddish thick oil (211 mg, 0.094 mmol, 100% yield).

MS (ERI) m/z 214.1 (M+H) ⁺ .

1752: prepared according to the methods described in example 1685 using 3-amino-1-(4-fluorophenyl)1-methoxy-2-methylpropan-2-ol and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2 ,1-1][1,2,4]triazin-7-yl)-2methylnicotinic acid to give the title compound (8.3 mg, 0.015 mmol, 15% yield).

MS (ERI) m/z 533.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.15 (d, J=2.2 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.34 (t, J=6.0 Hz, 1H), 8.16 (s , 1H), 7.68 (s, 1H), 7.36 (dd, J=8.4, 5.8 Hz, 2H), 7.17 (t, J=8.7 Hz, 2H), 4.66 (s, 1H), 4.15 (s, 1H) , 3.18 (s, 3H), 2.60 (s, 3H), 0.96 (s, 3H), 4 protons lost due to solvent suppression.

- 502 042342

Examples 1753 and 1753: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4fluorophenyl)-2- hydroxy-3-methoxy-2-methylpropyl)-2-methoxynicotinamide

Prepared according to the methods described in Example 1752 using 3-amino-1-(4-fluorophenyl)-1-methoxy-2-methylpropan-2-ol (1752B) and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-1][1,2,4]triazin7-yl)-2-methoxynicotinate, and by separation by preparative LC-MS to give the title compounds (1753: 3.1 mg, 0.0057 mmol, 5.7% yield; 1754: 2.0 mg, 0.035 mmol, 3.5% yield).

1753: MS (ERI) m/z 549.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=4.6 Hz, 2H), 8.39 (t, J=5.8 Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.36 (t, J=6.9Hz, 2H), 7.18 (t, J=8.7Hz, 2H), 4.16 (s, 1H), 4.09 (s, 3H), 3.19 (s, 3H), 0.93 (s, 3H) (lost five protons due to solvent suppression).

1754: MS (ERI) m/z 549.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (d, J=4.6 Hz, 2H), 8.39 (t, J=5.8 Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 7.36 (t, J=6.9 Hz, 2H), 7.18 (t, J=8.7 Hz, 2H), 4.16 (s, 1H), 4.09 (s, 3H), 3.19 (s, 3H), 0.93 (s, 3H ).

Example 1755: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(5,5,5 trifluoro -2-hydroxy-3-methoxy-2,4-dimethylpentyl)nicotinamide

1755A: 5,5,5-trifluoro-2,4-dimethylpent-1-en-3-ol: 3,3,3-trifluoro-2-methylpropanol (636 mg, 5.04 mmol ) in THF (5 ml) to give a colorless solution. Prop-1-en-2-ylmagnesium bromide (12.11 ml, 6.05 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was stopped with a saturated solution of NH ₄ Cl and diluted with Et ₂ O. The layers were separated. The organic layer was dried and concentrated to the crude material as a slightly tan oil (578 mg, 68%). The material may be very volatile and some of the compound may be evaporated at room temperature and used directly in the next step.

1755B: 3,3,3-trifluoro-2-methyl-1-(2-methyloxiran-2-yl)propan-1-ol: 5,5,5-trifluoro-2,4-dimethylpent was added to a 50 ml round bottom flask -1-en-3-ol (578 mg, 3.44 mmol) in CH2Cl2 (10 ml) to give a colorless solution. mCPBA (770 mg, 3.44 mmol) was added followed by sodium bicarbonate (289 mg, 3.44 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a colorless oil (520 mg, 2.82 mmol, crude, 82%, two steps yield).

1755C: 2-methyl-2-(3,3,3-trifluoro-1-methoxy-2-methylpropyl)oxirane: 3,3,3-trifluoro-2-methyl-1- (2-methyloxiran-2-yl)propan-1-ol (226 mg, 1.227 mmol) in THF (3 ml) to give a colorless solution. NaH (147 mg, 3.68 mmol) was added. The mixture was stirred at room temperature for 5 min, and MeI (0.230 mL, 3.68 mmol) was added. The mixture was stirred at room temperature overnight. The reaction was slowly stopped with a saturated NH ₄ Cl solution (gas evolved!). The reaction mixture was diluted with EtOAc and water. The layers were separated. The organic layer was washed with brine, dried and concentrated to the crude material as a light yellow oil (400 mg, 1.23 mmol, 100% yield with removal of some solvent) which was used in the next step.

1755D: 1-amino-5,5,5-trifluoro-3-methoxy-2,4-dimethylpentan-2-ol: 2-methyl-2-(3,3,3-trifluoro- 1-methoxy-2-methylpropyl)oxirane (243 mg, 1.227 mmol) (crude) and 7 N. ammonia in MeOH (2 ml, 14 mmol). The mixture was stirred at 65° C. for 18 hours. The volatiles were removed under vacuum to give the crude title compound as a slightly reddish thick oil (135 mg, 0.63 mmol, 51% yield).

MS (ERI) m/z 214.1 (M+H).

1755: Prepared according to the methods described in Example 1685 using 1-amino-5,5,5-trifluoro-3methoxy-2,4-dimethylpentan-2-ol and 5-(4-amino-5-(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-2methylnicotinic acid to give the title compound (9.7 mg, 0.018 mmol, 18% yield).

MS (ERI) m/z 535.3 (M+H).

- 503 042342

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 8.44-8.29 (m, 2H), 8.16 (s, 1H), 7.67 (d, J=3.9 Hz, 1H),

4.93 (d, J=72.4 Hz, 1H), 2.90 (dd, J=15.2, 8.0 Hz, 2H), 2.57 (d, J=3.7 Hz, 3H), 1.18-1.04 (m, 7H) (mixture of two diastereomers : ~2/1).

Example 1756: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)2-hydroxy -2-methyl-3-oxopropyl)-2-methylnicotinamide

A mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2,3dihydroxy- 2-methylpropyl)-2-methylnicotinamide (Example 1753) (87 mg, 0.168 mmol) and IBX (70.5 mg, 0.252 mmol) in DMSO (1 mL) were stirred at room temperature for 16 h. The crude product was purified by preparative LC -MS to give the title compound (18.0 mg, 0.033 mmol, 20% yield).

MS (ERI) m/z 517.1 (M+H).

*H NMR (500 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 8.52 (t, J=6.3 Hz, 1H), 8.27 (q, J=5.7 Hz, 3H), 8.17 (s, 1H) , 7.63 (s, 1H), 7.29 (t, J=8.8 Hz, 2H), 6.03 (d, J=2.6 Hz, 1H), 3.80-3.60 (m, 2H), 2.49 (s, 3H), 1.46 ( s, 3H).

Example 1757: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(2-fluorophenyl)2,3 -dihydroxy-2-methylpropyl)-2-methylnicotinamide

1757A: 1-(2-fluorophenyl)-2-methylprop-2-en-1-ol: 2-fluorobenzaldehyde (0.601 g, 4.84 mmol) in THF (10 ml) was added to a 50 ml oven dried round bottom flask to give a colorless solution. Prop-1-en-2-ylmagnesium bromide (10.7 mL, 5.33 mmol) was added dropwise at room temperature over 1 h. The reaction was quenched with saturated NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude material as a light oil (crude: 0.928 g, 4.84 mmol, 100% yield).

'H NMR (500 MHz, CDCl ₃ ) δ 7.47 (td, J=7.6, 1.8 Hz, 1H), 7.32-7.25 (m, 1H), 7.17 (td, J=7.5, 1.2 Hz, 1H), 7.05- (ddd, J=10.4, 8.2, 1.2 Hz, 1H), 5.49 (s, 1H), 5.21 (dt, J=1.5, 0.8 Hz, 1H), 5.00 (q, J=1.4 Hz, 1H), 1.69 ( d, J=0.7 Hz, 3H).

¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -119.07.

1757B: (2-fluorophenyl)(2-methyloxiran-2-yl)methanol: 1-(2-fluorophenyl)-2-methylprop-2-en-1-ol (804 mg, 4.84 mmol) in CH ₂ Cl ₂ (20 ml) to give a colorless solution. mCPBA (1085 mg, 4.84 mmol) was added followed by sodium bicarbonate (407 mg, 4.84 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a clear oil (830 mg, 4.56 mmol, 94%, crude, yield over two steps, diastereomer ratio was about 1/1).

1H NMR (500 MHz, CDCl ₃ ) δ 7.75-6.96 (m, 4H), 5.28-4.74 (m, 1H), 3.34-3.04 (m, 1H), 2.86-2.46 (m, 2H), 1.42-1.08 ( m, 3H).

¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -117.64, -117.84.

1757C: 3-amino-1-(2-fluorophenyl)-2-methylpropan-1,2-diol: (2-fluorophenyl)(2-methyloxiran-2-yl)methanol (307 mg, 1.685 mmol) and 7 n. ammonia in MeOH (3 ml, 21.00 mmol). The mixture was stirred at 65°C for 18 hours. The volatiles were removed under vacuum to give the crude title compound as a slightly tan thick oil (340 mg, 1.69 mmol, 100% yield) which was used immediately as is.

1757: prepared according to the methods described in example 1685 using 3-amino-1-(2-fluorophenyl)2-methylpropan-1,2-diol and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2, 1-D[1,2,4]triazin-7-yl)-2methoxynicotinate. The NMR characteristics were difficult to determine due to the presence of a diastereomeric mixture.

MS (ERI) m/z 519.2 (M+H).

LCMS, retention time using method 2 = 1.35 min.

- 504 042342

Example 1758: 5-(4-α-mino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl)-N-(3-(3-fluorophenyl)2,3 -dihydroxy-2-methylpropyl)-2-methylnicotinamide

F ₃ C

1758A: 1-(3-fluorophenyl)-2-methylprop-2-en-1-ol: 3-fluorobenzaldehyde (0.611 g, 4.92 mmol) in THF (10 ml) was added to a 50 ml oven dried round bottom flask to give a colorless solution. Prop-1-en-2-ylmagnesium bromide (10.83 mL, 5.42 mmol) was added dropwise at room temperature over 1 h. The reaction was quenched with saturated NH ₄ Cl and diluted with EtOAc. The layers were separated. The organic layer was dried and concentrated to the crude substance as a light oil (0.988 g, 4.92 mmol, crude, 100% yield, some solvent remained).

1H NMR (500 MHz, CDCl ₃ ) δ 7.36-7.26 (m, 1H), 7.20-7.08 (m, 2H), 6.98 (tdd, J=8.5, 2.7, 1.0 Hz, 1H), 5.21 (dt, J= 1.7, 0.9 Hz, 1H), 5.16 (s, 1H), 4.99 (td, J=1.6, 0.7 Hz, 1H), 1.63 (d, J=1.1 Hz, 3H).

¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -113.15.

1758B: (3-fluorophenyl)(2-methyloxiran-2-yl)methanol: 1-(3-fluorophenyl)-2-methylprop-2-en-1-ol (818 mg, 4.92 mmol) in CH ₂ Cl ₂ (20 ml) to give a colorless solution. mCPBA (1103 mg, 4.92 mmol) was added followed by sodium bicarbonate (413 mg, 4.92 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a light yellow oil (893 mg, 4.92 mmol, crude, 100%, yield over two steps, the ratio of the two diastereomers was ~1/1).

1H NMR (500 MHz, CDCl3) δ 7.47-6.88 (m, 4H), 4.61 (d, J=105.3 Hz, 1H), 3.23-2.98 (m, 1H), 2.81-2.45 (m, 2H), 1.33- 1.17(m, 3H).

¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -112.61, -112.73.

1758C: 3-amino-1-(3-fluorophenyl)-2-methylpropan-1,2-diol: (3-fluorophenyl)(2-methyloxiran-2-yl)methanol (309 mg, 1.696 mmol) and 7 n. ammonia in MeOH (3 ml, 21.00 mmol). The mixture was stirred at 65°C for 18 hours. The volatiles were removed under vacuum to give the crude title compound as a slightly tan thick oil (400 mg, 1.70 mmol, 100% yield) which was used as is.

1758: prepared according to the methods described in example 1685 using 3-amino-1-(3-fluorophenyl)2-methylpropan-1,2-diol and lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2, 1-f][1,2,4]triazin-7-yl)-2methoxynicotinate to give the title compound (13.0 mg, 0.025 mmol, 25% yield).

MS (ERI) m/z 519.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.16 (d, J=2.1 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.30 (t, J=6.1 Hz, 1H), 8.18 (s , 1H), 7.67 (s, 1H), 7.33 (q, J=7.4 Hz, 1H), 7.23-7.20 (m, 2H), 7.05 (t, J=8.5 Hz, 1H), 4.49 (s, 1H) , 3.213.11 (m, 2H), 2.58 (s, 3H), 1.03 (s, 3H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -73.93.

Examples 1759 and 1760: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-ul)-N-(3-(4fluorophenyl)-2, 3-dihydroxy-2-methylpropyl)-2-methylbenzamide

Prepared according to the methods described in Example 1743 using 3-amino-1-(4-fluorophenyl)-2methylpropane-1,2-diol (1743C) and 5-(4-αmino-5-(trifluoromethyl)pyrrolo[2.1 -f][1,2,4]triazin-7-yl)-2methylbenzoic acid, and by separation by preparative LC-MS to give the title compounds (1759: 6.1 mg, 0.012 mmol, 12% yield; 1760: 10.7 mg, 0.020 mmol, 20% yield).

MS (ERI) m/z 518.0 (M+H) for both compounds.

1759: 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.13 (s, 1H), 8.03-7.98 (m, 2H), 7.92 (d, J=6.1 Hz, 1H), 7.48 (s, 1H), 7.44 (dd, J=8.4, 5.7Hz, 2H), 7.37 (d, J=8.5Hz, 1H), 7.09 (t, J=8.8Hz, 2H), 5.38 (d, J=4.7Hz, 1H), 4.564 .40 (m, 2H), 2.41 (s, 3H), 1.03 (s, 3H).

1760: 1H NMR (500 MHz, DMSOA) δ 8.14 (d, J=6.8 Hz, 2H), 8.03 (d, J=7.4 Hz, 2H), 7.52 (s, 1H), 7.42 (dd, J=8.5, 5.6Hz, 2H), 7.37(d, J=8.0Hz, 1H), 7.10(t, J=8.7Hz, 2H), 4.51(d, J=4.2Hz, 1H), 3.53-3.36(m, 2H) , 2.40 (s, 3H), 0.91 (s, 3H).

- 505 042342

Examples 1761 and 1762: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4fluorophenyl)-2- hydroxy-3-methoxy-2-methylpropyl)-2-methylbenzamide

Prepared according to the methods described in Example 1752 using 3-amino-1-(4-fluorophenyl)-1-methoxy-2-methylpropan-2-ol (1752B) and 5-(4-amino-5-(trifluoromethyl)pyrrolo[2 ,1-1][1,2,4]triazin-7-yl)2-methylbenzoic acid, and by separation by preparative LC-MS to give the title compounds (1761: 7.9 mg, 0.014 mmol, 14% yield ; 1762: 16.1 mg, 0.030 mmol, 30% yield).

MS (ERI) m/z 532.1 (M+H) for both compounds.

1761: 1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 8.01 (d, J=6.2 Hz, 2H), 7.88 (t, J=5.9 Hz, 1H), 7.48 (s, 1H) , 7.41 (dd, J=8.3, 5.7 Hz, 2H), 7.37 (d, J=8.5 Hz, 1H), 7.15 (t, J=8.7 Hz, 2H), 4.49 (s, 1H), 4.12 (s, 1H), 3.51 (dd, J=13.3, 6.9 Hz, 1H), 3.30 (d, J=2.7 Hz, 3H), 2.41 (s, 3H), 1.03 (s, 3H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -51.08.

1762: 1H NMR (500 MHz, DMSO-d6) δ 88.18-7.99 (m, 4H), 7.54 (s, 1H), 7.37 (t, J=9.2 Hz, 3H), 7.17 (t, J=8.6 Hz, 2H), 4.67 (s, 1H), 4.15 (s, 1H), 3.18 (s, 2H), 2.42 (s, 3H), 0.95 (s, 3H); ¹⁹ F NMR (376 MHz, DMSO-d6) δ -51.08.

Example 1763: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3(difluoromethoxy)-3-(4- fluorophenyl)-2-hydroxy-2-methylpropyl)-2-methylnicotinamide

1763A: 1-(1-(difluoromethoxy)-2-methylallyl)-4-fluorobenzene: 1-(4fluorophenyl)-2-methylprop-2-en-1-ol (1743A) (0.504 g, 3.03 mmol) in CH ₂ Cl ₂ (1.8 ml) to give a colorless solution. (Bromodifluoromethyl)trimethylsilane (1.848 g, 9.10 mmol) was added followed by potassium acetate (1.786 g, 18.20 mmol). Water (1.8 ml) was added. The mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed with brine. The organic solution was then dried and concentrated. The residue was purified by silica gel chromatography to 40% EtOAc/hexanes to give the title compound (286 mg, 1.32 mmol, 44%) as a colorless oil.

1H NMR (500 MHz, CDCl ₃ ) δ 7.40-7.32 (m, 2H), 7.12-7.04 (m, 2H), 6.29 (t, J=75.3 Hz, 1H), 5.44 (s, 1H), 5.20 (dt , J=1.7, 1.0 Hz, 1H), 5.08 (td, J=1.5, 0.6 Hz, 1H), 1.65 (t, J=1.2 Hz, 3H); ¹⁹ F NMR (470 MHz, CDCl ₃ ) δ 82.79 (d, J=76.5 Hz), -114.14.

1763B: 2-((difluoromethoxy)(4-fluorophenyl)methyl)-2-methyloxirane: 1-(1-(difluoromethoxy)-2-methylallyl)-4-fluorobenzene (286 mg, 1.323 mmol) in CH ₂ Cl ₂ (6 ml) to give a colorless solution. mCPBA (296 mg, 1.323 mmol) was added followed by sodium bicarbonate (111 mg, 1.323 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with ether and water. The layers were separated. The organic layer was washed three times with NaHCO ₃ solution and brine. The organic solution was then dried and concentrated to the crude material as a colorless oil (320 mg, 1.32 mmol, crude, 100% yield).

1H NMR (500 MHz, CDCl ₃ ) δ 7.43-7.32 (m, 2H), 7.14-7.02 (m, 2H), 6.58-6.10 (m, 1H), 5.48-4.79 (m, 2H), 2.96-2.68 ( m, 1H), 1.67-1.24 (m, 3H); ¹⁹ F NMR (470 MHz, CDCl ₃ ) δ -82.16 (d, J=25.9 Hz), -82.87, -113.35 (d, J=72.2 Hz), -114.15. 1H NMR showed a mixture of two isomers.

1763C: 3-amino-1-(difluoromethoxy)-1-(4-fluorophenyl)-2-methylpropan-2-ol: 2-((difluoromethoxy)(4-fluorophenyl)methyl)-2 was added under pressure to a 20 ml vial -methyloxirane (307 mg, 1.323 mmol) and ammonia (3 ml, 21.00 mmol) (7N in MeOH). The mixture was stirred at 65°C for 18 hours. The volatiles were removed under vacuum to give the crude title compound as a slightly reddish thick oil (288 mg, 1.16 mmol, 87% crude yield over two steps) which was used immediately as is.

MS (ERI) m/z 250.1 (M+H).

1763: Prepared according to the methods described in Example 1685 using 3-amino-1(difluoromethoxy)-1-(4-fluorophenyl)-2-methylpropan-2-ol and 5-(4-amino-5-(trifluoromethyl)pyrrolo [2,11][1,2,4]triazin-7-yl)-2-methylnicotinic acid to give the title compound (24.3 mg, 0.042 mmol, 42% yield).

MS (ERI) m/z 569.1 (M+H).

1H NMR (500 MHz, DMSO-d6) δ 9.16 (d, J=2.2 Hz, 1H), 8.45-8.32 (m, 2H), 8.18 (d, J=1.6 Hz, 1H), 7.67

- 506 042342 (s, 1H), 7.47 (dt, J=8.7, 5.4 Hz, 2H), 7.20 (td, J=8.8, 1.7 Hz, 2H), 6.83-6.50 (m, 1H), 5.03 (d, J=4.2 Hz, 1H), 3.46 (s, 1H), 3.29-3.06 (m, 1H), 2.58 (s, 3H), 1.07 (d, J=24.4 Hz, 3H); ¹⁹ F NMR (471 MHz, DMSO-d ₆ ) δ -51.17 (showed a mixture of two isomers).

Examples 1764 and 1765: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3(difluoromethoxy)-3-( 4-fluorophenyl)-2-hydroxy-2-methylpropyl)-2-methylbenzamide

Prepared according to the methods described in Example 1763 using 3-amino-1-(difluoromethoxy)-1(4-fluorophenyl)-2-methylpropan-2-ol (1763C) and 5-(4-amino-5-(trifluoromethyl) pyrrolo[2,1-f][1,2,4]triazin7-yl)-2-methylbenzoic acid, and by separation by preparative LC-MS to give the title compounds (1764: 2.7 mg, 0.004 mmol, 4 % yield, 1765: 5.3 mg, 0.009 mmol, 9% yield).

MS (ERI) m/z 568.2 (M+H) for both isomers.

1764: 1H NM P(500 MHz, DMSO-d6) δ 8.12 (s, 1H), 8.06-7.92 (m, 3H), 7.52-7.45 (m, 3H), 7.37 (d, J=8.0 Hz, 1H) , 7.17 (t, J=8.9 Hz, 2H), 6.62 (dd, J=77.2, 74.8 Hz, 1H), 5.01 (s, 1H), 3.50 (dd, J=13.4, 6.7 Hz, 1H), 3.32 ( d, J=9.5 Hz, 1H), 2.40 (s, 3H), 1.06 (s, 3H).

1765: 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.19 (t, J=6.2 Hz, 1H), 8.15 (s, 1H), 8.08-8.01 (m, 2H), 7.54 (s, 1H), 7.47 (dd, J=8.5, 5.5Hz, 2H), 7.38 (d, J=8.1Hz, 1H), 7.20 (t, J=8.8Hz, 2H), 6.68 (t, J=75.6Hz, 1H), 5.04 (s, 1H), 4.98 (s, 1H), 3.50 (dd, J=13.5, 6.7 Hz, 1H), 3.28-3.14 (m, 1H), 2.41 (s, 3H), 1.09 (s, 3H).

Example 1766: N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxypyridin-3-yl)-4-( 4-chlorophenyl)-4-hydroxybutanamide

1766A: 7-(5-Amino-6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine: to a solution of 7-bromo- 5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (400 mg, 1.42 mmol) and 2methoxy-5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyridin-3-amine (427 mg, 1.708 mmol) in 1,4dioxane ₍ 5 ml) was added PdCl ₂ (dppf)-CH ₂ Cl followed by the addition of 2.0 M potassium triphosphate/H ₂ O (2.14 ml, 4.27 mmol). The mixture was stirred at 85°C for 2.5 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 ml). The organics were washed with water, dried over Na ₂ SO ₄ and concentrated. The residue was crystallized in EtOAc/hexanes to give 7-(5-amino-6-methoxypyridin-3-yl)-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazine-4-amine (240 mg , 0.740 mmol, 52% yield).

MS (ERI) m/z 325.1 (M+H) ⁺ .

1766B: N-(5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxypyridin-3 yl)-4-( 4-chlorophenyl)-4-oxobutanamide:

to solution

7-(5-Amino-6-methoxypyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (64 mg, 0.197 mmol), 4- (4-chlorophenyl)-4oxobutanoic acid (54.6 mg, 0.257 mmol) and DIPEA (0.069 ml, 0.395 mmol) in DMF (1 ml) was added HATU (105 mg, 0.276 mmol). The mixture was stirred at room temperature for 3 h, then at 40° C. for 3 h. Saturated aqueous sodium bicarbonate solution (5 ml) was added. The solid was collected by filtration and air dried to give crude N-(5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxypyridine -3-yl)-4-(4-chlorophenyl)-4oxobutanamide (56 mg, 0.108 mmol, 55% yield). The material was used in the next step without any purification.

MS (ERI) m/z 519.1 (M+H)+.

1H NMR (500 MHz, CDCl ₃ ) δ 9.11 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.3 Hz, 1H), 8.12-8.09 (m, 1H), 8.04-8.00 (m, 1H ), 7.99-7.96 (m, 2H), 7.49-7.46 (m, 2H), 7.18-7.15 (m, 1H), 4.13-4.12 (m, 3H), 3.47-3.43 (m, 2H), 2.942.91 (m, 2H).

1766: N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)4-( 4-chlorophenyl)-4-hydroxybutanamide: to a suspension of N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-2-methoxypyridin- 3-yl)-4-(4-chlorophenyl)-4-oxobutanamide (56 mg, 0.108 mmol) in THF (1 ml) was added NaBH4 (12.3 mg, 0.324 mmol) followed by the addition of a few drops of MeOH. The mixture was stirred at room temperature for 1 hour. MeOH was added to stop the reaction, then the mixture was concentrated. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 30% B, 30-70% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Collection

- 507 042342 fractions was initiated by MS signals. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (13.1 mg, 0.025 mmol, 23% yield).

MS (ERI) m/z 521.3 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.49-9.43 (m, 1H), 8.84-8.79 (m, 1H), 8.48-8.43 (m, 1H), 7.36 (s, 6H), 4.63-4.57 ( m, 1H), 3.97 (s, 3H), 2.48–2.42 (m, 2H), 1.93–1.86 (m, 2H).

Example 1767: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxy-5methylhexyl)-2- methoxynicotinamide

1767A: tert-butyl (3-oxopropyl)carbamate: to a solution of tert-butyl (3-hydroxypropyl)carbamate (1.75 g, 9.99 mmol) in CH ₂ Cl ₂ , DMSO and DIPEA (6.11 ml, 35.0 mmol) was slowly added the pyridine complex and sulfur trioxide (3.97 g, 24.97 mmol) at room temperature. The reaction proceeded with the evolution of heat. The reaction mixture was stirred at room temperature for 2 hours. After concentration, ether (100 ml) was added. The organics were washed with water (3x80 ml), dried over Na ₂ SO ₄ and concentrated to give crude tert-butyl (3oxopropyl)carbamate (1.2 g, 6.93 mmol, 69% yield). The material was used in the next step without any purification.

1H NMR (500 MHz, CDCl ₃ ) δ 9.85-9.82 (m, 1H), 3.48-3.41 (m, 2H), 2.76-2.70 (m, 2H), 1.45 (s, 9H).

1767B: tert-butyl (3-hydroxy-5-methylhexyl)carbamate: To a solution of tert-butyl (3oxopropyl)carbamate (200 mg, 1.16 mmol) in THF (3 ml) was slowly added isobutylmagnesium bromide/Et ₂ O (1.44 ml, 2.89 mmol) at -20°C under N2 atmosphere. The reaction was stirred at room temperature for 2 hours. Ether (50 ml) was added. The organics were washed with water, dried over Na2SO4 and concentrated to give crude tert-butyl (3-hydroxy-5methylhexyl)carbamate (215 mg, 0.929 mmol, 80% yield). The material was used in the next step without any purification.

1767C: 1-amino-5-methylhexan-3-ol, TFA: to a solution of tert-butyl (3-hydroxy-5methylhexyl)carbamate (215 mg, 0.929 mmol) in DCM (1 ml) was added TFA (0.4 ml, 5.19 mmol ) at room temperature. The reaction was stirred at room temperature for 2 hours. The mixture was concentrated to give the crude material. The material was used in the next step without any purification.

