EA045798B1 - SUBSTITUTED COMPOUNDS OF 6-AZABENZIMIDAZOLE - Google Patents

Description

This application claims benefit to U.S. Provisional Application No. 62/753339, filed October 31, 2018, and U.S. Provisional Application No. 62/868550, filed June 28, 2019, each of which is incorporated herein in its entirety for all purposes.

Technical field

The present invention generally relates to certain 6-azabenzimidazole compounds, pharmaceutical compositions containing said compounds, and methods for making and using said compounds and pharmaceutical compositions.

State of the art

Immuno-oncology is a rapidly developing area of cancer research, with a particular focus on inhibitory antibodies against the immune checkpoint receptors CTLA4, PD-1 and PD-L1. Targeted disruption of these control pathways frees the immune cell from key regulatory pathways, thereby enhancing the immune response against cancer cells. Current therapies using these antibodies have significant or durable responses across many different cancers, but have low overall response rates (<25%). Understanding and improving response rates is a monumental challenge, and combining checkpoint blockade with other immune activating agents or cell therapies may provide the impetus for expanding responses in patients.

Hematopoietic precursor kinase 1 (HPK1), an STE20 ser/thr kinase from the germinal center kinase family, regulates the function of various immune populations, including T cells, B cells and dendritic cells (Hu et al., Gens Dev, 1996; Alzabin et al. ., J Immunol 2009). In T cells, HPK1 serves as a negative regulator of T cell receptor (TCR) signaling (Liou et al., Immunity 2000; Sauer et al., JBC 2001) by phosphorylating SLP76 at serine 376, which induces the association of SLP76 with 14 -3- 3 proteins and leads to dissociation of the signaling complex (Di Bartolo et al., JEM 2007). In addition, the role of HPK1 as a negative regulator of TCR signaling is supported by the fact that HPK1-deficient mouse T cells or HPK1 kinase-inactive T-1114633.1 mutant cells have increased ERK 1/2 activation and secretion of effector cytokines upon TCR activation by compared to their wild-type counterparts (Shui et al., Nat Immunol 2007; Hernandez et al., Cell Reports 2018). Accordingly, a small molecule inhibitor of HPK1 may provide a new way to enhance antitumor immunity, as well as provide a way to increase the response to checkpoint receptor blockade.

Brief description of the invention

In one aspect, the present invention provides a compound having formula I:

R ^9d

Formula I or a pharmaceutically acceptable salt thereof, wherein:

one of R ¹ and R ² is H, -CN, -OH, halogen or C1-6 alkyl, and the other of R ¹ and R ² is H, halogen or C1-6 alkyl, where each C _1-6 alkyl optionally substituted with 1-3 groups independently selected from -OH and halogen, or

R ¹ and R ² together with the carbon atom to which they are attached form a C3-7 monocyclic cycloalkyl or 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where each of the specified C3 -7 monocyclic cycloalkyl and said 4-6 membered monocyclic heterocyclyl are optionally substituted with one R ¹¹ group and each is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and _C1-3 alkoxy, or

R ¹ and R ² together form =O;

R ¹¹ represents

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ C _1-6 alkyl,

- 1 045798 iii) -S(O) ₂ C ₃ - ₇ monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C ₃ - ₇ monocyclic cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) H, ii) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1_ ₃ alkyl and C1_ ₃ alkoxy, wherein said C1_ ₃ alkyl is optionally substituted with 1 -3 groups independently selected from -OH, halogen and C1_ ₃ alkoxy, iii) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, _C1-3 alkyl and _{C1_3} alkoxy, iv) 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N , O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _{C1_3} alkyl and _{C1_3} alkoxy,

v) -NH2, vi) -NH(C1_ ₆ alkyl), wherein said C1- ₆ alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1_ ₃ alkoxy, vii) -N(C _{1 -6} alkyl) ₂ wherein each _C1-6 alkyl may be the same or different and where each _C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy, viii ) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C 3-7 monocyclic cycloalkyl, or ix) C _1-6 alkyl, optionally substituted with 1-3 groups, independently selected from

a) -CN,

b) -OH,

c) halogen,

d) C1_ ₃ alkoxy,

e) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1- ₃ alkyl and Cm alkoxy,

f) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, and

g) -OC(O)C1- ₆ alkyl, optionally substituted with one -OH;

R ³ and R ¹³ are each H, R ³ and R ¹³ together form =O;

L ¹ is cyclobutene, optionally substituted with 1-6 groups independently selected from -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy, X is -NR15R ¹⁶ , where R ¹⁵ and R ¹⁶ are independently

i) H, ii) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1- ₃ alkyl and Cm alkoxy, iii) 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms , independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iv) - C(O) _C1-6 alkyl, wherein said _C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy, or

v) Ci- ₆ alkyl, optionally substituted with 1-6 groups independently selected from

a) -CN,

b) -OH,

c) halogen,

d) C1- ₃ alkoxy,

e) C ₃ - ₇ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C 1 _{- 3} alkyl and C 1 - ₃ alkoxy, and

f) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C1- ₃ alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ; each R ¹⁸ independently represents

- 2 045798

i) -CN, ii) halogen, iii) -OH, iv) _C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkoxy and C3-7 monocyclic cycloalkyl,

v) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _{3_7 monocyclic} cycloalkyl, vi) -COOH, or vii) -C(O)N (R ²² )2, where each R ²² independently represents H or C1-6 alkyl;

X ¹ represents N or CR ¹⁷ ;

R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹⁷ are each independently H, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R ⁷ represents

i) H, ii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or iii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and _C1-3 alkoxy;

Z represents -O-, -C(R ⁸ ) ₂ - or -NR ⁸ -;

each R ⁸ independently represents H or C1-3 alkyl;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) _C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C3-7 monocyclic cycloalkyl, iv) -NH2,

v) -NH( _C1-6 alkyl), wherein said _C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy, vi) -N( _C1-6 alkyl) ₂ , wherein each C _1-6 alkyl may be the same or different and wherein each C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy, vii) -P(O)(C _{1 -6} alkyl) ₂ wherein each C _1-6 alkyl may be the same or different and where each C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy, viii) -S (O) ₂ C _1-6 alkyl, ix) -S(O) ₂ N(R ²³ )2, where each R ²³ independently represents H or C 1-6 alkyl,

x) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

and he,

b) halogen,

c) C1-3 alkoxy,

d) C3- ₇ monocyclic cycloalkyl,

e) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C _1-3 alkyl, and

f) -NR ²⁰ C(O)OC1-3 alkyl, where R ²⁰ represents H or C1-3 alkyl, xi) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, xii) 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, xiii) 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where the specified 4 The -6-membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, xiv) -COOH, xv) -C(O)N(R ¹⁹ )2, or xvi) -C1-3 alkylC(O)N(R ¹⁹ )2, where one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N( R ¹⁹ )2 or -C1-3 alkyl C(O)N(R ¹⁹ ) ₂ ; and each R ¹⁹ independently represents

i) H, ii) -S(O) ₂ C _1-6 alkyl, iii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from - CN, -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, iv) C3-7 monocyclic cycloalkyl, optionally substituted with 1-6 groups, independently

- 3 045798 branes of -CN, -OH, halogen, C1-6 alkyl and C1-6 alkoxy, wherein said _C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1. 3 alkoxy, or

v) a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, oxo, C1.3 alkyl and C1.3 alkoxy.

In one aspect of the present invention, pharmaceutical compositions are provided containing a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments of the present invention, these pharmaceutical compositions contain a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In some embodiments of the present invention, the pharmaceutical compositions described herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salt. In some embodiments of the present invention, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or a pharmaceutically acceptable salt thereof .

In one aspect, the present invention provides methods of inhibiting HPK1 activity in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa , IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or XIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect of the present invention, methods are described for treating a disease or disorder associated with increased HPK1 activity in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in this document.

In one aspect of the present invention, methods are provided for increasing T cell activation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV , IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, the present invention provides methods for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, the present invention provides methods of inhibiting the growth or proliferation of cancer cells in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

Detailed Description of the Invention

I. Definitions.

It should be understood that the following description is to be considered as an example of the claimed subject matter and not as limiting the appended claims to the specific embodiments illustrated. The headings used herein are for convenience only and should not be construed as limiting the claims in any way. Embodiments illustrated after any heading may be combined with embodiments illustrated after any other heading.

Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one skilled in the art. It should be noted that in the specification and in the accompanying claims, a singular noun also refers to a plural noun unless the context clearly indicates otherwise. Thus, for example, a reference to a compound includes a plurality of such compounds and a reference to an assay includes a reference to one or more assays and their equivalents known to those skilled in the art, and so on.

As used herein, the following words, phrases and symbols generally have the meanings set forth below unless the context in which they are used indicates otherwise.

- 4 045798

A dash (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH2 is attached via a carbon atom. The dash before or at the end of a chemical group is provided for convenience; chemical groups may be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in the structure indicates the point of attachment of the group. Unless required chemically or structurally, the order in which a chemical group is written or named does not indicate or imply a specific focus. A solid line extending from the center of the ring indicates that the site of attachment of the substituent in the ring can be at any ring atom. For example, R ^a in the structure below can be attached to any of the five carbon atoms in the ring, or R ^a can replace the hydrogen attached to the nitrogen atom in the ring:

The prefix C _uv indicates that the following group contains from and to v carbon atoms. For example, _C1-6alkyl means that the alkyl group contains from 1 to 6 carbon atoms. Likewise, the term xy-membered rings, where x and y are numerical ranges such as 3-12 membered heterocyclyl, refers to a ring containing xy-atoms (e.g. 3-12), of which up to 80% may be heteroatoms , such as N, O, S, P, and the remaining atoms are carbon.

In addition, some commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent alkyl group, a divalent aryl group, etc. may also be referred to as an alkylene group or an alkylenyl group, or an alkyl group, an arylene group or an arylenyl group, or an aryl group, respectively.

The compound described herein, or the compound according to the present invention, or the compound presented herein, or the compound described herein refers to compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc. The specific compounds of Examples 1 to 297 are also included.

Reference to an exemplary value or parameter herein includes (and describes) implementations that address the specified value or parameter as such. In some embodiments, the term approximately includes the indicated amount ±10%. In other embodiments, the term approximately includes the indicated amount ±5%. In some other embodiments, the term approximately includes the indicated amount ±1%. In addition, the term about X includes a description of X.

Alkyl refers to a straight or branched saturated hydrocarbon chain. As used herein, alkyl contains 1 to 20 carbon atoms (i.e., _{C1_20} alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1_ ₆ alkyl) or 1 to 4 carbon atoms (i.e. C1_ ₄ alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl moiety containing a certain number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be included; thus, for example, butyl includes n-butyl (i.e. -(CH ₂ ) ₃ CH ₃ ), sec-butyl (i.e. -CH(CH ₃ )CH ₂ CH ₃ ), isobutyl (i.e. -CH ₂ CH(CH ₃ ) ₂ ) and tert-butyl (i.e. -C(CH ₃ ) ₃ ); and propyl includes n-propyl (ie -(CH ₂ ) ₂ CH ₃ ) and isopropyl (ie -CH(CH ₃ ) ₂ ).

Alkenyl refers to an aliphatic group containing at least one carbon-carbon double bond and containing from 2 to 20 carbon atoms (i.e. C ₂ - ₂₀ alkenyl), from 2 to 8 carbon atoms (i.e. C ₂ - ₈ alkenyl ), from 2 to ₆ carbon atoms (i.e. C _{2_6} alkenyl) or from 2 _to 4 carbon atoms (i.e. C _{2_4} alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2butadienyl and 1,3-butadienyl).

_{Alkynyl refers to an aliphatic group containing at least one carbon-carbon triple bond and containing 2 to 20 carbon atoms (i.e. C2_20 alkynyl} ), 2 to ₈ carbon atoms (i.e. _{C2_8} alkynyl ), from 2 to 6 carbon atoms (i.e. C ₂ - ₆ alkynyl) or from 2 to 4 carbon atoms (i.e. C ₂ - ₄ alkynyl). The term alkynyl also includes groups that have one triple bond and one double bond.

Alkoxy belongs to the alkyl-O- group. Examples of alkoxy groups include methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2dimethylbutoxy. Haloalkoxy refers to an alkoxy group, as defined above, where one or more hydrogen atoms are replaced by a halogen.

Acyl refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl,

- 5 045798 cyclohexylmethylcarbonyl and benzoyl.

Amido belongs to both the C-amido group, which belongs to the -C(=O)NR ^y R ^z group, and the group

N-amido, which belongs to the group -NR ^y C(=O)R ^z , where R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl or heterocyclyl; each of which may optionally be substituted.

Amino refers to the group -NR ^y R ^z , where R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; each of which may optionally be substituted.

Aryl refers to an aromatic carbocyclic group containing a single ring (eg, monocyclic) or multiple rings (eg, bicyclic or tricyclic), including fused systems. As used herein, aryl contains from 6 to 20 ring carbon atoms (i.e., _C6-20 aryl), from 6 to ₁₂ ring carbon atoms (i.e., _C6-12 aryl), or from 6 to 10 carbon atoms in the ring (ie C _6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl, as defined below. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

Cyano or carbonitrile belongs to the -CN group.

Cycloalkyl refers to a saturated or partially saturated cyclic alkyl group containing a single ring or multiple rings, including fused, bridged and spiro ring systems. The term cycloalkyl includes cycloalkenyl groups (ie, a cyclic group having at least one double bond). As used herein, cycloalkyl contains 3 to 20 ring carbon atoms (i.e., C _3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C _3-12 cycloalkyl), 3 to 10 ring carbon atoms carbon in the ring (i.e. C _3-10 cycloalkyl), 3 to 8 carbon atoms in the ring (i.e. C _3-8 cycloalkyl), or 3 to 6 carbon atoms in the ring (i.e. C _3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Bridging refers to a ring fusion in which non-adjacent atoms in the ring are joined by a divalent substituent such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

The term fused refers to a ring that is connected to an adjacent ring.

Spiro refers to a substituent on a ring that is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyldioxolane and 4-benzyl-4methylpiperidine, where cyclopentane and piperidine, respectively, are spiro substituents.

Halogen or halo includes fluorine, chlorine, bromine and iodine. Haloalkyl refers to a straight or branched alkyl group, as defined above, where one or more hydrogen atoms are replaced by halogen. For example, when a residue is substituted with more than one halogen, it can be named using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (di) or three (tri) halogen groups, which may, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl-(-CF ₃ ).

Heteroaryl refers to an aromatic group containing a single ring, multiple rings, or multiple fused rings with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains from 1 to 20 ring carbon atoms (i.e., C _1-20 heteroaryl), from 3 to 12 ring carbon atoms (i.e., C _3-12 heteroaryl), or from 3 to 8 carbon atoms in the ring (ie C _3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl and pyrazolyl. Heteroaryl does not span or overlap with aryl as defined above.

Heterocyclyl or heterocyclic ring or heterocycle refers to a non-aromatic cyclic alkyl group with one or more heteroatoms on the ring independently selected from nitrogen, oxygen and sulfur. As used herein, the term heterocyclyl or heterocyclic ring or heterocycle refers to rings that are saturated or partially saturated unless otherwise specified, for example, in some embodiments, heterocyclyl or heterocyclic ring or heterocycle refers to rings that are partially saturated where indicated. The term heterocyclyl or heterocyclic ring or heterocycle includes heterocycloalkenyl groups (ie, a heterocyclyl group having at least one double bond). The heterocyclyl may be a single ring or multiple rings, where the plurality of rings may be fused, bridged, or spiro-linked. As used herein, heterocyclyl contains 2 to 20 ring carbon atoms (i.e., C _2-20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C _2-12 heterocyclyl), 2 to 10 ring carbon atoms carbon in the ring (i.e. C _2-10 heterocyclyl), 2 to 8 carbon atoms in the ring (i.e. C _2-8 heterocyclyl), 3 to 12 carbon atoms in the ring (i.e. C ₃ _ ₁₂

- 6 045798 heterocyclyl), from 3 to 8 carbon atoms in the ring (ie C _3-8 heterocyclyl), or from 3 to 6 carbon atoms in the ring (ie C _3-6 heterocyclyl); contains from 1 to 5 heteroatoms in the ring, from 1 to 4 heteroatoms in the ring, from 1 to 3 heteroatoms in the ring, from 1 to 2 heteroatoms in the ring, or one heteroatom in the ring independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl and morpholinyl. As used herein, the term bridged heterocyclyl refers to a four- to ten-membered cyclic moiety linked to two non-adjacent heterocyclyl atoms with one or more (e.g., 1 or 2) four-to-ten-membered cyclic moieties containing at least one heteroatom, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur. As used herein, the term bridged heterocyclyl includes bicyclic and tricyclic ring systems. Also, as used herein, the term spiroheterocyclyl refers to a ring system in which a three- to ten-membered heterocyclyl contains one or more additional rings, wherein one or more additional rings is a three- to ten-membered cycloalkyl or a three-ten-membered heterocyclyl, wherein one atom of one or more additional rings is also an atom of a three- to ten-membered heterocyclyl. Examples of spiroheterocyclyl include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. As used herein, the terms heterocycle, heterocyclyl, and heterocyclic ring are used interchangeably. In some embodiments, the heterocyclyl is substituted with an oxo group.

Hydroxy or hydroxyl refers to the -OH group.

Oxo belongs to the group (=O) or (O).

Sulfonyl refers to the group -S(O) ₂ R ^c where R ^c is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

When the graphical representation of a group ends with a single-bonded nitrogen atom, the group is a -NH group unless otherwise noted. Likewise, unless otherwise stated, hydrogen atom(s) are intended and considered to be present where necessary, within the knowledge of one skilled in the art, to achieve full valency or ensure stability.

The terms optional or optional mean that the subsequently described event or circumstance may or may not occur, and that the description includes cases in which the specified event or circumstance has occurred and cases in which it has not. In addition, the term optionally substituted means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by another group other than hydrogen.

The term substituted means that any one or more hydrogen atoms on the designated atom or group are replaced by one or more substituents other than hydrogen, provided that the normal valency of the designated atom is not exceeded. One or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ether, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar undefined structures obtained by defining substituents with additional substituents added ad infinitum (e.g., a substituted aryl containing a substituted alkyl that is itself substituted by a substituted aryl group that is further substituted by a substituted heteroalkyl group, etc.) are not included herein. document. Unless otherwise stated, the maximum number of sequential substitutions in the compounds described herein is three. For example, successive substitutions of substituted aryl groups by two other substituted aryl groups are limited to ((substituted aryl)substituted aryl)substituted aryl. Likewise, the above definitions do not include unacceptable substitution variations (eg, methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen atoms on the ring). Such unacceptable substitution variations are well known to one skilled in the art. When used to modify a chemical group, the term substituted may describe other chemical groups as defined herein. For example, the term substituted aryl includes, but is not limited to, alkylaryl. Unless otherwise indicated, when a group is described as optionally substituted, any substituents on the group are themselves unsubstituted.

In some embodiments, the term substituted alkyl refers to an alkyl group containing one or more substituents, including hydroxyl, halogen, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In further embodiments, substituted cycloalkyl refers to a cycloalkyl group containing one or more substituents, including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halogen, oxo, and hydroxyl; substituted heterocyclyl refers to a heterocyclyl group containing one or more substituents, including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo and hydroxyl; substituted aryl refers to an aryl group containing one or

- 7,045,798 more substituents, including halogen, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano; substituted heteroaryl refers to a heteroaryl group containing one or more substituents including halogen, amino, alkyl, haloalkyl, heterocyclyl, heteroaryl, alkoxy and cyano, and substituted sulfonyl refers to a -S(O)2R group in which R is substituted by one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl. In other embodiments, one or more substituents may be further substituted with halogen, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halogen, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

In some embodiments, substituted cycloalkyl, substituted heterocyclyl, substituted aryl, and/or substituted heteroaryl includes a cycloalkyl, heterocyclyl, aryl, and/or heteroaryl that has a substituent on the ring atom through which said cycloalkyl, heterocyclyl, aryl, and/or heteroaryl is attached to the rest connection parts. For example, in the fragment below, cyclopropyl is replaced by a methyl group:

The compounds of the embodiments described herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, thereby allowing the formation of enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as ( R)- or (S)- or (D)- or (L)- in the case of amino acids. All of these possible isomers, as well as their racemic and optically pure forms, are intended to be included in the present specification. Optically active (+) and (-), (R)- and (S) or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or separated using traditional methods, for example, by chromatography and fractional crystallization. Traditional methods for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative), for example, by chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specifically stated otherwise, the compounds are intended to include E- and Z-geometric isomers. In addition, all tautomeric forms are intended to be included. When compounds are presented in their chiral form, the embodiment is intended to include, but is not limited to, the particular diastereomerically or enantiomerically enriched form. If chirality is not indicated but is present, it is understood that the embodiment is directed to a particular diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compounds. As used herein, the term scalemic mixture means a mixture of stereoisomers in a ratio other than 1:1.

As used herein, the term stereoisomer refers to a compound consisting of the same atoms linked by the same bonds, but having different three-dimensional structures that are not interchangeable. The present description covers various stereoisomers and mixtures thereof and includes enantiomers, which refer to two stereoisomers whose molecules are incompatible mirror images of each other.

Enantiomers are a pair of stereoisomers that cannot be superimposed on each other in a mirror image. A 1:1 mixture of a pair of enantiomers is a racemic mixture. A mixture of enantiomers in a ratio other than 1:1 is a scalemic mixture.

The term diastereoisomers refers to stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other.

A tautomer refers to a molecule made by transferring a proton to another atom of the same molecule. The present description includes tautomers of any compounds presented herein.

Some of the compounds of the present invention exist as tautomeric isomers. Tautomeric isomers are in equilibrium with each other. For example, amide-containing compounds can be in equilibrium with imido acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, those skilled in the art will understand that these include both amide and imido acid tautomers. Thus, amide-containing compounds are understood to include their imido-acid tautomers. Likewise, imido acid-containing compounds are meant to include their amide tautomers.

The solvate is formed by the interaction of a solvent and a compound. Also provided are solvates of salts of the compounds described herein. Hydrates of the compounds described herein are also provided.

Any formula or structure given herein is also intended to be

- 8 045798 values of unlabeled forms and isotopically labeled forms of compounds. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be included in the compounds herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ^2H (deuterium, D), ^3H (tritium), ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl and ¹²⁵ I. Various isotopically labeled compounds herein, for example compounds in which radioactive isotopes are included, such as ^2H , ^3H , ^13C and ^14C . Such isotopically labeled compounds may be useful in metabolic studies, reaction kinetics studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) , including tissue or substrate distribution assays, or during radioactive treatment of patients.

The present invention also includes compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc, in which 1 to n hydrogen atoms attached to the carbon atom are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc when administered to a mammal, especially a human. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized using methods well known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced by deuterium.

Deuterium-labeled or deuterium-substituted therapeutic compounds of the present invention may have improved drug metabolism and pharmacokinetics (DMPK) properties associated with absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits associated with greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, and/or improved therapeutic index. ^{The 18} F-labeled compound may be useful for PET or SPECT studies. The isotopically labeled compounds of the present disclosure and their prodrugs, in general, can be prepared by following the procedures described in the schemes or in the examples and preparations described below, by replacing a readily available isotopically labeled reagent with a non-isotopically labeled reagent. It should be understood that deuterium in this context is considered as a substituent in the compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc.

The concentration of such a heavier isotope, in particular deuterium, can be determined using an isotope enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is any stable isotope of that atom. Unless otherwise noted, when a position is specifically designated as H or hydrogen, the position is considered to contain hydrogen with the isotopic composition of a natural isotope. Accordingly, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to refer to deuterium.

In many cases, the compounds of the present disclosure are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or groups similar thereto.

The term pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines such as alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines , trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, mono-, di- and tri-cycloalkylamines or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid

- 9 045798 acid, p-toluenesulfonic acid, salicylic acid and the like.

As used herein, the term pharmaceutically acceptable carrier or pharmaceutically acceptable excipient includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorbent delay agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Any conventional vehicles or agents may be used in therapeutic compositions unless they are incompatible with the active ingredient. Additional active ingredients may also be included in the compositions.

Treatment or treat is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (eg, reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition); b) slowing or stopping the development of one or more clinical symptoms associated with a disease or condition (eg, stabilizing a disease or condition, preventing or slowing the worsening or progression of a disease or condition, and/or preventing or slowing the spread (eg, metastasis) of a disease or condition) ; and/or c) alleviation of the disease, that is, causing regression of clinical symptoms (for example, improving the state of the disease, providing partial or complete remission of the disease or condition, increasing the effect of another drug, delaying the progression of the disease, improving quality of life and/or prolonging survival) .

Prevention or prevent means any treatment of a disease or condition that prevents clinical symptoms of the disease or condition from developing. The compounds can, in some embodiments, be administered to a subject (including a human) who is at risk for or has a family history of a disease or condition.

Subject refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experiment. The methods described herein may be useful for human treatment and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

The term "therapeutically effective amount" or "effective amount" of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof means an amount sufficient to provide treatment when administered to a subject to provide a therapeutic effect, such as improving symptoms or slowing the progression of a disease. For example, a therapeutically effective amount may be an amount sufficient to reduce a symptom of a disease or condition responsive to inhibition of hematopoietic precursor kinase 1 (HPK1) activity. A therapeutically effective amount may vary depending on the subject and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the route of administration, and can be readily determined by one of ordinary skill in the art.

The term inhibition indicates a decrease in the baseline of a biological activity or process. Inhibition of HPK1 activity or variants thereof refers to a decrease in HPK1 activity as a direct or indirect response to the presence of a compound of the present invention relative to the activity of HPK1 in the absence of a compound of the present invention. Inhibition of HPK1 refers to a decrease in the activity of HPK1 as a direct or indirect response to the presence of a compound described herein relative to the activity of HPK1 in the absence of a compound described herein. In some embodiments, the inhibition of HPK1 activity can be compared with the same subject before treatment or with other subjects not receiving treatment.

II. Connections.

In one aspect, the present invention provides a compound having formula I:

Formula I

- 10 045798 or its pharmaceutically acceptable salt, where:

one of R ¹ and R ² is H, -CN, -OH, halogen or C1-6 alkyl, and the other of R ¹ and R ² is H, halogen or C1-6 alkyl, wherein each is C _1-6 alkyl optionally substituted with 1-3 groups independently selected from -OH and halogen, or

R ¹ and R ² together with the carbon atom to which they are attached form a C3-7 monocyclic cycloalkyl or 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where each of the specified C3 -7 monocyclic cycloalkyl and said 4-6 membered monocyclic heterocyclyl are optionally substituted with one R ¹¹ group and each is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and Ci-3 alkoxy, or R ¹ and R ² together form =O;

R ¹¹ represents

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ C ₁ - ₆ alkyl, iii) -S(O) ₂ C ₃ _ ₇ monocyclic cycloalkyl, iv) C _{1- 6} alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) H, ii) C ₃ - ₇ monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1 - 3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C ₁ _ ₃ alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, iii) 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, iv) 5-6 membered monocyclic heteroaryl, containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkyl and _{C1 -3} alkoxy,

v) -NH2, vi) -NH(C _1-6 alkyl), wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, vii) -N( _C1-6alkyl ) ₂ , wherein each _C1-6alkyl may be the same or different and wherein _{each C1-6alkyl} is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C ₁ . ₃ alkoxy, viii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C3-7 monocyclic cycloalkyl, or ix) C _1-6 alkyl, optionally substituted with 1 -3 groups independently selected from

a) -CN,

b) -OH,

c) halogen,

d) C _1-3 alkoxy,

e) C ₃ - ₇ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy,

f) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, and

g) -OC(O)C ₁ . ₆ alkyl, optionally substituted with one -OH;

R ³ and R ¹³ are each H, R ³ and R ¹³ together form =O;

L ¹ represents cyclobutene, optionally substituted with 1-6 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent yourself

i) H, ii) C _{3_7} monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected _from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl, containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _{1- 3} alkoxy, iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, or

v) C| _-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -CN,

- 11 045798

b) -OH,

c) halogen,

d) C ₁ . ₃ alkoxy,

e) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, and

f) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C1_ ₃ alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

each R ¹⁸ independently represents

i) -CN, ii) halogen, iii) -OH, iv) C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, _{C1_3} alkoxy and _C3-7 monocyclic cycloalkyl,

v) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, vi) -COOH, or vii) -C(O)N (R ²² ) ₂ wherein each R ²² independently represents H or C1-6 alkyl;

X ¹ represents N or CR ¹⁷ ;

R ⁴ , R ⁵ , R ⁶ , R ¹⁰ and R ¹⁷ are each independently H, halogen, C _1-3 alkyl or C _1-3 alkoxy;

R ⁷ represents

i) H, ii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _{1-3 alkoxy and C 3-7 monocyclic cycloalkyl, or iii) C 3-7 monocyclic cycloalkyl} , optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

Z represents -O-, -C(R ⁸ ) ₂ - or -NR ⁸ -;

each R ⁸ independently represents H or C _1-3 alkyl;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C3-7 monocyclic cycloalkyl, iv) -NH2,

v) -NH(C _1-6 alkyl), wherein said C 1-6 alkyl is optionally substituted with 1-3 _groups independently selected from -OH, halogen and C _1-3 alkoxy, vi) -N(C _1-6 alkyl) ₂ , wherein each _C1-6 alkyl may be the same or different and wherein each _C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and _C1-3 alkoxy, vii) -P(O) (C _1-6 alkyl) ₂ wherein each C 1-6 alkyl may be the same or different and where _each C 1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, viii) -S(O) ₂ C ₁ - ₆ alkyl, ix) -S(O) ₂ N(R ²³ ) ₂ , where each R ²³ independently represents H or C1-6 alkyl,

x) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from

and he,

b) halogen,

c) C _1-3 alkoxy,

d) C _3-7 monocyclic cycloalkyl,

e) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C1-3 alkyl , And

f) -NR ²⁰ C(O)OC1-3 alkyl, where R ²⁰ represents H or C1-3 alkyl, xi) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, xii) 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, xiii) 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms, independently selected

- 12 045798 branes of N, O and S, where said 4-6 membered monocyclic heterocyclyl is optionally substituted

1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, xiv) -COOH, xv) -C(O)N(R ¹⁹ )2, or xvi) - C _1-3 alkylC(O)N(R ¹⁹ ) ₂ , where one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ )2 or -C1 .3 αlkylC(O)N(R ¹⁹ )2; and each R ¹⁹ independently represents

i) H, ii) -S(O) ₂ C _1-6 alkyl, iii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from - CN, -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, iv) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy, wherein said C _{1 -6} alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy, or

v) a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments of the present invention, said compound of formula I is a compound of formula II,

R ¹⁰ N _R 9a _R 9d

Formula II, or a pharmaceutically acceptable salt thereof, wherein each R ¹² independently represents -OH, halogen, C _1-3 alkyl or C _1-3 alkoxy; and n is 0, 1, 2, 3 or 4;

and the remaining variables have the same values as defined for Formula I.

In some embodiments of the present invention, said compound of formula I or II is a compound of formula IIa,

Formula (Pa) or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

In some embodiments of the present invention, said compound of Formula I, II, or IIa is a compound of Formula IIb:

- 13 045798

Formula (lib) or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

In some embodiments of the compound of formula I or pharmaceutically acceptable salts thereof, L ¹ is cyclobutene, optionally substituted with 1, 2, 3, 4, 5, or 6 groups independently selected from -OH, halogen, C1-3 alkyl, and C1-3 alkoxy . In some embodiments of the compounds of Formula I or pharmaceutically acceptable salts thereof, L ¹ is cyclobutylene. In some embodiments of the compounds of formula I or pharmaceutically acceptable salts thereof, L ¹ is cyclobutylene substituted with one C1-3 alkyl group. In some embodiments of the compounds of formula I or pharmaceutically acceptable salts thereof, L ¹ is cyclobutylene substituted with one methyl group.

In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹² is OH. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹² is halogen. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹² is C1-3 alkyl. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹² is C1-3 alkoxy. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹² is methyl.

In some embodiments of a compound of Formula II or IIa, or pharmaceutically acceptable salts thereof, n is 0, 1, 2, 3, or 4. In some embodiments of a compound of Formula II or IIa, or pharmaceutically acceptable salts thereof, n is 0, 1, 2, or 3. In some embodiments of a compound of formula II or IIa or pharmaceutically acceptable salts thereof, n is 0, 1, or 2. In some embodiments of a compound of formula II or IIa or pharmaceutically acceptable salts thereof, n is 0 or 1. In some embodiments of a compound of formula II or IIa or pharmaceutically acceptable salts thereof, n is 0 or 1. IIa or pharmaceutically acceptable salts thereof, n is 0. In some embodiments of a compound of Formula II or IIa or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of a compound of Formula II or IIa or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments compounds of formula II or IIa, or pharmaceutically acceptable salts thereof, n is 3. In some embodiments of compounds of formula II or IIa, or pharmaceutically acceptable salts thereof, n is 4.

In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, n is 1 and R ¹² is C1-3 alkyl. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, n is 1 and R ¹² is methyl. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, n is 1 and R ¹² is C1-3 alkyl. In some embodiments of a compound of Formula II, IIa, or IIb, or pharmaceutically acceptable salts thereof, n is 1 and R ¹² is methyl.

In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁴ is H. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁴ is halogen. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁴ is fluorine. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁴ is C1-3 alkyl. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁴ is C1-3 alkoxy.

In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁵ is H. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁵ is halogen. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁵ is C _1-3 alkyl. In some embodiments, compounds of formula I, II, IIa, or

- 14 045798

IIb or their pharmaceutically acceptable salts R ⁵ represents C _1-3 alkoxy.

In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁶ is H. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁶ is halogen. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁶ is C1-3 alkyl. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ⁶ is C1-3 alkoxy.

In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹⁰ is H. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹⁰ is halogen. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹⁰ is C1-3 alkyl. In some embodiments of a compound of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, R ¹⁰ is C1-3 alkoxy.

In some embodiments, compounds of Formula I, II, IIa, or IIb, or pharmaceutically acceptable salts thereof, ^R4 , ^R5 , ^R6 , and ^R10 are H.

In some embodiments of the present invention, said compound of formula I, II or IIa is a compound of formula III,

Formula III or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, or III is a compound of Formula IIIa:

Formula Sha or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

In some embodiments of the present invention, said compound of formula I, II or IIa is a compound of formula III,

Formula III

- 15 045798 or its pharmaceutically acceptable salt, where:

one of R ¹ and R ² is -OH, halogen or C1-3 alkyl, and the other of R ¹ and R ² is halogen or C1-3 alkyl, or

R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted one R ¹¹ group and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, or R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ C ₁ - ₃ alkyl, iii) -S(O) ₂ C ₃ - ₅ monocyclic cycloalkyl, iv) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and _{C3-7 monocyclic} cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) C ₃ - ₇ monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optional substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, ii) 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where the specified 4-6 -membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iii) _C1-6 alkoxy, optionally substituted with 1-3 groups , independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, or iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

c) halogen and

d) C _1-3 alkoxy, R ³ and R ¹³ are each H, R ³ and R ¹³ together form =O;

n is 0 or 1;

R ¹² represents C _1-3 alkyl;

X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent

i) H, ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl, containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _{1- 3} alkoxy, iv) -C(O)C ₁ - ₆ alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, or

v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

g)-oh,

h) halogen and

i) C _1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

each R ¹⁸ independently represents

i) halogen, ii) -OH or ii i) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C ₃ - ₇ monocyclic cycloalkyl;

X ¹ represents N or CH;

R ⁷ represents

i) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or ii) C _3-7 monocyclic cycloalkyl, optionally _substituted with 1- 3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

Z represents -O- or NH;

- 16 045798

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and _C3-7 monocyclic cycloalkyl,

v) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C 1-3 alkyl and C 1-3 alkoxy, or vi) -C(O)N(R ¹⁹ )2, where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2;

each R ¹⁹ independently represents

i) H, ii) _C1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy and _{C3-7 monocyclic} cycloalkyl, or iii) C3-7 monocyclic cycloalkyl , optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkyl and C1-3 alkoxy, wherein said C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH , halogen and C1-3 alkoxy.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, or III is a compound of Formula IIIa:

Formula Sha or a pharmaceutically acceptable salt thereof, wherein:

one of R ¹ and R2 is -OH, halogen or C1-3 alkyl, and the other of R ¹ and R2 is halogen or C1-3 alkyl, or

R ¹ and R 2 together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with one group R ¹¹ and is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy, or R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy, ii) -S(O) ₂ C1_ ₃ alkyl, iii) -S(O) ₂ C ₃ - ₅ monocyclic cycloalkyl, iv) C1- ₆ alkyl, optionally substituted 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy and _{C3-7 monocyclic} cycloalkyl, or

v) -C(O)R ²¹ ; R ²¹ is

i) C3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkyl and C1-3 alkoxy, wherein said C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy, ii) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optional substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C3-7 monocyclic cycloalkyl, or iv) _C1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

- 17 045798

c) halogen and

d) C1.3 alkoxy, R ³ and R ¹³ are each H, R ³ and R ¹³ together form =O;

R ¹² represents C _1-3 alkyl;

X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent

i) H, ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl, containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _{1- 3} alkoxy, iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1-3 alkoxy, or

v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -OH,

b)halogen and

c) C _1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

each R ¹⁸ independently represents

i) halogen, ii) -OH or iii) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkoxy and _C3-7 monocyclic cycloalkyl;

X ¹ represents N or CH;

R ⁷ represents

i) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1- 3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

Z represents -O- or NH;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C 1-3 alkyl and C 3-7 monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkoxy and _C3-7 monocyclic cycloalkyl,

v) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, or vi) -C(O)N(R ¹⁹ )2 where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2;

each R ¹⁹ independently represents

i) H, ii) _C1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or iii) C3-7 monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy, wherein said _C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments, compounds of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, R ³ and R ¹³ together form =O. In some embodiments of a compound of Formula I, II, IIa, IIb, or IIIa, or pharmaceutically acceptable salts thereof, R ³ and R ¹³ are each H.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, X ¹ is CR ¹⁷ .

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R ¹⁷ is H. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof R ¹⁷ represents halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, R ¹⁷ is C1-3 alkyl. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, R ¹⁷ is C1-3 alkoxy.

- 18 045798

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, X ¹ is CH. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, X ¹ is N.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, Z is -NR ⁸ -. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, Z is -C(R ⁸ )2-.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof, R ⁸ is H. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or a pharmaceutically acceptable salt thereof R ⁸ represents C1-3 alkyl.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, Z is -NH-. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, Z is -CH2-. In some embodiments of a compound of Formula I, II, IIa, IIb, III, or Ia or pharmaceutically acceptable salts thereof, Z is -O-.

In some embodiments, compounds of formula I, II, IIa, IIb, III, or IIIa, or pharmaceutically acceptable salts thereof, R ⁴ , R ⁵ , R ⁶ , R ¹⁰ , and R ¹⁷ are H. In some embodiments, compounds of formula I, II, IIa, IIb, III or IIIa or their pharmaceutically acceptable salts R ⁴ , R ⁵ , R ⁶ and R ¹⁰ represent H, X ¹ represents CH; and Z represents NH. In some embodiments, compounds of formula I, II, IIa, IIb, III or IIIa, or pharmaceutically acceptable salts thereof, R ⁴ , R ⁵ , R ⁶ and R ¹⁰ are H, X ¹ is N; and Z represents NH.

In some embodiments of the present invention, said compound of Formula I, II, IIa, or III is a compound of Formula IV:

_R 9d

Formula IV or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

In some embodiments of the present invention, said compound of Formula I, II, IIa, or III is a compound of Formula IV:

Formula IV or a pharmaceutically acceptable salt thereof, wherein:

one of R ¹ and R ² is -OH, halogen or C1-3 alkyl, and the other of R ¹ and R ² is halogen or C1-3 alkyl, or

R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted one R ¹¹ group and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, or R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted

- 19 045798

1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ Ci. ₃ alkyl, iii) -S(O) ₂ C _3- 4 monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optional substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, ii) 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where the specified 4-6 -membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iii) C1-6 alkoxy, optionally substituted with 1-3 groups, independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, or iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

c) halogen and

d) C _1-3 alkoxy,

X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent

i) H, ii) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, or

v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -OH,

b) halogen and

c) C _1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

each R ¹⁸ independently represents

i) halogen, ii) -OH or iii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl;

R ⁷ represents

i) _C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or ii) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups, independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl,

v) C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy, or vi) -C(O)N( ^R19 )2, where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2; each R ¹⁹ independently represents

i) H, ii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or iii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-6 groups, independently

- 20 045798 branes of -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments of the present invention, said compound of formula I, II,

IIa or III is a compound of formula IVa:

_R 9d formula IVa or a pharmaceutically acceptable salt thereof, wherein the variables have the same meaning as defined for formula I.

In some embodiments of the present invention, said compound of Formula I, II, IIa, or III is a compound of Formula IVa:

>2

formula IVa or a pharmaceutically acceptable salt thereof, wherein:

one of R ¹ and R ² is -OH, halogen or C1.3 alkyl, and the other of R ¹ and R ² is halogen or C _1-3 alkyl, or

R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted one R ¹¹ group and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, or R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ C _1-3 alkyl, iii) -S(O) ₂ C _3-4 monocyclic cycloalkyl, iv) C _{1- 6} alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and _C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said is C1. ₃ alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, ii) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein The 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iii) _C1-6 alkoxy, optionally substituted with 1 -3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, or iv) C _1-6 alkyl optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

- 21 045798

c) halogen and

d) C _1-3 alkoxy,

X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent

i) H, ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl, containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _{1- 3} alkoxy, iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, or

v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -OH,

b) halogen and

c) C _1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

each R ¹⁸ independently represents

i) halogen, ii) -OH or iii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl;

R ⁷ represents

i) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1- 3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl,

v) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, or vi) -C(O)N(R ¹⁹ )2 where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2;

each R ¹⁹ independently represents

i) H, ii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl, or iii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-3 alkyl and _C1-3 alkoxy, wherein said _C1-3 alkyl is optionally substituted with 1-3 groups independently selected from - CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments of the present invention, said compound of formula I, II, IIa, IIb, III or IIIa is a compound of formula IVb or IVc:

or a pharmaceutically acceptable salt thereof, wherein the variables have the same meanings as defined for Formula I.

- 22 045798

In some embodiments of the present invention, said compound of formula I, II,

IIa, IIb, III or IIIa is a compound of formula IVb or IVc:

or a pharmaceutically acceptable salt thereof, where:

one of R ¹ and R ² is -OH, halogen or C1-3 alkyl, and the other of R ¹ and R ² is halogen or C1-3 alkyl, or

R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted one R ¹¹ group and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, or R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, ii) -S(O) ₂ C _1-3 alkyl, iii) -S(O) ₂ C _3-4 monocyclic cycloalkyl, iv) C _{1- 6} alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and _C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ ;

R ²¹ is

i) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optional substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, ii) 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where the specified 4-6 -membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy, iii) _C1-6 alkoxy, optionally substituted with 1-3 groups , independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl, or iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

c) halogen and

d) C _1-3 alkoxy, R ¹² represents C _1-3 alkyl;

X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent

i) H, ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy, iii) 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy , iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy, or

v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -OH,

b) halogen and

c) C _1-3 alkoxy; or

X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ ;

- 23 045798 each R ¹⁸ independently represents

i) halogen _{, ii) -OH or iii) C 1_6 alkyl} , optionally substituted with 1-3 groups independently selected from -OH, halogen,

C _1-h alkoxy and C _{_ 7} monocyclic cycloalkyl;

R ⁷ represents

i) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C 1 _{- s} alkoxy and C _{3_7} monocyclic cycloalkyl, or ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1- 3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H, ii) halogen, iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _{3_7 monocyclic} cycloalkyl, iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-s alkoxy and C ₃ _ ₇ monocyclic cycloalkyl,

v) C ₃ _ ₇ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, or vi) -C(O)N(R ¹⁹ )2 where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2;

each R ¹⁹ independently represents

i) H, ii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C ₃ _ ₇ monocyclic cycloalkyl, or iii) C ₃ _ ₇ monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy, wherein said _C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-z alkoxy.

In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R 2 is H, -CN, -OH, halogen, or C1- 6 alkyl, and the other of R ¹ and R2 is H, halogen or C1-6 alkyl, wherein each C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen, or R ¹ and R2 together with carbon atom to which they are attached form a C3_7 monocyclic cycloalkyl or a 4-6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where each of the specified C3_7 monocyclic cycloalkyl and the specified 4-6-membered monocyclic heterocyclyl optionally substituted with one R ¹¹ group and each optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, Cl-3 alkyl and Cl _-3 alkoxy, or R ¹ and R ² together form =O.

In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH, halogen, or Cl-3 alkyl, and the other of R ¹ and R ² is halogen or C1-3 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with one R ¹¹ group and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy .

In some embodiments, compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹ and R ² together form =O.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is H, -CN, -OH, halogen, or C1 -6 alkyl, and the other of R ¹ and R ² is H, halogen or C1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is H and the other of R ² and R ² is is H, halogen or C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -CN and the other is R ² and R ² is H, halogen or C1-6 alkyl, wherein said _C1-6 alkyl is optionally substituted with 1 to 3 groups independently selected from -OH and halogen. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH and the other of R ² and R ² is H, halogen or C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is halogen and

- 24 045798 the other of R ² and R ² is H, halogen or C1-6 alkyl, wherein said C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is C1-6 alkyl and the other is R ¹ and R ² represents H, halogen or C1-6 alkyl, wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is C1-3 alkyl and the other is R ¹ and R ² represents H, halogen or C1-6 alkyl, wherein said C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is C1-3 alkyl and the other of R ¹ and R ² is H, halogen or C1-6 alkyl, wherein said C1-3 alkyl is optionally substituted with 1-3 OH groups. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is methyl, ethyl, or propyl, and the other is R ¹ and R ² represents H, halogen or C1-6 alkyl, wherein each of said methyl, ethyl or propyl is replaced by one OH group.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH, halogen, or C1-3 alkyl, and the other of R ¹ and R ² is halogen or C1-3 alkyl. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH and the other of R ¹ and R ² is halogen or C1-3 alkyl. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is halogen and the other of R ¹ and R ² is is a halogen or C1-3 alkyl. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is C1-3 alkyl and the other is R ¹ and R ² represents halogen or C1-3 alkyl.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH, fluorine, methyl, or ethyl, and the other of R ¹ and R ² is fluorine, methyl or ethyl. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH and the other of R ¹ and R ² is fluorine, methyl or ethyl. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is fluorine and the other of R ¹ and R ² is is fluorine, methyl or ethyl. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is methyl and the other of R ¹ and R ² is is fluorine, methyl or ethyl. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is ethyl and the other of R ¹ and R ² is is fluorine, methyl or ethyl.

In some embodiments, compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹ and R ² are both fluorine, methyl, or ethyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² are both fluorine. In some embodiments, compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹ and R ² are both methyl. In some embodiments, compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹ and R ² are both ethyl. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, one of R ¹ and R ² is -OH and the other of R ¹ and R ² represents methyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a C3-7 monocyclic cycloalkyl or 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein each of said C3-7 monocyclic cycloalkyl and said 4-6 membered monocyclic heterocyclyl is optionally substituted with one R ¹¹ group and each is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and _C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a C3-7 monocyclic cycloalkyl, optionally substituted with one R ¹¹ and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a C3-7 monocyclic

- 25 045798 cycloalkyl substituted with one Rn. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, ^R1 and ^R2 , together with the carbon atom to which they are attached, form a C3 cycloalkyl substituted one Rn. In some embodiments, compounds of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹ and R ² together with the carbon atom to which they are attached form a C ₃ cycloalkyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a 4-6- membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with one R ¹¹ group and optionally substituted with 1-3 groups independently selected from OH, halogen, oxo , C _1-3 alkyl and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a 4-6- a membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is substituted with one R ¹¹ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form an optionally substituted azetidinyl one R ¹¹ and optionally substituted with 1 or 2 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form azetidinyl substituted with one ^R11 .

In some embodiments of the present invention, said compound of formula I, II, IIa, III or IV is a compound of formula V:

formula V or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, III, IIIa, or IVb is a compound of Formula Va:

N

R ^9a _R 9d formula Va or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of formula I, II, IIa, III or IVa is a compound of formula Vb:

- 26 045798

formula Vb or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, III, IIIa, or IVc is a compound of Formula Vc:

formula Vc or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form an optionally substituted piperidinyl one R ¹¹ and optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form a piperidinyl substituted with one ^R11 .

In some embodiments of the present invention, said compound of formula I, II,

IIa, III or IV is a compound of formula VI:

formula VI or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of formula I, II, IIa, IIb, III, Ia, or IVb is a compound of formula VIa:

- 27 045798

formula Via or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of formula I, II, IIa, III or IVa is a compound of formula VIb:

formula VIb or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of formula I, II, IIa, IIb, III, IIIa, or IVc is a compound of formula VIc:

formula VIc or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form tetrahydropyranyl, optionally substituted 1-3 groups independently selected from -OH, halogen, oxo, _C1-3 alkyl and _C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof R ¹ and R ² together with the carbon atom to which they are attached form tetrahydropyranyl.

In some embodiments of the present invention, said compound of formula I, II, IIa, III or IV is a compound of formula VII:

- 28 045798 o

_R 9d formula VII or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, III, IIIa, or IVb is a compound of Formula VIIa:

O

_R 9d

Formula Vila or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of formula I, II, IIa, III or IVa is a compound of formula VIIb:

_R 9d

Formula VIIb or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments of the present invention, said compound of Formula I, II, IIa, IIb, III, IIIa, or IVc is a compound of Formula VIIc:

_R 9d

Formula Vile or a pharmaceutically acceptable salt thereof, wherein the variables have the meanings as defined herein.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

- 29 045798

Va, Vb, Vc, Via, VIb or VIc or pharmaceutically acceptable salts thereof R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted

1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and Ci. ₃ alkoxy, ii) -S(O) ₂ C ₁ - ₆ alkyl;

iii) -S(O) ₂ C ₃ - ₇ monocyclic cycloalkyl;

iv) _C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ .

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy;

ii) -8(0)201.3 alkyl;

iii) -S(O) ₂ C ₃ - ₅ monocyclic cycloalkyl;

iv) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ .

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ¹¹ is

i) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, _ii ) -S(O) ₂ C _1-3 alkyl;

iii) -S(O) ₂ C ₃ -4 monocyclic cycloalkyl;

iv) _C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkoxy and C3-7 monocyclic cycloalkyl, or

v) -C(O)R ²¹ .

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is 4- A 6-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1- 3 alkyl and C1-3 alkoxy. In some embodiments of a compound of Formula I, II, IIa, IIb, II, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is 4- a membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl and C _1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is oxetanyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy. In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is oxetanil.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is S( O)2C1-6 alkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is -S (O)2C ₁ - ₃ alkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is -S ₍ O) _2CH3 .

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is S( O)2C3-7 monocyclic cycloalkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is -S (O)2C ₃ -5 monocyclic cycloalkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is -S (O)2C3-4 monocyclic cycloalkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is 8( O)2(cyclopropyl). In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VI, or pharmaceutically acceptable salts thereof, R ¹¹ are 30 045798 is -S(O) ₂ CH ₃ or -S(O) ₂ (cyclopropyl).

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ¹¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl. In certain embodiments of a compound of Formula I, II, IIa, IIb, III, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ¹¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ¹¹ is ethyl, optionally substituted with 1-3 halogens. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ¹¹ is -CH2CHF2 .

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹¹ is -C(O)R ²¹ .

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is

i) H;

ii) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optional substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy, iii) 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, where the specified 4-6 -membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy;

iv) a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

v) -NH2;

vi) -NH(C _1-6 alkyl), wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy;

vii) -N(C _1-6 alkyl) ₂ , wherein each C _1-6 alkyl may be the same or different and where each C _{b 6} alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy;

viii) C _and alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C ₃ - ₇ monocyclic cycloalkyl; or ix) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -CN,

b) -OH,

c) halogen,

d) With _1-3 alkoxy,

e) C ₃ - ₇ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy,

f) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy, and

g) -OC(O)C _1-6 alkyl, optionally substituted with one -OH.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is

i) C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optional substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy;

ii) a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy;

iii) _C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and C3-7 monocyclic cycloalkyl; or iv) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy,

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C _3-7 monocyclic or bridged bicyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein indicated

- 31 045798

C ₁ . _{The 3} alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is cyclopropyl, cyclobutyl, cyclopentyl or bicyclic cycloalkyl bridged at C5, each of which is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1-3 alkyl and Q.3 alkoxy, wherein G.3 is specified alkyl is optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is cyclopropyl, cyclobutyl, cyclopentyl or bicyclic cycloalkyl bridged at C5, each of which is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, methyl and -OCH ₃ . In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is cyclopropyl, optionally substituted with one group selected from CN, -OH, fluorine, methyl, -CH2OH and -OCH3. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is cyclobutyl, optionally substituted with one group selected from fluorine, methyl and OCH3. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is cyclopentyl, optionally substituted with one -OH. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is a bicyclic cycloalkyl bridged at C6, optionally substituted by one group selected from -OH and fluorine. As used herein, bicyclic cycloalkyl bridged at _C5 includes, but is not limited to:

which coincides with

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is H. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof R ²¹ represents -NH2. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is -NH(C1-6 alkyl), wherein _{said C1-6 alkyl} is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is -N(C ₁ - ₆ alkyl) ₂ wherein each C ₁ - ₆ alkyl may be the same or different and where each C ₁ - ₆ alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1 -3 alkoxy.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is oxetanyl, tetrahydrofuranyl or tetrahydropyranyl, each of which is optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and _C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is oxetanyl, optionally substituted with one group selected from methyl, ethyl and isopropyl. In some embodiments, compounds of formula I, II, IIa, IIb IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb or VIc or pharmaceutically acceptable salts thereof, R ²¹ is oxetanyl, optionally substituted with one methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is tetrahydrofuranyl , optionally substituted with one methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹

- 32 045798 represents tetrahydropyranyl, optionally substituted with one methyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, where said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C _{1 -3} alkyl and C _1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is A 5-membered heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-membered heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, -OH, halogen, methyl and -OCH3. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl or triazolyl, each of which is optionally substituted with 1-3 groups independently selected from -OH, halogen, Ci alkyl and Ci alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is oxazolyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is Thiazolyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is isoxazolyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is oxadiazolyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is triazolyl , optionally substituted with one methyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1.3 alkyl and C3-7 monocyclic cycloalkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1.3 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C3-7 monocyclic cycloalkyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is -OCH3.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from: -CN; -HE; halogen; Si alkoxy; C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, C1.3 alkyl and C1.3 alkoxy; 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy; and -OC(O)C1-6 alkyl, optionally substituted with one -OH. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN; -HE; halogen; C1-3 alkoxy; and a 4-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen , oxo, C1.3 alkyl and C1.3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxetanyl and C1.3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, each of which is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen, oxetanyl and C1.3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is 33 045798 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, each of which is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C1.3 alkoxy.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl, optionally substituted with one group selected from -CN, -OH and oxetanyl. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl, optionally substituted with one group selected from -CN and -OH. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is ethyl, optionally substituted with one group selected from -OH, fluorine and -OCH3. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is n -propyl, optionally substituted with one -OH. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is isopropyl, optionally substituted with one group selected from -CN, -OH and -OCH3. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc or pharmaceutically acceptable salts thereof, R ²¹ is isobutyl , optionally substituted with one -OH. In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is tert-butyl, optionally substituted with one group selected from -OH, fluorine and -OCH3.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl, optionally substituted with one group selected from -CN, -OH and oxetanyl; ethyl optionally substituted with one group selected from -OH, fluorine and -OCH3; n-propyl, optionally substituted with one -OH; isopropyl, optionally substituted with one group selected from -CN, -OH and -OCH3; isobutyl, optionally substituted with one -OH; tert-butyl, optionally substituted by one group selected from -OH, fluorine and -OCH ₃ ; -OCH3; cyclopropyl, optionally substituted with one group selected from -CN, -OH, fluorine, methyl, -CH ₂ OH and -OCH3; cyclobutyl, optionally substituted with one group selected from fluorine, methyl and -OCH ₃ ; cyclopentyl, optionally substituted with one -OH; bicyclic cycloalkyl bridged at C ₆ , optionally substituted by one group selected from -OH and fluorine; oxetanyl, optionally substituted with one group selected from methyl, ethyl and isopropyl; tetrahydrofuranyl, optionally substituted with one methyl; tetrahydropyranyl, optionally substituted with one methyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl, optionally substituted with one methyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl optionally substituted with one group selected from -CN and -OH; ethyl, optionally substituted by one group selected from -OH, fluorine and -OCH ₃ ; n-propyl, optionally substituted with one OH; isopropyl, optionally substituted with one group selected from -CN, -OH and -OCH ₃ ; isobutyl, optionally substituted with one -OH; tert-butyl, optionally substituted by one group selected from -OH, fluorine and -OCH ₃ ; -OCH ₃ ; cyclopropyl, optionally substituted with one group selected from -CN, -OH, fluorine, methyl, -CH2OH and -OCH3; cyclobutyl, optionally substituted with one group selected from fluorine, methyl and -OCH3; cyclopentyl, optionally substituted with one -OH; bicyclic cycloalkyl bridged at C ₅ , optionally substituted by one group selected from -OH and fluorine; or oxetanyl, optionally substituted with one group selected from methyl, ethyl and isopropyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl; methyl substituted with one oxetanyl; -CH ₂ OH; -CH ₂ (CN); ethyl; -CH(CH ₃ )OH; -CH(CH ₃ )CH ₂ OH; -CH(CH ₃ )OSH ₃ ; -CH(OH)CH ₂ CH ₃ ; isopropyl; -C(CH ₃ ) ₂ OH; -C(CH ₃ ) ₂ OCH ₃ ; -C(CH ₃ ) ₂ CN; tert-butyl; -C(CH ₃ ) ₂ CH ₂ OH; -C(CH ₃ ) ₂ CH ₂ OCH ₃ ; -C(CH ₃ ) ₂ CH ₂ F; -CH(OH)CH(CH ₃ ) ₂ ; -OCH3; cyclopropyl; cyclopropyl substituted with one methyl; cyclopropyl substituted with one fluoro; cyclopropyl substituted with one -OCH ₃ ; cyclopropyl substituted with one -OH; cyclopropyl substituted with one -CN; cyclopropyl substituted with one -CH2OH; cyclobutyl; cyclobutyl substituted with one -OCH3; cyclobutyl substituted with one methyl; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one OH; bicyclic cycloalkyl bridged at C ₅ ; bicyclic cycloalkyl bridged at _C5 , substituted with one fluoro; bicyclic cycloalkyl bridged at _C5 , substituted with one -OH; oxetanil; oxetanyl substituted with one methyl; oxetanyl substituted with ethyl alone; oxetanyl substituted with one isopropyl; tetrahydrofuranyl; tetrahydrofuranyl substituted with one methyl; tetrahydropyranyl; tetrahydropyranyl substituted with one methyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

- 34 045798

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl; -CH ₂ OH; -CH2(CN); ethyl; -CH(CH3)OH; -CH(CHz)SCCHON; -CH(CH3)OCН3; -CH(OH)SCHCHSNz; isopropyl; -C(CH3)2OH; -C(CH3)2OCН3; -QCH^CN; tert-butyl; -SCHNZESCHON; -C(CH3CH2OCH ₃ ; -C(CH ₃ ) ₂ CH ₂ F; -CH(OH)CH(CH ₃ ) ₂ ; -OCH3; cyclopropyl; cyclopropyl substituted with one methyl; cyclopropyl substituted with one fluoro; cyclopropyl substituted with one -OSH ₃ ; cyclopropyl substituted with one -OH; cyclopropyl substituted with one -CN; cyclopropyl substituted with one -CH ₂ OH; cyclobutyl; cyclobutyl substituted with one methyl; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one -OH; bicyclic cycloalkyl bridged at C5; bicyclic cycloalkyl bridged at _C5 , substituted with one fluoro; bicyclic cycloalkyl bridged at _C5 , substituted with one -OH; oxetanyl; oxetanyl substituted with one methyl; oxetanyl substituted with one ethyl; or oxetanyl, substituted with one isopropyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl; methyl substituted with one oxetanyl; ethyl; -CH(CH3)OH; -CH(CH3)OCH3; -CH(OH)CH2CH3; isopropyl; -C(CH3)2OH; -C(CH3)2OCH3; -C(CH3)2CN; tert-butyl; -C(CH3)2CH2OH; -C(CH3)2CH2OCH3; -C(CH ₃ ) ₂ CH ₂ F; -CH(OH)CH(CH ₃ ) ₂ ; -OSN ₃ ; cyclopropyl; cyclopropyl substituted with one methyl; cyclopropyl substituted with one fluoro; cyclopropyl substituted with one -OH; cyclopropyl substituted with one -OSH ₃ ; cyclopropyl substituted with one -CN; cyclobutyl; cyclobutyl substituted with one methyl; cyclobutyl substituted with one -OSH ₃ ; cyclobutyl substituted with one fluoro; cyclopentyl substituted with one -OH; bicyclic cycloalkyl bridged at C ₅ ; bicyclic cycloalkyl bridged at _C5 , substituted with one fluoro; bicyclic cycloalkyl bridged at _C5 , substituted with one -OH; oxetanil; oxetanyl substituted with one methyl; oxetanyl substituted with ethyl alone; oxetanyl substituted with one isopropyl; tetrahydrofuranyl; tetrahydrofuranyl substituted with one methyl; tetrahydropyranyl; tetrahydropyranyl substituted with one methyl; oxazolyl; thiazolyl; isoxazolyl; oxadiazolyl; or triazolyl substituted with one methyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl; ethyl; -CH(CH ₃ )OH; isopropyl; -C(CH ₃ ) ₂ OH; tert-butyl; -OCH3; cyclopropyl; cyclopropyl substituted with one methyl; cyclopropyl substituted with one -OH; cyclobutyl; cyclobutyl substituted with one methyl; bicyclic cycloalkyl bridged at C ₅ ; bicyclic cycloalkyl bridged at _C5 , substituted with one fluoro; bicyclic cycloalkyl bridged at _C5 , substituted with one -OH; oxetanil; or oxetanyl substituted with one methyl.

In some embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIb, VIb, or VIc, or pharmaceutically acceptable salts thereof, R ²¹ is methyl.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, or IVc, or pharmaceutically acceptable salts thereof, R ¹¹ is:

- 35 045798

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H;

ii) halogen;

iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl;

iv) -NH2;

v) -NH(C _1-6 alkyl), wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy;

vi) -N(C1_6 alkyl) ₂ wherein each C _1-6 alkyl may be the same or different and wherein each C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy ;

vii) -P(O)(C _1-6 alkyl) ₂ wherein each C _1-6 alkyl may be the same or different and wherein each C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C _1-3 alkoxy;

viii) -S(O) ₂ C _1-6 alkyl;

ix) -S(O) ₂ N(R ²³ )2, where each R ²³ independently represents H or C1_6 alkyl;

x) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from

a) -OH,

b) halogen,

c) C _1-3 alkoxy,

d) C _3-7 monocyclic cycloalkyl,

e) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C _1-3 alkyl, and

f) -NR ²⁰ C(O)OCi-3 alkyl, where R ²⁰ represents H or C1-3 alkyl;

xi) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

xii) 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy;

xiii) a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C _1-3 alkoxy;

xiv) -COOH; xv) -C(O)N(R ¹⁹ h; or xvi) -C _1-3 alkylC(o)N(R ¹⁹ ) ₂ ;

where one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H;

ii) halogen;

iii) C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _3-7 monocyclic cycloalkyl;

iv) -NH2;

v) -NH(C _1-3 alkyl), where said C _1-3 alkyl is optionally substituted with 1-3 groups, regardless of

- 36 045798 branes of -OH, halogen and C1-3 alkoxy;

vi) -N( _C1-3 alkyl)2, wherein each C1-3 alkyl may be the same or different and wherein each _C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and _C1-3 alkoxy;

vii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl; or viii) -C(O)N(R ¹⁹ )2; where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H;

ii) halogen;

iii) _C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and _C3-7 monocyclic cycloalkyl;

iv) Ci. ₆ alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl;

v) _C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and _C1-3 alkoxy; or vi) -C(O)N(R ¹⁹ )2; where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H;

ii) halogen;

iii) -NH2;

iv) -NH(C ₁ - ₃ alkyl);

v) -N( _C1-3 alkyl)2, where each _C1-3 alkyl is the same or different;

vi) C _1-3 alkyl, optionally substituted with 1-3 groups independently selected from -OH and halogen;

vii) -OCH ₃ optionally substituted with 1-3 halogen groups;

viii) cyclopropyl; or ix) -C(O)N(R ¹⁹ )2; where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e are independently

i) H;

ii) halogen;

iii) C _1-3 alkyl, optionally substituted with 1-3 groups independently selected from -OH and halogen;

iv) -OCH3, optionally substituted with 1-3 halogen groups;

v) cyclopropyl; or vi) -C(O)N(R ¹⁹ )2; where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is H and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O )N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is halogen and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O )N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is fluorine or chlorine and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C (O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or pharmaceutically acceptable salts, one or more of ^R9 is fluorine and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9 is fluorine and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is _C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkyl and C _3-7 monocyclic cycloalkyl and one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII,

- 37 045798

Vila, Vllb or VIIc or pharmaceutically acceptable salts thereof, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -OCH3, optionally substituted with 1-3 fluoro groups, and one or more of ^R9a , ^R9b , R ^9c , R ^9d and R ^9e represents -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -OCH3 or -OCF3, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is is -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, Vila, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -OCH3, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C( O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -OCF ₃ , and one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is - C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -NH2, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C (O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -NH(C1-6 alkyl), wherein said C1-6 alkyl is optionally substituted with 1-3 groups independently selected from - OH, halogen and C1-3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is NH(C1_3 alkyl), wherein said C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1_3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -NH(C1_3 alkyl), and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e represents -C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -N(C1_6 alkyl)2, wherein each C1-6 alkyl may be the same or different and wherein each C1- 6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -N(C1.3 alkyl)g, wherein each C1_3 alkyl may be the same or different and wherein each C1_3 alkyl optionally substituted with 1-3 groups independently selected from -OH, halogen and C1_3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2 . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is N(C1_3 alkyl)g, where each C1-3 alkyl is the same or different, and one or more of ^R9a . R ^9b , R ^9c , R ^9d and R ^9e are -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is N(CH3)2, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is is -C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -P(O)(C1.6 alkyl)2, wherein each C1-6 alkyl may be the same or different, and wherein each C1-6 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1_3 alkoxy and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N (R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -P(O)(C1-3 alkyl)2, wherein each C1-3 alkyl may be the same or different, and wherein each C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -OH, halogen and C1-3 alkoxy and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O )N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -P(O)(C1_3 alkyl)2, and one or more of ^R9a , ^R9b , ^R9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ )2. In some variants

- 38 045798 sales of compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, Via, VIb, VIc,

VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof, one or more of ^R9a , ^R9b , ^R9c , ^R9d and

R ^9e is -P(O)(CH ₃ ) ₂ and one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is

-C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -S(O)2C1_6 alkyl, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and R ^9e is -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -S(O)2N( ^R23 )2, wherein each ^R23 is independently H or C1-6 alkyl, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is a 5-6 membered monocyclic heteroaryl containing 1-4 heteroatoms independently selected from N, O and S, wherein said 5 The -6-membered monocyclic heteroaryl is optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e represents -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, where the specified 46 -membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e represents -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -COOH, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C (O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C3_7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C1- 3 alkoxy, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is cyclopropyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is cyclopropyl and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O) N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C _b6 alkyl, optionally substituted with 1-3 groups independently selected from:

a) -OH,

b) halogen,

c) C _1-3 alkoxy,

d) C ₃ - ₇ monocyclic cycloalkyl,

e) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from oxo and C _1-3 alkyl, and

f) -NR ²⁰ C(O)OC1_3 alkyl, where R ²⁰ represents H or C1-3 alkyl; and where one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and C3 -7 monocyclic cycloalkyl, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is Cb3 alkyl, optionally substituted with 1-3 groups independently selected from -OH and halogen, and one or more of ^R9a . R ^9b , R ^9c , R ^9d and R ^9e are -C(O)N(R ¹⁹ )2. In some

- 39 045798 embodiments of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, Via, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof, one or more of ^R9a , ^R9b , ^R9c , R9d and ^R9e is methyl, optionally substituted with 1-3 groups independently selected from -OH and fluorine, and one or more of ^R9a , R ^9b , R ^9c , R ^9d and R ^9e are -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is ethyl, optionally substituted with one -OH, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and R ^9e is -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or pharmaceutically acceptable salts thereof, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is methyl, ethyl, _-CF3 , -CHF2, -CH2OH or -CH( _CH3 )OH, and one or more of ^R9a , ^R9b , R ^9c , R ^9d and R ^9e represents -C(O)N(R ¹⁹ )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -CH2OH, and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C (O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C1.3alkylC(O)N( ^R19 )2, and one or more of ^R9a , ^R9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ^9a , R ^9b , R ^9c , R ^9d and R ^9e independently represent i) H; ii) fluorine; iii) chlorine; iv) methyl, optionally substituted with 1 to 3 groups independently selected from -OH and fluorine; v) ethyl, optionally substituted with one -OH; vi) -OCH3, optionally substituted with 1-3 fluoro groups; vii) cyclopropyl; or viii) -C(O)N(R ¹⁹ )2; and where one or more of R ^9a , R ^9b , R ^9c , R ^9d and R ^9e is -C(O)N(R ¹⁹ ) ₂ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts ^R9a , ^R9b , ^R9c , ^R9d and ^R9e are independently H, fluorine, chlorine, methyl, ethyl, -OCH3, -CF3, -CHF2, -CH2OH, -CH(CH3)OH, -OCF3, cyclopropyl, -N(CH3)2 or -C(O)N(R ¹⁹ )2; and where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts ^R9a , ^R9b , ^R9c , ^R9d and ^R9e are independently H, fluorine, chlorine, methyl, ethyl, -OCH3, _-CF3 , -CHF2, -CH2OH, -CH( _CH3 ) OH, -OCF ₃ , cyclopropyl or -C(O)N(R ¹⁹ )2; and where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts ^R9a , ^R9b , ^R9c , ^R9d and ^R9e are independently H, fluorine, chlorine, methyl, ethyl, -CH2OH, _-OCH3 , _-CF3 , _-OCF3 , cyclopropyl, -N (CH ₃ )2 or -C(O)N(R ¹⁹ )2; and where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts ^R9a , ^R9b , ^R9c , ^R9d and ^R9e are independently H, fluorine, chlorine, methyl, ethyl, _-CF3 , -OCF3, cyclopropyl or -C(O)N( ^R19 ) 2, and where one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -C(O)N( ^R19 )2. In some embodiments, compounds of formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or pharmaceutically thereof in suitable salts, ^R9a , ^R9b , ^R9c , ^R9d and ^R9e are independently H, fluorine, chlorine, methyl, ethyl or -C(O)N( ^R19 )2, and wherein one or more of ^R9a , R ^9b , R ^9c , R ^9d and R ^9e are -C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one of R ^9a , R ^9b , R ^9c and R ^9e is independently H, fluorine, chlorine, methyl or ethyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ^9a represents H or fluorine. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ^9b is H or methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ^9b is H, fluorine or methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ^9c is H, fluorine, chlorine, methyl, ethyl, -CF ₃ , -OCF ₃ or cyclopropyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa,

- 40 045798

IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, Via, VIb, VIc, VII, Vila, VIIb or VIIc or pharmaceutically acceptable salts thereof R ^9c represents H, fluorine and chlorine. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ^9c is methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, R ^9e is H. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or their pharmaceutically acceptable salts R ^9d represents C(O)N(R ¹⁹ )2.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ independently represents i) H; ii) -S(O) ₂ C ₁ - ₆ alkyl; iii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from - CN, -OH, halogen, C _1-3 alkoxy and C 3-7 monocyclic cycloalkyl; iv) C ₃ -7 monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-6 alkyl and C _1-6 alkoxy, wherein said C _1-6 alkyl is optionally substituted with 1- 3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy; or v) a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen , oxo, C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ independently represents i) H; ii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-3 alkoxy and C _{3-7 monocyclic} cycloalkyl; or iii) C ₃ - ₇ monocyclic cycloalkyl, optionally substituted with 1 - 6 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optionally substituted with 1 -3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or more R ¹⁹ is H. In some embodiments, compounds of formula I, II, IIa, IIb, III, IV, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa , VIIb or VIIc or pharmaceutically acceptable salts thereof, one R ¹⁹ is H. In some embodiments, compounds of formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof, both R ¹⁹ are H.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more R ¹⁹ is C1-6 alkyl, optionally substituted with 1 to 6 groups independently selected from -CN, -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more R ¹⁹ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and _C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more R ¹⁹ is C _1-4 alkyl, optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments of a compound of Formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, or Vc, or pharmaceutically acceptable salts thereof, one or more R ¹⁹ is a C3-7 monocyclic cycloalkyl , optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C1-6 alkyl and C1-6 alkoxy, wherein said C1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH , halogen and C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or pharmaceutically thereof in acceptable salts, one or more R ¹⁹ is C3_ ₇ monocyclic cycloalkyl, optionally substituted with 1-6 groups independently selected from -CN, -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more R ¹⁹ is a C ₃ - ₅ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, wherein said C _{1- The 3} alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more R ¹⁹ is -S(O) ₂ C ₁ - ₆ alkyl. In some embodiments, compounds of formula I, II, IIa, Ilb, III, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc or pharmaceutically acceptable salts thereof, one or more R ¹⁹ is a 4-6 membered monocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-6 membered monocyclic heterocyclyl is optionally substituted with 1-6 groups, independently selected from -CN, -OH, halogen, oxo, C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ independently represents i) H; ii) methyl; iii) ethyl, optionally substituted with 1 or 2 groups independently selected from -OH, fluorine and -OCH ₃ ; iv) n-propyl, optionally substituted with 1 or 2 groups independently selected from fluorine and -OCH ₃ ; v) isopropyl, optionally substituted with 1 or 2 fluoro groups; vi) n-butyl; vii) isobutyl, optionally substituted with 1 or 2 fluoro groups; viii) sec-butyl; ix) tert-butyl; x) cyclopropyl, optionally substituted with one methyl group, wherein said methyl is optionally substituted with 1-3 groups independently selected from fluorine and -OCH3; or xi) cyclobutyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ independently represents i) H; ii) methyl; iii) ethyl; iv) -CH2CH2OH; v) -CH ₂ CH ₂ OCH ₃ ; vi) -CH ₂ CHF ₂ ; vii) -CH ₂ C(CH ₃ )F ₂ ; vii) -CH(Ch ₃ )CH ₂ F; ix) -CH(CH ₂ F) ₂ ; x) n-propyl; xi) isopropyl; xii) -CH(CH ₃ )CHF ₂ ; xiii) -CH2CH2CHF2; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii) -CH ₂ CH ₂ CH ₂ OCH ₃ ; xviii) cyclopropyl; xix) cyclopropyl substituted with one group selected from -CH2F, -CHF2 and -CH2OCH3; or xxx) cyclobutyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ independently represents i) H; ii) methyl; iii) ethyl; iv) -CH2CH2OH; v) -CH2CH2OCH3; vi) -CH2CHF2; vii) -CH2C(CH3)F2; viii) n-propyl; ix) isopropyl; x) -CH(CH3)CH2F; xi) -CH(CH3)CHF2; xii) -CH(CH ₂ F) ₂ ; xiii) -CH ₂ CH ₂ CHF ₂ ; xiv) isobutyl; xv) sec-butyl; xvi) tert-butyl; xvii) cyclopropyl; xviii) cyclopropyl substituted with one group selected from -CH ₂ F, -CHF ₂ and -CH ₂ OCH ₃ ; or xix) cyclobutyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁹ is independently H, methyl, isopropyl or cyclopropyl, wherein said cyclopropyl is optionally substituted with one group selected from -CH ₂ F, -CHF ₂ and -CH ₂ OCH ₃ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one R ¹⁹ is H and the other R ¹⁹ is H, methyl, ethyl or isopropyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts ^R9a , ^R9b , ^R9c and ^R9e are independently H, fluorine, chlorine, methyl or ethyl and ^R9d is C(O)N( ^R19 )2; wherein each R ^9d is independently H or cyclopropyl, wherein said cyclopropyl is optionally substituted with methyl, and wherein said methyl is optionally substituted with 1-3 groups independently selected from fluorine and -OCH3. In some embodiments, R ^9a , R ^9b , R ^9c , and R ^9e are independently H, fluorine, chlorine, methyl, or ethyl and R ^9d is -C(O)N(R ¹⁹ ) ₂ ; wherein each R ¹⁹ independently represents H or cyclopropyl, wherein said cyclopropyl is optionally substituted with methyl, and wherein said methyl is optionally substituted with 1-3 fluoro groups. In some embodiments, R ^9a , R ^9b , R ^{9c ,} and R ^9e are independently H, fluorine, chlorine, methyl, or ethyl and R ^9d is -C(O)NH(R ¹⁹ ); wherein each R ¹⁹ is cyclopropyl, optionally substituted with methyl, and said methyl is optionally substituted with 1-3 fluoro groups. In some embodiments, R ^9a , R ^9b , R ^{9c ,} and R ^9e are independently H, fluorine, or chlorine and R ^9d is -C(O)NH(R ¹⁹ ); where R ¹⁹ represents cyclopropyl, optionally substituted with methyl, and said methyl is optionally substituted with 1-3 fluoro groups. In some embodiments, R ^9a , R ^9b , and R ^9c are independently fluorine or chlorine, R ^9e is H, and R ^9d is -C(O)NH(R ¹⁹ ); where R ¹⁹ represents cyclopropyl, optionally substituted with methyl, and said methyl is optionally substituted with 1-3 fluoro groups. In some embodiments,

ration R ^9d represents

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ⁷ represents i) H; ii) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, _C1-3 alkoxy and _{C3_7 monocyclic} cycloalkyl; or iii) C _{3_7 monocyclic} cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen,

- 42 045798

C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof R ⁷ is H.

In some embodiments, compounds of formula I, II, IIb, IIa, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ⁷ is C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ⁷ is methyl, ethyl, isopropyl or sec-butyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ⁷ is ethyl, isopropyl or sec-butyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ⁷ is isopropyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ⁷ is C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ⁷ is cyclopropyl, optionally substituted with one methyl group. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ⁷ is cyclopropyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, R ⁷ is methyl, ethyl, isopropyl, sec-butyl or cyclopropyl, wherein said cyclopropyl is optionally substituted with methyl alone. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or pharmaceutically acceptable salts R ⁷ is ethyl, isopropyl, sec-butyl or cyclopropyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, R ⁷ is isopropyl or cyclopropyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ independently represent i) H; ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy; iii) a 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C _1-3 alkoxy; iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy; or v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -CN,

b) -OH,

c) halogen,

d) C _1-3 alkoxy,

e) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy, and

f) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is NR ¹⁵ R ¹⁶ wherein R ¹⁵ and R ¹⁶ independently represent i) H; ii) C _3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C 1-3 alkyl and C 1-3 alkoxy; iii) a 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C _1-3 alkoxy; iv) -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy; or v) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -OH, halogen and C _1-3 alkoxy.

- 43 045798

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof X represents NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent i) H; or ii) C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from -OH, halogen and C _1-3 alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are H. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc , VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof, one of R ¹⁵ and R ¹⁶ is H.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are C3-7 monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and _C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are cyclobutyl, optionally substituted with 1 or 2 groups independently selected from OH and fluorine. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are cyclohexyl, optionally substituted with 1 or 2 fluoro groups. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are cyclobutyl; cyclobutyl substituted with one -OH; cyclobutyl substituted with 2 fluoro groups; or cyclohexyl substituted with 2 fluoro groups.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or more of R ¹⁵ and R ¹⁶ is a 4-7 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 4-7 membered monocyclic heterocyclyl is optionally substituted with 1 -3 groups independently selected from -OH, halogen, oxo, C1-3 alkyl and C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are a 5-7 membered monocyclic heterocyclyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkyl and _C1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are tetrahydropyranyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are tetrahydropyranyl, optionally substituted with one group selected from fluorine and methyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are tetrahydropyranyl; tetrahydropyranyl substituted with one fluoro group; or tetrahydropyranyl substituted with one methyl group.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are cyclobutyl, cyclopentyl, cyclohexyl or tetrahydropyranyl, each of which is optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkyl and C _{1- 3} alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are -C(O)C _1-6 alkyl, wherein said C _1-6 alkyl is optionally substituted with 1-3 groups independently selected from -CN, -OH, halogen and C _1-3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are -C(O)tert-butyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are C _1-6 alkyl, optionally substituted with 1-6 groups independently selected from

a) -CN,

b) -OH,

c) halogen,

d) C1_ ₃ alkoxy,

e) C ₃ - ₇ monocyclic cycloalkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1_ ₃ alkyl and C1_ ₃ alkoxy, and

f) a 5-6 membered monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O and S, wherein said 5-6 membered monocyclic heterocyclyl is optionally substituted with 1-3 groups independently selected from -OH, halogen, oxo , C _1-3 alkyl and C1_ ₃ alkoxy.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are C1-6 alkyl, optionally substituted with 1-6 groups independently selected from -OH, halogen and C1_3 alkoxy. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are C1.6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen and -OCH3. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are i) methyl; ii) isopropyl; iii) isobutyl, optionally substituted with one group selected from -OH, fluorine and -OCH3; iv) sec-butyl; or v) C5 alkyl, optionally substituted -OCH3. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one or both of R ¹⁵ and R ¹⁶ are i) methyl; ii) isopropyl; iii) isobutyl; iv) -CH2C(CH ₃ ) ₂ F; v) -CH ₂ C(CH3) ₃ OCH3; vi) -CH ₂ C(CH3)2OH; vii) sec-butyl; or viii) -CH ₂ C(CH3) ₂ CH ₂ OCH3.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ¹⁵ and R ¹⁶ independently represent i) H; ii) methyl; iii) isopropyl; iv) isobutyl, optionally substituted with one group selected from -OH, fluoro and -OCH ₃ ; v) sec-butyl; vi) C ₅ alkyl, optionally substituted -OCH ₃ ; vii) -C(O)(tert-butyl); viii) cyclobutyl, optionally substituted with 1 or 2 groups independently selected from -OH and fluorine; ix) cyclohexyl, optionally substituted with 1 or 2 fluoro groups; or x) tetrahydropyranyl, optionally substituted with one group selected from fluorine and methyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ¹⁵ and R ¹⁶ independently represent i) H; ii) methyl; iii) isopropyl; iv) isobutyl; v) -CH2C(CH3)2F; vi) CH2C(CH3)2OCН3; vii) -CH2C(CH3)2OH; viii) sec-butyl; ix) -CH2C(CH3)2CH2OCН3; x) -C(O)(tert-butyl); xi) cyclobutyl; xii) cyclobutyl substituted with one -OH; xiii) cyclobutyl substituted with 2 fluoro groups; xiv) cyclohexyl substituted with 2 fluoro groups; xv) tetrahydropyranyl; xvi) tetrahydropyranyl substituted with one fluoro group; or xvii) tetrahydropyranyl substituted with one methyl group. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ¹⁵ and R ¹⁶ independently represent i) H; ii) isopropyl; iii) -CH2C(CH ₃ ) ₂ F; iv) -CH ₂ C(CH ₃ ) ₂ OH; v) -CH ₂ C(CH ₃ ) ₂ OCH ₃ ; vi) -C(O)(tert-butyl); vii) cyclobutyl substituted with 2 fluoro groups; viii) cyclohexyl substituted with 2 fluoro groups; or ix) tetrahydropyranyl substituted with one methyl group.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ¹⁵ and R ¹⁶ are independently H, methyl or isobutyl, wherein said isobutyl is optionally substituted with one group selected from -OH, fluorine and -OCH3. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one of R ¹⁵ and R ¹⁶ is H or methyl, and the other of R ¹⁵ and R ¹⁶ is isobutyl, optionally substituted with one group selected from -OH, fluorine and -OCH3. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts R ¹⁵ and R ¹⁶ are independently H, methyl, isobutyl, -CH2C( _CH3 ) _2OCH3 , CH2C( _CH3 )2OH or CH2C(CH3)2F.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one of R ¹⁵ and R ¹⁶ is independently and the other of R ¹⁵ and R ¹⁶ is i) isopropyl; iii) -CH ₂ C(CH ₃ ) ₂ F; iv) -CH ₂ C(CH ₃ ) ₂ OH; v) -CH ₂ C(CH ₃ ) ₂ OCH ₃ ; vi) -C(O)(tert-butyl); vii) cyclobutyl substituted with 2 fluoro groups; viii) cyclohexyl substituted with 2 fluoro groups; or ix) tetrahydropyranyl substituted with one methyl group.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

- 45 045798

Va, Vb, Vc, VI, Via, VIb, VIc, VII, Vila, Vllb or VIIc or pharmaceutically acceptable salts thereof X is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms , independently selected from N, O and S, wherein said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is a 4-8 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, wherein said 4-8 membered monocyclic, fused bicyclic, the bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

represents an optionally substituted 1-5 R ¹⁸ . In this document

is a 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing at least one ring nitrogen atom, wherein said ring nitrogen atom is the point of attachment for said 4-10 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X is

each of which is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X is

each of which is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

- 46 045798

Va, Vb, Vc, VI, Via, VIb, VIc, VII, Vila, Vllb or VIIc or pharmaceutically acceptable salts thereof X represents

each of which is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, each of which is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is azetidinyl, optionally substituted with 1-4 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is azetidinyl, optionally substituted with 1-3 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is azetidinyl, optionally substituted with 1-2 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is pyrrolidinyl, optionally substituted with 1-5 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is piperidinyl, optionally substituted with 1-5 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof. X is morpholinyl, optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X\__J OR I is ' each of which is optionally substituted with 1-5 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof X

each of which is optionally substituted with 1-4 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

C/ or I

X _x ,. j each of which is optionally substituted with 1-3 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X represents

itself ' optionally substituted 1-3 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

- 47 045798

O θν represents '', each of which is optionally substituted with 1-3 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof; X is 'optionally substituted 1-4 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

represents 'optionally substituted 1-3 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

Oy represents optionally substituted 1-4 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X Oy represents 'optionally substituted 1-3 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is unsubstituted. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is substituted with 1-5 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is substituted with 1-4 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is substituted with 1-3 R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is substituted with 1-2 R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is replaced by one R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is replaced by two R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is replaced by three R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is replaced by four R ¹⁸ . In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, X is substituted with five R ¹⁸ .

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, two R ¹⁸ are attached to the same carbon atom.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁸ independently represents i) -CN; ii) halogen; iii) -OH; iv) C1-6 alkoxy, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl; v) C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl; vi) -COOH; or vii) -C(O)N(R ²² )2, where each

- 48 045798 R ²² is independently H or C _1-6 alkyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁸ independently represents i) halogen; ii) -OH; or iii) C _1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁸ independently represents -OH, fluoro or C1-3 alkyl, optionally substituted with 1-3 groups independently selected from -OH and halogen.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, each R ¹⁸ is independently -OH, fluorine or methyl, optionally substituted with 1-3 groups independently selected from -OH and fluorine.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ are -CN. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ are halogen. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ represent fluorine. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ represent -OH. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ represent -COOH. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ are C(O)N(R ²² )2, where each R ²² independently represents H or C1-6 alkyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable one, two, three, four or five salts, R ¹⁸ is C _1-6 alkoxy, optionally substituted with 1-3 groups independently selected from OH, halogen, C _1-3 alkoxy and C _3-7 monocyclic cycloalkyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable one, two, three, four or five salts, R ¹⁸ is C1-6 alkyl, optionally substituted with 1-3 groups independently selected from -OH, halogen, C1-3 alkoxy and C3-7 monocyclic cycloalkyl. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts one, two, three, four or five R ¹⁸ represents C1-3 alkyl, optionally substituted with 1-3 groups independently selected from -OH and halogen. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts one, two, three, four or five R ¹⁸ is methyl, optionally substituted with 1-3 groups independently selected from -OH and fluorine. In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or in their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ are methyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or In their pharmaceutically acceptable salts, one, two, three, four or five R ¹⁸ are fluorine or methyl.

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X is

- 49 045798

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

represents '

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

represents

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X

- 50 045798 _______... θ/ represents

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V,

Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutically acceptable salts thereof X is selected from the group consisting of:

In some embodiments, compounds of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc, or their pharmaceutically acceptable salts X is

- 51 045798

In some embodiments of a compound of Formula I, II, IIa, or III, said compound is selected from the group consisting of:

- 52 045798

- 53 045798

- 54 045798

- 55 045798

- 56 045798

- 57 045798

or pharmaceutically acceptable salts thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is selected from the group consisting of:

- 58 045798

- 59 045798

- 60 045798

- 61 045798

- 62 045798

- 63 045798

- 64 045798

-65 045798

or pharmaceutically acceptable salts thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is selected from the group consisting of:

- 66 045798

- 67 045798

or pharmaceutically acceptable salts thereof.

or IIIa, said compound. In some embodiments of compounds of formula I, II, IIa, IIb, III, the compound is:

- 68 045798

- 69 045798

- 70 045798

- 71 045798

- 72 045798

or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula I, II, IIa, IIb, III, or IIIa, said compound is:

- 73 045798

- 74 045798

- 75 045798

- 76 045798

- 77 045798

or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula I, II, IIa, IIb, III, or IIIa, said compound is:

- 78 045798 or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula I, II, Pa, IIb, III, or Ia, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula I, II, Pa, IIb, III, or Ia, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of compounds of formula I, II, Pa, IIb, III, or Ia, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, Pa, III, IV, or VI, the compound is:

-79045798

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, IV, or VI, said compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, IV, or VI, said compound is:

- 80 045798 or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, IV, or VI, said compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula I, II, IIa, III is:

or

IV indicated connection

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula I, II, IIa, III is:

or

IV indicated connection

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula I, II, IIa, III is:

or

IV indicated connection

- 81 045798 or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, IV, or VI, said compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

- 82 045798

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, or IV, the compound is:

or a pharmaceutically acceptable salt thereof.

In some embodiments of a compound of Formula I, II, IIa, III, IV, or V, the compound is:

or a pharmaceutically acceptable salt thereof.

III. Compositions and sets.

The compounds described herein are typically administered in the form of pharmaceutical components.

- 83 045798 positions. Thus, also provided herein are pharmaceutical compositions that contain one or more of the compounds described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and one or more pharmaceutically acceptable carrier vehicles selected from carriers, adjuvants, and excipients. . The compounds provided herein may be the sole active ingredient of pharmaceutical compositions or one of the active ingredients. Suitable pharmaceutically acceptable carrier media may include, for example, inert solid diluents and excipients, diluents including sterile aqueous solution and various organic solvents, penetration enhancers, solubilizers and adjuvants. Such compositions are prepared by a method well known in the field of pharmacy. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. ^17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. ^3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

In one aspect, provided herein are pharmaceutical compositions containing a compound provided herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments of the present invention, these pharmaceutical compositions contain a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

In some embodiments of the present invention, the pharmaceutical compositions described herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or pharmaceutically acceptable salt. In some embodiments of the present invention, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or a pharmaceutically acceptable salt thereof .

In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for hepatitis B virus (HBV) infection, human immunodeficiency virus (HIV) infection, cancer, or a hyperproliferative disease. In some embodiments, the one or more additional therapeutic agents include PD1 inhibitors and/or PDL1 inhibitors. In some embodiments, the one or more additional therapeutic agents that have a therapeutic effect on HBV infection include PDL1 inhibitors and/or PDL1 inhibitors. In some embodiments, the one or more additional therapeutic agents that have a therapeutic effect in cancer or a hyperproliferative disease include PD1 inhibitors and/or PDL1 inhibitors.

In some embodiments, the one or more additional therapeutic agents include agents that have a therapeutic effect on HBV infection. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: adefovir (Hepsera®), tenofovir disoproxil fumarate+emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine ( Epivirhbv®), tenofovir alafenamide, tenofovir, tenofovir dysoproxil, tenofovir alafenamide fumarat, tenofovir alafenamide hemifumarat, telbivudin (Tyzeka®), clovewood®, emricitabin (Emmtriva®), paginterona-2 (Peg-intron®), multiferona®, Interferon alpha 1b (Hapgen®), interferon alpha-2b (Intron A®), pegylated interferon alpha-2a (Pegasys®), interferon alpha-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron , bimutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alpha-2b (AXHO), Alfaferon, interferon alpha-2b, Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, Blauferon -B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alphainterferon 2b, Calferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alpha2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai , Alloferon and celmoleukin; or are a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, the one or more additional therapeutic agents include agents that have a therapeutic effect on HIV infection. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine and lamivudine or represent a pharmaceutically acceptable

- 84 045798 salt of any of the above compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents include PD1 inhibitors and/or PDL1 inhibitors. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of nivolumab, lambrolizumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, or avelumab, or a pharmaceutically acceptable salt of any of these compounds, or any their combinations.

In some embodiments, the one or more additional therapeutic agents include agents that have a therapeutic effect in cancer or a hyperproliferative disease. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of Rituxan, doxorubicin, gemcitabine, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N(cyanomethyl)-4-[2-(4-morpholinoanilino) pyrimidin-4yl]benzamide, XL147, VKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235 and GDC-0980, wortmannin, LY294002, PI3K II, TGR-1202, AMG-319, GSK22695 57, X -339, X-414, RP5090, KAR4141, XL499, 0XY111A, IPI-145, IPI-443, GSK2636771, BAY 10824391, buparlisib, BYL719, RG7604, MLN1117, WX-037, AEZS-129, PA799 , ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI-549, INCB050465, (S)-2-(1((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-6fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H- purin-6-yl)amino)ethyl)-3-(2,6-difluorophenyl)quinazolin4(3H)-one, (S)-4-amino-6-((1-(5-chloro-4-oxo- 3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5carbonitrile and ipilimumab, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

The pharmaceutical compositions can be administered as a single or multiple dose. The pharmaceutical composition can be administered by various routes, including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions can be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhaler.

One route of administration is parenteral, for example by injection. Forms in which the pharmaceutical compositions described herein may be formulated for administration by injection include, for example, aqueous or oleaginous suspensions or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solution and similar pharmaceutical carriers.

Oral administration may be another method of administering the compounds described herein. Administration can be carried out, for example, using enteric-coated capsules or tablets. In the manufacture of pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as a compound described herein) is typically diluted with an excipient and/or contained in such a carrier, which may be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid substance that acts as a carrier, carrier or vehicle for the active ingredient. Thus, pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions and sterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose or any combination thereof . Said pharmaceutical compositions may further contain lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxy benzoates; sweeteners and flavorings or any combination thereof.

Pharmaceutical compositions that include at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can be formulated to provide rapid, sustained, or sustained release of an active ingredient (such as a compound described herein) after administration to a subject using procedures known in the art. Drug delivery systems

- 85 045798 controlled release agents for oral administration include osmotic pump systems and dissolution systems containing polymer-coated containers or drug-polymer matrix formulations. Examples of controlled release systems are provided in US Pat. Nos. 3,845,770; 4326525; 4902514; and 5616345. Another formulation used in the methods of the present invention uses transdermal delivery devices (patches). Such transdermal patches can be used to provide continuous or intermittent infusion of the compounds described herein in controlled amounts. The design and use of transdermal patches for the delivery of pharmaceutical agents are well known in the art. See, for example, US Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches may be designed for continuous, pulsatile, or on-demand delivery of pharmaceutical agents.

To prepare solid compositions, such as tablets, the main active ingredient can be mixed with a pharmaceutical excipient to form a solid preformulation containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomers or mixtures thereof. When said preformulations are said to be homogeneous, the active ingredient may be uniformly dispersed throughout the composition such that the composition may be readily divided into equally effective unit dosage forms such as tablets, pills and capsules.

Tablets or pills of the compounds described herein may be coated or otherwise formulated into a dosage form to provide the benefit of long-acting or to protect against acidic conditions of the stomach. For example, a tablet or pill may include an internal dose component and an external dose component, the latter being in the form of a shell over the former. The two components may be separated by an enteric layer, which serves to resist degradation in the stomach and allows the internal component to pass unchanged into the duodenum or be delayed upon release. Various materials can be used for such enteric layers or coatings, such as a number of polymer acids and mixtures of polymer acids with substances such as shellac, cetyl alcohol and cellulose acetate.

Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments of the present invention, the compositions are administered through the oral or nasal respiratory tract for local or systemic effect. In other embodiments, the compositions in pharmaceutically acceptable solvents can be nebulized using inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to an inhalation mask or positive intermittent pressure breathing apparatus. The solution, suspension or powder compositions can be administered, preferably orally or nasally, from devices that deliver the composition in an appropriate manner.

In one aspect, provided herein are kits containing a compound provided herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc) or a pharmaceutically acceptable salt, stereoisomer, prodrug or solvate thereof, and suitable packaging. In some embodiments, the kit further contains instructions for use. In some embodiments, the set includes a compound provided herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc) or a pharmaceutically acceptable salt, stereoisomer, prodrug or solvate thereof, as well as labeling and/or instructions for use of the compounds for the treatment of indications, including diseases or conditions described herein.

In some embodiments of the present invention, the kits further contain one or more (eg, one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are articles containing a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, prefilled syringe, or intravenous bag.

IV. Ways.

The methods described herein can be applied to cell populations in vivo or ex vivo. In vivo means within a living individual, either animal or human. In this context, the methods described herein can be used therapeutically in an individual. Ex vivo means outside the living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained

- 86 045798 from individuals. Such samples can be prepared by methods well known in the art. Examples of body fluid samples include blood, cerebrospinal fluid, urine, and saliva. Examples of tissue samples include tumors and tumor biopsies. In this context, the invention can be used for various purposes, including therapeutic and experimental purposes. For example, the invention can be used ex vivo to determine the optimal regimen and/or dosage for HPK1 inhibitor administration for a given target, cell type, individual, and other parameters. Information obtained from such use can be used for experimental purposes or in the clinic to establish protocols for in vivo treatment. Other ex vivo applications for which the present invention may be suitable are described below or will be apparent to those skilled in the art. Selected compounds may be further characterized to study safety or dosage tolerance in humans or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

In one aspect, the present invention provides methods of inhibiting HPK1 activity in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa , IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect of the present invention, methods are described for treating a disease or disorder associated with increased HPK1 activity in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in this document.

In one aspect of the present invention, methods are provided for increasing T cell activation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, II, IIa, IIb, III, IIIa, IV , IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In one aspect, the present invention provides methods for treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In some embodiments, said cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, Hodgkin lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer , ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small cell lung cancer, transitional cell carcinoma and urothelial cancer. In some embodiments, said cancer is a solid tumor.

In one aspect, the present invention provides methods of inhibiting the growth or proliferation of cancer cells in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

In some embodiments, the methods described above further comprise administering a therapeutically effective amount of one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of inducible T cell costimulator (ICOS) agonists, cytotoxic T lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and/or PDL1 inhibitors, cluster of differentiation 47 (CD47), OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, T-cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors , inhibitors of the lymphocyte activation gene 3 (LAG-3), CEACAM1 inhibitors, inhibitors of the immunoreceptor T cells with Ig and ITIM domains (TIGIT), inhibitors of immunoglobulin (I-containing suppressor of T-cell activation (VISTA), inhibitors of anti-killer IgG- like receptors (KTR), STING agonists, chemokine C-X-C receptor type 4 (CXCR-4) inhibitors, B7-I3 inhibitors, CD73 inhibitors, inhibitory RNA, IL2/15/17 fusion proteins, MKNK1/2 inhibitors, inhibitors JAK and PI3K inhibitors, or a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, said one or more additional therapeutic

-87 045798 Agents are selected from a group consisting of rituxan, doxorubicin, hemcitabin, nivolumab, pembroralizumab, pydilizumab, PDR001, TSR-001, athelesolizumab, durvalumab, Avelumab, Pidilizumab, TSR-042, BMS-986016, oligylitinib, ours (cyanomethyl) -4-[2-(4-morpholinoanilino)pyrimidin-4yl]benzamide, XL147, VKM120, GDC-0941, BAY80-6946, PX-866, CH5132799, XL756, BEZ235 and GDC0980, wortmannin, LY294002, PI3K II, TGR- 1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, IPI-145, IPI-443, GSK2636771, BAY 10824391, buparlisiba, BYL719, RG7604, MLN1 117, WX-037, AEZS -129, PA799, ZSTK474, AS252424, TGX221, TG100115, IC87114, IPI549, INCB050465, (S)-2-(1-((9H-purin-6-yl)amino)propyl)-5-fluoro-3-phenylquinazoline -4(3H)-one, (S)-2-(1((9H-purin-6-yl)amino)ethyl)-6-fluoro-3-phenylquinazolin-4(3H)-one, (S)- 2-(1-((9H-purin-6-yl)amino)ethyl)-3(2,6-difluorophenyl)quinazolin-4(3H)-one, (S)-4-amino-6-((1 -(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2yl)ethyl)amino)pyrimidine-5-carbonitrile and ipilimumab, or a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of idelalisib, tirabrutinib, momelotinib, and entospletinib, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In one aspect, the present invention provides methods for treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein document.

In some embodiments, the method of treating or preventing HBV infection further comprises administering a therapeutically effective amount of one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HBV combination drugs, HBV vaccines, HBV DNA polymerase inhibitors, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligand, hyaluronidase inhibitors , hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, HBV entry inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNA (siRNA) modulators and ddRNAi endonucleases, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, cccDNA inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, inhibitors phosphatidylinositol 3-kinase (PI3K), indoleamine 2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, inhibitors replication of HBV, arginase inhibitors and other drugs for the treatment of HBV, or are a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: adefovir (Hepsera®), tenofovir disoproxil fumarate+emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread®), entecavir (Baraclude®), lamivudine ( Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtricitabine (Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon® , interferon alpha 1b (Hapgen®), interferon alpha 2b (Intron A®), pegylated interferon alpha 2a (Pegasys®), interferon alpha n1 (Humoferon®), ribavirin, interferon beta 1a (Avonex®), Bioferon , Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alpha-2b (AXHO), Alfaferon, interferon alpha-2b, Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG , Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, alphainterferon 2b, Calferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alpha-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen , Sinogen, Fukangtai, Alloferon and celmoleukin; or are a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate,

- 88 045798 tenofovir alafenamide hemifumarate, telbivudine or lamivudine, or a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In one aspect, the present invention provides methods for treating or preventing human immunodeficiency (HIV) infection in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound described herein (e.g., a compound of formula I, II, IIa, IIb, III , IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein .

In some embodiments, the method of treating or preventing HIV infection further comprises administering a therapeutically effective amount of one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of combination drugs for the treatment of HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic (or allosteric) site inhibitors of HIV integrase, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immunological therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, modulators HIV vif gene, HIV-1 viral infectious factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists , nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 capture nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, modulators complement factor H, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, protein convertase-PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, complex reverse transcriptase inhibitors, G6PD and NADPH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, vaccines HIV, or are a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, said one or more additional therapeutic agents are selected from the group consisting of compounds that inhibit HIV protease, non-nucleoside HIV reverse transcriptase inhibitors, non-nucleotide HIV reverse transcriptase inhibitors, nucleoside HIV reverse transcriptase inhibitors, nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors , gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs for the treatment of HIV, or are a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combination thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt any of these compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt any of these compounds, or any combinations thereof.

- 89 045798

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of emtricitabine and lamivudine or a pharmaceutically acceptable salt of each.

In some embodiments, the one or more additional therapeutic agents are emtricitabine or a pharmaceutically acceptable salt thereof.

In some embodiments, the method of treating or preventing HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate, or any pharmaceutically acceptable salt of any of these compounds or combinations thereof, and further includes the administration of another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each of them.

In some embodiments, the method of treating or preventing HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, and tenofovir alafenamide hemifumarate or any pharmaceutically acceptable salt of any of these compounds, or combinations thereof, and further comprises administering another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each.

In some embodiments, the method of treating or preventing HIV infection further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil fumarate and tenofovir disoproxil hemifumarate or any pharmaceutically acceptable salt of any of these compounds, or combinations thereof, and further comprises administering another therapeutic agent selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each.

In some embodiments, the methods described herein include administering a therapeutically effective amount of a compound provided herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va , Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc) or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein include administering a therapeutically effective amount of a pharmaceutical composition provided herein.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in therapy.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting hematopoietic progenitor kinase 1 (HPK1) activity in a subject in need thereof.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with increased hematopoietic precursor kinase 1 (HPK1) activity in a subject in need thereof.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of increasing T cell activation in a subject in need thereof.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject in need thereof.

In some embodiments, said cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, gastric cancer, squamous cell carcinoma of the head and neck, Hodgkin lymphoma, Merkel cell carcinoma, mesothelioma, melanoma, non-small cell lung cancer, lung cancer , ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, small cell lung cancer, transitional cell carcinoma and urothelial cancer. In some embodiments, said cancer is a solid tumor.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof.

In some embodiments of the present invention, use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering a therapeutically effective amount of one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof.

In some embodiments, use in a method of inhibiting growth or

- 90 045798 proliferation of cancer cells in a subject in need thereof, further includes the administration of one or more additional therapeutic agents selected from the group consisting of: inducible costimulator of T cells (ICOS) agonists, cytotoxic T lymphocyte antigen 4 blocking antibodies ( CTLA-4), PD1 and/or PD-L1 inhibitors, cluster of differentiation 47 (CD47) inhibitors, OX40 agonists, GITR agonists, CD27 agonists, CD28 agonists, CD40 agonists, CD137 agonists, Toll-like receptor 8 (TLR8) agonists, inhibitors of T-cell immunoglobulin and mucin domain-3 (TIM-3), inhibitors of lymphocyte activation gene 3 (LAG-3), inhibitors of CEACAM1, inhibitors of immunoreceptor T-cells with Ig and ITIM domains (TIGIT), inhibitors of immunoglobulin (Ig-containing suppressor of T-cell activation (VISTA), anti-killer IgG-like receptor (KIR) inhibitors, STING agonists, chemokine C-X-C receptor type 4 (CXCR-4) inhibitors, B7-H3 inhibitors, CD73 inhibitors, inhibitory RNA fusions IL2/15/17 proteins, MKNK1/2 inhibitors, JAK inhibitors and PI3K inhibitors, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: Rituxan, doxorubicin, gemcitabine, nivolumab, pembrolizumab, pidilizumab, PDR001, TSR-001, atezolizumab, durvalumab, avelumab, pidilizumab, TSR-042, BMS-986016, ruxolitinib, N(cyanomethyl)-4-[2-(4-morpholinoanilino)pyrimidin-4-yl]benzamide, XL147, VKM120 . XL499 , 0XY111A, IPI-145, IPI-443, GSK2636771, BAY 10824391, buparlisiba, BYL719, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, AS252424, TGX221, TG1001 15, IC87114, IPI-549, INCB050465, (S)-2-(1-((9H-purin-6yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one, (S)-2-(1-((9H- purin-6-yl)amino)ethyl)-6-fluoro-3phenylquinazolin-4(3H)-one, (S)-2-(1-((9H-purin-6-yl)amino)ethyl)-3- (2,6-difluorophenyl)quinazolin-4(3H)one, (S)-4-amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)ethyl)amino)pyrimidine-5carbonitrile and ipilimumab, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments of the present invention, use in a method of inhibiting the growth or proliferation of cancer cells in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of idelalisib, tirabrutinib, momelotinib and entospletinib or a pharmaceutically acceptable salt of any of the above compounds or any combinations thereof.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof.

In some embodiments of the present invention, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering a therapeutically effective amount of one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

In some embodiments, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further includes administering one or more additional therapeutic agents selected from the group consisting of HBV combination drugs, HBV vaccines, inhibitors HBV DNA polymerase, immunomodulators, Toll-like receptor (TLR) modulators, interferon alpha receptor ligand, hyaluronidase inhibitors, hepatitis B surface antigen (HBsAg) inhibitors, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, cyclophilin inhibitors, inhibitors HBV virus penetration, antisense oligonucleotide targeting viral mRNA, modulators of short interfering RNA (siRNA) and ddRNAi endonucleases, ribonucleotide reductase inhibitors, HBV E antigen inhibitors, covalently closed circular DNA (cccDNA) inhibitors, farnesoid X receptor agonists, HBV antibodies, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein modulators, retinoic acid-inducible gene 1 stimulators, NOD2 stimulators, phosphatidylinositol 3-kinase (PI3K) inhibitors, indoleamine 2,3-dioxygenase (IDO) pathway inhibitors, PD-1 inhibitors, PD-L1 inhibitors, recombinant thymosin alpha-1 agonists, Bruton's tyrosine kinase (BTK) inhibitors, KDM inhibitors, HBV replication inhibitors, arginase inhibitors and other drugs for the treatment of HBV, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: adefovir (Hepsera®), tenofovir disoproxil fumarate +emtricitabine (TRUVADA®), tenofovir disoproxil

- 91 045798 fumarate (Viread®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), Clevudine®, emtri citabine ( Emtriva®), peginterferon alfa-2b (PEG-Intron®), Multiferon®, interferon alfa 1b (Hapgen®), interferon alfa-2b (Intron A®), pegylated interferon alfa-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alpha-2b (AXHO), Alfaferon, interferon alpha- 2b, Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, Blauferon-B, Blauferon-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alpha 2b, Calferon, Pegnano, Feronsure, PegiHep, Optipeg A, Realfa 2B, Reliferon, peginterferon alfa-2b, Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b, Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, Intefen, Sinogen, Fukangtai, Alloferon and celmoleukin; or are a pharmaceutically acceptable salt of any of these compounds, or any combination thereof.

In some embodiments, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of entecavir, adefovir, tenofovir disoproxil fumarate, tenofovir alafenamide , tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine or lamivudine, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments of the present invention, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of tenofovir alafenamide, tenofovir alafenamide fumarate, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of these compounds or any combinations thereof.

In one aspect, provided herein is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing human immunodeficiency virus (HIV) infection in a subject in need thereof.

In some embodiments of the present invention, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents or pharmaceutically acceptable salts thereof.

In some embodiments, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of: combination drugs for the treatment of HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic (or allosteric) site inhibitors of HIV integrase, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents , compounds that target the HIV capsid, immunolytic therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cis modulators -trans-isomerase A, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, HIV-1 viral infectious factor inhibitors, TAT protein inhibitors, Nef HIV-1 modulators, Hck tyrosine kinase modulators , mixed lineage kinase 3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, inhibitors CDK-9, dendritic ICAM-3 capture nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, protein convertase-PC9 stimulators, ATP-inhibitors DDX3X dependent RNA helicase, complex reverse transcriptase inhibitors, G6PD and NADPH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of HIV protease inhibitor compounds, non-nucleoside HIV reverse transcriptase inhibitors, non-nucleotide HIV reverse transcriptase inhibitors,

- 92 045798 HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers and other drugs for the treatment of HIV, or a pharmaceutically acceptable salt any of these compounds, or any combinations thereof.

In some embodiments, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2fluoro-2'- deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of these compounds, or any combinations thereof.

In some embodiments of the present invention, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro -2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, and a pharmaceutically acceptable salt of any of these compounds or any combinations thereof.

In some embodiments of the present invention, use in a method of treating or preventing hepatitis B virus (HBV) infection in a subject in need thereof further comprises administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro -2'-deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, tenofovir disoproxil, tenofovir disoproxil hemifumarate or tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of these compounds or any combinations thereof.

In some embodiments of the present invention, the use described herein includes the administration of a therapeutically effective amount of a compound provided herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V , Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc) or a pharmaceutically acceptable salt thereof.

V. Introduction.

The compounds of the present invention (also referred to as active ingredients) can be administered by any route appropriate for the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It should be understood that the preferred route may vary, for example, depending on the patient's condition. Some of the compounds described herein have the advantage that they are orally bioavailable and can be administered orally.

A compound of the present invention may be administered to an individual according to an effective dosage regimen for a desired period of time or duration, for example, at least about one month, at least about 2 months, at least about 3 months, at least about 6 months or at least about 12 months or longer. In some embodiments, the compound is administered daily or intermittently throughout a person's life.

The specific dosage level of a compound herein for any particular subject will depend on a variety of factors, including the potency of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration and excretion rate, drug combination, and severity specific disease in the subject undergoing therapy. For example, dosage may be expressed as the number of milligrams of a compound described herein per kilogram of subject body weight (mg/kg). Doses between about 0.1 and 150 mg/kg may be acceptable. In some embodiments, from about 0.1 to 100 mg/kg may be acceptable. In other embodiments, dosages from 0.5 to 60 mg/kg may be suitable. Normalization according to subject body weight is particularly useful when adjusting dosages between subjects of disparate sizes, for example when using a drug in both children and adults, or when converting the effective dose for a non-human subject such as a dog , in a dosage suitable for humans.

A daily dose may also be described as the total amount of a compound described herein administered per dose or per day. Daily dose of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc or pharmaceutical thereof acceptable salt or pharmaceutically acceptable tautomer may be from about 1 mg to 4000 mg, from about 2000 to 4000 mg/day, from about 1 to 2000 mg/day, from about 1 to

- 93 045798

1000 mg/day, about 10 to 500 mg/day, about 20 to 500 mg/day, about 50 to

300 mg/day, about 75 to 200 mg/day, or about 15 to 150 mg/day.

The dosage or frequency of dosing of a compound of the present invention may be adjusted during treatment based on the judgment of the attending physician.

The compounds of the present invention can be administered to an individual (eg, a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.

The compounds provided herein can be administered by any suitable route and means, such as oral or parenteral (eg, intravenous) administration. Therapeutically effective amounts of a compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, for example, from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight body weight per day, or, for example, from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or, for example, from about 0.01 mg/kg body weight per day to about 1 mg/day kg body weight per day, or, for example, from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day. In some embodiments, a therapeutically effective amount of the compounds described herein includes from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 μg to about 30 mg per day or from about 30 mcg to about 300 mcg per day.

A compound of the present invention can be combined with one or more additional therapeutic agents at any amount of compound of the present invention per dose (eg, from 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, for example, from about 50 mg per dose to about 500 mg per dose, or, for example, from about 100 mg per dose to about 400 mg per dose. dose, or, for example, from about 150 mg per dose to about 350 mg per dose, or, for example, from about 200 mg per dose to about 300 mg per dose, or, for example, from about 0.01 mg per dose to about 1000 mg per dose, or, for example, from about 0.01 mg per dose to about 100 mg per dose, or, for example, from about 0.1 mg per dose to about 100 mg per dose, or, for example, from about 1 mg per dose to about 100 mg per dose, or, for example, from about 1 mg per dose to about 10 mg per dose, or, for example, from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc are approximately 1 mg per dose or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 , 80, 85, 90, 95 or approximately 100 mg per dose. Other therapeutically effective amounts of a compound of the present invention are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 or approximately 1000 mg per dose.

In some embodiments, the methods described herein include administering to a subject an initial daily dose of about 1 to 500 mg of a compound described herein and increasing the dose in increments until clinical efficacy is achieved. To increase the dose, increments of approximately 5, 10, 25, 50, or 100 mg can be used. The dosage can be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks or once a month.

When administered orally, the total daily dose for humans may be from about 1 mg to 1000 mg, about 10 to 500 mg/day, about 50 to 300 mg/day, about 75 to 200 mg/day, or about 100 to 150 mg/day. In some embodiments, the total daily dose for a human may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/day as a single dose. In some embodiments, the total daily dose for a human may be about 200, 300, 400, 500, 600, 700, or 800 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 300, 400, 500, or 600 mg/day as a single dose.

In some embodiments of the present invention, the total daily dose for a person may be about 100 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 150 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 200 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 250 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 300 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 350 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 400 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 450 mg/day as a single dose. In some implementations

- 94 045798 of the present invention, the total daily dose for humans may be approximately 500 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 550 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 600 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 650 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 700 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 750 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 800 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 850 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a human may be about 900 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 950 mg/day as a single dose. In some embodiments of the present invention, the total daily dose for a person may be about 1000 mg/day as a single dose.

A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, every 2, 3, 4, 6, 8, 12, 16, or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6 or once every 7 days. A single dose may also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In some embodiments of the present invention, a single dose may be administered once a week. A single dose can also be administered once a month. In some embodiments of the present invention, a compound described herein is administered once daily in a manner described herein. In some embodiments of the present invention, a compound described herein is administered twice daily in a manner described herein.

The dosing frequency of a compound of the present invention will be determined by the needs of the individual patient and may be, for example, once daily or twice or more times daily. Administration of the compound is continued as long as necessary for the treatment of HBV infection, HIV infection, cancer, hyperproliferative disease, or any other indication described herein. For example, the compound can be administered to a person infected with HBV for a period of 20 days to 180 days, or, for example, for a period of 20 days to 90 days, or, for example, for a period of 30 days to 60 days.

Administration can be done intermittently, with a period of several or more days where the patient receives a daily dose of a compound of the present invention, followed by a period of several or more days during which the patient does not receive a daily dose of the compound. For example, the patient may receive a dose of the compound every other day or three times a week. Again, by way of example, a patient may receive a dose of the compound every day for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a period (e.g., 1 up to 14 days), during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound followed by no administration of the compound may be repeated as clinically necessary to treat the patient.

The compounds of this application or pharmaceutical composition thereof can be administered once, twice, three or four times daily using any suitable method described above. In addition, administration or treatment of the compounds can be continued for several days; for example, treatment would typically be continued for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and are often interspersed with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles in other embodiments may also be continuous.

VI. Combination therapy.

In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

- 95 045798

In some embodiments, when a compound described herein is combined with one or more additional therapeutic agents described herein, the components of the composition are administered in a simultaneous or sequential manner. When administered sequentially, the combination may be administered over two or more administrations.

In some embodiments, a compound described herein is combined with one or more additional therapeutic agents in a unit dosage form for concurrent administration to a patient, for example, in an oral solid dosage form.

In some embodiments, a compound described herein is administered in conjunction with one or more additional therapeutic agents.

Co-administration includes the administration of single doses of the compounds described herein before or after the administration of single doses of one or more additional therapeutic agents. The compounds described herein can be administered within seconds, minutes or hours of administration of one or more additional therapeutic agents. For example, in some embodiments, a single dose of a compound described herein is first administered, followed by a single dose of one or more additional therapeutic agents over several seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is first administered, then a unit dose of a compound described herein is administered at intervals of several seconds or minutes. In some embodiments, a single dose of a compound described herein is first administered, followed by administration after a period of time (eg, 1-12 hours) of a single dose of one or more additional therapeutic agents. In other embodiments, a single dose of one or more additional therapeutic agents is administered first, followed by administration after a period of time (eg, 1-12 hours) of a single dose of a compound described herein.

In some embodiments, a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb, or VIIc is prepared in the form of a tablet, which may optionally contain one or more other compounds suitable for treating the disease being treated. In some embodiments, the tablet may contain another active ingredient for the treatment of HBV infection, HIV infection, cancer, or a hyperproliferative disease. In some embodiments, such tablets are suitable for once daily dosing.

Also provided herein are methods of treatment wherein a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc, or a tautomer or pharmaceutically acceptable salt thereof, is administered to a patient in combination with one or more additional therapeutic agents or therapy. In some embodiments, the total daily dose of a compound of Formula I, II, IIa, III, IV, or V, or a tautomer or pharmaceutically acceptable salt thereof, may be about 300 mg/day administered as a single dose to a human.

Combination therapy for the treatment of HBV.

In some embodiments, there is provided a method of treating or preventing HBV infection in a person who has or is at risk for infection, comprising administering to the person a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more ( for example, one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method of treating HBV infection in a person who has or is at risk for infection, comprising administering to the person a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (eg, one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

In some embodiments, provided herein is a method of treating HBV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to four) additional therapeutic agents suitable for the treatment of HBV infection.

The compounds described herein can be used with or combined with one or more of a chemotherapeutic agent, an immunomodulator, an immunotherapeutic agent, a therapeutic antibody, a therapeutic vaccine, a bispecific antibody, and an antibody-like therapeutic protein (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugate (ADC), gene modifiers or gene editors (such as CRISPR Cas9, zinc finger nucleases, homing endonucleases, synthetic nucleases, TALENs), cell therapies such as CAR-T (chimeric antigen receptor T cells) and

- 96 045798 TCR-T (engineered T-cell receptor) agent or any combination thereof.

In some embodiments, the compound of formula (J) is provided in the form of a tablet, which may optionally contain one or more other compounds suitable for the treatment of HBV. In some embodiments, the tablet may contain another active ingredient for the treatment of HBV, such as 3-dioxygenase inhibitors (IDO), an apolipoprotein A1 modulator, arginase inhibitors, B- and T-lymphocyte attenuator inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, a chemokine antagonist CCR2, CD137 inhibitors, CD160 inhibitors, CD305 inhibitors, CD4 agonist and modulator, HBcAg-targeting compounds, hepatitis B internal antigen (HBcAg)-targeting compounds, core protein allosteric modulators, cccDNA inhibitors, inhibitors cyclophilin, cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors, DNA polymerase inhibitor, endonuclease modulator, epigenetic modifiers, farnesoid X receptor agonist, HBsAg inhibitors, inhibitors of HBsAg secretion or assembly, HBV DNA polymerase inhibitors, HBV replication inhibitors, inhibitors HBV RNases, HBV entry inhibitors, HBx inhibitors, hepatitis B large envelope protein modulator, hepatitis B large envelope protein stimulator, hepatitis B structural protein modulator, hepatitis B surface antigen (HBsAg) inhibitors, inhibitors of hepatitis B surface antigen secretion or assembly (HBsAg), hepatitis B virus E antigen inhibitors, hepatitis B virus replication inhibitors, hepatitis virus structural protein inhibitor, HIV-1 reverse transcriptase inhibitor, hyaluronidase inhibitor, IAP inhibitors, IL-2 agonist, IL-7 agonist, immunomodulators, indoleamine inhibitors -2, ribonucleotide reductase inhibitors, interleukin-2 ligand, ipi4 inhibitors, lysine demethylase inhibitors, histone demethylase inhibitors, KDM1 inhibitors, KDM5 inhibitors, natural killer cell lectin-like receptor (member 1 subfamily G) inhibitors, lymphocyte activation gene 3 inhibitors, lymphotoxin beta receptor activators, Axl modulators, B7-I3 modulators, B7-H4 modulators, CD160 modulators, CD161 modulators, CD27 modulators, CD47 modulators, CD70 modulators, GITR modulators, HEVEM modulators, ICOS modulators, Mer modulators, NKG2A modulators, NKG2D modulators, OX40 modulators, modulators SIRP-alpha, TIGIT modulators, Tim-4 modulators, Tyro modulators, Na+taurocholate co-transporting polypeptide (NTCP) inhibitors, natural killer cell receptor 2B4 inhibitors, NOD2 gene stimulator, nucleoprotein inhibitor, nucleoprotein modulators, PD-1 inhibitors, inhibitors PD-L1, peptidyl prolyl isomerase inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitors, retinoic acid inducible gene 1 stimulator, reverse transcriptase inhibitor, ribonuclease inhibitor, RNA-DNA polymerase inhibitor, SLC10A1 gene inhibitor, SMAC mimetics, Src tyrosine kinase inhibitor, agonists stimulator of interferon gene (STING), NOD1 stimulators, T cell surface glycoprotein CD28 inhibitor, T cell surface glycoprotein CD8 modulator, thymosin agonist, thymosin alpha 1 ligand, Tim-3 inhibitors, TLR-3 agonist, TLR-7 agonist, agonist TLR-9, TLR9 gene stimulator, toll-like receptor (TLR) modulators, viral ribonucleotide reductase inhibitor and combinations thereof.

Combination drugs against HBV.

Examples of combination drugs for the treatment of HBV include TRUVADA® (tenofovir disoproxil fumarate + emtricitabine); ABX-203, lamivudine and PEG-IFN-alpha; ABX-203 adefovir and PEGIFNalfa; and INO-1800 (INO-9112 and RG7944).

Other anti-HBV drugs.

Examples of other drugs for the treatment of HBV include alpha-hydroxytropolone, amdoxovir, beta-hydroxycytosine nucleosides, AL-034, CCC-0975, elvucitabine, ezetimibe, cyclosporine A, gentiopicrin (gentiopicroside), JNJ-56136379, nitazoxanide, birinapant, NJK14047, NOV -205 (molixan, BAM-205), oligotide, mivotilate, feron, GST-HG-131, levamisole, Ka Shu Ning, alloferon, WS-007, Y-101 (TiFen Tai), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepBnRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbama, IBPB-006IA, Hepuyinfen, DasKloster 0014 -01, ISA-204, Jiangantai (Ganxikang), MIV-210, OB-AI-004, PF-06, picroside, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, RO- 6864018, RG-7834, UB-551 and ZH-2N, as well as compounds described in US 20150210682, (Roche), US 2016/0122344 (Roche), WO 2015173164, WO 2016023877, US 2015252057A (Roche), WO1612 8335A1 (Roche ), WO16120186A1 (Roche), US 2016237090A (Roche), WO16107833A1 (Roche), WO16107832A1 (Roche), US 2016176899A (Roche), WO16102438A1 (Roche), WO16012470A1 (Roche), US 2016220 586A (Roche) and US 2015031687A (Roche) .

HBV vaccines.

HBV vaccines include both preventive and therapeutic vaccines. Examples of preventive HBV vaccines are selected from the group consisting of Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP-Hepb vaccine -Hib-IPV, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, preventive vaccine against hepatitis B (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B®, recombinant hepatitis B vaccines

- 97 045798 (intramuscular, Kangtai Biological Products), recombinant vaccine against hepatitis B (yeast Hansenual polymorpha, intramuscular, Hualan Biological Engineering), Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccines, DTP-HBV vaccines, Yi Tai, Heberbiovac HB, Trivac HB , GerVax, DTwP-Hep vaccines B-Hib, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6 , rhHBsAG vaccine and DTaP-rHB-Hib vaccine.

Examples of therapeutic HBV vaccines are selected from the group consisting of HBsAG-HBIG complex, ARB-1598, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP- 02, FP-02.2, TG-1050, NU-500, HBVax, im/TriGrid/antigen vaccine, Mega-CD40L-adjuvanted vaccine, HepB-v, RG7944 (INO-1800), recombinant VLP-based therapeutic vaccine (HBV infection , VLP Biotech), AdTG17909, AdTG-17910 AdTG-18202, ChronVac-B and Lm HBV.

HBV DNA polymerase inhibitors.

Examples of HBV DNA polymerase inhibitors include adefovir (HEPSERA®), emtricitabine (EMTRIVA®), tenofovir disoproxil fumarate (VIREAD®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxy la fumarate, tenofovir disoproxil hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ether, CMX-157, bezifovir, entecavir (Baraclude®), entecavir maleate, telbivudine (Tyzeka®), filocylovir, pradefovir, clevudine, ribavirin, lamivudine (Epivir-HBV®), fos fazid, famciclovir, fusolin, metacavir, SNC-019754, FMCA, AGX-1009, AR-II-04-26, HIP-1302, tenofovir disoproxil aspartate, tenofovir disoproxil orotate and HS-10234.

Immunomodulators.

Examples of immunomodulators include rintatolimod, imidol hydrochloride, ingaron, dermavir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and mycophenolate mofetil ester derivative (MMF), JNJ-440, WF-10, AB-452, ribavirin, IL- 12, INO9112, polymer polyethylenimine (PEI), Gepon, VGV-1, MOR-22, CRV-431, JNJ-0535, TG-1050, ABIH2158, BMS-936559, GS-9688, RO-7011785, RG-7854, AB-506, RO-6871765, AIC-649 and IR-103.

Toll-like receptor (TLR) modulators.

TLR modulators include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13 modulators. Examples of TLR3 modulators include rintatolimod, polyICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475 and ND-1.1.

Examples of TLR7 modulators include GS-9620 (vesatolimod), GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052 , Limtop, D, telratolimod, SP-0509, TMX-30X, TMX-202, RG-7863, RG-7795, LHC-165, RG-7854 and compounds described in US 20100143301 (Gilead Sciences), US 20110098248 (Gilead Sciences) and US 20090047249 (Gilead Sciences).

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO4200, VTX-763, VTX-1463, GS-9688 and compounds described in US 20140045849 (Janssen), US 20140073642 (Janssen), WO 2014/056953 (Janssen), WO 2014/076221 (Janssen), WO 2014/128189 (Janssen), US 20140350031 (Janssen), WO 2014/023813 (Janssen), US 20080234251 (Array Biopharma), US 200803060 50 (Array Biopharma ), US 20100029585 (Ventirx Pharma), US 20110092485 (Ventirx Pharma), US 20110118235 (Ventirx Pharma), US 20120082658 (Ventirx Pharma), US 20120219615 (Ventirx Pharma), US 20140066432 (Ventirx Pharma), US 2 0140088085 (Ventirx Pharma) , US 20140275167 (Novira Therapeutics), US 20130251673 (Novira Therapeutics), US patent 9670205, US 20160289229, US patent applications 15/692161 and 15/692093.

Examples of TLR9 modulators include BB-001, BB-006, CYT-003, IMO-2055, MO-2125, MO-3100, IMO-8400, IR-103, IMO-9200, agatolimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, levolimod (MGN1703), litenimod and CYT-003-QbG10.

Examples of TLR7, TLR8 and TLR9 modulators include the compounds described in

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WO2017047769 (Teika Seiyaku), WO2015014815 (Janssen), W02018045150 (Gilead Sciences Inc), WO2018045144 (Gilead Sciences Inc), WO2015162075 (Roche), WO2017034986 (University of Kansas), WO201809542 6 (Jiangsu Hengrui Medicine Co Ltd), WO2016091698 (Roche) , WO2016075661 (GlaxoSmithKline Biologicals), WO2016180743 (Roche), WO2018089695 (Dynavax Technologies), WO2016055553 (Roche), WO2015168279 (Novartis), WO2016107536 (Medshine Discovery), WO201808659 3 (Livo (Shanghai) Pharmaceutical), WO2017106607 (Merck), WO2017061532 ( Sumitomo Dainippon Pharma), WO2016023511 (Chia Tai Tianqing Pharmaceutical), WO2017076346 (Chia Tai Tianqing Pharmaceutical), WO2017046112 (Roche), WO2018078149 (Roche), WO2017040233 (3M Co), WO2016141092 (Gilead Sciences), WO2018049089 (BristolMyers Squibb), WO2015057655 (Eisai Co Ltd) Novartis), WO2016142250 (Roche ), WO2015168269 (Novartis), WO201804163 (Roche), WO2018038877 (3M Co), WO2015057659 (Eisai Co Ltd), WO2017202704 (Roche), WO2018026620 (BristolMyers Squibb), WO2016029077 (Janus Bio therapeutics), WO201803143 (Merck), WO2016096778 (Roche ), WO2017190669 (Shanghai De Novo Pharmatech), US09884866 (University of Minnesota), WO2017219931 (Sichuan KelunBiotech Biopharmaceutical), WO2018002319 (Janssen Sciences), WO2017216054 (Roche), WO2017202703 (Roche), WO201 7184735 (IFM Therapeutics), WO2017184746 (IFM Therapeutics ), WO2015088045 (Takeda Pharmaceutical), WO2017038909 (Takeda Pharmaceutical), WO2015095780 (University of Kansas), WO2015023958 (University of Kansas).

Interferon alpha receptor ligands.

Examples of interferon-alpha receptor ligands are selected from the group consisting of interferon alpha-2b (INTRON A®), pegylated interferon alpha-2a (Pegasys®), pegylated interferon alpha-1b, interferon alpha-1b (Hapgen®), Veldona, Infradure , Roferon-A, YPEG-interferon alpha-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant supercomponent interferon), YPEG-interferon alpha-2b (YPEG -rhIFNalpha2b), MOR-22, peginterferon alpha-2b (PEG-Intron®), Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon alpha-n1 (Humoferon®), interferon beta-1a (Avonex®), Shaferon , interferon alpha-2b (AXHO), Alfaferon, interferon alpha-2b (BioGeneric Pharma), interferon alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon -B, interferon alpha 2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Calferon, Pegnano, Feronsure, PegiHep, interferon alpha 2b (Zydus-Cadila), interferon alpha 2a, Optipeg A, Realfa 2B, Reliferon, interferon alpha 2b (Amega), interferon alpha-2b (Virchow), ropeginterferon alpha-2b, rHSA-IFN alpha-2a (recombinant human serum albumin-interferon alpha 2a fusion protein), rHSA-IFN alpha 2b, recombinant human interferon alpha (1b, 2a, 2b), peginterferon alpha-2b (Amega), peginterferon alpha-2a, Reaferon-EC, Prokviferon, Uniferon, Urifron, interferon alpha-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, Laifferon, Shang Sheng Lei Tai , INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b, SFR-9216 and Interapo (Interapa).

Hyaluronidase inhibitors.

Examples of hyaluronidase inhibitors include astodrimer.

Hepatitis B surface antigen (HBsAg) inhibitors.

Examples of HBsAg inhibitors include HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP9AC, REP-9C, REP-9, REP-2139, REP-2139-Ca, REP-2165, REP- 2055, REP-2163, REP-2165, REP-2053, REP-2031, REP-006 and REP-9AC.

Examples of HBsAg secretion inhibitors include BM601.

Inhibitors of cytotoxic T-lymphocyte-associated protein 4 (ipi4).

Examples of cytotoxic T-lymphocyte-associated protein 4 (ipi4) inhibitors include

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AGEN-2041, AGEN-1884, ipilumimab, belatacept, PSI-001, PRS-010, Probody mAb, tremelimumab and

JHL-1155.

Cyclophilin inhibitors.

Examples of cyclophilin inhibitors include CPI-431-32, EDP-494, OCB-030, SCY-635, NVP-015, NVP-018, NVP-019, STG-175 and the compounds described in US8513184 (Gilead Sciences), US 20140030221 (Gilead Sciences), US 20130344030 (Gilead Sciences) and US 20130344029 (Gilead Sciences).

Inhibitors of HBV virus entry.

Examples of HBV entry inhibitors include Myrcludex B.

Antisense oligonucleotide targeting viral mRNA.

Examples of antisense oligonucleotide targeting viral mRNA include ISISHBVRx, IONIS-HBVRx, IONIS-GSK6-LRx, GSK-3389404, RG-6004.

Small interfering RNA (siRNA) and ddRNAi.

Examples of siRNAs include TKM-HBV (TKM-HepB), ALN-HBV, SR-008, HepB-nRNA, and ARC520, ARC-521, ARB-1740, ARB-1467.

Examples of DNA-directed RNA interference (ddRNAi) include BB-HB-331.

Endonuclease Modulators Examples of endonuclease modulators include PGN-514.

Ribonucleotide reductase inhibitors Examples of ribonucleotide reductase inhibitors include trimidox.