1767D: methyl 5-bromo-2-methoxynicotinate mixture (1.48 g, 6.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl 2,2'-bi(1,3, 2-dioxaborolane) (1.828 g, 7.20 mmol), PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (0.392 g, 0.480 mmol) and potassium acetate (0.883 g, 9.00 mmol) in dioxane (20 ml) were stirred at 85° C for 20 h. 7-bromo-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (1.518 g, 5.40 mmol) was added followed by the addition of 2.0 M K ₂ CO ₃ /water (7.50 ml, 15.00 mmol). After stirring at 90° C. for 2 h, the mixture was concentrated, then water was added. The solid was collected by filtration. EtOAc was added to dissolve all solids except for the black residue. The black residue was filtered off. The filtrate was concentrated and crystallized in EtOAc to give 1.1 g of pure material. The residual solution was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give an additional 300 mg of material.

MS (ERI) m/z 368.1 (M+H) ⁺ .

1H NMR (500 MHz, CD3OD) δ 8.95-8.94 (m, 1H), 8.85-8.83 (m, 1H), 8.09-8.06 (m, 1H), 7.39-7.36 (m, 1H), 4.08 (s, 3H ), 3.94 (s, 3H).

1767E: Lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinate: to a suspension of methyl 5-(4-amino -5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxynicotinate (1.4 g, 3.81 mmol) in THF (20 ml) was added a solution of lithium hydroxide hydrate ( 0.176 g, 4.19 mmol) in 4 ml of water. The mixture was stirred at room temperature for 4 hours. The mixture was concentrated to dryness to give 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2 lithium methoxynicotinate (1.369 g, 3.81 mmol, 100% yield). The material was used in the next step without any purification.

MS (ERI) m/z 354.0 (M+H) ⁺ .

1767: to a suspension of lithium 5-(4-amino-5-(trifluoromethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinate (36 mg, 0.100 mmol) in DMF ( 0.8 ml) was added HATU (53.4 mg, 0.140 mmol) followed by the addition of DIPEA (0.088 ml, 0.501 mmol). After stirring at room temperature for 20 min, crude 1-amino-5-methylhexan-3-ol 2,2,2-trifluoroacetate, TFA (49.2 mg, 0.200 mmol) was added. The mixture was stirred at room temperature for 4 h.

- 508 042342 The substance was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 µm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 29% B, 29-69% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 27% B, 27-67% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the target product were combined and dried by centrifugal evaporation to obtain the final product (6.1 mg, 0.013 mmol, 13% yield).

MS (ERI) m/z 467.1 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.90-8.85 (m, 1H), 8.80-8.76 (m, 1H), 8.54-8.47 (m, 1H), 8.18-8.15 (m, 1H), 7.62-7.56 (m, 1H), 4.05-3.99 (m, 3H), 3.67-3.57 (m, 1H), 3.46-3.35 (m, 3H), 1.79-1.62 (m, 2H), 1.55-1.46 (m, 1H) , 1.37-1.30 (m, 1H), 1.20-1.13 (m, 1H), 0.91-0.84 (m, 6H).

Example 1768: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(2,3-dihydroxy-3phenylpropyl)-2 -methoxynicotinamide

1768A: oxiran-2-yl(phenyl)methanol: mCPBA (3.61 g, 16.1 mmol) was slowly added to a solution of 1-phenylprop-2-en-1-ol (1.44 g, 10.7 mmol) in DCM (30 ml) at room temperature temperature. The mixture was stirred at room temperature for 18 hours. Saturated NaHCO ₃ /water was added and the organics were extracted with DCM and EtOAc. The organic layer was concentrated. The residue was purified by silica gel chromatography (24 g, hexanes-60% EtOAc) to give oxiran-2yl(phenyl)methanol (1.46 g, 9.72 mmol, 91% yield).

¹ H NMR (499 MHz, CDCl ₃ ) δ 7.47-7.39 (m, 4H), 7.38-7.34 (m, 1H), 4.99-4.50 (m, 1H), 3.29-3.24 (m, 1H), 3.02-2.88 (m, 1H), 2.88-2.78 (m, 1H).

1768B: 3-Amino-1-phenylpropan-1,2-diol: To oxiran-2-yl(phenyl)methanol (700 mg, 4.66 mmol) was added 7N. ammonia/MeOH (7 ml, 49.0 mmol) and ammonium hydroxide (7 ml, 50.3 mmol) at room temperature. The mixture was stirred at room temperature in a sealed pressure vessel overnight. The mixture was concentrated to dryness in vacuo to give 1-amino-2-phenylethane-1,2-diol (714 mg, 4.66 mmol, 100% yield).

1H NMR (499 MHz, CD3OD) δ 7.43-7.33 (m, 4H), 7.31-7.25 (m, 1H), 4.59-4.50 (m, 1H), 3.72-3.64 (m, 1H), 2.90-2.68 (m , 1H), 2.56–2.54 (m, 1H).

1768: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(2,3-dihydroxy-3-phenylpropyl)-2 -methoxynicotinamide: to a solution of lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,11][1,2,4]triazin-7-yl)-2-methoxynicotinate (45 mg, 0.125 mmol) in DMF (1 ml) was added BOP (78 mg, 0.175 mmol) followed by the addition of DIPEA (0.044 ml, 0.251 mmol). After stirring at room temperature for 10 min, 3-amino-1-phenylpropan-1,2-diol (27.2 mg, 0.163 mmol) was added. The reaction was stirred at room temperature for 20 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 18% B, 18-58% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was triggered by MC and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (8.9 mg, 14.4 µmol, 12% yield).

MS (ERI) m/z 503.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.92-8.81 (m, 2H), 8.42-8.33 (m, 1H), 8.19-8.12 (m, 1H), 7.62-7.56 (m, 1H), 7.41-7.29 (m, 4H), 7.27-7.20 (m, 1H), 4.61-4.52 (m, 1H), 4.05 (s, 3H), 3.81-3.73 (m, 1H), 3.16-3.07 (m, 1H).

- 509 042342

Example 1769: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(2,3-dihydroxy-3phenylpropyl)-2 -methylnicotinamide

To a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylnicotinic acid (40 mg, 0.12 mmol) in DMF ( 1 ml) BOP (73.4 mg, 0.166 mmol) was added followed by DIPEA (0.041 ml, 0.237 mmol). After stirring at room temperature for 10 min, 3-amino-1-phenylpropan-1,2-diol (25.8 mg, 0.154 mmol) was added. The reaction was stirred at room temperature for 20 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 12% B, 12-52% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (42.0 mg, 86.3 µmol, 73% yield).

MS (ERI) m/z 487.0 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.19-9.12 (m, 1H), 8.36-8.32 (m, 1H), 8.25-8.15 (m, 2H), 7.64-7.60 (m, 1H), 7.43- 7.38 (m, 2H), 7.36-7.30 (m, 2H), 7.27-7.21 (m, 1H), 5.32-4.69 (m, 1H), 4.60-4.50 (m, 1H), 3.85-3.75 (m, 1H ), 3.62-3.50 (m, 1H), 2.60-2.56 (m, 3H).

Example 1770: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyclopropyl-3hydroxypropyl)-2-methylnicotinamide

Using a method similar to that described in Example 1769, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyclopropyl- 3-hydroxypropyl)-2methylnicotinamide (13.8 mg, 31.8 µmol, 32% yield).

MS (ERI) m/z 435.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.00-8.94 (m, 1H), 8.17 (br d, J=1.9 Hz, 2H), 8.00 (s, 1H), 7.50-7.45 (m, 1H), 7.33-6.83 (m, 1H), 3.27-3.17 (m, 1H), 3.35-3.04 (m, 1H), 2.87-2.78 (m, 1H), 2.39 (s, 3H), 1.66-1.48 (m, 2H ), 0.71–0.62 (m, 1H), 0.25–0.16 (m, 2H), 0.12–0.01 (m, 2H).

Example 1771: tert-Butyl (1-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2methylnicotinamido)-3-phenylpropane -2-yl)carbamate

1771A: tert-Butyl (1-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2methylnicotinamido)-3-phenylpropan- 2-yl)carbamate: to a solution of 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylnicotinic acid (36 mg, 0.10 mmol) in DMF (0.5 ml) was added BOP (62.1 mg, 0.140 mmol) followed by the addition of DIPEA (0.035 ml, 0.200 mmol). After stirring at room temperature for 10 min, tert-butyl (1amino-3-phenylpropan-2-yl)carbamate (30.1 mg, 0.120 mmol) was added. The reaction was stirred at room temperature for 2 days. Water (20 ml) was added. The organic layer was extracted with DCM (3x30 ml) and concentrated to give tert-butyl (1-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl) -2-methoxynicotinamido)-3-phenylpropan-2-yl)carbamate (48 mg, 0.082 mmol, 82% yield). The material was used in the next step without any purification.

MS (ERI) m/z 570.2 (M+H)+.

1771: to a solution of tert-butyl (1-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2methoxynicotinamido)-3- phenylpropan-2-yl)carbamate (55 mg, 0.097 mmol) in DCM (1.5 ml) was added TFA (0.5 ml, 6.5 mmol). After stirring at room temperature for 3 hours, the mixture was concentrated. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 9% B, 9-49% B over 20 min, then 4 min hold at 100% B; flow rate: 510 042342 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals and

UV. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (28.3 mg, 0.060 mmol, 62% yield).

MS (ERI) m/z 470.2 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.19-9.13 (m, 1H), 8.56-8.48 (m, 1H), 8.41-8.36 (m, 1H), 8.17 (s, 1H), 7.69 (s, 1H), 7.33-7.23 (m, 4H), 7.23-7.17 (m, 1H), 3.22-3.02 (m, 2H), 2.91-2.72 (m, 2H), 2.58 (s, 4H).

Example 1772: N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxypyridin-3-yl)-1-benzyl -1 H-imidazole-4-carboxamide f ₃ c

1772A: Ethyl 1-benzyl-1H-imidazole-4-carboxylate: To a solution of ethyl 1H-imidazole-4-carboxylate (500 mg, 3.57 mmol) in DMF (5 ml) was added 1.0 M NaHMDS/THF (3.92 ml, 3.92 mmol ) at room temperature for 10 min. After stirring at room temperature for 15 min, (bromomethyl)benzene (671 mg, 3.92 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. Water (50 ml) was added and extracted with EtOAc (2x80 ml). The organic layer was concentrated. The residue was purified by silica gel chromatography (40 g, hexanes-100% EtOAc) to give first eluted ethyl 1-benzyl-1H-imidazole-5-carboxylate (60 mg, 0.261 mmol, 7% yield) and second eluted ethyl 1- benzyl 1H-imidazole-4-carboxylate (650 mg, 2.82 mmol, 79% yield).

MS (ERI) m/z 231.1 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.62-7.60 (m, 1H), 7.58-7.56 (m, 1H), 7.42-7.35 (m, 3H), 7.22-7.18 (m, 2H), 5.16-5.14 ( m, 2H), 4.40-4.34 (m, 2H), 1.39 (t, J=7.2 Hz, 3H).

1772B: 1-benzyl-1H-imidazole-4-carboxylic acid: to a solution of ethyl 1-benzyl-1H-imidazole-4-carboxylate (670 mg, 2.91 mmol) in THF (2 ml) was added a solution of lithium hydroxide hydrate (21.9 mg, 0.521 mmol) in water (0.2 ml) at room temperature. The mixture was stirred at room temperature for 20 hours. HCl (0.52 ml, 1 equiv.) to neutralize LiOH. The mixture was concentrated to dryness to give 1-benzyl-1H-imidazole-4-carboxylic acid (480 mg). The material was used in the next step without any purification.

MS (ERI) m/z 203.0 (M+H) ⁺ .

1H NMR (499 MHz, CD3OD) δ 7.93-7.89 (m, 1H), 7.81-7.75 (m, 1H), 7.44-7.36 (m, 3H), 7.35-7.32 (m, 2H), 5.30-5.29 (m , 2H).

1772: BOP (52.5 mg, 0.119 mmol) was added to a mixture of 1-benzyl-1H-imidazole-4-carboxylic acid (20 mg, 0.099 mmol) in DMF (0.5 ml) followed by DIPEA (0.052 ml, 0.297 mmol). After stirring at room temperature for 10 min, 7-(5-amino-6-methoxypyridin3-yl)-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-4-amine was added (35.3 mg, 0.109 mmol). The mixture was stirred at room temperature for 3 days, then stirred at 80° C. for 5 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 31% B, 31-71% B over 25 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (11.9 mg, 0.023 mmol, 24% yield).

MS (ERI) m/z 509.4 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.43-9.38 (m, 1H), 9.25-9.19 (m, 1H), 8.46-8.41 (m, 1H), 8.16-8.11 (m, 1H), 8.00- 7.95 (m, 2H), 7.47-7.42 (m, 1H), 7.40-7.30 (m, 5H), 5.36-5.25 (m, 2H), 4.11-4.00 (m, 3H).

Example 1773: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(1-(4fluorophenyl)ethyl) -1 N-imidazol-4-yl)-2-methylnicotinamide

1773A: 1-(1-(4-fluorophenyl)ethyl)-4-nitro-1H-imidazole: to a solution of 1,4-dinitro-1H-imidazole (155 mg, 0.981 mmol) in MeOH (3 ml) was added dropwise 1-(4-fluorophenyl)ethan-1-amine (164 mg, 1.177 mmol) at room temperature. The reaction was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (4 g, hexa-511 042342 ny-100% EtOAc) to give 1-(1-(4-fluorophenyl)ethyl)-4-nitro-1H-imidazole (190 mg, 0.808 mmol,

82% yield).

1H NMR (499 MHz, CDCl ₃ ) δ 7.76 (d, J=1.7 Hz, 1H), 7.51 (d, J=1.4 Hz, 1H), 7.23 (br t, J=6.5 Hz, 2H),

7.14 (t, J=7.7 Hz, 2H), 1.95 (d, J=7.0 Hz, 3H).

1773B: 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-amine: 1-(1-(4-fluorophenyl)ethyl) solution was added to 10% Pd-C (30 mg, 0.028 mmol) -4-nitro-1H-imidazole (190 mg, 0.808 mmol) in MeOH (4 ml) under N ₂ atmosphere. The mixture was stirred under balloon H2 at room temperature overnight. Pd/C was filtered off and washed with MeOH. The filtrate was concentrated to give 1-(1-(4fluorophenyl)ethyl)-1H-imidazol-4-amine (150 mg, 0.731 mmol, 90% yield). The material was used in the next step without any purification.

MS (ERI) m/z 206.1 (M+H)+.

¹ H NMR (499 MHz, CDCl3) δ 7.25-7.22 (m, 1H), 7.17-7.13 (m, 2H), 7.04 (s, 3H), 6.21-6.18 (m, 1H), 5.235.16 (m, 1H), 1.81 (d, J=7.0 Hz, 3H).

1773: to a solution of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methylnicotinic acid (34 mg, 0.10 mmol) in DMF ( 0.5 ml) was added BOP (58.0 mg, 0.131 mmol) followed by the addition of DIPEA (0.035 ml, 0.202 mmol) at room temperature. After stirring at room temperature for 10 min, 1-(1-(4-fluorophenyl)ethyl)-1Himidazol-4-amine (22.76 mg, 0.111 mmol) was added. The mixture was stirred at room temperature for 3 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; mobile phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate; gradient: 0 min hold at 22% B, 22-62% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target product were combined and dried by centrifugal evaporation. The material was further purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 10% B, 10-50% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (3.3 mg, 5.2 µmol, 5% yield).

MS (ERI) m/z 525.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.26-9.20 (m, 1H), 8.58-8.49 (m, 1H), 8.20-8.15 (m, 1H), 8.06-7.99 (m, 1H), 7.76- 7.69 (m, 1H), 7.54-7.41 (m, 3H), 7.27-7.17 (m, 3H), 5.63-5.57 (m, 1H), 2.59 (s, 3H), 1.86-1.79 (m, 3H).

Example 1774: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(1-(4fluorophenyl)ethyl) -1 H-imidazol-4-yl)-2-methoxynicotinamide

F

To a solution of lithium 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-D][1,2,4]triazin-7-yl)-2-methoxynicotinate (35 mg, 0.097 mmol) in DMF ( 0.5 ml) was added BOP (56.0 mg, 0.127 mmol) followed by the addition of DIPEA (0.034 ml, 0.195 mmol) at room temperature. After stirring at room temperature for 10 min, 1-(1-(4-fluorophenyl)ethyl)-1H-imidazol-4-amine (22.00 mg, 0.107 mmol) was added. The mixture was stirred at room temperature for 3 hours. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 18% B, 18-58% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (14.1 mg, 21.4 µmol, 22% yield).

MS (ERI) m/z 541.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.40-10.33 (m, 1H), 8.92-8.86 (m, 1H), 8.82-8.75 (m, 1H), 8.17-8.11 (m, 1H), 7.76- 7.71 (m, 1H), 7.59 (s, 1H), 7.40 (s, 3H), 7.19 (s, 2H), 5.58-5.49 (m, 1H), 4.08-4.03 (m, 3H), 1.821.76 ( m, 3H).

- 512 042342

Example 1775: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5(trifluoromethoxy )benzyl)-1 H-pyrazol-4-yl)-2-methylnicotinamide

F ₃ CO

1775A: 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-nitro-1H-pyrazole: 1.0 M NaHMDS/THF (1.524 ml, 1.524 mmol) dropwise at room temperature. After stirring at room temperature for 20 min, 2-(bromomethyl)-1-fluoro-4-(trifluoromethoxy)benzene (320 mg, 1.17 mmol) was added very slowly. The mixture was stirred at room temperature for 3 hours. EtOAc was added. The organics were washed with water and concentrated in vacuo. The residue was purified by silica gel chromatography (12 g, hexanes-50% EtOAc) to give 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-nitro-1H-pyrazole (310 mg, 1.016 mmol, 87% exit).

MS (ERI) m/z 541.2 (M+H)+.

'H NMR (499 MHz, CDCl ₃ ) δ 8.22 (s, 1H), 8.12 (s, 1H), 7.31-7.26 (m, 1H), 7.23-7.18 (m, 2H), 5.39-5.37 (m, 2H ).

1775B: 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-pyrazol-4-amine: a solution of 1-(2-fluoro-5-( trifluoromethoxy)benzyl)-4-nitro-III-pyrazole (310 mg, 1.016 mmol) in MeOH (5 ml) under N ₂ atmosphere. The mixture was stirred under ballooned H ₂ overnight. Pd/C was filtered off and washed with MeOH. The filtrate was concentrated to give 1-(2-fluoro-5(trifluoromethocCu)benzyl)-1H-pyrazol-4-amine (270 mg, 0.981 mmol, 97% yield).

MS (ERI) m/z 276.0 (M+H)+.

1H NMR (499 MHz, CDClj) δ 7.25-7.22 (m, 1H), 7.19-7.13 (m, 1H), 7.09 (s, 2H), 6.96-6.92 (m, 1H), 5.265.23 (m, 2H ).

1775: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-( 2-fluoro-5-(trifluoromethoxy)benzyl)-1H-pyrazol4-yl)-2-methylnicotinamide (7.2 mg, 12.1 µmol, 12% yield).

MS (ERI) m/z 595.5 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.68-10.61 (m, 1H), 9.23 (s, 1H), 8.52 (s, 1H), 8.20 (br d, J=10.7 Hz, 2H), 7.75-7.70 (m, 1H), 7.60-7.56 (m, 1H), 7.44-7.36 (m, 2H), 7.29-7.24 (m, 1H), 5.46-5.39 (m, 2H), 2.59 (s, 3H).

Example 1776: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(1-(4fluorophenyl)ethyl) -1 H-pyrazol-4-yl)-2-methoxynicotinamide

F

1776A: 1-(1-(4-fluorophenyl)ethyl)-4-nitro-III-pyrazole: 1.0 M NaHMDS/ THF (4.86 ml, 4.86 mmol) dropwise at room temperature. After stirring at room temperature for 20 min, 1-(1-bromoethyl)-4-fluorobenzene (1077 mg, 5.31 mmol) was added very slowly. The mixture was stirred at room temperature for 3 hours. EtOAc was added. The organic layer was washed with water and concentrated in vacuo. The residue was purified by silica gel chromatography (24 g, hexanes-50% EtOAc) to give 1-(1-(4-fluorophenyl)ethyl)-4-nitro-1H-pyrazole (980 mg, 4.17 mmol, 94% yield) .

1H NMR (499 MHz, CDCI3) δ 8.13-8.11 (m, 1H), 8.10-8.09 (m, 1H), 7.32-7.29 (m, 2H), 7.11 (s, 2H), 5.565.50 (m, 1H ), 1.95 (d, J=7.0 Hz, 3H).

1776B: 1-(1-(4-fluorophenyl)ethyl)-1H-pyrazol-4-amine: 1-(1-(4-fluorophenyl)ethyl) solution was added to 10% Pd-C (250 mg, 0.235 mmol) -4-nitro-1H-pyrazole (980 mg, 4.17 mmol) in MeOH (20 ml) at room temperature under N ₂ atmosphere. The mixture was stirred under ballooned H ₂ at room temperature for 3 hours. Pd/C was filtered off. The filtrate was concentrated to dryness to give 1-(1-(4fluorophenyl)ethyl)-1H-pyrazol-4-amine (800 mg, 3.90 mmol, 94% yield).

MS (ERI) m/z 206.1 (M+H)+.

1H NMR (499 MHz, CDCl ₃ ) δ 7.23-7.22 (m, 1H), 7.20-7.16 (m, 2H), 7.02 (s, 3H), 5.41-5.35 (m, 1H), 1.85 (d, J= 7.0 Hz, 3H).

1776: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1 -( 1-(4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-2methoxynicotinamide (20.4 mg, 31.2 µmol, 31% yield).

MS (ERI) m/z 541.1 (M+H)+.

- 513 042342

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.32-10.27 (m, 1H), 8.95-8.92 (m, 1H), 8.75 (s, 1H), 8.15 (d, J=17.7 Hz,

2H), 7.67-7.61 (m, 2H), 7.37-7.29 (m, 2H), 7.21-7.14 (m, 2H), 5.67-5.60 (m, 1H), 4.04 (s, 3H), 1.80 (br d , J=7.0

Hz, 3H).

Example 1777: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(1-(4fluorophenyl)ethyl) -1 H-pyrazol-4-yl)-2-methylnicotinamide

Following the procedure described for Example 1776, 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazin-7-yl)-N-(1-(1-( 4-fluorophenyl)ethyl)-1H-pyrazol-4-yl)-2-methylnicotinamide (24.1 mg, 46.0 µmol, 46% yield).

MS (ERI) m/z 525.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.64-10.59 (m, 1H), 9.24-9.19 (m, 1H), 8.53-8.49 (m, 1H), 8.21-8.11 (m, 2H), 7.74- 7.55 (m, 2H), 7.37-7.31 (m, 2H), 7.20-7.12 (m, 2H), 5.67-5.60 (m, 1H), 2.59 (s, 3H), 1.81-1.77 (m, 3H).

Example 1778: 5-(4-amino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(2-fluoro-5(trifluoromethoxy )benzyl)-1 H-imidazol-4-ul)-2-methylnicotinamide

F ₃ CO

1778A: 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-nitro-1H-imidazole: 1.0 M NaHMDS/ THF (1.524 ml, 1.524 mmol) dropwise at room temperature. After stirring at room temperature for 20 min, 2-(bromomethyl)-1-fluoro-4-(trifluoromethoxy)benzene (320 mg, 1.172 mmol) was added very slowly. The mixture was stirred at room temperature overnight. Added EtOAc. The organics were washed with water, then concentrated. The residue was purified by silica gel chromatography (12 g, hexanes-70% EtOAc) to give 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-4-nitro-1Himidazole (330 mg, 1.081 mmol, 92% yield) .

MS (ERI) m/z 306.0 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.84-7.82 (m, 1H), 7.57 (d, J=1.4 Hz, 1H), 7.33-7.29 (m, 1H), 7.25-7.20 (m, 1H), 7.20 -7.16 (m, 1H), 5.26 (s, 2H).

1778B: 1-(2-fluoro-5-(trifluoromethoxy)benzyl)-1H-imidazol-4-amine: a solution of 1-(2-fluoro-5-( trifluoromethoxy)benzyl)-4-nitro-1H-imidazole (310 mg, 1.016 mmol) in MeOH (5 mL) under N2 atmosphere. The mixture was stirred under ballooned H ₂ overnight. Pd/C was filtered off and washed with MeOH. The filtrate was concentrated to give 1-(2-fluoro-5(trifluoromethoxy)benzyl)-1H-imidazol-4-amine (270 mg, 0.981 mmol, 97% yield).

MS (ERI) m/z 276.0 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.25-7.23 (m, 1H), 7.22-7.18 (m, 1H), 7.16-7.12 (m, 1H), 6.96-6.93 (m, 1H), 6.25-6.23 ( m, 1H), 5.05–5.04 (m, 2H).

1778: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazun-7-yl)-N-( 1 -( 2-fluoro-5-(trifluoromethoxy)benzyl)-1 Himidazol-4-yl)-2-methylnicotinamide (10.2 mg, 14.4 µmol, 14% yield).

MS (ERI) m/z 595.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 11.02 (s, 1H), 9.23 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 7.76 (s, 1H), 7.73 (br s, 1H), 7.53-7.47 (m, 2H), 7.45 (br s, 2H), 5.32 (s, 2H), 2.59 (s, 3H).

Example 1779: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-( 1 (3.3, 3-trifluoro-2-hydroxy-2-methylpropyl)-1H-imudazol-4-yl)nicotinamide

1779A: 1-(4-nitro-1H-imudazol-1-yl)propan-2-one: 1.0 M NaHMDS/ THF (2.53 ml, 2.53 mmol) dropwise at room temperature. After stirring at room temperature for 20 min, 1-bromopropan-2-one (315 mg, 2.299 mmol) was added very slowly. The mixture was stirred at room temperature for

- 514 042342 throughout the night. Water was added and extracted with EtOAc (4x50 ml). The organic layer was concentrated. The residue was purified by silica gel chromatography (12 g, DCM-10% MeOH) to give

1-(4-nitro-1H-imidazol-1-yl)propan-2-one (180 mg, 1.064 mmol, 46% yield).

MS (ERI) m/z 170.0 (M+H)+.

1H NMR (499 MHz, CD3OD) δ 8.06-8.04 (m, 1H), 7.66-7.62 (m, 1H), 5.17-5.12 (m, 1H), 2.28 (s, 3H).

1779B: 4-nitro-1-(3,3,3-trifluoro-2-methyl-2-((trimethylsilyl)oxy)propyl)-1H-imidazole: to 1-(4-nitro-1H-imidazole-1 solution -yl)propan-2-one (100 mg, 0.591 mmol) in THF (3 ml) was added 1.0 M TBAF/THF (0.118 ml, 0.118 mmol) dropwise at room temperature. (Trifluoromethyl)trimethylsilane (109 mg, 0.769 mmol) was added very slowly. The mixture was stirred at room temperature for 2 h. Another 2.0 eq. TMS-CF3. The reaction was stirred at 60-80° C. for 1 hour. The mixture was concentrated. The residue was purified by silica gel chromatography (4 g, hexanes-70% EtOAc) to give 4-nitro-1-(3,3,3-trifluoro-2-methyl-2-((trimethylsilyl)oxy)propyl)-1H -imidazole (80 mg, 0.257 mmol, 44% yield).

MS (ERI) m/z 312.0 (M+H) ⁺ .

Ή NMR (499 MHz, CDCl ₃ ) δ 7.82 (d, J=1.5 Hz, 1H), 7.47 (d, J=1.4 Hz, 1H), 4.29-4.23 (m, 1H), 4.08-4.03 (m, 1H ), 1.41-1.39 (s, 3H).

1779C: 1,1,1-trifluoro-2-methyl-3-(4-nitro-1H-imidazol-1-yl)propan-2-ol: to a solution of 4-nitro-1(3,3,3-trifluoro -2-methyl-2-((trimethylsilyl)oxy)propyl)-1H-imidazole (70 mg, 0.225 mmol) in MeOH (2 ml) was added 1 ml of concentrated HCl. The mixture was stirred at room temperature for 3 h. The mixture was concentrated to dryness in vacuo to give clear 1,1,1-trifluoro-2-methyl-3-(4nitro-1H-imida-αzol-1-yl)propan-2-ol (53.8 mg, 0.225 mmol, 100% yield).