HBV E Antigen Inhibitors Examples of HBV E antigen inhibitors include wogonin.

Covalently closed circular DNA (cccDNA) inhibitors Examples of cccDNA inhibitors include BSBI-25 and CHR-101.

Farnesoid X receptor agonist.

Examples of farnesoid x receptor agonists include EYP-001, GS-9674, EDP-305, MET-409, Tropifexor, AKN-083, RDX-023, BWD-100, LMB-763, INV-3, NTX- 023-1, EP-024297 and GS-8670.

Antibodies to HBV.

Examples of HBV antibodies targeting hepatitis B virus surface antigens include GC-1102, XTL-17, XTL-19, KN-003, IV Hepabulin SN, and fully human monoclonal antibody therapy (Hepatitis B Virus Infection, Humabs BioMed).

Examples of anti-HBV antibodies, including monoclonal antibodies and polyclonal antibodies, are selected from the group consisting of Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe , Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088).

Fully human monoclonal antibodies include HBC-34.

CCR2 Chemokine Antagonists Examples of CCR2 chemokine antagonists include propagermanium.

Thymosin agonists.

Examples of thymosin agonists include thymalfasin, recombinant thymosin alpha 1 (GeneScience).

Cytokines.

Examples of cytokines include recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), IL-15, IL-21, IL-24 and celmoleukin.

Nucleoprotein modulators.

Nucleoprotein modulators may be inhibitors of the HBV core or capsid protein. Examples of nucleoprotein modulators include GS-4882, AB-423, AT-130, GLS4, NVR1221, NVR-3778, AL-3778, BAY 41-4109, morphothiadine mesylate, ARB-168786, ARB-880, JNJ-379, RG7907, NEC-72702, AB-506, ABI-H0731, JNJ-440, ABI-H2158 and DVR-23.

Examples of capsid inhibitors include those described in

- 100 045798

US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen),

WO2015/059212 (Janssen),

WO2014184365 (Janssen),

WO2013 096744 (Novira),

US20150315159 (Novira),

WO2015118057 (Janssen), W02014184350 (Janssen), US20150225355 (Novira), US20150197533 (Novira),

WO2015011281 (Janssen),

WO2014161888 (Janssen), US20140178337 (Novira), US20150274652 (Novira),

US20150259324, (Novira), US20150132258 (Novira), US9181288 (Novira), WO2014184350 (Janssen), WO2013144129 (Roche), WO2017198744 (Roche), US 20170334882 (Novira), US 2017033 4898 (Roche), WO2017202798 (Roche), WO2017214395 ( Enanta), WO2018001944 (Roche), WO2018001952 (Roche), WO2018005881 (Novira), WO2018005883 (Novira), WO2018011100 (Roche), WO2018011160 (Roche), WO2018011162 (Roche), WO20180 11163 (Roche), WO2018036941 (Roche), WO2018043747 ( Kyoto Univ), US20180065929 (Janssen), WO2016168619 (Indiana University), WO2016195982 (The Penn State Foundation),

WO2017001655 (Janssen), WO2017048950 (Assembly Biosciences), WO2017048954 (Assembly Biosciences), WO2017048962 (Assembly Biosciences), US20170121328 (Novira), US20170121329 (Novira).

Examples of transcript inhibitors include those described in

WO2017013046 (Roche), WO2017016960 (Roche), WO2017017042 (Roche), WO2017017043 (Roche), WO2017061466 (Toyoma chemicals), WO2016177655 (Roche), WO2016161268 (Enanta). WO2017001853 (Redex Pharma), WO2017211791 (Roche), WO2017216685 (Novartis), WO2017216686 (Novartis), WO2018019297 (Ginkgo Pharma), WO2018022282 (Newave Pharma), US20180030053 (Novartis), WO20 18045911 (Zhejiang Pharma).

Stimulators of retinoic acid-inducible gene 1.

Examples of retinoic acid inducible gene 1 stimulators include SB-9200, SB-40, SB44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI-7170, RGT-100.

NOD2 stimulants.

Examples of NOD2 stimulants include SB-9200.

Phosphatidylinositol 3-kinase (PI3K) inhibitors.

Examples of PI3K inhibitors include idelalisib, ACP-319, AZD-8186, AZD-8835, buparlisib, CDZ-173, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, IPI -549, UCB-5857, taselisib, XL-765, gedatolisib, ME-401, VS-5584, copanlisib, CAI orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK- 2126458, CUDC907, PQR-309, INCB-40093, piralalisib, BAY-1082439, pikquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib , LY-3023414, SAR-260301, TAK-117, HMPL-689, tenalisib, voxtalisib and CLR-1401.

Indoleamine 2,3-dioxygenase (IDO) pathway inhibitors.

Examples of IDO inhibitors include epacadostat (INCB24360), resminostat (4SC-201), indoximod, F-001287, SN-35837, NLG-919, GDC-0919, GBV-1028, GBV-1012, NKTR-218 and the compounds described in US 20100015178 (Incyte), US 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.) and WO 2015188085 (Flexus Biosciences, Inc.).

PD-1 inhibitors.

Examples of PD-1 inhibitors include cemiplimab, nivolumab, pembrolizumab, pidilizumab, BGB-108, STI-A1014, SHR-1210, PDR-001, PF-06801591, IBI-308, GB-226, STI-1110, JNJ-63723283, CA170, durvalumab, atezolizumab and mDX-400, JS-001, camrelizumab, sintilimab, sintilimab, tislelizumab, BCD-100, BGB-A333, JNJ-63723283, GLS-010 (WBP-3055), CX-072, AGEN-2034 , GNS-1480 (epidermal growth factor receptor antagonist; programmed cell death ligand 1 inhibitor), CS-1001, M-7824 (bifunctional PD-L1/TGF-P fusion protein), genolimzumab, BMS-936559.

PD-L1 inhibitors.

Examples of PD-L1 inhibitors include atezolizumab, avelumab, AMP-224, MEDI-0680, RG-7446, GX-P2, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI- A1014, GS-4224, CX-072 and BMS-936559.

Examples of PD-1 inhibitors include those described in

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WO2017112730 (Incyte Corp), WO2017087777 (Incyte Corp), WO2017017624, WO2014151634 (BristolMyers Squibb Co), WO201317322 (BristolMyers Squibb Co), WO2018119286 (Incyte Corp), WO2018119266 (Incyte Corp), WO2018119263 (Incyte Corp), WO2018119236 (Incyte Corp ), WO2018119221 (Incyte Corp), WO2018118848 (BristolMyers Squibb Co), WO20161266460 (BristolMyers Squibb Co), WO2017087678 (BristolMyers Squibb Co), WO2016149351 (BristolMyers Squibb Co), WO2015033299 (Aurigene Discovery Technologies Ltd), WO2015179615 (Eisai Co Ltd; Eisai Research Institute), WO2017066227 (BristolMyers Squibb Co), WO2016142886 (Aurigene Discovery Technologies Ltd), WO2016142852 (Aurigene Discovery Technologies Ltd), WO2016142835 (Aurigene Discovery Technologies Ltd; Individual), WO2016142833 (Aurigene Discovery Technologies Ltd), WO2018085 750 (BristolMyers Squibb Co), WO2015033303 (Aurigene Discovery Technologies Ltd), WO2017205464 (Incyte Corp), WO2016019232 (3M Co; Individual; Texas A&M University System), WO2015160641 (BristolMyers Squibb Co), WO2017079669 (Incyte Corp), WO2015033301 (Aurigen eDiscovery Technologies Ltd) , WO2015034820 (BristolMyers Squibb Co), WO2018073754 (Aurigene Discovery Technologies Ltd), WO2016077518 (BristolMyers Squibb Co), WO2016057624 (BristolMyers Squibb Co), WO2018044783 (Incyte Corp), WO2016100608 (B ristolMyers Squibb Co), WO2016100285 (BristolMyers Squibb Co), WO2016039749 (BristolMyers Squibb Co), WO2015019284 (Cambridge Enterprise Ltd), WO2016142894 (Aurigene Discovery Technologies Ltd), WO2015134605 (BristolMyers Squibb Co), WO2018051255 (Aurigene Discovery Technologies Ltd), WO2018051254 (Aurigene Discovery Technologies Ltd), WO2017222976 (Incyte Corp) , WO2017070089 (Incyte Corp), WO2018044963 (BristolMyers Squibb Co), WO2013144704 (Aurigene Discovery Technologies Ltd), WO2018013789 (Incyte Corp), WO2017176608 (BristolMyers Squibb Co), WO2018009505 (BristolMyers S quibb Co), WO2011161699 (Aurigene Discovery Technologies Ltd), WO2015119944 (Incyte Corp; Merck Sharp & Dohme Corp), WO2017192961 (Incyte Corp), WO2017106634 (Incyte Corp), WO2013132317 (Aurigene Discovery Technologies Ltd), WO2012168944 (Aurigene Discovery Technologies Ltd), WO2015036927 (Aurigene Discovery Technologies Ltd), WO2015044900 (Auri gene Discovery Technologies Ltd) , WO2018026971 (Arising International).

Other examples of PD-1 and/or PDL-1 inhibitors include the compounds described in US provisional patent applications Serial Numbers 62/630187, 62/640534, 62/736116 and 62/747029.

Recombinant thymosin alpha-1.

Examples of recombinant thymosin alpha-1 include NL-004 and PEGylated thymosin alpha-1. Bruton's tyrosine kinase inhibitors (BTK).

Examples of BTK inhibitors include ABBV-105, acalabrutinib (ACP-196), ARQ-531, BMS986142, dasatinib, ibrutinib, GDC-0853, PRN-1008, SNS-062, ONO-4059, BGB-3111, ML-319, MSC2364447 , RDX-022, X-022, AS-058, RG-7845, spebrutinib, TAS-5315, TR-0158, TR-4207, NM-71224, KVR7536, M-2951, TAK-020, AS-0025, and compounds described in US 20140330015 (Ono Pharmaceutical), US 20130079327 (Ono Pharmaceutical) and US 20130217880 (Ono Pharmaceutical).

KDM inhibitors.

Examples of KDM5 inhibitors include those described in WO 2016057924 (Genentech/Constellation Pharmaceuticals), US 20140275092 (Genentech/Constellation Pharmaceuticals), US 20140371195 (Epitherapeutics) and US 20140371214 (Epitherapeutics), US 20160102096 (Epi therapeutics), US 20140194469 (Quanticel), US 20140171432, US 20140213591 (Quanticel), US 20160039808 (Quanticel), US 20140275084 (Quanticel), WO 2014164708 (Quanticel).

Examples of KDM1 inhibitors include compounds described in US 9186337B2 (Oryzon Genomics), GSK-2879552 and RG-6016.

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STING agonists.

Examples of STING agonists include SB-11285, AdVCA0848, STINGVAX and the compounds described in WO 2018065360 (Biolog Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, Germany), WO 2018009466 (Aduro Biotech), WO 2017186711 (InvivoGen), WO 20171 61349 (Immune Sensor), WO 2017106740 (Aduro Biotech), US 20170158724 (Glaxo Smithkiline), WO 2017075477 (Aduro Biotech), US 20170044206 (Merck), WO 2014179760 (University of California), WO 2018098203 (Janssn), WO 2018118665 (Merck), WO 2018118664 (Merck), WO 2018100558 (Takeda), WO 2018067423 (Merck), WO 2018060323 (Boehringer).

Non-nucleoside reverse transcriptase inhibitors (NNRTIs).

Examples of NNRTIs include those described in WO 2018118826 (Merck), WO 2018080903 (Merck), WO 2018119013 (Merck), WO 2017100108 (Idenix), WO 2017027434 (Merck), WO 2017007701 (Merck), WO 20 08005555 (Gilead).

HBV replication inhibitors.

Examples of hepatitis B virus replication inhibitors include isothiafludine, IQP-HBV, RM-5038 and Xingantie.

Arginase inhibitors.

Examples of arginase inhibitors include CB-1158, C-201 and resmiostat.

Gene therapy and cell therapy.

Gene therapy and cell therapy involve genetic modification to silence a gene; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells or to activate the patient's own immune system to destroy infected cells or to detect and destroy infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

Gene editors.

Examples of genome editing systems include the CRISPR/Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system; for example, elimination of cccDNA through targeted cleavage and alteration of one or more hepatitis B virus (HBV) viral genes. A change (e.g., knockout and/or knockdown) of the PreC, C, X, PreSI, PreS2, S, P, or SP genes refers to (1) reducing or eliminating the expression of the PreC, C, X, PreSI, PreS2, S, P, or SP, (2) interference with Precore, Core, X, long surface protein, middle surface protein, S protein (also known as HBs antigen and HBsAg), polymerase protein, and/or hepatitis B spliced protein (HBe) function HBc, HBx, PreS1, PreS2, S, Pol and/or HBSP) or (3) reduction or elimination of intracellular, serum and/or intraparenchymal levels of HBe, HBc, HBx, LHB, MNV, SHB, Pol and/or HBSP proteins. Knockdown of one or more genes PreC, C, X, PreS1, PreS2, S, P and/or SP is accomplished by targeting the cccDNABrB gene(s) and/or integrated HBV DNA.

CAR-T cell therapy.

CAR-T cell therapy involves a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), where the CAR contains the HBV antigen-binding domain. The immune effector cell is a T cell or NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cells can be autologous or allogeneic.

TCR-T cell therapy.

TCR T cell therapy involves T cells expressing HBV-specific T cell receptors. TCR-T cells are engineered to target HBV-produced peptides presented on the surface of virus-infected cells. In some embodiments, the T cells express a TCR specific for HBV surface antigen (HBsAg). Examples of TCR-T therapies aimed at treating HBV include LTCR-H2-1.

In another specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with an inhibitor of HBV DNA polymerase, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, inhibitors of HBsAg secretion or assembly, therapeutic HBV vaccines, HBV antibodies, including anti-HBV antibodies targeting hepatitis B virus surface antigens, and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab or TCR derivatives -like antibodies), cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators, and one or two additional therapeutic agents selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigens, short interfering RNA (siRNA), microRNA agents for gene

- 103 045798 therapies, short hairpin RNAs (sshRNAs), KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

In another specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with an inhibitor of HBV DNA polymerase and at least a second additional therapeutic agent selected from the group consisting of: immunomodulators, TLR modulators, HBsAg inhibitors, therapeutic HBV vaccines, HBV antibodies, including anti-HBV antibodies targeting hepatitis B virus surface antigens, and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives, or TCR-like antibodies) , cyclophilin inhibitors, retinoic acid-inducible gene 1 stimulators, RIG-I-like receptor stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase inhibitors, PI3K inhibitors, IDO inhibitors and NOD2 stimulators.

In another specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA, anti-HBV antibodies targeting hepatitis B virus surface antigens, siRNAs, microRNA gene therapy agents, sshRNAs, KDM5 inhibitors and nucleoprotein modulators (HBV core or capsid protein modulators).

In a certain embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with compounds such as those described in US Publication No. 2010/0143301 (Gilead Sciences), 2011/0098248 (Gilead Sciences), 2009/0047249 (Gilead Sciences) , US Patent No. 8722054 (Gilead Sciences), US Publication No. 2014/0045849 (Janssen), US Publication No. 2014/0073642 (Janssen), WO 2014/056953 (Janssen), WO 2014/076221 (Janssen), WO 2014/128189 (Janssen), US Publication No. 2014/0350031 (Janssen), wO 2014/023813 (Janssen), US Publication No. 2008/0234251 (Array Biopharma), US Publication No. 2008/0306050 (Array Biopharma), US Publication No. 2010/0029585 (Ventirx Pharma), US Publication No. 2011/0092485 (Ventirx Pharma), US Publication No. 2011/0118235 (Ventirx Pharma), US Publication No. 2012/0082658 (Ventirx Pharma), US Publication No. 2012/0219615 (Ventirx Pharma), US Publication No. 2014/0066432 (Ventirx Pharma), US Publication No. 2014/0088085 (Ventirx Pharma), US Publication No. 2014/0275167 (Novira Therapeutics), US Publication No. (Novira Therapeutics), US Patent No. 8513184 (Gilead Sciences), US Publication No. 2014/0030221 (Gilead Sciences), US Publication No. 2013/0344030 (Gilead Sciences), US Publication No. 2013/0344029 (Gilead Sciences), US 20140275167 (Novira Therapeutics), US 20130251673 (Novira Therapeutics), US Publication No. 2014/03430 32 (Roche), WO 2014037480 (Roche), US Publication No. 2013/0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen), WO 2015/059 212 (Janssen ), WO 2015118057 (Janssen), WO 2015011281 (Janssen), WO 2014184365 (Janssen), WO 2014184350 (Janssen), WO 2014161888 (Janssen), WO 2013096744 (Novira), US 20150225355 (No. vira), US 20140178337 (Novira), US 20150315159 (Novira), US 20150197533 (Novira), US 20150274652 (Novira), US 20150259324, (Novira), US 20150132258 (Novira), US9181288 (Novira), WO 2014184350 (Janssen), WO 2013144129 (Roche), US 20100015178 (Incyte), US 2016137652 (Flexus Biosciences, Inc.), WO 2014073738 (Flexus Biosciences, Inc.), WO 2015188085 (Flexus Biosciences, Inc.), US Publication No. 2014/0330015 (Ono Pharmaceutical), US Publication No. 2013/ 0079327 (Ono Pharmaceutical), US Publication No. 2013/0217880 (Ono pharmaceutical), WO 2016057924 (Genentech/Constellation Pharmaceuticals), US 20140275092 (Genentech/ConstellationPharmaceuticals), US 20140371195 (Epitherapeutics) and US 2014037121 4 (Epitherapeutics), US 20160102096 (Epitherapeutics ), US 20140194469 (Quanticel), US 20140171432, US 20140213591 (Quanticel), US 20160039808 (Quanticel), US 20140275084 (Quanticel), WO 2014164708 (Quanticel), US 9186337 B2 (Oryzon Genomics), and other drugs for the treatment of VIV , and their combinations.

Combination therapy for the treatment of HIV.

In some embodiments, there is provided a method of treating or preventing HIV infection in a human or animal having or at risk of having said infection, comprising administering to the human or animal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, there is provided a method of treating HIV infection in a human or animal having or at risk of having said infection, comprising administering to the human or animal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents.

In one embodiment, pharmaceutical compositions are provided containing a compound described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents; and a pharmaceutically acceptable carrier, diluent or excipient.

In some embodiments, provided herein is a method of treating HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infections.

In some embodiments, the compounds described herein are formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site inhibitors of HIV integrase (allosteric inhibitors) , pharmacokinetic enhancers, and any combinations thereof.

In some embodiments, such tablets are suitable for once daily dosing.

In some embodiments, the additional therapeutic agent may be an anti-HIV agent. In some embodiments, said additional therapeutic agent is selected from the group consisting of HIV combination drugs, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic (or allosteric) site inhibitors HIV integrase, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cellular therapies (such as chimeric antigen receptor T cells, CAR-T, and engineered T cell receptor, TCR-T), latency reversing agents, compounds that target the HIV capsid (including capsid inhibitors), immunolytic therapies, phosphatidylinositol inhibitors3- kinase (PI3K), alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans isomerase A modulators, protein inhibitors -disulfide isomerase, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif polymerization antagonists, HIV-1 viral infectious factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-origin kinase inhibitors 3 (MLK-3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 capture nonintegrin 1, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, ATP-dependent RNA helicase DDX3X inhibitors, complex inhibitors reverse transcriptase, G6PD and NADPH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, or any combination thereof.

In some embodiments, said additional therapeutic agent is selected from the group consisting of combination drugs for the treatment of HIV, other drugs for the treatment of HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic (or allosteric) site inhibitors of HIV integrase, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immunolytic therapies, PI3K inhibitors, HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, or any combinations thereof.

Combination drugs against HIV.

Examples of combination drugs include the following: ATRIPLA® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), COMPLERA® (EVIPLERA® rilpivirine + tenofovir disoproxil fumarate + emtricitabine), STRIBILD® (elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine), TRUVADA® ( tenofovir disoproxil fumarate + emtricitabine, TDF + FTC), DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); BIKTARVY® (bictegravir, emtricitabine and tenofovir alafenamide); darunavir, tenofovir ala- 105 045798 fenamide hemifumarate, emtricitabine and cobicistat; efavirenz + lamivudine + tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir and lamivudine); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; doravirine, lamivudine and tenofovir disoproxil; dolutegravir+lamivudine, lamivudine+abacavir+zidovudine, lamivudine+abacavir, lamivudine+tenofovir disoproxil fumarate, lamivudine+zidovudine+nevirapine, lopinavir+ritonavir, lopinavir+ritonavir+abacavir+lamivudine, lopinavir+ritonavir+zidovudine+lamivudine, tenofovir+lamivudine and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and ARN-0812 or any combinations thereof.

HIV protease inhibitors.

Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, nelfinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100 ), T-169, BL-008 and TMS-310911.

HIV reverse transcriptase inhibitors.

Examples of non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005 and VM-1500.

Examples of nucleoside or nucleotide HIV reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir di Zoproxil hemifumarate, VIDEX® and VTDEX EU® (didanosine , ddl), abacavir, abacavir sulfate, alovudine, abricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, tenofovir disoproxil orotate, fosivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, GS-91 31, G.S. -9148, MK-8504 and KP-1461.

HIV integrase inhibitors.

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeine phenethyl ester derivatives oh acids, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting derivatives for injection), diketo-quinoline-4-1 derivatives, integrase inhibitor-LEDGF, leggins , M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169 and cabotegravir.

Examples of non-catalytic (allosteric) site inhibitors of HIV integrase (NCINI) include CX-05045, CX-05168 and CX-14442.

HIV entry inhibitors.

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gp120 inhibitors and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO140, adaptavir (RAP-101), nifeviroc (TD-0232), bispecific antibodies against GP120/CD4 or CCR5, B-07, MB-66, C25P polypeptide, TD- 0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Vars), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab and CADA analogues.

Examples of gp120 inhibitors include Radha-108 (recepol) ZV3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831 and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors.

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Agents that reverse latency.

Examples of latency reversing agents include histone deacetylase inhibitors

- 106 045798 (HDAC), proteasome inhibitors such as Velcade, protein kinase C (PKC) activators, inhibitors

Smyd2, BET bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid or suberoyl, anilide and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies , JQ1, disulfiram, amphotericin B and ubiquitin inhibitors such as largazole analogues and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat and panobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B and DAG lactones.

Capsid inhibitors.

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301 and a number of AVI- CAN1-15.

Immune therapy.

Examples of immune therapies include toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12 and TLR13; modulators of programmed cell death protein 1 (Pd-1); programmed death ligand 1 (PdL1) modulators; IL-15 modulators; DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-i3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and the ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, a polymer polyethylenimine (PEI); Gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107; interleukin-15/Fc fusion protein; normferon; peginterferon alfa-2a; peginterferon alpha-2b; recombinant interleukin-15; RPI-MN; GS-9620; STING modulators; modulators RIG-1; NOD2 modulators; IR-103.

Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO4200, VTX-763, VTX-1463, and those described in

US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen),

WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventir x Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira Therapeutics), US20130251673 (Novira Therapeutics), US Pat. Sciences Inc.), US20160289229 (Gilead Sciences Inc. .), US Patent Application No. 15/692161 (Gilead Sciences

Inc.) and US Patent Application No. 15/692093 (Gilead Sciences Inc.).

Phosphatidylinositol 3-kinase (PI3K) inhibitors.

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-31 9, AZD-8186, BAY -1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB040093, LY-3023414, MLN-1117, PQR-309, RG -7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

Alpha-4/beta-7 antagonists.

Examples of alpha-4/beta-7 integrin antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrad methyl and vedolizumab.

Antibodies to HIV, bispecific antibodies and antibody-like therapeutic proteins.

Examples of HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bnAB (HIV-1 broadly neutralizing antibodies), BMS-936559, TMB-360, and those targeting HIV gp120 or gp41, HIV-targeting antibody recruitment molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, single-domain anti-nef antibodies, anti-Rev antibodies, camelid antibodies anti-CD18, camelid anti-ICAM-1, DCVax-001, gp140-targeting antibodies, gp41-based therapeutic HIV antibodies, recombinant human mAb (PGT121), ibalizumab, Immuglo and MB-66.

Additional examples include bavituximab, UB-421, C2F5, 2G12, C4E10,

C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10 E8, 10E8v4, CAP256- VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, MGD-014 and VRC07.

- 107 045798

Additional examples of bispecific antibodies to HIV include MGD014.

Pharmacokinetic enhancers.

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV vaccines.

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-based peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) ( RV144), vaccine with monomeric gp120 HIV-1 subtype C, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade Recombinant adenovirus DNA-5 (rAd5), (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA51, poly-ICLC adjuvanted vaccines , Tatlmmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TVl+MF-59, rVSVINHIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC -M4, HIVAX, HIVAX2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVIHIV-1, Ad-4 (Ad4-env Clade C +Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01 , TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine, CombiVICHvac, LFn-p24 B/C hybrid vaccine, GTU DNA vaccine, HIV gag DNA vaccine pol/nef/env, anti-TAT HIV vaccine, polypeptide-based conjugate vaccine, dendritic cell vaccines, gag-based DNA vaccine, GI-2010, HIV-1 gp41 vaccine, HIV vaccine (PIKA adjuvant), hybrid peptide epitope I i-key/MHC class II vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNA active HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, CV1HIV gp120, Vacc-4x+romidepsin, variant polypeptide gp120 vaccine , rAd5 gag-pol env A/B/C vaccine, DNA.HT1 and MVA.HTI.

Additional therapeutic agents against HIV.

Examples of additional therapeutic agents against HIV include compounds described in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/ 003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania ), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 ( Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

Examples of other drugs for the treatment of HIV include acemannan, alisporivir, BanLec, deferiprone, gamimune, methenkephalin, naltrexone, prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl- TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, ARN-0812, BIT-225, CYT-107, HGTV-43, NRN-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, RA-1050040 (RA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR -452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

Gene therapy and cell therapy.

Gene therapy and cell therapy involve genetic modification to silence a gene; genetic approaches to directly kill infected cells; infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells or to activate the patient's own immune system to destroy infected cells or to detect and destroy infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response to infection.

Examples of dendritic cell therapies include AGS-004.

Gene editors.

Examples of gene editing systems include the CRISPR/Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

Examples of CRISPR/Cas9 systems targeting HIV include EBT101.

CAR-T cell therapy.

CAR-T cell therapy involves a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), where the CAR contains the antigen binding domain of HIV. HIV antigens include the HIV envelope protein or part thereof, gp120 or part thereof, the CD4 binding site on gp120, the binding site induced by CD4 on gp120, N-glycan on gp120, V2 gp120 and membrane proximal region on gp41. In some embodiments, the immune effector cell is a T cell or NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.

Examples of HIV CAR-T cell therapies include VC-CAR-T.

TCR-T cell therapy.

TCR-T cell therapy involves T cells engineered to target HIV-derived peptides present on the surface of virus-infected cells.

One skilled in the art will appreciate that the additional therapeutic agents listed above may fall into more than one of the classes listed above. Specific classes are not intended to limit the functionality of those connections that are listed in those classes.

In a specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor and an HIV protease inhibitor compound. In a further embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with at least one nucleoside HIV reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with two nucleoside or nucleotide HIV reverse transcriptase inhibitors.

In a specific embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from the following: ATRIPLA® (efavirenz+tenofovir disoproxil fumarate+emtricitabine); COMPLERA® (EVIPLERA®, rilpivirine + tenofovir disoproxil fumarate + emtricitabine); STRIBILD® (elvitegravir+cobicistat+tenofovir disoproxil fumarate+emtricitabine); TRUVADA® (tenofovir disoproxil fumarate + emtricitabine, TDF + FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); BIKTARVY® (bictegravir, emtricitabine and tenofovir alafenamide); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (prescription); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine and zidovudine; abacavir; abacavir sulfate.

In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with the following: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

In a specific embodiment, a compound described herein, or a pharmaceutically acceptable salt thereof, is combined with the following: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

In a certain embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate and bictegravir, and a second an additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

- 109 045798

In a certain embodiment, a compound described herein or a pharmaceutically acceptable salt thereof is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate and bictegravir, and a second additional therapeutic agent wherein the second additional therapeutic agent is emtricitabine.

A compound described herein can be combined with one or more additional therapeutic agents at any amount of compound per dose (eg, from 1 mg to 500 mg of compound).

In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. A compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa , VIIb or VIIc) can be combined with the agents provided herein at any amount of compound per dose (eg, from 1 mg to 500 mg of compound), as if each dosage combination were specifically and individually indicated.

In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound described herein or a pharmaceutically acceptable salt thereof is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. A compound described herein (e.g., a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa , VIIb or VIIc) can be combined with the agents provided herein at any amount of compound per dose (eg, from 1 mg to 500 mg of compound), as if each dosage combination were specifically and individually indicated.

Combination therapy for cancer and/or hyperproliferative disease.

In one embodiment, a compound described herein can be used with other therapeutic methods for treating cancer. Preferably, combination therapy is provided with chemotherapy, hormonal treatment, antibody treatment, surgery and/or radiotherapy.

In some embodiments, the additional anticancer therapy is surgery and/or radiation therapy. In some embodiments, the additional anticancer therapy is at least one additional anticancer drug.

In some embodiments, a combination is provided containing a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc, or a pharmaceutically acceptable salt thereof and at least one additional anti-cancer drug.

In some embodiments, a combination is provided containing a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc, or a pharmaceutically acceptable salt thereof, and at least one additional anti-cancer drug, for use in therapy.

Some embodiments provide the use of a combination containing a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa , VIIb or VIIc, or a pharmaceutically acceptable salt thereof and at least one additional anti-cancer drug, for the production of a drug for the treatment of cancer.

Examples of other anti-cancer drugs include intercalating agents such as anthracycline, doxorubicin, idarubicin, epirubicin and daunorubicin; topoisomerase inhibitors such as irinotecan, topotecan, camptothecin, lamellarin D, etoposide, teniposide, mitoxantrone, am

- 110 045798 sacrin, ellipticines and aurintricarboxylic acid; nitrosourea compounds such as carmustine (BCNU), lomustine (CCNU) and streptozocin; nitrogen mustards such as cyclophosphamide, mechlorethamine, uramustine, bendamustine, melphalan, chlorambucil, mafosfamide, trofosfamide and ifosfamide; alkylsulfonates such as busulfan and threosulfan; alkylating agents such as procarbazine, dacarbazine, temozolomide and thiotepa; platinum analogs such as cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin and triplatin tetranitrate; drugs that affect microtubules, such as vinblastine, colcemid and nocodazole; antifolates such as methotrexate, aminopterin, dichloromethotrexate, pemetrexed, raltitrexed and pralatrexate; purine analogues such as azathioprine, mercaptopurine, thioguanine, fludarabine, fludarabine phosphate, pentostatin and cladribine; pyrimidine analogs such as 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, gemcitabine; steroids such as progestin, androgen, glucocorticoids, dexamethasone, prednisolone and prednisone; anti-cancer antibodies such as monoclonal antibodies, for example, alemtuzumab, apolizumab, cetuximab, epratuzumab, galiximab, gemtuzumab, ipilimumab, labetuzumab, panitumumab, rituximab, trastuzumab, nimotuzumab, mapatumumab, matumzubam, rhMab ICR62 and pertuzumab; radiolabeled antibodies and antibody-drug conjugates; anticancer peptides such as radiolabeled peptides and peptide-drug conjugates; and taxanes and taxane analogs such as paclitaxel and docetaxel.

In some embodiments, there is provided a method of treating or preventing cancer or a hyperproliferative disease in a human or animal suffering from or at risk for cancer or a hyperproliferative disease, comprising administering to said human or animal a therapeutically effective amount of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc, as described herein, or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective an amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, there is provided a method of treating cancer or a hyperproliferative disease in a human or animal suffering from or at risk for cancer or a hyperproliferative disease, comprising administering to said human or animal a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, in combinations with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents.

In some embodiments, provided herein is a method of treating cancer or a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for the treatment of cancer or hyperproliferative disease.

The compounds described herein can be used with or combined with one or more of a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an antifibrotic agent, an immunotherapeutic agent, a therapeutic antibody, a bispecific antibody, and an antibody-like therapeutic protein (such as DARTs®, Duobodies®, Bites® , XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugate (ADC), radiotherapeutic agent, antitumor agent, antiproliferative agent, oncolytic virus, gene modifiers or gene editors (such as CRISPR/Cas9, zinc finger nucleases or synthetic nucleases, TALEN), T-cell immunotherapy agent CAR (chimeric antigen receptor), engineered T-cell receptor (TCR-T), or any combination thereof. These therapeutic agents may be in the form of compounds, antibodies, polypeptides or polynucleotides. In one embodiment, provided herein is a product comprising a compound described herein and an additional therapeutic agent in a combination formulation for simultaneous, separate or sequential use in therapy.

One or more additional therapeutic agents include, but are not limited to, an inhibitor, agonist, antagonist, ligand, modulator, stimulator, blocker, activator or suppressor of a gene, ligand, receptor, protein or factor. Non-limiting examples of additional therapeutic agents include the following: Abelson murine leukemia viral oncogene homolog 1 gene (ABL, such as ABL1), acetyl-CoA carboxylase (eg, ACC1/2), activated CDC kinase (ACK, such as ACK1), adenosine deaminase, adenosine receptor (such as A2B, A2a, A3), adenylate cyclase, ADP-ribosyl cyclase-1, adrenocorticotropic hormone (ACTH) receptor, aerolysin, AKT1 gene, Alk-5 protein kinase, alkaline phosphatase, alpha-1-adrenergic receptor, alpha-2-adrenergic receptor , alpha-ketoglutarate dehydrogenase (KDH) aminopeptidase N, AMP-activated protein kinase, anaplastic lymphoma kinase (ALK, e.g. ALK1), androgen receptor, angiopoietin (such as ligand1, ligand-2), angiotensinogen gene (AGT), viral oncogene homolog 1 protein kinase mouse thymomas

- 111 045798 (AKT) (such as AKT1, AKT2, AKT3), apolipoprotein A-I gene (APOA1), apoptosis-inducing factor, apoptosis protein (such as 1, 2), apoptosis signal-regulating kinase (ASK, such as ASK1) , arginase (I), arginine deiminase, aromatase, asteroid homologue 1 gene (ASTE1), serine/threonine protein kinase related to ataxia-telangiectasia and Rad 3 (ATR), Aurora protein kinase (e.g. 1, 2), Axl receptor tyrosine kinase gene , containing baculovirus IAP repeat 5 (BIRC5), basigin, B cell lymphoma 2 (BCL2) gene, Bcl2 binding component 3, Bcl2 protein, BCL2L11 gene, BCR (point break cluster region) protein and gene, beta-adrenergic receptor, beta-catenin , B-lymphocyte antigen CD19, B-lymphocyte antigen CD20, B-lymphocyte cell adhesion molecule, B-lymphocyte stimulator ligand, bone morphogenetic protein ligand-10, bone morphogenetic protein ligand modulator-9, brachyury protein, bradykinin receptor, proto-oncogene B-Raf ( BRAF), Brc-Abl tyrosine kinase, bromodomain and bromodomain outer domain (BET) containing protein (such as BRD2, BRD3, BRD4), Bruton's tyrosine kinase (BTK), calmodulin, calmodulin-dependent protein kinase (CaMK, such as CAMKII), cancer testicular antigen 2, cancer testicular antigen NY-ESO-1, cancer testicular antigen 1B gene (CTAG1), cannabinoid receptor (such as CB1, CB2), carbonic anhydrase, casein kinase (CK, e.g. CKI, CKII), caspase (e.g. caspase-3, caspase-7, caspase-9), regulator of CASP8-FADD-like cysteine peptidase, apoptosis-associated caspase 8, caspase recruitment domain-containing protein-15, cathepsin G, CCR5 gene, CDK-activating kinase (CAK), checkpoint kinase (such as CHK1, CHK2), chemokine (C-C motif) receptor (such as CCR2, CCR4, CCR5), chemokine (C-X-C motif) receptor (such as CXCR4, CXCR1 and CXCR2), chemokine CC21 ligand, cholecystokinin receptor CCK2, human chorionic gonadotropin, c-Kit (tyrosine protein kinase Kit or CD117), claudin (e.g. 6, 18), cluster of differentiation (CD) such as CD4, CD27, CD29, CD30, CD33, CD37, CD40 , CD40 ligand receptor, CD40 ligand, CD40LG gene, CD44, CD45, CD47, CD49b, CD51, CD52, CD55, CD58, CD66e, CD70 gene, CD74, CD79, CD79b, CD79B gene, CD80, CD95, CD99, CD117, CD122 , CDwl23, CD134, CDw137, CD158a, CD158b1, CD158b2, CD223, CD276 antigen; clusterin gene (CLU), clusterin, c-Met (hepatocyte growth factor receptor (HGFR)), complement C3, connective tissue growth factor, COP9 signalosome subunit 5, CSF-1 (colony stimulating factor receptor 1), CSF2 gene, CTLA- receptor 4 (cytotoxic T-lymphocyte protein 4), cyclin D1, cyclin G1, cyclin-dependent kinases (CDKs, such as CDK1, CDK1B, CDK2-9), cyclooxygenase (e.g. 1, 2), CYP2B1 gene, porcupine cysteine palmitoyltransferase, cytochrome P450 11B2, cytochrome P450 17, cytochrome P450 17A1, cytochrome P450 2D6, cytochrome P450 3A4, cytochrome P450 reductase, cytokine signaling-1, cytokine signaling-3, cytoplasmic isocitrate dehydrogenase, cytosine deaminase, cytosine-DNA methyltransferase , cytocytefinase, cytotoxic T lymphocyte protein 4, DDR2 gene, delta-like protein ligand (such as 3, 4), deoxyribonuclease, Dickkopf-1 ligand, dihydrofolate reductase (DHFR), dihydropyrimidine dehydrogenase, dipeptidyl peptidase IV, discoidin domain receptor (DDR, such as DDR1), DNA binding protein (e.g. HU-beta), DNA-dependent protein kinase, DNA gyrase, DNA methyltransferase, DNA polymerase (e.g. alpha), DNA primase, dUTP pyrophosphatase, L-dopachrome tautomerase, protein, echinoderm microtubule-associated protein-like type 4; EGFR tyrosine kinase receptor, elastase, elongation factor 1 alpha 2, elongation factor 2, endoglin, endonuclease, endoplasmin, endosialin, endostatin, endothelin (eg, ET-A, ET-B), enhancer of zeste homologue 2 (EZH2), ephrin (ERH ) tyrosine kinase (e.g. Epha3, Ephb4), ephrin B2 ligand, epidermal growth factor, epidermal growth factor receptors (EGFR), epidermal growth factor receptor gene (EGFR), epigen, epithelial cell adhesion molecule (EpCAM), Erb-b2 (v -erb-b2 avian erythroblastic anemia viral oncogene homologue 2) tyrosine kinase receptor, Erb-b3 tyrosine kinase receptor, Erb-b4 tyrosine kinase receptor, E-selectin, estradiol-17-beta dehydrogenase, estrogen receptor (e.g., alpha, beta), receptor, estrogen-related, eukaryotic translation initiation factor 5A (EIF5A) gene, exportin 1, extracellular signal-related kinase (e.g. 1, 2), extracellular signal-regulated kinases (ERK), factor (e.g. Xa, VIIa), farnesoid x receptor (FXR), Fas ligand, fatty acid synthase (FASN), ferritin, FGF-2 ligand, FGF-5 ligand, fibroblast growth factor (FGF, such as FGF1, FGF2, FGF4), fibronectin, Fms-related tyrosine kinase 3 (Flt3), focal adhesion kinase (FAK, e.g. FAK2), folate hydrolase prostate-specific membrane antigen 1 (FOLH1), folate receptor (e.g. alpha), folate, folate transporter 1, tyrosine kinase FYN, enzyme that cleaves protein at the site of paired basic amino acids (FURIN), beta-glucuronidase, galactosyltransferase, galectin-3, ganglioside GD2, glucocorticoid, glucocorticoid-induced TNFR-related protein receptor GITR, glutamate carboxypeptidase II, glutaminase, glutathione S-transferase P, glycogen synthase kinase (GSK, such as 3-beta ), glypican 3 (GPC3), gonadotropin-releasing hormone (GNRH), granulocyte macrophage colony-stimulating factor (GM-CSF) receptor, granulocyte colony-stimulating factor (GCSF) ligand, growth factor receptor-related protein 2 (GRB2), calcium- Grp78 binding protein (78 kDa, glucose regulated), groEL2 mentor gene, heat shock protein (e.g. 27, 70, 90 alpha, beta), heat shock protein gene, thermostable enterotoxin receptor, hedgehog protein, heparanase, hepatocyte growth factor, HERV-H LTR binding protein 2, hexosekinase, histamine H2 receptor,

- 112 045798 histone methyltransferase (DOT1L), histone deacetylase (HDAC, e.g. 1, 2, 3, 6, 10, 11), histone H1, histone H3, HLA class I antigen (A-2 alpha), HLA class II antigen, Homeobox protein NANOG, HSPB1 gene, human leukocyte antigen (HLA), human papillomavirus protein (e.g. E6, E7), hyaluronic acid, hyaluronidase, hypoxia-inducible factor-1 alpha (HIF1a), imprinted maternally expressed transcript (H19) gene, mitogen activated protein kinase 1 (MAP4K1), tyrosine protein kinase HCK, 1-kappa B kinase (IKK, e.g. IKKbe), IL-1 alpha, IL-1 beta, IL-12, IL-12 gene, IL-15, IL -17, IL-2 gene, IL-2 receptor alpha subunit, IL-2, IL-3 receptor, IL-4, IL-6, IL-7, IL-8, immunoglobulin (e.g. G, G1, G2 , K, M), immunoglobulin Fc receptor, immunoglobulin gamma Fc receptor (e.g. I, III, IIIA), indoleamine 2,3-dioxygenase (IDO, such as IDO1), indoleamine pyrrole 2,3-dioxygenase inhibitor 1, insulin receptor , insulin-like growth factor (e.g. 1, 2), integrin alpha 4/beta 1, integrin alpha 4/beta 7, integrin alpha 5/beta 1, integrin alpha V/beta 3, integrin alpha -V/beta-5, integrin αalpha-V/beta-6, intercellular adhesion molecule 1 (ICAM-1), interferon (such as alpha, alpha 2, beta, gamma), interferon-inducible protein missing in melanoma 2 (AIM2 ), interferon type I receptor, interleukin 1 ligand, interleukin 13 alpha 2 receptor, interleukin 2 ligand, interleukin-1 receptor associated kinase 4 (IRAK4), interleukin-2, interleukin-29 ligand, isocitrate dehydrogenase (such as IDH1, IDH2 ), Janus kinase (JAK, such as JAK1, JAK2), Jun N-terminal kinase, kallikrein-related peptidase 3 (KLK3) gene, Ig-like killer cell receptor, kinase insertion domain receptor (KDR), kinesin-like protein KIF11, homolog gene Kirsten's rat sarcoma viral oncogene (KRAS), kiss-peptin receptor (KiSS-1), KIT gene, tyrosine kinase v-kit Hardy-Zuckerman 4 homologs of feline sarcoma viral oncogene (KIT), lactoferrin, lanosterol-14 demethylase, protein-1, LDL receptor-associated, leukotriene A4 hydrolase, listeriolysin, L-selectin, luteinizing hormone receptor, lyase, lymphocyte activation gene protein 3 (LAG-3), lymphocyte antigen 75, lymphocyte functional antigen receptor 3, lymphocyte-specific protein tyrosine kinase (LCK), lymphotactin, Lyn tyrosine kinase (Lck/Yes novel), lysine demethylases (such as KDM1, KDM2, KDM4, KDM5, KDM6, A/B/C/D), lysophosphatidate receptor-1, lysosome-associated membrane protein (LAMP) family gene, lysyl oxidase homologue 2, lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL, such as LOXL2), hematopoietic precursor kinase 1 (HPK1), hepatocyte growth factor receptor gene (MET), macrophage colony stimulating factor (MCSF) ligand, macrophage migration inhibitory factor , MAGEC1 gene, MAGEC2 gene, major vault protein, MAPK-activated protein kinase (e.g. MK2), Mas-related G protein-coupled receptor, matrix metalloproteinase (MMP, such as MMP2, MMP9), differentiation protein Mcl-1, Mdm2 p53 -binding protein, Mdm4 protein, melanoma antigen Melan-A (MART-1), melanoma protein Pmel 17, melanocyte-stimulating hormone ligand, melanoma antigen family A3 gene (MAGEA3), melanoma-associated antigen (e.g. 1, 2, 3 , 6), membrane copper-containing amine oxidase, mesothelin, MET tyrosine kinase, metabotropic glutamate receptor 1, metal reductase STEAP1 (six transmembrane epithelial antigens of the prostate 1), metastin, methionine aminopeptidase-2, methyltransferase, mitochondrial 3-ketoacyl-CoA thiolase, mitogen activated protein kinase (MAPK), mitogen-activated protein kinase (MEK, such as MEK1, MEK2), mTOR (mechanistic target of rapamycin (serine/threonine kinase), mTOR complex (e.g. 1, 2), mucin (e.g. 1, 5A, 16) , mut T homolog (MTH, such as MTH1), Myc proto-oncogenic protein, myeloid cell leukemia 1 (MCL1) gene, myristic acid-associated protein kinase C alanine-rich substrate (MARCKS) protein, NAD ADP ribosyltransferase, natriuretic peptide receptor C, adhesion molecule nerve cell 1, neurokinin 1 receptor (NK1), neurokinin receptor, neuropilin 2, NF kappa B activating protein, NIMA-related kinase 9 (NEK9), nitric oxide synthase, NK cell receptor, NK3 receptor, NK activating receptor NKG2 AB, norepinephrine transporter, Notch (eg, Notch-2 receptor, Notch-3 receptor, Notch4 receptor), nuclear erythroid 2-related factor 2, nuclear factor (NF), kappa B, nucleolin, nucleophosmin, nucleophosmin-anaplastic lymphoma (NPM) kinase -ALK), oxoglutarate dehydrogenase 2,2,5oligoadenylate synthetase, O-methylguanine DNA methyltransferase, opioid receptor (e.g. delta), ornithine decarboxylase, orotate phosphoribosyltransferase, orphan nuclear hormone receptor NR4A1, osteoclast differentiation factor, osteopontin, OX-40 receptor (member of the superfamily tumor necrosis factor receptor 4 TNFRSF4 or CD134), P3 protein, p38 kinase, p38 MAP kinase, p53 tumor suppressor protein, parathyroid hormone ligand, peroxisome proliferator-activated receptors (PPARs, such as alpha, delta, gamma), P-glycoprotein (eg 1), phosphatase and tensin homolog (PTEN), phosphatidylinositol 3-kinase (PI3K), phosphoinositide 3-kinase (PI3K, such as alpha, delta, gamma), phosphorylase kinase (PK), PKN3 gene, factor placental growth factor, platelet-derived growth factor (PDGF, such as alpha, beta), platelet-derived growth factor (PDGF, such as alpha, beta), pleiotropic drug resistance transporter, plexin B1, PLK1 gene, polo-like kinase (PLK), polo- like kinase 1, poly-ADP-ribose polymerase (PARP, such as PARP1, 2 and 3), preferentially expressed melanoma antigen (PRAME) gene, prenyl binding protein (PrPB), probable PML transcription factor, progesterone receptor, programmed death cells 1 (PD-1), ingi

- 113 045798 inhibitor of programmed cell death ligand 1 (PD-L1), prosaposin gene (PSAP), prostanoid receptor (EP4), prostate specific antigen, prostatic acid phosphatase, proteasome, E7 protein, protein farnesyltransferase, protein kinase (PK, such as A , B, C), protein tyrosine kinase, protein tyrosine phosphatase beta, serine/threonine protein kinase proto-oncogene (PIM, e.g. PIM-1, PIM-2, PIM-3), P-selectin, purine nucleoside phosphorylase, purinergic receptor ligand-gated ion channel 7 P2X (P2X7), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase, pyruvate kinase (PYK), 5-alpha reductase, Raf protein kinase (e.g. 1, B), RAF1 gene, Ras gene, Ras GTPase, RET gene, Ret tyrosine kinase receptor , retinoblastoma-associated protein, retinoic acid receptor (such as gamma), retinoid X receptor, Rheb (enriched Ras homolog in the brain) GTPase, Rho (Ras homolog) protein kinase 2, ribonuclease, ribonucleotide reductase (such as M2 subunit), ribosomal protein kinase S6, RNA polymerase (e.g. I, II), Ron tyrosine kinase (Recepteur d'Origine Nantais), ROS1 gene (ROS proto-oncogene 1, receptor tyrosine kinase), Rosl tyrosine kinase, dwarfism-associated transcription factor 3, gamma secretase , calcium-binding protein S100 A9, Sarco calcium-ATPase, second mitochondrial activator of caspase (SMAC) protein, secreted burn-associated protein-2, semaphorin-4D, serine protease, serine/threonine kinase (STK), serine/threonine protein kinase (TSP, e.g. TBK1), signal transduction and transcription (STAT, e.g. STAT-1, STAT-3, STAT-5), signaling lymphocyte-activating molecule (SLAM) family member 7, six transmembrane domain prostate epithelial antigen (STEAP) gene, cytokine SL ligand, smoothened receptor (SMO), sodium iodide cotransporter, sodium phosphate cotransporter 2B, somatostatin receptor (e.g. 1, 2, 3, 4, 5), Sonic hedgehog protein, Son of sevenless (SOS), specific protein transcription factor 1 (Sp1), sphingomyelin synthase, sphingosine kinase (e.g. 1, 2), sphingosine 1-phosphate receptor-1, spleen tyrosine kinase (SYK), SRC gene, Src tyrosine kinase, STAT3 gene, steroid sulfatase, stimulator of interferon genes (STING) receptor, interferon gene protein stimulator, stromal cell-derived factor 1 ligand, SUMO (Small ubiquitin-like modifier), superoxide dismutase, survivin protein, synapsin 3, syndecan-1, synuclein alpha, T cell surface glycoprotein CD28, buck-binding kinase (TBK) , TATA box-binding protein-associated factor RNA polymerase I subunit B gene (TAF1B), CD3 T cell glycoprotein zeta chain, CD6 T cell differentiation antigen, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3 ), CD8 T cell surface glycoprotein, Tec protein tyrosine kinase, Tec receptor tyrosine kinase, telomerase, telomerase reverse transcriptase (TERT) gene, tenascin, TGF beta 2 ligand, thrombopoietin receptor, thymidine kinase, thymidine phosphorylase, thymidylate synthase, thymosin (eg, alpha-1) , thyroid hormone receptor, thyroid-stimulating hormone receptor, tissue factor, TNF-related apoptosis-inducing ligand, TNFR1-associated death domain protein, TNF-related apoptosis-inducing ligand receptor (TRAIL), TNFSF11 gene, TNFSF9 gene, Toll-like receptor (TLR, such as 1-13), topoisomerase (e.g. I, II, III), transcription factor, transferase, transferrin, transforming growth factor (TGF, e.g. beta) kinase, transforming growth factor receptor kinase TGF-P, transglutaminase, protein-related with translocation, transmembrane glycoprotein NMB, calcium signal transducer Trop-2, trophoblast glycoprotein gene (TPBG), trophoblast glycoprotein, tropomyosin receptor kinase (Trk) receptor (eg, TrkA, TrkB, TrkC), tryptophan 5-hydroxylase, tubulin, factor tumor necrosis alpha (TNF such as beta), tumor necrosis factor receptor 13C, tumor progression locus 2 (TPL2), tumor protein 53 gene (TP53), tumor suppressor candidate 2 gene (TUSC2), tyrosinase, tyrosine hydroxylase, tyrosine kinase (TK ), receptor tyrosine kinase, receptor tyrosine kinase with immunoglobulin-like and EGF-like domains (TIE), tyrosine protein kinase inhibitor ABL1, ubiquitin, ubiquitin carboxyl hydrolase isoenzyme L5, ubiquitin thioesterase14, ubiquitin-conjugated enzyme E2I (UBE2I, UBC9), urease, urokinase plasminogen activator, utero globin, vanilloid VR1, vascular endothelial adhesion protein 1, vascular endothelial growth factor receptor (VEGFR), V-domain Ig suppressor of T cell activation (VISTA), VEGF-1 receptor, VEGF-2 receptor, VEGF-3 receptor, VEGF-A, VEGF -B, vimentin, vitamin D3 receptor, Yes proto-oncogene tyrosine protein kinase, Wee-1 protein kinase, Wilms tumor antigen 1, Wilms tumor protein, X-linked inhibitor of apoptosis protein, zinc finger protein transcription factor, or any combination thereof.

Non-limiting examples of additional therapeutic agents can be divided according to their mechanism of action, for example, into the following groups:

antimetabolites/anticancer agents such as the pyrimidine analogues floxuridine, capecitabine, cytarabine, CPX-351 (liposomal cytarabine, daunorubicin) and TAS-118;

purine analogues, folate antagonists (such as pralatrexate) and related inhibitors;

antiproliferative/antimitotic agents including natural products such as vinca alkaloids (vinblastine, vincristine) and microtubule disruptors such as taxane (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, vinorelbine (Navelbine®) and epipodophyllotoxins (etoposide, teniposide);

DNA damaging agents such as actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide (CYTOXAN®), dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, merchlorethamine, mitomycin C, mitoxantrone, nit rose urea, procarbazine, taxol, taxotere, teniposide, etoposide and triethylene thiophosphoramide;

DNA hypomethylating agents such as guadecitabine (SGI-110) and ASTX727;

antibiotics such as dactinomycin, daunorubicin, doxorubicin, idarubicin, anthracyclines, mitoxantrone, bleomycins and plicamycin (mithramycin);

enzymes such as L-asparaginase, which systemically metabolizes L-asparagine and depletes cells that are unable to synthesize their own asparagine;

antiplatelet agents;

DNAi oligonucleotides targeting Bcl-2, such as PNT2258;

agents that activate or reactivate latent human immunodeficiency virus (HIV), such as panobinostat and romidepsin;

asparaginase stimulants such as chrysantaspase (Erwinase®) and GRASPA (ERY-001, ERY-ASP), and calaspargase pegol;

pan-Trk, ROS1 and ALK inhibitors such as entrectinib and TPX-0005;

anaplastic lymphoma kinase (ALK) inhibitors such as alectinib and ceritinib;

antiproliferative/antimitotic alkylating agents such as nitrogen mustard cyclophosphamide and its analogs (melphalan, chlorambucil, hexamethylmelamine, thiotepa), alkylnitrosoureas (carmustine) and analogs, streptozocin and triazenes (dacarbazine);

antiproliferative/antimitotic antimetabolites such as folic acid analogues (methotrexate);

platinum coordination complexes (cisplatin, oxyloplatin and carboplatin), procarbazine, hydroxyurea, mitotane and aminoglutethimide;

hormones, hormone analogues (estrogen, tamoxifen, goserelin, bicalutamide and nilutamide) and aromatase inhibitors (letrozole and anastrozole);

anticoagulants such as heparin, synthetic heparin salts and other thrombin inhibitors;

fibrinolytic agents such as tissue plasminogen activator, streptokinase, urokinase, aspirin, dipyridamole, ticlopidine and clopidogrel;

anti-migration agents;

antisecretory agents (breveldin);

immunosuppressants tacrolimus, sirolimus, azathioprine, mycophenolate;

growth factor inhibitors and vascular endothelial growth factor inhibitors;

fibroblast growth factor inhibitors such as FPA14;

anti-VEGFR antibodies such as IMC-3C5, GNR-011 and tanibirumab;

antibodies to VEGF/DDL4, such as ABT-165;

antibodies to cadherins, such as HKT-288;

anti-CD70 antibodies such as AMG-172; anti-leucine-rich repeat containing antibodies 15 (LRRC15), such as ABBV-085 and ARGX-110;

angiotensin receptor blockers and nitric oxide donors;

antisense oligonucleotides such as AEG35156, IONIS-KRAS-2.5Rx, EZN-3042, RX-0201, IONIS-AR-2.5Rx, BP-100 (prexigebersen) and IONIS-STAT3-2.5Rx;

DNA interfering oligonucleotides such as PNT2258 and AZD-9150;

antibodies to ANG-2, such as MEDI3617 and LY3127804;

antibodies to ANG-1/ANG-2, such as AMG-780;

antibodies to MET/EGFR, such as LY3164530;

anti-EGFR antibodies such as ABT-414, AMG-595, necitumumab, ABBV-221, depatuxizumab, mafodotin (ABT-414), tomzotuximab, ABT-806, Vectibix, modotuximab and RM-1929;

anti-CSF1R antibodies such as emactuzumab, LY3022855, AMG-820 and FPA-008 (cabiralizumab);

anti-CD40 antibodies such as RG7876, SEA-CD40, APX-005M and ABBV-428;

anti-endoglin antibodies such as TRC105 (carotuximab);

anti-CD45 antibodies such as 131I-BC8 (lomab-B);

antibodies to HER3, such as LJM716 and GSK2849330;

anti-HER2 antibodies such as margetuximab, MEDI4276 and BAT-8001;

antibodies to HLA-DR, such as IMMU-114;

antibodies to IL-3, such as JNJ-56022473;

OX40 antibodies such as MEDI6469, MEDI6383, MEDI0562 (tavolixizumab), MOXR0916, PF04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383 and ABBV-368;

antibodies to EphA3, such as KB-004;

anti-CD20 antibodies such as obinutuzumab, IGN-002;

anti-CD20/CD3 antibodies such as RG7828;

anti-CD37 antibodies such as AGS67E and otlertuzumab (TRU-016);

- 115 045798 antibodies to ENPP3, such as AGS-16C3F;

antibodies to FGFR-3, such as LY3076226 and B-701;

antibodies to FGFR-2, such as GAL-F2;

anti-C5 antibodies such as ALXN-1210;

anti-CD27 antibodies such as varlilumab (CDX-1127);

antibodies to TROP-2, such as IMMU-132;

antibodies to NKG2a, such as monalizumab;

antibodies to VISTA, such as HMBD-002;

antibodies to PVRIG, such as COM-701;

antibodies to EpCAM, such as VB4-845;

antibodies to BCMA, such as GSK-2857916;

anti-CEA antibodies such as RG-7813;

antibodies to cluster of differentiation 3 (CD3), such as MGD015;

alpha-folate receptor antibodies such as IMGN853;

MCL-1 inhibitors such as AMG-176, S-64315, AZD-5991, 483-LM, A-1210477, UMI-77 and JKY-5-037;

epha2 inhibitors such as MM-310;

antibodies to LAG-3, such as relatlimab (ONO-4482), LAG-525, MK-4280 and REGN-3767;

raf/VEGFR kinase inhibitors such as RAF-265;

polycomb protein inhibitors (EED) such as MAK683;

antibodies to fibroblast activation protein (FAP)/IL-2R, such as RG7461;

antibodies to fibroblast activation protein (FAP)/TRAIL-R2, such as RG7386;

anti-Fucosyl-GMI antibodies such as BMS-986012;

p38 MAP kinase inhibitors such as ralimetinib;

PRMT1 inhibitors such as MS203;

sphingosine kinase 2 (SK2) inhibitors such as opaganib;

FLT3-ITD inhibitors such as BCI-332;

nuclear erythroid 2-related factor 2 stimulants such as omaveloxolone (RTA-408);

tropomyosin receptor kinase (TRK) inhibitors such as LOXO-195 and ONO-7579;

antibodies to ICOS, such as JTX-2011 and GSK3359609;

antibodies to DR5 (TRAIL2), such as DS-8273;

anti-GD2 antibodies such as APN-301;

antibodies to interleukin-17 (IL-17), such as CJM-112;

antibodies to carbonic anhydrase IX, such as TX-250;

anti-CD38-attenukine such as TAK573;

antibodies to mucin-1, such as gatipotuzumab;

mucin-1 inhibitors such as GO-203-2C;

MARCKS protein inhibitors such as BIO-11006;

folic acid antagonists such as arfolythixorin;

galectin-3 inhibitors such as GR-MD-02;

phosphorylated P68 inhibitors such as RX-5902;

CD95/TNF modulators such as Ofranergene obadenovec;

PDK/Akt/mTOR inhibitors such as ABTL-0812;

pan-PIM kinase inhibitors such as INCB-053914;

IL-12 gene stimulators such as EGEN-001 and tavokinogen teleplasmid;

heat shock protein HSP90 inhibitors such as TAS-116 and PEN-866;

VEGF/HGF antagonists such as MP-0250;

SYK tyrosine kinase/FLT3 tyrosine kinase inhibitors such as TAK-659;

SYK tyrosine kinase/JAK tyrosine kinase inhibitors such as ASN-002;

an FLT3 tyrosine kinase inhibitor such as FF-10101;

an FLT3 tyrosine kinase agonist such as CDX-301;

FLT3/MEK1 inhibitors such as E-6201;

an IL-24 antagonist such as AD-IL24;

RIG-I agonists such as RGT-100;

aerolysin stimulants such as topsalisin;

P-glycoprotein 1 inhibitors such as HM-30181A;

CSF-1 antagonists such as ARRY-382 and BLZ-945;

antibodies to mesothelin, such as SEL-403;

thymidine kinase stimulants such as aglatimagen besadenovec;

polo-like kinase 1 inhibitors such as PCM-075;

TLR-7 agonists such as TMX-101 (imiquimod);

NEDD8 inhibitors such as pevonedistat (MLN-4924) and TAS-4464;

pleiotropic pathway modulators such as avadomide (CC-122);

- 116 045798 FoxMl inhibitors, such as thiostreptone;

antibodies to MUC1, such as Mab-AR-20.5;

anti-CD38 antibodies such as isatuximab and MOR-202;

UBA1 inhibitors such as TAK-243;

Src tyrosine kinase inhibitors such as VAL-201;

VDAC/HK inhibitors such as VDA-1102;

BRAF/PI3K inhibitors such as ASN-003;

Elf4a inhibitors such as roinitib, eFT226;

TP53 gene stimulators such as ad-p53;

PD-L1/EGFR inhibitors such as GNS-1480;

retinoic acid receptor alpha (RARa) inhibitors such as SY-1425;

SIRT3 inhibitors such as YC8-02;

inhibitors of stromal cell-derived factor 1 ligand such as olapthetic pegol (NOX-A12);

IL-4 receptor modulators such as MDNA-55;

arginase-1 stimulants such as pegcylarginase;

topoisomerase 1 inhibitor/hypoxia-inducible factor-1 alpha inhibitors such as PEG-SN38 (firtecan pegol);

hypoxia-inducible factor-1 alpha inhibitors such as PT-2977 and PT-2385;

CD122 agonists such as NKTR-214;

stimulators of the p53 tumor suppressor protein, such as kevetrin;

p53 binding protein Mdm4/Mdm2 inhibitors such as ALRN-6924;

kinesin spindle protein (KSP) inhibitors such as filanesib (ARRY-520);

CD80-fc fusion protein inhibitors such as FPT-155;

menin-mixed lineage leukemia (MLL) inhibitors such as KO-539;

liver X receptor agonists such as RGX-104;

IL-10 agonists such as AM-0010;

EGFR/ErbB-2 inhibitors such as varlitinib;

VEGFR/PDGFR inhibitors such as vorolanib;

IRAK4 inhibitors such as CA-4948;

antibodies to TLR-2, such as OPN-305;

calmodulin modulators such as SVR-501;

glucocorticoid receptor antagonists such as relacorilant (CORT-125134);

second mitochondrial activator of caspase (SMAC) protein inhibitors such as BI-891065;

lactoferrin modulators such as LTX-315;

receptor alpha tyrosine kinase/PDGF antagonists such as DCC-2618;

KIT inhibitors such as PLX-9486;

exportin 1 inhibitors such as eltanexor;

EGFR/ErbB2/Ephb4 inhibitors such as tesevatinib;

antibodies to CD33, such as IMGN-779;

anti-CMA antibodies such as MDX-1097;

antibodies to TIM-3, such as TSR-022, LY-3321367 and MBG-453;

anti-CD55 antibodies such as PAT-SC1;

anti-PSMA antibodies such as ATL-101;

antibodies to CD100, such as VX-15;

antibodies to EHA3, such as fibatuzumab;

anti-Erbb antibodies such as CDX-3379, HLX-02 and seribantumab;

antibodies to APRIL, such as BION-1301;

Tigit antibodies such as BMS-986207 and RG-6058;

CHST15 gene inhibitors such as STNM-01;

RAS inhibitors such as NEO-100;

a somatostatin receptor antagonist such as OPS-201;

SEVPA gene stimulators such as MTL-501;

DKK3 gene modulators such as MTG-201;

p70s6k inhibitors such as MSC2363318A;

methionine aminopeptidase 2 (MetAP2) inhibitors such as M8891 and APL-1202;

arginine N-methyltransferase 5 inhibitors such as GSK-3326595;

antibodies to programmed cell death protein 1 (anti-PD-1), such as nivolumab (OPDIVO®, BMS-936558, MDX-1106), pembrolizumab (KEYTRUDA®, MK-3477, SCH-900475, lambrolizumab, per. CAS number 1374853-91-4), pidilizumab, PF-06801591, BGB-A317, GLS-010 (WBP-3055), AK103 (HX-008), MGA-012, BI-754091, REGN-2810 (cemiplimab), AGEN- 2034, JS-001, JNJ-63723283, genolimzumab (SVT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, BAT-1306 and antibodies to programmed death ligand 1 (anti- PD-Ll), such as BMS-936559, atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, CK-301, (MSB0010718C), MEDI0680, CX-072, CBT-502, PDR-001 (spartalizumab), TSR- 042 (dostarlimab), JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155), KN-035, IBI-308,

FAZ-053 and MDX1105-01;

PD-L1/VISTA antagonists such as CA-170;

antibodies to PD-L1/TGFp, such as M7824;

anti-transferrin antibodies such as CX-2029;

antibodies to IL-8 (interleukin-8), such as HuMax-Inflam;

ATM (ataxia telangiectasia) inhibitors such as AZD0156;

CHK1 inhibitors such as GDC-0575, LY2606368 (prexasertib), SRA737 and RG7741 (CHK1/2);

CXCR4 antagonists such as BL-8040, LY2510924, burixafor (TG-0054), X4P-002 and X4P-001-10;

EXH2 inhibitors such as GSK2816126;

HER2 inhibitors such as neratinib and tucatinib (ONT-380);

KDM1 inhibitors such as ORY-1001, IMG-7289, INCB-59872 and GSK-2879552;

CXCR2 antagonists such as AZD-5069;

GM-CSF antibodies such as lenzilumab;

DNA-dependent protein kinase inhibitors such as MSC2490484A (nedisertib), VX-984 and AsiDNA (DT-01);

protein kinase C (PKC) inhibitors such as LXS-196 and sotrastaurin;

selective estrogen receptor negative regulators (SERDs) such as fulvestrant (Faslodex®), RG6046, RG6047, elacestrant (RAD-1901) and AZD9496;

selective covalent estrogen receptor antagonists (SERCA), such as H3B-6545;

a selective androgen receptor modulator (SARM), such as GTX-024, and darolutamide;

transforming growth factor beta (TGF-beta) kinase antagonists such as galunisertib;

antibodies to transforming growth factor beta (TGF-beta), such as LY3022859, NIS793 and HOMA 089;

bispecific antibodies, such as MM-141 (IGF-1/ErbB3), MM-111 (Erb2/Erb3), JNJ-64052781 (CD19/CD3), PRS-343 (CD-137/HER2), AFM26 (BCMA/CD16A) , JNJ-61186372 (EGFR/cMET), AMG-211 (CEA/CD3), RG7802 (CEA/CD3), ERY-974 (CD3/GPC3) vancizumab (angiopoietins/VEGF), PF-06671008 (cadherins/CD3), AFM-13 (CD16/CD30), APVO436 (CD123/CD3), flotetuzumab (CD123/CD3), REGN1979 (CD20/CD3), MCLA-117 (CD3/CLEC12A), MCLA-128 (HER2/HER3), JNJ- 0819, JNJ-7564 (CD3/heme), AMG-757 (DLL3-CD3), MGD-013 (PD-1/LAG-3), AK-104 (CTLA-4/PD-1), AMG-330 ( CD33/CD3), AMG-420 (BCMA/CD3), BI-836880 (VEFG/ANG2), JNJ-63709178 (CD123/CD3), MGD-007 (CD3/gpA33) and MGD-009 (CD3/B7H3);

mutant selective EGFR inhibitors such as PF-06747775, EGF816 (nazartinib), ASP8273, ACEA-0010 and BI-1482694;

antibodies to GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein), such as MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248 and GWN-323;

antibodies to delta-like protein ligand 3 (DDL3), such as rovalpituzumab-tesirine;

antibodies to clusterin, such as AB-16B5;

antibodies to ephrin-A4 (EFNA4), such as PF-06647263;

antibodies to RANKL, such as denosumab;

antibodies to mesothelin, such as BMS-986148, and to MSLN-MMAE;

antibodies to sodium phosphate cotransporter 2B (NaP2B), such as lifastuzumab;

antibodies to c-Met, such as ABBV-399;

adenosine A2A receptor antagonists such as CPI-444, AZD-4635, preladenant and PBF-509;

alpha-ketoglutarate dehydrogenase (KGDH) inhibitors such as CPI-613;

XPO1 inhibitors such as selinexor (KPT-330);

isocitrate dehydrogenase 2 (IDH2) inhibitors such as enasidenib (AG-221);

IDH1 inhibitors such as AG-120 and AG-881 (IDH1 and IDH2), IDH-305 and BAY-1436032;

interleukin-3 receptor (IL-3R) modulators such as SL-401;

arginine deiminase stimulators such as pegargiminase (ADI-PEG-20);

Antibody-drug conjugates such as MLN0264 (anti-GCC, guanylyl cyclase C), T-DM1 (trastuzumab emtansine, Cadcycla), milatuzumab-doxorubicin (hCD74-DOX), brentuximab vedotin, dCdT2980S, brentuximab vedotin, DCDT2980S, polatuzumab vedo tin, SGN-CD70A, SGNCD19A, inotuzumab ozogamicin, lorvotuzumab mertansine, SAR3419, isactuzumab govitecan, enfortumab vedotin (ASG-22ME), ASG-15ME, DS-8201 (trastuzumab deruxtecan), 225Ac-lintuzumab, U3-1402, 177L u-tetraxetane-tetuloma , tizotumab vedotin, anetumab ravtansine, CX-2009, SAR-566658, W-0101, polatuzumab vedotin and ABBV-085;

claudin-18 inhibitors such as claudiximab;

- 118 045798 β-catenin inhibitors, such as CWP-291;

anti-CD73 antibodies such as MEDI-9447 (oleclumab), CPX-006, IPH-53 and BMS-986179;

CD73 antagonists such as AB-680, PSB-12379, PSB-12441 and PSB-12425;

CD39/CD73 antagonists such as PBF-1662;

chemokine receptor 2 (CCR) inhibitors such as PF-04136309, CCX-872 and BMS-813160 (CCR2/CCR5);

thymidylate synthase inhibitors such as ONX-0801;

ALK/ROS1 inhibitors such as lorlatinib;

tankyrase inhibitors such as G007-LK;

Mdm2 p53 binding protein inhibitors such as CMG-097 and HDM-201;

c-PIM inhibitors such as PIM447;

BRAF inhibitors such as dabrafenib, vemurafenib, encorafenib (LGX818) and PLX8394;

sphingosine kinase-2 (SK2) inhibitors such as Yeliva® (ABC294640);

cell cycle inhibitors such as selumetinib (MEK1/2) and sapacitabine;

AKT inhibitors such as MK-2206, ipatasertib, afuresertib, AZD5363, ARQ-092, capivasertib and triciribine;

anti-CTLA-4 (cytotoxic T-lymphocyte protein-4) inhibitors such as tremelimumab, AGEN-1884 and BMS-986218;

c-MET inhibitors such as AMG-337, savolitinib, tivantinib (ARQ-197), capmatinib and tepotinib, ABT-700, AG213, AMG-208, JNJ-38877618 (OMO-1), merestinib and HQP-8361;

c-Met/VEGFR inhibitors such as BMS-817378 and TAS-115;

c-Met/RON inhibitors such as BMS-777607;

BRAF/EGFR inhibitors such as BGB-283; bcr/abl inhibitors such as rebastinib and asciminib; MNK1/MNK2 inhibitors such as eFT-508;

mTOR inhibitor/cytochrome P450 3A4 stimulators such as TYME-88; lysine-specific demethylase-1 (LSD1) inhibitors such as CC-90011; Pan-RAF inhibitors such as LY3009120, LXH254 and TAK-580; Raf/MEK inhibitors such as RG7304;

CSF1R/KIT and FLT3 inhibitors such as pexidartinib (PLX3397); kinase inhibitors such as vandetanib; E-selectin antagonists such as GMI-1271; differentiation inducers such as tretinoin;

epidermal growth factor receptor (EGFR) inhibitors such as osimertinib (AZD-9291);

topoisomerase inhibitors such as doxorubicin, daunorubicin, dactinomycin, eniposide, epirubicin, etoposide, idarubicin, irinotecan, mitoxantrone, pixantrone, sobuzoxan, topotecan, irinotecan, MM-398 (liposomal irinotecan), vosaroxin and GPX-150, aldoxorubicin, AR-67 , mavelertinib, AST-2818, avitinib (ACEA-0010) and irofulven (MGI-114); corticosteroids such as cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone and prednisolone; growth factor signaling kinase inhibitors; nucleoside analogs such as DFP-10917; Axl inhibitors such as BGB-324 (bemcentinib) and SLC-0211; BET inhibitors such as INCB-054329, InCB057643, TEN-010, AZD-5153, AUT-767, BMS-986158, SSK525762 (Molibresib), NHWD-870, ODM-207, GSK2820151, GSK-121015151A , ZBC246, ZBC260, ZEN3694, FT-1101, RG-6146, CC-90010, miwebresib, BI894999, PLX-2853, PLX-51107, CPI-0610 and GS-5829; PARP inhibitors such as olaparib, rucaparib, veliparib, talazoparib, ABT-767 and BGB-290;

proteasome inhibitors such as ixazomib, carfilzomib (Kyprolis®) and marizomib;

glutaminase inhibitors such as CB-839;

vaccines such as peptide vaccine TG-01 (RAS), GALE-301, GALE-302, nelipepimut-s, SurVaxM, DSP-7888, TPIV-200, PVX-410, VXL-100,DPX-E7, ISA-101 , 6MHP, OSE-2101, galinpepimut-S, SVN5367/M57-KLH, IMU-131;

bacterial vector vaccines such as CRS-207/GVAX, axalimogene filolisbac (ADXS11001); adenoviral vector vaccines such as nadofaragen firadenovec; autologous Gp96 vaccine; dendritic cell based vaccines such as CVactm, stapuldencel-T, eltrapuldencel-T, SL-701, BSK01TM, rocapuldencel-T (AGS-003), DCVAC, CVac ^tm , stapuldencel-T, eltrapuldencel-T, SL-701, BSK01™, ADXS31-142; oncolytic vaccines such as talimogene laherparepvec, pexastimogene devacirepvec, GL-ONC1, MG1-MA3, parvovirus H-1, ProstAtak, enadenotucirev, MG1MA3, ASN-002 (TG-1042);

therapeutic vaccines such as CVAC-301, CMP-001, PF-06753512, VBI-1901, TG-4010, ProscaVax™; tumor cell vaccines such as Vigil® (MD-14205), Oncoquest-L vaccine; live attenuated recombinant poliovirus serotype 1 vaccine such as PVS-RIPO; adagloxad simolenin; MEDI-0457; DPV-001 is a tumor-derived cancer vaccine enriched in autophagosomes; RNA vaccines such as CV-9209, LV-305; DNA vaccines such as MEDI-0457, MVI816, INO-5401; a p53-expressing modified vaccinia virus Ankara vaccine such as MVA-p53; DPX-Survivac; BriaVax™; GI-6301; GI-6207; and GI-4000;

antibodies to DLL4 (delta-like ligand 4), such as demcizumab; STAT-3 inhibitors such

- 119 045798 as napabucasin (BBI-608); p97 ATPase inhibitors such as CB-5083;

smoothened receptor inhibitors (SMOs), such as Odomzo® (sonidegib, formerly LDE-225), LEQ506, vismodegib (GDC-0449), BMS-833923, glasdegib (PF-04449913), LY2940680 and itraconazole;

interferon alpha ligand modulators, such as interferon alpha-2b, interferon alpha2a biosimilar (Biogenomics), rhopeginterferon alpha-2b (AOP-2014, P-1101, PEG IFN alpha-2b), multiferon (Alfanative, Viragen), interferon alpha 1b, roferon-A (kanferon, Ro-25-3036), bioanalogue of interferon alpha-2a (Bioside) (Inmutag, Inter 2A), bioanalogue of interferon alpha-2b (Biosidus - Bioferon, Cytoferon, Ganapar, Beijing Kawin Technology - Kaferon), alfaferon , pegylated interferon alpha-1b, peginterferon alpha-2b biosimilar (Amega), recombinant human interferon alpha-1b, recombinant human interferon alpha-2a, recombinant human interferon alpha-2b, veltuzumab-IFN alpha 2b conjugate, Dinavax (SD-101) and interferon alpha-n1 (Humoferon, SM-10500, Sumiferon); interferon gamma ligand modulators such as interferon gamma (OH-6000, Ogamma 100);

IL-6 receptor modulators such as tocilizumab, siltuximab and AS-101 (CB-06-02, IVX-Q-101);

telomerase modulators such as tertomotide (GV-1001, HR-2802, Riavax) and imetelstat (GRN-163, JNJ-63935937);

DNA methyltransferase inhibitors such as temozolomide (CCRG-81045), decitabine, guadecitabine (S-110, SGI-110), KRX-0402, RX-3117, RRx-001 and azacitidine;

DNA gyrase inhibitors such as pixantrone and sobuzoxan;

Bcl-2 family protein inhibitors such as ABT-263, venetoclax (ABT-199), ABT-737 and AT-101;

Notch inhibitors such as LY3039478 (crenigacestat), tarextumab (anti-Notch2/3) and BMS906024;

myostatin inhibitors such as landogrosumab;

hyaluronidase stimulators such as PEGPH-20;

Wnt pathway inhibitors such as SM-04755, PRI-724 and WNT-974;

gamma secretase inhibitors such as PF-03084014, MK-0752 and RO-4929097;

Grb-2 (growth factor receptor-associated protein-2) inhibitors such as BP1001;

TRAIL pathway inducing compounds such as ONC201 and ABBV-621;

focal adhesion kinase inhibitors such as VS-4718, defactinib and GSK2256098;

hedgehog inhibitors such as saridegib, sonidegib (LDE225), glasdegib and vismodegib;

Aurora kinase inhibitors such as alisertib (MLN-8237) and AZD-2811, AMG-900, barasertib and ENMD-2076;

HSPB1 (heat shock protein 27, HSP27) modulators such as brivudine and apatorsen;

ATR inhibitors such as BAY-937, AZD6738, AZD6783, VX-803, VX-970 (berzosertib) and VX-970;

mTOR inhibitors such as sapanisertib and vistusertib (AZD2014) and ME-344;

mTOR/PI3K inhibitors such as gedatolisib, GSK2141795, omipalisib and RG6114;

Hsp90 inhibitors such as AUY922, onalespib (AT13387), SNX-2112 and SNX5422;

murine two-minute oncogene (mdm2) inhibitors such as DS-3032b, RG7775, AMG-232, HDM201 and idasanutlin (RG7388);

CD137 agonists such as urelumab and utomilumab (PF-05082566);

STING agonists such as ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1 and SR-8291;

FGFR inhibitors such as FGF-401, INCB-054828, BAY-1163877, AZD4547, JNJ-42756493, LY2874455 and Debio-1347;

fatty acid synthase (FASN) inhibitors such as TVB-2640;

anti-KIR monoclonal antibodies such as lirilumab (IPH-2102) and IPH-4102;

CD19 antigen inhibitors such as MOR208, MEDI-551, AFM-11 and inebilizumab;

CD44 binders such as A6;

protein phosphatase 2A (PP2A) inhibitors such as LB-100;

CYP17 inhibitors such as seviteronel (VT-464), ASN-001, ODM-204, CFG920 and abiraterone acetate;

RXR agonists such as IRX4204;

hedgehog/smoothened (hh/Smo) antagonists such as taladegib and patidegib;

C3 complement modulators such as Imprime PGG;

IL-15 agonists such as ALT-803, NKTR-255 and hetIL-15;

EZH2 (zeste homolog 2 enhancer) inhibitors such as tazemetostat, CPI-1205 and GSK-2816126;

oncolytic viruses such as pelareorep, CG-0070, MV-NIS therapy, HSV-1716, DS-1647, VCN-01, ONCOS-102, TBI-1401, tasadenoturev (DNX-2401), vokimagen amiretrorepvec, RP-1, CVA21, Celyvir, LOAd-703 and OVR-301;

DOT1L (histone methyltransferase) inhibitors such as pinometostat (EPZ-5676);

toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, diphtheria toxin and caspase activators;

DNA plasmids such as BC-819;

- 120 045798 PLK 1, 2 and 3 inhibitors, such as volasertib (PLK1);

WEE1 inhibitors such as AZD1775 (adavosertib);

Rho kinase (ROCK) inhibitors such as AT13148 and KD025;

ERK inhibitors such as GDC-0994, LY3214996 and MK-8353;

IAP inhibitors such as ASTX660, debio-1143, birinapant, APG-13 87 and LCL-161;

RNA polymerase inhibitors such as lurbinectin (PM-1183) and CX-5461;

tubulin inhibitors such as PM-184, BAL-101553 (lizavanbulin), OXI-4503, fluorapacin (AC-0001) and plinabulin;

Toll-like receptor 4 (TL4) agonists such as G100, GSK1795091 and PEPA-10;

elongation factor 1 alpha 2 inhibitors such as plitidepsin;

CD95 inhibitors such as APG-101, APO-010 and asunercept;

WT1 inhibitors such as DSP-7888;

splicing factor 3B subunit 1 (SF3B1) inhibitors such as H3B-8800;

inhibitors specific for PDGFR alpha/KIT mutants, such as BLU-285;

SHP-2 inhibitors such as TNO155 (SHP-099) and RMC-4550; and retinoid receptor Z gamma (RORy) agonists such as LYC-55716.

In some embodiments, provided herein are methods of treating or preventing cancer or a hyperproliferative disease in a human or animal suffering from or at risk for cancer or a hyperproliferative disease, comprising administering to the human or animal a therapeutically effective amount of a compound of formula I, II, IIa, IIb, III, IIIa, IV, IVa, IVb, IVc, V, Va, Vb, Vc, VI, VIa, VIb, VIc, VII, VIIa, VIIb or VIIc described herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents selected from the group consisting of apoptotic signal-regulating kinase (ASK) inhibitors; Bruton's tyrosine kinase inhibitors (BTK); cluster of differentiation 47 (CD47) inhibitors; cyclin-dependent kinase (CDK) inhibitors; discoidin domain receptor (DDR) inhibitors; histone deacetylase (HDAC) inhibitors; indoleamine pyrrole 2,3-dioxygenase (IDO1) inhibitors; Janus kinase (JAK) inhibitors; lysyl oxidase-like protein (LOXL) inhibitors; matrix metalloproteinase (MMP) inhibitors; mitogen-activated protein kinase (MEK) inhibitors; phosphatidylinositol 3-kinase (PI3K) inhibitors; spleen tyrosine kinase (SYK) inhibitors; toll-like receptor 8 (TLR8) inhibitors; toll-like receptor 9 (TLR9) inhibitors; tyrosine kinase inhibitors (TKIs) or a pharmaceutically acceptable salt of any of the above or any combinations thereof.

Non-limiting examples include:

Apoptosis signal-regulating kinase (ASK) inhibitors: ASK inhibitors include ASK1 inhibitors. Examples of ASK1 inhibitors include, but are not limited to, those described in WO 2011/008709 (Gilead Sciences) and WO 2013/112741 (Gilead Sciences);

Bruton's Tyrosine Kinase (BTK) Inhibitors: Examples of BTK inhibitors include, but are not limited to, (S)-6-amino-9-(1-(but-2-inoyl)pyrrolidin-3-yl)-7-(4-phenoxyphenyl) )-7H-purin-8(9H)-one, acalabrutinib (ACP-196), BGB-3111, SV988, HM71224, ibrutinib, M-2951 (evobrutinib), M7583, tirabrutinib (ONO-4059), PRN-1008, spebrutinib (CC-292), TAK-020, vecabrutinib, ARQ-531, SHR1459, DTRMWXHS-12 and TAS-5315;

Cluster of differentiation 47 (CD47) inhibitors: Examples of CD47 inhibitors include, but are not limited to, anti-CD47 mAb (Vx-1004), human anti-CD47 mAb (CNTO-7108), CC-90002, CC90002-ST-001, humanized anti-CD47 antibody (Hu5F9-G4), NI-1701, NI-1801, RCT-1938 and TTI-621.

Cyclin-dependent kinase (CDK) inhibitors: CDK inhibitors include CDK 1, 2, 3, 4, 6, 7 and 9 inhibitors such as abemaciclib, alvocidib (HMR-1275, flavopiridol), AT-7519, dinaciclib, Ibrance, FLX-925 , LEE001, palbociclib, ribociclib, rigosertib, selinexor, UCN-01, SY1365, CT-7001, SY-1365, G1T38, milciclib, trilaciclib and TG-02.

Discoidin Domain Receptor (DDR) Inhibitors: DDR inhibitors include DDR1 and/or DDR2 inhibitors. Examples of DDR inhibitors include, but are not limited to, those described in WO 2014/047624 (Gilead Sciences), US 2009-0142345 (Takeda Pharmaceutical), US 20110287011 (Oncomed Pharmaceuticals), WO 2013/027802 (Chugai Pharmaceutical), and WO 2013/034933 (Imperial Innovations).

Histone deacetylase (HDAC) inhibitors: Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, belinostat, CKD-581, CS-055 (HBI-8000), CUDC-907 (fimepinostat ), entinostat, givinostat, mocetinostat, panobinostat, pracinostat, chisinostat (JNJ-26481585), resminostat, ricolinostat, SHP-141, valproic acid (VAL-001), vorinostat, tinostamustine, remetinostat and entinostat.

Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors: Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GbV-1012, GBV-1028, GDC-0919, indoximod, NKTR- 218, vaccine based on NLG-919, PF-06840003, pyranonaphthoquinone derivatives (SN-121 045798

35837), resminostat, SBLK-200802, BMS-986205 and shlDO-ST, EOS-200271, KNK-2455 and LY-3381916.

Janus kinase (JAK) inhibitors: JAK inhibitors inhibit JAK1, JAK2 and/or JAK3. Examples of JAK inhibitors include, but are not limited to, AT9283, AZD1480, baricitinib, BMS-911543, fedratinib, filgotinib (GLPG0634), gandotinib (LY2784544), INCB039110 (itacitinib), lestaurtinib, momelotinib (CYT0387), NS-018, PA critinib ( SB1518), pecitinib (ASP015K), ruxolitinib, tofacitinib (formerly tasocitinib), INCB052793 and XL019.

Lysyl oxidase-like protein (LOXL) inhibitors: LOXL inhibitors include inhibitors of LOXL1, LOXL2, LOXL3, LOXL4 and/or LOXL5. Examples of LOXL inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Biosciences). Examples of LOXL2 inhibitors include, but are not limited to, the antibodies described in WO 2009/017833 (Arresto Biosciences), WO 2009/035791 (Arresto Biosciences) and WO 2011/097513 (Gilead Biologics); Matrix metalloproteinase (MMP) inhibitors: MMP inhibitors include MMP1-MMP10 inhibitors. Examples of MMP9 inhibitors include, but are not limited to, marimastat (BB-2516), cipemastat (Ro 32-3555), GS-5745 (andecaliximab) and the inhibitors described in WO 2012/027721 (Gilead Biologics). Mitogen-activated protein kinase (MEK) inhibitors: MEK inhibitors include anthroquinonol, binimetinib, cobimetinib (GDC-0973, XL-518), MT-144, selumetinib (AZD6244), sorafenib, trametinib (GSK1120212), uprosertib+trametinib, PD-0325901 , pimasertib, LTT462, AS703988, CC-90003 and refametinib.

Phosphatidylinositol 3-kinase (PI3K) inhibitors PI3K inhibitors include PI3Ky, PI3Kδ, PI3Ke, PI3Ka and/or pan-PI3K inhibitors. Examples of PI3K inhibitors include, but are not limited to, ACP-319, AEZA-129, AMG-319, AS252424, AZD8186, BAY 10824391, BEZ235, buparlisib (BKM120), BYL719 (alpelisib), CH5132799, copanlisib (BAY 80-694 6) , duvelisib, GDC-0032, GDC-0077, GDC0941, GDC-0980, GSK2636771, GSK2269557, idelalisib (Zydelig®), INCB50465, IPI-145, IPI-443, IPI549, KAR4141, LY294002, LY30234 14, MLN1117, OXY111A, PA799 , РХ-866, RG7604, rigosertib, RP5090, RP6530, SRX3177, taselisib, TG100115, TGR-1202 (umbralisib), TGX221, WX-037, X-339, X414, XL147 (SAR245408), XL499, XL75 6, Wortmannin, ZSTK474 , and compounds described in WO 2005/113556 (ICOS), WO 2013/052699 (Gilead Calistoga), WO 2013/116562 (Gilead Calistoga), WO 2014/100765 (Gilead Calistoga), WO 2014/100767 (Gilead Calistoga) and WO 2014/201409 (Gilead Sciences).

Spleen tyrosine kinase (SYK) inhibitors: Examples of SYK inhibitors include, but are not limited to, 6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo[1,2-a]pyrazin-8-amine, BAY-61-3606, cerdulatinib (PRT-062607), entospleginib, fostamatinib (R788), HMPL-523, NVP-QAB 205 AA, R112, R343, tamatinib (R406), GS-9876 and compounds described in US 8450321 ( Gilead Connecticut) and US 2015/0175616.

Toll-like receptor 8 (TLR8) inhibitors: Examples of TLR8 inhibitors include, but are not limited to, E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, motolimod, resiquimod, VTX- 1463 and VTX-763. Toll-like receptor 9 (TLR9) inhibitors: Examples of TLR9 inhibitors include, but are not limited to, AST-008, IMO-2055, IMO-2125, lefitolimod, lithenimod, MGN-1601 and PUL-042; And

Tyrosine kinase inhibitors (TKIs): TKIs can target epidermal growth factor receptors (EGFR) and fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) receptors. Examples of TKIs include, but are not limited to, afatinib, ARQ-087 (derazantinib), asp5878, AZD3759, AZD4547, bosutinib, brigatinib, cabozantinib, cediranib, crenolanib, dacomitinib, dasatinib, dovitinib, E-6201, erdafitinib, erlotinib, Gefi tinib, gilteritinib ( ASP-2215), FP-1039, HM61713, icotinib, imatinib, KX2-391 (Src), lapatinib, lestaurtinib, lenvatinib, midostaurin, nintedanib, ODM-203, osimertinib (AZD-9291), ponatinib, poziotinib, hizartinib, radotinib , rociletinib, sulfatinib (HMPL-012), sunitinib, tivoanib, TH-4000 and MEDI-575 (anti-PDGFR antibody).

As used herein, the term chemotherapeutic agent or chemotherapeutic (or chemotherapy, in the case of treatment with a chemotherapeutic agent) includes any non-protein (ie, non-peptide) chemical compound useful for treating cancer. Examples of chemotherapeutic agents include, but are not limited to:

alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa and uredopa; ethylene imines and methyl melamines, including altretamine, triemylene melamine, triethylene phosphoramide, triethylene thiophosphoramide and trimethylol melamine; acetogenins, especially bullatacin and bullatacinone; camptothecin, including the synthetic analogue of topotecan; bryostatin; kallistatin; CC1065, including synthetic analogues of adozelesin, carzelesin and bizelesin; cryptophycins, in particular cryptophycin 1 and cryptophycin 8; dolastatin;

duocarmycin, including synthetic analogues, KW-2189 and CBI-TMI; eleutherobin; 5-azacytidine; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphasine, cyclophosphamide, glufosfamide, evofosfamide, bendamustine, estramustine, ifosfamide, mechlorethamine,

- 122 045798 mechlorethamine oxide hydrochloride, melphalan, novembiquin, phenesterol, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorosotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as enediyne antibiotics (eg calicheamicin, especially calicheamicin gamma II and calicheamicin phi II); dinemycin, including dinemycin A; bisphosphonates such as clodronate, esperamycin, as well as neocarcinostatin-based chromophore and similar chromoprotein chromophores based on enediyne antibiotics, aclacinomysins, actinomycin, outramycin, azaserine, bleomycins, sactinomycin, carabicin, carminomycin, carcinophilin, chromomycins, dactinomycin, daunorubicin , detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, ezorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprin, thioguanine; pyrimidine analogues such as antsitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epithiostanol, mepithiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; a folic acid compensator such as frolinic acid; radiotherapeutic agents such as radium-223; trichothecenes, especially T-2 toxin, verracurine A, roridin A and anhydrine; taxoids such as paclitaxel (TAXOL®), abraxane, docetaxel (TAXOTERE®), cabazitaxel, BIND-014, tesetaxel; platinum analogues such as cisplatin and carboplatin, NC-6004 nanoplatinum; aceglatone;

aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquon; elfornitine; elliptinium acetate; epothilone; ethoglucide; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamole; nitracrine; pentostatin; phenomet; pirarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllic acid; 2ethylhydrazide; procarbazine; polysaccharide-K (PSK®); razoxane; rhizoxin; sisofiran; spirogermanium; tenuazonic acid; trabectedin, triaziquone; 2,2',2-trichlorotriethylamine; urethane; vindesine; dacarbazine; mannomustin; mitobronitol; mitolactol; pipobromance; gacytosine; arabinoside (Ara-S); cyclophosphamide; thiotepa; chlorambucil; gemcitabine (GEMZAR®); 6-thioguanine; mercaptopurine; methotrexate; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vancristine; vinorelbine (NAVELBINE®); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; SRT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFAO); retinoids such as retinoic acid; capecitabine; NUC-1031; FOLFIRI (fluorouracil, leucovorin and irinotecan) and pharmaceutically acceptable salts, acids or derivatives of any of the above.

Also included within the definition of a chemotherapeutic agent are antihormonal agents such as antiestrogens and selective estrogen receptor modulators (SERMs), aromatase enzyme inhibitors, antiandrogens, and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing that act by regulating or inhibiting hormonal effects on tumors.

Antihormonal agents.

Examples of antiestrogens and SERMs include, for example, tamoxifen (including NOLVADEX™), raloxifene, droloxifene, 4-hydroxytamoxifene, trioxifene, keoxifene, LY117018, onapristone and toremifene (FARESTON®).

Aromatase enzyme inhibitors regulate estrogen production in the adrenal glands. Examples include 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace®), exemestane, formestane, fadrozole, vorozole (RIVISOR®), letrozole (Femara®), and anastrozole (Arimidex®).

Examples of antiandrogens include apalutamide, abiraterone, enzalutamide, flutamide, galeterone, nilutamide, bicalutamide, leuprolide, goserelin, ODM-201, APC-100 and ODM-204.

Examples of a progesterone receptor antagonist include onapristone. Antiangiogenic agents.

Antiangiogenic agents include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, ANGIOSTATIN, ENDOSTATIN, regorafenib, necuparanib, suramin, squalamine, tissue metalloproteinase-1 inhibitors, tissue metalloproteinase-2 inhibitors, plasminogen activator inhibitor-1 inhibitor plasminogen activator-2, cartilage inhibitor, paclitaxel (nab-paclitaxel), platelet factor 4, protamine sulfate (clupein), sulfated chitin derivatives (derived from king crab shells), sulfated peptidoglycan polysaccharide complex (sp-pg), staurosporine, matrix metabolism modulators , including, for example, proline analogues ((1-azetidine-2-carboxylic acid (LACA), cishydroxyproline, D,L-3,4dehydroproline, thiaproline, α,α'-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5- (4

- 123 045798 pyridinyl)-2(3h)-oxazolone, methotrexate, mitoxantrone, heparin, interferons, serum 2 macroglobulin, chicken metalloprotease-3 inhibitor (ChIMP-3), chymostatin, betacyclodextrin tetradecasulfate, epineomycin, fumagillin, sodium gold thiomalate, d- penicillamine, serum beta-1-anticollagenase, alpha-2-antiplasmin, bisanthen, disodium lobenzarite, disodium N-2-carboxyphenyl-4-chloranthronilic acid or SCA, thalidomide; angiostatic steroid, carbohexine aminolimidazole; metalloproteinase inhibitors such as BB-94 and S100A9 inhibitors such as tasquinimod. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies, to the following angiogenic growth factors: beta-FGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.

Antifibrotic agents.

Antifibrotic agents include, but are not limited to, compounds such as beta-aminopropionitrile (BAPN), as well as compounds described in US 4,965,288 relating to lysyl oxidase inhibitors and their use for the treatment of diseases and conditions associated with abnormal collagen deposition and US 4,997,854 relates to compounds that inhibit LOX for the treatment of various pathological fibrotic conditions, which are incorporated herein by reference. Additional exemplary inhibitors are described in US 4,943,593 relating to compounds such as 2-isobutyl-3-fluoro-, chloro- or bromoallylamine, US 5,021,456, US 5,059,714, US 5,120,764, US 5,182,297, US 5,252,608 relating to 2- (1-naphthyloxymemyl)3-fluoroallylamine, and US 2004-0248871, which are incorporated herein by reference.

Typical antifibrotic agents also include primary amines that react with the active site carbonyl group of lysyl oxidases, and in particular, which upon coupling with the carbonyl produce a resonance stabilized product, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine and their derivatives, semicarbazide and urea derivatives , aminonitriles such as BAPN or 2-nitroethylamine, unsaturated or saturated halogenamines such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine and p-halobenzylamines, and selenium homocysteine lactone.

Other antifibrotic agents are copper chelating agents that may or may not penetrate cells. Examples of compounds include indirect inhibitors that block aldehyde derivatives resulting from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidases. Examples include thiolamines, especially D-penicillamine, and analogs such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl3-((2-acetamidoethyl)dithio)butanoic acid, p-2- amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, sodium 4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulfurate, 2-acetamidoethyl-2acetamidoethanethiol sulfonate and sodium 4-mercaptobutanesulfinate trihydrate.

Immunotherapeutic agents.

Examples of immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating patients. Some examples of therapeutic antibodies include abagovomab, ABP-980, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bektumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, CC49, cetu ximab, citazumab, cixutumumab, clivatuzumab . votumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab , igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab (YERVOY®, MDX-010, BMS-734016 and MDX-101), iratumumab, labetuzumab, lexatumumab, lintuzumab, lorvotuzumab, lucatumumab, mapatumumab, matuzumab, milatuzumab b, minretumomab, mitumomab , mogamulizumab, moxetumomab, naptumomab, narnatumab, necitumumab, nimotuzumab, nofetumomab, OBI-833, obinutuzumab, ocaratuzumab, ofatumumab, olaratumab, onartuzumab, oportuzumab, oregovomab, panitumumab, parsatuzumab, pasudotox, patritumab, pem tumomab, pertuzumab, pintumomab, pritumumab, racotumomab , radretumab, ramicirumab (Cyramza®), rilotumumab, rituximab, robatumumab, samalizumab, satumomab, sibrotuzumab, siltuximab, solitomab, simtuzumab, takatuzumab, taplitumomab, tenatumomab, teprotumomab, tigatuzumab, tositumomab, trastuzumab, tukot uzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab , zalutumumab and 3F8. Rituximab can be used to treat indolent forms of B-cell cancer, including marginal zone lymphoma, WM, CLL, and small lymphocytic lymphoma. In some embodiments, the combination of rituximab and chemotherapy agents is particularly effective.

Typical therapeutic antibodies may be further labeled or combined with a radioisotope moiety such as indium-111, yttrium-90 (90Y-clivatuzumab), or iodine-131.

Gene therapy and cell therapy for cancer.

Gene therapy and cell therapy for cancer involve introducing a normal gene into cancer cells to replace a mutated or altered gene; genetic modifications that silence mutiro

- 124 045798 valid gene; genetic approaches to directly destroy cancer cells; including infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to cancer cells or activate the patient's own immune system (T cells or natural killer cells) to destroy cancer cells, or to seek out and destroy cancer cells; and genetic approaches to modify cellular activity to further alter the endogenous immune response against cancer.

Gene editors.

Examples of gene editing systems include the CRISPR/Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

CAR-T cell therapy and TCR-T cell therapy.

CAR-T cell therapy involves a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), where the CAR contains a cancer antigen-binding domain. The immune effector cell is a T cell or NK cell. TCR-T cell therapy involves TCR-T cells engineered to target tumor-derived peptides present on the surface of tumor cells. The cells can be autologous or allogeneic.

In some embodiments, the CAR comprises an antigen binding domain, a transmembrane domain, and an intracellular signaling domain.

In some embodiments, the intracellular domain includes a primary signaling domain, a co-stimulatory domain, or both.

In some embodiments, the primary signaling domain includes a functional signaling domain of one or more proteins selected from the group consisting of CD3-zeta, CDS-gamma, CD3-delta, CDS-epsilon, general FcR-gamma (FCERIG), FcR-beta ( Fc Epsilon Rlb), CD79a, CD79b, Fcgamma Rlla, DAP10 and DAP 12.

In some embodiments, the co-stimulatory domain includes a functional domain of one or more proteins selected from the group consisting of CD27, CD28, 4-1BB(CD137), OX40, CD30, CD40, PD-1, ICOS, function-associated antigen-1 lymphocytes (LFA-I), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160 , CD19, CD4, CD8 alpha, CD8 beta, IL2R beta, IL2R gamma, IL7R alpha,

ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD 1 Id, ITGAE, CD 103, ITGAL, CD 1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD1 1c , ITGB1, CD29, HGB2, CD 18, LFA-1, ITGB7, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD 160 (BY55), PSGL1, CD 100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, NKp44, NKp30, NKp46 and NKG2D.

In some embodiments, the transmembrane domain comprises a transmembrane domain of a protein selected from the group consisting of T cell receptor alpha, beta, or zeta chain, CD28, CD3 epsilon,

CD45, CD4, CD5, CD8, CD9,

CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD1 la, CD18), ICOS (CD278), 4-lBB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFI), CD160, CD 19, IL2R6eTa, IL2R gamma, IL7Ru, HGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 Id, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 lb, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD 18, LFA1, ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244 , 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3 ), BLAME (SLAMF8), SELPLG (CD162), LTBR, PAG/Cbp, NKp44, NKp30, NKp46, NKG2D and NKG2C.

In some embodiments, the antigen binding domain binds a tumor antigen.

In some embodiments, the tumor antigen is selected from the group consisting of: CD19; CD123; CD22; CD30; CD171; CS-1 (also referred to as CD2 subset 1, CRACC, SLAMF7, CD319 and 19A24); C-type lectin-like molecule-1 (CLL-1 or CLECLI); CD33; option III

- 125 045798 epidermal growth factor receptor (EGFRvIII); ganglioside G2 (GD2); ganglioside GD3 (aNeuSAc(2-8)aNeuSAc(2-3)bDGaip(1-4)bDGIcp(1-1)Cer); maturation of TNF receptor family member B cells (BCMA); antigen Tn ((Tn Ag) or (GaINAcu-Ser/Thr)); prostate-specific membrane antigen (PSMA); receptor tyrosine kinase-like orphan receptor 1 (RORI); Fms-like tyrosine kinase 3 (FLT3); tumor associated glycoprotein 72 (TAG72); CD38; CD44v6; carcinoembryonic antigen (CEA); epithelial cell adhesion molecules (EPCAM); B7H3 (CD276); KIT (CD117); interleukin-13 receptor alpha-2 subunits (IL-13Ra2 or CD213A2); mesothelin; interleukin 11 receptor alpha (IL-llRa); prostate stem cell antigen (PSCA); serine protease 21 (testisin or PRSS21); vascular endothelial growth factor receptor 2 (VEGFR2); Lewis(Y) antigen; CD24; platelet-derived growth factor receptor beta (PDGFR-beta); stage-specific embryonic antigen-4 (SSEA-4); CD20; delta-like 3 (DLL3); folate receptor alpha; receptor tyrosine protein kinase, ERBB2 (Her2/neu); cell surface associated mucin 1 (MUC1); epidermal growth factor receptor (EGFR); nerve cell adhesion molecules (NCAM); prostases; prostatic acid phosphatase (PAP); mutated elongation factor 2 (ELF2M); ephrin B2; fibroblast activation protein alpha (FAP); insulin-like growth factor receptor 1 (IGF-I receptor), carbonic anhydrase IX (CAIX); proteasome subunits (prosome, macropain), beta type, 9 (LMP2); glycoprotein 100 (gp100); an oncogene fusion protein consisting of the breakpoint cluster region (BCR) and Abelson murine leukemia viral oncogene (Abl) homolog 1 (bcr-abl); tyrosinase; ephrin receptor type A 2 (EphA2); fucosyl GM1; sialyl Lewis adhesion molecules (sLe); ganglioside GM3 (aNeuSAc(2-3)bDGalp(1-4)bDGlcp(1-1)Cer); transglutaminase 5 (TGS5); high molecular weight melanoma-associated antigen (HMWMAA); oacetyl-GD2 ganglioside (OAcGD2); folic acid receptor beta; tumor endothelial marker 1 (TEM1/CD248); tumor endothelial marker 7-related (TEM7R); six transmembrane epithelial antigens of prostate I (STEAP1); claudin 6 (CLDN6); thyroid stimulating hormone receptor (TSHR); G protein-coupled receptor class C, group 5, member D (GPRCSD); chromosome X open reading frame 61 (CXORF61); CD97; CD179a; anaplastic lymphoma kinase (ALK); polysialic acid; placenta-specific 1 (PLAC1); the hexasaccharide portion of the glycoceramide globoH (GloboH); breast differentiation antigen (NY-BR-1); uroplakin 2 (UPK2); hepatitis A virus cellular receptor 1 (HAVCR1); adrenergic receptor beta 3 (ADRB3); pannexin 3 (PANX3); G protein-coupled receptor 20 (GPR20); lymphocyte antigen complex 6, locus K 9 (LY6K); olfactory receptor 51E2 (ORS IE2); TCR gamma alternative reading frame protein (TARP); Wilms tumor protein (WT1); cancer testicular antigen 1 (NY-ESO-1); cancer testicular antigen 2 (LAGE-1a); melanoma associated antigen 1 (MAGE-A1); gene 6 variant of ETS translocation located on chromosome 12p (ETV6-AML); sperm protein 17 (SPA17); X antigen family member 1A (XAGE1); cell surface receptor 2 that binds to angiopoietin (Tie 2); testicular melanoma antigen-1 (MADCT-1); testicular melanoma antigen-2 (MADCT-2); Fos-related antigen 1; tumor protein p53 (p53); p53 mutant; simple; survivina; telomerase; prostate carcinoma tumor antigen-1 (PCTA-1 or galectin 8), melanoma T-cell recognized antigen 1 (MelanA or MARTI); mutant rat sarcoma (Ras); human telomerase reverse transcriptase (hTERT); control points for sarcoma translocation; melanoma inhibitor of apoptosis (ML-IAP); ERG (transmembrane protease serine 2 (TMPRSS2) ETS fusion gene); N acetylglucosaminyltransferase V (NA17); paired box protein Pax-3 (PAX3); androgen receptor; cyclin B1; avian myelocytomatosis virus oncogene homolog v-myc neuroblastoma-derived (MYCN); member C of the Ras Homolog (RhoC) family; tyrosinase-related protein 2 (TRP-2); cytochrome P450 1B1 (CYP IBI); CCCTS-binding factor (zinc finger protein)-like (BORIS, Brother of the Regulator of Imprinted Sites), squamous cell carcinoma antigen recognized by T cells 3 (SART3); paired box protein Pax-5 (PAX5); proacrosin-binding protein sp32 (OY-TES I); lymphocyte-specific protein tyrosine kinase (LCK); anchor kinase protein 4 (AKAP-4); synovial sarcoma X breakpoint 2 (SSX2); receptor for advanced glycation end products (RAGEI); renal ubiquitous 1 (RUI); renal ubiquitous 2 (RU2); legumaina; human papillomavirus E6 (HPV E6); human papilloma virus E7 (HPV E7); intestinal carboxylesterase; mutated heat shock protein 70-2 (mut hsp70-2); CD79a; CD79b; CD72; leukocyte-associated immunoglobulin receptor 1 (LAIRI); Fc fragment of the IgA receptor (FCAR or CD89); leukocyte immunoglobulin-like receptor subfamily A member 2 (LILRA2); CD300 family member f like (CD300LF); C-type lectin domain family 12 member A (CLEC12A); bone marrow stromal cell antigen 2 (BST2); mucin-like hormone receptor-2 containing EGF-like module (EMR2); lymphocyte antigen 75 (LY75); glypican-3 (GPC3); Fc receptor-like 5 (FCRL5); and immunoglobulin lambda-like polypeptide 1 (IGLL1).

In some embodiments, said tumor antigen is selected from

- 126 045798

CD150, 5T4, ActRIIA, B7, BMCA, CA-125, CCNA1, CD123, CD126, CD138, CD14, CD148, CD15, CD19, CD20, CD200, CD21, CD22, CD23, CD24, CD25, CD26, CD261, CD262, CD30, CD33, CD362, CD37, CD38, CD4, CD40, CD40L, CD44, CD46, CD5, CD52, CD53, CD54, CD56, CD66a-d, CD74, CD8, CD80, CD92, CE7, CS-1, CSPG4, ED-B fibronectin, EGFR, EGFRvin, EGP-2, EGP-4, EPHa2, ErbB2, ErbB3, ErbB4, FBP, GD2, GD3, HER1-HER2 in combination, HER2-HER3 in combination, HERV-K, HIV envelope glycoprotein -1 gp120, HIV-1 envelope glycoprotein gp41, HLA-DR, HM1.24, HMW-MAA, Her2, Her2/neu, IGF-1R, IL-UR-alpha, IL-13R-alpha2, IL-2, IL -22R-alpha, IL-6, IL-6R, Ia, Ii, L1-CAM, L1-cell adhesion molecule, Lewis Y, L1CAM, MAGE A3, MAGE-A1, MART-1, MUC1, NKG2C ligands, NKG2D Ligands , NYESO-1, OEPHa2, PIGF, PSCA, PSMA, R0R1, T101, TAC, TAG72, TIM-3, TRAIL-R1, TRAIL-R1 (DR4), TRAIL-R2 (DR5), VEGF, VEGFR2, WT-I , G-protein coupled receptor, alphafetoprotein (AFP), angiogenesis factor, exogenous cognate binding molecule (ExoCBM), oncogene product, antifolate receptor, c-Met, carcinoembryonic antigen (CEA), cyclin (D1), ephrin B2, epithelial tumor antigen, estrogen receptor, fetal acetycholine e receptor, folate binding protein, gp100, hepatitis B surface antigen, kappa chain, kappa light chain, kdr, lambda chain, livin, melanoma associated antigen, mesothelin, mouse two-minute oncogene (MDM2), mucin 16 (MUC16), mutated p53, mutated ras, necrosis antigens, oncofetal antigen, R0R2, progesterone receptor, prostate specific antigen, tEGFR, tenascin, P2microglobulin and Fc receptor-like 5 (FcRL5).

Non-limiting examples of cell therapies include Algenpantucel-L, Sipuleucel-T, (BPX501) rivogenlecleucel US9089520, WO 2016100236, AU-105, ACTR-087, activated allogeneic natural killer cells CNDO-109-AANK, MG-4101, AU-101, BPX-601, fAtE-NK100, LFU-835 hematopoietic stem cells, Imilecleucel-T, baltaleucel-T, PNK-007, UCARTCS1, ET-1504, ET-1501, ET-1502, ET-190, CD19-ARTEMIS, ProHema , bone marrow stem cell therapy with FT-1050 treatment, CD4CARNK-92 cells, CryoStim, AlloStim, lentivirus-transduced huCART-meso cells, CART-22 cells, EGFRt/19-28z/4-1BBL CART cells, autologous 4H11 -28z /fIL12/EFGRt T cell, CCR5-SBC-728-HSPC, CAR4-1BBZ, CH-296, dnTGFbRII-NY-ESOc259T, Ad-RTS-IL12, IMA-101, IMA-201, CARMA-0508, TT- 18, CMD-501, CMD-503, CMD-504, CMD-502, CMD-601, CMD602 and CSG-005.

In some embodiments, the tumor-targeting antigen includes: alpha-fetoprotein, such as ET-1402 and AFP-TCR; anthrax toxin receptor 1 such as anti-TEM8 CAR T cell therapy; B cell maturation antigens (BCMA) such as bb-2121, UCART-BCMA, ET-140, KITE-585, MCM-998, LCAR-B38M, CART-BCMA, SEA-BCMA, BB212, UCART-BCMA, ET -140, PBCMA-101, and AUTO-2 (APRIL-CAR); antibodies to CLL-1, such as KITE-796; 6 B7 homolog such as CAR-NKp30 and CAR-B7H6; CD19 B lymphocyte antigen such as TBI-1501, CTL-119 huCART-19 T cells, JCAR-015 US7446190, JCAR-014, JCAR-017, (WO 2016196388, WO 2016033570, WO 2015157386), axicabtagene siloleucel (KTE-C19 ), US7741465, US6319494, UCART-19, EBV-CTL, T Tusagenleklyl-T (CTL019), Wo 2012079000, Wo 2017049166, CD19CAR-CD28-CD3DZETA-EGFRTEXPESITION TIME, CD19/4-1BBL ARMORTEP ED Cart cells, C -CAR-011, CIKCAR.CD19, CD19CAR-28-zeta T cells, PCAR-019, MatchCART, DSCAR-01 and IM19 CAR-T; Blymphocyte antigen CD20, such as ATTCK-20; cell adhesion of B lymphocytes, for example, UCART-22 and JCAR-018 (WO 2016090190); NY-ESO-1 such as GSK-3377794 and TBI-1301; carbonic anhydrase such as DC-Ad-GMCAIX; suicide caspase 9 gene such as CaspaCIDe DLI and BPX-501; CCR5 such as SB-728; CDw123 such as MB-102 and UCART-123; CD20m, such as CBM-C20.1; CD4 such as ICG-122; CD30, such as CART30 (CBM-C30.1); CD33, such as CIK-CAR.CD33; CD38 such as T-007 and UCART-38; a CD40 ligand such as BPX-201; SEACAM protein 4 modulators such as MG7CART; claudin 6, such as CSG-002; targeting EBV, such as CMD-003; EGFR, such as autologous 4H11-28z/fIL-12/EFGRt T cell; endonuclease such as PGN-514 and PGN-201; Epstein-Barr virus-specific T lymphocytes, such as TT-10; Erbb2, such as CST-102 and CIDeCAR; ganglioside (GD2), such as 4SCAR-GD2; glutamate carboxypeptidase II such as CIK-CAR.PSMA, CARTPSMA-TGFeRDN and P-PSMA-101; glypican-3 (GPC3), such as TT-16 and GLYCAR; hemoglobin such as PGN-236; hepatocyte growth factor receptor such as anti-cMet RNA CAR T; human papillomavirus E7 protein such as KITE-439; Immunoglobulin gamma Fc receptor III such as ACTR087; IL-12 such as DC-RTS-IL-12; an IL-12/mucin 16 agonist such as JCAR-020; IL-13 alpha 2, such as MB-101; IL-2 such as CST-101; K-Ras GTPase, such as anti-KRAS G12V mTCR cell therapy; L1 neural cell adhesion molecule L1CAM (CD171), such as JCAR-023; latent membrane protein 1/latent membrane protein 2, such as autologous dendritic cells transduced with Ad5f35-LMPd1-2; melanoma associated antigen 10 such as MAGE-A10C796T and MAGE-A10 TCR; melanoma-associated antigen 3/melanoma-associated antigen 6 (MAGE A3/A6),

- 127 045798 such as KITE-718; mesothelin such as CSG-MESO and TC-210; NKG2D, such as NKR-2; receptor tyrosine kinase Ntrkr1, such as JCAR-024; T cell receptors such as BPX-701 and IMCgp100; T lymphocyte such as TT-12; tumor infiltrating lymphocytes such as LN-144 and LN-145; and Wilms tumor protein such as JTCR-016, WT1-CTL.

Combination therapy for lymphoma or leukemia.

In some embodiments, the additional therapeutic agents are suitable for treating lymphoma or leukemia. These agents include aldesleukin, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, arsenic trioxide, Bcl-2 protein inhibitor ABT-263, beta-alethin, BMS-345541, bortezomib (Velcade®), bortezomib (Velcade®, PS-341), bryostatin 1, busulfan, carboplatin, Campath-1H, carboplatin, carfilzomib (Kyprolis®), carmustine, caspofungin acetate, CC-5103, chlorambucil, CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) , cisplatin, cladribine, clofarabine, curcumin, CVP (cyclophosphamide, vincristine and prednisone), cyclophosphamide, cyclosporine, cytarabine, denileukina diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin, doxorubicin hydrochloride, DT-PACE (dexamethasone, thalidomide, cisplatin, doxorubicin , cyclophosphamide and etoposide), enzastaurine, epoetin alfa, etoposide, everolimus (RAD001), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide and rituximab), fenretinide, filgrastim, flavopiridol, fludarabine, FR (fludarabine and rituximab ) , geldanamycin (17-AAG), hyper CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine), ICE (ifosfamide, carboplatin and etoposide), ifosfamide, irinotecan hydrochloride, interferon alfa-2b, ixabepilone, lenalidomide (REVLIMID® , CC-5013), lymphokine-activated killer cells, MCP (mitoxantrone, chlorambucil and prednisolone), melphalan, mesna, methotrexate, mitoxantrone hydrochloride, motexafin gadolinium, mycophenolate mofetil, nelarabine, obatoclax (GX15-070), oblimersen, octreotide acetate , omega-3 fatty acids, Omr-IgG-am (WNIG, Omrix), oxaliplatin, paclitaxel, palbociclib (PD0332991), pegfilgrastim, pegylated liposomal doxorubicinb hydrochloride, perifosine, prednisolone, prednisone, recombinant flt3 ligand, recombinant human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, R-CHOP (rituximab and CHOP), R-CVP (rituximab and CVP), R-FCM (rituximab and FCM), R-ICE (rituximab and ICE), and R-MCP (rituximab and MCP), R-roscovitine (seliciclib, CYC202), sargramostim, sildenafil citrate, simvastatin, sirolimus, styryl sulfones, tacrolimus, tanespimycin, temsirolimus (CC1-779), thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, SAHA (suberanilohydroxamic acid or suberoyl, anilide and hydroxamic acid), vemurafenib (Zelboraf®) and venetoclax (AVT-199).

One example of a modified approach is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle such as indium-111, yttrium-90, iodine131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab (BEXXAR), yttrium-90 ibritumomab tiuxetan (Zevalin®), BEXXAR CHOP.

The therapies mentioned above can be complemented or combined with stem cell transplantation or stem cell treatment. Therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, stem cell supported bone marrow ablation, peripheral stem cell transplantation blood processed in vitro, umbilical cord blood transplantation, enzyme immunoassay, low LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Combination therapy for non-Hodgkin's lymphomas.

In some embodiments, additional therapeutic agents are suitable for the treatment of non-Hodgkin's lymphomas (NHL), especially lymphomas of B-cell origin, and include monoclonal antibodies, standard chemotherapy approaches (e.g., CHOP, CVP, FCM, MCP, etc.), radioimmunotherapy, and their combinations, especially the integration of antibody therapy with chemotherapy.

Examples of unconjugated monoclonal antibodies for the treatment of NHL/B-cell cancer include rituximab, alemtuzumab, human or humanized anti-CD20 antibodies, lumiximab, anti-TNF-related apoptosis-inducing ligand (anti-TRAIL), bevacizumab, galiximab, epratuzumab, SGN -40 and anti-CD74.

Examples of experimental antibodies used to treat NHL/B cell cancer include ofatumumab, ha20, PRO131921, alemtuzumab, galiximab, SGN-40, CHIR-12.12, epratuzumab, lumiximab, apolizumab, milatuzumab and bevacizumab.

Examples of standard chemotherapy regimens for NHL/B-cell cancer include CHOP, FCM, CVP, MCP, R-CHOP, R-FCM, R-CVP, and R-MCP.

Examples of radioimmunotherapy for NHL/B-cell cancer include yttrium-90 ibritumomab ti-128 045798 uxetan (Zevalin®) and iodine-131 tositumomab (BEXXAR®).

Combination therapy for mantle cell lymphoma.

In some embodiments, these additional therapeutic agents are suitable for the treatment of mantle cell lymphoma (MCL) and include combination chemotherapeutic agents such as CHOP, hyperCVAD and FCM. These regimens can also be supplemented with rituximab with monoclonal antibodies to form combination therapies R-CHOP, hyperCVAD-R and RFCM. Any of the above therapies can be combined with stem cell transplant or ICE to treat MCL.

Other examples of therapeutic agents suitable for the treatment of MCL include:

immunotherapies such as monoclonal antibodies (eg, rituximab) and cancer vaccines such as GTOP-99, which are based on the genetic makeup of an individual patient's tumor;

radioimmunotherapy, where a monoclonal antibody is combined with a radioisotope particle such as iodine-131 tositumomab (BEXXAR), yttrium-90 ibritumomab tiuxetan (ZEVALIN®) and BEXXAR® in sequential treatment with CHOP;

autologous stem cell transplantation in combination with high-dose chemotherapy, administration of proteasome inhibitors such as bortezomib (VELCADE® or PS-341), or administration of antiangiogenesis agents such as thalidomide, especially in combination with rituximab;

drugs that cause degradation of the Bcl-2 protein and sensitize cancer cells to chemotherapy, such as oblimersen, in combination with other chemotherapeutic agents;

mTOR inhibitors, which can lead to suppression of cell growth and even cell death. Non-limiting examples include sirolimus, temsirolimus (Torisel®, CCI-779), CC-115, CC-223, SF1126, PQR-309 (bimiralisib), voxtalisib, GSK-2126458 and temsirolimus in combination with RITUXAN®, VELCADE® or others chemotherapeutic agents;

other agents such as flavopiridol, palbociclib (PD0332991), R-roscovitine (seliciclib, CYC202), styryl sulfones, obatoclax (GX15-070), TRAIL, death receptor antibodies TRAIL DR4 and DR5, temsirolimus (TORISEL®, CC1-779) , everolimus (RAD001), BMS-345541, curcumin, SAHA, thalidomide, lenalidomide (REVLIMID® CC-5013) and geldanamycin (17-AAG).

Combination therapy for Waldenström's macroglobulinemia.

In some embodiments, these additional therapeutic agents are suitable for the treatment of Waldenström's macroglobulinemia (WM) and include aldesleukin, alemtuzumab, alvocidib, amifostine trihydrate, aminocamptothecin, antineoplaston A10, antineoplaston AS2-1, antithymocyte globulin, arsenic trioxide, autologous human tumor protein HSPPC-96 , ABT-263 inhibitor of the Bel-2 family protein, beta aletin, bortezomib (VELCADE®), bryostatin 1, busulfan, Campath-III, carboplatin, carmustine, caspofungin acetate, CC-5103, cisplatin, clofarabine, cyclophosphamide, cyclosporine, cytarabine, denileukin diftitox, dexamethasone, docetaxel, dolastatin 10, doxorubicin hydrochloride, DT-PACE, enzastaurin, epoetin alfa, epratuzumab (hLL2-anti-CD22 humanized antibodies), etoposide, everolimus, fenretinide, filgrastim, fludarabine, ifosfamide, indium-111-mon oclonal MN-14 antibodies, iodine-131 tositumomab, irinotecan hydrochloride, ixabepilone, lymphokine-activated killer cells, melphalan, mesna, methotrexate, mitoxantrone hydrochloride, CD19 monoclonal antibody (such as tisagenlecleucel-T, CART-19, CTL-019), CD20 monoclonal antibody, motexafin gadolinium, mycophenolate mofetil, nelarabine, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin, paclitaxel, pegfilgrastim, pegylated liposomal doxorubicin hydrochloride, pentostatin, perifosine, prednisone, recombinant flt3 ligand, recombinant ny human thrombopoietin, recombinant interferon alpha, recombinant interleukin-11, recombinant interleukin-12, rituximab, sargramostim, sildenafil citrate (VIAGRA®), simvastatin, sirolimus, tacrolimus, tanespimycin, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, tositumomab, veltuzumab, vincristine sulfate , vinorelbine ditartrate , vorinostat, peptide vaccine WT1 126-134, WT-1 analogue peptide vaccine, yttrium-90 ibritumomab tiuxetan, yttrium-90 humanized epratuzumab and any combinations thereof.

Other examples of therapeutic procedures for treating WM include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow ablation with stem cell support , in vitro-processed peripheral blood stem cell transplantation, umbilical cord blood transplantation, enzyme-linked immunosorbent techniques, low LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiation therapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Combination therapy for diffuse B-cell lymphoma.

In some embodiments, said additional therapeutic agents are suitable for the treatment of diffuse large B cell lymphoma (DLBCL) and include cyclophosphamide,

- 129 045798 doxorubicin, vincristine, prednisone, anti-CD20 monoclonal antibodies, etoposide, bleomycin, many of the agents listed for WM, and any combinations thereof, such as ICE and R-ICE.

Combination therapy for chronic lymphocytic leukemia.

In some embodiments, these additional therapeutic agents are suitable for the treatment of chronic lymphocytic leukemia (CLL) and include chlorambucil, cyclophosphamide, fludarabine, pentostatin, cladribine, doxorubicin, vincristine, prednisone, prednisolone, alemtuzumab, many of the agents listed for WM and combination chemotherapy and chemoimmunotherapy, including the following common combination regimens: CVP, R-CVP, ICE, R-ICE, FCR and FR.

Combination therapy for myelofibrosis.

In some embodiments, these additional therapeutic agents are suitable for the treatment of myelofibrosis and include hedgehog inhibitors, histone deacetylase (HDAC) inhibitors, and tyrosine kinase inhibitors. Non-limiting examples of hedgehog inhibitors include saridegib and vismodegib.

Examples of HDAC inhibitors include, but are not limited to, pracinostat and panobinostat.

Non-limiting examples of tyrosine kinase inhibitors include lesturtinib, bosutinib, imatinib, gilteritinib, radotinib and cabozantinib.

Combination Therapy for Hyperproliferative Diseases In some embodiments, said additional therapeutic agents are suitable for treating a hyperproliferative disease and include gemcitabine, nab-paclitaxel, and gemcitabine/nab-paclitaxel with a JAK inhibitor and/or a PI3Kδ inhibitor.

Combination therapy for bladder cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of bladder cancer and include atezolizumab, carboplatin, cisplatin, docetaxel, doxorubicin, fluorouracil (5-FU), gemcitabine, idosfamide, interferon alpha-2b, methotrexate, mitomycin, nab-paclitaxel, paclitaxel, pemetrexed, thiotepa, vinblastine and any combination thereof.

Combination therapy for breast cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of breast cancer and include albumin-bound paclitaxel, anastrozole, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, epirubicin, everolimus, exemestane, fluorouracil, fulvestrant, gemcitabine, ixabepilone, lapatinib , letrozole, methotrexate, mitoxantrone, paclitaxel, pegylated liposomal doxorubicin, pertuzumab, tamoxifen, toremifene, trastuzumab, vinorelbine and any combination thereof.

Combination therapy for triple negative breast cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of triple negative breast cancer and include cyclophosphamide, docetaxel, doxorubicin, epirubicin, fluorouracil, paclitaxel, and combinations thereof.

Combination therapy for colorectal cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of colorectal cancer and include bevacizumab, capecitabine, cetuximab, fluorouracil, irinotecan, leucovorin, oxaliplatin, panitumumab, ziv-aflibercept, and any combination thereof.

Combination therapy for castration-resistant prostate cancer

In some embodiments, these additional therapeutic agents are suitable for the treatment of castration-resistant prostate cancer and include abiraterone, cabazitaxel, docetaxel, enzalutamide, prednisone, sipuleucel-T, and any combination thereof.

Combination therapy for cancer of the esophagus and esophagogastric junction.

In some embodiments, these additional therapeutic agents are suitable for the treatment of esophageal and gastroesophageal junction cancer and include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Combination therapy for gastric cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of gastric cancer and include capecitabine, carboplatin, cisplatin, docetaxel, epirubicin, fluoropyrimidine, fluorouracil, irinotecan, leucovorin, mitomycin, oxaliplatin, paclitaxel, ramucirumab, trastuzumab, and any combinations thereof.

Combination therapy for head and neck cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of head and neck cancer and include afatinib, bleomycin, capecitabine, carboplatin, cetuximab, cisplatin, docetaxel, fluorouracil, gemcitabine, hydroxyurea, methotrexate, nivolumab, paclitaxel, pembrolizumab, vinorelbine, and any combination thereof .

Combination therapy for hepatobiliary cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of hepatobiliary cancer and include capecitabine, cisplatin, fluoropyrimidine, 5-fluorourcil,

- 130 045798 gemcitabine, oxaliplatin, sorafenib and any combinations thereof.

Combination therapy for hepatocellular carcinoma.

In some embodiments, these additional therapeutic agents are suitable for the treatment of hepatocellular carcinoma and include capecitabine, doxorubicin, gemcitabine, sorafenib, and any combination thereof.

Combination therapy for non-small cell lung cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of non-small cell lung cancer (NSCLC) and include afatinib, albumin-bound paclitaxel, alectinib, bevacizumab, bevacizumab, cabozantinib, carboplatin, cisplatin, crizotinib, dabrafenib, docetitaxel, erlotinib, etoposide, gemcitabine , nivolumab, paclitaxel, pembrolizumab, pemetrexed, ramucirumab, trametinib, trastuzumab, vandetanib, vemurafenib, vinblastine, vinorelbine and any combination thereof.

Combination therapy for small cell lung cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of small cell lung cancer (SCLC) and include bendamustine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, gemcitabine, ipillimumab, irinotecan, nivolumab, paclitaxel, temozolomide, topotecan, vincristine, vinorelbine and any combinations thereof.

Combination therapy for melanoma.

In some embodiments, these additional therapeutic agents are suitable for the treatment of melanoma and include albumin-bound paclitaxel, carboplatin, cisplatin, cobiemtinib, dabrafenib, dacrabazine, IL-2, imatinib, interferon alfa-2b, ipilimumab, nitrosourea, nivolumab, paclitaxel, pembrolizumab, pilimumab, temozolomide, trametinib, vemurafenib, vinblastine and any combination thereof.

Combination therapy for ovarian cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of ovarian cancer and include 5-furouracil, albumin-bound paclitaxel, altretamine, anastrozole, bevacizumab, capecitabine, carboplatin, cisplatin, cyclophosphamide, docetaxel, doxorubicin, etoposide, exemestane, gemcitabine, ifosfamide , irinotecan, letrozole, leuprolide acetate, liposomal doxorubicin, megestrol acetate, melphalan, olaparib, oxaliplatin, paclitaxel, pazopanib, pemetrexed, tamoxifen, topotecan, vinorelbine and any combination thereof.

Combination therapy for pancreatic cancer.

In some embodiments, these additional therapeutic agents are suitable for the treatment of pancreatic cancer and include 5-fluorouracil, albumin-bound paclitaxel, capecitabine, cisplatin, docetaxel, erlotinib, fluoropyrimidine, gemcitabine, irinotecan, leucovorin, oxaliplatin, paclitaxel, and any combination thereof.

Combination therapy for renal cell carcinoma.

In some embodiments, these additional therapeutic agents are suitable for the treatment of renal cell carcinoma and include axitinib, bevacizumab, cabozantinib, erlotinib, everolimus, levantinib, nivolumab, pazopanib, sorafenib, sunitinib, temsirolimus, and any combination thereof.

VII. Receiving connections.

Some embodiments of the present invention relate to methods and intermediates useful for preparing the compounds provided herein, or pharmaceutically acceptable salts thereof.

The compounds described herein can be purified by any of the methods known in the art, including chromatographic means such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phases, as well as ionic resins. Most often, the described compounds are purified using chromatography on silica gel and/or alumina.

In general, during any of the processes for preparing the compounds described herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules for which it may be necessary. This can be achieved using conventional protecting groups as described in standard works such as T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, ^4th ed., Wiley, New York 2006. Protecting Groups Indicated can be removed in suitable subsequent steps using methods known in the art.

Exemplary chemical compounds suitable for the methods of the embodiments will be described with reference to illustrative synthesis schemes for general preparation herein and the specific examples that follow. Those skilled in the art will appreciate that in order to prepare the various compounds described herein, starting materials can be suitably selected such that the desired substituents end up undergoing a protected or protected reaction scheme.

- 131 045798 without it, if this is necessary to obtain the required product. Alternatively, it may be necessary or desirable to use, in place of the final desired substituent, a suitable group that can be carried through the reaction scheme and replaced accordingly with the desired substituent. In addition, one skilled in the art will appreciate that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably carried out at a temperature from about 0° C. to the boiling point of the organic solvent used.

The methods of the present invention generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer has not been determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not determined, the compound is shown without any stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomeric or disatereomeric pure.

Typical synthetic schemes for the compounds of the present invention are described in the schemes below and in the specific examples that follow.

List of abbreviations and abbreviations.

Abbreviation Meaning °C Degree Celsius Ace Acetyl ACN or MeCN Acetonitrile AcOH Acetic acid aq. Water Ag Argon ATP Adenosine triphosphate Vos tert-butyloxycarbonyl

- 132 045798

lat. wide approx. approximately CH(OSNz)z Trimethyl orthoformate s-Pr or c-propyl Cyclopropyl Su Cyclohexyl d Doublet or deuterated EDC Dichloroethene DXM or CH2CI2 Dichloromethane dd Doublet of doublets DIEA or DIPEA Diisopropylethylamine DMAc or DMA Dimethylacetamide DMAP Dimethylaminopyridine DM FA Dimethylformamide DMSO Dimethyl sulfoxide DME Dimethoxyethane dt Doublet-triplet eq. Equivalents ES/MS Electrospray mass spectrometry Et Ethyl EA or EtOAc Ethyl acetate G Grams HATU 1-[bis(dimethylamino)methylene]-1//-1,2,3-triazolo[4,5- />]pyridinium 3-oxide hexafluorophosphate UNDC Formic acid Not X Hexanes HPLC High Pressure Liquid Chromatography h Watch Hz Hertz IPA Isopropyl alcohol i-pr or i-Pr Isopropyl J Interaction constant (MHz) K2CO3 Potassium carbonate kg or kg Kilogram l Liter LCMS or LC-MS Liquid chromatography - mass spectrometry

- 133 045798

M Molar m multiplet M+ Mass peak Me Methyl MeOH Methanol mg Milligram MHz Megahertz ml Milliliter mm Millimolar mmol Millimole mole Mole MS Mass spectroscopy Ms Methanesulf oni l n. Normal NaH Sodium hydride n-Bu or Vi Butyl NH ₄ C1 Ammonium chloride NMR Nuclear magnetic resonance NMP N-methylpyrrolidinone Pd-C/Pd/C Palladium on coal Pd ₂ (dba)3 Tris(dibenzylideneacetone)dipalladium RE Petroleum ether Ph Phenyl q Quartet R.P. Reverse phase KT or CT Room temperature s Singlet sat. Saturated sec Second (s) sec-Bu sec-butyl t Triplet TZR Propylphosphonic anhydride solution TEA Triethy lamin t-Bu, tert-Bu or t-butyl Tert-butyl TFC Trifluoroacetic acid

- 134 045798

tune Triflic acid THF T ethrahydrofuran TR-FRET Time-resolved fluorescence energy transfer May. by weight δ Chemical shift (ppm) µl Microliter µM Micromolar

General synthesis schemes.