MS (ERI) m/z 240.0 (M+H) ⁺ .

Ή NMR (499 MHz, CD3OD) δ 8.25 (d, J=1.3 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 4.45-4.35 (m, 2H), 1.31 (s,

3H).

1779D: 3-(4-amino-1H-imidazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol: solution 1 was added to 10% Pd-C (25 mg, 0.023 mmol) ,1,1-trifluoro-2-methyl-3-(4-nitro-1H-imidazol-1-yl)propan-2-ol (50 mg, 0.209 mmol) in MeOH (3 ml) under N2 atmosphere. The mixture was stirred under balloon H ₂ at room temperature for 4 hours. Pd/C was filtered off and washed with MeOH. The filtrate was concentrated to dryness to give 3-(4-amino-1H-imidazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol (43.7 mg, 0.209 mmol, 100% yield).

MS (ERI) m/z 210.0 (M+H) ⁺ .

¹ H NMR (499 MHz, CDCl3) δ 7.14 (d, J=1.3 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 4.13 (d, J=14.5 Hz, 1H), 3.88 (d, J=14.4 Hz, 1H), 3.51 (s, 2H), 1.29 (s, 3H).

1779: Following the procedure described for Example 1774, 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N -(1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-1Himidazol-4-yl)nicotinamide (15.6 mg, 23.7 µmol, 34% yield).

MS (ERI) m/z 545.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.95 (s, 1H), 8.84 (s, 1H), 8.18 (s, 1H), 7.82 (s, 1H), 7.64 (s , 1H), 7.58 (s, 1H), 4.30 (br d, J=14.3 Hz, 1H), 4.21 (br d, J=14.0 Hz, 1H), 4.08 (s, 3H), 1.18 (s, 3H) .

Example 1780: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(3.3 ,3trifluoro-2-hydroxy-2-methylpropyl)-1H-imidazol-4-yl)nicotinamide h ₂ n

N.

Example 1780 was prepared following the methods described for example 1779 to give the title compound (6.4 mg, 12.1 µmol, 17% yield).

MS (ERI) m/z 529.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.93 (s, 1H), 9.22 (s, 1H), 8.52 (s, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.53 (br d, J=7.9 Hz, 2H), 4.24 (br d, J=14.3 Hz, 1H), 4.15 (br d, J=14.3 Hz, 1H), 2.60 (s, 3H), 1.17 (s, 3H).

Example 1781: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(4,4 ,4trifluoro-3-hydroxy-3-methylbutyl)-1H-imidazol-4-yl)nicotinamide

1781A: 4-(4-nitro-III-imidazol-1-yl)butan-2-one: to a solution of 4-nitro-III-imidazole (500 mg, 4.42 mmol) in DMSO (3 ml) en-2-one (465 mg, 6.63 mmol) followed by the addition of DMAP (32.4 mg, 0.265 mmol). The mixture was stirred at 70°C for 1.5 h. Water was added and extracted with EtOAc (3x50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated to give 4-(4-515 042342 nitro-1H-imidazol-1-yl)-butan-2-one (420 mg, 2.293 mmol, 52% yield).

MS (ERI) m/z 184.0 (M+H)+.

1H NMR (499 MHz, CDCl ₃ ) δ 7.82 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.4 Hz, 1H), 4.35-4.31 (m, 2H), 3.01 (t, J=6.0 Hz, 2H), 2.23(s, 3H).

1781B: 4-nitro-1-(4,4,4-trifluoro-3-methyl-3-((trimethylsilyl)oxy)butyl)-1H-imidazole: to 4-(4-nitro-1H-imidazole-1 solution -yl)butan-2-one (420 mg, 2.293 mmol) in THF (6 ml) was added TBAF (0.229 ml, 0.229 mmol) dropwise at room temperature. (Trifluoromethyl)trimethylsilane (1304 mg, 9.17 mmol) was added dropwise. The mixture was stirred at 65° C. for 2 h. The reaction was concentrated and the crude residue was purified by silica gel chromatography (12 g, hexanes-70% EtOAc) to give 4-nitro-1-(4,4,4-trifluoro- 3-methyl-3-((trimethylsilyl)oxy)butyl)-1H-imidazole (386 mg, 1.19 mmol, 52% yield).

MS (ERI) m/z 326.0 (M+H) ⁺ .

¹ H NMR (499 MHz, CDCl ₃ ) δ 7.80-7.79 (m, 1H), 7.48-7.46 (m, 1H), 4.26-4.13 (m, 2H), 2.37-2.29 (m, 1H), 2.10-2.03 (m, 1H), 1.50-1.47 (m, 3H), 0.23-0.22 (m, 9H).

1781C: 1,1,1-trifluoro-2-methyl-4-(4-nitro-1H-imidazol-1-yl)butan-2-ol: to a solution of 4-nitro-1(4,4,4-trifluoro -3-methyl-3-((trimethylsilyl)oxy)butyl)-1H-imidazole (386 mg, 1.186 mmol) in MeOH (5 ml) was added 3 ml of concentrated HCl dropwise at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction was concentrated to dryness in vacuo to give 1,1,1-trifluoro-2-methyl-4-(4-nitro-1H-imidazol-1-yl)butan-2-ol ( 300 mg, 1.186 mmol, 100% yield).

MS (ERI) m/z 254.0 (M+H) ⁺ .

1H NMR (499 MHz, CD ₃ OD) δ 8.41 (s, 1H), 8.21 (s, 1H), 5.11-5.07 (m, 2H), 4.41 (ddd, J=12.4, 9.6, 6.1 Hz, 2H), 2.34-2.17 (m, 2H), 1.42 (s, 3H).

1781D: 4-(4-amino-1H-imidazol-1-yl)-1,1,1-trifluoro-2-methylbutan-2-ol: used a method similar to that described for 1779D to give the title compound.

MS (ERI) m/z 224.1 (M+H) ⁺ .

1771: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N- ( 1 -(4,4,4-trifluoro-3-hydroxy-3methylbutyl)-1H-imidazol-4-yl)nicotinamide (10.4 mg, 15.8 µmol, 22% yield).

MS (ERI) m/z 543.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 9.25 (s, 1H), 8.57 (s, 1H), 8.20 (s, 1H), 8.17-8.05 (m, 1H), 7.74 ( s, 1H), 7.63 (s, 1H), 4.30–4.12 (m, 2H), 2.63 (s, 3H), 2.17–2.06 (m, 2H), 1.32 (s, 3H).

Example 1782: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(4,4,4trifluoro- 3-hydroxy-3-(trifluoromethyl)butyl)nicotinamide

Using a method similar to that described in Example 1769, the title compound was obtained (21.3 mg, 32.3 μmol, 32% yield).

MS (ERI) m/z 546.9 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.88 (s, 1H), 8.84-8.79 (m, 1H), 8.55 (br s, 1H), 8.22-8.12 (m, 2H), 7.58 (s, 1H ), 4.03 (s, 3H), 3.45–3.33 (m, 2H), 2.24–2.16 (m, 2H).

Example 1783: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(4,4,4trifluoro- 3-hydroxy-3-(trifluoromethyl)butyl)nicotinamide

F ₃ Cj? %F ₃ n nXY^n^Af, \=NU J. ^H

N

Using a method similar to that described in Example 1769, the title compound was obtained (28.5 mg, 44.2 μmol, 44% yield).

MS (ERI) m/z 531.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.63 (br s, 1H), 8.38 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.68 (s , 1H), 3.54-3.44 (m, 1H), 2.54 (s, 3H), 2.27-2.16 (m, 2H).

Example 1784: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1phenethyl-1H-imidazole -4-yl)nicotinamide

- 516 042342

1784A: 4-nitro-1-phenethyl-1H-imidazole: To a solution of 4-nitro-Ni-imidazole (500 mg, 4.42 mmol) in DMF (10 ml) was added 1.0 M NaHMDS/THF (4.86 ml, 4.86 mmol). After stirring at room temperature for 10 min, (2-bromoethyl)benzene (818 mg, 4.42 mmol) was added dropwise. The reaction was stirred at room temperature overnight. Additional bromide (0.8 equiv.) was added. The mixture was stirred at 70° C. for 2 hours. EtOAc was added, washed with water and concentrated. The residue was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give 4-nitro-1-phenethyl-1H-imidazole (810 mg, 3.73 mmol, 84% yield).

MS (ERI) m/z 218.0 (M+H)+.

1H NMR (499 MHz, CDCl3) δ 7.62 (d, J=1.5 Hz, 1H), 7.37-7.29 (m, 3H), 7.22 (d, J=1.5 Hz, 1H), 7.08 (d, J=6.8 Hz , 2H), 4.29 (t, J=6.9 Hz, 2H), 3.13 (t, J=6.9 Hz, 2H).

1784B: 1-phenethyl-1H-imidazole-4-amine: to 10% Pd-C (80 mg, 0.075 mmol) was added a solution of 4-nitro-1-phenethyl-1H-imidazole (180 mg, 0.829 mmol) in MeOH (5 ml ) in an N2 atmosphere. The mixture was stirred under ballooned H ₂ at room temperature overnight. Pd/C was filtered off. The filtrate was concentrated to give 1-phenethyl-1H-imidazole-4-amine (140 mg, 0.748 mmol, 90% yield).

MS (ERI) m/z 188.1 (M+H) ⁺ .

1H NMR (499 MHz, CDCl3) δ 7.33-7.24 (m, 3H), 7.11-7.08 (m, 2H), 6.95-6.93 (m, 1H), 6.22-6.20 (m, 1H), 4.07-4.02 (m , 2H), 3.02 (t, J=7.1 Hz, 2H).

1784: Following the method described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N- ( 1 -phenethyl-1 H-imidazol-4yl)nicotinamide (6.3 mg, 12.1 µmol, 12% yield).

MS (ERI) m/z 523.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.32-10.28 (m, 1H), 8.94-8.91 (m, 1H), 8.85-8.82 (m, 1H), 8.20-8.17 (m, 1H), 7.65-7.61 (m, 1H), 7.48-7.44 (m, 1H), 7.39-7.36 (m, 1H), 7.30-7.23 (m, 5H), 4.25-4.20 (m, 2H), 4.094.06 (m, 3H) , 3.09–3.03 (m, 2H).

Example 1785: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 phenethyl-1 H- imidazol-4-yl)nicotinamide

Following the methods described for Example 1784, the title compound was obtained (7.6 mg, 15.0 μmol, 15% yield).

MS (ERI) m/z 507.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.87-10.83 (m, 1H), 9.24-9.19 (m, 1H), 8.52-8.47 (m, 1H), 8.23-8.19 (m, 1H), 7.76 -7.72 (m, 1H), 7.52-7.49 (m, 1H), 7.40-7.37 (m, 1H), 7.33-7.28 (m, 2H), 7.27-7.20 (m, 3H), 4.264.19 (m, 2H), 3.10-3.02 (m, 2H), 2.62-2.57 (m, 3H).

Example 1786: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-( 1 phenethyl-1H-pyrazole -4-yl)nicotinamide

1786A: 4-nitro-1-phenethyl-1H-pyrazole: To a solution of 4-nitro-1H-pyrazole (520 mg, 4.60 mmol) in DMF (10 ml) was added 1.0 M NaHMDS/THF (5.06 ml, 5.06 mmol). After stirring at room temperature for 20 min, (2-bromoethyl)benzene (1702 mg, 9.20 mmol) was added dropwise. The reaction was stirred at room temperature for 4 hours. EtOAc was added and the organic layer was washed with water and concentrated. The residue was purified by silica gel chromatography (24 g, hexanes 70% EtOAc) to give clear 4-nitro-1-phenethyl-1H-pyrazole (960 mg, 4.42 mmol, 96% yield).

1H NMR (499 MHz, CDCl ₃ ) δ 8.12 (s, 1H), 7.83 (s, 1H), 7.34-7.29 (m, 3H), 7.10-7.06 (m, 2H), 4.40 (t, J=7.0 Hz , 2H), 3.22 (t, J=7.0 Hz, 2H).

1786B: 1-phenethyl-1H-pyrazol-4-amine: to 10% Pd-C (80 mg, 0.075 mmol) was added a solution of 4-nitro1-phenethyl-1H-pyrazole (215 mg, 0.990 mmol) in MeOH (5 ml ) in an N2 atmosphere. The mixture was stirred under balloon H2 for 4 h. Pd/C was filtered off. The filtrate was concentrated to give 1-phenethyl-1H-pyrazole-4-amine (175 mg, 0.935 mmol, 94% yield).

MS (ERI) m/z 188.1 (M+H) ⁺ .

1H NMR (499 MHz, CDCl3) δ 7.33-7.22 (m, 3H), 7.20 (d, J=0.7 Hz, 1H), 7.14 (d, J=7.1 Hz, 2H), 6.86 (d, J=0.8 Hz , 1H), 4.27-4.20 (m, 2H), 3.14 (t, J=7.5 Hz, 2H).

1786: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N- (1-phenethyl-1 H-pyrazole-4

- 517 042342 yl)nicotinamide (8.0 mg, 15.3 µmol, 15% yield).

MS (ERI) m/z 523.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.92 (s, 1H), 8.72 (s, 1H), 8.16 (s, 1H), 7.99 (s, 1H), 7.62 (s , 1H), 7.60 (br s, 1H), 7.31-7.23 (m, 2H), 7.20 (br d, J=6.7 Hz, 3H), 4.32 (br t, J=7.2 Hz, 2H), 4.03 (s , 3H), 3.09 (br t, J=7.2 Hz, 2H).

Example 1787: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 phenethyl-1 H- pyrazol-4-yl)nicotinamide

Following the methods described for Example 1786, the title compound was obtained (17.8 mg, 35.1 μmol, 35% yield).

MS (ERI) m/z 507.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 9.21 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.99 (s, 1H), 7.72 (s , 1H), 7.54 (s, 1H), 7.31-7.24 (m, 2H), 7.21 (br d, J=7.3 Hz, 3H), 4.33 (br t, J=7.3 Hz, 2H), 3.09 (br t , J=7.3 Hz, 2H), 2.58 (s, 3H).

Example 1788: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-( 1 (3.3, 3-trifluoro-2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)nicotinamide

1788A: 1-(4-nitro-1H-pyrazol-1-yl)propan-2-one: 1.0 M NaHMDS/ THF (4.86 ml, 4.86 mmol) dropwise at room temperature. After stirring at room temperature for 10 min, 1-bromopropan-2-one (424 mg, 3.10 mmol) was added dropwise over 20 min. The mixture was stirred at room temperature for 4 hours, at 70° C. for 2 hours, then at room temperature overnight. EtOAc was added, washed with water, then concentrated. The residue was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give 1-(4-nitro-1H-pyrazol-1-yl)propan-2one (180 mg, 1.064 mmol, 24% yield).

MS (ERI) m/z 170.0 (M+H) ⁺ .

1H NMR (499 MHz, _CDCl3 ) δ 8.21 (s, 1H), 8.13 (s, 1H), 5.04 (s, 2H), 2.31 (s, 3H).

1788B: 4-nitro-1-(3,3,3-trifluoro-2-methyl-2-((trimethylsilyl)oxy)propyl)-1H-pyrazole: to 1-(4-nitro-1H-pyrazole-1 solution -yl)propan-2-one (180 mg, 1.064 mmol) in THF (8 ml) was added 1.0 M TBAF/THF (0.106 ml, 0.106 mmol) at room temperature. Trimethyl(trifluoromethyl)silane (378 mg, 2.66 mmol) was added dropwise over 20 min. The mixture was stirred at room temperature for 4 hours. The reaction was concentrated. The residue was purified by silica gel chromatography (12 g, hexanes-100% EtOAc) to give 4-nitro-1-(3,3,3-trifluoro-2-methyl-2((trimethylsilyl)oxy)propyl)-1H- pyrazole (130 mg, 0.418 mmol, 39% yield).

MS (ERI) m/z 312.0 (M+H) ⁺ .

1H NMR (499 MHz, CDC13) δ 8.22 (s, 1H), 8.11 (s, 1H), 4.32 (d, J=5.7 Hz, 2H), 1.41 (s, 3H), 0.14 -0.12 (m, 9H) .

1788C: 4-nitro-1-(3,3,3-trifluoro-2-methyl-2-(hydroxy)-propyl)-1H-pyrazole: to a solution of 4-nitro-1(3,3,3-trifluoro- 2-methyl-2-((trimethylsilyl)oxy)propyl)-1H-pyrazole (130 mg, 0.418 mmol) in MeOH (2 mL) concentrated HC1 (1 mL, 32.9 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give the alcohol intermediate.

MS (ERI) m/z 239.9 (M+H) ⁺ .

1H NMR (499 MHz, CD3OD) δ 8.56 (s, 1H), 8.15 (s, 1H), 4.48-4.38 (m, 2H), 1.29 (s, 3H).

1788D: 3-(4-Amino-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol: 4-nitro-1-(3,3,3-trifluoro2- methyl 2-(hydroxy)-propyl)-1H-pyrazole was reduced using Pd/C (30 mg, 0.282 mmol) under balloon H ₂ atmosphere. in MeOH for 3 h. Pd/C was filtered off. The filtrate was concentrated to dryness to give 3-(4-amino-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylpropan-2-ol (80 mg, 0.382 mmol, 92% yield).

1H NMR (499 MHz, CD3OD) δ 7.30 (d, J=0.8 Hz, 1H), 7.19 (d, J=0.8 Hz, 1H), 4.22 (d, J=8.5 Hz, 2H), 1.17 (s, 3H ).

1788: Following the procedure described for Example 1796, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N- (1-(3,3,3-trifluoro-2-hydroxy-2methylpropyl)-1H-pyrazol-4-yl)nicotinamide (17.4 mg, 26.4 µmol, 26% yield).

- 518 042342

MS (ERI) m/z 545.3 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 8.94 (s, 1H), 8.74 (s, 1H), 8.18 (s, 1H), 8.14 (s, 1H), 7.64 (br d, J=5.8 Hz, 2H), 6.42 (s, 1H), 4.29 (br d, J=15.3 Hz, 2H), 4.04 (s, 3H), 1.15 (s, 3H).

Example 1789: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-2-methyl-N-( 1-(3,3 ,3trifluoro-2-hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)nicotinamide

Following the methods described for Example 1788, the title compound was obtained (21.9 mg, 41.4 μmol, 41% yield).

MS (ERI) m/z 529.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 10.65 (s, 1H), 9.23 (s, 1H), 8.53 (s, 1H), 8.21 (s, 1H), 8.12 (s, 1H), 7.74 (s , 1H), 7.59 (s, 1H), 4.30 (br d, J=18.0 Hz, 2H), 2.56-2.52 (m, 3H), 1.16 (s, 3H).

Example 1790: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1(4,4, 4-trifluoro-3-hydroxy-3-methylbutyl)-1 H-pyrazol-4-yl)nicotinamide

1790A: 4-(4-nitro-1H-pyrazol-1-yl)butan-2-one: but-3- en-2-one (465 mg, 6.63 mmol) followed by the addition of DMAP (32.4 mg, 0.265 mmol). The mixture was stirred at 70° C. for 2 hours. EtOAc was added. The organic layer was washed with water (3x), dried over Na ₂ SO ₄ and concentrated to dryness. 4-(4-Nitro1H-pyrazol-1-yl)butan-2-one (630 mg, 3.44 mmol, 78% yield) was obtained. The material was used in the next step without any purification.

MS (ERI) m/z 184.0 (M+H) ⁺ .

1H NMR (499 MHz, CDCl3) δ 8.25 (s, 1H), 8.06 (s, 1H), 4.43 (t, J=6.0 Hz, 2H), 3.11 (t, J=6.0 Hz, 2H), 2.21 (s , 3H).

1790B: 4-nitro-1-(4,4,4-trifluoro-3-methyl-3-((trimethylsilyl)oxy)butyl)-1H-pyrazole: to a solution of 4(4-nitro-1H-pyrazole-1- yl)butan-2-one (630 mg, 3.44 mmol) in THF (12 mL) was added 1.0 M TBAF/THF (0.344 mL, 0.344 mmol) followed by dropwise addition of trimethyl(trifluoromethyl)silane (1712 mg, 12.04 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The reaction was concentrated. The residue was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give 4-nitro-1-(4,4,4-trifluoro-3-methyl-3-((trimethylsilyl)oxy)butyl)1H- pyrazole (290 mg, 0.891 mmol, 26% yield).

MS (ERI) m/z 326.0 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 8.10 (s, 1H), 4.39-4.26 (m, 2H), 2.41-2.33 (m, 1H), 2.27-2.18 (m, 1H) , 1.46 (s, 3H), 0.22 (s, 9H).

1790C: 4-(4-Amino-1H-pyrazol-1-yl)-1,1,1-trifluoro-2-methylbutan-2-ol was prepared following the method described for example 1788D.

MS (ERI) m/z 224.0 (M+H) ⁺ .

1H NMR (499 MHz, CD3OD) δ 7.24 (s, 1H), 7.17 (s, 1H), 4.21 (ddd, J=12.1, 9.4, 6.4 Hz, 2H), 2.70 (s, 1H), 2.14 (ddd, J=14.0, 9.5, 6.0 Hz, 2H), 1.32 (s, 3H).

1790: Following the method described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N- (1-(4,4,4-trifluoro-3-hydroxy-3methylbutyl)-1I-pyrazol-4-yl)nicotinamide (13.5 mg, 20.1 µmol, 20% yield).

MS (ERI) m/z 559.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 8.93 (s, 1H), 8.77-8.72 (m, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.62 (br d, J=8.2 Hz, 2H), 4.29 (br d, J=6.7 Hz, 1H), 4.21 (br d, J=5.2 Hz, 1H), 4.04 (s, 3H), 2.15-2.04 (m , 2H), 1.26 (s, 3H).

Example 1791: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][ 1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(4,4 ,4trifluoro-3-hydroxy-3-methylbutyl)-1 H-pyrαzol-4-yl)nicotinamide

Following the methods described for Example 1790, the title compound was obtained (11.6 mg, 21.4 μmol, 21% yield).

- 519 042342

MS (ERI) m/z 543.4 (M+H)+.

1Н NMR (500 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 9.21 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 8.11 (s, 1H), 7.72 (s , 1H), 7.55 (s, 1H), 4.33-4.17 (m, 2H), 2.60 (s, 3H), 2.15-2.02 (m, 2H), 1.27 (s, 3H).

Example 1792: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1-benzyl-1Himidazol-4-yl) -2-methylbenzamide

1792A: methyl 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate: to a mixture of methyl 5bromo-2-methylbenzoate (2.0 g, 8.7 mmol) in dioxane (30 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'bi(1,3,2-dioxaborolane) (2.66 g, 10.5 mmol), adduct PdCl ₂ (dppf)-CH ₂ Cl ₂ (0.499 g, 0.611 mmol) and potassium acetate (2.57 g, 26.2 mmol). The mixture was sparged with N2, then stirred at 110°C for 1.5 h and cooled to room temperature. Dioxane (5 ml), 7-bromo-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (2.443 g, 8.69 mmol), PdCl ₂ ( dppf)-CH ₂ Cl ₂ (0.355 g, 0.435 mmol) and 2 M K3PO4 (13.0 ml, 26.1 mmol). The mixture was stirred at 110° C. for 1 hour. Water (50 ml) was added and extracted with EtOAc (2x150 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated. The residue was crystallized in EtOAc/hexanes to give methyl 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-D][1,2,4]triazin-7-yl)-2-methylbenzoate (2.7 g, 7.71 mmol, 89% yield).

MS (ERI) m/z 351.0 (M+h) ⁺ .

1792B: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylbenzoic acid: a mixture of methyl 5-(4-amino- 5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylbenzoate (2.7 g, 7.71 mmol), lithium hydroxide hydrate (0.647 g, 15.42 mmol) in THF (25 ml) and water (5 ml) were stirred at room temperature overnight. Water was added followed by 1N. HCl (15.5 ml) to neutralize the acid. After stirring at room temperature for 1 hour, the fine solids were filtered off, washed with water, then air dried to give clear 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazin-7-yl)-2-methylbenzoic acid (1.5 g, 4.46 mmol, 57.9% yield). Additional material (200 mg) was extracted from the aqueous layer with EtOAc (2x100 ml).

MS (ERI) m/z 337.1 (M+H) ⁺ .

1792: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl -1H-imidazol-4-yl)-2-methylbenzamide (9.9 mg, 16.4 µmol, 16% yield).

MS (ERI) m/z 492.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-de) δ 10.72 (s, 1H), 8.15 (s, 1H), 8.11-8.01 (m, 2H), 7.64 (s, 1H), 7.58 (s, 1H), 7.43- 7.23 (m, 7H), 5.18 (s, 2H), 2.47-2.32 (m, 3H).

Example 1793: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1Hpyrazol-3-yl) -2-methylbenzamide

Following the methods described for Example 1774, the title compound was obtained (12.9 mg, 21.3 μmol, 21% yield).

MS (ERI) m/z 492.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.80 (s, 1H), 8.15 (s, 1H), 8.08 (br s, 2H), 7.80 (br s, 1H), 7.59 (s, 1H), 7.39 -7.19 (m, 6H), 6.67 (br s, 1H), 5.24 (s, 2H), 2.41 (s, 3H).

Example 1794: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(1-(4fluorophenyl)ethyl) -1 H-pyrazol-4-yl)-2-methylbenzamide

F

Following the methods described for Example 1776, the title compound was obtained (24 mg, 45.8 μmol, 46% yield).

MS (ERI) m/z 524.0 (M+H) ⁺ .

1Н NMR (500 MHz, DMSO-d ₆ ) δ 10.42 (s, 1Н), 8.16 (s, 1Н), 8.13-8.06 (m, 3Н), 7.56 (br d, J=7.6 Hz, 2H), 7.40 ( br d, J=7.9 Hz, 1H), 7.37-7.30 (m, 2H), 7.16 (br t, J=8.7 Hz, 2H), 5.62 (br d, J=7.0 Hz, 1H), 2.40 (s, 3H),

- 520 042342

1.79 (br d, J=7.0 Hz, 3H).

Example 1795: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl1H-imidazol- 4-yl)-2-methylbenzamide

1795A: 1-benzyl-5-methyl-4-nitro-1H-imidazole: To a solution of 5-methyl-4-nitro-1H-imidazole (1.0 g, 7.87 mmol) in DMF (20 ml) was added dropwise 1.0 M NaHMDS /THF (9.44 ml, 9.44 mmol) at room temperature. After stirring at room temperature for 20 min, (bromomethyl)benzene (2.02 g, 11.8 mmol) was added very slowly. The mixture was stirred at room temperature for 3 hours. EtOAc was added. The organic layer was washed with water and concentrated. The residue was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give 1-benzyl-5methyl-4-nitro-1H-imidazole (800 mg, 3.68 mmol, 46.8% yield).

MS (ERI) m/z 218.1 (M+H)+.

1H NMR (499 MHz, CDCl ₃ ) δ 7.47-7.37 (m, 4H), 7.13 (d, J=6.9 Hz, 2H), 5.16 (s, 2H), 2.58 (s, 3H).

1795B: 1-benzyl-5-methyl-1H-imidazol-4-amine: a solution of 1benzyl-5-methyl-4-nitro-1H-imidazole (300 mg, 1.38 mmol) was added to Pd-C (60 mg, 0.06 mmol). ) in MeOH (20 ml) under N ₂ atmosphere. The mixture was stirred under balloon H ₂ for 3 h. Pd/C was filtered off and the filtrate was concentrated to give 1-benzyl-5-methyl-1H-imidazol-4-amine (250 mg, 1.34 mmol, 97% yield).

MS (ERI) m/z 188.1 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.39-7.29 (m, 4H), 7.15-7.01 (m, 2H), 4.99 (s, 2H), 1.98 (s, 3H).