General reaction schemes I, II, III, IV, V, VI, VII, VIII and IX are provided as additional embodiments of the present invention and illustrate general methods that have been used to prepare certain compounds of the present invention and that can be used to prepare additional compounds according to the present invention. Each of the variables (for example, R ¹ , R ² , R ³ , R ⁴ ) of formulas (1) - (27) has the meanings specified in this document.

The compounds of the present invention can be prepared using the methods described herein and conventional modifications thereof, which will be apparent to one skilled in the art in light of the above description and methods well known in the art. Traditional and known synthesis methods can be used in addition to those described herein. The synthesis of typical compounds described herein can be carried out as described in the following examples. If possible, reagents can be purchased commercially, for example from Sigma Aldrich or other chemical suppliers. In general, the compounds described herein are generally stable and can be isolated at room temperature and pressure. The compounds produced herein can be purified using methods known to one of ordinary skill in the art, including those described herein. One skilled in the art will appreciate that when acids (eg, TPA) are present in purification solvents, the final product may be isolated as a salt (eg, TPA salt).

Exemplary embodiments of the compounds described herein can be synthesized using the general reaction schemes described below. From the foregoing description, one skilled in the art will appreciate that the general patterns can be modified by replacing the starting materials with other substances having similar structures to produce products that are correspondingly different. Descriptions of syntheses are provided to provide numerous examples of how the starting materials can be modified to provide the corresponding products. For a given desired product for which groups of substituents are defined, the required starting materials can usually be determined by monitoring. Starting materials are usually obtained from commercial sources or synthesized using published methods. For the synthesis of compounds that are embodiments described herein, control of the structure of the synthesized compound will ensure the identity of each group of substituents. The identity of the final product will generally be determined to correspond to the identity of the required starting materials through a simple control process, taking into account the examples given herein.

The terms solvent, inert organic solvent, or inert solvent refer to a solvent that is inert under the reaction conditions described in combination with it (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (THF), dimethylformamide (DMF), chloroform, methylene chloride (or dichloromethane) ), diethyl ether, methanol and the like). Unless otherwise stated, the solvents used in the reactions of the present invention are inert organic solvents and the reactions are carried out under an inert gas, preferably nitrogen or argon.

Reaction scheme I.

Compounds of formula I can be prepared using methods similar to reaction scheme I below.

- 135 045798

Reaction scheme I.

Step 1. Preparation of the compound of formula (3).

Compounds of formula (3) can be prepared by combining compounds (1) and (2). Compounds (1) and (2) are commercially available or can be prepared by methods known in the art. Compounds (1) and (2) can be mixed in a suitable solvent such as THF. The reaction mixture is stirred at a temperature of 0°C to 100°C for 10 minutes to 24 hours or until the reaction is complete, then the reaction mixture is allowed to cool to room temperature. The compound of formula (3) can be obtained by filtration or precipitation.

Step 2. Preparation of the compound of formula (4).

Compounds of formula (4) can be prepared by chlorinating compounds of formula (3) by methods known in the art. The compound of formula (3) can be mixed with POCl ₃ in a suitable solvent such as toluene. The reaction mixture is stirred at a temperature of 0°C to 100°C for 10 minutes to 24 hours or until the reaction is complete, then the reaction mixture is allowed to cool to room temperature. The solvent can then be removed under reduced pressure. To extract the compound of formula (4), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (4). The compound of formula (4) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 3. Preparation of the compound of formula (5).

Compounds of formula (5) can be prepared by reducing compounds of formula (4) by methods known in the art. The compound of formula (4) can be mixed with zinc dust and ammonium chloride in a suitable solvent such as THF, MeOH or water, or a solvent mixture consisting of THF, MeOH and water. The reaction mixture is stirred at 0°C to 100°C for 10 minutes to 24 hours or until the reaction is complete, then the reaction mixture is allowed to cool to room temperature and filtered through a pad of celite. To extract the compound of formula (5), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (5). The compound of formula (5) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 4. Preparation of the compound of formula (6).

Compounds of formula (6) can be prepared by cyclization of compounds of formula (5) by methods known in the art. The compound of formula (5) can be mixed with trimethyl orthoformate and formic acid. Then stir at a temperature of from 0°C to 100°C for 1 to 24 hours or until the reaction is complete, then the remaining solvent is removed by distillation. To extract the compound of formula (6), an organic solvent such as dichloromethane can be added, followed by

- 136 045798 by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (6). The compound of formula (6) can be purified by any suitable methods known in the art, such as chromatography on silica gel, trituration, precipitation, crystallization, or washing with an organic solvent such as ether, including, but not limited to, methyl tert-butyl ether.

Step 5. Preparation of the compound of formula (7).

Compounds of formula (7) can be prepared by fluorinating compounds of formula (6) by methods known in the art. The compound of formula (6) can be mixed with cesium fluoride in a solvent such as DMF. The reaction mixture is stirred at room temperature to 110°C for 1 to 24 hours or until the reaction is complete, then the reaction mixture is cooled to 0°C to room temperature by adding ice water or adding the reaction mixture to ice water. To extract the compound of formula (7), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (7). The compound of formula (7) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 6. Preparation of the compound of formula (9).

Compounds of formula (9) can be prepared by combining compounds of formulas (6) and (8) or combining compounds of formulas (7) and (8) by methods known in the art. The compounds of formula (8) are commercially available or can be prepared by methods known in the art. The compound of formula (8) can be mixed with compounds of formula (6) or (7) in the presence of a base such as sodium hydride in a suitable solvent such as NMP or DMA. After stirring at room temperature to 100°C for 1 hour to 24 hours or until the reaction is complete, water can be added to the reaction mixture and treated with an acid such as 10% citric acid. The compound of formula (7) can be obtained by filtration or precipitation.

Step 7. Preparation of the compound of formula (12).

Compounds of formula (12) can be prepared by combining compounds of formulas (10) and (11) by methods known in the art. The compounds of formulas (10) and (11) are commercially available or can be prepared by methods known in the art. The compounds of formulas (10) and (11) can be mixed in the presence of a base such as potassium carbonate in a suitable solvent such as DMF. The reaction mixture is stirred at room temperature to 50° C. for 1 hour to 24 hours or until the reaction is complete , then the reaction mixture is allowed to cool to room temperature. To extract the compound of formula (12), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (12). The compound of formula (12) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 8. Preparation of the compound of formula (13).

Compounds of formula (13) can be prepared by reductive amination of compounds of formula (12) by methods known in the art. Compounds of formula (12) and amines that are commercially available or synthesized by methods known in the art can be mixed with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of an acid such as acetic acid or a Lewis acid such as zinc chloride, in a suitable solvent such as dichloroethane or methanol. After stirring at 0°C to room temperature for 1 to 24 hours or until the reaction is complete, the reaction mixture can be added to an aqueous solution such as saturated aqueous sodium bicarbonate. To extract the compound of formula (13), an organic solvent such as methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (13). The compound of formula (13) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 9. Preparation of the compound of formula I.

Compounds of formula I can be prepared by combining compounds of formula (9) and compounds of formula (13) by methods known in the art. The compounds of formulas (9) and (13) can be mixed in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate or potassium tribasic phosphate, in a suitable solvent such as a mixture of dimethoxyethane and water or a mixture of DMAc and water. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. The compounds of formula I can be filtered and concentrated under reduced pressure. To extract the compound of formula I, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated to give a compound of formula I. The compound of formula I can be purified

- 137 045798 by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Reaction scheme II.

Compounds of formula I can be prepared using alternative methods similar to reaction scheme II below.

Reaction scheme II.

R ^9d /-d-on ¹

G = ' /\ or IZ ¹ = NH(R ⁸ ) or OH or CH(R ⁸ ) ₂ °-< OH

Step 1. Preparation of the compound of formula (14).

Compounds of formula (14) can be prepared by combining compounds of formulas (6) and (13) by methods known in the art. The compounds of formulas (9) and (13) can be mixed in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate or potassium tribasic phosphate, in a suitable solvent such as a mixture of dimethoxyethane and water or a mixture of DMAc and water. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula (14) can be filtered and concentrated under reduced pressure. To extract the compound of formula (14), an organic solvent such as methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (14). The compound of formula (14) can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Step 2. Preparation of the compound of formula I.

Compounds of formula I can be prepared by combining compounds of formulas (8) and (14) by methods known in the art. The compounds of formulas (8) and (14) can be mixed in the presence of a catalyst such as tris(dibenzylideneacetone)dipalladium, a ligand such as xanthos and a base such as cesium carbonate in a suitable solvent such as dioxane. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. The compounds of formula I can be filtered and concentrated under reduced pressure. To extract the compound of formula I, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula I. The compound of formula I can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Reaction scheme III.

Compounds of formula I can be prepared using alternative methods similar to reaction scheme III below.

- 138 045798

Reaction scheme III.

R ⁵

Step 1. Preparation of the compound of formula (15).

Compounds of formula (15) can be prepared by amination of compounds of formula (6) by methods known in the art. The compound of formula (6) can be mixed with a solution of ammonium hydroxide in a suitable solvent such as N-methylpyrrolidone. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 48 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula (15) can be added to water and further cooled to 0° C. while stirring. The compound of formula (15) can be isolated by any suitable methods known in the art, such as filtration or precipitation.

Step 2. Preparation of the compound of formula (16).

Compounds of formula (16) can be prepared by combining compounds of formulas (13) and (15) by methods known in the art. The compounds of formulas (13) and (15) can be mixed in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate or tribasic potassium phosphate, in a suitable solvent such as a mixture of dimethoxyethane and water, a mixture of dimethylacetamide and water or a mixture of dimethylformamide, dimethoxyethane and water. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula (16) can be filtered and concentrated under reduced pressure. To extract the compound of formula (16), an organic solvent such as methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (16). The compound of formula (16) can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Step 3. Preparation of the compound of formula I.

Compounds of formula I can be prepared by combining compounds of formulas (16) and (20) by methods known in the art. The compounds of formulas (16) and (20) can be mixed in the presence of a catalyst such as tris(dibenzylideneacetone)dipalladium, a ligand such as xanthos, and a base such as cesium carbonate in a suitable solvent such as dioxane. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula I can be filtered and concentrated

- 139 045798 at reduced pressure. To extract the compound of formula I, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula I. The compound of formula I can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Reaction scheme IV.

Compounds of formula (I-B) can be prepared using methods similar to reaction scheme IV shown below. Reaction scheme IV.

Step 1. Preparation of the compound of formula (18).

Compounds of formula (18) can be prepared by removing the tert-butyloxycarbonyl protecting group of compounds of formula (17) by methods known in the art. The compound of formula (17) can be mixed with an acidic solution such as 4M hydrochloric acid in a suitable solvent such as dichloromethane or dioxane. After stirring at room temperature for 10 minutes to 24 hours, the solvent is evaporated in vacuo. The compound of formula (18) can be isolated by any suitable methods known in the art, such as filtration, trituration or precipitation.

Step 2: Preparation of the compound of formula (I-B).

Compounds of formula (I-B) can be prepared by reductive amination or synthesis of amides of compounds of formula (18) by methods known in the art. The compounds of formula (18) can be mixed with amines that are commercially available or synthesized by methods known in the art, or acid chlorides that are commercially available or synthesized by methods known in the art, or carboxylic acids that are commercially available or synthesized by methods known in the art. in the art, in the presence of a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride, with an acid such as acetic acid or Lewis acid such as zinc chloride, in a suitable solvent such as dichloroethane or methanol, or in the presence of a coupling reagent, such as HATU or a solution of propylphosphonic anhydride, in a suitable solvent such as acetonitrile, dimethylformamide and dichloroethane. After stirring at 0°C to 100°C for 1 to 24 hours, the reaction mixture can be added to an aqueous solution such as saturated aqueous sodium bicarbonate. To extract the compound of formula (I-B), an organic solvent such as ethyl acetate or methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain a compound of formula (I-B). The compound of formula (I-B) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Reaction scheme V.

Compounds of formula (21) can be prepared using alternative methods similar to reaction scheme V below.

- 140 045798

Reaction scheme V.

Step 1. Preparation of the compound of formula (20).

Compounds of formula (20) can be prepared by combining compounds of formulas (19) and (12) by methods known in the art. With respect to compounds (20), R ⁷ and G have the meanings defined herein. The compounds of formulas (19) and (12) can be mixed in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate or tribasic potassium phosphate, in a suitable solvent such as a mixture of dimethoxyethane and water, a mixture of dimethylacetamide and water or a mixture of dimethylformamide, dimethoxyethane and water. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula (20) can be filtered and concentrated under reduced pressure. To extract the compound of formula (20), an organic solvent such as methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (20). The compound of formula (20) can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Step 2. Preparation of the compound of formula (21).

Compounds of formula (21) can be prepared by reductive amination of compounds of formula (20) by methods known in the art. Compounds of formula (20) and amines that are commercially available or synthesized by methods known in the art can be mixed with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of an acid such as acetic acid or a Lewis acid such as zinc chloride, in a suitable solvent such as dichloroethane or methanol. After stirring at 0°C to room temperature for 1 to 24 hours or until the reaction is complete, the reaction mixture can be added to an aqueous solution such as saturated aqueous sodium bicarbonate. To extract the compound of formula (21), an organic solvent such as ethyl acetate or methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (21). The compound of formula (21) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Reaction scheme VI.

Compounds of formula (22) can be prepared using alternative methods similar to reaction scheme VI below.

Reaction scheme VI.

For 27: ^R9a , ^R9b , ^R9c , ^R9d , ^R9e are as defined herein and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -COOH

For 22: ^R9a , ^R9b , ^R9c , ^R9d , ^R9e are as defined herein and one or more of ^R9a , ^R9b , ^R9c , ^R9d and ^R9e is -CON( ^R19 ) ₂

- 141 045798

Step 1. Preparation of the compound of formula (22).

Compounds of formula (22) can be prepared by combining compounds of formula (27) with commercially available or synthetically produced amines by methods known in the art. The compound of formula (27) can be mixed with commercially available or synthetically prepared amines in the presence of a coupling reagent such as HATU and a base such as diisopropylethylamine in a suitable solvent such as acetonitrile. The reaction mixture is stirred at room temperature to 100°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. Compounds of formula (22) can be filtered and concentrated under reduced pressure. To extract the compound of formula (22), an organic solvent such as methylene chloride may be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (22). The compound of formula (22) can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Reaction scheme VII.

Compounds of formula I can be prepared using alternative methods similar to reaction scheme VII below.

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Reaction scheme VII.

Step 1. Preparation of the compound of formula (23).

Compounds of formula (23) can be prepared by borylation of compounds of formula (9) by methods known in the art. The compound of formula (9) can be mixed with reagents such as bis(pinacolato)diboron, in the presence of a base such as potassium acetate and a catalyst such as [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane in a suitable solvent such as dioxane. After stirring at room temperature to 100° C. for 1 to 24 hours or until the reaction is complete, the compound of formula (23) can be prepared by any suitable methods known in the art, such as trituration, precipitation or crystallization.

Step 2. Preparation of the compound of formula (25).

Compounds of formula (25) can be prepared by combining compounds of formulas (24) and (11) by methods known in the art. The compounds of formulas (24) and (11) are commercially available or can be prepared by methods known in the art. The compounds of formulas (24) and (11) can be mixed in the presence of a base such as potassium carbonate in a suitable solvent such as DMF. The reaction mixture is stirred at room temperature to 50°C for 1 hour to 24 hours or until the reaction is complete, then the reaction mixture is allowed to cool to room temperature. To extract the compound of formula (25), an organic solvent such as ethyl acetate can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (25). The compound of formula (25) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 3. Preparation of the compound of formula (26).

Compounds of formula (26) can be prepared by reductive amination of compounds of formula (25) by methods known in the art. Compounds of formula (25) and amines that are commercially available or synthesized by methods known in the art can be mixed with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in the presence of an acid such as acetic acid or a Lewis acid such as zinc chloride, in a suitable solvent such as dichloroethane or methanol. After stirring at 0°C to room temperature for 1 to 24 hours or until the reaction is complete, the reaction mixture can be added to an aqueous solution such as saturated aqueous sodium bicarbonate. To extract the compound of formula (26), an organic solvent such as ethyl acetate can be added

- 143 045798 or methylene chloride, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula (26). The compound of formula (26) can be purified by any suitable methods known in the art, such as silica gel chromatography, trituration, precipitation or crystallization.

Step 4. Preparation of the compound of formula I.

Compounds of formula I can be prepared by combining compounds of formulas (26) and (23) by methods known in the art. The compounds of formulas (26) and (23) can be mixed in the presence of a catalyst such as tetrakis(triphenylphosphine)palladium and a base such as cesium carbonate, sodium carbonate or potassium tribasic phosphate, in a suitable solvent such as a mixture of dimethoxyethane and water or a mixture of DMAc and water. The reaction mixture is stirred at a temperature of 50°C to 150°C for 1 hour to 24 hours, then the reaction mixture is allowed to cool to room temperature. The compounds of formula I can be filtered and concentrated under reduced pressure. To extract the compound of formula I, an organic solvent such as methylene chloride can be added, followed by washing with water and brine. The organic phase can be concentrated to obtain the compound of formula I. The compound of formula I can be purified by any suitable methods known in the art, such as silica gel chromatography, reverse phase chromatography, trituration, precipitation or crystallization.

Reaction scheme VIII.

Compounds of formula I can be prepared using alternative methods similar to reaction scheme VIII below.

Reaction scheme VIII.

Reaction scheme IX.

Compounds of formula I can be prepared using alternative methods similar to reaction scheme IX below.

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Reaction scheme IX.

Reaction scheme X.

Compounds of formula I can be prepared using the following reaction scheme X below.

Reaction scheme X.

alternative methods, similar

VIII. Examples.

Representative chemical compounds according to the present invention are presented in the specific examples that follow. Those skilled in the art will appreciate that for the preparation of the various compounds described herein, the starting materials can be suitably selected such that the desired substituents will ultimately proceed through the reaction scheme with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the final desired substituent, a suitable group that can be carried through the reaction scheme and replaced by the desired substituent as appropriate. In addition, one skilled in the art will appreciate that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

The examples given here describe the synthesis of the compounds described herein, and

- 145 045798 also intermediate compounds used to obtain these compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that individual batches of a compound may be combined and then used in the next step of the synthesis.

The following description of examples describes specific embodiments of the present invention. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present invention. Other embodiments may also be used, and logical and other changes may be made without departing from the scope of the present invention. Therefore, the following description is not intended to limit the scope of the present invention.

Procedure 1. Preparation of compounds of formula (6) according to reaction scheme I.

2-Bromo-5-fluoro-4-nitropyridine 1-oxide (1500.0 g, 6.3 mol) in THF (1.5 L) was placed in a round bottom multi-neck flask and cooled to 0°C. Isopropylamine (600.0 mL, 7.0 mol) was then added dropwise at 0°C for 30 min. The reaction mixture was slowly warmed to room temperature and stirred for 24 hours. The reaction mixture was then filtered, washed with THF to obtain 2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide, which was used in the next step without further purification.

B. Preparation of 6-bromo-2-chloro-N-isopropyl-4-nitropyridin-3-amine.

2-bromo-5-(isopropylamino)-4-nitropyridine 1-oxide (1400.0 g, 5.1 mol) was placed in toluene (21 L). Triethylamine (4.2 L) was then slowly added dropwise to it at room temperature over 30 minutes and stirred for 10 minutes. The reaction mixture was then cooled to 0°C followed by the addition of POCl ₃ (1.4 L) dropwise over 30 minutes. The reaction mixture was slowly warmed to room temperature and heated to 65°C for 4 hours. The solution was then cooled to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated NaHCO ₃ solution, then brine, then dried over sodium sulfate and concentrated under reduced pressure. The crude mixture was purified by column chromatography using 100-200 mesh silica gel, and the column was gradually eluted with 10% ethyl acetate in petroleum ether to give 6-bromo-2-chloro-K-isopropyl-4-nitropyridin-3-amine.

C. Preparation of 6-bromo-2-chloro-K3-isopropylpyridine-3,4-diamine.

To a solution of 6-bromo-2-chloro-K-isopropyl-4-nitropyridin-3-amine (1000.0 g, 3.4 mol) in THF/MeOH

- 146 045798 (20 l/20 l) added zinc dust (1775.0 g, 27.2 mol) followed by dropwise addition of a solution of NH ₄ Cl (1816.0 g, 34.0 mol) in water (20 l) at room temperature, then the resulting reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then diluted with ethyl acetate and filtered through a pad of celite. The filtrate was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by washing with methyl t-butyl ether to give 6-bromo-2-chloro-K3-isopropylpyridine-3,4-diamine.

D. Preparation of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine.

HCOOH (65 ml) was added to a solution of 6-bromo-2-chloro-K3-isopropylpyridine-3,4-diamine (800.0 g, 3.0 mol) in CH(OCH ₃ ) ₃ (5.2 L). After stirring the reaction mixture at 70°C for 3 hours, the remaining solvent was removed by distillation. Water was then added and the resulting mixture was extracted with CH ₂ Cl ₂ . The combined organic layers were dried over anhydrous Na ₂ SO ₄ , concentrated and purified by washing with methyl tert-butyl ether to give 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5c]pyridine.

The following compounds were prepared using a similar procedure, except that commercially available amines were used instead of isopropylamine, including ethylamine, cyclopropylamine, and (S)-butylamine:

6-bromo-4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridine

6-bromo-4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridine

(S)-6-bromo-3-(sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridine

Procedure 2. Preparation of compounds of formula (7) according to reaction scheme I.

A mixture of 6-bromo-3-isopropyl-4-chloro-3H-imidazo[4,5-c]pyridine (148 g, 0.54 mol) and cesium fluoride (819 g, 5.40 mol) in DMF (1, 2 L) was heated at 110°C for 24 hours. The reaction mixture was poured into ice water (1 L). The aqueous layer was extracted with ethyl acetate (3x1 L). The organic layers were dried over sodium sulfate, concentrated and the crude mixture was further purified by column chromatography (EA/Hex=2:3-1:1) to give 6-bromo-4-fluoro-3-isopropyl-3H- imidazo[4,5c]pyridine.

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 1 were used instead of 6-bromo-3-isopropyl-4-chloro-3Nimidazo[4,5-c]pyridine:

6-bromo-3-ethyl-4-fluoro-3H-imidazo[4,5-c]pyridine

6-bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine

(S)-6-bromo-3-(sec-butyl)-4-fluoro-3H-imidazo[4,5-c]pyridine

Procedure 3. Preparation of compounds of formula (9) according to reaction scheme I.

A. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-Y2-dimethylbenzamide.

6bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (200 mg, 0.77 mmol), 5-amino-^2dimethylbenzamide (381, 74 mg, 2.32 mmol) and pyridine-HCl (268.65 mg, 2.32 mmol) in IPA (4 ml). The mixture was placed in a microwave reactor and heated at 150°C for 6 hours. Without treatment, the reaction mixture was purified by flash chromatography (100% hexane to 100% EtOAc, then 100% DCM to 25% MeOH in DCM). Fractions were collected and concentrated. The resulting residue was redissolved in EtOAc and water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. DME was added to this residue and the suspension was filtered to obtain 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications: compounds listed in procedure 1 or 2 were used instead of 6-bromo-4-fluoro-3-isopropyl-148 045798

3H-imidazo[4,5-c]pyridine; and/or an optionally substituted aminobenzamide below was used in place of 5-amine o-N,2dimethylbenzamide:

5-amino-2-methylbenzamide was used to prepare 5-((6-bromo-3-cyclopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide.

5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide

5-Amino-2-chloro-N-methylbenzamide was used to prepare 5-((6-bromo-3-cyclopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N- methylbenzamide.

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5-amino-2-chloro-K-methylbenzamide was used to prepare 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-K- methylbenzamide.

Procedure 4. Preparation of compounds of formula (9) according to reaction scheme I.

A. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2methylbenzoic acid.

To a solution of 5-amino-4-fluoro-2-methylbenzoic acid (2.0 g, 18 mmol) in DMF (40 ml) was added sodium hydride (1.4 g, 36 mmol) over 5 min. The mixture was stirred at room temperature for 15 minutes followed by the addition of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (5.5 g, 21 mmol). After stirring at room temperature for 16 hours, the reaction mixture was quenched with water (200 ml). The suspension was stirred for 1 hour, filtered and washed with water to give 6-bromo-K-(3-fluoropyridin-4-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

The following compounds were prepared by a similar procedure with the following modifications:

5-amino-2-methylbenzoic acid was used instead of 5-amino-4-fluoro-2-methylbenzoic acid; and/or

6-bromo-3-ethyl-4-fluoro-3H-imidazo[4,5-c]pyridine was used instead of 6-bromo-4-fluoro-3isopropyl-3H-imidazo[4,5-c]pyridine; and/or

5-amino-K-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide was used instead of 5-amino-4-fluoro-2-methylbenzoic acid:

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic acid

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5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)3,4-difluoro-2-methylbenzamide

Procedure 5. Preparation of compounds of formula (19) according to reaction scheme V.

A. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-K,2dimethylbenzamide.

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2methylbenzoic acid (1.00 g, 2.46 mmol) was placed in a test tube ), HATU (1.12 g, 2.95 mmol, 1.2 eq.), MeCN (12 ml), DIPEA (4.28 ml, 24.6 mmol, 10.0 eq.) and methylamine (4. 9 ml, 9.8 mmol, 4.0 eq., 2.0 M in THF). The tube was hermetically sealed and the resulting mixture was heated at 40°C for 2 hours. Then the reaction was quenched with sat. NaHCO ₃ and extracted with DCM. The combined organic layers were washed with 1M K ₂ CO ₃ , dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography (100% DCM to 100% MeOH) to give 5-((6-bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-K,2dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used instead of methylamine; and/or the compounds listed in Procedure 4 were used instead of 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid:

2,2-Difluoroethane-1-amine was used instead of methylamine to obtain 5-((6-bromo-3-isopropyl- 151 045798

3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-(2,2-difluoroethyl)-2-methylbenzamide

1,1-Difluoropropan-2-amine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-(1,1-difluoropropane- 2-yl)-2-methylbenzamide

1-(difluoromethyl)cyclobutan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl) cyclobutyl)-2-methylbenzamide

1-(difluoromethyl)cyclopropan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl) cyclopropyl)-2-methylbenzamide

1,3-Difluoropropan-2-amine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-(1,3-difluoropropane- 2-yl)-2-methylbenzamide

- 152 045798

(S)-1-fluoropropan-2-amine was used to prepare (S)-5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-( 1-fluoropropan-2-yl)-2-methylbenzamide

(R)-1-fluoropropan-2-amine was used to prepare (R)-5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-( 1-fluoropropan-2-yl)-2-methylbenzamide

Ethylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-C-ethyl-2-methylbenzamide.

Isopropylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-isopropyl-2-methylbenzamide.

- 153 045798

Cyclobutanamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin4-yl)amino)-C-cyclobutyl-2-methylbenzamide.

Cyclopropylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-C-cyclopropyl-2-methylbenzamide.

n-propylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2-methyl-K-propylbenzamide.

3,3-difluoropropan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-(3,3-difluoropropyl) -2-methylbenzamide

- 154 045798

2,2-difluoropropan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-(2,2-difluoropropyl) -2-methylbenzamide

O NH

Ethylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-C-ethyl-4-fluoro-2-methylbenzamide.

O NH iso-propylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro-K-isopropyl-2-methylbenzamide

F

1-(difluoromethyl)cyclopropan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl) cyclopropyl)-4-fluoro-2-methylbenzamide

O NH iso-propylamine was used to prepare 5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro-N-isopropyl-2-methylbenzamide.

- 155 045798

Ethylamine was used to prepare 5-((6-bromo-3-ethyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)4-fluoro-N-ethyl-2-methylbenzamide.

tert-butylamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-(tert-butyl)-4-fluoro-2-methylbenzamide .

Cyclobutanamine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin4-yl)amino)-N-cyclobutyl-4-fluoro-2-methylbenzamide.

2-Methylpropan-1-amine was used to prepare 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-4-fluoro-N-isobutyl-2-methylbenzamide .

Procedure 6. Preparation of compounds of formula (13) according to reaction scheme I.

A. Preparation of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

- 156 045798

A mixture of 6-bromo-3,3-dimethylindolin-2-one (150 g, 625 mmol), bis(pinacolato)diboron (206 g, 812 mmol), Pd(dppf)Cl ₂ /CH ₂ Cl ₂ (45 g, 62.5 mmol) and potassium acetate (184 g, 1875 mmol) in dimethyl sulfoxide (2000 ml) were stirred at 100°C under Ar atmosphere for 3 hours. The reaction mixture was diluted with IDO (10 L) and extracted with ethyl acetate (4 L). The organic phase was washed with water, then with brine, dried over Na ₂ SO ₄ and purified on a silica gel column (PE/EA=10:1) to obtain 3,3-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indolin-2-one.

B. Preparation of 3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one.

To a mixture of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one (200 g, 696 mmol) and K ₂ CO ₃ (240 g, 1740 mmol) to DMF (2 L) was added 3-bromocyclobutanone (160 g, 1356 mmol). After stirring the mixture at 50°C under Ar for 2.5 hours, it was cooled to room temperature, diluted with EtOAc and filtered to remove solids. The filtrate was diluted with additional EtOAc and water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered, concentrated and purified by flash chromatography on silica gel (PE/EA=20:1) to give 3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4 ,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

The following compounds were prepared using a similar procedure, except:

Commercially available 6-bromo-3,3-difluorindolin-2-one was used instead of 3,3-dimethyl-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2 -one for the preparation of 6-bromo-3,3-difluoro-1-(3oxocyclobutyl)indolin-2-one.

6-Bromo-3,3-diethylindolin-2-one (prepared according to the procedure described in paragraph [1008] of WO 2009078481) was used instead of 3,3-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2yl)indolin-2-one to obtain 6-bromo-3,3-diethyl-1-(3-oxocyclobutyl)indolin-2-one.

- 157 045798

Commercially available 6-bromo-3,3-dimethylindolin-2-one was used instead of 3,3-dimethyl-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2 -one to obtain 6-bromo-3,3-dimethyl-1-(3oxocyclobutyl)indolin-2-one.

C. Preparation of 3,3-dimethyl-1-((1S,3S)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -yl)indolin-2-one.

To a solution of 3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one (7.0 g, 19.7 mmol) in dichloroethane (130 ml), piperidine (3.4 g, 39.4 mmol) and acetic acid (3.6 g, 59.1 mmol) were added. The reaction mixture was cooled to 0°C in an ice bath and sodium triacetoxyborohydride (6.26 g, 29.56 mmol) was added portionwise. After addition was complete, the reaction mixture was removed from the ice bath and stirred at room temperature for 2 hours. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride (3x200 ml). The combined organic layers were washed with saturated NaHCO ₃ solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3,3-dimethyl-1-((1S,3S)-3-(piperidin-1-yl)cyclobutyl)- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)indolin-2-one, which was used in the next step without purification.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used instead of piperidine; or optionally substituted oxindoles that are commercially available or can be prepared by methods known in the art, such as 6-bromo-3,3-difluoro-1-(3-oxocyclobutyl)indolin-2one and 6-bromo-3,3- Diethyl-1-(3-oxocyclobutyl)indolin-2-one was used instead of 3,3-dimethyl-1-(3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)indolin-2-one:

3,3-dimethylpyrrolidine was used to prepare 1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indolin-2-one.

(R)-3-fluoropyrrolidine was used to prepare 1-((1S,3S)-3-((R)-3-fluoropyrrolidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

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^Fc ' (S)-3-fluoropyrrolidine was used to prepare 1-((1R,3S)-3-((S)-3-fluoropyrrolidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3-oxa-6-azabicyclo[3.1.1]heptane was used to prepare 1-((1s,3s)-3-(3-oxa-6azabicyclo[3.1.1]heptan-6-yl)cyclobutyl)-3,3 -dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one (1R,4S)-2-azabicyclo[2.2.1]heptane was used to prepare 1 -((1S,3s)-3-((1R,4S)-2azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2yl)indolin-2-one

3-oxa-8-azabicyclo[3.2.1]octane was used to prepare 1-((18.38)-3-(3-oxa-8azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-3,3 -dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one

8-oxa-3-azabicyclo[3.2.1]octane was used to prepare 1-((18.38)-3-(8-oxa-3azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-3,3 -dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one

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6,6-difluoro-3-azabicyclo[3.1.0]hexane was used to prepare 1-((18.38)-3-(6,6-difluoro-3azabicyclo[3.1.0]hexan-3-yl)cyclobutyl) -3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one

N.H.

2-fluoro-2-methylpropan-1-amine was used to prepare 1-((18.38)-3-((2-fluoro-2methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin2-one

3,3-Dimethylpiperidine was used to prepare 1-((1S,3S)-3-(3,3-dimethylpiperidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

(8)-piperidin-3-ol was used to prepare l-((lR,3s)-3-((S)-3-hydroxypiperidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

HO (K)-piperidin-3-ol was used to prepare 1-((18.38)-3-((K)-3-hydroxypiperidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

2,2-Dimethylmorpholine was used to prepare 1-((18,38)-3-(dimethylmorpholino)cyclobutyl)3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)indolin-2-one.

- 160045798

Morpholine was used to obtain 3,3-dimethyl-1-((1S,3S)-3-morpholinocyclobutyl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2 -she

(R)-3-fluoropiperidine was used to prepare 1-((1S,3s)-3-((R)-3-fluoropiperidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one

3,3-Dimethylazetidine was used to prepare 1-((1s,3s)-3-(3,3-dimethylazetidin-1yl)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indolin-2-one.

1-Amino-2-methylpropan-2-ol was used to prepare 1-((1s,3s)-3-((2-hydroxy-2methylpropyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin2-one

Isopropylamine was used to prepare 1-((1s,3s)-3-(isopropylamino)cyclobutyl)-3,3dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-2-one.

- 161 045798 (3R,4R)-3-methyltetrahydro-2H-pyran-4-amine was used to obtain 3,3-dimethyl-1-((1S,3s)-3(((3R,4R)-3-methyltetrahydro -2H-pyran-4-yl)amino)cyclobugyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indolin-2-one.

(3S,4R)-3-methyltetrahydro-2H-pyran-4-amine was used to prepare 3,3-dimethyl-1-((1S,3s)-3 (((3S,4R)-3-methyltetrahydro-2H- pyran-4-yl)amino)cyclobugyl)-6-(4,4,5,5-tetramethyl-1,3,2 dioxaborolan-2-yl)indolin-2-one.

4,4-difluorocyclohexane-1-amine was used to prepare 1-((1s,3s)-3-((4,4difluorocyclohexyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2 yl)indolin-2-one

3,3-Difluorocyclobutan-1-amine was used to prepare

1-((1s,3s)-3-((3,3difluorocyclobutyl)amino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl )indolin-2-one

6-bromo-3,3-difluoro-1-(3-oxocyclobutyl)indolin-2-one was used instead of 3,3-dimethyl-1-(3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one to obtain 6-bromo- 162 045798

3,3-difluoro-1-((18.38)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one

6-bromo-3,3-diethyl-1-(3-oxocyclobutyl)indolin-2-one was used instead of 3,3-dimethyl-1-(3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)indolin-2-one to obtain 6-bromo3,3-diethyl-1-((1 s,3 s)-3-(piperidin-1 -yl)cyclobutyl)indolin- 2 -she.

Procedure 7. Preparation of compounds of formula (13) according to reaction scheme I.

A. Preparation of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridine -2-she.

To a stirred solution of 6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (4 g, 16.59 mmol) in dioxane (100 ml) was added bis(pinacolato)diboron (12.64 g, 49.77 mmol), potassium acetate (4.88 g, 49.77 mmol) and P4(4pp1)C1 ₂ /DCM (1354.92 mg, 1.66 mmol) . The reaction mixture was degassed with N ₂ for 5 minutes, sealed and heated at 100°C for 15 hours. The reaction mixture was cooled to room temperature and then filtered through a pad of celite. The filtrate was diluted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and then concentrated to give 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one, which was used in the next step without further purification.

The following compound was prepared by a similar procedure, except that 6bromo-3,3-diethyl-1-((18,38)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one was used instead of 6- bromo3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one:

3,3-diethyl-1-((18,38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) indolin-2-one

B. Preparation of (3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6yl)boronic acid.

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To a stirred solution of 3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3dihydro-2H-pyrrolo[3,2-b]pyridine -2-one (1.1 g, 3.82 mmol) to NMP (20 ml) was added 3bromocyclobutanone (1354.15 μl, 15.27 mmol) and K ₂ CO ₃ (2.64 g, 19.09 mmol) . The resulting mixture was heated at 50°C for 15 hours. The reaction mixture was cooled to room temperature and then diluted with EtOAc. The organic layer was washed with water, then brine, dried over Na ₂ SO ₄ , filtered, then concentrated to give (3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1Hpyrrolo[3, 2-b]pyridin-6-yl)6oronic acid, which was used in the next step without further purification.

C. Preparation of (3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro-1Hpyrrolo[3,2-b]pyridine -6-yl)6oronic acid.

To a stirred solution of (3,3-dimethyl-2-oxo-1-(3-oxocyclobutyl)-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-6-yl)6oronic acid (2 g, 5. 61 mmol) in DCE (30 ml) was added piperidine (1.11 ml, 11.2 mmol), Na(OAc) ₃ BH (1.78 g, 8.42 mmol) and AcOH (0.97 ml, 16. 8 mmol) at room temperature. The resulting mixture was stirred for 2 hours, then quenched with a saturated solution of NaHCO3. The aqueous layer was extracted with DCM and the combined organic layer was dried over Na ₂ SO ₄ then concentrated to give (3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl )-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)6oronic acid, which was used in the next step without further purification.

The following compound was prepared by a similar procedure, except that the following amine was used instead of piperidine:

(1R,4S)-2-azabicyclo[2.2.1]heptane was used instead of piperidine to prepare (1-((1S,3s)-3((1R,4S)-2-azabicyclo[2.2.1]heptane)-2 -yl)cyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyRidin-6-yl)6oPronic acid.

Procedure 8. Preparation of compounds of formula (13) according to reaction scheme I.

A. Preparation of 3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2Hpyrrolo[3,2-b ]pyridin-2-one.

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HE

To a stirred solution of 6-bromo-3-hydroxy-3-methylindolin-2-one (4 g, 16.5 mmol) in dioxane (80 ml) was added bis(pinacolato)diboron (8.4 g, 33 mmol), acetate potassium (3.2 g, 33 mmol) and Pd(dppf)Cl ₂ -i(XM (1.4 g, 1.65 mmol). Nitrogen gas was bubbled through the resulting suspension for 3 min, then heated overnight at 90° C. After cooling to room temperature, the reaction mixture was filtered and the filter cake was washed with EtOAc, then concentrated in vacuo.The crude product was purified by silica gel chromatography (hexanes/EtOAc) to give 3hydroxy-3-methyl-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one.

B. Preparation of 3-hydroxy-3-methyl-1 -(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)indolin-2-one.

To a stirred solution of 3-hydroxy-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1,3-dihydro-2H-pyrrolo[3,2- b]pyridin-2-one in NMP (100 ml) was added 3-bromocyclobutanone (5.53 ml, 62.4 mmol) and potassium carbonate (325 mesh, 10.8 g, 78 mmol). The resulting suspension was heated at 50°C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc (100 ml) and the organic layer was washed with water (100 ml), brine (100 ml), then dried over Na ₂ SO4, concentrated and purified by flash chromatography (hexanes/EtOAc) to give 3 -hydroxy-3-methyl-1-(3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one.

C. Preparation of 3-hydroxy-3-methyl-1-((15,38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolane -2-yl)indolin-2-one.

HE

To a solution of 3-hydroxy-3-methyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one (3.0 g, 8.4 mmol) in dichloroethane (60 ml) was added piperidine (1.4 g, 16.8 mmol), acetic acid (1.5 ml, 25.2 mmol) and sodium triacetoxyborohydride (2.7 g, 12 .6 mmol). After stirring at room temperature for 5 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride (3x200 ml). The combined organic phases were washed with saturated NaHCO ₃ solution, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3-hydroxy-3-methyl-1-((18.38)-3-(piperidin-1yl)cyclobutyl)- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one, which was used in the next step without purification.

Procedure 9. Preparation of compounds of formula (17) shown in reaction schemes I and IV.

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A. Preparation of tert-butyl 2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'- piperidine]-1'-carboxylate.

To a mixture of tert-butyl 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'piperidine]-1'-carboxylate ( 0.81 g, 1.89 mmol), which can be prepared according to a literature procedure (intermediate 7.33 in WO 2015017610 A1, also published as), and powdered potassium carbonate (0.65 g, 325 mesh, 4.73 mmol) in DMF (7.5 ml) was added 3-bromocyclobutanone (0.21 ml, 2.53 mmol). The mixture was heated to 50°C for 1 hour, then cooled to room temperature and filtered to remove potassium carbonate. The filtrate was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated and purified by flash silica gel chromatography with gradient elution (0-100% EtOAc/hexanes) to give tert-butyl 2-oxo-1-( 3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'carboxylate.

B. Preparation of tert-butyl 2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolane- 2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

To a mixture of tert-butyl2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]- 1'-carboxylate (0.5 g, 1.0 mmol) in DCE (10 ml) added piperidine (0.3 ml, 3.0 mmol), AcOH (0.2 ml, 3.0 mmol) and sodium triacetoxyborohydride (320 mg, 1.5 mmol). After stirring at room temperature for 16 hours, the reaction mixture was diluted with a saturated solution of NaHCO ₃ and DCM and stirred vigorously for 5 minutes. The organic layer was separated, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give tert-butyl 2oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

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The following compounds were prepared by a similar procedure, except that the following amines were used instead of piperidine:

3,3-Dimethylpyrrolidine was used to prepare tert-butyl 1-((1s,3s)-3-(3,3dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

1,1-difluoro-5-azaspiro[2.4]heptane was used to prepare tert-butyl 1-((1s,3s)-3-(1,1difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl) -2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

3,3-Dimethylpiperidine was used to prepare tert-butyl 1-((1s,3s)-3-(3,3dimethylpiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

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3,3,5,5-tetramethylpiperidine was used to prepare tert-butyl 2-oxo-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((1s, 3s)-3-(3,3,5,5-tetramethyliieridin-1yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

5-azaspiro[2.5]octane was used to prepare tert-butyl 1-((1s,3s)-3-(5-azaspiro[2.5]octan5-yl)cyclobutyl)-2-oxo-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'piperidine]-1'-carboxylate

1,1-difluoro-5-azaspiro[2.5]octane was used to prepare tert-butyl 1-((1s,3s)-3-(1,1difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl) -2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

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(1R,4S)-2-azabicyclo[2.2.1]heptane was used to prepare tert-butyl 1-((1S,3s)-3-((1R,4S)-2azabicyclo[2.2.1]heptan-2-yl )cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

3-oxa-8-azabicyclo[3.2.1]octane was used to prepare tert-butyl 1-((1s,3s)-3-(3-oxa-8azabicyclo[3.2.1]octan-8-yl)cyclobutyl)- 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

8-oxa-3-azabicyclo[3.2.1]octane was used to prepare tert-butyl 1-((1s,3s)-3-(8-oxa-3azabicyclo[3.2.1]octan-3-yl)cyclobutyl)- 2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

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(R)-3-fluoropyrrolidine was used to prepare tert-butyl 1-((1S,3s)-3-((R)-3fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

(S)-3-fluoropyrrolidine was used to prepare tert-butyl 1-((1R,3s)-3-((S)-3fluoropyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

6,6-difluoro-3-azabicyclo[3.1.0]hexane was used to prepare tert-butyl 1-((1s,3s)-3-(6,6difluoro-3-azabicyclo[3.1.0]hexane-3- yl)cyclobutyl)-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

C. Preparation of tert-butyl 1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5tetramethyl-1, 3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

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To a solution of tert-butyl 2-oxo-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine ]-1'-carboxylate (250 mg, 0.5 mmol) in MeOH (6 ml) was added (R)-3fluoropiperidine hydrochloride (211 mg, 1.5 mmol), zinc chloride (103 mg, 0.76 mmol) and sodium cyanoborohydride (95 mg, 1.5 mmol). After stirring overnight at room temperature, the reaction mixture was diluted with a saturated solution of NaHCO ₃ and DCM and stirred vigorously for five minutes. The organic layer was then separated, dried (Na ₂ SO ₄ ) and concentrated to give tert-butyl 1-((1s,3s)3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

Procedure 10. Preparation of compounds of formula (18) according to reaction scheme IV.

A. Preparation of 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indoline -3,4'-piperidine]-2-one.

To a solution of tert-butyl 2-oxo-1-((1s,3s)-3-(nunerudin-1-ul)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (2.27 g, 4.01 mmol) in dioxane (20 ml) was added 4 M hydrochloric acid solution (19.07 ml). The mixture was stirred at room temperature for 10 min, after which LC-MS showed complete conversion. The mixture was concentrated and trace amounts of acid were removed by rotary evaporation using methanol (three times). The residue was dissolved in a minimal amount of DCM and then broken up with ether and hexanes. The precipitates were filtered and washed with hexanes to give 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl )spiro[indoline-3,4'-piperidine]-2-one.

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The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 9 were used instead of tert-butyl 2-okco-1-((1s,3s)-3(piperidin-1-yl)cyclobutyl)- 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'piperidine]-1'-carboxylate:

1-((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro [indoline-3,4'-piperidine]-2-one

1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

1-((1s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1, 3,2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

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1-((18.38)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3, 2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

1-((18,38)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) spiro[indoline-3,4'-piperidine]-2-one

1-((18.38)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[ indoline-3,4'-piperidine]-2-one

1-((1R,38)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) spiro[indoline-3,4'-piperidine]-2-one

1-((1s,3s)-3-(1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4,4,5,5-tetramegyl-1,3 ,2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

Procedure 11. Preparation of compounds of formula (13) according to reaction scheme I.

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A. Preparation of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'-tetrahydrospiro[indoline3,4'-pyran] -2-she.

To a stirred solution of 6-bromo-2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one (4 g, 16.5 mmol) in DMSO (1160 ml) was added bis(pinacolato)diboron (20.1 g, 24.7 mmol), potassium acetate (80.7 g, 822 mmol) and Pd(dppf)Cl ₂ (20.1 g, 24.7 mmol). Nitrogen gas was bubbled through the resulting suspension for 5 minutes, and then the suspension was heated at 90°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried (Na ₂ SO ₄ ), filtered, concentrated, triturated with petroleum ether/EtOAc and filtered to give 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one.

B. Preparation of 1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'tetrahydrospiro[ indoline-3,4'-pyran]-2-one.

To a stirred solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'tetrahydrospiro[indoline-3,4'-pyran ]-2-one (67.0 g, 203 mmol) in DMF (500 ml) was added potassium carbonate (70.3 g, 509 mmol). After stirring at 50°C for 4 hours, 3-bromocyclobutanone (60.6 g, 407 mmol) was added to the mixture. The resulting suspension was stirred at 50°C for 1 hour. After cooling to room temperature, the reaction mixture was filtered, concentrated and purified by flash chromatography (petroleum ether/EtOAc) to give 1-(3-oxocyclobutyl)-6(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one.

C. Preparation of 1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl )-2',3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one.

To a solution of 1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'tetrahydrospiro[indoline -3,4'-pyran]-2-one (3.0 g, 8.4 mmol) in dichloroethane (30 ml) was added 3.3

- 174 045798 dimethylpyrrolidine (1.5 g, 15.1 mmol), acetic acid (1.4 ml, 22.7 mmol) and sodium triacetoxyborohydride (2.4 g, 11.3 mmol). After stirring at room temperature for 48 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic phases were washed with saturated NaHCO ₃ , brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 1-((1s,3s)-3-(3,3dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2',3',5',6'tetrahydrospiro[indolin-3,4'-pyran]-2-one, which was used at the next stage without cleaning.

The following compound was prepared by a similar procedure, except that piperidine was used instead of 3,3dimethylpyrrolidine:

1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2', 3',5',6'tetrahydrospiro[indolin-3,4'-pyran]-2-one.

Procedure 12. Preparation of compounds of formula (I-B) according to reaction scheme IV.

A. Preparation of 1 '-acetyl-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2 -yl)spiro[indoline-3,4'-piperidine]-2-one.

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To a suspension of 1-((1 s,3s)-3-(nunepuguH-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indoline -3,4'-piperidin]-2-one (1810 mg, 3.89 mmol) and triethylamine (5.42 ml, 38.89 mmol) in dichloromethane (8 ml) was added acetic anhydride (0.55 ml, 5 .83 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with DCM and water and extracted with DCM. The combined organic layers were washed with brine and concentrated to give 1'-acetyl-1-((1s,3s)-3(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl)-1. 3,2-dioxaborolan-2-yl)spiro[indolin-3,4'piperidin]-2-one.

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 10 were used instead of 1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one.

1'-acetyl-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -yl)spiro[indoline-3,4'-piperidine]-2-one

1-((1S,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)cyclobutyl)-1'-acetyl-6-(4,4,5,5-tetramethyl1 ,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

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1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)cyclobutyl)-1'-acetyl-6-(4,4,5,5-tetramethyl1 ,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-1'-acetyl-6-(4,4,5,5 -tetramethyl1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one

B. Preparation of 1'-(2-hydroxy-2-methylpropanoyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) was placed in a 20 ml test tube. spiro[indolin-3,4'-piperidin]-2-one (200.0 mg, 0.4 mmol), 2hydroxy-2-methylpropanoic acid (103.7 mg, 1.0 mmol), HATU (364.6 mg, 1.0 mmol) and N,Ndiisopropylethylamine (0.7 ml, 4.0 mmol) in ACN (9 ml). The mixture was stirred at room temperature for 16 hours. The mixture was then quenched with saturated NaHCO ₃ and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ), concentrated and used in the next step without purification.

The following compounds were prepared using a similar procedure, except that the following carboxylic acids were used instead of 2-hydroxy-2-methylpropanoic acid:

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(R)-2-hydroxypropanoic acid was used to prepare 1'-(^)-2-hydroxypropanoyl)-1((18,38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline3,4'-piperidin]-2-one.

Propionic acid was used to prepare 1-((1S,3s)-3-(piperidin-1-yl)cyclobutyl)1'-propionyl-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

C. Preparation of 1'-(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

To a suspension of 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indolin- 3,4'-piperidin]-2-one (0.3 g, 0.6 mmol) in DMF (3 ml) was added 1methylcyclopropane-1-carboxylic acid (0.12 g, 1.2 mmol), DIEA (1 .04 ml, 5.97 mmol), then a 50% solution of propylphosphonic anhydride (T3P) in EtOAc (0.31 ml, 0.53 mmol) and the mixture was stirred at room temperature for 72 hours. The mixture was then quenched with water and extracted twice EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated to give 1'(1-methylcyclopropane-1-carbonyl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)- 6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one, which was used in the next step without purification.

The following compounds were prepared by a similar procedure with the following modifications:

the following carboxylic acids were used instead of 1-methylcyclopropane-1-carboxylic acid; and/or the compounds listed in procedure 10 were used instead of 1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one:

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3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare 1'-(3fluorobicyclo[1.1.1]pentane-1-carbonyl)-1-((1s,3s)-3-(piperidine-1- yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

bicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare (bicyclo[1.1.1]pentane-1carbonyl)-1-((1s,3 s)-3-(piperidin-1-yl)cyclobutyl)-6 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidin]-2-one

oxetane-3-carboxylic acid was used to prepare 1-((1S,3s)-3-((1R,4S)-2azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-G-(oxetane-3- carbonyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one

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Bicyclo[1.1.1]pentane-1-carboxylic acid was used to prepare 1-((1S,3s)-3-((1R,4S)2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)- 1'-(bicyclo[1.1.1]pentan-1-carbonyl)-6-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine ] -2-she.

D. Preparation of methyl 2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2- yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate.

To a suspension of 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indolin- 3,4'-piperidin]-2-one (0.3 g, 0.6 mmol) in DCM (5 ml) was added DIEA (1.0 ml, 5.6 mmol) and methyl carbonochloridate (0.1 g, 1 .1 mmol). The mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give methyl 2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'carboxylate, which was used in the next step without purification.

The following compounds were prepared by a similar procedure with the following modifications: the carboxylic acid chloride below was used instead of methyl carbonochloridate; and/or the compounds listed in procedure 10 were used instead of 1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one:

Cyclopropanecarbonyl chloride was used to prepare 1'-(cyclopropanecarbonyl)-1-((1s,3s)3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)spiro[indoline-3,4'- 180 045798 piperidine]-2-one.

Isobutyryl chloride was used to prepare 1'-isobutyryl-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)spiro[indoline-3,4'-piperidin]-2-one.

Propionyl chloride was used to prepare 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1'propionyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)spiro[indolin-3,4'-piperidine]-2-one.

E. Preparation of 1'-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

To a suspension of 1-((18.38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indolin- 3,4'-piperidin]-2-one (1.50 g, 2.79 mmol) and 3-oxetanone (0.49 ml, 0.60 g, 8.4 mmol) in methanol (28 ml) chloride was added zinc (570 mg, 4.18 mmol), then sodium cyanoborohydride (525 mg, 8.36 mmol). The mixture was sealed and heated to 40°C with stirring for 2 hours. The reaction mixture was cooled, saturated aqueous sodium bicarbonate was added, and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was dissolved in EtOAc, washed again with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 1'-(oxetan-3-yl)-1-((1s,3s)-3-( piperidin-1-yl)cyclobutyl)-6(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one, which used in the next step without purification.

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 10 were used instead of 1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one

1-((1s,3s)-3-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)cyclobutyl)-1'-(oxetan-3-yl)-6-(4 ,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one

1-((1s,3s)-3-((R)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1'-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl -1,3,2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

1-((1R,3s)-3-((S)-3-fluoropyrrolidin-1-yl)cyclobutyl)-1'-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl -1,3,2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one

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1-((18.38)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-G-(oxetan-3-yl)-6-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

F. Preparation of 1'-(2,2-difluoroethyl)-1-((18.38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3, 2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one.

Mixture of 1 -((18.38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)spiro[indoline-3 ,4'-piperidine]-2-one (1.00 g, 1.86 mmol), 1,1-difluoro-2-iodoethane (196 µl, 2.23 mmol) and potassium carbonate (1.03 g, 7 .43 mmol) in DMF (1.3 ml) was placed in a sealed tube and stirred at 70°C overnight. After stirring overnight, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with DCM. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated to give 1'-(2,2difluoroethyl)-1-((18.38)-3-(piperidin-1-yl)cyclobutyl)-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indolin-3,4'-piperidin]-2-one.

Procedure 13. Preparation of compounds of formula I according to reaction scheme I.

A. Preparation of 5-((6-(3,3-dimethyl-2-oxo-1 -((1 S,38)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide (example 1).

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5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-R,2-dimethylbenzamide (50 mg, 0. 12 mmol), 3,3-dimethyl-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2yl)indolin-2-one (52.75 mg, 0.12 mmol), Pd(PPh ₃ ) ₄ (10.05 mg, 0.01 mmol) and cesium carbonate (80.99 mg, 0. 25 mmol) in DME (2 ml)/H ₂ O (1 ml). The mixture was placed in a microwave reactor and heated at 125°C for 25 minutes. The mixture was then purified by flash chromatography (100% DCM to 50% MeOH in DCM) and reverse phase chromatography to give 5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s) -3-(piperidin-1yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-R,2dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in Procedures 3, 4 or 5 were used instead of 5-((6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-R,2-dimethylbenzamide; and/or the compounds listed in Procedures 6, 7, 8, 9, 11, 12, 34 or 35 were used in place of 3,3dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl) -6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2-one:

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o \ \ Ζ^^Λ II. V^'z^^C °ν)=\ w ζζΗ/ζΓ ⁴ 9 ₀ <П ό / /к .NH /— lЛ /О 0^ (Т O^N^ Н 10 Z^zA. χ ^ζ ΪΧ-Η \=^Ο Yk z^i / π \ V ^T II ν^*ζ ° eleven °=<jxl nAA^vn A %ЦХ> ,___ i /^^NH /^ / \-ΝΗ if V ⁷ ο^ Г II J Ο^Ν^ Η 12 °=<dhxl Г-^ · ΧΧ./ΝΗ Γ \—ΝΗ Π °\^> Ο^Ν^ Η 13

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°4τΊ Λ _F \ * .ΝΗ Λ~~ γ-ΝΗ <у ' ΟτΆ Η 14 θ^ο^ι Ν-Άχ/^Ν A / /k^NH /-- ^ΝΗ l| J 'em T CrA H 15 N'^VVNx / Ai ^Аь er nh ₂ 16 °^j^l ^n y y L> sgAn ₂ 17 o \ U vj^x G ^z -=< ^x 18

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°c d X L * lAN A- 0 A AC F 19 °sdG1 d -Huh? 0 ex ΗΝ^Ο F^F 20 f\o ,ρ γ^ 21 / ^ο λ °AjOl _Ν ΑΛ^γΝ Λ ^ν ^ν ^Ζ ό XC ngA^o 22

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°=\XTjl ΑΛ^Ν Λ ^Ν γ^Ν ό ΑΑ ^Η FF 28 α *υΑ / NH Ж О AA o^n' ^x ^ ^/F Η 29 °xjOl Λ γί _Ν > / χΐ^.ΝΗ /— ο αα ₀ A _n ^ ^f Η thirty ό 'О'У / ζ<χ^ΝΗ /— ⁰ Η 31 ΖθΆ °ajOl A 'Q'v 0 AA O^n^ ^FH ί 32

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f \ o \ Ζ<^ II i \ lЛ 0^4 -=< v^ ² 33 Z^Z^ ° Zy^° O \ t“ ^A\ ^z *v^\ P V^z \ O \ ) 34 0-, °^jOl NN 6 0 0^ N ^x H 35 °%jOl N'%<s= ⁱ \<^< 4 _r -' ^N . Λ ^Ν II 1 ^H0 'V-7 ' ^χΛ | O^MN ₂ 36 °^jOl ^N f| ] ho-%_7 o^nh ₂ 37

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ο<η O^N^H 38 o \ Ζ^/Λ II o ¹ Λ ZE \__/ 39 °4χΊ nAYw+xN λ ^ν Ιι 1 \__J ci-^^y O^NH 1 40 Oh o? \ Z^xA II JJ >7 \ A z^\ XA^z γ. J '-l o \___/ 1—jI O \=\ p TZ ⁷ X—\ z=/ x ^- 41

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O O /? \ >k / Z^\ V^*Z γ. / O \=\ ^< \ ^- / ^x 46 °У N-, N N rN f| jT \__/Cl^y O^N^ Η 47 ^ν ά °yjOl A aQQ * /^^NH //-/ 0 СгЭТ Н 48 0=^ ⁿ a °yyOl N-^^X^sz^rN ό Q'v • ^ΝΗ '— 0 o^y ^x Η 49

- 194 045798

Ά th oA A H 50 ^ν ά nAA^^n A γΑ * /^/ ^NH to ζ^2) -''^r CT N ^X H 51 O o ° \ II r—4 J/ <^z *\ \ JI / z-^X^ v^*z X. J i o ^=\ ^y ^- / z/vJ -=( ^x \^ ^z ^ ^z 52 °^ °xzOl nA/wn <5 fYQ 0 'U^A O^N^H 53

- 195 045798

- 196 045798

58a

To prepare this compound, a mixture of dioxane and water was used as a solvent instead of a mixture of DME and water.

To obtain this compound, Na ₂ CO ₃ was used as a base instead of Cs ₂ CO ₃

To obtain this compound, we used as a base

Na2CO ₃ instead of Cs ₂ CO ₃

- 197 045798

To obtain this compound, Na ₂ CO3 was used as a base instead of Cs ₂ CO ₃

To obtain this compound, Na ₂ CO3 was used as a base instead of CS2CO3

To obtain this compound, Na ₂ CO3 was used as a base instead of CS2CO3

To obtain this compound, Na ₂ CO3 was used as a base instead of CS2CO3

- 198 045798

5-(((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid was used instead of 5-((6-bromo -3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2dimethylbenzamide to prepare 5-((6-(3,3-dimethyl-2-oxo-1-(( 1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro- 2-methylbenzoic acid.

B. Preparation of 2-chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3(piperidine-1- yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluorobenzamide (Example 244).

2-χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3 -(piperidin-1 yl)cyclobutyl )indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide was prepared by a similar procedure, except that 5-(( 6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 5-( (6-bromo-3-isopropyl-3 H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide.

C. Preparation of 6-(4-((3-fluoropyridin-4-yl)amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1((1s,3s)- 3-(4-hydroxy-3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-1'-(oxetan-3-yl)spiro[indolin-3,4'piperidin]-2-one (Example 68).

- 199 045798

1'-(oxetan-3-yl)-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl)-1 was placed in the scintillation vial. 3,2-dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one (78 mg, 0.15 mmol), 5-((6-bromo-3-isopropyl-3H-imidazo [4,5-c]pyridin-4-ul)amino)-4-fluoro-N,2dimethylbenzamide (82 mg, 0.195 mmol, 1.3 eq.), Pd(PPh ₃ ) ₄ (17 mg, 0.015 mmol, 0.1 eq.) in DME (0.6 ml) and Na ₂ CO ₃ (0.3 ml, 0.6 mmol, 4.0 eq., 2.0 M in water). The mixture was purged with nitrogen, hermetically sealed, and stirred overnight at 100°C. The mixture was then allowed to cool to room temperature and quenched with 1 M K ₂ CO ₃ . The mixture was extracted with DCM/MeOH, filtered through celite and concentrated. The crude material was purified using a combiflash system (12 g gold column, DCM to 15% MeOH in DCM to 50% to 100% MeOH) then reversed phase HPLC to give 6-(4-((3fluoropyridine-4 -yl)amino)-3 -isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1 -((1 s,3s)-3 -(4-hydroxy-3,3dimethylpyrrolidin-1 - yl)cyclobutyl)-1'-(oxetan-3-yl)spiro[indoline-3,4'-piperidin]-2-one.

The following compounds were prepared by a similar procedure with the following modifications: the compounds listed in procedures 3, 4 or 5 were used in place of 5-((6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl) amino)-4-fluoro-N,2-dimethylbenzamide, the compounds listed in procedures 6 or 12 were used instead of 1'-(oxetan-3-yl)-1((1s,3s)-3-(piperidin-1- yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spuro[indoline3,4'-piperidine]-2-one:

- 200 045798

-201 045798

f \ o 1 \ ^Z ^^A II ° °О=\ _m 0 Jtr _z= f 75 (\ o 1 \ II J. ° vJ^vn w x/V< _Z= < b ^E m 'Y' ² ^ ² 76 o /9 \< II Jj '-^z *< \ JI / ^z ^\ O 5=\ ^< \ ^- / b ^E u* ^ ² χ^ ² 77 o Ρ \^J II r^ ⁴ L 'O \ JI / ^z ^\ V^*z y. / O 5=\ ^< \ ^- / xx^4>' _r= % + ^4 ^ ² χ^ ² 78

- 202 045798

To prepare this compound, a mixture of DMAc and water was used as a solvent and K3PO4 as a base instead of a mixture of DME and water and ArCO3, respectively.

To prepare this compound, a mixture of DMAc and water was used as a solvent and K3PO4 as a base instead of a mixture of DME and water and ArCO3, respectively.

To prepare this compound, a mixture of DMAc and water was used as a solvent and K3PO4 as a base instead of a mixture of DME and water and ArCO3, respectively.

- 203 045798

Procedure 14. Preparation of compounds of formula (14) according to reaction scheme II.

A. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3(piperidin- 1 -yl)cyclobutyl)indolin-2-one.

To a solution of 3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2- yl)indolin-2-one (1.0 g, 0.305 mmol) in DME (100 ml) was added 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (0.97 g, 3.53 mmol), Pd(PPh ₃ ) ₄ (55 mg, 0.047 mmol) and 2M Na ₂ CO ₃ (1.77 ml, 3.53 mmol). The resulting mixture was degassed by passing argon gas through it for 3 minutes, and then the reaction vessel was sealed. After heating at 90°C for 1 hour, the reaction mixture was cooled, then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (DCM/MeOH 50%) to give 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c] pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)indolin-2-one.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in Procedure 1 were used instead of 6-bromo-4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridine; and/or the compounds listed in Procedures 6, 7, 9, 11 or 36 were used instead of 3,3-dimethyl-1((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one; and/or Cs ₂ CO ₃ was used as a base for the compounds below:

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-(3,3-dimethylpiperidin-1yl)cyclobutyl) -3,3-dimethylindolin-2-one

- 204 045798

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-(3,3-dimethylazetidin-1yl)cyclobutyl) -3,3-dimethylindolin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1S,3s)-3-(piperidin-1yl) cyclo6util)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-((R)-3-fluoropiperidin-1yl) cyclobutyl)-3,3-dimethylindolin-2-one

2M Cs ₂ CO ₃ was used as a base instead

2M Na ₂ CO ₃ to obtain 6-(4-chloro-3cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1 s,3s)-3 -(piperidin-1 yl)cyclobutyl)indolin-2-one

2M Cs ₂ CO ₃ was used as a base instead of 2M Na ₂ CO ₃ to obtain 6-(3-((S)-btopbutyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl) -3,3-dimethyl-1-((1s,3R)-3-(piperidin-1yl)cyclobutyl)indolin-2-one

- 205 045798

6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3R)-3-((R )-3-fluoropyrrolidin1 -yl)cyclobutyl)-3,3-dimethylindolin-2-one

6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3R)-3-((R )-3-fluoropiperidin-1yl)cyclobutyl)-3,3-dimethylindolin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)2' ,3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one

tert-butyl 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

- 206 045798

tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 s,3s)-3-(3,3-dimethylpyrrolidin- 1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3s)-3-(3,3 ,5,5tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl 6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((1s,3R )-3(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

F tert-butyl 6-(3-((S)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3R)-3 -((R)-3fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

- 207 045798

tert-butyl 6-(3-((8)-sec-butyl)-4-chloro-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 S,3R)-3 -(l,l-difluoro5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((18.38)-3-(1,1-difluoro5-azaspiro [2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((18.38)-3(piperidine-1 - yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

-208 045798 tert-butyl

6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpiperidin-1-yl)cyclobutyl) -2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl

1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(4-chloro-3-cyclopropyl-3Nimidazo[4,5-c]pyridin-6- yl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

2M Cs ₂ CO ₃ was used as a base instead of 2M Na ₂ CO ₃ to obtain tert-butyl 6-(4chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo- 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate

tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-((R)-3-fluoropiperidine -1yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

- 209 045798

tert-butyl 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(1,1-difluoro-5azaspiro [2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.