1795: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl -5-methyl-1H-imidazol-4-yl)-2methylbenzamide (14.2 mg, 28.1 µmol, 28% yield).

MS (ERI) m/z 506.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.18 (s, 1H), 8.15-8.05 (m, 2H), 7.65 (s, 1H), 7.59 (s, 1H), 7.39 (br t, J=7.5 Hz, 3H), 7.32 (br d, J=7.0 Hz, 1H), 7.19 (br d, J=7.3 Hz, 2H), 5.20 (s, 2H), 2.47-2.42 (m , 3H), 2.01 (s, 3H).

Example 1796: 5-(4-Amino-5-(trifluoromethyl)-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl1H-imidazol- 4-yl)-2-methoxynicotinamide

Following the methods described for Example 1795, the title compound was obtained (5.3 mg, 8.3 μmol, 8% yield).

MS (ERI) m/z 523.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.96 (br s, 1H), 8.80 (br s, 1H), 8.34 (br s, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 7.48 -7.31 (m, 3H), 7.31-7.19 (m, 2H), 5.33 (s, 2H), 4.09 (s, 3H), 2.09 (s, 3H).

Example 1797: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl1H-imidazol- 4-yl)-2-methylnicotinamide

Following the methods described for Example 1795, the title compound was obtained (5.7 mg, 11.3 μmol, 11% yield).

MS (ERI) m/z 507.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.74 (s, 1H), 7.67 (s, 1H), 7.39 (br d , J=7.3 Hz, 2H), 7.32 (br d, J=7.3 Hz, 2H), 7.20 (br d, J=7.3 Hz, 2H), 5.21 (s, 2H), 2.64 (s, 3H), 2.03 (s, 3H).

Example 1798: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-( 1 (2.2, 2-trifluoro-1-phenylethyl)-1 H-imidazol-4-yl)nicotinamide

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1798A: 4-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-imidazole: to a solution of 1,4-dinitro-III-imidazole (80 mg, 0.51 mmol) in MeOH (2 ml) 2,2,2-trifluoro-1-phenylethane-1-amine (106 mg, 0.607 mmol) was added. The reaction mixture was stirred at 60-80° C. behind a protective screen for 4 h. The mixture was concentrated. The residue was purified by silica gel chromatography (4 g, hexanes-60% EtOAc) to give 4-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-imidazole (60 mg, 0.221 mmol, 44 % exit).

MS (ERI) m/z 272.2 (M+H)+.

1H NMR (499 MHz, CDCl3) δ 7.91 (s, 1H), 7.63 (s, 1H), 7.58-7.47 (m, 5H), 5.84 (q, J=7.4 Hz, 1H).

1798B: 1-(2,2,2-trifluoro-1-phenylethyl)-1H-imidazol-4-amine: a solution of 4-nitro-1-(2, 2,2-trifluoro-1-phenylethyl)-1H-imidazole (60 mg, 0.22 mmol) in MeOH (2 ml) under N2 atmosphere. The mixture was stirred in an atmosphere of ballooned H ₂ at room temperature for 2.5 h. Pd/C was filtered off. The filtrate was concentrated to give 1-(2,2,2-trifluoro-1-phenylethyl)1H-imidazol-4-amine (52 mg, 0.216 mmol, 97% yield).

MS (ERI) m/z 242.3 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.49-7.42 (m, 7H), 7.28-7.27 (m, 1H), 6.36 (s, 1H), 5.57-5.51 (m, 1H).

1798: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N- ( 1 -(2,2,2-trifluoro-1-phenylethyl)-1 Himidazol-4-yl)nicotinamide (2.3 mg, 3.3 µmol, 4% yield).

MS (ERI) m/z 578.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.94 (d, J=2.4 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H), 8.18 (s, 1H), 7.85 (s, 1H), 7.66-7.59 (m, 4H), 7.59-7.48 (m, 3H), 6.77 (br d, J=8.7 Hz, 1H), 4.06 (s, 3H).

Example 1799: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(2,2 ,2trifluoro-1-phenylethyl)-1 H-imidazol-4-yl)nicotinamide

Following the methods described for Example 1798, the title compound was obtained (3.0 mg, 5.4 μmol, 7.6% yield).

MS (ERI) m/z 561.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 11.12 (s, 1H), 9.24 (d, J=1.9 Hz, 1H), 8.55-8.53 (m, 1H), 8.21 (s, 1H), 7.96 (s , 1H), 7.86 (s, 1H), 7.75 (s, 1H), 7.66-7.61 (m, 3H), 7.53 (s, 2H), 6.81-6.73 (m, 1H), 2.60 (s, 3H).

Example 1800: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(2,2 ,2trifluoro-1-phenylethyl)-1 H-imidazol-4-yl)benzamide

Following the methods described for Example 1798, the title compound was obtained (5.1 mg, 7.6 μmol, 10% yield).

MS (ERI) m/z 560.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.91 (s, 1H), 8.18-8.16 (m, 1H), 8.13-8.08 (m, 2H), 7.84-7.82 (m, 1H), 7.65-7.60 ( m, 4H), 7.57-7.51 (m, 3H), 7.41-7.38 (m, 1H), 6.78-6.71 (m, 1H), 2.41 (s, 3H).

Example 1801: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)1H-imidazole -4-yl)-2-methoxynicotinamide

F ₃ C ^ΗΛ Α IXA %

1801A: 1-(4-Fluorobenzyl)-4-nitro-1H-imidazole: To a solution of 4-nitro-1H-imidazole (500 mg, 4.42 mmol) in DMF (6 mL) was slowly added 1.0 M NaHMDS/THF (4.9 mL , 4.9 mmol) at room temperature. After stirring at room temperature for 15 min, 1-(bromomethyl)-4fluorobenzene (1003 mg, 5.31 mmol) was added. The mixture was stirred at room temperature for 4 hours. EtOAc (50 ml) was added. The organic layer was washed with brine and water then concentrated in vacuo. The residue was purified by silica gel chromatography (24 g, hexanes-100% EtOAc) to give 1-(4-fluorobenzyl)-4-nitro-1H-imidazole (800 mg, 3.62 mmol, 82% yield).

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MS (ERI) m/z 222.2 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.71 (d, J=1.5 Hz, 1H), 7.50-7.47 (m, 1H), 7.26-7.23 (m, 2H), 7.16-7.11 (m, 2H), 5.16 (s, 2H).

1801B: 1-(4-fluorobenzyl)-1H-imidazole-4-amine: to 10% Pd-C (50 mg, 0.047 mmol) was added a solution of 1-(4-fluorobenzyl)-4-nitro-1H-imidazole (260 mg, 1.175 mmol) in MeOH (5 mL) under N2 atmosphere. The mixture was stirred under ballooned H ₂ at room temperature for 4 hours. Pd/C was filtered off. The filtrate was concentrated to give 1-(4-fluorobenzyl)-III-imidazole-4-amine (225 mg, 1.175 mmol, 100% yield).

MS (ERI) m/z 192.2 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.25-7.12 (m, 3H), 7.10-7.00 (m, 2H), 6.18 (d, J=1.5 Hz, 1H), 4.96 (s, 2H).

1801: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1 -( 4-fluorobenzyl)-1 H-imidazol-4-yl)-2methoxynicotinamide (7.0 mg, 10.9 µmol, 11% yield).

MS (ERI) m/z 527.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 8.90 (d, J=2.4 Hz, 1H), 8.80 (d, J=1.8 Hz, 1H), 8.16-8.14 (m, 1H), 7.627.59 (m, 1H), 7.42-7.37 (m, 4H), 7.23-7.18 (m, 3H), 5.20-5.17 (m, 2H), 4.08-4.05 (m, 3H).

Example 1802: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)1H-imidazole -4-yl)-2-methylnicotinamide

Following the methods described for Example 1801, the title compound was obtained (25 mg, 40 μmol, 40% yield).

MS (ERI) m/z 511.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 11.00 (s, 1H), 9.22 (d, J=2.1 Hz, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.20 (s, 1H), 7.77 (s, 1H), 7.73 (s, 1H), 7.48-7.39 (m, 3H), 7.23 (t, J=8.9 Hz, 3H), 5.21 (s, 2H), 2.59 (s, 3H), 2.57 -2.52 (m, 1H).

Example 1803: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)1H-imidazole -4-yl)-2-methylbenzamide

Following the methods described for Example 1801, the title compound was obtained (3.6 mg, 7.1 μmol, 7% yield).

MS (ERI) m/z 510.3 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 10.72 (s, 1H), 8.15 (s, 1H), 8.09 (s, 2H), 7.64 (s, 1H), 7.58 (s, 1H), 7.487.33 (m, 4H), 7.22 (t, J=8.7 Hz, 2H), 5.18 (s, 2H), 2.40 (s, 3H).

Example 1804: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-(4(trifluoromethyl) )benzyl)-1 H-imidazol-4-yl)nicotinamide

Following the methods described for Example 1801, the title compound was obtained (2.6 mg, 4.5 μmol, 5% yield). MS (ERI) m/z 577.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.43-10.41 (m, 1H), 8.94-8.92 (m, 1H), 8.81-8.79 (m, 1H), 8.18-8.17 (m, 1H), 7.79 -7.76 (m, 2H), 7.74-7.72 (m, 1H), 7.64-7.63 (m, 1H), 7.54-7.51 (m, 2H), 7.46-7.44 (m, 1H), 5.355.33 (m, 2H), 4.07 (s, 3H).

Example 1805: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1-(4(trifluoromethyl )benzyl)-1 H-imidazol-4-yl)nicotinamide

Following the methods described for Example 1801, the title compound (20 mg,

- 523 042342

35.7 µmol, 36% yield).

MS (ERI) m/z 561.1 (M+H) ⁺ .

L NMR (500 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.19 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.81-7.66 (m, 4H), 7.53 ( br d, J=7.9 Hz, 2H), 7.46 (s, 1H), 5.32 (s, 2H), 2.62-2.53 (m, 3H).

Example 1806: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(4(trifluoromethyl )benzyl)-1 H-imidazol-4-yl)benzamide

Following the methods described for Example 1801, the title compound was obtained (13.4 mg, 19.9 μmol, 20% yield).

MS (ERI) m/z 560.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 10.80 (s, 1H), 8.15 (s, 1H), 8.10 (s, 1H), 8.09-8.06 (m, 1H), 7.77 (br d, J=7.6 Hz, 3H), 7.61-7.50 (m, 3H), 7.46 (s, 1H), 7.38 (d, J=8.2 Hz, 1H), 5.33 (s, 2H), 2.49-2.37 (m, 3H).

Example 1807: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)1H-imudazole -4-yl)-2-methoxynicotinamide

Following the methods described for Example 1801, the title compound was obtained (3.0 mg, 4.6 μmol, 5% yield).

MS (ERI) m/z 543.4 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.40-10.38 (m, 1H), 8.92-8.90 (m, 1H), 8.82-8.79 (m, 1H), 8.16-8.14 (m, 1H), 7.72 -7.70 (m, 1H), 7.62-7.59 (m, 2H), 7.46-7.43 (m, 2H), 7.41-7.39 (m, 2H), 5.21-5.19 (m, 2H), 4.084.06 (m, 3H).

Example 1808: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)1H-imudazole -4-yl)-2-methylnicotinamide

Following the methods described for Example 1801, the title compound was obtained (4.7 mg, 7.3 μmol, 7% yield).

MS (ERI) m/z 527.3 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.95 (s, 1H), 9.20-9.17 (m, 1H), 8.50-8.48 (m, 1H), 8.19-8.17 (m, 1H), 7.72-7.68 (m, 2H), 7.47-7.41 (m, 3H), 7.39-7.35 (m, 2H), 5.20 (s, 2H), 2.57 (s, 3H).

Example 1809: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)1H-imidazole -4-yl)-2-methylbenzamide

Following the methods described for Example 1801, the title compound was obtained (4.5 mg, 7.0 μmol, 7% yield).

MS (ERI) m/z 526.2 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 8.06 (d, J=8.1 Hz, 1H), 7.69 (s, 1H ), 7.57 (s, 1H), 7.48-7.33 (m, 6H), 5.19 (s, 2H), 2.50-2.32 (m, 3H).

Example 1810: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)1 H- pyrazol-3 -yl)-2-methylnicotinamide

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1810A: 1-(4-Fluorobenzyl)-3-nitro-1H-pyrazole was prepared in a manner analogous to that described in Example 1801A.

MS (ERI) m/z 222.4 (M+H)+.

1H NMR (499 MHz, CDCl ₃ ) δ 7.40 (d, J=2.6 Hz, 1H), 7.32 (t, J=6.4 Hz, 2H), 7.11 (t, J=8.1 Hz, 2H), 6.93 (d, J=2.5 Hz, 1H), 5.37 (s, 2H).

1810B: 1-(4-Fluorobenzyl)-1H-pyrazole-3-amine was prepared in a manner analogous to that described in Example 1801B.

MS (ERI) m/z 192.3 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.21-7.15 (m, 3H), 7.07-7.00 (m, 2H), 5.65 (d, J=2.3 Hz, 1H), 5.08 (s, 2H).

1810: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 1 -( 4-fluorobenzyl)-1 H-nirazol-3-yl)-2methylnicotinamide (11.0 mg, 7.6 µmol, 18% yield).

MS (ERI) m/z 511.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 9.21 (s, 1H), 8.49 (s, 1H), 8.19 (s, 1H), 7.82 (s, 1H), 7.71 (s, 1H), 7.30 (br d, J=5.8 Hz, 2H), 7.17 (br t, J=8.9 Hz, 2H), 6.67 (s, 1H), 5.24 (s, 2H), 2.59 (s, 3H).

Example 1811: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)1H-pyrazole -3-yl)-2-methylbenzamide f ₃ c

Following the methods described for Example 1810, the title compound was obtained (40 mg, 78.5 μmol, 79% yield).

MS (ERI) m/z 510.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 8.14 (s, 1H), 8.10-8.02 (m, 2H), 7.87-7.75 (m, 1H), 7.57 (s, 1H), 7.39 (br d, J=7.9 Hz, 1H), 7.30 (br dd, J=7.8, 6.0 Hz, 2H), 7.21-7.13 (m, 2H), 6.66 (s, 1H), 5.22 (s, 2H) , 2.40 (s, 3H).

Example 1812: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)5-methyl -1 H-pyrazol-3 -yl)-2 -methylnicotinamide

1812A: 1-(4-fluorobenzyl)-5-methyl-3-nitro-1H-pyrazole: 1.0 M NaHMDS/ THF (4.33 ml, 4.33 mmol) at room temperature. After stirring at room temperature for 15 min, 1(bromomethyl)-4-fluorobenzene (892 mg, 4.72 mmol) was added. The mixture was stirred at room temperature for 2 hours. EtOAc (50 ml) was added and the organics were washed with brine and water, then concentrated in vacuo. The residue was purified by silica gel chromatography (24 g, hexanes 60% EtOAc) to give the first spot as 1-(4-fluorobenzyl)-3-methyl-5-nitro-1H-pyrazole (150 mg, 0.638 mmol, 16% yield) , and a second spot as 1-(4-fluorobenzyl)-5-methyl-3-nitro-1H-pyrazole (700 mg, 2.98 mmol, 76% yield).

1H NMR (499 MHz, CDCl ₃ ) δ 7.20 (t, J=6.5 Hz, 2H), 7.07 (t, J=8.2 Hz, 2H), 6.72 (s, 1H), 5.34 (s, 2H), 2.28 ( s, 3H).

1812B: 1-(4-Fluorobenzyl)-5-methyl-1H-pyrazole-3-αmin was prepared in a manner analogous to that described in Example 1801B.

MS (ERI) m/z 206.4 (M+H) ⁺ .

1H NMR (499 MHz, CDCl3) δ 7.07 (br d, J=5.4 Hz, 2H), 7.05-6.97 (m, 2H), 5.48 (d, J=0.7 Hz, 1H), 5.06 (s, 2H), 2.15 (d, J=0.7 Hz, 3H).

1812: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-( 4-fluorobenzyl)-5-methyl-1H-pyrazol-3-yl)-2methylnicotinamide (7.9 mg, 15.1 µmol, 15% yield).

MS (ERI) m/z 525.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.94 (s, 1H), 9.21 (s, 1H), 8.52-8.45 (m, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7.25 -7.11 (m, 4H), 6.54 (s, 1H), 5.20 (s, 2H), 2.64-2.53 (m, 3H), 2.27 (s, 3H).

Example 1813: 5-(4-Amino-5-(trifluoromethyl)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-N 1 -(4-fluorobenzyl)5-methyl-1 H-pyrazol-3 -yl)-2 -methylbenzamide

- 525 042342

Following the methods described for Example 1812, the title compound was obtained (40 mg, 62.7 µmol, 63% yield).

MS (ERI) m/z 524.0 (M+H)+.

Ή NMR (500 MHz, DMSO-d6) δ 10.73 (s, 1H), 8.17 (s, 1H), 8.11-8.06 (m, 2H), 7.60 (s, 1H), 7.39 (br d, J=8.5 Hz , 1H), 7.22-7.15 (m, 4H), 6.54 (s, 1H), 5.20 (s, 2H), 2.42 (s, 3H), 2.26 (s, 3H).

Example 1814: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(2,2 ,2trifluoro-1-phenylethyl)-1 H-pyrazol-4-yl)nicotinamide

1814A: 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate: to a solution of 2,2,2-trifluoro-1-phenylethan1-ol (1.06 g, 6.00 mmol) and 2,6-lutidine (1.12 ml, 9.60 mmol) triflate anhydride (1.52 ml, 9.00 mmol) was added to DCM (12 ml) at -40°C under N2 atmosphere for 15 min. The mixture was stirred and allowed to warm to room temperature over 1.5 h. DCM (50 ml) was added and the organic layer was washed with 1N HCl. HCl and water, dried over Na ₂ SO ₄ then concentrated in vacuo without heating to give 2,2,2-trifluoro-1-phenylethyl trifluoromethanesulfonate (1.849 g, 6.00 mmol, 100% yield). The material was immediately used in the next step.

1814B: 4-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazole was prepared in a manner analogous to that described in Example 1786A.

1H NMR (499 MHz, chloroform-d) δ 8.30 (s, 1H), 8.18 (s, 1H), 7.57-7.49 (m, 5H), 5.96 (d, J=7.4 Hz, 1H).

1814C: 1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazole-4-amine was prepared in a manner analogous to that described in Example 1786B.

MS (ERI) m/z 242.4 (M+H)+.

1814: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N- (1-(2,2,2-trifluoro-1-phenylethyl)-1Hpyrazol-4-yl)nicotinamide (29 mg, 51.7 µmol, 52% yield).

MS (ERI) m/z 561.1 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.84-10.79 (m, 1H), 9.26-9.21 (m, 1H), 8.60-8.46 (m, 1H), 8.39 (s, 1H), 8.22-8.17 ( m, 1H), 7.76-7.66 (m, 4H), 7.51-7.45 (m, 3H), 6.86-6.66 (m, 1H), 2.59 (s, 3H).

Example 1815: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(2,2 ,2trifluoro-1-phenylethyl)-1H-pyrazol-4-yl)benzamide

Following the methods described for Example 1814, the title compound was obtained (39 mg, 69.7 μmol, 70% yield).

MS (ERI) m/z 560.3 (M+H)+.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.38 (s, 1H), 8.20-8.08 (m, 3H), 7.75-7.66 (m, 3H), 7.637.55 (m , 1H), 7.51-7.41 (m, 4H), 6.81-6.70 (m, 1H), 2.41 (s, 3H).

Example 1816: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(2,2 ,2trifluoro-1-phenylethyl)-1 H-pyrazol-3-yl)nicotinamide

1816A: 3-nitro-1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazole was prepared in a manner analogous to that described in Example 1810A.

1H NMR (499 MHz, CDCl3) δ 7.66 (d, J=2.5 Hz, 1H), 7.56-7.47 (m, 5H), 7.00 (d, J=2.6 Hz, 1H), 6.04 (d, J=7.5 Hz , 1H).

1816B: 1-(2,2,2-trifluoro-1-phenylethyl)-1H-pyrazol-3-amine was prepared in a manner analogous to that described in Example 1810B.

MS (ERI) m/z 242.4 (M+H)+.

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1816: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N- (1-(2,2,2-trifluoro-1-phenylethyl)-1Hpyrazol-3-yl)nicotinamide (12 mg, 21.3 µmol, 22% yield).

MS (ERI) m/z 561.0 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 11.30-11.24 (m, 1H), 9.28-9.23 (m, 1H), 8.57-8.52 (m, 1H), 8.24-8.20 (m, 1H), 8.00- 7.95 (m, 1H), 7.78-7.73 (m, 1H), 7.73-7.67 (m, 2H), 7.48 (br d, J=2.0 Hz, 3H), 6.85-6.80 (m, 1H), 6.73-6.65 (m, 1H), 2.62 (s, 3H).

Example 1817: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1 -f [ 1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(2,2, 2trifluoro-1-phenylethyl)-1 H-pyrazol-3 -yl)benzamide

Following the methods described for Example 1816, the title compound was obtained (25 mg, 37.1 μmol, 38% yield).

MS (ERI) m/z 560.1 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.19 (s, 1H), 8.16-8.11 (m, 2H), 7.96 (s, 1H), 7.70 (br d, J=3.8 Hz , 2H), 7.64 (s, 1H), 7.47 (br d, J=4.2 Hz, 3H), 7.40 (br d, J=8.0 Hz, 1H), 6.82 (s, 1H), 6.68 (br d, J =7.8 Hz, 1H), 2.43 (s, 3H).

Example 1818: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f] [ 1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(2,2 ,2trifluoro- 1 -(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)benzamide

1818A: 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-ol:

NaBH ₄ (165 mg, 4.37 mmol) was added to a solution of 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1one (840 mg, 4.37 mmol) in MeOH (15 ml) at -10°C. The mixture was stirred and allowed to warm to room temperature over 3 hours. EtOAc (50 ml) was added. The organic layer was washed with 1 N. HCl and water, dried over Na ₂ SO ₄ then concentrated to give crude 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-ol (730 mg, 3.76 mmol, 86% yield).

1H NMR (499 MHz, CDCl3) δ 7.49 (dd, J=8.6, 5.5 Hz, 2H), 7.13 (t, J=8.3 Hz, 2H), 5.05 (br dd, J=6.5, 2.9 Hz, 1H), 2.67 (br d, J=3.5 Hz, 1H).

1818B: 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl trifluoromethanesulfonate was prepared in a manner analogous to that described in Example 1814A.

1818C: 4-nitro-1-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole was prepared in a manner analogous to that described in Example 1801A.

MS (ERI) m/z 290.1 (M+H) ⁺ .

1H NMR (499 MHz, CDCl ₃ ) δ 7.89 (s, 1H), 7.62 (s, 1H), 7.50 (dd, J=8.7, 4.9 Hz, 2H), 7.30-7.20 (m, 2H), 5.84 (d , J=7.3 Hz, 1H).

1818C: 1-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazole-4-amine was prepared in a manner analogous to that described in Example 1801B.

MS (ERI) m/z 260.3 (M+H) ⁺ .

1818: Following the procedure described for Example 1774, 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N- (1-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)1H-imidazol-4-yl)benzamide (5.0 mg, 8.7 µmol, 9% yield).

MS (ERI) m/z 578.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.90 (s, 1H), 8.15 (s, 1H), 8.13-8.05 (m, 2H), 7.81 (s, 1H), 7.69 (br dd, J=7.9 , 5.5 Hz, 2H), 7.62 (s, 1H), 7.59 (br s, 1H), 7.43-7.32 (m, 3H), 6.76 (br d, J=8.9 Hz, 1H), 2.48-2.37 (s, 3H).

Example 1819: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1 -f [ 1,2,4]triazin-7-yl)-2-methyl-N-( 1 -(2,2, 2trifluoro-1-(4-fluorophenyl)ethyl)-1H-imidazol-4-yl)nicotinamide

Following the methods described for Example 1818, the title compound was obtained (3.0 mg, 4.3 μmol, 4% yield).

MS (ERI) m/z 579.2 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.21 (s, 1H), 8.56-8.47 (m, 1H), 8.18 (s, 1H), 7.83 (s, 1H),

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7.75-7.65 (m, 3H), 7.62 (s, 1H), 7.37 (br t, J=8.9 Hz, 2H), 6.76 (br d, J=8.5 Hz, 1H), 2.58 (s, 3H).

Example 1820: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)-2-methoxynicotinamide

To a mixture of 3-bromo-1,1,1-trifluoro-2-methylpropan-2-ol (15.51 mg, 0.075 mmol) and 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1 _K CO ₃ (62.1 mg, 0.449 mmol). The resulting mixture was heated at 60° C. for 12 hours. The mixture was then diluted with DMF and filtered. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 13% B, 13-53% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the target compound were combined and dried by centrifugal evaporation to give the title compound (13 mg, 0.022 mmol, 30% yield).

MS (ERI) m/z 566.2 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.91 (d, J=2.4 Hz, 1H), 8.84 (d, J=2.4 Hz, 1H), 8.45 (br d, J=7.9 Hz, 1H), 8.38- 8.24 (m, 1H), 8.16 (s, 1H), 7.59 (s, 1H), 5.32-5.08 (m, 1H), 4.68-4.47 (m, 1H), 4.05 (s, 3H), 2.98-2.85 ( m, 4H), 2.55 (s, 2H), 1.33 (s, 3H). MS: 566.2 (M+H) ⁺ .

Example 1821: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(4,4,4-trifluoro-2-hydroxybutyl)pyrrolidin-3-yl)-2-methoxynicotinamide

To a mixture of 5-(4-amino-5-(trifluoromethyl)πirrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4fluoropyrrolidin-3-yl )-2-methoxynicotinamide, 2 TFA salt (10 mg, 0.015 mmol) in 2-(2,2,2trifluoroethyl)oxirane (50 μl, 0.495 mmol) was added triethylamine (8.35 μl, 0.060 mmol). The resulting mixture was stirred at room temperature for 5 minutes. Then 50 µl of DMF was added and the mixture was heated to 80° C. and stirred for 30 minutes. The mixture was then diluted with DMF and filtered. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 13% B, 13-53% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (4.5 mg, 7.89 µmol, 53% yield).

MS (ERI) m/z 566.1 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.90 (d, J=2.4 Hz, 1H), 8.83 (br d, J=1.8 Hz, 1H), 8.36 (br d, J=7.5 Hz, 1H), 8.15 (d, J=2.4 Hz, 1H), 7.55 (br d, J=2.8 Hz, 1H), 5.25 (br s, 1H), 5.14 (br s, 1H), 4.55 (dt, J=13.9, 7.1 Hz, 1H), 4.07 (s, 3H), 3.90 (br s, 1H), 3.09–2.86 (m, 2H), 2.78–2.69 (m, 1H), 2.34–2.17 (m, 1H).

Connections in the table. 65 was obtained by the methods detailed in 1820 and 1821. When the diastereomers were separated, they were included as separate data. If the stereochemistry is not determined, the compound has been isolated as a mixture of diastereomers.