N-((1S,3s)-3-(3,3-dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1yl )cyclobutyl)pivalamide (synthesis described in procedure 36) and 6-bromo-4-chloro-3-ethyl-3H-imidazo[4,5c]pyridine were used instead of 3-dimethyl-1-((1S,3s)-3- (piperidin-1-yl)cyclobutyl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-2-one and 6-bromo-4-chloro-3-isopropyl -3H-imidazo[4,5c]pyridine, respectively, to obtain N-((1s,3s)-3-(6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin- 6yl)-3,3-dimethyl-2-oxoindolin-1-yl)cyclobutyl)pivalamide.

Procedure 15. Preparation of compounds of formula (14) according to reaction scheme II.

A. Preparation of 1'-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one.

- 210 045798

1'-acetyl-1-((18.38)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5tetramethyl-1,3,2-dioxaborolane-2) was placed in a round-bottom flask -yl)spiro[indolin-3,4'-piperidin]-2-one (0.8 g, 1.6 mmol), 6-bromo-4chloro-3-isopropyl-3H-imidazo[4,5-c] pyridine (866 mg, 3.2 mmol), Pd(PPh ₃ ) ₄ (91 mg, 0.08 mmol) and cesium carbonate (668 mg, 6.3 mmol). DME (10 ml) and water (3 ml) were added to this mixture, and the resulting mixture was heated to 120° C. for 1 hour under a nitrogen atmosphere. It was then diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by column chromatography (0-10% DCM/MeOH) to give G-acetyl-6-(4-chloro-3-isopropyl-3-imidazo[4,5c]pyridin-6-yl )-1 -((1 S,3 s)-3-(piperidin-1 -yl)cyclobugyl)spiro[indoline-3,4-piperidin]-2-one.

The following compounds were prepared by a similar procedure with the following modifications: the compounds listed in Procedure 1 were used in place of b-bromo-4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridine; and/or the compounds listed in procedures 11, 12 or 36 were used instead of G-acetyl-1-((18,38)-3(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indolin-3,4'piperidin]-2-one:

^but \Ό

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1'-((K)-2-hydroxypropanoyl)-1-((1 s,3S) -3(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one.O

G-acetyl-6-(3-((8)-sec-butyl)-4-chloro-3N-imidazo[4,5-c]pyridin-6-yl)-1-((18,3K)-3 -(piperidin-1yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one.

-211 045798

Na2CO ₃ was used as a base instead of Cs ₂ CO ₃ to obtain 1'-acetyl-6-(4-chloro-3cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s, 3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline3,4'-piperidine]-2-one

6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-2', 3',5',6'-tetrahydrospiro[indolin-3,4'-pyran]-2-one

N-((1s,3s)-3-(6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-2-oxoindolin- 1yl)cyclobutyl)pivalamide.

- 212 045798

Procedure 16. Preparation of compounds of formula (I-B) according to reaction schemes II and IV.

A. Preparation of tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidin- 1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.

Tert-butyl 1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6(4,4,5,5-tetramethyl-1,3) was loaded into the flask ,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (1.0 g, 1.7 mmol), 6-bromo-4-chloro-3-isopropyl-3H -imidazo[4,5-c]pyridine (0.9 g, 3.4 mmol), Pd(PPh ₃ ) ₄ (0.2 g, 0.17 mmol) and cesium carbonate (2.0 g, 6. 8 mmol). DME (10 ml) and water (3 ml) were added and the reaction mixture was heated to 120°C for 1 hour under nitrogen atmosphere. The reaction mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and purified by column chromatography (100% DCM to 10% MeOH/DCM) to give tert-butyl 6(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridinium- 6-yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate.

B. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidin-1-yl )cyclobutyl)spiro[indoline-3,4'-piperidin]2-one.

- 213 045798

To a suspension of tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate (550 mg, 0.85 mmol) in dichloromethane (5 ml) was added 4 N. HCl in dioxane (1 ml). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure to give 6(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s )-3-(3,3-dimethylpyrrolidin-1yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one.

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 14 were used instead of tert-butyl 6-(4-chloro-3isopropyl-3H-imidazo[4,5-c]pyridine-6- yl)-1-((1s,3s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2oxospiro[indoline-3,4'-piperidine]-1'-carboxylate:

6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indolin- 3,4'-piperidine]-2-one

C. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1 s,3s)-3-(3,3-dimethylpyrrolidin- 1 -yl)cyclobutyl)-1'-(oxetane-3-carbonyl)spiro[indoline-3,4'-piperidine]-2-one.

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidine)-1- yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one (82 mg, 0.14 mmol), oxetane-3-carboxylic acid (17 mg, 0.17 mmol) and DIPEA (0.70 ml, 0.12 mmol) in DMF (1 ml). HATU (80 mg, 0.21 mmol) was added to this mixture. The mixture was stirred at room temperature for 1 hour, then quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ), concentrated and purified by reverse phase HPLC to give 6-(4chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl) -1-((1S,3s)-3-(3,3-dimethylpyrrolidin-1yl)cyclobutyl)-1'-(oxetan-3-carbonyl)spiro[indoline-3,4'-piperidin]-2-one.

The following compounds were prepared using a similar procedure, except:

the compounds listed in Procedure 1 were used instead of 6-bromo-4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridine; and/or the compounds listed in procedure 10 were used instead of tert-butyl 1-((1s,3s)-3-(3,3dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolane-2-214 045798 yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate; and/or the following carboxylic acids were used instead of o xetane-3-carboxylic acid:

. OH _Λ

1-Hydroxycyclopropane-1-carboxylic acid was used to prepare 6-(4-chloro-3isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-G-(1-hydroxycyclopropane-1-carbonyl) -l-((ls,3s)-3(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-2-one

1-Hydroxycyclopropane-1-carboxylic acid was used to prepare 6-(4-chloro-3cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1'-(1-hydroxycyclopropane-1-carbonyl) -1-((15.38)-3(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-2-one

3-Methyloxetane-3-carboxylic acid was used to prepare 6-(4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-1'-(3-methylxetane-3-carbonyl )-1 -((1 s,3 s)-3 -(piperidin-1 yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one

-215 045798

3-methyloxetane-3-carboxylic acid was used to prepare 6-(4-chloro-3-cyclopropyl3H-imidazo[4,5-c]pyridin-6-yl)-1'-(3-methyloxetane-3-carbonyl) -1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one.

D. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidin-1-yl )cyclobutyl)-1'-(oxetan-3-yl)spiro[indoline-3,4'-piperidin]-2-one.

Into a flask loaded with 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(3,3dimethylpyrrolidine)-1 -yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one (460 mg, 0.84 mmol) and 3oxetanone (182 mg, 2.5 mmol) in methanol (3 ml) was added zinc chloride ( 172 mg, 1.3 mmol), followed by sodium cyanoborohydride (159 mg, 2.5 mmol). The mixture was sealed and heated to 40°C, stirred for 2 hours, cooled and then quenched with saturated aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo and purified by reverse phase HPLC to give 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1 -((1s,3s)-3-(3,3-dimethylpyrrolidin-1yl)cyclobutyl)-1'-(oxetan-3-yl)spiro[indolin-3,4'-piperidin]-2-one.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in procedure 9 were used instead of tert-butyl 1-((ls,3s)-3-(3,3dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxo-6-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate:

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1 -((1s,3s)-3-((R)-3-fluoropiperidin-1 yl )cyclobutyl)-1'-(oxetan-3-yl)spiro[indoline-3,4'-piperidin]-2-one

6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1 '-(oxetan-3-yl)-1 -((1 s,3s)-3 -(piperidin-1 yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one.

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Procedure 17. Preparation of compounds of formula (22) according to reaction scheme V.

A. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-(3oxocyclobutyl)indolin-2-one.

To a solution of 6-bromo-4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (2 g, 7.29 mmol) in DME (30 ml) was added Pd(PPh ₃ ) ₄ (589 mg , 0.51 mmol), 2M Na ₂ CO ₃ (18.2 ml, 36 mmol) and 3,3-dimethyl-1-(3oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)indolin-2-one (3.1 g, 8.74 mmol). The resulting suspension was degassed by bubbling argon gas (2 min), sealed, then heated to 90°C for 4 hours. The reaction mixture was cooled to room temperature, then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (hexanes/EtOAc) to give 6-(4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridine-6- yl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one.

B. Preparation of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3 (pyrrolidin- 1 -yl)cyclobutyl)indolin-2-one.

To a stirred solution of 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl1-(3-oxocyclobutyl)indolin-2-one (200 mg , 0.47 mmol) pyrrolidine (67 mg, 0.95 mmol), Na(OAc) ₃ BH (150 mg, 0.79 mmol) and AcOH (0.081 ml, 1.42 mmol) were added to DCE (5 ml) at room temperature. The resulting mixture was stirred for 2 hours, then quenched with saturated NaHCO ₃ solution and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ then concentrated and purified by flash chromatography (hexanes/EtOAc) to give 6-(4-chloro-3-isopropyl-3H-imidazo[4,5c]pyridin-6-yl)- 3,3-dimethyl-1-((1s,3s)-3-(pyrrolidin-1-yl)cyclobutyl)indolin-2-one.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used in place of pyrrolidine; and/or the compounds listed in procedure 1 were used instead of 6-bromo-4-chloro-3-isopropyl-3Nimidazo[4,5-c]pyridine:

Piperidine was used to prepare 6-(4-chloro-3-ethyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3dimethyl-1-((1s,3s)-3-(piperidine -1-yl)cyclobutyl)indolin-2-one

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F

3-(difluoromethyl)pyrrolidine was used to prepare 6-(4-chloro-3-isopropyl-3H-imidazo[4,5c]pyridin-6-yl)-1-((1s,3s)-3-(3-( difluoromethyl)pyrrolidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

F

3-(difluoromethyl)piperidine was used to prepare 6-(4-chloro-3-isopropyl-3H-imidazo[4,5c]pyridin-6-yl)-1 -((1 s,3s)-3 -(3 - (difluoromethyl)piperidin-1-yl)cyclobutyl)-3,3-dimethylindolin-2-one

F(R)-3-fluoropyrrolidine was used to prepare 6-(4-chloro-3-isopropyl-3H-imidazo[4,5c]pyridin-6-yl)-1-((1S,3s)-3-(( R)-3-fluoropyrrolidin-1 -yl)cyclobutyl)-3,3-dimethylindolin-2-one

Piperidine was used to prepare 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidine -1 -yl)cyclobutyl)indolin-2-one.

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Procedure 18. Preparation of compounds of formula I according to reaction scheme II.

A. Preparation of 5-((6-(1'-acetyl-2-oxo-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'piperidine] -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide (Example 83).

1'-Acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-(( 1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one (880 mg, 1.53 mmol), 5-amino-K-isopropyl-2methylbenzamide (588 .33 mg, 3.06 mmol), Pd ₂ (dba) ₃ (98.08 mg, 0.11 mmol), xanthos (110.25 mg, 0.21 mmol) and Cs ₂ CO ₃ (1995.15 mg , 6.12 mmol) in dioxane (6 ml). The mixture was sonicated and degassed for 15 s, placed in a microwave reactor and heated at 150°C for 1 h. The mixture was then purified by flash chromatography (100% DCM to 80% MeOH in DCM) followed by reverse phase chromatography with producing 5-((6-(1'-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-6-yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-isopropyl-2-methylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

compounds listed in Procedures 14, 15, 16, 17, or 37 were used in place of 1'-acetyl-6-(4-chloro3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1- ((1S,3s)-3-(piperidin-1-yl)cyclobutyl)spuro[indolin-3,4'piperidin]-2-one; and/or optionally substituted benzamides available commercially, such as 5-amino-K,2-dimethylbenzamide, 5-amino-4-fluoro-K,2-dimethylbenzamide, 5-amino-2-chloro-M-methylbenzamide and 5-amino -2-chloro-K-isopropylbenzamide, or can be prepared by methods known in the art, for example, the compounds listed in procedure 27 were used instead of 5-amino-Kisopropyl-2-methylbenzamide:

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° 5=\ ° a /Y 86 Mni .....( ^Λ/ ^ζτ О ^ ° γΟγχχθ 87 ^р ⁿ a <рЛ ό /V 0 ^<ί ^'Ν'^'—” Η 88 f\ o 1 \ ιι J. ν> _ζ ΑΓ A o \__ o ^>=\ \/ J^-C\=r Ν 89

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^ν ά °cjAl d^pc r\ η- LX CT NH 94 N— νΑΑ/^ν. th A i /%NH K (A pRd SG~g+ H 95 ^f ^{O n} A °cjAl a ⁿ y^n O^N^ H 96 A° ^N % °cjOl n-+>wn И r?{ • +^/ ^NH to O O^N^ H 97

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l ό cXlY Η 102 N-^Y^V^r-N III ό XX Ο^Ν^ Η 103 °ΙχΙ Λ ^Ν ηΑ _Ν ^Ζ 104 * /^/ ^ΝΗ Τ' + / F Ο^Ν^ Η °xjO. Ν-^Υί+Χγ/^γ-Ν l / ,ΝΗ /— ^F >-0 XI FX / CT N Η 105 °xjOl Ν^ΧγγΝ Λ • Λ- <\ίΎ 106 ^F \X Ο^Ν^ Η

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νΑΛ^Ν Λ _F ^Ν γΑ|/ * /А/NH /— fj H 107 °<дП1 nAA^N Λ _F ^N yA/ < A^ah A- A JU F*^ ⁷ A N ^Z H 108 °=<jOl nAA/vX jJ (τΆ H 109 _Ν ΑΛ^γΝ Λ _F ^N yA/ * /A/NH /— l\ fj ^ρ ΆΑ i ο^νΆ H 110 nL/A °a jf a nAA/vn 6 /A.NH/— 0 JU cAn''H 111

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Λ ^Ν γ^Ν • ^NH to h ₂ n^o 112 °υύΥ νΑΛ^Ν Λ _F ^Ν ν^Ν / J^NH l\ ij ^F 'v-> O^NH 1 113 ^o= \jOl Ν^χχΑ^γΝ Α ^Ν γ^Ν * /NH r\ ' \^J O^N^ H 114 °yyx nAYw\ A uQZ • ^.NH /— l\ Ci \_/ CI-^YI O^N^ ⁴ H 115 f \ o \ ^Ζ *^Λ II o \=\ Т/ ° \^Ζ ,Ζ / / 116

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νΑΑ/ΛΑ l\XQ i A>NH A' LK JO \A CI'A^ I H 117 °¥POl nAA/on ί a1 • Aah /— lk JO A ci^y CT A H 118 NAAAk aAp _M > / A' lk jA \A ci'A^ O^N^ H 119 °¥zOl N^VOOA ό fQP 7 Ϋ O^N^H 120 ^o ¥¥X nAA/v ⁿ ₄ A Ar( to Al O^NH 121

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A.A. Ο^Ν^ Η 122 f\Ο V-^z γ. / Ο \=\ f A xz^vJ _ζ Η ⁴ \^.ζ^ζ 123 f \ ο Α/ ² *<ά ΑΛ^° V-^z J Ο \=χ A χζ^Μ _Ζ= Χ ¥ - k 124 0-, °AjOl _Ν Λ>γγΝ Λ _F ^Ν ^Ν / ^L^NH A- 0 -^Ά Ο^Ν^' Η 125

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\ \ O / \II J'H/ O x X O zzH? ) M 130 ( \ o / \ II r^X 1 o ο Υ θ zzO _Z= Y ? Λα o y ^z \/ 131 ^f° / Ж °YjOi A О /Q ^NH O^N^ ⁴ ^ ⁰⁴ H 132 \ ^τ θ II UV^zyC О \__/ Ож о 133 f \ o \ Ζ^^Λ II V^z ⁷ )^ °O=\ C ^z zz' ^M H -=< Λα ⁴¹ ^ ^ζ ^ ^η 134

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Methyl 5-amino-2-methylbenzoate and 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3dimethyl-1-((15.35)- 3-(piperidin-1-yl)cyclobutyl)indolin-2-one was used instead of 5-amino-Misopropyl-2-methylbenzamide and G-acetyl-6-(4-chloro-3-isopropyl-3H-imidazo[4,5 -c]pyridin-6-yl)-1((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one, respectively, to obtain methyl 5 -((6-(3,3-dim ethyl-2-oxo-1 -((1 s,3 s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate

B. Preparation of tert-butyl 6-(3-isopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3Nimidazo[4,5-c]pyridin-6-yl)-2-oxo- 1-((15,35)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'piperidine]-1'-carboxylate.

To a solution of tert-butyl 6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxo-1-((15.35)-3(piperidin- 1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-G-carboxylate (0.7 g, 1.1 mmol) in dioxane (9 ml) was added 5-amino-L1,2-dimethylbenzamide (0 .91 g, 5.5 mmol), Pd ₂ (dba) ₃ (0.11 g, 0.11 mmol), xanthos (0.13 g, 0.22 mmol) and Cs ₂ CO ₃ (1.8 g , 5.5 mmol). The resulting mixture was degassed by passing nitrogen gas through it for several minutes, and then the reaction vessel was sealed. After heating for 30 min at 150°C in a microwave oven, the reaction mixture was filtered, concentrated and purified by chromatography on silica gel (100% DCM to 50% MeOH in DCM) to give tert-butyl 6-(3-isopropyl-4-( (4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-2-oxo-1 -((15.35)-3-(piperidine-1 - yl)cyclobutyl)spiro[indoline-3,4'-piperidine] - Hcarboxylate.

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedure 14 were used instead of tert-butyl 6-(4-chloro-3isopropyl-3H-imidazo[4,5-c]pyridine-6- yl)-2-oxo-1-((15.35)-3-(piperidin-1yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'-carboxylate:

-232 045798 tert-butyl 6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-2-oxo- 1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'carboxylate

O NH tert-butyl 6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridine-6- yl)-2-oxo-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-1'carboxylate

O NH tert-butyl 6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridine-6- yl)-1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate

About NH tert-butyl

6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5

c]pyridin-6-yl)-1-((1S,3R)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3, 4'piperidine]-1'-carboxylate

C. Preparation of 5-((6-(3,3-dimethyl-2-oxo-1 -((1s,3 s)-3-pivalamidocyclobutyl)indolin-6-yl)-3isopropyl-3H-imidazo[4,5 -c]pyridin-4-yl)amino)-2-methylbenzamide (Example 135).

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N((1s,3s)-3-(6-(4-chloro-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3 was placed in a test tube to carry out the reaction under the influence of microwave radiation ,3-dimethyl-2-oxoindolin-1yl)cyclobutyl)pivalamide (83 mg, 0.5 mmol), 5-amino-N,2-dimethylbenzamide (103 mg, 0.2 mmol), methyl tert-butyl ether adduct RuPhos Pd G1 (10 mg 0.01 mmol) and Cs ₂ CO ₃ (130 mg, 0.41 mmol) in dioxane (2 ml). The mixture was degassed with nitrogen, placed in a microwave reactor and heated at 150°C for 1 hour. Then purified by flash chromatography (100% EtOAc to 60% MeOH in EtOAc) to give 5-((6(3,3-dimethyl- 2-oxo-1-((1s,3s)-3-pivalamidocyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2-methylbenzamide.

Procedure 19. Preparation of compounds of formula (16) according to reaction scheme III.

A. Preparation of 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

A 500 mL high pressure vessel equipped with a magnetic stirrer was charged with 6-bromo-4fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (10.0 g, 38.8 mmol) followed by N- methylpyrrolidone (100 ml). The resulting solution was treated with ammonium hydroxide solution (28% NH ₃ , 54 ml, 390.0 mmol). The vessel was sealed and the mixture was stirred at 80°C in a heating block for 48 hours. The reaction mixture was then cooled to room temperature and carefully poured into water (900 ml). The mixture was further cooled in an ice bath while stirring, and then the mixture was filtered to obtain 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine.

B. Preparation of 6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1'-(oxetan-3-yl)-1-((1s,3s) 3-(piperidin-1-yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-2-one.

Suspension of 1 '-(oxetan-3 -yl)-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3 ,2dioxaborolan-2-yl)spiro[indolin-3,4'-piperidin]-2-one (736 mg, 1.41 mmol), 6-bromo-3-isopropyl-3H- 234 045798 imidazo[4,5- c]pyridin-4-amine (300 mg, 1.18 mmol) and tetrakis(triphenylphosphine) palladium (136 mg, 118 μmol) in 1:1 DMF/DME (12 ml) were treated with 2 M aqueous Na ₂ CO ₃ solution ( 4.1 ml, 8.2 mmol). The mixture was purged with N ₂ for 1 minute, then sealed and stirred vigorously at 120°C overnight. The reaction mixture was cooled to room temperature, diluted with water and extracted three times with EtOAc. The combined organic layers were concentrated in vacuo and purified by flash silica gel chromatography with gradient elution (0-100% EtOAc/hexanes, then 0-100% MeOH/DCM) to give 6-(4-amino-3-isopropyl-3N -imidazo[4,5c]pyridin-6-yl)-1 '-(oxetan-3-yl)-1 -((1 s,3 s)-3 -(piperidin-1 -yl)cyclobutyl)spiro[indoline -3,4'piperidine] -2-ona.

The following compounds were prepared by a similar procedure, except that the compounds listed in procedures 6, 7, 8, 9, 12, or 35 were used instead of G-(oxetan-3-yl)-1((1s,3s )-3 -(piperidin-1 -yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[indoline3,4'-piperidine]-2 -she:

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1 s, 3s)-3-(piperidin-1yl )cyclobutyl)indolin-2-one

1-((15.35)-3-((1K.48)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4-amino-3-isopropyl-3Nimidazo[4, 5-c]pyridin-6-yl)-3,3-dimethylindolin-2-one

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((18.38)-3-(piperidin-1yl) cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one but, /

6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3-hydroxy-3-methyl-1-((1 s,3s)-3(piperidin- 1 -yl)cyclobutyl)indolin-2-one

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6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((18.35)-3-(3,3-dimethylazetidin-1yl)cyclobutyl) -3,3-dimethylindolin-2-one

G-acetyl-6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((15.38)-3-(piperidin-1yl)cyclobutyl) spiro[indoline-3,4'-piperidine]-2-one

tert-butyl 6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((18.35)-3-((K)-3fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate

C. Preparation of 6-(4-amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-G-((K)-2-hydroxypropanoyl)1-((1 s,3 S)-3-(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'-piperidin]-2-one.

G((K)-2-hydroxypropanoyl)-1-((1 s,3 8)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4 ,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)spiro[indoline-3,4'-piperidin]-2-one (130 mg, 0.242 mmol), 6-bromo-3-isopropyl-3Nimidazo[ 4,5-c]pyridin-4-amine (62 mg, 0.242 mmol), palladium tetrakis (28 mg, 0.024 mmol) and cesium carbonate (154 mg, 0.726 mmol) in DMAc (2 ml) and water (0.4 ml). The mixture was degassed with N ₂ , sealed and heated to 90°C for 2 hours, partitioned between EtOAc and water and then extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered, concentrated in vacuo and purified by flash chromatography (DCM/MeOH/NEtj) to give 6-(4-amino-3-isopropyl-3H-imidazo[4,5c]pyridine-6- yl)-G-((K)-2-hydroxypropanoyl)-1-((15.38)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline3,4'-piperidin]-2-one.

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Procedure 20. Preparation of compounds of formula I according to reaction scheme III.

A. Preparation of 5-((6-(3,3-dimethyl-2-oxo-1 -((Is,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3isopropyl-ZN -imidazo[4,5-c]pyridin-4-yl)amino)-M-isopropyl-2-methylbenzamide (Example 136).

To a mixture of 5-bromo-M-isopropyl-2-methylbenzamide (44 mg, 0.171 mmol), 6-(4-amino-3-isopropyl-3-Nimidazo[4,5-c]pyridin-6-yl)-3,3 -dimethyl-1-((15.35)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one (80 mg, 0.114 mmol), Pd ₂ (dba) ₃ (11 mg, 0.011 mmol), xantphos (13 mg, 0.023 mmol) and Cs ₂ CO ₃ (186 mg, 0.571 mmol) freshly degassed dioxane was added. The reaction mixture was heated to 90°C and stirred overnight. The reaction mixture was then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (0-80% MeOH/DCM with 0.5% NEt3) and HPLC (0-75% ACN/H ₂ O) to give 5-(( 6-(3,3dimethyl-2-oxo-1-((15.38)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4.5c] pyridin-4-yl)amino)-M-isopropyl-2-methylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in procedure 19 were used instead of 6-(4-amino-3-isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((18.35)- 3-(piperidin-1-yl)cyclobutyl)indolin-2-one; and/or the benzamides listed in procedure 28 were used instead of 5-bromo-M-isopropyl-2methylbenzamide:

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Structure Example No. A 1 Λ— 0Ά Η 137 °=(jPX nAAq^n Α ^Ν γΆ * ^s^NH Α~ 0 Ά Η 138 °Xjf^l 7 γν /.ΝΗ/— 0 ΧΧ η 1 139 °xjO χ ^Ι; / ^^/ΝΗ Λ— _C JL· Ο^Ν^ ^F T ^{F Η} 140 _Ν ΧΑγ^γΝ A * Τ''F Η 141

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Commercially available methyl 5-bromo-2,4-difluorobenzoate and 1'-acetyl-6-(4-amino-3-isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-1-((1s, 3s)-3 -(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'-piperidine] 2-one was used instead of 5-bromo-N-isopropyl-2-methylbenzamide and 6-(4-amino-3 -isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3 -(piperidin-1 -yl)cyclobutyl)indolin-2-one, accordingly, to obtain methyl 5-((6-(1'-acetyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indoline-3,4'-piperidine] -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2,4-difluorobenzoate.

- 239 045798

Commercially available methyl 5-bromo-2,4-difluorobenzoate was used instead of 5-bromo-kisopropyl-2-methylbenzamide to produce methyl 5-((6-(3,3-dimethyl-2-oxo-1-((1S, 3s)-3-(piperidin-1yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate

5-bromo-4-fluoro-K-isopropyl-2-methylbenzamide and tert-butyl 6-(4-amino-3-isopropyl-3H imidazo[4,5-c]pyridin-6-yl)-1-(( 1s,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine]-1'-carboxylate was used instead of 5-bromo-K-isopropyl-2 -methylbenzamide and 6-(4amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1yl )cyclobutyl)indolin-2-one, respectively, to obtain tert-butyl 6-(4-((2-fluoro-5(isopropylcarbamoyl)-4-methylphenyl)amino)-3-isopropyl-3H-imidazo[4,5 -c]pyridin-6-yl)-1-((1S,3s)-3((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine] - 1'-carboxylate

tert-butyl

5-bromo-C-ethyl-4-fluoro-2-methylbenzamide and

6-(4-amino-3-isopropyl-3H-imidazo[4,5c]pyridin-6-yl)-1-((1s,3s)-3-((R)-3-fluoropiperidin-1-yl) Cyclobutyl)-2-oxospiro[indoline-3,4'-piperidine]1'-carboxylate was used instead of 5-bromo-K-isopropyl-2-methylbenzamide and 6-(4-amino-3-isopropyl-3Nimidazo[4,5 -c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one, respectively, to obtain tert-butyl 6 -(4-((5-(ethylcarbamoyl)-2-fluoro-4-methylphenyl)amino)-3-isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-1-((1S,3s) -3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate.

B. Preparation of 5-((6-(1-((1s,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl -2oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl) - 240 045798

3,4-difluoro-2-methylbenzamide (Example 145).

F

1-((1 s,3s)3-((lR,48)-2-azabicyclo[2.2.1]heptan-2-yl)cyclobutyl)-6-(4- amino-3-isopropyl-3N-imidazo[4,5-c]pyridin-6yl)-3,3-dimethylindolin-2-one (85.21 mg, 0.18 mmol), 5-6poM-N-( 1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide (46 mg, 0.14 mmol), Pd ₂ (dba) ₃ CHCl ₃ (6.19 mg, 0.01 mmol), xantphos (7.83 mg, 0.01 mmol) and cesium carbonate 99.9% (132.2 mg, 0.41 mmol) in dioxane (1 ml). The mixture was degassed with nitrogen, placed in a microwave reactor and heated at 150°C for 30 min. The mixture was purified by silica gel chromatography (100% DCM to 100% MeOH) and reverse phase chromatography to give 5-((6(1-((18.35)-3-((1B,48)-2-azabicyclo[ 2.2.1]heptan-2-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6-yl)-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M -(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

Procedure 21. Preparation of compounds of formula I according to reaction scheme I.

A. Preparation of tert-butyl 6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3Nimidazo[4,5-c]πpyridin-6-yl)- l-((lS,3s)-3-((R)-3-φτopπpipipiridin-l-yl)cyclobytyl)-2-oκcocopypo[indoline-3,4'piperidine]-1'-carboxylate.

Tert-butyl 1-((18.35)-3-((B)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6(4,4,5,5-tetramethyl-1) was placed in the flask ,3,2-dioxaborolan-2-yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate (192 mg, 0.33 mmol), 5-((6-bromo-3-isopropyl-3N -imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-K,2

-241 045798 dimethylbenzamide (115 mg, 0.27 mmol), Pd(PPh ₃ ) ₄ (22 mg, 0.02 mmol) and sodium carbonate (116 mg, 1.0 mmol) in DME (3 ml) and water ( 1 ml). The reaction mixture was purged with nitrogen gas and heated at 120°C in a microwave reactor for 25 minutes. The reaction mixture was filtered through a pad of Celite with MeOH, concentrated and purified by reverse phase HPLC to give tert-butyl 6-(4-((2-fluoro4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3H- imidazo[4,5-c]pyridin-6-yl)-1-((18.38)-3((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4 '-piperidine]-1'-carboxylate.

The following compounds were prepared by a similar procedure with the following modifications: the compounds listed in procedure 3 or 34 were used instead of 5-((6-bromo-3-isopropyl-3-Nimidazo[4,5-c]pyridin-4-yl)amino) -4-fluoro-M,2-dimethylbenzamide; and/or the compounds listed in Procedure 9 were used instead of tert-butyl l-((ls,3s)-3-((R)-3fluoropiperidin-1-yl)cyclobutyl)-2-oxo-6-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[indoline-3,4'-piperidine]-1'-carboxylate:

tert-butyl 6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-1 -((18.3 s)-3-(3,3-dimethylpyrrolidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate

tert-butyl 6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-2-oxo-1-( (18,38)-3-(3,3,5,5-tetramethylpiperidin-1-yl)cyclobutyl)spiro[indoline-3,4'piperidine]-1'-carboxylate

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tert-butyl 6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-1 -((1 s, 3s)-3-(3,3-dimethylpiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate

tert-butyl 1 -((1 s,3s)-3 -((R)-3 -fluoropiperidin-1 -yl)cyclobutyl)-6-(3-isopropyl-4-((4-methyl-3 (methylcarbamoyl) phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4'-piperidine]1'-carboxylate

tert-butyl 1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-6-(3-isopropyl-4-((4methyl-3 -(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate

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tert-butyl 6-(3-cyclopropyl-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl)-1-((1s,3s )-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine]-1'-carboxylate

tert-butyl 1-((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-6-(3-isopropyl-4-((4-methyl-3(methylcarbamoyl)phenyl) amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4'-piperidine]1'-carboxylate

tert-butyl 1-((1s,3s)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-6-(3-cyclopropyl-4-((4-methyl-3(methylcarbamoyl)phenyl )amino)-3H-imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4'-piperidine]1'-carboxylate

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tert-butyl 6-(3-((S)-sec-butyl)-4-((4-methyl-3-(methylcarbamoyl)phenyl)amino)-3H-imidazo[4,5c]pyridin-6-yl) -1 -((1 S,3R)-3 -((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-1'-carboxylate

tert-butyl 1-((1s,3s)-3-(3,3 -dimethylpyrrolidin-1 -yl)cyclobutyl)-6-(3 -isopropyl-4-(3 -(methoxycarbonyl)-4-methylphenoxy)-3H -imidazo[4,5-c]pyridin-6-yl)-2-oxospiro[indoline-3,4'-piperidine]-1'carboxylate.

Procedure 22. Preparation of compounds of formula (18) according to reaction scheme IV.

A. Preparation of 4-fluoro-5 -((6-(1-((1S,3s)-3 -((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4'- piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

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To a solution of tert-butyl 6-(4-((2-fluoro-4-methyl-5-(methylcarbamoyl)phenyl)amino)-3-isopropyl-3Nimidazo[4,5-c]pyridin-6-yl)-1 -((1s,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine]-1'-carboxylate (110 mg, 0.14 mmol ) in dichloromethane (1 ml) was added 4 N. HCl in dioxin (0.5 ml). After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure to give 4-fluoro-5-((6-(1-((1s,3s)-3-((R)-3-fluoropiperidine-1) yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-K,2-dimethylbenzamide .

The following compounds were prepared by a similar procedure, except that the compounds listed in Procedures 18, 20, or 21 were used instead of tert-butyl 6-(4-((2fluoro-4-methyl-5-(methylcarbamoyl)phenyl) amino)-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)- 2-oxospiro[indoline-3,4'-piperidine]-1'-carboxylate:

5-((3-cyclopropyl-6-(1 -((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine]-6 -yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

5-((3-cyclopropyl-6-(2-oxo-1-((1 s,3s)-3-(3,3,5,5-tetramethylpiperidin-1 -yl)cyclobutyl)spiro[indoline-3, 4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

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5-((3-cyclopropyl-6-(1 -((1 s,3s)-3-(3,3-dimethylpiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine]- 6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

5-((6-(1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4' )piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

5-((3-cyclopropyl-6-(1-((1s,3s)-3-(1,1-difluoro-5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2oxospiro[indoline-3, 4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

5-((6-(1-((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indolin-3,4'piperidin]-6-yl) -3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

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5-((3-isopropyl-6-(2-oxo-1-((1 s,3 s)-3 -(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'piperidine]-6- yl)-3N-imidazo[4,5-c]pyridin-4-yl)amino)-I, 2-dim ethylbenzamide

I

5-((3 -cyclopropyl-6-(2-oxo-1 -((1 s,3 s)-3 -(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'piperidine]-6 -yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dim ethylbenzamide n

I

5-((6-(1-((18.38)-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidin]-6yl) -3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

I

5-((3-((8)-sec-butyl)-6-(1-((18,3K)-3-((K)-3-fluoropiper idin-1-yl)cyclobutyl)-2-oxospiro [indolin3,4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)M,2-dimethylbenzamide

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5-((3-((S)-sec-butyl)-6-(2-oxo-1-((1s,3R)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4 'piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide

5-((3-((S)-sec-butyl)-6-(1-((1S,3R)-3-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)cyclobutyl )-2oxospiro[indolin-3,4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M,2-dimethylbenzamide

4-fluoro-5-((6-(1 -((1 s,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine ]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-isopropyl-2-methylbenzamide

N-ethyl-4-fluoro-5-((6-(1 -((1 s,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4 '-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide

- 249 045798

methyl-5 -((6-(1 -((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine]-6- yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate.

Procedure 23. Preparation of compounds of formula I according to reaction scheme IV.

A. Preparation of 5-((6-(1'-(2-hydroxy-2-methylpropanoyl)-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[indoline-3 ,4'-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-M,2-dimethylbenzamide (Example 146).

To a solution of 5-((3 -isopropyl-6-(2-oxo-1 -((1s,3s)-3 -(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4'piperidine]]-6 -yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M,2-dimethylbenzamide (0.10 g, 0.11 mmol) in DMF (1 ml) was added 2-hydroxy- 2-methylpropanoic acid (0.024 g, 0.23 mmol), DIEA (0.2 ml, 1.1 mmol) and HATU (0.087 g, 0.23 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), concentrated and purified by reverse phase chromatography (0.01% TFA in ACN/0.01% TFA in water) to give 5-((6-(1'- (2-hydroxy-2-methylpropanoyl)-2-oxo-1((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-6-yl) -3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-M,2-dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in procedure 22 were used instead of 5-((3-isopropyl-6-(2-oxo-1-((1s,3s)3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4 '-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)-M,2-dimethylbenzamide; and/or carboxylic acids that are commercially available or can be prepared by methods known in the art, such as (R)-2-hydroxypropanoic acid, 3-hydroxybicyclo[1.1.1]pentane-1-carboxylic acid, 1-methylcyclobutane -1-carboxylic acid and 1-250 045798 methylcyclopropane-1-carboxylic acid were used instead of 2-hydroxy-2-methylpropanoic acid:

- 251 045798

- 252 045798

B. Preparation of 5-((3-isopropyl-6-(1'-(1-methylcyclopropane-1-carbonyl)-2-oxo-1-((1s,3s)-3(piperidin-1-yl)cyclobutyl) spiro[indolin-3,4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)-K,2-dimethylbenzamide (example 152).

To a solution of 5-((3-isopropyl-6-(2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'piperidine])-6 -yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide (0.11 g, 0.11 mmol) in DMF (1 ml) was added 1-methylcyclopropane- 1-carboxylic acid (0.023 g, 0.23 mmol), DIEA (0.2 ml, 1.1 mmol) and 50% propylphosphonic anhydride (T3P) in EtOAc (0.14 ml, 0.23 mmol). The resulting mixture was stirred at room temperature for 30 minutes and then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried ( _Na2SO4 ), concentrated and purified by silica gel chromatography (10% NH4OH in MeOH/ _EtOAc /hexanes) followed by reverse phase chromatography (0.01% TFA in ACN/0.01% TPA in water) to give 5-((3-isopropyl-6-(1'-(1methylcyclopropan-1-carbonyl)-2-oxo-1-((1s,3s)-3-(pineridin-1)-yl )cyclobutyl)spiro[indolin-3,4'piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

the compounds listed in procedure 22 were used instead of 5-((3-isopropyl-6-(2-oxo-1-((1s,3s)3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4 '-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)-R,2-dimethylbenzamide; and/or carboxylic acids that are commercially available or can be prepared by methods known in the art, such as 1-methylcyclopropane-1-carboxylic acid, oxetane-3-carboxylic acid, 3-fluorobicyclo[1.1.1]pentane- 1-Carboxylic acid, cyclobutanecarboxylic acid and bicyclo[1.1.1]pentane-1-carboxylic acid were used instead of 2-hydroxy-2methylpropanoic acid:

- 253 045798

- 254 045798

Procedure 24. Preparation of compounds of formula I according to reaction scheme IV.

A. Preparation of 5-((6-(1'-acetyl-1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2oxospiro[indoline-3,4' -piperidin]-6-yl)-3-((S)-sec-butyl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)N,2-dimethylbenzamide (Example 157).

To a mixture of 5-((3-((S)-sec-butyl)-6-(1-((1S,3R)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2

- 255 045798 oxospiro[indolin-3,4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide (45 mg, 0. 07 mmol) and triethylamine (0.1 ml, 0.64 mmol) in dichloromethane (2 ml), acetic anhydride (0.01 ml, 0.1 mmol) was added. After stirring at room temperature for 20 min, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give 5-((6-(1'-acetyl-1-((1S,3R)-3-((R) -3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indolin-3,4'piperidin]-6-yl)-3-((S)-sec-butyl)-3H-imidazo[4,5- c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications: the compounds listed in procedure 22 were used in place of 5-((3-isopropyl-6-(2-oxo-1-((1s,3s)3-(piperidine-1- yl)cyclobutyl)spiro[indolin-3,4'-piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)-K,2-dimethylbenzamide; and/or

Instead of acetic anhydride, alkylsulfonyl chlorides such as cyclopropanesulfonyl chloride and methanesulfonyl chloride were used:

- 256 045798

Structure Example No. Ή / O / o O d H -ζΗτ ₂ Η X 158 οχ ^{7 Ν} χ ° \ PM nAAaV-N P?{ ''t^ (Г A Η 159 O Ν-. °hPM f Vl x A H 160 f \ o / \ Zk II <^X 1 ° ^=\ ^x \A ² ^ ² 161

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Λ ^Ν γ^Ν γ\ ΓΎ ^F \Y SG Ι\Γ Η 162 ^ρ ^ν Α °УхУ _Ν ΥΥγ4ρΝ Λ ^Ν γ^Ν ,Α Ϋ ^{ь F} Ο^ΝΗ 1 163 And / \ Ο / ν%ζΑγ/ ό ° 5=\ -=< ¹ 164 ζ ζ^\ dn χ /=< ^ζ ^Уч ^χ Ο \ ° / Ο \ / 165

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- 259 045798

methyl 5-((6-( 1 '-acetyl-1 -((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine] -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate

methyl 5-((6-( 1 '-acetyl-1 -((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4'-piperidine] -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate.

Procedure 25. Preparation of compounds of formula I according to reaction scheme IV.

A. Preparation of 4-fluoro-5-((6-(1-((1s,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-1'-(oxetan-3-yl) )2-oxospiro[indolin-3,4'-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2dimethylbenzamide (example 170) .

To a mixture of 4-fluoro-5-((6-(1-((1s,3s)-3-((R)-3-fluoropiperidin-1-yl)cyclobutyl)-2-oxospiro[indoline-3,4' piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide (70 mg,

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0.10 mmol) and 3-oxetanone (21 mg, 0.30 mmol) in methanol (3 ml), zinc chloride (21 mg, 0.15 mmol) was added, followed by sodium cyanoborohydride (19 mg, 0.30 mmol) . The mixture was sealed and heated at 50°C for 16 hours, then cooled, quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, concentrated and purified by reverse phase HPLC (Gilson) to give 4-fluoro-5-((6-(1-((1s,3s)-3-((R) -3-fluoropiperidin-1-yl)cyclobutyl)-1'-(oxetan-3-yl)-2oxospiro[indoline-3,4'-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4, 5-c]pyridin-4-yl)amino)-K,2dimethylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications: 5-((3-cyclopropyl-6-(2-oxo-1-((1 s,3s)-3 -(piperidin-1-yl)cyclobutyl)spiro[indoline -3,4'piperidin]-6-yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide was used instead of 4fluoro-5-((6-(1 - ((1 S,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidin]6-yl)-3-isopropyl-3H- imidazo[4,5-c]pyridin-4-yl)amino)-K,2-dimethylbenzamide; and/or

K-ethyl-4-fluoro-5-((6-(1 -((1 s,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline3,4 '-piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide and 4-fluoro-5((6-(1 -( (1 S,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'-piperidin]-6-yl)-3 isopropyl-3H-imidazo [4,5-c]pyridin-4-yl)amino)-N-isopropyl-2-methylbenzamide was used instead of 4-fluoro-5-((6-( 1-((1 s,3s)-3-(( R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4- yl)amino)-K,2-dimethylbenzamide; and/or

4-fluoro-5-((6-(1 -((1 s,3s)-3-((R)-3-fluoropiperidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine ]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-R-isopropyl-2-methylbenzamide:

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Procedure 26. Preparation of compounds of formula I according to reaction scheme II.

A. Preparation of 5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic acid.

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To a stirred solution of methyl 5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)indolin-6-yl)-3-isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate (430 mg, 0.69 mmol) in THF (20 ml) and MeOH (10 ml) was added with LiOH-H ₂ O (33 mg, 1.39 mmol). The resulting mixture was heated to 40°C and then stirred for 2 days. After cooling to room temperature, the reaction mixture was concentrated to give 5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3(piperidin-1-yl)cyclobutyl)indoline-6- yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2methylbenzoic acid, which was used in the next step without further purification.

The following compounds were prepared by a similar procedure with the following modifications:

NaOH was used instead of LiOH; and/or methyl-5 -((6-(1 '-acetyl-2-oxo-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[indoline-3,4' piperidin]-6-yl)-3-isopropyl-3n-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate was used instead of methyl 5 -((6-(3,3 -dimethyl-2-oxo-1-((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl-3n-imidazo[4,5-c]pyridin- 4-yl)amino)-2-methylbenzoate; and/or methyl-5 -((6-(1 '-acetyl-1-((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2oxospiro[indoline-3,4 '-piperidin]-6-yl)-3-isopropyl-3n-imidazo[4,5-c]pyridin-4-yl)oxy)-2methylbenzoate was used instead of methyl 5-((6-(3,3-dimethyl -2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3n-imidazo[4,5-c]pyridin-4-yl) amino)-2-methylbenzoate;

and/or methyl-5 -((6-(3,3-dimethyl-2-oxo-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)- 3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoate was used instead of methyl 5-((6(3,3-dimethyl-2-oxo-1 -( (1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoate:

5-((6-(1'-acetyl-2-oxo-1-((1 s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-6yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic acid

5-((6-(1'-acetyl-1 -((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'- 263 045798 piperidin]-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoic acid

5-((6-(3,3-dimethyl-2-oxo-1-((1 s,3s)-3-(nunepuguH-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo [4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic acid.

B. Preparation of 5-((6-(3,3-dimethyl-2-oxo-1 -((1 s,3s)-3-(nunepuguH-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide (Example 174).

To a stirred solution of 5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic acid (1.45 g, 2.4 mmol) in DMF (5 ml) was added 1-(fluoromethyl)cyclopropan-1-amine hydrochloride (300 mg, 2.4 mmol), HATU (1.8 g, 4.7 mmol) and DIEA (2.5 ml, 14.4 mmol). The resulting mixture was stirred until the starting material was sufficiently consumed. The reaction solution was quenched with water, and the aqueous layer was extracted with EtOAc. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by reverse phase chromatography (ACN/water) to give 5-((6-(3,3-dimethyl-2-oxo-1-((1S, 3s)-3-(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(fluoromethyl) cyclopropyl)-2-methylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications:

5-((6-(3,3-dimethyl-2-oxo-1-((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo [4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid was used instead of 5-((6(3,3-dimethyl-2-oxo-1 -((1 s, 3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzoic acid; or

5-((6-(1 -acetyl-2'-oxo-1'-((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[azetidine-3,3'-indoline]- 6yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid was used instead of 5-((6-(3,3-dimethyl-2 -oxo-1 -((1 S,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl) amino)-2-methylbenzoic acid; or

5-((6-(1'-acetyl-2-oxo-1-((1 s,3s)-3-(piperidin-1-yl)cyclobutyl)spiro[indoline-3,4'-piperidine]-6yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic acid was used instead of 5-((6-(3,3-dimethyl-2-oxo- 1 -((1 s,3s)-3 -(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-2 -methylbenzoic acid; or

5-((6-(1'-acetyl-1-((1 s,3s)-3-(3,3-dimethylpyrrolidin-1 -yl)cyclobutyl)-2-oxospiro[indoline-3,4'piperidine] -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoic acid was used instead of 5-((6-(3,3-dimethyl-2- oxo-1 -((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino )-2-methylbenzoic acid; or

5-((6-(3,3-dimethyl-2-oxo-1-((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3Nimidazo [4,5-c]pyridin-4-yl)amino)-2,4-difluorobenzoic acid was used instead of 5-((6-(3,3dimethyl-2-oxo-1-((1s,3s)-3 -(piperidin-1-yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2-methylbenzoic acid; And

Instead of 1-(fluoromethyl)cyclopropane-1-amine hydrochloride, commercially available amines such as methylamine, ethylamine and isopropylamine were used:

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Structure Example No. ό fQQ • A, χΝΗ 0 Η 175 ά fQQ • AsxNH ό Χφ Η 176 0==^ Ns νΑΑ^χ-Ν A _F ΝγΑ/ * AsxNH /~— 0 Η 177 ο 9 ν ^Η **Α\ II /^ JJ \ Л/ ζΑ \^”ζ ⁴ ° ^>=\ ? A 178

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Procedure 27. Preparation of compounds of formula (8) according to reaction scheme I.

A. Preparation of 5-amino-4-fluoro-N-(1-(methoxymethyl)cyclopropyl)-2-methylbenzamide.

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To a mixture of 5-amino-4-fluoro-2-methylbenzoic acid (200.0 mg, 1.2 mmol), 1(methoxymethyl)cyclopropan-1-amine (235.4 mg, 2.4 mmol) and DIPEA (1 .0 ml, 5.9 mmol) T3P (1.4 ml, 2.4 mmol) was added. After stirring at room temperature for 48 hours, the reaction was quenched with water and the organic layers were extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to give 5-amino-4-fluoro-K-(1-(methoxymethyl)cyclopropyl)-2methylbenzamide, which was used in the next step without purification.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used in place of 1-(methoxymethyl)cyclopropan-1-amine; and/or the following benzoic acids were used instead of 5-amino-4-fluoro-2-methylbenzoic acid:

isopropylamine and 5-amino-2-methylbenzoic acid were used to prepare 5-aminoK-isopropyl-2-methylbenzamide.

(R)-butan-2-amine methylbenzamide.

(S)-butan-2-amine methylbenzamide was used.

used

for getting

for getting

(R)-5-amino-N-(sec-bugyl)-4-fluoro-2(S)-5-amino-N-(sec-butyl)-4-fluoro-22-methoxyethane-1-amine was used methylbenzamide.

for getting

5-amino-4-fluoro-K-(2-methoxyethyl)-2- 267 045798 nh ₂

Cyclopropanamine was used to prepare 5-amino-M-cyclopropyl-4-fluoro-2methylbenzamide.

N.H.

A

NH ₂

N.H.

Isopropylamine and 5-amino-2-chloro-4-fluorobenzoic acid were used to prepare 5-amino-2-chloro-4-fluoro-M-isopropylbenzamide.

NH ₂

O NH

Cyclopropylamine and 5-amino-2-methylbenzoic acid were used to prepare 5amino-M-cyclopropyl-2-methylbenzamide.

NH ₂

About NH

I

Methylamine and 5-amino-2,3-dimethylbenzoic acid were used to prepare 5-aminoH,2,3-trimethylbenzamide.

NH ₂

O NH I

Methylamine and 5-amino-2-chloro-4-fluorobenzoic acid were used to prepare 5-aminoH,2,3-trimethylbenzamide.

B. Preparation of 3-amino-4-fluoro-M-methylbenzamide. F

NH ₂

N.H.

To a mixture of 3-amino-4-fluorobenzoic acid (100.0 mg, 0.7 mmol) and TEA (0.2 ml, 1.4 mmol) in DMF (2 ml) was added HATU (367.67 mg, 0 mol ), followed by methylamine in 1 M THF (1.9 mL, 1.9 mmol). After stirring at room temperature overnight, the reaction was quenched with water and the organic layers were extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na ₂ SO4) and concentrated to give 3-amino-4-fluoro-M-methylbenzamide, which was used in the next step without purification.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used instead of methylamine; and/or the following benzoic acids were used instead of 3-amino-4-fluorobenzoic acid:

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isopropylamine and 5-amino-4-fluoro-2-methylbenzoic acid were used to prepare 5-amino-4-fluoro-K-isopropyl-2-methylbenzamide.

1-(fluoromethyl)cyclopropan-1-amine and 5-amino-4-fluoro-2-methylbenzoic acid were used to prepare 5-amino-4-fluoro-K-(1-(fluoromethyl)cyclopropyl)-2-methylbenzamide.

Ethylamine and 5-amino-2-methylbenzoic acid were used to prepare 5-amino-K-ethyl2-methylbenzamide.

Oxetan-3-amine and 5-amino-2-methylbenzoic acid were used to prepare 5-amino2-methyl-K-(oxetan-3-yl)benzamide.

2-Aminoethan-1-ol and 5-amino-2-methylbenzoic acid were used to prepare 5-amino-K-(2-hydroxyethyl)-2-methylbenzamide.

2-methoxyethane-1-amine and 5-amino-2-methylbenzoic acid were used to prepare 5-amino-K-(2-methoxyethyl)-2-methylbenzamide.

Procedure 28. Preparation of compounds of formula I according to reaction scheme III.

A. Preparation of 5-bromo-K-isopropyl-2-methylbenzamide.

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DIPEA (1 .01 ml, 5.81 mmol). The reaction mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, the resulting precipitate was separated by filtration and washed with a 1 N solution. HC1 to obtain b-bromo-Nisopropyl-2-methylbenzamide.

The following compounds were prepared by a similar procedure with the following modifications: the following amines were used instead of isopropylamine; and/or the following benzoic acids were used instead of 5-amino-2-methylbenzoic acid

O^NH

Ethylamine was used to prepare 5-bromo-M-ethyl-2-methylbenzamide.

Isobutylamine was used to prepare 5-bromo-M-isobutyl-2-methylbenzamide

2-methoxyethane-1-amine was used to prepare 5-bromo-M-(2-methoxyethyl)-2-methylbenzamide

Methylamine and 5-bromo-2-(trifluoromethoxy)benzoic acid were used to prepare 5bromo-M-methyl-2-(trifluoromethoxy)benzamide.

Methylamine and 5-bromo-2-(trifluoromethyl)benzoic acid were used to prepare 5bromo-M-methyl-2-(trifluoromethyl)benzamide.

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Methylamine and 5-bromo-2-cyclopropylbenzoic acid were used to prepare 5-bromo2-cyclopropyl-K-methylbenzamide.

Methylamine and 5-bromo-2-ethylbenzoic acid were used to prepare 5-bromo-2-ethyl-Kmethylbenzamide.

5-bromo-4-fluoro-2-methylbenzoic acid was used to prepare 5-bromo-4-fluoro-kisopropyl-2-methylbenzamide.

Ethylamine and 5-bromo-4-fluoro-2-methylbenzoic acid were used to prepare 5-bromo-Cethyl-4-fluoro-2-methylbenzamide.

1-(difluoromethyl)cyclopropan-1-amine and 5-bromo-3,4-difluoro-2-methylbenzoic acid were used to prepare 5-bromo-K-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro- 2-methylbenzamide

Procedure 29. Preparation of compounds of formula (26) according to reaction scheme VII.

A. Preparation of (1 s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1 -yl)-1 -(piperidin-1 -yl)cyclobutan-1 carbonitrile.

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Piperidine (2.1 ml, 20.8 mmol) and TMS-CN (1.0 ml, 8.3 mmol) at 0°C. The reaction mixture was warmed to room temperature and then stirred for another 15 hours. The reaction mixture was concentrated, the residue was redissolved in EtOAc and the organic layer was washed with saturated NaHCO ₃ solution, water, then brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (hexanes/EtOAc) to give (1s,3s)-3-(6-bromo-3,3-dimethyl-2oxoindolin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

B. Preparation of 6-bromo-3,3-dimethyl-1 -((1 s,3s)-3 -methyl-3-(piperidin-1 -yl)cyclobutyl)indolin-2-one.

To a stirred solution of (1S,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1yl)cyclobutan-1-carbonitrile (300 mg 0.75 mmol ) in THF (10 ml) was added 1.0 M MeMgBr (2.2 ml, 2.24 mmol, THF) at 0°C. The resulting mixture was allowed to warm to room temperature and then stirred for an additional 15 hours. The reaction mixture was quenched with saturated NH4Cl solution and the aqueous layer was extracted with EtOAC. The combined organic layer was washed with brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (hexanes/EtOAc) to give 6-bromo-3,3dimethyl-1-((1s,3s)-3-methyl-3- (piperidin-1-yl)cyclobutyl)indolin-2-one.

Procedure 30. Preparation of compounds of formula (23) according to reaction scheme VII.

A. Preparation of (4-((3-carbamoyl-4-methylphenyl)amino)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6yl)boronic acid.

To a stirred solution of 5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2methylbenzamide (200 mg, 0.52 mmol) in dioxane (20 ml) bis(pinacolato)diboron (263 mg, 1.0 mmol), KOAc (102 mg, 1.0 mmol) and Pd(dppf)Cl ₂ DCM (42 mg, 0.052 mmol) were added. The resulting suspension was degassed by bubbling argon gas (2 min), sealed and then heated at

- 272 045798

90°C for 15 hours. The reaction mixture was cooled to room temperature, filtered and concentrated to give (4-((3-carbamoyl-4-methylphenyl)amino)-3-cyclopropyl-3H-imidazo[4,5c]pyridin- 6-yl)boronic acid, which was used in the next step without further purification.

Procedure 31. Preparation of compounds of formula I according to reaction scheme VII.

A. Preparation of 5-((3-cyclopropyl-6-(3,3-dimethyl-1 -((1 s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2oxoindoline-6- yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide (Example 183).

To a solution of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one (40 mg, 0.026 mmol) in DME (3 ml) added Pd(PPh ₃ ) ₄ (2.0 mg, 0.002 mmol), 2M Na ₂ CO ₃ (0.06 ml, 0.12 mmol) and (4-((3-carbamoyl-4-methylphenyl )amino)-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6yl)boronic acid (18 mg, 0.051 mmol). The resulting suspension was degassed by bubbling with argon gas, sealed, and then heated to 120°C for 30 min. The reaction mixture was cooled to room temperature, then diluted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (Hex/EtOAc) to give 5-((3cyclopropyl-6-(3,3-dimethyl-1-((1s,3s) -3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide.

The following compound was prepared by a similar procedure, except that 6bromo-3,3-difluoro-1-((1S,3s)-3-(piperidin-1-yl)cyclobutyl)indolin-2-one was used instead of 6bromo -3,3-dimethyl-1-((1 S,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)indolin-2-one:

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Procedure 32. Preparation of the compounds of formula (13) shown in Reaction Scheme I.

A. Preparation of tert-butyl-3-((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1-carboxylate.

To a stirred solution of 1-(tert-butyl)3-methylazetidine-1,3-dicarboxylate (12.5 g, 58.1 mmol, commercially available) and 2-bromo-5-chloroaniline (10 g, 48.4 mmol) in DCM (200 ml) was added trimethylaluminum (2.0 M in toluene, 34 ml, 68 mmol) at 0°C. The resulting mixture was heated at 40°C overnight. After the starting material was consumed, the reaction mixture was cooled to 0°C and then quenched with water. The aqueous layer was extracted with DCM and the combined organic layer was dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (hexane/EtOAc) to give tert-butyl-3((2-bromo-5-chlorophenyl)carbamoyl)azetidine-1- carboxylate.

B. Preparation of tert-butyl 3-((2-bromo-5-chlorophenyl)(4-methoxybenzyl)carbamoyl)azetidine-1carboxylate.

K ₂ CO 3 (10.6 _g , 77 mmol) and PMBcl (3.83 ml, 28.2 mmol) at room temperature. The resulting mixture was heated to 85°C and stirred overnight. The resulting suspension was then cooled and filtered. The filtrate was concentrated and purified by flash chromatography (hexane/EtOAc) to give tert-butyl 3-((2-bromo-5-chlorophenyl)(4methoxybenzyl)carbamoyl)azetidine-1-carboxylate.

C. Preparation of tert-butyl-6'-chloro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]1-carboxylate.

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PCy ₃ ( 0.165 g, 0.588 mmol), Pd(OAc) ₂ (0.132 g, 0.588 mmol) and sodium tert-butoxide (3.39 g, 35.3 mmol) at room temperature. The resulting mixture was degassed by bubbling argon gas for 3 min. The reaction vessel was sealed and heated at 80°C for 15 minutes. After cooling to room temperature, the reaction mixture was quenched with a saturated solution of NH ₄ Cl. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₃ and concentrated to give tert-butyl 6'-chloro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'-indoline]-1-carboxylate, which was used in the next step without further purification.

D. Preparation of 6'-chloro-1'-(4-methoxybenzyl)spiro[azetidin-3,3'-indolin]-2'-one.

To a stirred solution of tert-butyl-6'-chloro-1'-(4-methoxybenzyl)-2'-oxospiro[azetidine-3,3'indoline]-1-carboxylate (5.05 g, 11.8 mmol) in methanol (50 ml) was added 4 M HCl in dioxane (14.7 ml, 58.9 mmol). The reaction mixture was stirred overnight and then concentrated. The resulting residue was redissolved in a minimal amount of DCM and then added to stirred Et2O. The suspension was stirred for a further 30 min, filtered, washed with Et2O and dried to give 6'chloro-1'-(4-methoxybenzyl)spiro[azetidin-3,3'-indolin]-2'-one.

E. Preparation of 1-acetyl-6'-chloro-1'-(4-methoxybenzyl)spiro[azetidine-3,3'-indolin]-2'-one.

To a stirred solution of 6'-chloro-1'-(4-methoxybenzyl)spiro[azetidine-3,3'-indolin]-2'-one (2.23 g, 6.11 mmol) in DCM (20 ml) was added acetic anhydride (0.866 ml, 9.16 mmol) and triethylamine (8.51 ml, 61.1 mmol) at room temperature. After 10 min, the reaction mixture was concentrated and

- 275 045798 was purified by flash chromatography to give 1-acetyl-6'-chloro-1'-(4-methoxybenzyl)spiro[azetidin-3,3'indolin]-2'-one.

F. Preparation of 1-acetyl-6'-chlorospiro[azetidine-3,3'-indolin]-2'-one.

To a stirred solution of 1-acetyl-6'-chloro-1'-(4-methoxybenzyl)spiro[azetidine-3,3'-indolin]2'-one (0.7 g, 1.89 mmol) in DCM (10 ml) TfOH (0.835 ml, 9.44 mmol) and TFA (7.22 ml, 94.4 mmol) were added at room temperature. The reaction mixture was stirred overnight and then concentrated. The residue was dissolved in EtOAc. The organic layer was washed with saturated NaHCO ₃ solution and brine, dried over Na ₂ SO ₄ , concentrated and purified by flash chromatography (DCM/MeOH) to give 1-acetyl-6'-chlorospiro[azetidine-3,3'-indoline]-2 '-she.

G. Preparation of 1-acetyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidin-3,3'indolin]-2'-one.

Bis(pinacolato)diboron (1.06 g) was added to a stirred solution of 1-acetyl-6'-chlorospiro[azetidine-3,3'-indolin]-2'-one (0.35 g, 1.4 mmol) in dioxane , 4.19 mmol), potassium acetate (0.411 g, 4.19 mmol), Pd ₂ dba ₃ (77 mg, 0.084 mmol) and xantphos (100 mg, 0.209 mmol). The resulting suspension was degassed by bubbling argon gas for 5 min. The reaction vessel was sealed and then heated at 100°C overnight. After cooling to room temperature, the reaction mixture was concentrated to give 1-acetyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidin-3,3'-indoline ]-2'-one, which was used in the next step without further purification.

H. Preparation of 1-acetyl-1'-(3-oxocyclobutyl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[azetidine-3,3'-indoline ] -2'-she.

To a stirred solution of 1-acetyl-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[azetidin-3,3'-indolin]-2'-one (0.478 g , 1.4 mmol) to NMP (5 ml) was added bromocyclobutanone (0.495 ml, 5.58 mmol) and K2CO3 (0.964 g, 6.68 mmol) at room temperature. The resulting mixture was heated to 50°C and stirred overnight. When all the starting material had been consumed, the reaction mixture was cooled to room temperature and then filtered. The filtrate was diluted with EtOAc. The organic layer was washed with water, then brine, dried over Na ₂ SO ₄ and concentrated to give 1-acetyl-1'-(3oxocyclobutyl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)spiro[azetidin-3,3'-indolin]-2'-one, which was used in the next step without further purification.

I. Preparation of 1-acetyl-1'-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6'-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -yl)spiro[azetidine-3,3'-indolin]-2-one.

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To a solution of 1-acetyl-1'-(3-oxocyclobutyl)-6'-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)spiro[azetidine-3,3'-indoline] -2'-one (1 g, 2.44 mmol) and piperidine (0.96 ml, 9.75 mmol) in DCM (10 ml) added acetic acid, ACS reagent (0.88 ml, 14.62 mmol) and sodium triacetoxyborohydride (1.55 g, 7.31 mmol). After stirring the mixture for 2 hours at room temperature, the mixture was quenched with saturated NaHCO ₃ solution and extracted with DCM. The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated to give 1-acetyl-1'-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-6'-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)spiro[azetidin-3,3'-indolin]-2'-one, which was used in the next step without further purification.

Procedure 33. Preparation of compounds of formula (27) according to reaction scheme VI.

A. Preparation of 5-((6-(1 -acetyl-2'-oxo-1'-((1 s,3s)-3-(piperidin-1 -yl)cyclobutyl)spiro[azetidine-3,3'indoline ]-6'-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid.

To a mixture of 1 -acetyl-1'-((1s,3s)-3 -(piperidin-1 -yl)cyclobutyl)-6'-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2- yl)spiro[azetidin-3,3'-indolin]-2'-one (0.5 g, 1.04 mmol), 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c] pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid (0.25 g, 0.63 mmol) and Pd(PPh ₃ ) ₄ (120.51 mg, 0.1 mmol) were added in a sealed tube 2M Na ₂ CO ₃ (3.65 ml) and DME (10 ml). The mixture was heated at 90°C for 1 hour, then the mixture was diluted with EtOAc and water. Citric acid was added to the resulting mixture to adjust the pH to approximately 6. The organic layers were extracted with DCM and the combined organic layers were concentrated and purified by flash chromatography (100% DCM to 100% MeOH) to give 5-((6-(1 -acetyl-2'-oxo-1'-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[azetidine-3,3'-indolin]-6'-yl)-3-isopropyl-3H -imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro-2-methylbenzoic acid.

Procedure 34. Preparation of the compounds of formula (9) shown in Reaction Scheme I.

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To a mixture of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (150 mg, 0.58 mmol) and methyl 5hydroxy-2-methylbenzoate in DMF (3 ml) was added cesium carbonate (568 mg, 1.7 mmol). After stirring for 1 hour at 100°C, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase HPLC to give methyl 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate.

The following compound was prepared by a similar procedure, except that 6bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine and potassium carbonate were used instead of 6bromo-4-fluoro-3-isopropyl- 3H-imidazo[4,5-c]pyridine and cesium carbonate, respectively:

Methyl 5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzoate.

The following compound was prepared using a similar procedure, except that 6bromo-3-cyclopropyl-4-fluoro-3H-imidazo[4,5-c]pyridine, 5-hydroxy-2-methylbenzamide and potassium carbonate were used instead of 6-bromo -4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine, methyl 5-hydroxy-2methylbenzoate and cesium carbonate, respectively:

5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2-methylbenzamide.

B. Preparation of 5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)2-methylbenzoic acid.

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Methyl 5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2methylbenzoate (784.4 mg, 2.0 mmol) and hydroxide were placed in the vial lithium (818 mg, 20 mmol) in THF (10 ml)/water (5 ml). The mixture was heated at 60°C for 16 hours, cooled to room temperature, concentrated and used in the next step without purification.

C. Preparation of 5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2dimethylbenzamide.

5-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)-2methylbenzoic acid (769 mg, 2.0 mmol), methylamine hydrochloride (668 mg, 9.9 mmol), diethylisopropylamine (4.2 ml, 24 mmol) and HATU (3774 mg, 9.9 mmol) in ACN (20 ml). The mixture was stirred at room temperature for 1 hour. The mixture was then quenched with water and extracted with EtOAc. The combined organic layers were washed with brine, dried, concentrated and purified by flash chromatography (100% hexane to 100% EtOAc, then 100% DCM to 100% MeOH) to give 5-((6-bromo-3-cyclopropyl3H-imidazo[ 4,5-c]pyridin-4-yl)oxy)-N,2-dimethylbenzamide.

Procedure 35. Preparation of compounds of formula (13) according to reaction scheme I.

A. Preparation of 3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2 -yl)indoline.

3,3-dimethyl-1-((1S,3s)-3-(piperidin-1-yl)cyclobutyl)-6(4,4,5,5-tetramethyl-1,3,2) was placed in a 20 ml bottle -dioxaborolan-2-yl)indolin-2-one (490 mg, 1.15 mmol) in toluene (5 ml). To this mixture was added 60 wt.% Red-Al in toluene (563.25 μl, 2.89 mmol). The mixture was heated at 85°C for 2 hours and then quenched with sat. _NaHCO3 . Na ₂ SO ₄ was added to this mixture, the mixture was stirred at room temperature for 1 hour and then filtered. The filtrate was concentrated and used in the next step without further purification.

Procedure 36. Preparation of compounds of formula (13) according to reaction scheme I.

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A. Preparation of 1-((1s,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indoline -2-she.

To a stirred solution of 3,3-dimethyl-1-(3-oxocyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indolin-2-one (10 g, 28 .1 mmol), diphenylmethanamine (9.7 ml, 56.3 mmol) and acetic acid (4.87 ml, 84.5 mmol) in DCE (100 ml) was added NaBH(OAc) ₃ (8.9 g, 42 .2 mmol). The resulting suspension was stirred overnight, then quenched with sat. _NaHCO3 . The mixture was filtered and then the aqueous layer was extracted with DCM. The combined organic layer was dried over Na ₂ SO ₄ , filtered, then concentrated to give 1-((1s,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)indolin-2-one, which was used in the next step without further purification.

B. Preparation of 1-((1s,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indolin-2- she.

_H2N

To a solution of 1-((1S,3s)-3-(benzhydrylamino)cyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indolin- 2-one (23.2 g) in MeOH (30 ml) Pd/C (10% w/w, 3.0 g, 2.8 mmol) was added to the Parr flask. The flask was then attached to a Parr shaker, charged with H2 (40 psi) and shaken overnight. The resulting suspension was filtered through celite and then concentrated to give the crude product. The residue was redissolved in Et ₂ O (200 ml) and 4 N was added slowly. HCl (dioxane, 28.2 ml, 112.6 mmol) at 0°C with stirring. After 30 minutes, the residue was filtered and dried to give 1-((1S,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2- yl)indolin-2-one.

C. Preparation of N-((1s,3s)-3-(3,3-dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)indoline) -1 -yl)cyclobutyl)pivalamide.

To a solution of 1-((1s,3s)-3-aminocyclobutyl)-3,3-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)indolin-2-one (2.9 g, 6.9 mmol) and triethylamine (4.8 mL, 34.6 mmol) in DCM (70 mL) were added dropwise with pivaloyl chloride over 10 min. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then loaded onto a silica gel column and purified (100% hexane to 60% EtOAc in hexane) to give N-((1s,3s)-3-(3,3 -dimethyl-2-oxo-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)indolin-1-yl)cyclobutyl)pivalamide.

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Procedure 37. Preparation of compounds of formula (14) according to reaction schemes II and IV.

A. Preparation of 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)- 1'-pivaloylspiro[indoline-3,4'-piperidine]-2-one.

To a suspension of 6-(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)spiro[ indoline-3,4'-piperidin]-2-one (0.092 g, 0.16 mmol) in DCM (2 ml) was added triethylamine (0.23 ml, 1.6 mmol) followed by pivaloyl chloride (0.03 ml , 0.24 mmol). The resulting mixture was stirred at room temperature for 3 hours and then quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ) and concentrated to give 6(4-chloro-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-1-((1S, 3s)-3-(piperidin-1-yl)cyclobutyl)-1'pivaloylspiro[indolin-3,4'-piperidin]-2-one, which was used in the next step without further purification.

Procedure 38. Preparation of 5-bromo-3,4-difluoro-2-methylbenzoic acid.

To a solution of tetramethylpiperidine (2.67 ml, 15.8 mmol) in THF (10 ml) at 0°C n-butyllithium (6.60 ml, 15.2 mmol) was continuously added dropwise. The mixture was stirred for 15 minutes. The mixture was then added dropwise to a solution of 3-bromo-4,5-difluorobenzoic acid (1.50 g, 6.33 mmol) in THF (90 ml) at -78°C. The resulting reaction mixture was stirred at -78°C for 30 minutes followed by the addition of iodomethane (1.97 ml, 31.7 mmol). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 16 hours. The mixture was quenched with H ₂ O, acidified with 2M HCl and extracted with EtOAc. The combined organic layers were dried over MgSO ₄ , filtered, concentrated and used in the next step without further purification.

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Procedure 39. Preparation of 5-amino-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

F

F^X,NH ₂ аУ

O^NH vX ^F F

5-bromo-M-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (100 mg, 0.29 mmol), Pd ₂ (dba) ₃ (13 mg, 0.015 mmol) was placed in the vial. , xanthos (17 mg, 0.029 mmol), benzophenonymine (0.055 ml, 0.33 mmol) and cesium carbonate (287 mg, 0.88 mmol) in dioxane (2 ml). The mixture was degassed with argon and heated at 90°C for 18 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The resulting imine intermediate was dissolved in THF (3 ml) followed by the addition of 2 M HCl in water (1.1 ml). This mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. Ethyl acetate and sat. were added to the resulting residue. _NaHCO3 . The layers were separated and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO ₄ ), filtered, concentrated and purified by flash chromatography (0.5% NEt ₃ in DCM/MeOH) to give 5-amino-N-(1-(difluoromethyl)cyclopropyl)-3,4 -difluoro-2-methylbenzamide.

Chiral separation.

1. Separation of isomers 5-((6-(1-((1s,3s)-3 -(3 -(difluoromethyl)pyrrolidin-1 -yl)cyclobutyl)-3,3-dimethyl2-oxoindolin-6-yl)- 3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

5-((6-(1 -((1 s,3s)-3-(3-(Difluoromethyl)pyrrolidin-1 -yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6yl)-3-isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide (Example 104) was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min to produce two separate isomers:

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Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(3(difluoromethyl)pyrrole idin-1yl)cyclobutyl)-3,3 dimethyl-2oxoindolin-6-yl)-3isopropyl-3Nimidazo[4, 5c]pyridin-4yl)amino)-M,2dimethylbenzamide Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min 1st eluted peak Example 104A: 2nd eluted peak Example 104B:

2. Separation of isomers 5 -((6-( 1 -((1 s,3s)-3-(3-(difluoromethyl)piperidin-1 -yl)cyclobutyl)-3,3-dimethyl-2oxoindolin-6-yl) -3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N,2-dimethylbenzamide.

5-((6-(1-((1s,3s)-3-(3-(Difluoromethyl)nirrolidin-1-yl)cyclobutyl)-3,3-dimethyl-2-oxoindolin-6yl)-3-isopropyl- 3H-Imidazo[4,5-c]piperidin-4-yl)amino)-N,2-dimethylbenzamide (Example 105) was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min to produce two separate isomers:

Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(3(difluoromethyl)piperidin-1yl)cyclobutyl)-3,3dimethyl-2oxoindolin-6-yl)-3isopropyl-3Nimidazo[4.5c] pyridin-4yl)amino)-M,2dimethylbenzamide Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO2 at 60 ml/min 1st eluted peak Example 105A: 2nd eluted peak Example 105B:

3. Separation of isomers N-(1,1-difluoropropan-2-yl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3(piperidin-1- yl)cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2methylbenzamide.

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N-(1,1-difluoropropan-2-yl)-5 -((6-(3,3-dimethyl-2-oxo-1 -((1 s,3 s)-3 -(piperidin-1 -yl )cyclobutyl)indolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide (example 21) was separated on a CHIRALPAK IC SFC 5um 21x250 mm column 50% MeOH-NH ₃ at 60 ml/min to produce two separate isomers:

Name Separation method Peak Example No. N-(l, 1 -difluoropropan-2yl)-5-((6-(3,3-dimethyl-2oκco-l-((ls,3s)-3(piperidin-1yl)cyclobutyl)indolin-6yl)-3 -isopropyl-3Nimidazo[4,5-c]pyridin-4yl)amino)-2methylbenzamide Column CHIRALPAK IC SFC 5 µm 21x250 mm in 50% MeOH-NH ₃ at 60 ml/min 1st eluted peak Example 21A: 2nd eluting peak Example 21B:

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Procedure 40. Preparation of compounds of formula 1 according to reaction scheme VIII.

Commercially available 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-pyridin-2-one (15 g, 62 mmol) and K ₂ CO ₃ (13 g, 93 mmol) in acetonitrile (140) were placed in a round-bottom flask. ml) in a nitrogen atmosphere. 3-bromocyclobutanone (6.8 mL, 75 mmol) was then added slowly. The mixture was stirred at room temperature for 1 hour, filtered and the filtrate was concentrated. Acetonitrile was added to the resulting solid. After stirring the mixture for 30 minutes, the precipitate was filtered to obtain 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one .

The following compounds were prepared using a similar procedure.

-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo,2-Spyridin-1-yl)cyclobutan-1-one.

3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrroloAl,2-Spyridin-1-yl)cyclobutan-1-one was prepared by a similar procedure, except that 6- Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2Npyridine was used instead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6'-Bromo-1'-(3-oxocyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-2'(1Ή)-one.

- 285 045798 o—.

YzYn ji 2l ^N '^r% _Br o

6'-Bromo-1'-(3-oxocyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'(1H)one was obtained following a similar procedure, except that 6'-bromo-2,3,5,6tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'(1'H)-one was used instead of 6-bromo-3,3dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one θγ d t o

6-bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, using except that 6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro2H-pyPPROlo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl- 1H-pyrrolo[3,2b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one

6-bromo-4-(difluoromethyl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one was prepared by a similar procedure, except that 6-bromo-4-(difluoromethyl)-3 ,3-dimethylindolin-2-one was used instead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

6'-Bromo-1'-(3-oxocyclobutyl)spiro[cyclopropane-1,3'-indolin]-2'-one

6'-bromo-G-(3-oxocyclobutyl)spiro[cyclopropane-1,3'-indolin]-2'-one was prepared by a similar procedure, except that 6'-bromospiro[cyclopropane-1,3' -indolin]-2'-one was used instead of 6-bromo-3,3-dimethyl-1H-pyrrolo[3,2-b]pyridin-2-one.

B. Preparation of (1 s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)- 1 (piperidin-1-yl)cyclobutan-1-carbonitrile

6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H was placed in a round bottom flask

- 286 045798 pyrrolo[3,2-b]pyridin-2-one (20 g, 65 mmol) in acetic acid (110 ml). To this mixture were added piperidine (7.7 ml, 78 mmol) and TMS-CN (16 ml, 130 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 18 hours. The mixture was then concentrated, diluted with EtOAc and filtered. The solid was re-dissolved in DCM, washed with sat. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ) and concentrated to give (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2 -b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

The following compounds were prepared using a similar procedure.

(i) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidine1 - yl)cyclobutane-1-carbonitrile.

νΧΧ' _Βγ

X (1s,3s)-3-(6-Bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1yl) Cyclobutane-1-carbonitrile was prepared by a similar procedure, except that 3-(6-bromo3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan- 1-one was used instead of 6bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(ii) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-1-yl)-1 -morpholinocyclobutane-1-carbonitrile.

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-morpholinocyclobutan- 1-Carbonitrile was prepared by a similar procedure, except that morpholine was used instead of piperidine.

(iii) (1s,3s)-3-(6'-Bromo-2'-oxo-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]- 1'(2Ή)-yl)-1 -(piperidin-1-yl)cyclobutan-1-carbonitrile ογΎ 1 N V g

Χ· (1s,3s)-3-(6'-bromo-2'-oxo-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-1 '(2Ή)-yl)-1(piperidin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 6'-bromo-1'-(3-oxocyclobutyl)-2,3,5 ,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-2'(1Ή)-one was used instead of 6-bromo-3,3-dimethyl-1-(3-oxocyclo6util)- 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin2-one.

(iv) Preparation of (1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl )-1-(piperidin-1-yl)cyclobutan-1-carbonitrile

- 287 045798

(1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)- 1(piperidin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 6-bromo-5-fluoro-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro -2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2 -b]pyridin-2one.

C. Preparation of (1 s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)- 1 (1,4-oxazepan-4-yl)cyclobutan-1-carbonitrile.

6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)pyrrolo[3,2fpyridin-2-one (1.0 g, 3.2 mmol), 1,4-oxazepane hydrochloride was placed in a 20 ml flask (0.53 g, 3.9 mmol), Ti(OiPr) ₄ (1.9 ml, 6.5 mmol) in AcOH (5 ml). After stirring at room temperature for 5 min, the mixture was cooled to 0°C, followed by the addition of TMS-CN (0.81 ml, 6.5 mmol). The reaction mixture was warmed to room temperature and stirred for 16 hours. It was then concentrated, diluted with DCM and sat. NaHCO ₃ and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), filtered through a pad of celite, concentrated and purified by flash chromatography (100% DCM to 100% EtOAc) to give (1s,3s)-3-(6-bromo-3,3 -dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2fpyridin-1-yl)-1-(1,4-oxazepan-4-yl)cyclobutan-1-carbonitrile.

The following compounds were prepared using a similar procedure.

(i) (1s,3s)-1-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2, 3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile

(1s,3s)-1-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 6-oxa-2-azabicyclo[3.2.1] was used instead of 1,4-oxazepane hydrochloride. octane hydrochloride.

(ii) (1s,3s)-1-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2, 3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared according to a similar procedure, except that instead of 1,4-oxazepane hydrochloride, 2-oxa-5-azabicyclo[ 2.2.2]octane hydrochloride.

(iii) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(5azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile.

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5azaspiro [2.5]octan-5-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 5-azaspiro[2.5]octane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(iv) (1s,3s)-1-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3 ,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared using a similar procedure, except that 3azabicyclo[3.2.0]heptane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(v) (1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3 ,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared using a similar procedure, except that 3azabicyclo[4.1.0]heptane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(vi) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(2,2 dimethylmorpholino)cyclobutane-1-carbonitrile.

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(2 ,2dimethylmorpholino)cyclobutane-1-carbonitrile was prepared using a similar procedure, except that 2,2-dimethylmorpholine hydrochloride was used instead of 1,4oxazepane hydrochloride.

(vii) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 ((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutan-1-carbonitrile.

- 289 045798

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(( 3aR,6aS)tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that hexahydro-1H-furo[3,4- c]pyrrole hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(viii) (1s,3s)-1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2, 3-dihydro1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 8-oxa-3-azabicyclo[3.2.1] was used instead of 1,4-oxazepane hydrochloride. octane hydrochloride.

(ix) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(4-oxa-7azaspiro[2.5]octan-7-yl)cyclobutan-1-carbonitrile.

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4 -oxa-7azaspiro[2.5]octan-7-yl)cyclobutan-1-carbonitrile was prepared using a similar procedure, except that 4-oxa-7azaspiro[2.5]octane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(x) (1s,3s)-1-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2, 3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 3-oxa-8-azabicyclo[3.2.1] was used instead of 1,4-oxazepane hydrochloride. octane hydrochloride.

(xi) (1s,3s)-1-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

- 290 045798

(1s,3s)-1-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3 ,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared using a similar procedure, except that 3azabicyclo[3.1.0]hexane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(xii) (1s,3s)-1-(Azepan-1-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2- b]pyridin1 -yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(Azepan-1-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine -1yl)cyclobutane-1-carbonitrile was prepared by a similar procedure, except that azepane was used instead of 1,4-oxazepane hydrochloride.

(xiii) (1s,3s)-1-(3-Azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

(1s,3s)-1-(3-Azabicyclo[3.2.1]octan-3-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3 ,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared using a similar procedure, except that 3azabicyclo[3.2.1]octane was used instead of 1,4-oxazepane hydrochloride.

(xiv) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -((R)-3fluoropiperidin-1 -yl)cyclobutan-1-carbonitrile

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(( R)-3fluoropiperidin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that (R)-3-fluoropiperidine was used instead of 1,4-oxazepane hydrochloride.

(xv) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(4fluoropiperidin-1-yl)cyclobutan-1-carbonitrile.

- 291 045798

V,N.

0 ⁴ F (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(4fluoropiperidin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 4-fluoropiperidine was used instead of 1,4-oxazepane hydrochloride.

(xvi) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(4fluoropiperidin-1-yl)cyclobutan-1-carbonitrile.

°Х Jl A

Λ o (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1- (4fluoropiperidin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that (1R,4S)-2-azabicyclo[2.2.1]heptane hydrochloride was used instead of 1,4-oxazepane hydrochloride.

(xvii) (1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2, 3-dihydroIII-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile.

nLxN.,f °=<J[ t A (1s,3s)-1-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-(6-bromo-5-fluoro-3,3- Dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 3-azabicyclo[4.1.0] hydrochloride heptane and 6-bromo-5-fluoro-3,3-dimethyl-1-(3oxocyclo6util)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one were used instead of 1,4 hydrochloride -oxazepane and 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2one, respectively.

(xviii) (1s,3s)-3-(6-Bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- yl)-1(5-azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile.

(1s,3s)-3-(6-Bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)- 1-(5azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that 5-azaspiro[2.5]octane hydrochloride and 6-bromo-5-fluoro-3,3-dimethyl -1-(3-oxocyclobutyl)-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 1,4-oxazepane hydrochloride and 6-bromo3,3-dimethyl-1-(3- oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one, respectively.

(xix) (1s,3s)-3-(6-Bromo-4-(difluoromethyl)-3,3-dimethyl-2-oxoindolin-1-yl)-1-(piperidin-1yl)cyclobutan-1-carbonitrile.

- 292 045798

(1s,3s)-3 -(6-Bromo-4-(difluoromethyl)-3,3-dimethyl-2-oxoindolin-1 -yl)-1 -(piperidin-1 -yl)cyclobutan-1 carbonitrile was prepared using similar procedure except that 6-bromo-4(difluoromethyl)-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one was used instead of 6-bromo-3,3dimethyl-1-(3 -oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xx) (1s,3s)-3-(6'-Bromo-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)-1-(niperidin-1-yl)cyclobutan-1 carbonitrile.

(1 s,3s)-3-(6'-Bromo-2'-oxospiro[cyclopropane-1,3'-indolin]-1'-yl)-1-(piperidin-1-yl)cyclobutan-1 carbonitrile was prepared by a similar procedure, except that 6'-bromo-1'-(3oxocyclobutyl)spiro[cyclopropane-1,3'-indolin]-2'-one was used instead of 6-bromo-3,3-dimethyl- 1(3-oxocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xxi) (1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(8hydroxy-5-azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile.

(1s,3s)-3-(6-Bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8 -Hydroxy5-azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile was prepared by a similar procedure, except that the reaction was carried out with 5-azaspiro[2.5]octan-8-ol hydrochloride at 40°C instead of hydrochloride 1 ,4-oxazepane at room temperature.

D. Preparation of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 (8-fluoro-5-azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile.

3-(6-bromo-3,3-dimethyl-2-oxopyrrolo[3,2-b]pyridin-1-yl)-1-(8hydroxy-5-azaspiro[2.5]octane-5) was placed in a 25 ml flask -yl)cyclobutanecarbonitrile (0.16 g, 0.36 mmol) in DCM (2 ml). To this mixture was added (diethylamino)sulfur trifluoride (0.090 ml, 0.72 mmol) at 0°C. After heating the mixture to room temperature and stirring for 1 hour, it was quenched with sat. K ₂ CO ₃ and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (100% DCM to 100% EtOAc) to give (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo- 2,3dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-fluoro-5-azaspiro[2.5]octan-5-yl)cyclobutan-1-293 045798 carbonitrile.

E. Preparation of 6'-bromo-2,3,5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-2'(1Ή)-one.

Commercially available 6bromo-1,3-dihydropyrrolo[3,2-b]pyridin-2-one (1.0 g, 4.7 mmol) and K,K,K',K' were placed in a 250-mL one-neck round-bottom flask. -tetramethylethylenediamine (1.4 ml, 9.0 mmol) in THF (20 ml). The mixture was cooled to -78°C and a solution of nBuLi (4.7 ml, 12 mmol, 2.5 M) was added dropwise. The resulting reaction mixture was warmed to room temperature for 1 hour. The mixture was cooled to -78°C and 1-iodo-2-(2-iodoethoxy)ethane (4.59 g, 14.1 mmol) was added dropwise. The mixture was heated to room temperature for 18 hours. Then it was quenched with sat. NH ₄ Cl and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (100% hexanato 100% EtOAc) to give 6'-bromo-2,3,5,6tetrahydrospiro[pyran-4,3'-pyrrolo[ 3,2-b]pyridine]-2'(1Ή)-one.

F. Preparation of 6-bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3-(piperidin-1 -yl)cyclobutyl)-1,3-dihydro2H-pyrrolo[3,2 -b]pyridin-2-one.

D 1 νΑΑ _Βγ th o

(1s,3s)-3-(6-bromo-3,3-dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-1- yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile (5.0 g, 12 mmol) and AgOTf (5.1 g, 20 mmol) in THF (100 ml) under nitrogen. The mixture was stirred at room temperature for 10 minutes and then cooled to -78°C. MeMgBr (12 mL, 3.0 M in ether) was added dropwise to the mixture. The mixture was then immediately heated to -10°C. After stirring at -10°C for 15 minutes, the reaction mixture was quenched with sat. NH4Cl and sat. NaHCO ₃ and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (100% DCM to 100% EtOAc) to give 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl -3-(piperidin-1ul)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

The following compounds were prepared using a similar procedure.

(i) 6-Bromo-3,3-dimethyl-1 -((1s,3 s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2,3-dihydro-1H-pyrrolo[3 ,2-b]pyridine.

< D 1 o

6-Bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2,3-dihydro-1 Hpyrrolo[3,2-b ]pyridine was prepared by a similar procedure, except that (1s,3s)-3-(6-6pom3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-ul )-1-(piperidin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1 N-pyrrolo[3,2-b]pyridin-1yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(ii) 6-Bromo-1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2- b]pyridin-2-one.

- 294 045798

6-Bromo-1-((1r,3s)-3-ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2b]pyridine -2-one was prepared using a similar procedure, except that EtMgBr was used instead of MeMgBr.

(iii) 6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro2H-pyrrolo[ 3,2-b]pyridin-2-one.

6-Bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3 -(1,4-oxazepan-4-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3, 2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-III- pyrrolo[3 _r 2-b]pyridin-1-yl)-1-(1,4-oxazepan-4yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3 -dimethyl-2-oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(iv) 6'-Bromo-1'-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3' pyrrolo[3,2-b]pyridine]-2'(1'H)-one.

6'-Bromo-1'-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3'pyrrolo[3 ,2-b]pyridine]-2'(1'H)-one was prepared by a similar procedure, except that (1s,3s)-3-(6'-bromo-2'-oxo-2,3, 5,6-tetrahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-1'(2Ή)-yl)-1(piperidin-1 -yl)cyclobutan-1-carbonitrile was used instead of (1 S,3s)-3-(6-bromo-3,3-dimethyl-2-oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(piperidin-1 - yl)cyclobutane-1-carbonitrile.

(v) 1-((1s,3s)-3-(2-Oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

1-((1s,3s)-3-(2-Oxa-5-azabiclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro- 2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(2-oxa-5-azabicyclo[2.2.2]octane-5 -yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s ,3s)-3-(6-5poM-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl )cyclobutane-1carbonitrile.

(vi) 6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro2H- pyrrolo[3,2-b]pyridin-2-one.

- 295 045798

6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2HpiPPROlo[3 ,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-III -pyrrolo[3 _r 2-b]pyridin-1-yl)-1-(5-azaspiro[2.5]octan-5yl)cyclobutane-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3 ,3-dimethyl-2-oxo-2,3-dihydro1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(vii) 6-Bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3dihydro -2H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5-ul)-3-methylcyclobutyl)-3,3-dimethyl-1,3dihydro-2H- pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3- Dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(8-fluoro-5azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)- 3-(6-6pom-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1carbonitrile .

(viii) 1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H -pyrrolo[3,2-b]pyridin-2-one.

1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro2H-pyrrolo[ 3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-azabicyclo[3.2.0]heptan-3-yl)-3-(6 -bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-( 6-bromo-3,3-dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile .

(ix) 1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H -pyrrolo[3,2-b]pyridin-2-one.

1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro2H-pyrrolo[ 4,1-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)-3-(6 -bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-( 6-bromo-3,3-dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile .

- 296 045798 (x) 6-Bromo-1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3, 2-b]pyridin-2-one.

6-Bromo-1 -((1 s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2H pyrrolo[3,2-b] Pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-III-pyrrolo[3, 2-b]pyridin-1-yl)-1-(2,2-dimethylmorpholino)cyclobutan-1-carbonitrile was used instead of (1 s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo -2,3-dihydro1H-pyPPROlo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xi) 6-Bromo-3,3-dimethyl-1-((1S,3s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]nirrole-5 (3H)ul)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-3,3-dimethyl-1-((1S,3s)-3-methyl-3-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole-5(3H) ul)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1 s,3S)-3-(6-bromo -3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1ul)-1-((3aR,6aS)-tetrahydro-III-furo[3 ,4-c]pyrrol-5(3H)-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin1-yl)cyclobutan-1-carbonitrile.

(xii) 1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3 -dihydro-2H-pyrrolo[3,24e]pyridin-2-one.

1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro- 2H-pyrrolo[3,24e]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(2-oxa-3-azabicyclo[3.2.1]octan-3-yl )-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s )-3-(6-5poM-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutane -1 carbonitrile.

(xiii) 6-Bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one .

6-Bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2- 297 045798

b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3-(6-6poM-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3 ,2-b]pyridin-1-yl)-1-morpholinocyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3- Dihydro-1 H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xiv) 6-Bromo-1-((1S,3s)-3-((R)-3-fluopiperidin-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3dihydro-2H-pyrrolo [3,2-b]pyridin-2-one.

°A d 1

Λ'Ν '' ^f \A

6-Bromo-1 -((1 S,3s)-3-((R)-3-fluopiperidin-1 -yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3 ,2+]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-1-yl)-1-((R)-3-fluoropiperidin-1 yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3 ,3-dimethyl-2-oxo-2,3-dihydro1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xv) 6-Bromo-1 -((1s,3s)-3-(4-fluoropiperidin-1 -yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2 -b]pyridin-2-one.

oD D D y O F

6-Bromo-1 -((1 s,3s)-3-(4-fluopiperidin-1 -yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2+] Pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3, 2-b]pyridin-1-yl)-1-(4-fluoropiperidin-1 yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo -2,3-dihydro1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xvi) 1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3-dihydro-2H -pyrrolo[3,2-b]pyridin-2-one.

HA.

°h d d

1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro2H-pyrrolo[ 3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-azabicyclo[3.1.0]hexan-3-yl)-3-(6 -bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-( 6-bromo-3,3-dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile .

(xvii) 1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

- 298 045798

1-((18.38)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro- 2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-oxa-8-azabicyclo[3.2.1]octane-8 -yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s ,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3dihydro-1 H-pyrrolo[3,2-b]pyridin-1-yl)-1 -(piperidin-1 - yl)cyclobutane-1-carbonitrile.

(xviii) 1-((18.38)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

1-((1S,3s)-3-(6-Oxa-2-azabucyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro- 2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1 -(6-oxa-2-azabicyclo[3.2.1]octane-2 -yl)-3 -(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s ,3s)-3-(6-6pom-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl )cyclobutane-1carbonitrile.

(xix) 6-Bromo-3,3-dimethyl-1-((18,38)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1, 3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-3,3-dimethyl-1-((18,38)-3-methyl-3-(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1,3dihydro-2H -pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(4-oxa-7azaspiro[2.5]octan-7-yl)cyclobutan-1-carbonitrile was used instead of (18.38) -3-(6-bromo-3,3-dimethyl2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan- 1-carbonitrile.

(xx) 1-((18.38)-3-(Azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2b ]pyridin-2-one.

-((18,33)-3-(Azepan-1 -yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2b]pyridine-2 -one was prepared by a similar procedure, except that (1s,3s)-1-(azenan-1yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro- 1H-pyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro -1H-pyrrolo[3,2b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xxi) 1-((18.38)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl1,3-dihydro-2H -pyrrolo[3,2-b]pyridin-2-one.

- 299 045798 ^A+ _Br

1-((18.38)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro2H-pyrrolo[ 3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-azabicyclo[3.2.1]octan-3-yl)-3-(6 -bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1 s,3s)-3-( 6-bromo-3,3-dimethyl-2-oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xxii) 1-((1S,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3dimethyl-1 ,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

^o= d 1

1-((1s,3s)-3-((1R,4S)-2-Azabicyclo[2.2.1]gentan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1, 3dihydrPO-2H-pyPPROlo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3S)-1-((1R,4S)-2-azabicyclo[2.2.1 ]heptan-2-yl)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-6pom-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-( piperidin-1-yl)cyclobutan-1carbonitrile.

(xxiii) 1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-5-fluoro-3,3dimethyl-1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

^o= d X

1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-5-fluoro-3,3-dimethyl-1,3dihydro- 2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-1-(3-azabicyclo[4.1.0]heptan-3-yl)- 3-(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3,2-b]pyridin-1-yl)cyclobutan-1-carbonitrile was used instead of ( 1s,3s)-3-(6-6pom-3,3dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1- yl)cyclobutane-1carbonitrile.

(xxiv) 6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1, 3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3dihydro-2H -pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3-(6-bromo-5-fluoro-3,3-dimethyl-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(5azaspiro[2.5]octan-5-yl)cyclobutan-1-carbonitrile was used instead of (1s,3s) -3-(6-bromo-3,3-dimethyl2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan- 1-carbonitrile.

- 300 045798 (xxv) 6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro2H -pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2 -b]pyridin-2-one was prepared by a similar procedure, except that (1s,3s)-3(6-bromo-5-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro -1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1 yl)cyclobutan-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3 -dimethyl-2-oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-1-(piperidin-1-yl)cyclobutan-1-carbonitrile.

(xxvi) 6-Bromo-4-(difluoromethyl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin2-one.

6-Bromo-4-(difluoromethyl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2one was prepared by a similar procedure, except that (1s,3s)-3-(6-bromo-4-(difluoromethyl)3,3-dimethyl-2-oxoindolin-1 -yl)-1-(piperidin-1 -yl)cyclobutan-1 -carbonitrile was used instead of (1 s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridine- 1 - yl)-1-(piperidin-1 yl)cyclobutan-1-carbonitrile.

(xxvii) 6'-Bromo-1'-((1 s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)spiro[cyclopropane-1,3'-indolin] 2'-one.

6'-Bromo-1'-((1 s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)spiro[cyclopropan-1,3'-indolin]-2'-one was prepared from similar procedure except that (1s,3s)-3-(6'-6pom-2'oxospiro[cyclopropan-1,3'-indolin]-1'-yl)-1-(piperidin-1-yl )cyclobutane-1-carbonitrile was used instead of (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridinium- 1-yl)-1(piperidin-1-yl)cyclobutan-1-carbonitrile.

G. Preparation of 6-bromo-4-(hydroxymethyl)-3,3-dimethylindolin-2-one.

Methyl 6-bromo-3,3-dimethyl-2-oxoindoline 4-carboxylate (2.6 g, 8.7 mmol) in MeOH (17 mL) was placed in a 100 mL one-neck round bottom flask. NaBH ₄ (3.4 g, 88 mmol) was then added and the resulting mixture was heated at 50°C for 18 hours. The mixture was then cooled to room temperature, concentrated and diluted with DCM and water. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated and used in the next step without purification.

- 301 045798

6-bromo-4-(hydroxymethyl)3.3 N. Preparation of 6-bromo-3,3-dimethyl-2-oxoindoline-4-carbaldehyde.

a 100 ml round bottom flask was placed

To one-neck dimethylindolin-2-one (1.8 g, 6.6 mmol) in DCM (26 ml). Dess Martin periodinan (4.2 g, 10 mmol) was then added and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then extracted with DCM and the combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered, concentrated and used at the next stage without cleaning.

I. Preparation of 6-bromo-4-(difluoromethyl)-3,3-dimethylindolin-2-one.

a 100 ml round bottom flask was placed

One-necked

6-bromo-3,3-dimethyl-2-oxoindoline-4 carbaldehyde (0.8 g, 3.0 mmol) in DCM (15 ml). Deoxo-Fluor solution (1.0 g, 4.4 mmol) was added to this mixture and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then extracted with DCM and the combined organic layers were washed with brine, dried (Na2SO4), filtered, concentrated and purified by flash chromatography (100% hexane to 100% EtOAc, then 100% DCM to 100% MeOH) to give 6-bromo-4-(difluoromethyl)-3,3-dimethylindolin-2-one.

J. Preparation of tert-butyl 5-bromo-2-chloro-3,4-difluorobenzoate.

2,2,6,6-tetramethylpiperidine (10.7 mL, 63.3 mmol) in THF (300 mL) was placed in a 1000 mL round bottom one neck flask. The solution was cooled to -78°C and n-BuLi (25 mL, 63 mmol, 2.5 M in hexane) was added dropwise. The resulting reaction mixture was stirred at -78°C for 15 minutes, then a solution of 3-bromo-4,5-difluorobenzoic acid (6.00 g, 25.3 mmol) in THF (50 ml) was added dropwise at -78° WITH. The mixture was stirred at -78°C for 30 minutes, after which hexachloroethane (30.0 g, 126 mmol) in 50 ml THF was added dropwise. The mixture was warmed to room temperature and stirred for 18 hours, then quenched with H2O, concentrated, redissolved in H2O and washed with hexanes. The aqueous layer was acidified with conc. HCl. The solids were collected by filtration, dissolved in EtOAc, dried (Na ₂ SO ₄ ), concentrated and redissolved in THF (100 ml), then Boc ₂ O (12.2 g, 55.7 mmol) and DMAP (620 mg, 5.1 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The mixture was then concentrated and purified by flash column chromatography (10% EtOAc in hexanes to 25% EtOAc in hexanes) to give tert-butyl-5-bromo-2-chloro-3,4 -difluorobenzoate.

K. Preparation of 5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride.

Tert-butyl-5-bromo-2-chloro-3,4difluorobenzoate (4.75 g, 14.5 mmol), Pd ₂ (dba) ₃ (664 mg, 0.725 mmol), xanthos was placed in a 500 ml one-neck round bottom flask (839 mg, 1.45 mmol), Cs ₂ CO ₃ (7.09 g, 21.8 mmol) and BocNH ₂ (2.04 g, 17.4 mmol) in dioxane (50 ml). The reaction mixture was purged with nitrogen and stirred at 100°C for 18 hours. The mixture was then cooled to room temperature, filtered through a pad of celite, washed with DCM and concentrated. The residue was passed through a silica column (10% EtOAc in hexane to 100% EtOAc), concentrated and dissolved in dioxane (15 mL), then HCl (73.0 mL, 289 mmol, 4.0 M in dioxane) was added. The resulting mixture was stirred at 55°C for 5 hours, then cooled to 0°C and the resulting precipitate was collected

- 302 045798 by filtration to obtain 5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride. This compound was used without further purification.

L. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid.

5-Amino-2-chloro-3,4-difluorobenzoic acid hydrochloride (4.10 g, 16.8 mmol) in DMF (17 mL) was placed in a 250 mL one-neck round-bottom flask equipped with a reflux condenser. The mixture was cooled to 0°C and NaH (2.67 g, 67.2 mmol, 60% dispersion in mineral oil) was added. The resulting mixture was stirred at 0°C for 5 min followed by the addition of 6-bromo-4chloro-3-isopropyl-3H-imidazo[4,5-c]pyridine (5.07 g, 18.5 mmol). After stirring the reaction mixture at 60°C for 30 minutes, it was cooled to room temperature and quenched with an aqueous solution of citric acid. The precipitates were collected by filtration, washed with H ₂ O and dried in vacuo to give 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4 -difluorobenzoic acid. This compound was used without further purification.

The following compounds were prepared using a similar procedure.

(i) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoic acid.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoic acid was prepared by a similar procedure, except that commercially available 5-amino-2-chloro-4-fluorobenzoic acid was used instead of 5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride.

(ii) 3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoic acid.

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoic acid was prepared by a similar procedure, except that commercially available 3- amino-4fluorobenzoic acid was used instead of 5-amino-2-chloro-3,4-difluorobenzoic acid hydrochloride.

M. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl)-3, 4-difluorobenzamide.

- 303 045798

5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid (1, 50 g, 3.37 mmol), 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (0.725 g, 5.05 mmol) and HATU (2.30 g, 6.06 mmol) in DMF (15 ml). N(iPr)2Et (2.93 mL, 16.8 mmol) was added to this mixture at room temperature, and the resulting mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature and quenched with H2O. The precipitates were collected by filtration, washed with H2O and then with Et ₂ O and dried in vacuo to give 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro -N-(1-(difluoromethyl)cyclopropyl)-3,4difluorobenzamide. This compound was used without further purification.

The following compounds were prepared using a similar procedure.

(i) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4 -fluorobenzamide.

5-((6-Bromo-3-isonropyl-3H-imudazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclonropyl)4-fluorobenzamide was obtained following a similar procedure, except that 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoic acid was used instead of 5 -((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid.

(ii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)3,4-difluoro- 2-methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4difluorobenzoic acid.

(iii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl) -2-methylbenzamide.

- 304 045798

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-I-(1-(fluoromethyl)cyclopropyl)-2- methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid and 1-(fluoromethyl)cyclopropan-1-amine hydrochloride was used instead of 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4 -difluorobenzoic acid and 1(difluoromethyl)cyclopropane-!-amine hydrochloride.

(iv) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-X-(2,2-difluoroethyl)-3,4difluoro-2- methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-X-(2,2-difluoroethyl)-3,4-difluoro-2methylbenzamide was prepared following a similar procedure, except that 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid and 2 ,2difluoroethane-1-amine was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2-chloro-3,4-difluorobenzoic acid and hydrochloride 1 -(difluoromethyl)cyclopropane-1-amine.

(v) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-X-isopropyl-2methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-X-isopropyl-2methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid and propan-2-amine were used instead of 5 -((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid and 1 -(difluoromethyl)cyclopropane-1 hydrochloride -amine.

(vi) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-X-cyclopropyl-3,4-difluoro-2methylbenzamide.

N

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-X-cyclopropyl-3,4-difluoro-2methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-305 045798 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid and cyclopropanamine were used instead 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro3,4-difluorobenzoic acid and 1-(difluoromethyl)cyclopropane-1-hydrochloride amine.

(vii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-3,4-difluoro-2methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-3,4-difluoro-2methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzoic acid and ethylamine were used instead of 5-(( 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4difluorobenzoic acid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(viii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-K-(1(trifluoromethyl )cyclopropyl)benzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-K-(1(trifluoromethyl)cyclopropyl) benzamide was prepared by a similar procedure, except that commercially available 1-(trifluoromethyl)cyclopropan-1-amine hydrochloride was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(ix) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-K-(1(fluoromethyl )cyclopropyl)benzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-K-(1(fluoromethyl)cyclopropyl) benzamide was prepared by a similar procedure, except that 1-(fluoromethyl)cyclopropan-1-amine hydrochloride was used instead of 1(difluoromethyl)cyclopropan-1-amine hydrochloride.

(x) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-K-(2,2-difluoroethyl)-3, 4difluorobenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-K-(2,2-difluoroethyl)-3,4- 306 045798 difluorobenzamide was prepared by a similar procedure, except that 2,2difluoroethane-1-amine hydrochloride was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(xi) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-X-cyclopropyl-3,4difluorobenzamide.

5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-X-cyclopropyl-3,4difluorobenzamide was prepared by a similar procedure, except that cyclopropanamine hydrochloride was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(xii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-X-ethyl-3,4difluorobenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide was prepared by a similar procedure, using except that ethylamine hydrochloride was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(xiii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-Xmethylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-Nmethylbenzamide was prepared by a similar procedure, except that methylamine hydrochloride was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(xiv) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-Chisopropylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-Nisopropylbenzamide was prepared by a similar procedure, except that instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride, isopropylamine hydrochloride was used.

(xv) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-4-fluoro-2methylbenzamide.

- 307 045798

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-(2,2-difluoroethyl)-4-fluoro-2methylbenzamide was prepared by a similar method procedure, except that 2,2difluoroethane-1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro -2methylbenzoic acid was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride and 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro -3,4-difluorobenzoic acid, respectively.

(xvi) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-ethyl-4-fluoro-2-methylbenzamide was prepared by a similar procedure, except that ethylamine hydrochloride and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzoic acid were used instead of 1-(difluoromethyl) cyclopropan-1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid, respectively.

(xvii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-M-(2,2-difluoroethyl)-4fluorobenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-M-(2,2-difluoroethyl)-4fluorobenzamide was prepared using a similar procedure except that 2,2difluoroethane-1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro -4fluorobenzoic acid was used instead of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2 -chloro-3,4-difluorobenzoic acid, respectively.

(xviii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-4fluorobenzamide.

- 308 045798

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-M-ethyl-4-fluorobenzamide was prepared using a similar procedure except that ethylamine hydrochloride and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluorobenzoic acid were used instead of 1-( difluoromethyl)cyclopropan-1-amine and 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid, respectively.

(xix) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-M-(1(fluoromethyl)cyclopropyl )benzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-M-(1(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 1-(fluoromethyl)cyclopropan-1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin4-yl)amino) -2-chloro-4-fluorobenzoic acid was used instead of 1-(difluoromethyl)cyclopropan1-amine hydrochloride and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl) amino)-2-chloro-3,4difluorobenzoic acid, respectively.

(xx) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4 -fluoro-3-methylbenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro- 3-Methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro -3-methylbenzoic acid was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid.

(xxi) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-A1-(difluoromethyl)cyclopropyl)-2,3,4-trifluorobenzamide.

- 309 045798

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-(1-(difluoromethyl)cyclopropyl)2,3,4-trifluorobenzamide was prepared following a similar procedure, except that 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic acid was used instead of 5- ((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid.

(xxii) 5 -((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-ethyl-2,3,4-trifluorobenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-ethyl-2,3,4-trifluorobenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic acid and ethylamine hydrochloride were used instead of 5-((6- bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride, respectively.

(xxiii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-(2,2-difluoroethyl)-2,3,4trifluorobenzamide.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-(2,2-difluoroethyl)-2,3,4trifluorobenzamide was prepared using a similar procedure except that 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic acid and 2,2-difluoroethane -1amine hydrochloride was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2-chloro-3,4-difluorobenzoic acid and 1-( difluoromethyl)cyclopropan-1-amine, respectively.

(xxiv) 3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamide.

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-(1-(difluoromethyl)cyclopropyl)4-fluorobenzamide was prepared by a similar procedure, using except that 3-((6-bromo-3-isopropyl- 310 045798

3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzoic acid was used instead of 5-((6-bromo3-isopropyl-3H-imidazo[4,5-c]pyridin-4- yl)amino)-2-chloro-3,4-difluorobenzoic acid.

(xxv) 3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-ethyl-4-fluorobenzamide.

N.H.

3-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-ethyl-4-fluorobenzamide was prepared by a similar procedure, except that 3- ((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)4-fluorobenzoic acid and ethylamine were used instead of 5-((6-bromo-3isopropyl-3H-imidazo[4, 5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid and 1-(difluoromethyl)cyclopropan-1-amine hydrochloride.

(xxvi) 3-Bromo-N-(1 -(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide.

3-Bromo-N-(1-(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide was prepared using a similar procedure, except that 3-bromo-4,5-difluorobenzoic acid was used instead of 5((6-bromo -3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluorobenzoic acid.

N. Preparation of 5-bromo-3,4-difluoro-2-methylbenzoic acid.

HE

2,2,6,6-tetramethylpiperidine (10.7 mL, 63.3 mmol) in THF (30 mL) was placed in a 1 L one-neck round bottom flask. The solution was cooled to 0°C under nitrogen and nBuLi (24.3 mL, 60.8 mmol, 2.5 M in hexane) was added dropwise. After stirring at 0°C for 15 minutes, the mixture was added dropwise to a stirred solution of 3-bromo-4,5-difluorobenzoic acid (6.00 g, 25.3 mmol) in THF (300 ml) at -78°C in a nitrogen atmosphere. The mixture was stirred at -78°C for 30 minutes. To this solution was added iodomethane (7.89 mL, 127 mmol) dropwise at -78°C. The resulting reaction mixture was slowly warmed to room temperature and stirred for 18 hours, then quenched with H ₂ O, acidified with 2 M HCl and extracted with EtOAc. The combined organic layers were washed with water, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 5-bromo-3,4-difluoro-2methylbenzoic acid, which was used in the subsequent reaction without further purification.

A. Preparation of tert-butyl-5-bromo-3,4-difluoro-2-methylbenzoate.

ABOUT

5-bromo-3,4-difluoro-2methylbenzoic acid (5.00 g, 19.9 mmol) and 4-(dimethylamino)pyridine (730 mg, 5.98 mmol) in DCM ( 40 ml) and tert-BuOH (40 ml). Di-tert-butyl dicarbonate (8.69 g, 39.8 mmol) was added to this mixture. After stirring the reaction mixture at room temperature for 18 hours, it was concentrated in vacuo. The resulting crude product was dissolved in EtOAc, washed with 10% aqueous citric acid and brine, dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (100% hexane to 5% EtOAc in hexane) to give tert-butyl-5- bromo-3,4-difluoro-2-methylbenzoate.

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R. Preparation of tert-butyl 5-((tert-butoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate.

Tert-butyl 5-bromo-3,4-difluoro-2-methylbenzoate (4.86 g, 15.8 mmol), tert-butylcarbamate (7.42 g, 63.3 mmol), Pd ₂ ( dba) ₃ -CHCl ₃ (724 mg, 791 µmol), xanthos (916 mg, 1.58 mmol) and Cs ₂ CO ₃ (7.73 g, 23.7 mmol) in dioxane (67 ml). The reaction mixture was purged with nitrogen and stirred at 100°C for 3 hours. It was then cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (100% hexane to 30% EtOAc in hexane) to give tert-butyl 5-((tertbutoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate.

Q. Preparation of 5-amino-3,4-difluoro-2-methylbenzoic acid.

F

Tert-butyl 5-((tert-butoxycarbonyl)amino)-3,4-difluoro-2-methylbenzoate (3.29 g, 9.58 mmol) in dioxane (20 mL) was placed in a 100 mL one-neck round bottom flask. HCl (24.0 mL, 96.0 mmol, 4M in dioxane) was added to this mixture and the resulting reaction mixture was stirred at room temperature for 18 hours. The mixture was then cooled to 0° C., the precipitates were collected by filtration and washed with cold dioxane and obtaining 5-amino-3,4-difluoro-2methylbenzoic acid hydrochloride. This compound was then used without further purification.

R. Preparation of 2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid.

F

2-chloro-4-fluoro-3-methylbenzoic acid (2.0 g, 11 mmol) in conc. sulfuric acid solution (20 ml). 69% HNO3 (0.69 ml) was added dropwise to this mixture at 0°C. The resulting mixture was warmed to room temperature and stirred for 3 hours. It was then poured into a flask containing 300 ml of ice water. The resulting precipitates were collected by filtration, washed with water and dried to obtain 2-chloro-4-fluoro-3-methyl-5-nitrobenzoic acid.

S. Preparation of 5-amino-2-chloro-4-fluoro-3-methylbenzoic acid.

F

2-chloro-4-fluoro-3-methyl-5nitrobenzoic acid (1.0 g, 4.3 mmol) and 10 wt.% Pd/C (0.22 g, 0.21 mmol) in THF (10 ml). The mixture was purged with N ₂ for 10 min, purged with H ₂ and then a balloon filled with H ₂ . HCl in dioxane (2.2 ml, 4 M) was added to this mixture. The mixture was stirred at room temperature for 16 hours, dissolved in MeOH, filtered through a pad of celite, concentrated, and resuspended in dioxane. The resulting solids were collected by filtration to give 5-amino-2-chloro-4-fluoro-3-methylbenzoic acid.

T. Preparation of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2methylbenzoic acid.

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5-Amino-3,4-difluoro-2-methylbenzoic acid hydrochloride (1.17 g, 5.23 mmol) in NMP (12 mL) was placed in a 100 mL one-neck round bottom flask equipped with a reflux condenser. The mixture was cooled to 0°C and NaH (0.837 g, 20.9 mmol, 60% dispersion in mineral oil) was added. The resulting mixture was stirred at room temperature for 15 minutes followed by the addition of 6-bromo-4-fluoro-3-isopropyl-3H-imidazo[4,5-c]pyridine (1.62 g, 6.28 mmol). This reaction mixture was stirred at 60°C for 18 hours, then cooled to room temperature and quenched with an aqueous solution of citric acid. The precipitates were collected by filtration, washed with H2O and dried in vacuo to give 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluoro-2-methylbenzoic acids. This compound was then used without further purification.

The following compounds were prepared using a similar procedure.

(i) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-3-methylbenzoic acid.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-4-fluoro-3-methylbenzoic acid was prepared by a similar procedure, using except that 5-amino-2-chloro-4-fluoro-3methylbenzoic acid was used instead of 5-amino-3,4-difluoro-2-methylbenzoic acid.

(ii) 5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic acid.

5-((6-Bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2,3,4-trifluorobenzoic acid was prepared by a similar procedure, except that 5-amino-2,3,4-trifluorobenzoic acid was used instead of 5-amino-3,4-difluoro-2-methylbenzoic acid.

U. Preparation of N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)- 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-3, 4-difluoro-2-methylbenzamide (Example 185).

6bromo-3,3-dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-1,3-dihydro- 2H-pyrrolo[3,2b]piRidin-2-one (120 mg, 0.31 mmol), bis(pinacolato)diboron (93.2 mg, 0.37 mmol), Pd(PPh ₃ ) ₄ (35.3 mg,

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0.03 mmol) and COAc (90.1 mg, 0.92 mmol). The mixture was sonicated and degassed with N ₂ , placed in a microwave reactor, heated at 150°C for 45 minutes and cooled to room temperature. 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]πpyridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-3,4-difluoro was added to this mixture -2-methylbenzamide (157 mg, 0.31 mmol) and 2M Na ₂ CO ₃ (0.31 ml). The mixture was placed in a microwave reactor, heated at 125°C for 25 min and cooled to RT. The mixture was then purified by flash chromatography (100% DCM to 100% MeOH) followed by reverse phase chromatography (0.1% TFA in water/0.1% TFA in ACN) to give N-(1(difluoromethyl)cyclopropyl )-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2oxo-2,3-dihydro-1H- pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)3,4-difluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

(i) 5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro -1Hnirrolo[3,2-b]pyridin-6-yl)-3-isopronyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1( fluoromethyl)cyclopropyl)-2-methylbenzamide (Example 186).

5-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1Hnirrolo [3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1(fluoromethyl) Cyclopropyl)-2-methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isonropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4 -difluoro-N-(1-(fluoromethyl)cyclopropyl)2-methylbenzamide was used instead of 5-((6-bromo-3-uzoproyl-3Π-umidazo|4.5-c]pyridium-4-yl)αmuno)-N( 1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(ii) N-(1-(Difluoromethyl)cyclononyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(8-fluoro-5-azacyro[2.5]octane -5yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4, 5-c]pyridin-4-yl)amino)-2-methylbenzamide (Example 187).

N-(1-(Difluoromethyl)cyclopronyl)-3,4-difluoro-5-((6-(1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octan-5yl) -3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4,5-c ]pyridin-4-yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-1-((1s,3s)-3-(8-fluoro-5-azaspiro[2.5]octane -5-yl)-3-methylcyclobutyl)-3,3dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1 ((1s,3s)-3-methyl-3-(nineridin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]niridin-2-one.

(iii) N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)3,3-dimethyl- 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3, 4-difluoro-2-methylbenzamide (example 188).

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N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)3,3-dimethyl-2-oxo -2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopronyl-3H-imidazo[4,5-c]pyridin4-yl)amino)-3,4-difluoro -2-methylbenzamide was prepared by a similar procedure, except that 6bromo-1-((1s,3s)-3-(2,2-dimethylmorpholino)-3-methylcyclobutyl)-3,3-dimethyl-1,3- Dihydro-2H-pyrrolo[3,2b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl) -1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(iv) N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3 -((3aR,6aS)- tetrahydro-1HFuPo[3,4-c]pyrrol-5(3H)-yl)cyclo6util)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3 -isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide (Example 189).

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-((3aR,6aS)-tetrahydro1H-Furo[ 3,4-c]pyrrol-5(3H)-yl)cyclo6util)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3isopropyl-3H-imidazo [4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s ,3s)-3-methyl-3-((3aR,6aS)-tetrahydro1H-Furo[3,4-c]pyrrol-5(3H)-yl)cyclo6util)-1,3-dihydro-2H-pyrrolo[3 ,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1, 3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one.

(v) 5-((6-(1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3- dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)N -(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 190).

5-((6-(1-((1s,3s)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2 -oxo2,3-dihydro-1H-nirrolo[3,2-b]niridin-6-yl)-3-isonronyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-( 1(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(6-oxa-2-azabicyclo[3.2.1] octan-2-yl)-3-methylcyclobutyl)-6-bromo-3,3dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3, 3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

Chiral separation: separation of isomers 5-((6-(1-((1s,3s)-3-(6-oxa-2-azabicyclo[3.2.1]octan-2yl)-3-methylcyclobutyl)-3,3- dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4,5-c]niridin-4-yl)amino)- N-(1-(difluoromethyl)cyclononyl)-3,4-difluoro-2-methylbenzamide.

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5-((6-(1-((18.38)-3-(6-Oxa-2-azabicyclo[3.2.1]octan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl-2 -oxo2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M- (1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min to obtain two separate isomers that were further purified by reverse phase chromatography (0.1% TPA in water/0.1% TPA in ACN):__________________________________________________________

Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(6oxa-2azabicyclo[3.2.1]octa n-2-yl)-3methylcyclobutyl)3,3-dimethyl-2-oxo2,3-dihydro -1Hpyrrolo[3,2b]pyridin-6-yl)-3isopropyl-3H- Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min 1st eluted peak Example 191 2nd eluted peak Example 192 imidazo[4,5- c]pyridine-4- yl)amino)-M-(1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide

(vi) 1-(Difluoromstyl)piclopropyl)-5-((6-(3,3-dimethyl-1-((18,38)-3-methyl-3-(4-oxa-7-azaspiro[2.5] octan-7-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin- 4-yl)amino)-3,4-difluoro-2-methylbenzamide (Example 193).

N-(l -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((18,38)-3-methyl-3-(4-oxa-7-azaspiro[2.5] octan7-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4- yl)amino)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(4-oxa-7-azaspiro[2.5]octan-7-yl)cyclobutyl)-1,3 -316045798 dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo- 3,3-dimethyl-1-((1s,3s)-3-methyl-3(piperudin-1-yl)cyclobugyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2- heα.

(vii) N-(1-(Dufluoromethyl)cyclonronyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-αsαsnuro[2.5]octane -5yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl )amino)-3,4-difluoro-2-methylbenzamide (Example 194).

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-αcniro[2.5]octan-5yl) cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino) -3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[ 2.5]octan-5-yl)cyclobutyl)-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s )-3-methyl3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(viii) N-(1-(Dufluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl- 3(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c] pyridin-4-yl)amino)-2-methylbenzamide (Example 195).

N-(1 -(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1 -((1 s,3s)-3-methyl-3( piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-nirrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin- 4-yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-( piperidin-1-yl)cyclobutyl)-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)- 3-methyl3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(ix) N-(1 -(Difluoromethyl)cyclopropyl)-3,4-difluoro-5 -((6-( 1 -((1 s,3s)-3-((R)-3 -fluoropiperidine-1 - yl)-3 methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-πpyrrolo[3,2-b]πpyridin-6-yl)-3-isopropyl-3Nimidazo[4,5- c]pyridin-4-yl)amino)-2-methylbenzamide (Example 196).

N-( 1 -(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-( 1 -((1 s,3 s)-3 -((R)-3-fluoropiperidin-1 -yl) -3 methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-πpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c] Pyridin-4-yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-1-((1S,3s)-3-((R)-3-fluoropiperidin-1-yl )-3-methylcyclobutyl)-3,3-dimethyl-1,3dihydro-2H-πpyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s ,3s)-3-methyl3-(πpiperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-πpyrrolo[3,2-b]πpyridin-2-one.

- 317 045798 (x) N-(1 -(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-( 1 -((1 s,3s)-3-((4-fluoropiperidine-1 - yl)-3methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c ]pyridin-4-yl)amino)-2-methylbenzamide (Example 197).

N-(1 -(Difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-( 1-((1s,3s)-3 -(4-fluoropiperidin-1 -yl)-3 methylcyclobutyl)-3 ,3-dimethyl-2-oxo-2,3-dihydro-1H-nirrolo[3,2-b]pyridin-6-yl)-3-isonronyl-3Nimidazo[4,5-c]pyridin-4-yl) amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-1-((1s,3s)-3-(4-fluoropiperidin-1-yl)-3-methylcyclobutyl)-3,3- dimethyl-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl3-(piperidin- 1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xi) 2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3 -(1, 4-oxazepan-4yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-nirrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin- 4-yl)amino)-3,4-difluorobenzamide (example 198).

2-Chloro-K-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1 -((1 s,3s)-3-methyl-3-(1,4-oxazepane -4yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-nirrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl )Amino)-3,4-difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepane -4-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c] pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3methyl -3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-nirrolo[3,2-b]niridin-2-one and 5-((6-bromo-3isopropyl-3H-imudazo[4 ,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xii) 2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3-morpholinocyclobutyl )-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)- 3,4-difluorobenzamide (example 199).

2-χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-2-oxo- 2,3-dihydro-1H-nirrolo[3,2-b]niridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4-difluorobenzamide was prepared following a similar procedure, except that 6-bromo-3,3- 318 045798 dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3 ,2-b]pyridin-2-one and 5-((6bromo-3-isonponyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-( difluoromethyl)cyclopropyl)-3,4difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((18,38)-3-methyl-3-(piperidin-1yl)cyclobutyl)-1,3-dihydro-2H -pyrrolo[3,2-b]niridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)αmino)-N-(1-( difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xiii) 2-chloro-N-(1-(difluoromethyl)cyclononyl)-3,4-difluoro-5-((6-(1-((1S,3s)-3-((R)-3-fluoropyrrolidine -1yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4, 5-c]pyridin-4-yl)amino)benzamide (Example 200).

2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-( 1-((1 s,3s)-3-((R)-3-fluoropyrrolidine-1 yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4,5 -c]pyridin-4-yl)amino)benzamide was prepared by a similar procedure, except that 6-bromo-1-((1s,3s)-3-((R)-3-fluoropyrrolidin-1-yl) -3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4, 5-c]pyridin-4-yl)amino)-2chloro-N-( 1 -(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1 ((1s,3s) -3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl)-3,4difluoro-2-methylbenzamide.

(xiv) 2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5 -((6-( 1-((1S,3s)-3 -((R)-3-fluoroineridine1 -yl)-3-methylcyclobugyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-πpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4, 5-c]pyridin-4-yl)amino)benzamide (Example 201).

2-ΧΛορ-Ν-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5 -((6-(1-((1s,3s)-3 -((R)-3 -fluoropiperidine-1 - yl)-3 methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]niridin-6-yl)-3-isonronyl-3Nimidazo[4,5- c]pyridin-4-yl)amino)benzamide was prepared by a similar procedure (Example 185), except that 6-bromo-1-((1S,3s)-3-((R)-3-fluoroniperidin-1 -yl)-3-methylcyclobutyl)-3,3-dimethyl-1,3-dihydro2H-pyrrolo[3,2-b]pyrudin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo [4,5-c]niridin-4-yl)amino)-2-chloro-N(1 -(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1 -( (1s,3s)-3methyl-3-(πpiperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-πpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo- 3isonronyl-3H-imudazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xv) 2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin1-yl )cyclobutyl)-2-oxo-2,3-dihydro-1H-nirrolo[3,2-b]niridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino )-4-fluorobenzamide (Example 202).

- 319 045798

2-ΧΛορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1yl)cyclobutyl )-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)- 4-fluorobenzamide was prepared by a similar procedure, except that 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-( 1-(difluoromethyl)cyclopropyl)-4fluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N(1-(difluoromethyl) cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xvi) 2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro [2.5] octan-5 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1 H-pyrrolo [3,2-b]pyridin-6-yl)-3 -isopropyl-3 Nimidazo [4,5 -c]pyridin-4-yl)amino)-3,4-difluorobenzamide (Example 203).

2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(5-azaspiro [2.5] octan5-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4- yl)amino)-3,4-difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[ 2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5 -c]pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s )-3methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H- imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xvii) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo2,3 -dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluoro-N-( 1-(trifluoromethyl)cyclopropyl)benzamide (Example 204).

2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3- dihydro1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-(1 (trifluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- 3,4-difluoro-N-(1-(trifluoromethyl)cyclopropyl)benzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin4-yl)amino)-N -(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xviii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-N- (1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 205).

- 320 045798

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]gentan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3.2-b]pyridin-6-yl)-3-isoiropyl-3H-imidazo[4,5-c]iiridin-4-yl)amino)-2-chloro-N-(1( Difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1 -((1 s,3s)-3 -(3 -azabicyclo[3.2.0]heptan-3 -yl)-3 - methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4 ,5-c]pyridin-4-yl)amino)-2-chloro-I-(1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s ,3s)-3methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-nirrolo[3,2-b]niridin-2-one and 5-((6-bromo-3isopropyl- 3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xix) N-(1 -(Difluoromethyl)cyclopropyl)-4-fluoro-5-((3-isopropyl-6-( 1'-((1 s,3s)-3-methyl-3-(piperidine-1 - yl)cyclobutyl)-2'-oxo-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-nurrolo[3,2-b]pyridin]-b'-yl) -3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-methylbenzamide (Example 206).

N-(1 -(Difluoromethyl)cyclopropyl)-4-fluoro-5-((3-isopropyl-6-( 1'-((1 s,3 s)-3 -methyl-3 -(piperidin-1 yl) cyclobutyl)-2'-oxo-1',2,2',3,5,6-hexahydrospyro[pyran-4,3'-pyrrolo[3,2-b]pyridin]-6'-yl)-3Nimidazo[ 4,5-c]pyridin-4-yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6'-bromo-1'-((1s,3s)-3-methyl-3-( piperidin-1-ul)cyclobutyl)-2,3,5,6-tetrahydro[pyran-4,3'pyrrolo[3,2-b]pyridin]-2'(1'H)-one and 5-(( 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide was used instead of 6-bromo- 3,3-dimethyl-1-((1s,3s)-3methyl-3-(πiperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]πpyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xx) 2-Chloro-N-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3 -(piperidine1- yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]niridin-6-yl)-3-isonronyl-3H-imidazo[4,5c]pyridin-4-yl) amino)-3,4-difluorobenzamide (Example 207).

2-Chloro-N-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1ul)cyclobutyl )-2-oxo-2,3-dihydro-1H-nurrolo[3,2-b]pyridin-6-yl)-3-uzonropyl-3H-umidazo[4,5c]pyridin-4-yl)amino)- 3,4-difluorobenzamide was prepared by a similar procedure (Example 185), except that 5-((6-bromo-3-isopronyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)- 2-chloro-N-(1-321 045798 (difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl )amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxi) N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3-methyl-3 -(1,4-oxazepan- 4yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl )amino)-3,4-difluoro-2-methylbenzamide (Example 208).

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan-4yl)cyclobutyl) -2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-3 ,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(1,4-oxazepan- 4-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3- methyl-3(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xxii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 209).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl) Cyclopropyl)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3 -methylcyclobutyl)-6-bromo-3,3dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1((1s ,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xxiii) 2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((3-isopropyl-6-( 1'-((1s,3 s)-3-methyl3- (piperidin)-1-yl)cyclobutyl)-2'-oxo-G,2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2b]pyridine] -6'- yl)-3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide (Example 210).

2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((3-isopropyl-6-( 1'-((1s,3 s)-3 -methyl-3 (piperidine -1-yl)cyclobutyl)-2'-oxo-1',2,2',3,5,6-hexahydrospiro[pyran-4,3'-pyrrolo[3,2-b]pyridine]-6'- yl)3H-imidazo[4,5-c]pyridin-4-yl)amino)benzamide was prepared by a similar procedure, except that 6'-bromo-1'-((1s,3s)-3-methyl- 3-(piperidin-1-yl)cyclobutyl)-2,3,5,6-tetrahydrospiro[pyran-4,3'pyrrolo[3,2-b]pyridin]-2'(1'H)-one and 5 -((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro

- 322 045798

N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1((1s,3 s)-3 -methyl-3-(piperidin-1 -yl )cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3 isopropyl-3H-imidazo[4,5-c]pyridin-4 -yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xxiv) 2-Chloro-5-((6-(3,3-dimethyl-1 -((1s,3 s)-3-methyl-3-(piperidin-1 -yl)cyclobutyl)-2-oxo- 2,3 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluoro-N -(1-(fluoromethyl)cyclopropyl)benzamide (Example 211).

2-Chloro-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3 -dihydro1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-( 1(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- 3,4-difluoro-N-(1(fluoromethyl)cyclopropyl)benzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N- (1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxv) 5-((6-(1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3-methylcyclobutyl)-3,3- dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)N -(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide (Example 212).

5-((6-( 1-((1s,3s)-3-(3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)-3 -methylcyclobutyl)-3,3-dimethyl-2 -oxo-2,3 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N- (1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3-oxa-8-azabicyclo[3.2.1] octan-8-yl)-3 -methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo- 3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide was used instead of 6-bromo-3,3- dimethyl-1((1s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5 -((6-bromo-3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xxvi) N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-( 1 -((1r,3s)-3-ethyl-3 -(piperidin-1 -yl)cyclobutyl)3,3 -dimethyl -2-oxo-2,3-dihydro-1H-pyrrolo,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-4- fluoro-2-methylbenzamide (Example 213).

- 323 045798

N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-( 1 -((1 r,3 s)-3 -ethyl-3-(piperidin-1 -yl)cyclobutyl)-3,3 -dimethyl2 -oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isonpopyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4fluoro -2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-1-((1r,3s)-3ethyl-3-(piperidin-1-yl)cyclobutyl)-3,3-dimethyl-1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo3-isonpopyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N- (1-(difluoromethyl)cyclonpopyl)-4-fluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(niperidin-1-yl)cyclobutyl) 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino) -N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxvii) N-(1-(Difluoromethyl)cycloπpoπyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(πiperidin-1yl)cyclobutyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4-difluoro- 2-methylbenzamide (example 214).

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-2,3 -dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4-difluoro-2-methylbenzamide were prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3-dihydro -1H-pyrrolo[3,2b]pyridine was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-1,3- Dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xxviii) N-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3-morpholinocyclobutyl)-2-oxo -2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isonpopyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro-2 -methylbenzamide (example 215).

N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-( 1 -((1 r,3s)-3 -ethyl-3 -(piperidin-1 -yl)cyclobutyl)-3,3dimethyl-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro- 2-Methylbenzamide was prepared by a similar procedure, except that 6-bromo3,3-dimethyl-1-((1s,3s)-3-methyl-3-morpholinocyclobutyl)-1,3-dihydro-2H-pyrrolo[3 ,2-b]pyridin-2-one and 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl )-4-fluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-(1-(difluoromethyl )cyclopropyl)-3,4-diflutop-2-methylbenzamide.

(xxix) N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)- 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-4- fluoro-2-methylbenzamide (Example 216).

- 324 045798

N-( 1 -(Difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 yl)cyclobutyl)- 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino) -4-fluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M -(1-(difluoromethyl)cyclopropyl)-4fluoro-2-methylbenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-( 1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxx) 1M-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((18,38)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)3, 4-difluoro-2-methylbenzamide (Example 217).