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Table 65

Example 1822 1823 Name 5-(4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [1,2,4]triazine-7wi)-N-((3R,4S)-4fluoro-1 -(2-hydroxy2- (trifluoromethyl)butyl)pyrrolidin-3-yl)-2methoxynicotinamide 5-(4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7wi)-N-((3R,4S)-4fluoro-1 -(2-hydroxy2(trifluoromethyl) butyl)pyrrolidin-3-yl)-2methoxynicotinamide R And he Observe May in MS the mass of the ion 580.0 580.0 Assignment of signals in the NMR spectrum Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.92 (d, ./=21 Hz, 1H), 8.85 (f/=2.1Hz, 1H), 8.41 (brd, /=7.6 Hz, 1Н), 8.37 - 8.28 (t, 1Н), 8.18 (s, 1Н), 7.62 (s, 1Н), 5.24 (brs, 1Н), 5.13 (br s, 1Н), 4.64 - 4.49 (m, 1H), 4.06 (s, 3H), 3.03 -2.91 (m, 3H), 2.86 2.67 (m, 2H), 1.75 (q, /=7.3 Hz, 2H), 1.17 (t, /=7.3 Hz, 4H), 0.94 ( brt,/=7.5 Hz, 3H) Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.93 (d,/=1.8 Hz, 1H), 8.83 (d,/=2.1 Hz, 1H), 8.51 (brd, / =7.3 Hz, 1H), 8.17 (s, 1H), 7.61 (s, 1H), 7.27 (s, 1H), 7.29 - 7.23 (m, 1H), 7.16 (s, 1H), 7.13 7.12 (m, 1H ), 7.06 (s, 1H), 7.03 -7.01 (m, 1H), 5.34 (br s, 1H), 5.23 (br s, 1H), 4.86-4.61 (m, 1H), 4.06 (s, 3H), 3.45 (br s, 1H), 3.17 (brd,/=10.4 Hz, 1H), 1.78 (quin, /=6.7 Hz, 2H), 0.95 (brt,/=7.3 Hz, VN)

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1824 5-(4-Amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7im)-N-((3R,4S)-4fluoro-1-(3,3,3trifluoro- 2-hydroxy2phenylpropyl)pyrrole idin-3-yl)-2methoxynicotinamide A ^SRz /=/ OH 628.3 Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.92 - 8.86 (m, 1H), 8.77 (br d, /=2.4 Hz, 1H), 8.32 (br s, 1H), 8.16 (s, 1H), 7.59 (brd,/=9.8 Hz, 4H), 7.46 - 7.23 (m, 4H), 5.11 (br d,/=4.9 Hz, 1H), 5.00 (br d, /=4.9 Hz, 1H), 4.46 - 4.33 ( m, 1H), 3.57 -3.46 (m, 1H), 3.43 - 3.30 (m, 1H), 3.24 - 3.14 (m, 1H), 3.09 -2.97 (m, 1H), 2.92 - 2.75 (m, 2H), 2.68 - 2.47 (m, 7H) 1825 5-(4-amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7mi)-N-((3R,4S)-l-(2cyclopropyl-3,3,3 trifluoro-2hydroxypropyl)-4fluoropyrrolidine-3 - yl)-2methoxynicotinamide A 592.3 Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.96 - 8.88 (m, 1H), 8.82 (br s, 1H), 8.36 (br d, /=7.6 Hz, 1H), 8.15 (s, 1H), 7.56 (s, 1H), 5.25 (br s, 1H), 5.14 (br s, 1H), 4.664.51 (m, 1H), 4.07 (s, 3H), 3.85 - 3.77 (m, 1H), 3.76-3.69 (m, 1H), 3.19 (s, 2H), 3.01-2.80 (m, 3H), 2.22 (br d, /=15.1 Hz, 1H), 2.10-1.99 (m, 1H), 1.181.03 (m, 2H), 0.69-0.36 (m, 7H) 1826 5-(4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7mi)-N-((3R,4S)-l-(2cyclopropyl-3,3,3 trifluoro -2hydroxypropyl)-4fluoropyrrolidin-3 yl)-2- methoxynicotinamide A 592.4 ¹ H NMR (400 MHz, methanol A) 9.10-8.87 (m, 1H), 8.09 (s, 1H), 7.42 (s, 1H), 5.27 (s, 1H), 5.21-5.07 (m, 1H), 4.77 - 4.60 (m, 1H), 4.18 (s, 2H), 3.272.78 (m, 3H), 0.83 - 0.63 (m, 1H), 0.61 - 0.36 (m, 1H) 1827 5-(4-amino-5(trifluoromethyl)pyrr olo[2,1f] [ 1,2,4]triazine-7mi)-N-((3R,4S)-l-(2cyclopropyl-3,3,3 trifluoro -2hydroxypropyl)-4fluoropyrrolidine-3 - silt) -2- methoxynicotinamide A 592.3 ¹ H NMR (400 MHz, methanol A) δ 8.97 (s, 2H), 8.08 (s, 1H), 7.41 (s, 1H), 5.32 - 5.07 (m, 1H), 4.77 -4.58 (m, 1H), 4.17 (s, 3H), 3.48 -2.75 (m, 6H, methanol overlap), 1.08 (s, 3H), 0.60 -0.36 (m, 2H), 4 proton exchangeable protons not observed

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1828 5-(4-amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7m)-N-((3R,4S)-4fluoro-1-(3,3,3trifluoro- 2-hydroxy2-(thiazol-2yl)propyl)pyrrolide in-3-yl)-2methoxynicotinamide N=^ OH A ^s 635.3 Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.90 (s, 1H), 8.80 (dd, 7=5.3, 2.3 Hz, 1H), 8.33 (br t, 7=8.5 Hz, 1H), 8.16 (s, 1H), 7.88 (brd, 7=1.2 Hz, 1H), 7.80 (d, 7=2.1 Hz, 1H), 7.59 (s, 1H), 5.20 5.08 (m, 1H), 5.05 -4.96 (m, 1H) , 4.51 -4.29 (m, 1H), 4.03 (s, 3H), 3.56 -3.42 (m, 1H), 3.36-3.11 (m, 1H), 3.06 (brt, 7=8.1 Hz, 1H), 2.98 - 2.92 (m, 1H), 2.87 (br d, 7=12.5 Hz, 1H), 2.84 - 2.64 (m, 2H) 1829 5-(4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7wi)-N-((3R,4S)-4fluoro-1-(3,3,3trifluoro- 2-hydroxy2(trifluoromethyl)propyl)pyrrolidin-3yl)-2- methoxynicotinamide 6< ^CF 3 F ₃ C OH 620.3 Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.88 (d, 7=1.9 Hz, 1H), 8.80 (d, 7=2.0 Hz, 1H), 8.36 (br d, 7=7.5 Hz, 1H), 8.13 (s, 1H), 7.52 (s, 1H), 5.28 - 5.21 (m, 1H), 5.12 (brt, 7=4.4 Hz, 1H), 4.634.53 (m, 1H), 4.15-4.08 (m, 1H ), 3.59 - 3.53 (m, 8H), 3.302.97 (m, 5H), 2.86 (brt, 7=8.6 Hz, 1H) 1830 5-(4-Amino-5(trifluoromethyl)pyrrolo[2,11][1,2,4]triazine-7m)-N-((3R,4S)-4fluoro-1 -(3-fluoro-2hydroxypropyl) pyrrolide in-3-yl)-2methoxynicotinamide s/ NS) \ 516.3 Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.94 - 8.87 (m, 1H), 8.82 (d, 7=2.2 Hz, 1H), 8.37 (br d, 7=7.7 Hz, 1H), 8.14 (s, 1H), 7.54 (s, 1H), 5.24 (br t, 7=4.6 Hz, 1H), 5.13 (brt, 7=4.2 Hz, 1H), 4.644.23 (m, 3H), 4.07 (s, 3H) , 3.91 - 3.77 (m, 1H), 3.26 - 2.84 (m, 3H), 2.76 - 2.57 (m, 2H) 1831 5-(4-Amino-5(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazine-7m)-N-((3R,4S)-4fluoro-1-(2-hydroxy3,3dimethylbutyl )pyrrolidin-3-yl)-2methoxynicotinamide Ά BUT \ 539.9 'H NMR (500 MHz, DMSO-d ₆ ) 5 8.94 - 8.88 (m, 1H), 8.84 (d, 7=2.1 Hz, 1H), 8.43 (br d, 7=7.6 Hz, 1H), 8.17 (s , 1H), 7.60 (s, 1H), 5.24 (br s, 1H), 5.13 (brs, 1H), 4.62 -4.35 (m, 1H), 4.05 (s, 3H), 3.23 -2.67 (m, 4H) , 2.60 (br d, 7=9.8 Hz, 1H), 2.46 2.31 (m, 1H) 1832 5-(4-Amino-5(trifluoromethyl)pyrr olo[2,11][1,2,4]triazine-7m)-N-((3R,4S)-4fluoro-1 -(2-hydroxy3-(1 ,1,2,2tetrafluoroethoxy)propyl)pyrrolidin-3 yl)-2- methoxynicotinamide F 614.3 Ή NMR (500 MHz, DMSO-d ₆ ) 5 8.93 - 8.89 (m, 1H), 8.84 (s, 1H), 8.42 (br d, 7=7.9 Hz, 1H), 8.17 (s, 1H), 7.60 ( s, 1H), 6.59 (br s, 1H), 6.49 (br s, 1H), 6.39 (brs, 1H), 5.24 (brs, 1H), 5.13 (br s, 1H), 4.64 - 4.50 (m, 1H ), 4.05 (s, 3H), 4.01 (br dd, 7=10.1, 3.4 Hz, 1H), 3.93 - 3.86 (m, 1H), 3.82 (brs, 1H), 3.44 (brs, 1H), 3.17 (br d, 7=4.9 Hz, 1H), 2.99 (br s, 1H), 2.68 (br d, 7=4.9 Hz, 1H)

Examples 1833 and 1834: Isomers A and B amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamide

To a mixture of 2-amino-3,3,3-trifluoro-2-methylpropanoic acid (2.354 mg, 0.015 mmol), 5-(4amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4 ]triazin-7-yl)-N-((3R,4S)-4-fluoropyrrolidin-3-yl)-2methoxynicotinamide, 2 TFA (10 mg, 0.015 mmol) and HATU (7.12 mg, 0.019 mmol) in DMF (59.9 µl) up to

- 531 042342 N-methylmorpholine (6.59 µl, 0.060 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, diluted with EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 minute hold at 15% B, 15-55% B over 22 minutes, then 4 minute hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give example 1833 as isomer A (3.3 mg, 5.32 µmol, 36% yield) and example 1834 as isomer B (1.8 mg, 2.96 µmol, 20% yield). The absolute stereochemistry on the amine is not known.

1833: isomer A: MS (ERI) m/z 578.9 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (d, J=1.8 Hz, 1H), 8.78 (br d, J=8.5 Hz, 1H), 8.54 (br dd, J=16.3, 6.3 Hz, 1H ), 8.17 (s, 1H), 7.61 (s, 1H), 7.25 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 5.46-5.18 (m, 1H), 4.83-4.57 ( m, 1H), 4.41 (br t, J=9.3 Hz, 1H), 4.32-4.15 (m, 1H), 4.05 (s, 3H), 3.91-3.63 (m, 1H), 3.43 (br s, 1H) , 1.49 (3H, s).

1834: isomer B: MS (ERI) m/z 578.9 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.99-8.89 (m, 1H), 8.79 (s, 1H), 8.45 (br d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.57 ( s, 1H), 7.66-7.51 (m, 1H), 7.22 (s, 1H), 7.11 (s, 1H), 7.01 (s, 1H), 5.34 (br s, 1H), 5.23 (br s, 1H) , 4.794.55 (m, 1H), 4.26-4.13 (m, 1H), 4.07 (s, 3H), 1.49 (s, 3H).

Example 1835: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(4,4-difluoro-1(3, 3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1833/1834 to give 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( 4,4-difluoro-1-(3,3,3-trifluoro-2-hydroxy-2(trifluoromethyl)propanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide (4.3 mg, 6.27 µmol, 29% yield).

MS (ERI) m/z 652.4 (M+H)+.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.98 (s, 1H), 8.94-8.87 (m, 1H), 8.44-8.05 (m, 1H), 7.45 (s, 1H), 5.235.04 (m, 1H), 4.79-4.20 (m, 2H), 4.17 (s, 3H), 4.14-3.60 (m, 2H).

Example 1836: 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R)- 3,3,3-trifluoro2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-(methoxy-d ₃ )nicotinamide

Prepared using the method described in Example 1833/1834 to give the title compound (60 mg, 95.5 µmol, 23% yield).

MS (ERI) m/z 515.1 (M+H)+.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.97-8.92 (m, 1H), 8.78 (dd, J=8.8, 2.4 Hz, 1H), 8.57-8.47 (m, 1H), 8.168.02 (m, 1H), 7.28-7.23 (m, 1H), 7.23-7.18 (m, 1H), 7.07 (br s, 1H), 5.41-5.14 (m, 1H), 4.76-4.58 (m, 1H), 4.554.25 (m, 1H), 4.12-3.70 (m, 2H), 3.65-3.32 (m, 1H), 1.54 (s, 3H).

Example 1837: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1(cyclopentylcarbamoyl) -4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

To a mixture of cyclopentyl isocyanate (1.689 µl, 0.015 mmol) and 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-4-Fluoropyrrolidin-3-yl)-2methoxynicotinamide, 2 TFA (10 mg, 0.015 mmol) in DMF (59.9 μL) was added triethylamine (8.35 μL, 0.060 mmol). The resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with DMF and filtered. The crude material was purified by preparative LCMS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with

- 532 042342

0.1% trifluoroacetic acid; gradient: 0 min hold at 22% B, 22-62% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (7.5 mg, 0.014 mmol, 91% yield).

MS (ERI) m/z 551.4 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (d, J=2.1 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.50 (br d, J=7.3 Hz, 1H), 8.17 (s, 1H), 7.60 (s, 1H), 6.07 (br d, J=7.0 Hz, 1H), 5.30 (br s, 1H), 5.20 (br s, 1H), 4.76-4.58 (m, 1H) , 4.04 (s, 3H), 3.97-3.78 (m, 2H), 3.69-3.58 (m, 1H), 3.54-3.41 (m, 2H), 3.20-3.13 (m, 1H), 1.88-1.73 (m, 2H), 1.63 (br s, 2H), 1.51–1.31 (m, 4H).

Example 1838: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(tert-butylcarbamoyl )-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1837 to give the title compound (3.7 mg, 6.89 µmol, 46% yield).

MS (ERI) m/z 539.4 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.95-8.87 (m, 1H), 8.80 (d, J=2.2 Hz, 1H), 8.41 (br d, J=7.6 Hz, 1H), 8.16 (d, J =1.8 Hz, 1H), 7.56 (d, J=2.0 Hz, 1H), 5.37 (s, 1H), 5.31 (br s, 1H), 5.20 (br s, 1H), 4.75-4.57 (m, 1H) , 4.07 (s, 3H), 3.84 (br t, J=9.0 Hz, 1H), 3.75-3.59 (m, 1H), 3.17 (t, J=9.8 Hz, 1H), 1.28 (s, 9H).

Example 1839: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(pentylcarbamoyl)pyrrolidin-3-yl)-2-methoxynicotinamide ^F \ ^{F F} V 4

A 1 TW

SG U ' ^Η Ά NO \

I

Prepared using the method described in Example 1837 to give the title compound (7.3 mg, 0.012 mmol, 80% yield). MS (ERI) m/z 552.9 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.96-8.86 (m, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.52 (br d, J=7.6 Hz, 1H), 8.17 (s, 1H ), 7.60 (s, 1H), 7.26 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 6.29 (br s, 1H), 5.31 (br s, 1H), 5.20 (br s , 1H), 4.80-4.55 (m, 1H), 4.04 (s, 3H), 3.80 (br t, J=9.2 Hz, 1H), 3.21-3.12 (m, 1H), 3.10-2.98 (m, 2H) , 1.53-1.37 (m, 2H), 1.34-1.14 (m, 4H), 0.87 (t, J=7.0 Hz, 3H).

Example 1840: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 (isopropylcarbamoyl)pyrrolidin-3-yl)-2-methoxynicotinamide ^F \ F F-U \ Fk ^H 2 ^N . #71°)--\P

JL _ JJ / n-# ,

U CE A nA I

Prepared using the method described in Example 1837 to give the title compound (6.2 mg, 0.012 mmol, 79% yield).

MS (ERI) m/z 525.0 (M+H)+.

1H NMR (500 MHz, DMSO-d6) δ 8.98-8.87 (m, 1H), 8.80 (d, J=1.9 Hz, 1H), 8.42 (br d, J=7.5 Hz, 1H), 8.22-8.09 (m , 1H), 7.57 (d, J=1.7 Hz, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 7.01 (s, 1H), 5.32 (br s, 1H), 5.20 (br d, J=3.0 Hz, 1H), 4.76-4.60 (m, 1H), 4.07 (s, 3H), 3.90-3.54 (m, 4H), 3.18 (br d, J=9.9 Hz, 1H), 1.09 (d, J=6.5Hz, 6H).

Example 1841: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(3 ,3difluoropyrrolidine-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1837 to give the title compound (1.6 mg, 2.59 µmol, 12% yield).

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MS (ERI) m/z 573.2 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.93 (d, J=2.4 Hz, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.49 (br d, J=7.6 Hz, 1H),

8.18 (s, 1H), 7.62 (s, 1H), 7.27 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 5.31 (br s, 1H), 5.21 (br s, 1H) , 4.81-4.51 (m,

1H), 4.06 (s, 3H), 3.92–3.53 (m, 4H), 2.44–2.28 (m, 2H).

Example 1842: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1(cyclohexylcarbamoyl) -4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1837 to give the title compound (1.5 mg, 2.66 µmol, 18% yield).

MS (ERI) m/z 565.4 (M+H)+.

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.92 (d, J=2.1 Hz, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.50 (br d, J=7.6 Hz, 1H), 8.18 (s, 1H), 7.62 (s, 1H), 5.97 (br d, J=7.9 Hz, 1H), 5.31 (br s, 1H), 5.20 (br s, 1H), 4.81-4.62 (m, 1H) , 4.05 (s, 3H), 3.82 (t, J=9.2 Hz, 1H), 3.71-3.48 (m, 1H), 3.16 (br t, J=9.9 Hz, 1H), 1.89-1.52 (m, 6H) , 1.36-1.00 (m, 5H).

Example 1843: 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1 ((2,2,2-trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1837 to give the title compound (1.2 mg, 8.46 µmol, 13% yield).

MS (ERI) m/z 565.1 (M+H) ⁺ .

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.99-8.88 (m, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.53 (br d, J=7.6 Hz, 1H), 8.18 (s , 1H), 7.62 (s, 1H), 7.06 (br t, J=6.1 Hz, 1H), 5.33 (br s, 1H), 5.22 (br s, 1H), 4.81-4.70 (m, 1H), 4.04 (s, 3H), 3.95-3.59 (m, 5H), 3.24 (br t, J=10.1 Hz, 1H).

Example 1844: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro- 1(piperidine-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide

mixtures

5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4 fluoropyrrolidin-3-yl) -2-methoxynicotinamide, 2 TFA (10 mg, 0.015 mmol) and 1-piperidinecarbonyl chloride (5.62 µl, 0.045 mmol) in DCM (150 µl) was added Et ₃ N (10.44 µl, 0.075 mmol). The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with EtOAc, washed with water (2x), brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The crude material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, particles 5 μm; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 28% B, 28-68% B over 20 min, then 6 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (6.2 mg, 0.011 mmol, 73% yield).

MS (ERI) m/z 551.5-(M+H) ⁺ .

Ή NMR (500 MHz, DMSO-d ₆ ) δ 8.97-8.89 (m, 1H), 8.79 (d, J=2.1 Hz, 1H), 8.43 (br d, J=7.4 Hz, 1H), 8.16 (s, 1H), 7.57 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 5.30 (br s, 1H), 5.19 (br s, 1H), 4.70-4.53 (m, 1H), 4.07 (s, 3H), 3.93-3.77 (m, 1H), 3.66 (br t, J=9.1 Hz, 1H), 3.55-3.40 (m, 4H), 3.26-3.07 (m, 3H), 1.67-1.38 (m, 6H).

- 534 042342

Example 1845: 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1(ethyl( methyl)carbamoyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide

Prepared using the method described in Example 1844 to give the title compound (6.1 mg, 0.011 mmol, 75% yield).

MS (ERI) m/z 525.4 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.95-8.87 (m, 1H), 8.79 (d, J=1.9 Hz, 1H), 8.43 (br d, J=7.6 Hz, 1H), 8.16 (s, 1H), 7.56 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 5.36-5.27 (m, 1H), 5.19 (t, J=3.1 Hz, 1H ), 4.75-4.41 (m, 1H), 4.07 (s, 3H), 3.91-3.83 (m, 1H), 3.78 (dd, J=13.1, 3.1 Hz, 1H), 3.67 (t, J=9.1 Hz, 1H), 3.563.39 (m, 5H), 3.16 (dt, J=12.8, 6.6 Hz, 2H), 1.08 (t, J=7.1 Hz, 3H).

Example 1846: 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((2RS,3SR)-3fluoro-8, 8-dimethyl-6,10-dioxaspiro[4.5]decan-2-yl)-2-methoxynicotinamide

To a mixture of 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinic acid, Na+ (109 mg, 0.290 mmol), Hunig's base (203 µl, 1.161 mmol). The resulting mixture was stirred at room temperature for 1 hour. A small portion of the reaction mixture was diluted with DMF, filtered and purified with SCP for application. The remainder of the reaction mixture was then diluted with EtOAc, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, 24 g, 0-70% EtOAc/hexanes) gave 5-(4-amino-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl )-N-(3-fluoro-8,8-dimethyl-6,10-dioxaspiro[4.5]decan-2yl)-2-methoxynicotinamide (isolate 02) (90 mg, 0.168 mmol, 58% yield).

MS (ERI) m/z 539.3 (M+H) ⁺ .

1H NMR (500 MHz, DMSO-d ₆ ) δ 8.91 (br d, J=1.8 Hz, 1H), 8.86 (s, 1H), 8.52-8.39 (m, 1H), 8.18 (s, 1H), 7.62 ( s, 1H), 5.17-4.96 (m, 1H), 4.57-4.37 (m, 1H), 4.04 (s, 3H), 3.59-3.25 (m, 3H), 2.55 (s, 1H), 2.47-2.33 ( m, 2H), 2.26-1.95 (m, 2H), 0.94 (br d, J=4.3 Hz, 6H).

Example 1847: 5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-chloro1H-pyrazol- 3-yl)-2-methoxynicotinamide

V

Prepared using the method described for Unity (7.5 mg, 0.013 mmol, 19% yield).

MS (ERI) m/z 543.1 (M+H)+.

example 1846, obtaining the title with ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.99-8.85 (m, 1H), 8.74 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (br d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.43-7.27 (m, 3H), 7.20 (br d, J=7.4 Hz, 2H), 6.81 (s, 1H), 5.33 (s, 2H), 4.04 (s, 3H).

Example 1848: 5-(4-Amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N( (3R,4S)-4-fluoro-1-isobutyrylpyrrolidin-3-yl)-2-(methoxy-d ₃ )nicotinamide

To a mixture of 5-(4-amino-5-((3,3-difluoroazetidin-1-yl)methyl)πpyrrolo[2,1-f][1,2,4]triazin-7-yl)-N(( _in DMF (6257 μl) was added Hunig's base (546 μl, 3.13 mmol). The resulting mixture was stirred at room temperature for

- 535 042342 for 2 hours. The determined mass was the target -14. NMR analysis of the starting acid showed that it was actually isobutyric acid, given the difference in mass 14. The reaction mixture was diluted with EtOAc, washed with water (2x), brine, dried over MgSO ₄ , filtered and concentrated under vacuum. A batch of this material was purified by preparative LC-MS under the following conditions: column: XBridge C18, 200 mm x 19 mm, 5 µm particles; mobile phase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; mobile phase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid; gradient: 0 min hold at 10% B, 10-50% B over 20 min, then 4 min hold at 100% B; flow rate: 20 ml/min; column temperature: 25°C. Fraction collection was initiated by MS and UV signals. Fractions containing the desired product were combined and dried by centrifugal evaporation to give the title compound (7.5 mg, 0.013 mmol, 19% yield).

MS (ERI) m/z 550.1 (M+H)+.

¹ H NMR (500 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.77-8.69 (m, 1H), 8.53 (br dd, J=17.4, 7.3 Hz, 1H), 8.07 (br d, J= 2.4 Hz, 1H), 7.94 (s, 1H), 7.26 (s, 1H), 7.22 (br s, 1H), 7.16 (s, 1H), 7.06 (s, 1H), 5.43-5.14 (m, 1H) , 4.85-4.42 (m, 1H), 4.20 (br s, 2H), 4.11-3.87 (m, 4H), 3.78-3.41 (m, 2H), 3.33-3.25 (m, 1H), 2.89 (s, 1H ), 2.782.61 (m, 2H), 1.11–0.93 (m, 6H).

Claims (15)

1 H-imidazol-1-yl)propanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide. 1,1,1-trifluorobutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1,1,1 -trifluoro-3,3-dimethylbutan-2-yl(3R,4S)-3 -(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2 ,1-f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1-cyclopropyl-2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1,1,1-trifluorobutαn-2-yl(3R,4S)-3-(5-{4-αmino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-588 042342 f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; propyl(3R,4S)-3 -(5-{4-amino-5-[(4,4-difluoropiperidin-1 -yl)methyl]pyrrolo[2,1-f][1,2,4]triazine- 7 yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1,1,1 -trifluoro-3,3-dimethylbutan-2-yl(3R,4S)-3 -(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2 ,1-f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1-cyclopropyl-2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1,1,1-trifluoro-3-methylbutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1,1,1,3,3,3-hexafluoropropan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1 yl)methyl]pyrrolo[ 2,1-f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; [1,1'-bi(cyclopropan)]-1-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1 yl)methyl]pyrrolo[2, 1-f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1-methylcyclopropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1-cyclopropylethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1-(trifluoromethyl)cyclobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2,4 ]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; (1s,3s)-3-fluorocyclobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [1, 2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; [1-(trifluoromethyl)cyclopropyl]methyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1, 2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 1,1,1-trifluoropropan-2-yl(3 R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1 f ][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1,1,1-trifluoropropan-2-yl(3 R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1 f ][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 1,1,1,3,3,3-hexafluoropropan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4 ]triazin-7-yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 1,1,1 -trifluoropropan-2-yl(3 R,4S)-3 - {5-[4-amino-5 -(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine- 7 yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclopropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2- 585 042342 methoxypyridine- 3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclobutyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; (2S)-1-hydroxypropan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl ]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; (2R)-1-hydroxypropan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl ]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; (2S)-2-hydroxypropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]2 -methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; (2R)-1-cyclopropyl-3-hydroxypropan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine -7-yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 1-methylcyclopropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; [1,1'-bi(cyclopropane)]-1-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4 ]triazin-7yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclopentyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; prop-2-yn-1-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ]-2methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 1-methoxypropan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]- 2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 1) phenyl or pyridyl, each optionally substituted with 1-3 halo; or 1) phenyl, naphthalenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl quinolinyl, benzisoxazolyl or benzthiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _{1- 3} alkoxy, halo-C _1-3 alkoxy and C _1-3 alkyl-SO ₂ ; or 1) H or CF3; or 1) C _1-6 (phenyl)alkyl, where alkyl is optionally substituted with 1-3 groups selected from hydroxy, =O, C _1-3 alkoxy and halo-C _1-3 alkyl or halo-C _1-3 alkoxy, where phenyl is optionally substituted with 1-3 groups selected from halo, C _1-3 haloalkyl, halo-C _1-3 alkoxy and phenoxy; 1) phenyl, naphthalenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, quinolinyl, benzisoxazolyl or benzthiazolyl, each optionally substituted with 1-3 groups selected from halogen, cyano, C _1-3 alkyl, C _1-3 haloalkyl, C _{1 -3} alkoxy, halo-C _1-3 alkoxy and C _1-3 alkyl-SO ₂ ; or 1) ; or 1) hydrogen, halogen, cyano, C ₁ _ ₃ alkyl, C ₁ _ ₃ haloalkyl, halo-C ₁ _ ₃ alkoxy, C ₁ _ ₃ hydroxyalkyl, C ₁ _ ₃ alkoxy-C ₁ _ ₃ alkyl, amino-C ₁ _ ₃ alkyl, C ₁ _ ₃ alkylamino-C ₁ _ ₃ alkyl, C ₁ _ ₃ dialkylamino-C ₁ _ ₃ alkyl, (C ₁ _ ₃ alkylCONH)-C ₁ _ ₃ alkyl or (C ₁ _ ₃ alkyl-SO ₂ NH)-C ₁ _ ₃ alkyl, -(CH ₂ )n-NH-OCH ₃ , C ₃ _ ₆ cycloalkyl, methylphenyl-SO ₂ O-; or 1. The compound of formula I or its salt where A is N or CR; R is hydrogen, halogen, C ₁ _ ₃ alkyl; R ¹ is hydrogen, C ₁ _ ₃ alkoxy-C ₁ _ ₃ alkyl or C ₂ _ ₃ hydroxyalkyl, C(O)-C ₁ _ ₃ alkyl, QO)C ₁ _ ₃ haloalkyl; R ² is hydrogen, halogen, C ₁ _ ₃ alkyl, C ₁ _ ₃ haloalkyl, C ₁ _ ₃ alkoxy, C ₁ _ ₃ deutero-C ₁ _ ₃ alkoxy, halo-C ₁ _ ₃ alkoxy, amino, C ₁ _ ₃ alkylamino or C ₁ _ ₃ dialkylamino; R ³ is hydrogen, halogen, C ₁ _ ₃ alkyl; R ⁴ is hydrogen, halogen, cyano, tetrazolyl, C ₁ _ ₃ alkyl tetrazolyl; R ⁵ is 2,2,2-trifluoroethyl(3R,4S)-3-(5-(4-amino-5-(morpholinomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-[5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1f] [ 1,2 ,4]triazin-7-yl)-2-methoxypyridine-3-amido]-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-{5-[4-αmino-5-({1,1-difluoro-6-α3αspiro[2.5]octαn-6yl}methyl)pyrrolo[2,1 -f][1,2,4]triazin-7-yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1 carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(morpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4] triazin-7yl}-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-(4-amino-5-((1,1-dioxidothiomorpholino)methyl)pyrrolo[2,1f] [1,2,4]triazine- 7-yl)-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2, 4]triazin-7-yl}-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-[5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1f] [ 1,2 ,4]triazin-7-yl)-2-methylbenzamido]-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4] triazin-7yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2, 4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-(5-(4-amino-5-((3,3-difluorocyclobutyl)methyl)pyrrolo[2,1f] [1,2,4]triazine- 7-yl)-2-(methoxy-d3)nicotinamido)-4-fluoropyrrolidine-1-carboxylate; 2,2,3,3-tetrafluorocyclobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1 yl)methyl]pyrrolo[2,1-f][1 ,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 2,2,3,3-tetrafluorocyclobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1 yl)methyl]pyrrolo[2,1-f][1 ,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 2,2,3,4,4,4-hexafluorobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f ][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; (2,2-difluorocyclopropyl)methyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][1,2 ,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 2,2,3,3,4,4,4-heptafluorobutyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 2,2,3,3,3-pentafluoropropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2,3,3-tetrafluoropropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [1, 2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2-difluoropropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4] triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2-dimethylpropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4] triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; (1R)-1-cyclopropylethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 2,2-difluoroethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [1,2,4] triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; ethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazine- 7 yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; cyclopropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1 -yl)methyl]pyrrolo[2,1 f] [ 1,2,4]triazine-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; propan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4] triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; (2,2-difluorocyclopropyl)methyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7 -yl]-2 -methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; (2,2-difluorocyclopropyl)methyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [1,2,4]triazin-7 -yl]-2 -methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 2-hydroxyethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; 2,2,2-trifluoroethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]- 2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; but-2-yn-1-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ]-2methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclopropylmethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; but-3-en-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ]-2methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 2-ethoxyethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; 2,2-difluoroethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin- 3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclobutylmethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; 2,2-dimethylpropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin- 3-amido}-4-fluoropyrrolidine-1-carboxylate; 2-methylpropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; prop-2-en-1-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl ]-2methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 2-methoxyethyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; propyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; phenyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; ethyl(3R,4S)-3-{5-[4-αmino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4]truαzin-7-yl]-2-methoxuniridine3-amido} -4-fluoropyrrolidine-1-carboxylate; butyl-(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido } -4-fluoropyrrolidine-1-carboxylate; butan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin- 3-amido}-4-fluoropyrrolidine-1-carboxylate; 2,2,3,3-tetrafluorocyclobutyl(3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7yl)- 2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate; (R)-1-hydroxy-4-methylpentan-2-yl(3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine -7-yl)-2-methoxynicotinamido)-4-fluoropyrrolidine-1-carboxylate; 2-methoxypyridine-3-carboxamide; cis-racemic-5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1(cyclohexylmethyl)-4-fluoropyrrolidine- 3-yl]-2-methoxypyridine-3-carboxamide; 2-amino-5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-tert-butyl-1Hpyrazol-4 -yl)pyridine-3-carboxamide; 2-amino-5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4- chlorophenyl)3-hydroxypropyl]pyridine-3-carboxamide; 2) C _2-3 alkyl, C _2-3 haloalkyl, C _2-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl or C _1-3 halocycloalkyl, each of which is optionally substituted with 1-3 groups selected from halogen, hydroxyl and C _1-6 haloalkyl; or 2) thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, C _1-3 alkyl, C _1-3 phenylalkyl; or 2) - 538 042342 2. The compound according to claim 1, where A represents N; R ¹ is hydrogen; R ² is C1-3 alkoxy; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is halo-C1-3alkoxy; R ⁶ is hydrogen; a is a single bond, b pre- ^R8b R ⁹ is a double bond, R ¹⁸ is absent, and R ⁷ is ⁿ 2) C _0-6 (cyclopropyl)alkyl, where alkyl is optionally substituted with 1-3 groups selected from hydroxy; 2) thiazolyl, oxazolyl, imidazolyl, thiadiazolyl, each of which is optionally substituted with 1-3 groups selected from halogen, C _1-3 alkyl, C _1-3 phenylalkyl; or 2) 2) or R ^11a ,R ^10a • _R 10b ' or 3,3-dimethylbutyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 3,3,4,4,4-pentafluorobutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 3,3,3-trifluoro-2-methylpropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f][ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 3,3,4,4,4-pentafluorobutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1 -f][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; 3,3-difluorocyclobutyl(3R,4 S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1 f] [ 1,2, 4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 3-fluoropropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; cyclopropylmethyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 3,3,3-trifluoro-2,2-dimethylpropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1yl)methyl]pyrrolo[2,1-f ][1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1 carboxylate; cyclobutyl-(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1- 587 042342 f] [ 1,2,4]triazin-7 -yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 3,3,3-trifluoropropyl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [1,2, 4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 3,3,4,4,4-nenmafluorobutan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4 ]mruazin7-yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 3,3,4,4,4-nentmαfluorobutan-2-yl(3R,4S)-3-{5-[4-αmino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4 ]mruαzin7-yl]-2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 3,3-difluorocyclobutyl(3R,4 S)-3 - {5-[4-amino-5 -(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl] -2methoxypyridine -3-amido}-4-fluoropyrrolidine-1-carboxylate; 3-fluoropropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 - amido}-4-fluoropyrrolidine-1-carboxylate; 3,3,3-trifluoropropyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] - 2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 3-methylbutan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]- 2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(4,4-difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-dimethylpropanoyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1cyclobutanecarbonyl-4-fluoropyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; - 576 042342 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylpropanoyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidine-3 -yl]-2-fluorobenzamide; - 563 042342 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluoro-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluoro-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluoro-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluoro-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-6-methylbenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-6-ethyl-2-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-6-ethyl-2-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-6-ethyl-2-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-6-ethyl-2-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-difluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; - 562 042342 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-difluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-difluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-difluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-2,6-difluoro-N-[(3R,4S)-4 -fluoro-1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-fluorobenzamide; - 558 042342 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidine-3 -yl]-5-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylpropanoyl) -4-fluoropyrrolidin-3-yl]-5-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(2methylpropanoyl)pyrrolidin-3 -yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-5-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbutanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-5-methoxybenzamide; - 557 042342 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-5-methoxybenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-6-ethyl-2-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]benzamide; - 552 042342 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2methylpropanoyl)pyrrolidin-3 -yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 3 -yl]-2-methoxypyridine-3-carboxamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]benzamide; - 542 042342 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorocyclohexanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorocyclohexanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(trifluoromethyl)cyclopentanecarbonyl]pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(trifluoromethyl)cyclobutanecarbonyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine4-carbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3dimethylbutanoyl) -4-fluoropyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-fluoro-2,2dimethylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclopentanecarbonyl)pyrrolidin-3-yl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4hydroxyoxane-4-carbonyl)pyrrolidin-3-yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-benzylpiperidin-3yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-benzoylpyrrolidin-3yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-benzylpyrrolidin-3yl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1H-pyrazol-4yl)benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(cyclopropylmethyl)-1Hpyrazol-4-yl]benzamide ; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenyl)-3hydroxypropyl]benzamide; 3-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ] benzamide; - 541 042342 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-hydroxy-3-phenylpropyl)benzamide; 3-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)benzamide; 3-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-hydroxy-3-phenylpropyl)benzamide; 3-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-phenylbutyl)benzamide; 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)benzamide; 3-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxy-3-phenylpropyl)benzamide; 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-phenylbutyl)benzamide; 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)benzamide; 3-{4-amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-hydroxy-3-phenylpropyl)benzamide; 3-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(2-phenoxyphenyl)methyl]benzamide; 3-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-phenylbutyl)benzamide; 3-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-phenylbutyl)benzamide; 3) C _1-2 (C _3-6 cycloalkyl)alkyl which is optionally substituted with 1-4 groups selected from halo, hydroxy, C _1-3 alkyl and C _1-3 haloalkyl. 3) C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl or C _1-3 halocycloalkyl, each optionally substituted with 1-3 groups selected from halo, NH2, -NC(O)OC _1-6 alkyl, NHC(O)OC _1-6 alkyl, -N(CH ₃ )C(O)OC _{1- 6} alkyl, -C(O)-C _1-3 alkyl, hydroxyl, C _1-6 alkoxy and C _1-6 haloalkyl, halo-C _1-3 alkoxy, phenyl, thiazolyl, pyridinyl, where phenyl, pyridinyl and thiazolyl are optional substituted with 1-2 halogen, nitro or C _1-6 haloalkyl; or 3) 3. The compound according to claim 1, where A represents N; R ¹ is hydrogen; R ² is C1-3 alkoxy; R ³ is hydrogen; R ⁴ is hydrogen; R ⁵ is halo-C1-3alkoxy; R ⁶ is hydrogen; a is a single bond, b is a double bond, and R ¹⁸ is absent. ^R8b R% --\ R ⁹ * IN—in 3) C _1-3 (phenoxy)alkyl, C _1-3 ((phenyl)(C _1-3 alkyl)amino)alkyl, where phenoxy or phenyl is optionally substituted with 1-3 groups selected from C _1-3 alkyl; 3) dihydro-1H-indenyl, tetrahydro-5H-benzo[7]annulene, tetrahydronaphthalene and 6,7-dihydro-5Hcyclopenta[b]pyridine, any of which are substituted with 1-3 groups selected from halo, C _1-3 alkyl ; or 3) 3) or ^{R b} ' where L is methylene, -C(R ^5a ) ₂ -, amino, C ₁ _ ₃ alkylamino, SO2 or O; 4-amino-7-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]carbamoyl}-6methoxypyridin-3-yl)pyrrolo[2,1- f][1,2,4]triazin-5-yl-4-methylbenzene-1-sulfonate; 4,4,4-trifluorobutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 4,4,4-trifluorobutan-2-yl(3R,4S)-3-(5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1f] [ 1,2,4]triazin-7-yl}-2-methoxypyridine-3-amido)-4-fluoropyrrolidine-1-carboxylate; 4,4,4-trifluorobutan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine-7 -yl]2-methoxypyridine-3-amido}-4-fluoropyrrolidine-1-carboxylate; cyclohexyl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido} -4-fluoropyrrolidine-1-carboxylate; propan-2-yl(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin- 3-amido}-4-fluoropyrrolidine-1-carboxylate; 4-fluoro-1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 4-amino-7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-N,Ndimethylpyrrolo[2,1-f] [1,2,4]triazine-5-carboxamide; 4-amino-7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-N-(2hydroxyethyl)pyrrolo[2,1 -f][1,2,4]triazine-5-carboxamide; 4-amino-N-(cyanomethyl)-7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6methoxypyridin-3-yl}pyrrolo[2,1-f ][1,2,4]triazine-5-carboxamide; 4-amino-N-ethyl-7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3yl}pyrrolo[2,1-f][ 1,2,4]triazine-5-carboxamide; 4) C _0-2 (C _3-7 cycloalkyl) alkyl, cyclohexenyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, pyridinonyl or tetrahydrothiophenyl dioxide, each of which is optionally substituted with 1-4 groups selected from halogen, hydroxy, C _{1 -3} alkyl and C _1-3 haloalkyl, C _1-3 alkoxy, hydroxyl-C _1-3 haloalkyl, C _3-6 cycloalkyl, C(O)OC _1-6 alkyl and amino; 4) where L represents CH2, -O-, CF2 or -CH(CF ₃ )-; or or 4. The compound according to claims 1 and 3, where R ⁷ represents ⁿ 4) C _1-3 (pyrazinyl)alkyl, wherein the pyrazinyl is optionally substituted with 1-2 groups selected from halo; 4) C _1-3 alkyl, C _2-3 alkenyl, C _2-3 alkynyl, C _1-3 haloalkyl, C _1-3 alkoxy-C _1-3 alkyl, C _3-6 cycloalkyl or C _1-3 halocycloalkyl, each optionally substituted with 1-3 groups selected from halo, NH2, -NHC(O)OC _1-6 alkyl, -N(CH ₃ )C(O)OC _1-6 alkyl, -C(O)-C _1-3 alkyl, hydroxyl, C _1-6 alkoxy and C _1-6 haloalkyl, halo-C _1-3 alkoxy, phenyl, thiazolyl, pyridinyl, where phenyl, pyridinyl and thiazolyl are optionally substituted with 1-2 halogen, nitro or C _{1 -6} haloalkyl; or 4) 4) 5-(4-Amino-5-((3,3-difluoroazetidin-1-yl)methyl)pyrrolo[2,1-f] [ 1,2,4]Tpna3HH-7-Hn)-N-((3R ,4S)-4fluoro-1-isobutyrylpyrrolidin-3-yl)-2-(methoxy-43)nicotinamide, or a pharmaceutically acceptable salt thereof. 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-K-(1-benzyl-5-chloro-1H-pyrazol- 3 yl)-2-methoxynicotinamide and 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((2RS,3SR)-3-φtorop-8,8-dimethyl6 ,10-dioxaspiro[4.5]decan-2-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-l(ethyl(methyl)carbamoyl)- 4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1] [1,2,4]τpiazin-7-yl)-N-((ЗR,4S)-4-φτop-l -( piper idine-1 carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-4-φτop-l-((2 ,2,2trifluoroethyl)carbamoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-l(cyclohexylcarbamoyl)-4-fluoropyrrolidine- 3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-l-(3,3difluoropyrrolidin-1- carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-4-φτop-l(isopropylcarbamoyl)pyrrolidine -3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-4-φτop-l(pentylcarbamoyl)pyrrolidine -3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-l-(τpetbutylcarbamoyl)-4-fluoropyrrolidine -3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S)-l(cyclopentylcarbamoyl)-4-fluoropyrrolidine- 3-yl)-2-methoxynicotinamide; 5-(4-aminopyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((3R,4S)-4-φτop-l-((R)-3,3,3 -τpiφτop-2-hydroκci-2methylpropanoyl)pyrrolidin-3-yl)-2-(methoxy-43)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazin-7-yl)-K-(4,4-difluoro-1-(3,3, 3-trifluoro-2hydroxy-2-(trifluoromethyl)propanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((3R,4S)-4-φτop-l-(2- hydroxy-3(1,1,2,2-tetrafluoroethoxy)propyl)pyrrolidin-3-yl)-2-methoxynicotinamide; N-((3R,4S)-1 -(2-amino-3,3,3-trifluoro-2-methylpropanoyl)-4-fluoropyrrolidin-3-yl)-5-(4-amino-5(trifluoromethyl)pyrrolo [2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((3R,4S)-4-φτop-l-(2- hydro- 5-(4-amino-5-(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((3R,4S)-4-φτop-l-(3- φτop-2hydroxypropyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(τpiφtormethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((3R,4S)-4-φtorop-l-(3, 3,3trifluoro-2-hydroxy-2-(trifluoromethyl)propyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-hydroxy-2-(thiazol-2-yl)propyl)pyrrolidin-3-yl)-2-methoxynicotinamide; - 597 042342 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl)-N-((3R,4S)-1-(2-cyclopropyl- 3,3,3trifluoro-2-hydroxypropyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl)-N-((3R,4S)-1-(2-cyclopropyl- 3,3,3trifluoro-2-hydroxypropyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl)-N-((3R,4S)-1-(2-cyclopropyl- 3,3,3trifluoro-2-hydroxypropyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-hydroxy-2-phenylpropyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 2-hydroxy-2(trifluoromethyl)butyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 2-hydroxy-2(trifluoromethyl)butyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 4,4,4trifluoro-2-hydroxybutyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-hydroxy-2-methylpropyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1-(4fluorophenyl)ethyl)-1H-imidazol-4-yl)nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1-(4fluorophenyl)ethyl)-1H-imidazol-4-yl)benzamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1-phenylethyl)-1H-pyrazol-3-yl)benzamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1-phenylethyl)-1H-pyrazol-3-yl)nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1-phenylethyl)-1H-pyrazol-4-yl)benzamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N -(1 -(2,2,2- trifluoro-1 phenylethyl)-1 H-pyrazol-4-yl) nicotinamide; 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)-5-methyl-1Hpyrazole -3-yl)-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)-5-methyl-1Hpyrazole -3-yl)-2-methylnicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)-1H-nirazol-3 yl)-2-methylbenzamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)-1H-nirazol-3 yl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-T|[1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)-III-imidazol4-yl )-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-T|[1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)-III-imidazol4-yl )-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-T|[1,2,4]triazin-7-yl)-N-(1-(4-chlorobenzyl)-III-imidazol4-yl )-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(4(trifluoromethyl)benzyl) )-1H-imidazol-4-yl)benzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-(4(trifluoromethyl)benzyl) )-1H-imidazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1 -(4(trifluoromethyl)benzyl) )-1H-imidazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-T|[1,2,4]triazin-7-yl)-M-(1-(4-fluorobenzyl)-III-imidazol4-yl )-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-T|[1,2,4]triazin-7-yl)-M-(1-(4-fluorobenzyl)-III-imidazol4-yl )-2-methylnicotinamide; 5-(4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-(4-fluorobenzyl)-1H-imidazol4-yl )-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(2,2,2- trifluoro-1-phenylethyl)-1H-imidazol-4-yl)benzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(2,2,2- trifluoro-1 phenylethyl)-1 H-imidazol-4-yl) nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-K-(1 -(2,2,2- trifluoro-1 phenylethyl)-1 H-imidazol-4-yl) nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl-1H-imidazol4-yl )-2-methylnicotinamide; - 596 042342 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl-1H-imidazol4-yl )-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-5-methyl-1H-imidazol4-yl )-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(1-(4-fluorophenyl)ethyl)- 1Hpyrazol-4-yl)-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-benzyl-1 H-pyrazol-3-yl) -2 methylbenzamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-imidazol-4-yl)- 2methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(4,4,4- trifluoro-3hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-methoxy-M-(1-(4,4,4- trifluoro-3hydroxy-3-methylbutyl)-1H-pyrazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(3,3,3- trifluoro-2hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-K-(1 -(3,3,3- trifluoro-2hydroxy-2-methylpropyl)-1 H-pyrazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-phenethyl-1H-pyrazol4-yl ) nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-K-(1-phenethyl-1Hpyrazol-4-yl ) nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(1-phenethyl-1Himidazol-4-yl ) nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-K-(1-phenethyl-1Himidazol-4-yl ) nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(4,4,4-trifluoro-3 hydroxy-3-(trifluoromethyl)butyl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-methoxy-M-(4,4,4-trifluoro-3hydroxy -3-(trifluoromethyl)butyl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(4,4,4- trifluoro-3hydroxy-3-methylbutyl)-1 H-imidazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-K-(1 -(3,3,3- trifluoro-2hydroxy-2-methylpropyl)-1H-imidazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-I-(1 -(3,3,3- trifluoro-2hydroxy-2-methylpropyl)-1H-imidazol-4-yl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-M-(1-(2-fluoro-5(trifluoromethoxy)benzyl) )-1H-imidazol-4-yl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(1-(4-fluorophenyl)ethyl)- 1Hpyrazol-4-yl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(1-(4-fluorophenyl)ethyl)- 1Hpyrazol-4-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-M-(1-(2-fluoro-5(trifluoromethoxy)benzyl) )-1H-pyrazol-4-yl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(1-(4-fluorophenyl)ethyl)- 1Himidazol-4-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(1-(4-fluorophenyl)ethyl)- 1Himidazol-4-yl)-2-methylnicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-cyclopropyl-3hydroxypropyl)-2-methylnicotinamide; N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)-1 benzyl-1 H-imidazole-4-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-M-(2,3-dihydroxy-3phenylpropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-M-(2,3-dihydroxy-3phenylpropyl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-M-(3-hydroxy-5-methylhexyl)-2methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(difluoromethoxy)-3-(4fluorophenyl)-2 -hydroxy-2-methylpropyl)-2-methylbenzamide; - 595 042342 N-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)-4-(4chlorophenyl) )-4-hydroxybutanamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(difluoromethoxy)-3-(4fluorophenyl)-2 -hydroxy-2-methylpropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-3methoxy -2-methylpropyl)-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2,3dihydroxy-2 -methylpropyl)-2-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(3-fluorophenyl)-2,3dihydroxy-2 -methylpropyl)-2-methylnicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(2-fluorophenyl)-2,3dihydroxy-2 -methylpropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-2methyl -3-oxopropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methyl-M-(5,5,5-trifluoro-2hydroxy -3-methoxy-2,4-dimethylpentyl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-3methoxy -2-methylpropyl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-3methoxy -2-methylpropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methyl-K-(5,5,5-trifluoro-2 ,4dihydroxy-4-(trifluoromethyl)pentyl)nicotinamide; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-(4fluorobenzyl)) -3,5-dihydroxypiperidin-1-yl) methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)-3-hydroxypiperidin-1-yl)methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)-3-hydroxypiperidin-1-yl)methanone; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(2-hydroxy-2,4,4trimethylpentyl)-2- methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2,3dihydroxy-2 -methylpropyl)-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2,3dihydroxy-2 -methylpropyl)-2-methoxynicotinamide; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-(4fluorobenzyl)) -3-hydroxypiperidin-1 -yl) methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)(3-(4fluorobenzyl)- 3-hydroxypiperidin-1-yl) methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)-3-methylpiperidin-1-yl)methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)-3-methylpiperidin-1-yl)methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-(1 -( 4fluorophenyl)-1-hydroxyethyl)piperidin-1-yl)methanone; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxypyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)piperidin-1-yl)methanone; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-2methylpropyl )-2-methoxynicotinamide; (5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methylpyridin-3-yl)(3-((4fluorophenyl) (hydroxy)methyl)piperidin-1-yl)methanone; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-N-(3-(4-fluorophenyl)-2-hydroxy-2methylpropyl )-2-methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-benzyl-1 H-pyrazol-3-yl) -2 methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-benzyl-1 H-pyrazol-3-yl) -2 methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-M-(1-benzyl-III-imidazol-4-yl)- 2methylnicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-M-(1-benzyl-III-imidazol-4-yl)- 2 methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(2-(3phenylpiperidin-1-yl) ethyl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(2-(3-phenylmorpholino)ethyl)nicotinamide ; - 594 042342 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methyl-N-(2-(2phenylmorpholino)ethyl)nicotinamide; 5-(4-amino-5-(morpholinomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -( (2,2,2trifluoroethyl)sulfonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(morpholinomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( (3,3,3trifluoropropyl)sulfonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-((tetrahydropyridazin-1(2H)-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R, 4S)1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-((3-oxotetrahydropyridazin-1(2H)-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N((3R ,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-((methoxyamino)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3 ,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((2H-tetrazol-2-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) -1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((III-tetrazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) -1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((1H-pyrazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) -1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((1H-benzo[d]imidazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(( 3R,4S)-1(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((1H-1,2,4-triazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N- ((3R,4S)-1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-((4-chloro-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-( (3R,4S)-1(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-((4-methyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl)-N-( (3R,4S)-1(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl)-N-( (3R,4S)-1(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(5-((III-imidazol-1-yl)methyl)-4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S) -1-(3,3difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-2-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -((R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3S,5S)-5-((benzyloxy)methyl )1-(3,3-difluorocyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-((3 SR,5SR)-1 -(3,3difluorocyclobutane -1-carbonyl)-5-(methoxymethyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((1SR,3RS)-3-(4chlorophenyl)cyclohexyl) -2-methoxynicotinamide; tert-butyl(2SR,4SR)-4-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2methoxynicotinamido)-2 -(methoxymethyl)pyrrolidine-1-carboxylate; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((1SR,2RS)-2phenylcyclopropyl)nicotinamide ; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((1SR,3RS)-3-(4fluorophenyl)cyclohexyl) -2-methoxynicotinamide; 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-K ((1SR,3RS)-3-phenylcyclohexyl)nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-phenylpiperidin-3yl)nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((1SR,3RS)-3 phenylcyclohexyl) nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-((1RS,3RS)-3 phenylcyclohexyl) nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl)-2-methoxy-M-(3phenylcycloheptyl)nicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-hydroxy-3-phenylcyclopentyl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylcyclohexyl)nicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3phenylcyclopentyl)nicotinamide; - 593 042342 5-(4-amino-5-(trifluoromethyl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-N-((1SR,3RS)-3-(4bromophenyl)cyclopentyl)-2 -methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2D-Sch1,2,4]triazin-7-yl)-M-(5-benzyl-1,3,4-oxadiazol-2-yl)2- methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 2-methyl-3oxobutan-2-yl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 2,2,5trimethyl-1,3-dioxane-5-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3(trifluoromethyl)pyrrolidine-3-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3-hydroxy2,2-dimethylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; N-((3R,4S)-1-(2-amino-4-methyl-2-(trifluoromethyl)pentanoyl)-4-fluoropyrrolidin-3-yl)-5-(4-amino-5(trifluoromethyl)pyrrolo[ 2,1-f][1,2,4]triazin-7-yl)-2-methoxynicotinamide; tert-butyl-3-((3R,4S)-3 -(5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)- 2methoxynicotinamido)-4-fluoropyrrolidine-1-carbonyl)-3-(trifluoromethyl)pyrrolidine-1-carboxylate; tert-Butyl-(3-((3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-2methoxynicotinamido )-4-fluoropyrrolidin-1 -yl)-2,2-dimethyl-3-oxopropyl)carbamate; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(1-aminocyclopentane1-carbonyl) -4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(but-2- inoyl)-4fluoropyrrolidin-3-yl)-2-methoxynicotinamide; N-((3R,4S)-1-(2-amino-3,3,3-trifluoropropanoyl)-4-fluoropyrrolidin-3-yl)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1 -f][1,2,4]triazin-7-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 1(trifluoromethyl)cyclopropane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(3, 3,3trifluoro-2,2-dihydroxypropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(2-chlorothiazol- 5-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; N-((3R,4S)-1-(2-amino-2-(trifluoromethyl)pentanoyl)-4-fluoropyrrolidin-3-yl)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-methoxynicotinamide; tert-Butyl-(1-((3R,4S)-3-(5-(4-amino-5-(trifluoromethyl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-2methoxynicotinamido )-4-fluoropyrrolidin-1 -yl)-2-methyl-1-oxopropan-2-yl)(methyl)carbamate; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( thiazole-5carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7 -yl} -M-{4- fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]piperidin-3-yl}-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-M-[4- fluoro-1(2-fluorobenzoyl)piperidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7 -yl} -Ν-{4- φτορ-1 [(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]piperidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7 -yl} -N-[ 1 - (3,3difluorocyclobutanecarbonyl)-4-fluoropiperidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[4,4,4- trifluoro-3hydroxy-3-(trifluoromethyl)butanoyl]piperidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-φτορ-Ν [(3R,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-φτορ-Ν [(3R,4S)-4-fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-φτορ-Ν [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-φτορ-Ν [(3R,4S)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-φτορ-Ν [(3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1-592 042342 (2,2-difluorocyclopropanecarbonyl)-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-1-(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoroN- [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxybenzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-fluoro-N [(3R,4S)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-fluoro-N [(3R,4S)-4-fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-fluoro-N [(3R,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-4-fluoro-N [(3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxybenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-10[1,2,4]triazin-7-yl)-M[(3R, 4S)-4-fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-10[1,2,4]triazin-7-yl)-M[(3R, 4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-10[1,2,4]triazin-7-yl)-M[(3R, 4S)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-10[1,2,4]triazin-7-yl)-M[(3R, 4S)-4-fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-10[1,2,4]triazin-7-yl)-M[(3R, 4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-1-(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; - 591 042342 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-dimethylpropanoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 4-fluoro-1-(2fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-amino-5-{[(1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl]methyl}pyrrolo[2,1f] [ 1.2, 4]triazin-7-yl)-N-[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2methoxypyridine-3-carboxamide; 5-[4-Amino-5-({1,1-difluoro-6-azaspiro[2.5]octan-6-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7- yl]-N[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-({1,1-difluoro-6-azaspiro[2.5]octan-6-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7- yl]-N[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide ; 5-{4-amino-5-[(4,4-dimethylpiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-(4-amino-5-{[(1R,5S)-3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl]methyl}pyrrolo[2,1f][1,2, 4]triαzin-7-yl)-N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2methylpropanoyl]pyrrolidin-3-yl]- 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-({6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin- 7yl]-N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridin-3- carboxamide; 5-[4-Amino-5-(difluoromethoxy)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-αmino-6-fluoropyrrolo[2,1-f][1,2,4]triαzin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(difluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]n-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N - 590 042342 [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide; 5-[4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3, 3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methoxypyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N[(3R ,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Aminopyrrolo[2,1-f^[1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R)-3,3 ,3-trifluoro-2-hydroxy2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-chloro-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoropyrrolidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(pyrrolidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} -N-[(3R,4S)- 4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-Amino-5-[(3,3-dimethylazetidin-1-yl)methyl]n-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(piperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} -N-[(3R,4S)- 4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(3-fluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S )-1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoropyrrolidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4R)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]piperidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2,2difluorocyclopropanecarbonyl)-4-fluoropiperidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R ,4S)-1 ((R)-2,2-difluorocyclopropane-1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1[(1S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-(4-Amino-5-((4,4-difluoropiperidin-1-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N ((3R,4S)-4-fluoro-1-((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2methoxybenzamide; 5-{4-Amino-5-cyano-pyrrolo[2,1-f^[1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-[(2R) -3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; - 589 042342 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-3-fluoro-N [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2methylbenzamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1 [(1 R)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; tert-Bumul(3R,4S)-3-(5-{4-αmino-5-[(3,3-difluoroαzetudin-1-yl)methyl]pyrrolo[2,1-f][1,2,4] triαzin7-yl}-3-fluoro-2-methylbenzamido)-4-fluoropyrrolidine-1-carboxylate; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1[(1S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1[(1 R)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1[(1 S)-2,2-difluorocyclopropanecarbonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3 carboxamide; 5-{4-amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 4-fluoro-1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-({2-azaspiro[3.3]heptan-2-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ (3R,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(pyrrolidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} -N-[(3R,4S)- 1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3-hydroxy-3(trifluoromethyl)cyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(1,1,1-trifluoropropane-2-sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; N-((3R,4S)-1-(2-amino-2-(trifluoromethyl)pentanoyl)-4-fluoropyrrolidin-3-yl)-5-(4-amino-5(trifluoromethyl)pyrrolo[2,1- f][1,2,4]triazin-7-yl)-2-methoxynicotinamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(1,1,1-trifluoropropane-2-sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2,2,2-trifluoroethanesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoropropanesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,2,2trifluoro-1-phenylethanesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2fluorophenyl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-{ [2(trifluoromethyl)phenyl]methanesulfonyl}pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (3nitrophenyl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (pyridin-2yl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(2chlorophenyl)methanesulfonyl ]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(2,6dichlorophenyl )methanesulfonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(3chlorophenyl)methanesulfonyl ]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (3fluorophenyl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(2,5difluorophenyl )methanesulfonyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (4fluorophenyl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2nitrophenyl)methanesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(cyclohex-1- en-1sulfonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxane-4sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2hydroxycyclohexyl)sulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(butan-1- sulfonyl)4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(1,1dioxidotetrahydrothiophene -3-yl)sulfonyl]-4-fluoropyrrolidin-3 -yl]-2-methoxypyridine-3 carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1{bicyclo[2.2.1 ]heptan-2-sulfonyl}-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4]pruαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oksolαn-3-586 042342 sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-methylbenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylbenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methoxy-5methylbenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methoxybenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1phenylmethanesulfonylpyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( naphthalene-1sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5dimethoxybenzenesulfonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4dimethylbenzenesulfonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (Z)-2fluoroethenesulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4]pruαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,2,2trifluoroethanesulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1,1,1 trifluoropropane-2-sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-methylpentan-2-sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbutane2-sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1(cyclopentanesulfonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1(cyclohexanesulfonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1(cyclopropanesulfonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1(isopropylsulfonyl )pyrrolidin-3-yl)-2-methoxynicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-hydroxy-3methylbutan-2-yl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; methyl(3R,4S)-3-(5-(4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzin-7-ul)-2-584 042342 methoxynicotinamido) -4-fluoropyrrolidine-1-carboxylate; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylcyclohexyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3hydroxybutan-2-yl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylcyclopentyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3hydroxybutan-2-yl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylcyclohexyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3hydroxybutan-2-yl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylcyclopentyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-hydroxy-3methylbutan-2-yl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2hydroxycyclopentyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3-hydroxy2,3-dimethylbutan-2-yl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,4-dimethyl-1,3thiazol-5-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,5-dimethyl-1,2oxazol-4-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(1,3-thiazol4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,5-dimethyl-1,2oxazol-4-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2-methyl1,3-thiazol-5-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzin-7-ul]-N-[(3R,4S)-1-[1-(4 -chloro-1,3-tuαzol2-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,5-dibromo-1,3thiazol-4-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 -chloro-4-methyl1,3-thiazol-5-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,4dimethylpyrimidin-5-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(pyrimidin-5-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-{ 1-[3(trifluoromethoxy)phenyl]ethyl}pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,5-difluoro-2hydroxyphenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2hydroxyphenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-{ 1-[4(trifluoromethyl)phenyl]ethyl}pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2,4,6trifluorophenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(pyrimidin-5-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,6difluoropyridin-4-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,3difluoropyridin-4-yl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5,5,5trifluoro-4-hydroxypentan-2-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-1-[1-(3 ,3-583 042342 difluorocyclopentyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 5,5,5trifluoro-4-hydroxy-4-(trifluoromethyl)pentan-2-yl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5,5,5trifluoro-4-hydroxy-4-phenylpentan-2-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,3difluorocyclopentyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5,5,5trifluoro-4-hydroxypentan-2-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (6-oxo-1,6dihydropyridin-2-yl)methyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylcyclopentyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylcyclopentyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(2,2,2trifluoro-1-hydroxyethyl)cyclopentyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(2,2,2trifluoro-1-hydroxyethyl)cyclopentyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(2,2,2trifluoro-1-hydroxyethyl)cyclopentyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2-difluoro-1hydroxyethyl)cyclopentyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2-difluoro-1hydroxyethyl)cyclopentyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2-difluoro-1hydroxyethyl)cyclopentyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2methoxyphenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; methyl 2-[(3R,4S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3 -amido}-4-fluoropyrrolidin-1-yl]cyclopentan-1-carboxylate; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2methoxyphenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 6-fluoro-2,3dihydro-III-inden-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methyl-2,3dihydro-III-inden-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2-difluoro-1hydroxyethyl)cyclopentyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylcyclopentyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-{5H,6H, 7H-cyclopenta[b]pyridin-5-yl}-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylcyclopentyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(2,2,2trifluoro-1-hydroxyethyl)cyclopentyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1,2,3,4tetrahydronaphthalene-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(7-chloro- 2,3-dihydro 1 H-inden-1-yl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(5-bromo- 1,2,3,4tetrahydronaphthalene-1-yl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-methyl1,2,3,4-tetrahydronaphthalene-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-{ 6,7,8,9tetrahydro-5H-benzo[7]annulen-5-yl}pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5-fluoro-2,3dihydro-1H-inden-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-fluoro-2,3dihydro-1H-inden-1-yl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-1-(2,3- dihydro-1H-582 042342 inden-1-yl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( 3-methyl-2,3dihydro-III-inden-1-yl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(2phenoxyphenyl)methyl]pyridine-3 - carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(1R)-1-[2-fluoro-5( trifluoromethyl)phenyl]ethyl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(3,3-difluoroazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S) -1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-(4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl)-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3trifluoro-2-methoxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxy-N-methylnicotinamide; (2R)-1 -{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxypyridin-3 -yl} - 2[2-fluoro-5-(trifluoromethoxy)phenyl]propan-1-one; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-( (R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxy-N-methylnicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3,3difluorocyclobutanecarbonyl)-4,4-difluoropyrrolidine -3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1H-1,2,4-triazole -3 yl)-2-methoxypyridine-3-carboxamide; 5-[4-acetamido-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; N-[(3R,4S)-1-[(1R)-3,3-difluorocyclopentanecarbonyl]-4-fluoropyrrolidin-3-yl]-5-[4-acetamido-5(trifluoromethyl)pyrrolo[2,1-f ][1,2,4]triazin-7-yl]-2-methoxypyridine-3-carboxamide; N-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-5-[4-(2fluoro -2-methylpropanamido)-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-2-methoxypyridine-3carboxamide; 5-[4-acetamido-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethyl-3-fluorobenzamide; N-[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-5-[4-acetamido-5(trifluoromethyl)pyrrolo[2,1-f][1, 2,4]triazin-7-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,3-difluoro-N-[(3R,4S)-4 -fluoro-1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,3-difluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,3-difluoro-N-[(3R,4S)-4 -fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,3-difluoro-N-[(3R,4S)-4 -fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,3-difluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,3-difluoro-N-[(3R,4S)-4 -fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine4-carbonyl)-4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(5fluoropyridine-3-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluoropyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1(pyridine-3-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; - 581 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1{spiro[2.2]pentan-1-carbonyl}pyrrolidin-3-yl]-2-methylbenzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-K [(3R,4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-K [(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]benzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-{4-amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-1][1,2,4]triazin-7-yl}-2-chloro-4 -fluoroN-[(3R,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-K-[5-({[2-fluoro-5(trifluoromethoxy) phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-K-{4[(cyclopropylmethyl)(propyl)carbamoyl]-1, 3-oxazol-2-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-K-[4-(cyclopentylcarbamoyl)-1,3oxazol-2-yl ]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-2-methoxy-N-{4-[(propan-2yl)carbamoyl ]-1,3-oxazol-2-yl}pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-K-{4[(cyclopropylmethyl)carbamoyl]-1,3-oxazole -2-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-1][1,2,4]triazin-7-yl]-K-[4-(tert-butylcarbamoyl)-1,3oxazol-2 -yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(methoxyd3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(propane-2-sulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-phenylethanesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-phenylmethanesulfonylpyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-methoxybenzenesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-methanesulfonylpyrrolidin-3-yl]-2-(methoxyL3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2,2,2-trifluoro-1-phenylethanesulfonyl)pyrrolidin-3-yl]-2-(methoxyL3)nicotinamide; 5-{4-αmino-5-[(3,3-difluoroαzetudin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]truαzin-7-yl}-N-[(3R ,4S)-1-580 042342 cyclopropylmethanesulfonyl-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4,4,4-trifluorobutanesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-methylpropanesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[2-(trifluoromethoxy)benzenesulfonyl]pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(cyclopropanesulfonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(ethanesulfonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(cyclohexanesulfonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4-fluorobenzenesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoropropanesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2,2,2-trifluoroethanesulfonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,2-dimethylpropanoyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4-fluorobenzoyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(methoxy-d3)nicotinamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2-Chloro-6-fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3-chloropyridine-4-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,5-Difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1 (2-chloro-3-fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(5-fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,5-difluoropyridine-2-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1 (3,4-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4-579 042342 fluoro-1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(5-fluoro-2-methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(5-chloropyridine-2-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(1,3-thiazole-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[4-(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(pyridine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2-Chloro-4-fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(4-chloropyridine-3-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2,4,6-trifluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluoropyridine-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(2-methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3-chloropyridine-2-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,5-difluoropyridine-4-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,6-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(2,5-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1 (2-chlorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(3-fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1 (4-chlorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-4fluoro-1-(pyridine-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-methoxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,3,3,3tetrafluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; - 578 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,2,2trifluoroacetyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1{spiro [2.2]pentane-1-carbonyl}pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-methoxy-2-phenylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(tert .butoxy)acetyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2-difluoroethoxy)2-methylpropanoyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyclohexylacetyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(6-chloropyridazin- 4carbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methylpyrimidine-5-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5-methylpyrazine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 6-methylpyrazine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methoxypyrimidine-5-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridazine-3carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 6methoxypyrazine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(1hydroxycyclohexyl)acetyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-(1methylcyclopropyl)acetyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyclopropylacetyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(2 ,2difluorocyclopropyl)acetyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyclobutylacetyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyclopentylacetyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(3 ,3difluorocyclobutyl)acetyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]truαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,6- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; - 577 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluoropyridine-4-carbonyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorobenzoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-benzoyl-4fluoropyrrolidin-3 -yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine4-carbonyl)-4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chlorobenzoyl) -4fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2methylpropanoyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-1-(4,4-difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-(4-amino-5-{[4-(trifluoromethyl)piperidin-1-yl]methyl}pyrrolo[2,1-G|[1,2,4]triazin-7-yl)-2-chloroN- [(3R,4S)-4-fluoro-1-(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-1-(3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-1-(4,4-difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-{4-Amino-5-[(4,4-difluoropiperidin-1-yl)methyl]pyrrolo[2,1-L][1,2,4]triazin-7-yl}-2-chloro-M [(3R,4S)-4-fluoro-1-[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(methylamino)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(methylamino)benzamide; - 575 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(methylamino)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]benzamide; - 574 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethoxy-N-[(3R,4S)-4-fluoro -1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(difluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(difluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1 -(2-fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(difluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(difluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-(difluoromethoxy)-N-[(3R,4S)-4fluoro -1-(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbutanoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; - 573 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(2,2,2-trifluoroethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-(trifluoromethoxy)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[2-(3 ,3difluorocyclobutyl)acetyl]-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyclopentylacetyl)-4 -fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 4-fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; - 572 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5-fluoro-2methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 6fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methyl-1,3oxazole-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,3- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3-chloropyridin- 4-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methanesulfonylbenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(5-cyano- 2fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 3fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(1,3- dimethyl-1Hpyrazole-5-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1-methyl-1Hpyrazole-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 6(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1-methyl-1Himidazole-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methoxypyridine-3-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,4,5trifluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 4,5-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,4,6trifluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4methylpyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chlorobenzoyl) -4fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridine-2carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridine-4carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-benzoyl-4fluoropyrrolidin-3 -yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chloropyridin- 2carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,6- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chloropyridin- 3carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chlorobenzoyl) -4fluoropyrrolidin-3-yl]-2-methylbenzamide; - 571 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine 2-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluoropyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine4-carbonyl)-4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1,3-thiazole-4carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4(trifluoromethyl)pyridine-2-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; - 570 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 2,6difluorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2chlorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4-chloropyridin-2-carbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3fluoropyridine-4-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2methylpyridine-4-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4-chloropyridin-3-carbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(5fluoropyridine-2-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 2,5-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1(pyridine-2-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,5-difluoropyridin-4-carbonyl)-4-fluoropyrrolidin-3-yl]-benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-benzoyl-4fluoropyrrolidin-3 -yl]-2-chlorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1 (pyridine-4-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3fluoropyridine-2-carbonyl)pyrrolidin-3-yl]benzamide; - 569 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 3,4difluorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4-chlorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(1,3thiazole-4-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,5-difluoropyridin-2-carbonyl)-4-fluoropyrrolidin-3-yl]-benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2,4difluorobenzoyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4(trifluoromethyl)pyridine-2-carbonyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4,4-difluorocyclohexanecarbonyl)-4-fluoro-pyrrolidin-3-yl]-benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(fluoromethyl)benzamide; - 568 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 2-hydroxy-2(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-(trifluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; - 567 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(6methylpyridazin-3-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1(pyridazine-3-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(6-chloropyridazin- 3-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1(2,3,3,3-tetrafluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; - 566 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[4(trifluoromethyl)pyridine-3-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3-bromopyridine- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[6-chloro- 3(trifluoromethyl)pyridine-2-carbonyl]-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(6-chloropyridin- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(5-chloropyridin- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[3fluoro-5-(trifluoromethyl)pyridine-2-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chloropyridin- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[6(trifluoromethyl)pyridine-2-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(6-bromo- 5fluoropyridine-2-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[3(trifluoromethyl)pyridine-2-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(5-bromo- 3-fluoro-pyridin-2-carbonyl)-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(6-bromopyridine- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[5(trifluoromethoxy)pyridine-2-carbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(6methylpyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3-chloropyridin- 2carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- dimethyl-1,3thiazole-4-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4methylpyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3-chloropyridin- 4-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,3- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine4-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluoropyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(1,3thiazole-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,6- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1(pyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1(pyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chlorobenzoyl) -4fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 6fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; - 565 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chlorobenzoyl) -4fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2,4,6trifluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(5fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(5fluoro-2-methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluoropyridine 2-carbonyl)-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4-chloropyridin- 3-carbonyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-αmino-5-(triformomethyl)pyrrolo[2,1-f][1,2,4]pyαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2,4,5trifluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(mpu-formethyl)pyrrolo[2,1-f][1,2,4]priazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4methyl-1,3-thiazole-2-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(mpu-formethyl)pyrrolo[2,1-f][1,2,4]priazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2methyl-1,3-thiazole-4-carbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(5-cyano- 2fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 3-fluoro-benzoyl)-4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 4fluorobenzoyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2-chloro- 4,5-difluorobenzoyl)-4-fluoropyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(1hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(1hydroxycyclopentanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(mrufluoromethyl)pyrrolo[2,1-f][1,2,4]pruαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[1(trifluoromethyl)cyclobutanecarbonyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1cyclopentanecarbonyl-4-fluoropyrrolidine-3 -yl]-4-fluoro-2-methylbenzamide; 5-[4-αmino-5-(mrufluoromethyl)pyrrolo[2,1-f][1,2,4]pruαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylpropanoyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; - 564 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidine-3 -yl]-4-fluoro-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-difluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-difluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-difluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-(3methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2,4-difluoro-N-[(3R,4S)-4 -fluoro-1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f|[1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4,4difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-3-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-3-methylbenzamide; - 561 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-3-fluoro-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorocyclohexanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-3-fluoro-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3 -yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-3-fluoro-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidine-3 -yl]-3-fluoro-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-2-methoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(1hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; - 560 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2dimethylpropanoyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-cyclobutanecarbonyl4-fluoropyrrolidine-3 -yl]-3-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethyl-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethyl-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1[2-hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-ethyl-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-ethyl-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4,4-difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; - 559 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(1-fluorocyclopropanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1[4,4,4-trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-3-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-3-fluoro-N-[(3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[2hydroxy-2-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-N-((3R,4S)-4-fluoro -1-(3fluorocyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-3-fluoro-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-(1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,3-dimethoxybenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2,3-dimethoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2,3-dimethoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2,3-dimethoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4,4,4trifluoro-3-methylbutanoyl)pyrrolidin-3-yl]-2,3-dimethoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl]pyrrolidin-3-yl]-2-(fluoromethyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methoxybenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-ethyl-3-fluoro-N-((3R,4S) -4-fluoro-1(4,4,4-trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)benzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3,3difluorocyclobutan- 1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-(methylamino)benzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-4-fluoro-N-((3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2-methoxybenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(4,4-difluoro-1 -((R)- 3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3-fluoro-N-((3R,4S)-4-fluoro -1-(4,4,4trifluoro-3-hydroxy-3-(trifluoromethyl)butanoyl)pyrrolidin-3-yl)-2-methylbenzamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(2-fluoro -2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(3,3 ,3-trifluoro-2,2dimethylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1 -(3-hydroxy -3(trifluoromethyl)cyclobutane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(4-hydroxy -4(trifluoromethyl)cyclohexane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(4(trifluoromethyl )cyclohexane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(4(trifluoromethyl )cyclohexane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(4,4-difluorocyclohexane-1 carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-(1(trifluoromethyl )cyclopropane-1-carbonyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(3,3-difluorocyclopentan-1 carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(3,3-difluorocyclobutan-1 carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(2,2-difluorocyclopropan-1 carbonyl)-4-fluoropyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)-2methoxynicotinamide; 5-(4-Amino-6-(2-methyl-2H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R, 4S)-4-fluoro-1 ((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; - 556 042342 (S)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(3-(4-chlorophenyl)-3 -hydroxypropyl)-2methoxynicotinamide; (R)-5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3-hydroxypropyl) 2-methoxynicotinamide; (R)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(2-fluoro-5(trifluoromethoxy)phenyl )ethyl)-2-methoxynicotinamide; (R)-5-(4-amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-K-(1-(2-fluoro-5(trifluoromethyl)phenyl )ethyl)-2-methoxynicotinamide; 5-(4-amino-6-(1-methyl-1H-tetrazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R, 4S)-4-fluoro-1 ((R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-(III-tetrazol-5-yl)pyrrolo[2D-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro -1-((R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-6-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-4-fluoro-1-((R) -3,3,3-trifluoro-2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl)-2-methoxynicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxolane-3carbonyl)pyrrolidin-3-yl]-2,4-dimethylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2,6-dimethylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-chloro-N-[(3R,4S)-1-( 3,3difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-chloro-2-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-chloro-2-fluoro-N-[(3R,4S) -4-fluoro-1(1-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; (5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1 -(3,3difluorocyclobutane -1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-(methoxy-d3)-6-methylnicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridine-3-carboxamide; - 555 042342 5-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(4fluorocyclohexanecarbonyl)pyrrolidine -3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(4fluorobenzoyl)pyrrolidine -3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(oxane-4carbonyl )pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-{4-Amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridine-3sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridine-3sulfonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-fluorobenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-fluorobenzenesulfonyl)pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2-methyl-1,3thiazol-5-yl)sulfonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2cyanobenzenesulfonyl)-4 -fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(4-methylpiperazin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S )-1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(1,1-dioxothiomorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(3-aminoazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S )-1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-({2-oxa-6-azaspiro[3.3]heptan-6-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(acetamidomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(methanesulfonamidomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; methyl N-{[4-amino-7-(5-{[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3yl]carbamoyl}-6-methoxypyridin-3-yl)pyrrolo [2,1-f][1,2,4]triazin-5-yl]methyl}carbamate; 5-{4-amino-5-[(propan-2-yloxy)methyl]pyrrolo[2,1-f][1,2,4]triazin-7 -yl} -N-[(3R,4S)- 1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(2,6-dimethylmorpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-Amino-5-[(3,3-difluoroazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R ,4S)-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(3-hydroxyazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S )-1(3,3-difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(morpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(methylamino)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3 ,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(dimethylamino)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3 ,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-αmino-5-[(1,1-dioxothiomorpholin-4-yl)methyl]n-pyrrolo[2,1-f][1,2,4]triαzin-7-yl}-N-[(3R ,4S)- 554 042342 5-{4-amino-5-[(azetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 4-fluoro-1-(3,3,3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(3-aminoazetidin-1-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} -N-[(3R,4S )-4-fluoro1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(morpholin-4-yl)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)- 4-fluoro-1(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-({2-oxa-6-azaspiro[3.3]heptan-6-yl}methyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N[(3R,4S)-4-fluoro-1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3carboxamide; 5-{4-amino-5-[(dimethylamino)methyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro- 1-(3,3,3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(methylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(dimethylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-7 -yl] -N-[(3 S)-3-(4-chlorophenyl)- 3hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(propylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(2-hydroxyethyl)carbamoyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4chlorophenyl )-3-hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-[(cyanomethyl)carbamoyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl} -N-[(3S)-3-(4- chlorophenyl)3-hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(ethylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2phenylethyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (5fluoropyridin-2-yl)methyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(4fluorophenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(4fluorophenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,4difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,4difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,5-difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3 ,5-difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(pyridin-3yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(pyridin-3yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(3fluoropyridin-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(3fluoropyridin-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(pyrimidin-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(pyrimidin-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1[phenyl (deutero)methyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; - 553 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(3fluoropyridin-2-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2fluorophenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2fluorophenyl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-1-phenylpropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-1-phenylpropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(1,3-thiazol5-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(1,3-thiazol5-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2-methyl1,3-thiazol-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(2-methyl1,3-thiazol-4-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(5fluoropyridin-3-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(5fluoropyridin-3-yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(pyridin-4yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1-(pyridin-4yl)ethyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,4difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(2 ,4difluorophenyl)ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3cyanophenyl )ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[1-(3cyanophenyl )ethyl]-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1phenylethyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1phenylethyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1phenylethyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2-hydroxypropyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(2,2difluorocyclopropyl )methyl]-4-fluoropyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-[(2,2difluorocyclopropyl )methyl]-4-fluoropyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-4-fluoro-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(2fluorobenzoyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-4-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylbenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3-difluorocyclopentanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1 -( 4,4-difluorocyclohexanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-N-[(3R,4S)-1-( 3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidin-3-yl]-4-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(4-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3-fluoropyridine-2-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3,3,3-trifluoropropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1[(2R)-3,3,3-trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(2-fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(1-hydroxycyclopentanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(3-hydroxy-3-methylbutanoyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-chloro-4-fluoro-N-[(3R,4S) -4-fluoro-1(1-hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-αmino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triαzin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-4-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3methylbutanoyl)pyrrolidin-3-yl]-4-methylbenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoro-pyrrolidin-3-yl]-2-fluoro-4-methylbenzamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3,3difluorocyclobutan- 1-carbonyl)-4-fluoropyrrolidin-3-yl)-2-(methoxy-d3)nicotinamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; - 551 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3dimethylbutanoyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-hydroxy-3methylbutanoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylpropanoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-2hydroxy-3,3-dimethylbutanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-2hydroxy-4-methylpentanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-2hydroxy-4-methylpentanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclopentanecarbonyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3- yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3- yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(4,4difluorocyclohexanecarbonyl)-4-fluoropyrrolidine-3 -yl]-2-methylpyridine-3-carboxamide; - 550 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3- yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3- yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3 -yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2,2difluorocyclopropanecarbonyl)-4-fluoropyrrolidin-3 -yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylpropanoyl)pyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-M-(4-fluoro-1-(3-fluorocyclobutan-1carbonyl) pyrrolidin-3-yl)-2-methoxynicotinamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G][1,2,4]triazin-7-yl)-M-(4-fluoro-1-(3-fluorocyclobutan-1carbonyl) pyrrolidin-3-yl)-2-methoxynicotinamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxetane-3carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-methyl-2-phenylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,5- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methoxypropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2-methylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3dimethylbutanoyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoro-2,2-dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyridine-3carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3,3,3trifluoropropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( pyrrolidine 1 -carbonyl)pyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(dimethylcarbamoyl)4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclopropanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1fluorocyclobutanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-methyloxetane-3-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2,6,6trimethyloxane-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxane-3carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; - 549 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxane-2carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( oxolane-2carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-2hydroxy-4-methylpentanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-2hydroxy-3,3-dimethylbutanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-2hydroxy-4-methylpentanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclopropanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-hydroxy-2methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-hydroxypropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-hydroxy-3methylbutanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclobutanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 1hydroxycyclopentanecarbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 3-fluoro-2,2dimethylpropanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2methylpyridine-4-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ 1(trifluoromethyl)cyclohexanecarbonyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2R)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1propanoylpyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 5fluoropyridine-2-carbonyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4-methylpentanoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-[ (2S)-3,3,3trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,6- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,4- difluorobenzoyl)4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2- difluoro-1-methylcyclopropanecarbonyl)-4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3- yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(4fluorocyclohexanecarbonyl)pyrrolidin-3- yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-K-[(3S,4S)-1-(4,4difluorocyclohexanecarbonyl )-4-methylpyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-methylpyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-methylpyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-cyclohexanecarbonyl4-methylpyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; - 548 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3 S,4S)-1-benzoyl-4methylpyrrolidin- 3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-methylpyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(4,4difluorocyclohexanecarbonyl )-4-methylpyrrolidin-3-yl]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-methylpyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3 S,4S)-1-benzoyl-4methylpyrrolidin- 3-yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopropylmethyl)-1Hpyrazol-4-yl] - 2-methoxy-6-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxy-6-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-6-methyl-N-(4,4,4trifluoro -3-hydroxy-3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 2-fluoro-2-methylpropanoyl)pyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4yl)pyridine- 3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-phenylbutyl)pyridine-3carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-(4,4,4-trifluoro-3hydroxy -3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[3-(4-fluorophenyl)-3hydroxypropyl ]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-(3-phenylbutyl)pyridine3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4-yl) -2fluoropyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-fluoropyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopropylmethyl)-1Hpyrazol-4-yl] - 2-fluoropyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-(3,3difluorocyclopentanecarbonyl)pyrrolidine- 3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-(3,3difluorocyclobutanecarbonyl)pyrrolidine- 3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3S)-1cyclobutanecarbonylpyrrolidin-3 -yl] -2- methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1cyclopentanecarbonylpyrrolidin-3-yl]-2- methoxypyridine-3-carboxamide; - 547 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3S)-1cyclohexanecarbonylpyrrolidin-3 -yl] -2- methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(3S)-1-[3, 3,3trifluoro-2-methyl-2-(trifluoromethyl)propanoyl]pyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-(3,3dimethylbutanoyl)pyrrolidin- 3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(2,2difluorocyclopropanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(oxane4-carbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(4fluorobenzoyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(3R,4S)-4-fluoro -1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl]benzamide; 5-[4-amino-5-(trifluoromethyl)nirrolo[2,1-f][1,2,4]triazin-7-yl]-2-fluoro-N-[(2-phenyloxan-3yl)methyl] benzamide; tert-Butyl(3S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2fluorobenzamido}pyrrolidin-1 -carboxylate; 5-[4-Amino-5-(Trifluoromethyl)nirrolo[2,1-f][1,2,4]mruazin-7-yl]-2-fluoro-N-(4,4,4-Trufluoro-3hydroxy -3-phenylbutyl)benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-H1,2,4]triazin-7-yl]-2-fluoro-N-[3-(4-fluorophenyl)-3hydroxypropyl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-fluorobenzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-H1,2,4]triazin-7-yl]-2-fluoro-M-(3-hydroxy-3phenylpropyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-H1,2,4]triazin-7-yl]-2-fluoro-M-[(2phenoxyphenyl)methyl]benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-H1,2,4]triazin-7-yl]-2-fluoro-M-(3-phenylbutyl)benzamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{4-fluoro-1-[(5-methyl-1,2- oxazol3-yl)methyl]pyrrolidin-3-yl}-2-methoxypyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{1-[(4-cyanophenyl)methyl]-4fluoropyrrolidin-3-yl } -2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{4-fluoro-1-[(naphthalene-1yl)methyl]pyrrolidin- 3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{ 1 -[(5-bromopyridin-3yl)methyl] - 4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{1-[(3,5-difluorophenyl)methyl]-4fluoropyrrolidin-3 -yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{4-fluoro-1-[(3methylphenyl)methyl]pyrrolidin-3- yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-(4-fluoro-1-{[3-fluoro-4(trifluoromethoxy) phenyl]methyl}pyrrolidin-3-yl)-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{4-fluoro-1-[(4-fluoro-3methylphenyl)methyl] pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-{1-[(2,5-difluorophenyl)methyl]-4fluoropyrrolidin-3 -yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(4-546 042342 methylphenyl )methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(4-fluoro-1-{[2(trifluoromethyl)phenyl ]methyl}pyrrolidin-3-yl)-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(pyridin-4yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(5-fluoropyridin-3yl )methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(2,6-dichlorophenyl)methyl]- 4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(4-fluoro-1-{[3(trifluoromethyl)phenyl ]methyl}pyrrolidin-3-yl)-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(3-cyanophenyl)methyl]-4fluoropyrrolidine- 3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(quinolin-8yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(quinolin-2yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(4-chlorophenyl)methyl]-4fluoropyrrolidine- 3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{ 1 -[(1,3-benzothiazol-2yl)) methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{ 1 -[(3-bromo-1,2-oxazole )-5yl)methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-{1-[(1-ethyl-1 H-imidazol- 5)yl)methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(1-benzyl-1 H-imidazol- 5)yl)methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-{1 -[(2-bromo-1,3-thiazole )-5 yl)methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(2fluorophenyl)methyl]pyrrolidine -3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(4-fluoro-1-{[4(trifluoromethyl)phenyl ]methyl}pyrrolidin-3-yl)-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-4-fluoropyrrolidin-3yl)-2- methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(2-cyanophenyl)methyl]-4fluoropyrrolidine- 3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(4fluorophenyl)methyl]pyrrolidine -3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-{1-[(3,4-difluorophenyl)methyl] - 4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(pyridin-2yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{ 1 -[(3,5-dimethyl-1,2 -oxazol-4yl)methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(2-methyl-1 ,3-thiazol4-yl)methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(1,3-thiazole -4yl)methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(6-methylpyridin-2yl )methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(4-fluoro-1-{[6(trifluoromethyl)pyridine -2-yl]methyl}pyrrolidin-3-yl)-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(pyridin-3yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(quinolin-4yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(1,3-benzoxazol-2yl)) methyl]-4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-]4-fluoro-1-[(3-methyloxetan-3yl )methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-αmino-5-(trifluoromethyl)nurrolo[2,1-f][1,2,4]truαzen-7-yl]-N-(1-cyclonentyl-4- 545 042342 fluoropyrrolidin-3-yl )-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-G|[1,2,4]triazin-7-yl]-M-[4-fluoro-1-(4,4,4trifluorobutyl) pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopropylmethyl)-4fluoropyrrolidin-3-yl] - 2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-{1-[(2,2difluorocyclopropyl)methyl]-4- fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(oxolan-2yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopentylmethyl)-4fluoropyrrolidin-3-yl] - 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[4,4,4- trifluoro-3(trifluoromethyl)butyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2-ethoxyethyl)-4fluoropyrrolidin-3-yl ]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1-[(oxan-2yl)methyl ]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(2-cyclopropylethyl)-4fluoropyrrolidin-3-yl ]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclobutylmethyl)-4fluoropyrrolidin-3-yl] - 2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-{1-[2-(2,2difluorocyclopropyl)ethyl] - 4-fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(3methoxypropyl)pyrrolidin-3- yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{4-fluoro-1 -[(oxolan-3yl) methyl]pyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{1-[(3,3difluorocyclobutyl)methyl]-4- fluoropyrrolidin-3-yl}-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4-yl) -2(trifluoromethyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-(trifluoromethyl)pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-(trifluoromethyl)pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methyl-N-[2-(3-phenylpiperidin1-yl) ethyl]pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methyl-N-[2-(3-phenylpyrrolidin1-yl) ethyl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 methoxypropyl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -2-methyl-N-[ 1 -(2,2,2- trifluoroethyl)1H-pyrazol-4-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-cyclopentanecarbonyl4-methylpyrrolidin-3 -yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methyl-N-(3-phenylbutyl)pyridine3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopropylmethyl)-1Hpyrazol-4-yl] - 2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenyl)-3- 544 042342 hydroxypropyl ]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-hydroxy-3-phenylpropyl)-2methylpyridin-3- carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4-yl) -2methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methylpyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3-chloropyrazin-2-yl)methyl]-2methoxybenzamide ; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(2phenoxyphenyl)methyl]benzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-hydroxy-3-phenylpropyl)-2methoxybenzamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-(3phenylbutyl)benzamide; 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(4-fluorobenzoyl)pyrrolidin-3yl ]-2-methoxypyridine-3-carboxamide; 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(4,4-difluorocyclohexanecarbonyl)-4fluoropyrrolidine-3- yl]-2-methoxypyridine-3-carboxamide; 5-{4-Aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(3fluorocyclobutanecarbonyl)pyrrolidin-3-yl ]-2-methoxypyridine-3-carboxamide; 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(2,2-difluorocyclopropanecarbonyl)-4fluoropyrrolidine-3- yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-4-fluoro-1-(oxane-4-carbonyl)n-irrolidine - 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R,4S)-1-(3,3-difluorocyclobutanecarbonyl)-4fluoropyrrolidine-3- yl]-2-methoxypyridine-3-carboxamide; 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)-2-methoxypyridine-3-carboxamide; 5-{4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(3-hydroxy-3-phenylpropyl)-2-methoxypyridine-3carboxamide; 5-{4-aminopyrrolo[2,1H[1,2,4]triazin-7-yl}-2-methoxy-N-(3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenyl)-3-oxopropyl]2 -methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-[3-(4-chlorophenyl)-3-oxopropyl]2-methoxypyridin- 3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[3 -(4-chlorophenyl)-3hydroxypentyl] -2- methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-M-[3-(4-chlorophenyl)-3-hydroxy-4methylpentyl]-2 -methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[3 -(4-chlorophenyl)-3hydroxybutyl] -2- methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-tert-butyl-1H-pyrazol-4-yl )2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-{2[methyl(phenyl)amino]ethyl }pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-(4,4,4-trifluoro-3hydroxy -3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-(4,4,4-trifluoro-3hydroxy -3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3hydroxypropyl ]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-5-oxopyrrolidin-3yl)-2 -methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-2-oxopyrrolidin-3 yl)-2 -methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[3 -(3,4-difluorophenyl)-3hydroxypropyl] - 2-methoxypyridine-3-carboxamide; - 543 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[3 -(3,4-difluorophenyl)-3hydroxypropyl] - 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-2-methoxy-N-[(2-phenyloxan-3yl)methyl]pyridin-3 -carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-2-methoxy-N-[(2-phenyloxan-3yl)methyl]pyridin-3 -carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-N1,2,4]triazin-7-yl]-2-methoxy-N-[(2-phenyloxan-3yl)methyl]pyridin-3 -carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenyl)-3hydroxypropyl] -2- methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3 S)-1-benzoylpyrrolidin-3yl]-2 -methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-1-benzylpyrrolidin-3-yl]2 -methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S)-1-benzylpyrrolidin-3-yl] 2 -methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-{[(1S,2S)-2-[3,5bis (trifluoromethyl)phenyl]cyclopropyl]methyl}-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-hydroxy-3-phenylpropyl)-2methoxypyridin-3- carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(3-hydroxy-3-phenylpropyl)-2methoxypyridin-3- carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-H1,2,4]triazin-7-yl]-2-methoxy-M-[1-(2,2,2trifluoroethyl)-1 H -pyrazol-4-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[1 -(cyclopropylmethyl)-1Hpyrazol-4-yl] - 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenoxy)propyl]-2methoxypyridin-3 -carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(tert-butoxy)propyl]-2methoxypyridin-3 -carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[3-(2methylpropoxy)propyl]pyridine- 3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4-yl) -2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-(3phenylbutyl)pyridine-3-carboxamide; 5-{4-amino-5-[(2-acetamidoethyl)carbamoyl]pyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4chlorophenyl )-3-hydroxypropyl]-2-methoxypyridine-3-carboxamide; 5-(4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-((3R,4S)-1-(3,3difluorocyclobutan- 1-carbonyl)-4-fluoropyrrolidin-3-yl)-4-fluoro-2-methylbenzamide; 5-{4-amino-5-fluoronurrolo[2,1-f][1,2,4]triazin-7-ul}-N-[(3R,4S)-1-(3,3difluorocyclobutanecarbonyl)-4- fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzyl-1 H-pyrazol-4-yl) -2 methoxybenzamide; 5-(4-amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)-2methoxynicotinamide; (S)-5-(4-amino-5-(aminomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3hydroxypropyl )-2-methoxynicotinamide; 5-(4-Amino-6-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(3-phenylbutyl)nicotinamide; 5-(4-amino-5-(aminomethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)- 2 methoxynicotinamide; (S)-N-(3-(4-chlorophenyl)-3-hydroxypropyl)-5-(4-((2-hydroxyethyl)amino)pyrrolo[2,1f] [1,2,4]triazine-7 - yl)-2-methoxynicotinamide; N-(1-benzyl-1H-pyrazol-4-yl)-5-(4-((2-hydroxyethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-7-yl) -2 methoxynicotinamide; N-(1-benzyl-1H-pyrazol-4-yl)-2-methoxy-5-(4-((2-methoxyethyl)amino)pyrrolo[2,1-f][1,2,4]triazine7- yl) nicotinamide; 5-(4-amino-5-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)- 2 methoxynicotinamide; (S)-5-(4-amino-5-(hydroxymethyl)pyrrolo[2,1-f][1,2,4]triazine-7-ul)-N-(3-(4-chlorophenyl)-3hydroxypropyl )-2-methoxynicotinamide; 5-(4-amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(1-benzyl-1H-pyrazol-4-yl)- 2 methoxynicotinamide; (S)-5-(4-amino-5-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N-(3-(4-chlorophenyl)-3hydroxypropyl )-2-methoxynicotinamide; 5-(4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-neopentyl-1Hpyrazol-4-yl ) nicotinamide; 5-(4-Amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl)-2-methoxy-N-(1-neopentyl-1H-pyrazol-4yl)nicotinamide ; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-(deutero)methoxy-6-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-(deutero)methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(3,3,3- trifluoro-2hydroxypropyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)-2methoxypyridin-3 -carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4R)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-4-fluoro-1-( 4fluorobenzoyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-{4-amino-5-methylpyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl] - 540 042342 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[1-(3,3difluorocyclobutanecarbonyl)-4-fluoropyrrolidine-3 -yl]-2-methoxypyridine-3-carboxamide (homochiral, trans); 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3R)-3-(4-chlorophenyl)-3-hydroxypropyl] 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ 1-(3,3difluorocyclopentanecarbonyl)-(3R,4S) 4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)-2methoxypyridin-3 -carboxamide; 5-{4-amino-5-chloropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-[(3S)-3-(4-chlorophenyl)-3-hydroxypropyl] 2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ 1-(3,3difluorocyclobutanecarbonyl)-(3S,4R) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ 1-(3,3difluorocyclobutanecarbonyl)-(3R,4S) -4-fluoropyrrolidin-3-yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-(methylamino)pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 methoxypropyl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R)-3-(4-chlorophenyl)-3methoxypropyl ]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[4-fluoro-1-(4fluorobenzoyl)pyrrolidin-3- yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3R,4S)-1-(4,4difluorocyclohexanecarbonyl) -4-fluoropyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(4,4difluorocyclohexanecarbonyl )-4-methylpyrrolidin-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-methylpyrrolidin-3-yl]-2-(trifluoromethyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-(3,3difluorocyclopentanecarbonyl) -4-(fluoromethyl)pyrrolidin-3-yl]-2-methylpyridin-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-cyclohexanecarbonyl4-methylpyrrolidin-3 -yl]-2-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-methoxy-6-methylpyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[(3S,4S)-1-cyclopentanecarbonyl4-methylpyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[3-(4-fluorophenyl)-3hydroxypropyl]pyridine-3 -carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-fluoropyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-cyclohexanecarbonyl-4methylpyrrolidin-3-yl)-2- methoxypyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-[ 1 -(3,3-dimethylbutanoyl)-4methylpyrrolidin-3 -yl]-2-methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)n-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-(1-benzoyl-4-methyln-irrolidin3-yl)-2- methoxypyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methyl-N-(4,4,4-trifluoro-3 hydroxy-3-phenylbutyl)pyridine-3-carboxamide; 5-[4-Amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-methoxy-N-[(3S)-1-(4methylbenzoyl )pyrrolidin-3-yl]pyridine-3-carboxamide; 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl] -N-[(3 S)-3-(4-chlorophenyl)- 3 hydroxypropyl]-2-methoxypyridine-3-carboxamide; tert-butyl(3S)-3-{5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2methoxypyridin-3-amido } pyrrolidine-1-carboxylate; 5-{4-Amino-5-cyanopyrrolo[2,1-f][1,2,4]triazin-7-yl}-M-(1-benzyl-III-pyrazol-4-yl)-2methoxypyridin-3 -carboxamide; 5-{4-Amino-5-fluoropyrrolo[2,1-f][1,2,4]triazin-7-yl}-N-(1-benzyl-1H-pyrazol-4-yl)-2methoxypyridin-3 -carboxamide; - 539 042342 5-[4-amino-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-N-( 1-benzyl-1 H-pyrazol-4-yl) -2fluorobenzamide; 5) tetrahydropyranyl optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl and phenyl. 5) -(CH ₂ ) _r -phenyl, -(CH ₂ ) _g -pyrrolidinyl, -(CH ₂ ) _r -piperidinyl, -(CH ₂ ) _r- azetidinyl, -(CH2)-azaspiroheptanyl, -(CH ₂ ) _r -benzimidazolyl, -(CH ₂ ) _r -azabicyclooctane, -(CH ₂ ) _r -azaspirooctane, -(CH ₂ ) _r- tetrazolyl, -(CH ₂ ) _r -tetrahydroquinolinyl, -(CH ₂ ) _r -pyrazolyl, -(CH ₂ ) _r -imidazolyl, or -(CH ₂ ) _r -triazolyl, any of which may be substituted with 0-3 halogen, C _1-3 alkyl or amino. 5. The compound according to claims 1 and 3, where R ⁷ represents ^R · 5) C _3-7 cycloalkyl, where cycloalkyl is substituted with 0-3 OH, (-OCH ₂ C(CH ₃ ) ₂ CH ₂ O-), phenyl, which is substituted with 0-3 F, Cl, Br; 5) C _0-2 (C _3-7 cycloalkyl) alkyl, cyclohexenyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, dioxanyl, pyridinonyl or tetrahydrothiophenyl dioxide, each of which is optionally substituted with 1-4 groups selected from halogen, hydroxy, C _{1 -3} alkyl and C _1-3 haloalkyl, C _1-3 alkoxy, hydroxyl-C _1-3 haloalkyl, C _3-6 cycloalkyl, C(O)OC _1-6 alkyl and amino; 5) ' or ' or ' or ' or ' or p16 n' ^{r R17} B is absent or is CO, C(O)O, C(O)NR ^12a , SO ₂ or CR ^12a R ^12b ; Z is CH ₂ or CF2; R ^8a and R ^8b are each independently selected from hydrogen, halogen, C _1-3 alkyl and C _1-3 haloalkyl; R ^8c is hydrogen or CH2-O-CH3 or CH ₂ -O-CH ₂ -phenyl; R ⁹ is 5) *N' R ^5c ' or o, Λ Λ o _h b ^N /X> ) * or * NH ^; or 6. The compound according to claims 1 and 3, where R ⁵ represents 6) C _1-3 (C _1-4 alkoxy)alkyl; R ^{1 9} is -CH ₂ -phenyl or -C(O)-NR ^19a R ^19b ; R ^19a is hydrogen or C _1-3 alkyl; R ^19b is hydrogen, C _1-6 alkyl, C _3-6 cycloalkyl-C _0-3 alkyl-, phenyl-C _0-3 alkyl-, each independently substituted with 0-3 halogen, halo-C _1-3 alkoxy ; R ²⁰ is H, -CH ₂ -phenyl, -CH(OH)-phenyl, -C(CH ₃ )(OH)-phenyl, where each of the phenyls is independently substituted with 0-1 F; R ^{2 0a} is independently methyl or OH; R ^{2 1} is phenyl, CO-C _3-6 cycloalkyl, any of which is substituted with 0-4 F; R ²² is C _0-1 phenylalkyl, where phenyl is optionally substituted with 1-3 groups selected from halo, C _1-3 alkyl, C _1-3 haloalkyl, C _1-3 alkoxy; BUT. _p / ^OH 1 1 ά . and either R ¹ or R ¹⁸ are ' a is a single or double bond; and b is a single or double bond; with the proviso that when a is a single bond then b is a double bond and R ¹⁸ is absent, and when a is a double bond then b is a single bond and R ¹ is absent; n is 0, 1, or 2; m is 1 or 2; and r is 1. 6) tetrahydropyranyl optionally substituted with 1-4 groups selected from halogen, hydroxy, C _1-3 alkyl and phenyl; 6) 6) -(CH ₂ ) _r -phenyl, -(CH ₂ ) _r - 4- to 10-membered heterocycle or -(CH ₂ ) _r - 4- to 10-membered heteroaryl, where said heterocycle and heteroaryl contain 1 , 2, 3 or 4 heteroatoms selected from N, O and S, and where any phenyl, heterocycle or heteroaryl may be substituted with 0-3 halogen, =O, C ₁ _ ₃ alkyl or amino; or R ^5a independently represents hydrogen, halogen, C ₁ _ ₃ haloalkyl; R ^5c is independently selected from hydrogen, C ₁ _ ₃ alkyl, C ₁ _ ₃ cyanoalkyl-, C ₁ _ ₃ hydroxyalkyl, and C ₁ _ ₃ (C ₁ _ ₃ alkyl-CO) alkyl; R ⁶ is hydrogen; R ⁷ is - 536 042342 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-2,4-dimethylphenyl}-5(trifluoromethyl)pyrrolo[2,1-f][1,2 ,4]triazine-4-amine; 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-2,6-dimethylpyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-2,6-dimethylpyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f] [1,2,4]triazine-4-amine; 7-[5-(2-benzylmorpholine-4-carbonyl)-2,6-dimethylpyridin-3-yl]-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-5-{2-oxa-6azaspiro[3.3]heptan-6 -carbonyl}pyrrolo[2,1-f][1,2,4]triazine-4-amine; 7-[5-(2-benzylmorpholine-4-carbonyl)pyridin-3-yl]-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine; 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine; 7-[3-(2-benzylmorpholine-4-carbonyl)-4-fluorophenyl]-5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine4-amine; 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-(trifluoromethyl)pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f ][1,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-(trifluoromethyl)pyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f ][1,2,4]triazine-4-amine; 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methylpyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(3-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methylpyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methylpyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-[5-(3-benzyl-1,3-diazinan-1-carbonyl)-6-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrrolo[2,1 - f] [ 1,2,4]triazine-4-amine; 7-[5-(2-benzylmorpholine-4-carbonyl)-6-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrrolo[2,1- f] [ 1,2,4]triazine-4-amine; 7-[5-(3-benzyl-4,4-difluoropiperidin-1-carbonyl)-6-methoxypyridin-3-yl]-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazine -4-amine; 7-{5-[(3S)-3-[(3-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-(5-{3-[(4-chlorophenyl)methyl]piperidine-1-carbonyl}-6-methoxypyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4 ]triazine-4-amine; 7-(6-methoxy-5-{3-[(4-methoxyphenyl)methyl]piperidine-1-carbonyl}pyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine; 7-(6-methoxy-5-{3-[(4-methylphenyl)methyl]piperidine-1-carbonyl}pyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1-f][1,2, 4]triazine-4-amine; 7-(5-{3-[(3-fluorophenyl)methyl]piperidine-1-carbonyl}-6-methoxypyridin-3-yl)-5(trifluoromethyl)pyrrolo[2,1-f][1,2,4 ]triazine-4-amine; 7-[5-(3-benzylpyrrolidin-1-carbonyl)-6-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrrolo[2,1f][1,2,4]triazine-4-amine; 7-{5-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-{5-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]-6-methoxypyridin-3-yl}-5(trifluoromethyl)pyrrolo[2,1-f][1 ,2,4]triazine-4-amine; 7-{3-[(3S)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]phenyl}-5-(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-4 -amine; 7-{3-[(3R)-3-[(4-fluorophenyl)methyl]piperidine-1-carbonyl]phenyl}-5-(trifluoromethyl)pyrrolo[2,1f] [ 1,2,4]triazine-4 -amine; (7-(5-(((3R,4S)-1-(3,3-difluorocyclobutan-1-carbonyl)-4-fluoropyrrolidin-3-yl)carbamoyl)-6methoxypyridin-3-yl)-4-imino- 5-(trifluoromethyl)pyrrolo[2,1-f][1,2,4]triazin-3(4H)yl)methyl dihydrogen phosphate; 7. The compound according to claim 1, 3 or 6 or its salt, where R1 is H; R ² is H, F, CH ₃ or OCH ₃ ; R ³ is H or F; And R ⁴ is H. 7) C _1-4 alkylamino, C _1-4 dialkylamino; R ^10a and R ^10b are independently selected from hydrogen, halogen, hydroxy, amino; R ^11a and R ^11b are independently selected from hydrogen and C _1-6 alkyl; R ^12a and R ^12b are independently selected from hydrogen, deuterium, methyl; R ¹⁴ is C _1-3 (phenyl)alkyl-; - 537 042342 R ¹⁵ is Aralkyl, C _1-3 haloalkyl, hydroxy-C _1-6 haloalkyl, C _1-3 (C _3-6 cycloalkyl) alkyl, phenyl-C _1-3 alkyl, phenyl-C _1-3 haloalkyl-, where phenyl is optionally substituted with 1-3 groups selected from halogen, C _1-3 haloalkyl, halo-C _1-3 alkoxy; R ^15a is hydrogen, halogen or C _1-3 alkyl; R ¹⁶ is hydrogen; R ¹⁷ is 7) 8. A compound according to claim 1, 3, 6 or 7 or a salt thereof, where R ⁷ is 9. The compound according to claims 1-4 or its salt, where R ^8a is halogen; R ^8b is hydrogen; B is absent or is CO, C(O)O, C(O)NR ^12a , SO2 or CR ^12a R ^12b ; ^R9 is: 10. The compound according to claim 9 or its salt, where B is CO, C(O)O or SO2; And R ⁹ is 11. The compound according to claim 1 or its salt, where the compound is: 12. A compound or salt thereof, wherein the compound is 5-(4-amino-5-{[3(τpiφτopmethyl)pyrpolidin-l-yl]methyl}pyrpolo[2,l-f|[l,2,4]τpyazin-7 -yl)-N-[(3R,4S)-4-φτop-l-[(2R)3,3,3-trifluoro-2-hydroxy-2-methylpropanoyl]pyrrolidin-3 -yl]-2-methoxypyridin- 3-carboxamide. 13. A compound or salt thereof, wherein the compound is 5-(4-amino-5(τpiφτopmethyl)pyrpolo[2,l-f|[l,2,4]τpiazin-7-yl)-N-((ЗR,4S) -4-φτop-l-(2-methyl-2-(4-(τpiφtormethyl)- 14. A pharmaceutical composition containing a compound according to claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 15. A method of inhibiting RIPK1 casein kinase activity in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of one or more of the compounds of claims 1-13.