M-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((18,38)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2- oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imide azo[4,5-c]pyridin-4-yl)amino)-3, 4-difluoro-2methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(2,2 -difluoroethyl)-3,4-difluoro-2-methylbenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-( 1-(difluoromethyl)cyclopropyl)-3,4difluoro-2-methylbenzamide.

(xxxi) N-( 1 -(Difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 -yl )cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino )-4-fluorobenzamide (Example 218).

1M-(2,2-D iforoethyl)-5-((6-(3,3-dimethyl-1 -((1 s,3 s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -2-oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3 ,4difluoro-2-methylbenzamide was prepared by a similar procedure, except that 3-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-(1- (difluoromethyl)cyclopropyl)-4-fluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-(1(difluoromethyl) cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxxii) N-( 1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 -yl )cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4- fluoro-2-methylbenzamide (Example 219).

- 325 045798

N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 yl)cyclobutyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro- 2-Methylbenzamide was prepared by a similar procedure, except that 6-bromo3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2,3 -dihydro-1H-pyrrolo[3,2-b]pyridine and 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 -(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl) 1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino) -N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(xxxiii) 5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro1H -pyrrolo[3,2-b]pyridin-6-ul)-3-uisopropyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-Nisopropyl-2-methylbenzamide (example 220).

5-((6-(3,3-Dimethyl-1 -((1 s,3 s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N-isopropyl2-methylbenzamide was prepared following a similar procedure, except that 5-((6-bromo-3-isopropyl-3Numidazo[4,5-c]nuridin-4-yl)amino)-3,4-difluoro-N-isopropyl-2- methylbenzamide was used instead of 5-((6bromo-3-uzopronyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro- 2methylbenzamide.

(xxxiv) N-Cyclopropyl-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2oxo-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imudazo[4,5-c]pyridin-4-yl)amino)3,4-difluoro-2 -methylbenzamide (example 221).

N-Cyclopropyl-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3-methyl-3-(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3dihydro -1H-pyrrolo[3,2-b]pyrudin-6-yl)-3-isopropyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2methylbenzamide was prepared from similar procedure except that 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-N-cyclopropyl-3,4-difluoro-2-methylbenzamide was used instead of 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyrudin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro2- methylbenzamide.

(xxxv) 5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro1H -pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4difluoro-2-methylbenzamide (example 222).

- 326 045798

5-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1Hpyrrolo [3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2methylbenzamide was prepared from similar procedure except that 5-((6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-3,4-difluoro-2-methylbenzamide was used instead of 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4difluoro-2- methylbenzamide.

(xxxvi) 3-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro1H -pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4fluorobenzamide (Example 223).

3-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1Hpyrrolo [3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4fluorobenzamide was prepared by a similar procedure, except that 3-((6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide was used instead of 5-((6-bromo-3isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(xxxvii) 2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-2-oxo-1-((1 s,3s)-3-(piperidine- 1 ul)cyclobutyl)-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-ul)-3-uzopropyl-3H-imudazo[4,5-c]pyridin-4yl)amino)3 ,4-difluorobenzamide (example 245).

2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1 -((1 s,3s)-3-(piperidin-1 yl) cyclobutyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4 -difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-nirrolo [3,2-b]pyridin-2-one and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1 -(difluoromethyl)cyclopropyl)-3,4difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-1,3-dihydro -2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-( 1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xxxviii) N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4-difluoro- 2-methylbenzamide (example 246).

- 327 045798

N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-2-oxo-1-((1s,3s)-3-(piperidin-1yl)cyclobutyl)-2,3 -dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4-difluoro-2-methylbenzamide were prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1 ,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(xxxix) 6-(4-Amino-3-isonropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl- 3(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that 6-bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-amine was used instead of 5-((6bromo-3-isonropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

V. Preparation of 5-((6-(1-((1s,3s)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)-3-methylcyclobutyl)-3,3dimethyl) -2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin4-yl)amino)-N -(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 224).

6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan5-yl)cyclo6util]pyrrolo[3,2-b] was placed in a sealed tube. pyridin-2-one (150 mg, 0.36 mmol), bis(pinacolato)diboron (109 mg, 0.43 mmol), Pd(PPh ₃ ) ₄ (80.0 mg, 0.07 mmol) and COAS ( 105 mg, 1.07 mmol) in dioxane (1 ml) under nitrogen. After stirring at 140°C for 1 hour, the mixture reached room temperature. 5-[(6-bromo-3-isopropyl-imidazo[4,5-c]pyridin-4-yl)amino]-N-[1-(difluoromethyl)cyclopropyl]-3,4-difluoro- 2methylbenzamide (184 mg, 0.36 mmol) and 2M Na ₂ CO ₃ (0.89 ml, 1.78 mmol). The resulting mixture was heated at 90°C for 1 hour and then quenched with water. The mixture was extracted with EtOAc, concentrated and purified by flash chromatography (100% DCM to 100% MeOH in DCM) and reverse phase chromatography (0.1% TFA in water/0.1% TFA in ACN) to give 5- ((6-(1-((1s,3s)-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)3-methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-N-(1-( difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

- 328 045798 (i) 5-((6-(1-((1s,3s)-3-(3-Azabucyclo[4.1.0]heptan-3-ul)-3-methylcyclobutyl)-3,3-dimethyl -2-oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-uzopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2 -chloroN-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 225).

5-((6-( 1-((1s,3s)-3 -(3 -Azabicyclo[3.2.0]heptan-3 -yl)-3 -methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-usopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-( 1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1 -((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)- 3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo [4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-( (1s,3s)-3methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo- 3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(ii) 5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3-uzopropyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl )-3,4-difluorobenzamide (Example 226).

5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo [4,5-c]pyridin-4-yl)amino)-2-chloro-N-( 1 -(difluoromethyl)cyclopropyl )-3,4-difluorobenzamide was prepared by a similar procedure, except that 1((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl -1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl )amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3- (piperidin-1yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c] pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide.

(iii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ul)-3-isopropyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-2chloro-3, 4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide (example 227).

5-((6-( 1 -((1 s,3s)-3 -(3-Azabicyclo[4.1.0]heptan-3 -yl)-3 -methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro3,4- Difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 1 -((1s,3s)-3-(3-azabicyclo[3.2.0]heptane-3 -yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl -3H-imidazo[4,5-c]pyridin-4yl)amino)-2-chloro-3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide was used instead of 6-bromo-3,3dimethyl-1 -((1s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2one and 5-((6- bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)3,4-difluoro-2-methylbenzamide.

(iv) 5-((6-(1-((1s,3s)-3-(8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-3,3- dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)N -(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 228).

5-((6-( 1 -((1s,3 s)-3-(3 -Azabicyclo[3.2.0]heptan-3 -yl)-3 -methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-( 1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(8-oxa-3-azabicyclo[3.2.1]octane-3 -yl)-3-methylcyclobutyl)-6-bromo-3,3dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl -1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(v) 5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3 -isopropyl-3 H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-3 , 4-difluoro-2-methylbenzamide (Example 229).

5-((6-( 1 -((1s,3 s)-3-(3 -Azabicyclo[3.2.0]heptan-3 -yl)-3 -methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3 dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-( 1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo -3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3- methyl-3(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(vi) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.1]octan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 230).

- 330 045798

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.2.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroK-(1- (difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3-azabicyclo[3.2.1]octan-3-yl)-3- methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1-((1s ,3s)-3-methyl3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

(vii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 231).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl) Cyclopropyl)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3-azabicyclo[3.2.0]heptan-3-yl)-3 -methylcyclobutyl)-6-bromo-3,3dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-bromo-3,3-dimethyl-1((1 s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

Chiral separation: separation of isomers 5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)-3,3-dimethyl-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide (Example 231).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl) cyclopropyl)-3,4-difluoro-2-methylbenzamide was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO2 at 60 ml/min to obtain two separate isomers, which were further purified in reverse -phase chromatography (0.1% TFA in water/0.1% TFA in ACN):

- 331 045798

Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(3azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)3,3-dimethyl-2-oxo- 2,3-dihydro-1Hpyrrolo[3,2b]pyridin-6-yl)-3isopropyl-3Nimidazo[4,5c]pyridin-4- yl)amino)-M-(1 (difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min 1st eluted peak Example 232 2nd eluted peak Example 233

(viii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[3.1.0]hexan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-N- (1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 234).

5-((6-( 1-((1s,3s)-3 -(3 -Azabicyclo[3.1.0]hexan-3 -yl)-3 -methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-( 1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3-azabicyclo[3.1.0]hexan-3-yl)-3 -methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[ 4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-(( 1s,3s)-3methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

(ix) 5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4difluorobenzamide ( example 247).

5-((6-( 1-((1s,3s)-3 -(Azepan-1 -yl)-3 -methylcyclobutyl)-3,3 -dimethyl-2-oxo-2,3-dihydro-1 H- pyrrolo[3,2b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(azepan-1-yl)-3methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-ethyl -3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[ 3,2-b]pyridin2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl )3,4-difluoro-2-methylbenzamide, respectively.

- 332 045798 (x) 5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3 -dihydro-1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2, 2difluoroethyl)-3,4-difluorobenzamide (example 248).

5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-K-(2,2-difluoroethyl)-3 ,4difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(azepan-1-yl)-3methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro- 2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-K -(2,2-difluoroethyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2.2]octane- 5yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-K-( 1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xi) 5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N( 1-(fluoromethyl)cyclopropyl)benzamide (Example 249).

5-((6-(1-((1s,3s)-3-(Azepan-1-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1Hpyrrolo[3 ,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-N(1-( fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 1((1s,3s)-3-(azepan-1-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1, 3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2 -chloro-3,4-difluoro-K(1-(fluoromethyl)cyclopropyl)benzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5azabicyclo[2.2.2 ]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino )-K-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xii) 2-Chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidine-1- yl)cyclobutyl))2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4- yl)amino)3,4-difluorobenzamide (example 250).

2-chloro-N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl )-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)- 333 045798

3,4-difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobugyl)-1 ,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)- 2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2 .2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4 -yl)amino)-N-(1(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xiii) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-umidazo[4,5-c]pyridin-4-yl)amino)-2chloro-N- ethyl 3,4-difluorobenzamide (Example 251).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-ethyl-3 ,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo- 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin- 4-yl)amino)-2-chloro-N-ethyl-3,4difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5-azabicyclo[2.2. 2]octan-5yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5 -((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino) -N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

Chiral separation: Separation of isomers 5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)-3,3-dimethyl-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- N-ethyl-3,4-difluorobenzamide (Example 251).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-ethyl-3 ,4-Difluorobenzamide was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ /CO ₂ at 60 ml/min to obtain two separate isomers, which were further purified by reverse phase chromatography (0.1% TPA in water/0.1% TPA in ACN):

Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(3azabicyclo[4.1.0] heptan-3-yl)-3methylcyclobutyl)-3,3-dimethyl-2oxo-2,3-dihydro-1H -pyrrolo[3,2b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4yl)amino)-2-chloro-N-ethyl-3,4difluorobenzamide Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min 1st eluted peak 252 2nd eluting peak 253

(xiv) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo- 334 045798

2,3-dihydro-1H-nirrolo[3,2-b]niridin-6-yl)-3-isonronyl-3H-imidazo[4,5-c]niridin-4-yl)amino)-2chloro-3, 4-difluoro-N-isopropylbenzamide (Example 254).

5-((6-(1-((1 s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-ul)-3-uzopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro3,4- Difluoro-N-isopropylbenzamide was prepared by a similar procedure, except that 1((18.38)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo- 3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin- 4-yl)amino)-2-chloro3,4-difluoro-N-usopropylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5azabicyclo[2.2.2] octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino) -N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xv) 5-((6-(1-((18.38)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-5-fluoro-3,3- dimethyl-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyrudin-6-yl)-3-u-isopropyl-3H-imidazo[4,5-c]pyrudin-4-yl)amino)N -ethyl-3,4-difluoro-2-methylbenzamide (example 255).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-5-fluoro-3,3-dimethyl-2 -oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl -3,4difluoro-2-methylbenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-(3azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl))-6 -bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5 -((6-bromo-3-isopropyl-3H-imidazo[ 4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2- oxa-5-azabicyclo[2.2.2]octan-5 yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5 -c]pyridin-4yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xvi) 5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-K- (2,2-difluoroethyl)-3,4-difluorobenzamide (Example 256).

5-((6-( 1 -((1 s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo- 2,3dihydro-1H-nirrolo[3,2-b]niridin-6-yl)-3-isonronyl-3H-imidazo[4,5-c]niridin-4-yl)amino)-2-chloroN-(2 ,2-difluoroethyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that

- 335 045798

-((1 s,3s)-3 -(3-azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[ 3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]niridin-4-yl)amino)-2-chloro-N(2 ,2-difluoroethyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-[3-methyl-3-(2-oxa-5azabicyclo[2.2.2]octan-5-yl)cyclobutyl ]pyrrolo[3,2-b]pyridin-2-one and 5 -((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-N-(1-( difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

(xvii) 5 -((6-( 1 -((1 s,3s)-3 -(3 -Azabicyclo[4.1.0]heptan-3-yl)-3 -methylcyclobutyl)-3,3-dimethyl-2 -oxo2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-3 ,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide (Example 257).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isonropyl-3H-imidazo[4,5-c]niridin-4-yl)amino)-2-chloro-3,4difluoro -N-(1-(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 1-((1s,3s)-3 -(3-azabicyclo[4.1.0]heptan-3-yl)-3 -methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[ 4,5-c]pyridin-4-yl)amino)-2-chloro-3,4difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide was used instead of 6-bromo-3,3-dimethyl-1-[3 -methyl-3-(2oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl- 3Nimidazo[4,5-c]niridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide, respectively.

Chiral separation: separation of isomers 5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)-3,3-dimethyl-2- oxo-2,3-dihydro-1H-nirrolo[3,2-b]pyridin-6-yl)-3-isopronyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- 3,4-difluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide (Example 257).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]niridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro3,4-difluoro -N-(1-(fluoromethyl)cyclopropyl)benzamide was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min to obtain two separate isomers, which were further purified reverse phase chromatography (0.1% TPA in water/0.1% TPA in ACN):________________________________________________________________

Name Separation method Peak Example No. 5-((6-(1-(( Is,3s)-3-(3azabicyclo[4.1.0]hept an-3-yl)-3methylcyclobutyl)3,3-dimethyl-2-ox o- Column CHIRALPAK ΙΑ SFC 5 µm 21x250 mm in 35% MeOH (modified 1st eluted peak 258

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2,3-dihydro-1Hpyrrolo[3,2b]pyridin-6-yl)-3isopropyl-3Nimidazo[4,5c]pyridin-4yl)amino)-2-chloro-3,4difluoro-M-(1(fluoromethyl)cyclopro pyl)benzamide ohm 10 mM

NH ₃ )/CO ₂ at 60 ml/min

2nd elutable

(xviii) 5-((6-(1-((18.38)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2- oxo2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-N- (1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 260).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-(1- (difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1 -((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3- methylcyclobutyl)-6-bromo-3,3-dimethyl-1,3dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4 ,5-c]pyridin-4-yl)amino)-2chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1[3-methyl- 3-(2-oxa-5-azabicyclo[2.2.2]octan-5-yl)cyclobutyl]pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo [4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide, respectively.

Chiral separation: separation of isomers 5-((6-(1-((1s,3s)-3-(3-azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)-3,3-dimethyl-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 260).

5-((6-(1-((1s,3s)-3-(3-Azabicyclo[4.1.0]heptan-3-yl)-3-methylcyclobutyl)-3,3-dimethyl-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloroN-(1- (difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was separated on a CHIRALPAK IA SFC 5 µm 21x250 mm column in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min to obtain two separate isomers, which were further purified in reverse -phase chromatography (0.1% TFA in water/0.1% TFA in ACN):

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Name Separation method Peak Example No. 5-((6-(1-((Is,3s)-3-(3azabicyclo[4.1.0]heptan-3-yl)-3methylcyclobutyl)3,3-dimethyl-2-oxo- 2,3-dihydro-1Hpyrrolo[3,2b]pyridin-6-yl)-3isopropyl-3Nimidazo[4,5c]pyridin-4yl)amino)-2-chloro-M(1(difluoromethyl)cyclopropyl)-3, 4difluorobenzamide Column CHIRALPAK IA SFC 5 µm 21x250 mm in 35% MeOH (modified with 10 mM NH ₃ )/CO ₂ at 60 ml/min 1st eluted peak 261 2nd eluted peak 262

(ix) 6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl- 3(piperidin-1-yl)cyclobutyl)indolin-2-one.

6-(4-Amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s)-3-methyl-3(piperidine -1-yl)cyclobutyl)indolin-2-one was prepared by a similar procedure, except that 5-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-amine was used instead of -((6-bromo3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2methylbenzamide.

W. Preparation of 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one.

6-Bromo-3,3-dimethylindolin-2-one (5.0 g, 20.8 mmol) and Cs ₂ CO ₃ (20.4 g, 62.5 mmol) in NMP were placed in a 500 ml one-neck round bottom flask. (80 ml.). 3bromocyclobutan-1-one (4.7 g, 31.2 mmol) was then added dropwise under nitrogen. The mixture was stirred at room temperature for 1.5 hours, then quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography to give 6-bromo-3,3-dimethyl-1-(3-oxocyclobutyl)indolin-2-one.

X. Preparation of (1s,3s)-3 -(6-bromo-3,3-dimethyl-2-oxoindolin-1 -yl)-1 -(piperidin-1 -yl)cyclobutan-1 carbonitrile.

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6-Bromo-3,3-dimethyl-1-(3oxocyclobutyl)indolin-2-one (4.0 g, 12.9 mmol) in AcOH (22 mL) was placed in a 250 mL one-neck round bottom flask and the mixture was cooled to 0 °C. Piperidine (2.2 g, 25.9 mmol) was added dropwise followed by TMS-CN (2.9 g, 29.8 mmol) in portions. The reaction mixture was heated to room temperature and stirred for 18 hours, then concentrated, quenched with sat. NaHCO ₃ and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated. The residue was resuspended in EtOAc and stirred at room temperature for 10 minutes. The solid was collected by filtration, washed with EtOAc and dried to give (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin1-yl)-1-(piperidin-1-yl)cyclobutan-1- carbonitrile. This compound was then used without further purification.

Y. Preparation of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

Silver triflate (352.5 mg, 1.4 mmol) and (1s,3s)-3-(6-bromo-3,3-dimethyl-2-oxoindolin-1-yl)- were placed in a 250 mL single-neck round-bottom flask. 1-(piperidin-1-yl)cyclobutan-1-carbonitrile (345.0 mg, 0.9 mmol) in THF (9 ml). The mixture was stirred at room temperature for 5 minutes and cooled to -78°C. MeMgBr (1.0 mL, 3.4 mmol, 3.0 M in ether) was added dropwise to this mixture. The resulting mixture was stirred at -78°C for 45 minutes, quenched with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (100% hexane to 100% EtOAc) to give 6-bromo-3,3-dimethyl-1-((1s, 3s)-3-methyl-3-(pineridin-1-yl)cyclobutyl)indolin-2-one.

Z. Preparation of N-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3(piperidin-1-yl)cyclobutyl) -2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)4-fluoro-2-methylbenzamide (Example 235).

6-bromo-3,3-dimethyl-1-((1s,3s)-3methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one (145.0 mg) was placed in a 100 ml one-neck round bottom flask , 0.4 mmol), bispinacolato diboron (112.9 mg, 0.4 mmol), potassium acetate (109.1 mg, 1.1 mmol) and Pd(dppf)Cl ₂ -DCM adduct (42.8 mg, 0.04 mmol) in dioxane (3 ml) under nitrogen atmosphere. The mixture was stirred at 90°C for 18 hours, then cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated. To this residue was added 5-((6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2- methylbenzamide (91.0 mg, 0.2 mmol), Pd(PPh ₃ ) ₄ (21.1 mg, 0.02 mmol) and 2M Cs ₂ CO ₃ (0.46 ml, 0.9 mmol) in DME ( 2 ml) under nitrogen atmosphere. After stirring at 100°C for 2 hours, the mixture was cooled to room temperature and filtered through a celite pad. The filtrate was concentrated and purified by flash chromatography (10% NH ₄ OH/MeOH/EtOAc/hexane) followed by reverse phase chromatography (0.1% TFA in water/0.1% in ACN) to give N-(1-( difluoromethyl)cyclononyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)- 3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-4-fluoro-2-methylbenzamide.

The following compounds were prepared using a similar procedure.

(i) N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)- 2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2methylbenzamide (Example 236).

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N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-2-oxoindoline -6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2methylbenzamide was prepared by a similar procedure, except that 5-(( 6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide was used instead of 5-( (6-bromo-3-isopropyl-3H-imidazo[4,5-c]niridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(ii) N-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl )indolin)6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2methylbenzamide (Example 237).

N-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)indoline )6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6- bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3(piperidin-1-yl)cyclobutyl)indoline and 5-((6-bromo-3-isopropyl-3H-imidazo[4 ,5-c]pyridin-4-yl)amino)-N(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-2-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1((1s, 3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl) amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(iii) N-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)- 2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4fluorobenzamide (Example 238).

N-(1 -(Difluoromethyl)cyclopropyl)-3 -((6-(3,3-dimethyl-1-((1s,3 s)-3 -methyl-3 -(piperidin-1 yl)cyclobutyl)-2 -oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide was prepared by a similar procedure, except that 3-((6- bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamide was used instead of 5-((6bromo-3-isopropyl- 3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide.

(iv) 5-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) -3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide (Example 239).

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5-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl)-3 isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo -3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-I-ethyl-3,4-difluoro-2-methylbenzamide was used instead of 5-((6-bromo-3-isopropyl-3Nimidazo [4,5-c]pyridin-4-yl)amino)-H-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(v) 3 -((6-(3,3-Dimethyl-1 -((1 s,3s)-3 -methyl-3-(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) -3 - isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-H-ethyl-4-fluorobenzamide (example 240).

3-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl)-3 isopropyl -3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluorobenzamide was prepared by a similar procedure, except that 3-((6-bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-ethyl-4-fluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridine- 4yl)amino)-X-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(vi) 2-chloro-X-( 1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidine-1 yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluorobenzamide (Example 241).

2-Chloro-X-(1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1yl)cyclobutyl )-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluorobenzamide was prepared by a similar procedure, except that 5-( (6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-X-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 5- ((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-X-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(vii) 5-((6-( 1 -((1 s,3s)-3-(( 1 R,4S)-2-azabicyclo[2.2.1 ]heptan-2-yl)-3 -methylcyclobutyl)- 3,3-dimethyl)2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]niridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl )amino)-2-chloro-I-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide (Example 263).

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5-((6-(1-((1s,3s)-3-((1R,4S)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methylcyclobutyl)-3,3-dimethyl )-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)2 -chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was prepared by a similar procedure, except that 1-((1s,3s)-3-((1R,4S)-2-azabicyclo [2.2.1]heptan-2-yl)-3-methylcyclobutyl)-6bromo-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-( (6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide were used instead of 6 -bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2one and 5-((6-bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)4-fluoro-2-methylbenzamide, respectively.

(viii) 2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin1-yl )cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino )-4-fluoro-3-methylbenzamide (Example 264).

2-Χλορ-Ν-( 1 -(difluoromethyl)cyclopropyl)-5 -((6-(3,3-dimethyl-1-((1 s,3s)-3-methyl-3 -(piperidin-1 yl) cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino) -4-fluoro-3-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidine-1- yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4 -yl)amino)-2-chloro-N-(1 (difluoromethyl)cyclopropyl)-4-fluoro-3-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3methyl- 3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-( 1 -(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(ix) 2-Chloro-N-cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-3,4- difluorobenzamide (example 265).

2-Chloro-N-cyclopropyl-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2oxo-2, 3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)3,4-difluorobenzamide was prepared from similar procedure except that 6-bromo-3,3-dimethyl1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo [3,2-b]pyridin-2-one and 5-((6- 342 045798 bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- N-cyclopropyl-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3-(piperidin-1 -yl)cyclobutyl)indolin-2one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)4-fluoro-2-methylbenzamide, respectively .

(x) N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -2oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide (Example 266).

N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2oxoindolin- 6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-((6 -bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-4-fluoro-2-methylbenzamide was used instead of 5-((6-bromo -3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1 -(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide.

(xi) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluoro-N-isopropylbenzamide (example 267).

2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3- Dihydro1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-Nisopropylbenzamide was prepared in a similar manner procedure, except that 6-bromo-3,3-dimethyl1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[ 3,2-b]pyridin-2-one and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro -N-Isopropylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3-(piperidin-1 -yl)cyclobutyl)indolin-2-one and 5-( (6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4fluoro-2-methylbenzamide, respectively.

(xii) N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -2oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide (Example 268).

- 343 045798

N-(2,2-Difluoroethyl)-5 -((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2oxoindolin- 6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-( 6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-(2,2-difluoroethyl)-3,4-difluoro-2-methylbenzamide was used instead of 5-(( 6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide.

(xiii) N-(2,2-Difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1 s,3s)-3-methyl- 3-(piperidin-1yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4.5c] pyridin-4-yl)amino)-2-methylbenzamide (Example 269).

N-(2,2-Difluoroethyl)-3,4-difluoro-5 -((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidine -1ul)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ul)-3-isopropyl-3H-imidazo[4,5c]pyridin-4- yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidine- 1 -yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridine -4-yl)amino)-N-(2,2difluoroethyl)-3,4-difluoro-2-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl- 3 (piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4ul)amino)-N-( 1 - (difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xiv) 2-Chloro-N-ethyl-3,4-difluoro-5 -((6-(5 -fluoro-3,3 -dimethyl- 1-((1s,3s)-3 -methyl-3 -( 5-azaspiro[2.5]octan-5 yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]niridin-6-yl)-3-isopropyl-3H-imidazo[4 ,5c]pyridin-4-yl)amino)benzamide (Example 270).

2-Chloro-N-ethyl-3,4-difluoro-5 -((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(5-azaspiro [2.5] octane-5ul)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-ul)-3-isopropyl-3H-imidazo[4.5c] Pyridin-4-yl)amino)benzamide was prepared by a similar procedure, except that 6-bromo5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro [2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4, 5-c]pyridin-4-ul)amino)-2-chloro-N- 344 045798 ethyl-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1 s,3s)- 3-methyl-3-(piperidin-1yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino) -M-(1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xv) N-Ethyl-3,4-difluoro-5 -((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidine-1 - yl)cyclobutyl))-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl )amino)-2methylbenzamide (example 271).

N-Ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1 s,3s)-3-methyl-3-(piperidin-1 -yl) cyclobutyl))2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino )-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-5fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl) cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl )amino)-Nethyl-3,4-difluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)indolin- 2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-4-fluoro-2 -methylbenzamide, respectively.

(xvi) 2-Chloro-Al2,2-difluoroethyl)-3,4-difluoro-5 -((6-(5-fluoro-3,3-dimethyl- 1-((1s,3s)-3-methyl- 3 -(piperidin1 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo [4.5с] pyridin-4-yl)amino)benzamide (example 272).

2-Chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl- 3-(piperidin-1yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo [4.5c] Pyridin-4-yl)amino)benzamide was prepared by a similar procedure, except that 6-bromo-5fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidine-1 -yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin- 4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-M-(1 ( difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xvii) 2-Chloro-N-ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-( piperidin-1yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4- yl)amino)benzamide (example 273).

- 345 045798

2-Chloro-N-ethyl-3,4-difluoro-5 -((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidine-1 yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl) amino)benzamide was prepared by a similar procedure, except that 6-bromo-5fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -1,3-dihydro-2H-pyrrolo[3,2-b]pyridin2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino )-2-chloro-N-ethyl-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1 -((1s,3 s)-3 -methyl-3 -(piperidin-1 -yl) cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)- 4-fluoro-2methylbenzamide, respectively.

(xviii) N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) -2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)2, 3,4-trifluorobenzamide (example 274).

N-(2,2-Difluoroethyl)-5 -((6-(3,3-dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)- 2-oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2, 3,4Trifluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3 -dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N( 2,2-difluoroethyl)-2,3,4-trifluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl) indolin-2-one and 5-((6-bromo-3isopropyl-3H-imudazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro- 2methylbenzamide, respectively.

(xix) 2-Chloro-N-(2,2-difluoroethyl)-3,4-difluoro-5-((3-isopropyl-6-(1'-((1s,3s)-3-methyl-3- (piperidin-1yl)cyclobutyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)benzamide (Example 275) .

2-Χλορ-Ν-(2,2-difluoroethyl)-3,4-difluoro-5-((3-isopropyl-6-( 1'-((1s,3s)-3 -methyl-3 -(piperidin- 1 yl)cyclobutyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-6'-yl)-3H-imidazo[4,5-c]pyridin-4yl)amino)benzamide was prepared according to a similar procedure, for except that 6'-6pom-1'-((1s,3s)-3methyl-3-(piperidin-1-yl)cyclobutyl)spiro[cyclopropan-1,3'-indolin]-2'-one and 5 -((6-bromo-3 -isopropyl- 346 045798

3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(2,2-difluoroethyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl- 1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)indolin-2-one and 5 -((6bromo-3-uzopropyl-3H-imudazo[4,5-s ]pyridin-4-ul)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide, respectively.

(xx) 5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6-yl)- 3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide (Example 276).

5-((6-(3,3-Dimethyl-1 -((1 s,3 s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl)-3 isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide was prepared by a similar procedure, except that 5-((6-bromo- 3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-ethyl-4-fluoro-2-methylbenzamide was used instead of 5-((6-bromo-3-isopropyl-3Nimidazo[4, 5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(xxi) N-(2,2-Difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(5-α3αspuro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H- imidazo[4,5c]pyridin-4-yl)amino)-2-methylbenzamide (Example 277).

N-(2,2-Difluoroethyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5 -azaspiro[2.5]octan-5yl)cyclobutyl)-2-oxo-2,3-dihydro-1 H-pyrrolo[3,2-b]pyridin-6-yl)-3 -isopropyl-3H-imidazo[4, 5c]pyridin-4-yl)amino)-2-methylbenzamide was prepared by a similar procedure, except that 6bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H -imidazo[4,5-c]pyridin-4-yl)amino)-K-(2,2difluoroethyl)-3,4-difluoro-2-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1 -( (1 s,3s)-3 -methyl-3 (piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridine -4yl)amino)-K-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xxii) 5-((6-(3,3-Dimethyl-1 -((1 s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3- dihydro-1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4trifluorobenzamide ( example 278).

5-((6-(3,3-Dimethyl-1 -((1 s,3 s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro- 1Hpyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-2,3,4trifluorobenzamide was prepared in a similar manner procedure except that 6-bromo-3,3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one and 5-((6-347 045798 bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl -2,3,4-trifluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide, respectively.

(xxiii) N-Ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[ 2.5]octan-5yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5с]pyridin- 4-yl)amino)-2-methylbenzamide (Example 279).

N-Ethyl-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octane -5yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl )Amino)-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azacino [2.5]octan-5-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4, 5-c]pyridin-4-yl)amino)-Nethyl3,4-difluoro-2-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1 s,3s)-3-methyl-3 -(piperidin1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N(1(difluoromethyl )cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xxiv) N-(1-(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)- 2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2, 3,4-trifluorobenzamide (example 280).

⁰⁼ d 1

AF, Λ _Ζ ΝΗ r ^N < AG ^{w F} AV ⁿ i

N-(1 -(Difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)-2- oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2,3, 4-Trifluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1 ,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)- N-(1(difluoromethyl)cyclopropyl)-2,3,4-trifluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)3-methyl-3-(piperidin-1-yl) cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4- fluoro-2-methylbenzamide, respectively.

(xxv) 2-Chloro-5-((6-(3,3-dimethyl-1-((18,38)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2 ,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluoro-N-methylbenzamide (example 281).

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3- Dihydro1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-N- 348 045798 methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro -2H-pyrrolo[3,2-b]pyridin-2-one and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro- 3,4-difluoro-K-methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)-4-fluoro2-methylbenzamide, respectively.

(xxvi) 2-Chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[ 2.5]octan-5yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin- 4-yl)amino)-3,4-difluorobenzamide (Example 282).

2-Chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octane -5yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl )Amino)-3,4-difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5 ]octan-5-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5- c]pyridin-4-yl)amino)-2-chloro-K(2,2-difluoroethyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)- 3-methyl-3 (piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-K -(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xxvii) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl) -2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)K- ethyl 3,4-difluorobenzamide (Example 283).

N

2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2- oxo-2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl3, 4-difluorobenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl )-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl) amino)-2-chloro-K-ethyl-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl) cyclobutyl)indolin-2one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl)4-fluoro -2-methylbenzamide, respectively.

(xxviii) N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octane- 5yl)cyclobutyl)-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl) amino)-3,4-difluoro-2-methylbenzamide (Example 284).

- 349 045798

N-(2,2-Difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl )cyclobutyl)-2oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino )-3,4difluoro-2-methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3-dimethyl1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octane -5-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5((6-bromo-3-isopropyl-3H-imidazo[4,5-c ]pyridin-4-yl)amino)-K-(2,2-difluoroethyl)-3,4-difluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3- methyl-3-(piperidin-1yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K- (1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xxix) 5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo -2,3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl3,4 -difluoro-2-methylbenzamide (example 285).

5-((6-(3,3-Dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl)-2-oxo-2, 3dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl3,4-difluoro- 2-Methylbenzamide was prepared by a similar procedure, except that 6-bromo-3,3dimethyl-1-((1s,3s)-3-methyl-3-(5-azaspiro[2.5]octan-5-yl)cyclobutyl )-1,3-dihydro-2H-pyrrolo[3,2b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl) amino)-C-ethyl-3,4-difluoro-2methylbenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl)indolin- 2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-(1(difluoromethyl)cyclopropyl)-4-fluoro-2 -methylbenzamide, respectively.

(xxx) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo2,3 -dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-Nethyl-3,4-difluorobenzamide (example 286).

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3- Dihydro1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-ethyl-3,4difluorobenzamide was prepared in a similar manner procedure except that 6-bromo-3,3-dimethyl-1((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2H-pyrrolo [3,2-b]pyridin-2-one and 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-C-ethyl- 3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5(( 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl)-4-fluoro2-methylbenzamide, respectively.

(xxxi) 2-Chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl) cyclobutyl))-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluorobenzamide (Example 287).

- 350 045798

2-Chloro-K-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3 s)-3-methyl-3-(piperidin-1-yl) Cyclobutyl))2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluorobenzamide was prepared by a similar procedure, except that 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2-chloro-K-(2,2-difluoroethyl)-3,4-difluorobenzamide was used instead 5-((6-bromo3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide.

(xxxii) 2-Chloro-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3 -methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindoline6- yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-3,4-difluorobenzamide (Example 288).

N

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) 3-Isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-3,4-difluorobenzamide was prepared by a similar procedure, except that 5-((6-bromo- 3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2-chloro-C-ethyl-3,4-difluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3Nimidazo[ 4,5-c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(xxxiii) 2-Chloro-N-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl) cyclobutyl))-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4fluorobenzamide (Example 289).

2-Chloro-K-(2,2-difluoroethyl)-5-((6-(3,3-dimethyl-1-((1s,3 s)-3-methyl-3-(piperidin-1-yl) Cyclobutyl))2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide was prepared by a similar procedure, except that 5- ((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-2-chloro-K-(2,2-difluoroethyl)-4-fluorobenzamide was used instead of 5-(( 6-bromo-3-isopropyl-3Nimidazo[4,5-c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(xxxiv) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxoindolin-6yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-4-fluorobenzamide (Example 290).

- 351 045798

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) 3-Isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-C-ethyl-4-fluorobenzamide was prepared by a similar procedure, except that 5-((6-bromo-3- isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2chloro-K-ethyl-4-fluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4 ,5c]pyridin-4-yl)amino)-C-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(xxxv) 2-Chloro-K-(1-(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl-1-((1s,3s)- 3methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl3H-imidazo[4,5 -c]pyridin-4-yl)amino)benzamide (Example 291).

2-Chloro-K-(1 -(difluoromethyl)cyclopropyl)-3,4-difluoro-5-((6-(5-fluoro-3,3-dimethyl- 1-((1s,3s)-3-methyl3 -(piperidin-1 -yl)cyclobutyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3Nimidazo[4,5-c] Pyridin-4-yl)amino)benzamide was prepared by a similar procedure, except that 6-bromo-5-fluoro-3,3-dimethyl-1-((1s,3s)-3-methyl-3-( piperidin-1-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c ]pyridin-4-yl)amino)-2-chloro-K(1 -(difluoromethyl)cyclopropyl)-3,4-difluorobenzamide was used instead of 6-bromo-3,3-dimethyl-1 -((1s,3s)3 -methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one and 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K -(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide, respectively.

(xxxvi) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-K-(1-(fluoromethyl)cyclopropyl)benzamide (Example 292).

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) 3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4-difluoro-K-(1(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 5 -((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-3,4-difluoro-K-(1(fluoromethyl)cyclopropyl)benzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-K-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

(xxxvii) 2-Chloro-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6yl )-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-K-(1-(fluoromethyl)cyclopropyl)benzamide (Example 293).

- 352 045798

2-Chloro-5 -((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3 -(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl) 3-Isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-N-(1-(fluoromethyl)cyclopropyl)benzamide was prepared by a similar procedure, except that 5- ((6-bromo-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)-2-chloro-4-fluoro-M-(1-(fluoromethyl)cyclopropyl)benzamide was used instead of 5( (6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro2-methylbenzamide.

(xxxviii) 2-Chloro-N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin1-yl )cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluorobenzamide (Example 294).

2-Chloro-K-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1 -((1 s,3s)-3 -methyl-3-(piperidin-1 yl) Cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4fluorobenzamide was prepared by a similar procedure, except that 5-(( 6-bromo-3-isopropyl3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-4-fluorobenzamide was used instead of 5-(( 6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

AA. Preparation of 6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one.

6-Bromo-3,3-dimethyl-1,3-dihydro2H-pyrrolo[3,2-b]pyridin-2-one (250 mg, 1.04 mmol), DMAP (13 .0 mg, 0.10 mmol) and Boc ₂ O (294 mg, 1.35 mmol) in THF (5 ml). After stirring at room temperature for 18 hours, the mixture was concentrated and purified by flash column chromatography (100% hexane to 100% EtOAc) to give tert-butyl-6-bromo-3,3-dimethyl-2-oxo-2,3 -dihydro-1H-pyrrolo[3,2-b]pyridine-1-carboxylate, which was dissolved in MeCN (dried over sieves, 10 ml). AgF2 (438 mg, 3.0 mmol) was then added and the resulting reaction mixture was stirred at 40°C for 18 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and purified by flash column chromatography (100% hexane to 100% EtOAc) to give tert-butyl-6-bromo-5fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo [3,2-b]pyridine-1-carboxylate, which was dissolved in DCM (3 ml). TFA (0.45 mL, 5.93 mmol) was added to this mixture. After stirring at room temperature for 30 minutes, the reaction mixture was quenched with sat. NaHCO ₃ and extracted with DCM. The combined organic layers were dried (Na ₂ SO ₄ ), concentrated and purified by flash column chromatography (100% hexanes to 100% EtOAc) to give 6-bromo-5-fluoro-3,3-dimethyl-1,3-dihydro -2Ppyrrolo[3,2-b]pyridin-2-one.

Procedure 41. Preparation of compounds of formula I according to reaction scheme IX.

- 353 045798

A. Preparation of N-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl) )-2-oxo-2,3-dihydro-III-pyrrolo[3,2-b]pyridin-6-yl)-3-isonropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)- 4,5-difluorobenzamide (example 242).

6-(4amino-3-isopropyl-3H-imidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-((1s,3s) was placed in a test tube to carry out the reaction under the influence of microwave radiation. -3-methyl-3-(piperidin-1yl)cyclo6util)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one (95.0 mg, 0.19 mmol), 3- 6pom-N-(1(difluoromethyl)cyclopropyl)-4,5-difluorobenzamide (127 mg, 0.39 mmol), Pd ₂ (dba)3 (17.8 mg, 0.02 mmol), Xanthphos (20 mg, 0.04 mmol) and Cs ₂ CO3 (254 mg, 0.78 mmol) in dioxane (3 ml) under nitrogen. The mixture was placed in a microwave reactor and heated at 150°C for 45 minutes. The mixture was then purified by flash chromatography (100% DCM to 100% MeOH) followed by reverse phase chromatography (0.1% TFA in water/0.1% TFA in ACN) to give N-(1-(difluoromethyl)cyclopropyl )-3-((6-(3,3dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2-oxo-2,3-dihydro-1H- pyrrolo[3,2b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide.

B. Preparation of N-(1-(difluoromethyl)cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1yl)cyclobutyl) -2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5difluorobenzamide (Example 243).

6-(4-amino-3-isopropylimidazo[4,5-c]pyridin-6-yl)-3,3-dimethyl-1-[3-methyl-3-(1-piperidyl) was placed in a 100 ml one-neck round-bottom flask. cyclobutyl]indolin-2one (127 mg, 0.26 mmol), 3-bromo-N-[1-(difluoromethyl)cyclopropyl]-4,5-difluorobenzamide (170 mg, 0.52 mmol), XantPhos Pd G4 (50, 2 mg, 0.05 mmol) and cesium carbonate (48.6 mg, 0.78 mmol) in dioxane (10 ml) under nitrogen. After stirring at 150°C for 18 hours, the reaction mixture was transferred to a microwave reaction tube, placed in a microwave reactor and heated at 150°C for 1 hour. The mixture was then filtered through a celite pad, washed with MeOH, concentrated and purified by flash chromatography (DCM/5% NEt ₃ in MeOH) and reverse phase chromatography (0.1% TFA in water/0.1% TFA in ACN) to give N-(1(difluoromethyl )cyclopropyl)-3-((6-(3,3-dimethyl-1-((1s,3s)-3-methyl-3-(piperidin-1-yl)cyclobutyl)-2oxoindolin-6-yl)-3 -isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4,5-difluorobenzamide.

Procedure 42. Preparation of compounds of formula I according to reaction scheme X.

A. Preparation of methyl 2-(2-bromo-4-chlorophenyl) acetate.

Commercially available 2-(2-bromo4-chlorophenyl)acetic acid (5 g, 20.0 mmol) in methanol (30 mL) was placed in a 100 mL one-neck round bottom flask. H ₂ SO ₄ (0.3 ml) was then added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was then concentrated, redissolved in DCM and sat. NaHCO ₃ and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ), purified by flash chromatography (100% hexane to 100% EtOAc) to give methyl 2-(2-bromo-4-chlorophenyl) acetate.

B. Preparation of methyl 2-(2-bromo-4-chlorophenyl)-2-methylpropanoate.

- 355 045798

Methyl 2-(2-bromo-4chlorophenyl) acetate (5.0 g, 19 mmol) in THF (30 mL) was placed in a 100 mL one-neck round bottom flask. To this mixture was added NaH (2.3 g, 57 mmol) at 0° C. and the resulting mixture was stirred for 20 min followed by the addition of MeI (8.1 g, 57 mmol). The mixture was heated to room temperature and stirred for 5 hours, then quenched with sat. NH ₄ Cl and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and purified by flash chromatography (100% hexane to 100% EtOAc) to give methyl 2-(2-bromo-4chlorophenyl)-2-methylpropanoate.

Methyl 2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoate was prepared by a similar procedure, except that commercially available methyl 2-(3-bromo-5-chloropyridin-2-yl) acetate was used instead of methyl 2-(2-bromo-4-chlorophenyl) acetate.

C. Preparation of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid.

BUT.

Methyl 2-(2-bromo-4-chlorophenyl)-2-methylpropanoate (2.2 g, 7.5 mol) in methanol (10 ml) and water (10 ml). NaOH (2 g, 50 mmol) was then added and the resulting mixture was stirred at 110°C for 16 hours. The mixture was then cooled to RT, concentrated under reduced pressure, and redissolved in water. Citric acid was added to this mixture to reduce the pH to 6. The precipitates were collected by filtration, washed with water and dried to give 2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid, which was used in the next step without further purification.

BUT.

2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoic acid was prepared by a similar procedure, except that methyl 2-(3-bromo-5-chloropyridin-2-yl)-2- Methyl propanoate was used instead of methyl 2-(2-bromo-4-chlorophenyl)-2-methylpropanoate.

D. Preparation of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride.

2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid (800 mg, 2.9 mmol) was placed in a 100 mL single-neck round-bottom flask equipped with a reflux condenser. Thionyl chloride (6.3 ml, 86 mmol) and DMF (0.5 ml) were then added. The resulting mixture was stirred at 80°C for 3 hours. The mixture was then cooled to room temperature and concentrated to give 2-(2-bromo-4chlorophenyl)-2-methylpropanoyl chloride, which was used in the next step without further purification.

2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoyl chloride was prepared by a similar procedure, except that 2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanoic acid was used instead of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoic acid.

E. Preparation of tert-butyl-((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate.

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2-(2-bromo-4-chlorophenyl)-2methylpropanoyl chloride (820 mg, 2.8 mmol) in dichloromethane (10 mL) was placed in a 100 mL one-neck round bottom flask. Then tert-butyl ((1s,3s)-3amino-3-methylcyclobutyl)carbamate (560 mg, 2.8 mmol) and DIPEA (5 ml, 29 mmol) were added. The resulting mixture was stirred at room temperature for 16 hours, then quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na ₂ SO ₄ ) and concentrated to give tert-butyl-((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)- 3-methylcyclobutyl)carbamate, which was used in the next step without purification.

Tert-butyl-((1s,3s)-3-(2-(3-bromo-5-chloropyridin-2-yl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate was prepared by a similar procedure, except that 2-(3-bromo-5-chloropyridin-2-yl)-2methylpropanoyl chloride was used instead of 2-(2-bromo-4-chlorophenyl)-2-methylpropanoyl chloride.

F. Preparation of 1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one.

Place tert-butyl-((1s,3s)-3-(2-(2-bromo-4chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate (600 mg, 1.3 mmol) into a 100 mL single-neck round-bottom flask. ) and KOH (600 mg, 11 mmol) in DMSO (6 ml). After stirring the mixture at 120°C for 16 hours, it was cooled to room temperature, diluted with water, and neutralized with 2 N. HCl and extracted with DCM:1PA (3:1). The combined organic layers were concentrated and purified by flash chromatography (100% DCM to 100% MeOH) to give 1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindoline-2 -she.

-((1s,3s)-3-Amino-1-methylcyclobutyl)-6-chloro-3,3-dimethyl-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin2-one was prepared by a similar method procedure, except that tert-butyl((1s,3s)-3-(2-(3-bromo-5chloropyridin-2-yl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate was used instead of tert-butyl ((1s,3s)-3-(2-(2-bromo-4-chlorophenyl)-2-methylpropanamido)-3-methylcyclobutyl)carbamate.

G. Preparation of 6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

1-((1s,3s)-3-amino-1methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one (40 mg 0.14 mmol) in dichloromethane (20 ml) was placed in a 200 ml one-neck round bottom flask ). Glutaraldehyde (120 mg, 0.86 mmol) in dichloromethane (40 ml) was then added followed by sodium triacetoxyborohydride (91 mg, 0.43 mmol) and acetic acid (26 mg, 0.43 mmol). After stirring the mixture at room temperature for 3 hours, it was quenched with sat. NaHCO ₃ and extracted with DCM. The combined organic layers washed us over. NaHCO ₃ and brine, concentrated and purified by flash chromatography (100% DCM to 100% MeOH) to give 6-chloro-3,3-dimethyl-1-((1s,3s)1-methyl-3-(piperidin- 1-yl)cyclobutyl)indolin-2-one.

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6-Chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-1,3-dihydro-2Hpyrrolo[3,2-b]pyridine -2-one was prepared by a similar procedure, except that 1((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethyl-1,3-dihydro-2H- pyrrolo[3,2-b]pyridin-2-one was used instead of 1-((1s,3s)-3-amino-1-methylcyclobutyl)-6-chloro-3,3-dimethylindolin-2-one.

H. Preparation of 3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl1,3,2 -dioxaborolan-2-yl)indolin-2-one.

6-chloro-3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1yl)cyclobutyl)indolin-2-one (40 mg, 0.12 mmol) was placed in a sealed tube. , bis(pinacolato)diboron (88 mg, 0.35 mmol), potassium acetate (45 mg, 0.46 mmol), Pd ₂ dba ₃ (5.3 mg, 0.0058 mmol) and XPhos (8.3 mg , 0.017 mol) in dioxane (2 ml). The mixture was purged with nitrogen for 5 minutes and stirred at 100°C for 72 hours. The mixture was then cooled to room temperature, diluted with EtOAc and filtered through a pad of celite. The filtrate was concentrated to give 3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)indolin-2-one, which was used in the next step without purification.

3,3-Dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2dioxaborolane- 2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one was prepared by a similar procedure, except that 6-chloro-3,3-dimethyl-1-( (1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)1,3-dihydrO-2H-pyrrolo[3,2-b]pyridin-2-one was used instead of 6-chloro-3, 3-dimethyl-1-((1s,3s)-1-methyl3-(piperidin-1-yl)cyclobutyl)indolin-2-one.

I. Preparation of N-(1-(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin1-yl)cyclobutyl)- 2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2methylbenzamide (Example 295).

3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl)indolin-2-one (40 mg, 0.046 mmol), 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)- K-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2methylbenzamide (110 mg, 0.23 mmol), Pd(PPh ₃ ) ₄ (2.6 mg, 0.0023 mmol), 2 M Na ₂ CO ₃ (0.068 ml) in dioxane (4 ml). The mixture was degassed with N2 and stirred at 90°C for 2 hours. The mixture was then cooled to room temperature, diluted with EtOAc (4 ml) and filtered through a pad of celite. The filtrate was concentrated and purified by flash chromatography (100% DCM to 100% MeOH) and reverse phase chromatography (0.1% TFA in ACN/0.1% TFA in water) to give Na(1-(difluoromethyl)cyclopropyl) 5-((6-(3,3-dimethyl-1-((1s,3s)-1 -methyl-3-(piperidin-1 -yl)cyclobutyl)-2-oxoindolin-6-yl)-3-isopropyl3H -imidazo[4,5-c]pyridin-4-yl)amino)-4-fluoro-2-methylbenzamide.

2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1yl)cyclobutyl )-2-oxoindolin-6-yl)-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-3,4difluorobenzamide (Example 296) was prepared by a similar procedure, except that 5-((6bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4difluorobenzamide was used instead of 5-((6-bromo-3-isopropyl-3H-imidazo[4,5-c]pyridin-4yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro-2-methylbenzamide.

2-Χλορ-Ν-(1 -(difluoromethyl)cyclopropyl)-5-((6-(3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1yl)cyclobutyl )-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-3-isopropyl-3H-imidazo[4,5c]pyridin-4-yl)amino)- 3,4-Difluorobenzamide (Example 297) was prepared by a similar procedure, except that 3,3-dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1-yl)cyclobutyl)- 6-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-pyrrolo[3,2-b]pyridin-2-one and 5-(( 6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-2-chloro-N-(1-(difluoromethyl)cyclopropyl)-3,4difluorobenzamide were used instead of 3,3- dimethyl-1-((1s,3s)-1-methyl-3-(piperidin-1yl)cyclobutyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) indolin-2-one and 5-((6-bromo-3isopropyl-3H-imidazo[4,5-c]pyridin-4-yl)amino)-N-(1-(difluoromethyl)cyclopropyl)-4-fluoro- 2methylbenzamide, respectively.

Analytical data for examples 1 -297 are presented in table. 1.

HPK1 IC ₅₀ Assay

The enzymatic activity of human HPK1 (MAP4K1) was monitored by biochemical assay in the presence or absence of compounds and using a synthetic peptide substrate. Increased phosphorylation of the HPK1 peptide indicates its kinase activity.

Recombinant kinase domain HPK1, produced by baculovirus infection of insect cells, was obtained from Proteros (Proteros Biostructures #PR-0322) and was preactivated in the presence of 2 mM ATP (Sigma-Aldrich, catalog number GE27-2056-01) and 2 mM magnesium chloride for 16 hours at 4°C. The protein reaction mixture was then loaded onto a desalting column (Thermo Fisher Scientific, part no. 89889) to remove excess ATP. HPK1 was eluted with a buffer containing 20 mM Tris (2-amino-2-(hydroxymethyl)propane-1,3-diol) pH 8.0, 150 mM NaCl, 2 mM dithiothreitol and 5% glycerol, and frozen at -80°C for further usage. Dual phosphorylation of HPK1 was confirmed by mass spectrometry data.

Ten nanoliters of test compounds dissolved in DMSO at various concentrations were added to a 384-well ProxiPlate (PerkinElmer #6008289). Five microliters of recombinant HPK1 solution diluted in HPK1 kinase assay buffer (50 mM BES[N,N-6uc(2hydroxyethyl)-2-aminoethanesulfonic acid], pH 7.0; 10 mM magnesium chloride; 0.01% Triton X- 100; 1 mM dithiothreitol; 0.01% bovine serum albumin; 0.1 mM sodium orthovanadate) was added to the plate containing the compound and incubated for 15 min at 25°C. Five microliters of a mixture of ATP (Sigma-Aldrich no. A6559) and STK S1 peptide substrate (Cisbio no. 61ST1BLC) diluted in HPK1 kinase assay buffer was then added to initiate the reaction. The final concentrations were 0.15 nM for HPK1, 10 µM for ATP and 1 µM for the STK S1 peptide substrate. The reaction mixture was incubated at 25°C for 3 hours, then the reaction was stopped by adding 10 μ1 μl of detection buffer containing EDTA (ethylenediaminetetraacetic acid) (Cisbio No. 62SDBRDF), with the addition of europium cryptate-labeled antiphosphoserine/threonine antibodies (Cisbio No. 62ST1PEJ) and XL665-labeled streptavidin (Cisbio no. 610S). The mixture was incubated for 16 h at room temperature, and peptide phosphorylation was measured using time-resolved fluorescence energy transfer (665 nm/620 nm) on an Envision plate reader (PerkinElmer).

Data in table. 1 were normalized to positive (staurosporine) and negative (DMSO) controls. Least squares curve fitting was performed using a four-parameter variable slope nonlinear regression model. IC ₅₀ is defined as the concentration of compound required to inhibit 50% of maximal phosphorylation. IC ₅₀ values from multiple experiments were averaged as the geometric mean and the standard deviation was calculated.

Table 1

Example No. ES/MS m/z Ή-NMR HPK1 IC ₅₀ (nM) 1 620.4 Ή NMR (400 MHz, DMSO-ab) δ 9.42 (d, J = 9.5 Hz, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.15 (q , J = 4.5 Hz, 1H), 7.86 (s, 1H), 7.75 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 - 7.46 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.23 - 7.06 0.08 (m, 1H), 5.30 (p, J = 6.5 Hz, 1H), 4.34 - 4.08 (m, 1H), 3.43 (dd, J = 51.1, 10.0 Hz, 3H), 2.97 - 2.65 (m, 8H), 2.30 (s, 3H), 1.82 (d, J = 14.0 Hz, 2H), 1.55 (d, J = 6.5 Hz, 9H), 1.28 (s, 8H). 2 660.4 Ή NMR (400 MHz, DMSO-de) δ 9.35 - 9.25 (m, 1H), 8.66 (s, 1H), 8.54 - 8.38 (m, 2H), 7.89 ( s, 1H), 7.78 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.59 (d, J = 2 .4 Hz, 1H), 7.50 (dd, J = 8.2, 2.4 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 4.37 (hex, J = 8.2 Hz, 1H), 4.26 (p, J = 7.8 Hz, 1H), 3.49 (q, J = 8.5 Hz, 1H), 3.42 - 3.35 (m, 2H), 2.99 - 2.87 (m, 2H), 26.87 2.72 (m, 4H), 2.30 (s, 3H), 2.21 - 2.12 (m, 2H), 2.00 1.88 (m, 2H), 1.87 - 1.79 (m, 2H), 1.75 - 1.67 (m, 1H), 1.67 - 1.53 (m, 10H), 1.47 - 1.35 (m, 1H), 1, 29 (s, 6H). 0D 3 634.4 Ή I MP (400 MHz, DMSO-de) δ 10.40 - 10.05 (m, 2H), 8.81 (s, 1H), 8.74 (s, 1H), 8.40 - 8.25 (m, 2H), 7.79 (d, J = 7.9 Hz, 1H), 7.67 (s, 1H), 7.65 - 7.52 (m, 2H), 5.19 - 5, 07 (m, 1H), 4.50 (q, J = 6.5 Hz, 1H), 4.44 - 4.30 (m, 1H), 4.04 - 3.46 (m, 6H), 3 .28 - 3.09 (m, 1H), 3.09 - 2.90 (m, 2H), 2.85 - 2.75 (m, 2H), 2.48 - 2.05 (m, 3H) , 1.90 - 1.64 (m, 5H), 1.58 - 1.34 (m, 9H), 1.24 (t, J = 6.5 Hz, 3H), 0.91 (t, J = 7.4 Hz, 3H). 0.1 4 624.4 Ή NMR (400 MHz, DMSO-de) δ 10.70 - 10.46 (m, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.16 (q, J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52 7.46 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.62 - 5.40 (m, 1H), 5.29 (p, J = 6.6 Hz, 1H), 4.35 (q, J = 8.4 Hz, 1H), 3.95 - 3.50 (m, 6H), 3.03 - 2.92 (m, 2H), 2.86 - 2.72 (m, 6H), 2.31 (s, 3H), 1.55 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). 0.1 5 624.4 'NMR (400 MHz, DMSO-de) δ 10.71 - 10.52 (m, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 8.17 (q, J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52 7.46 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 5.52 (d, J = 51.4 Hz, 1H), 5.31 (p, J = 6.6 Hz, 1H), 4.33 (p , J = 8.1 Hz, 1H), 3.96 - 3.49 (m, 3H), 3.42 - 3.20 (m, 1H), 2.98 (q, J = 10.2 Hz, 2H), 2.86 - 2.72 (m, 5H), 2.60 - 2.05 (m, 3H, intersecting with solvent), 2.32 (s, 3H), 1.57 (d, J= 6.4 Hz, 6H), 1.30 (s, 6H). 0.2 6 634.4 Ή NMR (400 MHz, DMSO-de) δ 9.29 - 9.10 (m, 1H), 8.62 (s, 1H), 8.44 (s, 1H), 8.17 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.78 (dt, J = 7.8, 2.0 Hz, 1H), 7.63 0.1

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- 7.54 (m, 2H), 7.49 - 7.44 (m, 1H), 7.42 - 7.34 (m, 1H), 7.20 (d, J = 8.4, 1H) , 5.28 (p, J = 6.5 Hz, 1H), 4.56 - 4.41 (m, 1H), 4.38 - 4.16 (m, 5H), 4.14 - 4.02 (m, 1H), 3.19 - 3.11 (m, 1H), 2.99 - 2.69 (m, 7H), 2.33 (s, 3H), 2.20 - 1.99 (m , 1H), 1.55 (d, J = 6.6 Hz, 6H), 1.30 (s, 6H). 7 654.3 'NMR (400 MHz, DMSO-ab) δ 11.25 - 10.15 (m, 1H), 8.73 (s, 1H), 8.49 (s, 1H), 8.21-8.15 ( m, 1H), 7.87 (s, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.57 (s, 1H), 7.55 (d, J = 2.4 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 5.37 - 5.21 (m, 1H), 4.29 (p, J = 8.2 Hz, 1H), 3.85 (s, 2H), 3.69 (s, 2H), 3.14 (s, 1H), 3.04 - 2.85 (m, 4H), 2.81 - 2.70 (m, 5H), 2.32 (s, 3H), 1.56 (d, J = 6 .5 Hz, 6H), 1.30 (s, 6H). 0.4 8 666.4 Ή NMR (400 MHz, DMSO+b) δ 9.92 (s, 1H), 8.66 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 4.7 Hz , 1H), 7.83 (s, 1H), 7.68 (d, J = 7.9 Hz, 2H), 7.43 - 7.34 (m, 2H), 7.20 (d, J = 12.0 Hz, 1H), 5.32 - 5.22 (m, 1H), 4.08 (p, J = 8.6 Hz, 1H), 3.95 (s, 2H), 3.87 ( d, J = 12.4 Hz, 2H), 3.72 (d, J = 12.2 Hz, 2H), 3.54 (q, J = 8.2 Hz, 1H), 2.96 (q, J = 9.8, 9.2 Hz, 2H), 2.91 - 2.82 (m, 2H), 2.73 (d, J = 4.5 Hz, ZN), 2.36 (s, ZN ), 2.22 2.13 (m, 2H), 2.13 - 2.05 (m, 2H), 1.59 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H ). 0.08 9 652.3 'NMR (400 MHz, DMSO-de) δ 10.42 - 9.15 (m, 1H), 8.71 (s, 1H), 8.40 - 8.33 (m, 1H), 8.23 - 8.17 (m, 1H), 7.84 (s, 1H), 7.73 - 7.60 (m, 2H), 7.43 (s, 1H), 7.37 (d, J = 7, 8 Hz, 1H), 7.23 (dd, J = 12.1, 2.9 Hz, 1H), 5.29 (p, J = 6.8 Hz, 1H), 4.53 - 3.99 ( m, 8H), 3.22 - 2.76 (m, 5H), 2.74 (d, J = 4.5 Hz, ZN), 2.41 2.37 (m, ZN), 2.16 - 2.04 (m, 1H), 1.59 (d, J = 6.6 Hz, 6H), 1.29 (d, J = 1.8 Hz, 6H). 0.1 10 666.3 'NMR (400 MHz, DMSO+b) δ 9.35 (s, 1H), 8.65 (s, 1H), 8.35 (s, 1H), 8.21-8.16 (m, 1H) , 7.85 (s, 1H), 7.68 (dd, J = 7.9, 1.4 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.43 ( s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 12.1 Hz, 1H), 5.27 (p, J = 6.6 Hz, 1H), 4.52 (s, 2H), 4.13 (p, J - 8.5 Hz, 1H), 3.70 - 3.58 (m, 1H), 3.41 - 3.33 (m , 2H), 3.06 (t, J = 10.9 Hz, 2H), 3.00 2.88 (m, 2H), 2.79 - 2.69 (m, 5H), 2.38 (s , 3H), 2.04 1.92 (m, 4H), 1.59 (d, J = 6.5 Hz, 6H), 1.29 (s, 6H). 0.1 AND 594.3 'NMR (400 MHz, methanol^4) δ 9.06 (s, 1H), 7.79 - 7.71 (m, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7 .60 (d, J = 1.4 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 5.33 (p, J = 6.6 Hz, 1H), 4.37 (p, J = 8.2 Hz, 1H), 3.81 (p, J = 8.1 Hz, 1H), 3.39 (p, J = 6.4 Hz, 1H), 2.91 (t, J = 8.0 Hz, 4H), 2.85 (s, 3H), 2.40 (s, 0.1

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ZN), 1.68 (d, J = 6.6 Hz, 6H), 1.38 - 1.28 (m, 12H). 12 650.3 Ή NMR (400 MHz, methanol-44) δ 9.08 (s, 1H), 7.78 - 7.71 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 7 .61 (d, J = 1.4 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.26 (d, J = 8.3 Hz, 1H), 5.33 (p, J = 6.6 Hz, 1H), 4.36 (p, J = 8.2 Hz, 1H), 4.01 (dd, J = 11.8, 4.8 Hz, 1H), 3.88 ( p, J = 7.8 Hz, 1H), 3.76 (d, J = 11.7 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.54 - 3, 38 (m, 2H), 2.96 (d, J = 4.0 Hz, 4H), 2.85 (s, 3H), 2.40 (s, 3H), 2.10 (s, 1H), 1.94 1.82 (m, 1H), 1.77 (d, J = 12.7 Hz, 1H), 1.68 (d, J = 6.6 Hz, 6H), 1.35 (s, 6H), 1.15 (d, J = 7.1 Hz, ZN). 0.09 13 650.3 Ή NMR (400 MHz, methanol-44) δ 9.09 (s, 1H), 7.80 (d, J = 8.9 Hz, 2H), 7.74 (d, J = 2.3 Hz, 1H ), 7.66 (d, J = 1.3 Hz, 1H), 7.44 - 7.37 (m, 2H), 7.31 (d, J = 8.3 Hz, 1H), 5.37 (q, J = 6.6 Hz, 1H), 4.46 (q, J = 7.7 Hz, 1H), 4.06 (d, J = 12.3 Hz, 1H), 4.03 - 3 .88 (m, 2H), 3.54 - 3.42 (m, 1H), 3.15 (t, J= 11.3 Hz, 2H), 3.10 2.97 (m, 3H), 2 .90 (s, 4H), 2.45 (s, 3H), 2.06 (d, J = 12.4 Hz, 1H), 1.94 - 1.81 (m, 1H), 1.73 ( dd, J = 6.5, 5.2 Hz, 7H), 1.41 (s, 6H), 1.11 (d, J = 6.6 Hz, ZN). θ,ι 14 612.3 Ή NMR (400 MHz, methanol-44) δ 8.98 (s, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.77 (s, 1H), 7.72 (dd , J = 7.8, 1.5 Hz, 1H), 7.54 (d, J = 1.3 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 11.7 Hz, 1H), 5.33 (p, J = 6.5 Hz, 1H), 4.32 (q, J = 8.1 Hz, 1H), 3.85 (t , J = 7.8 Hz, 1H), 3.43 (p, J = 6.5 Hz, 1H), 2.92 (t, J = 8.0 Hz, 4H), 2.87 (s, 3H ), 2.45 (s, 3H), 1.73 (d, J = 6.5 Hz, 6H), 1.43 1.33 (m, 12H). 0.3 15 642.3 Ή NMR (400 MHz, methanol-44) δ 9.08 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.42 - 7.36 (m, 1H), 7.26 7.18 (m, 1H), 5 .37 (p, J = 6.8 Hz, 1H), 4.41 (p, J = 8.1 Hz, 1H), 3.81 (q, J = 7.4 Hz, 1H), 3.05 - 2.93 (m, 6H), 2.91 (s, 3H), 2.50 (d, J = 1.8 Hz, ZN), 1.77 (dd, J = 6.7, 1.9 Hz, 6H), 1.41 (d, J = 1.9 Hz, 6H), 1.38 (d, J = 1.9 Hz, 6H). 0.1 16 634.4 'H NMR (400 MHz, chloroform-d) δ 8.24 (s, 1H), 8.18 (s, 1H), 8.02 (s, OH), 7.93 (d, J = 2.4 Hz, OH), 7.66 (d, J = 0.5 Hz, 1H), 7.55 - 7.47 (m, 1H), 7.43 (dd, J = 7.8, 1.4 Hz , 1H), 7.36 - 7.29 (m, 1H), 7.23 7.16 (m, 2H), 6.09 (s, 1H), 4.90 (t, J = 8.9 Hz , 1H), 4.38 (s, 1H), 4.01 (s, 1H), 3.67 (d, J = 53.6 Hz, 2H), 3.43 (s, 3H), 2.90 (s, 1H), 2.71 - 2.54 (m, 4H), 2.44 (s, 1H), 1.23 (d, J = 16.2 Hz, 8H), 1.07 (s, 3H), 0.97 0.81 (m, 2H). 0.1 17 622.4 Ή NMR (400 MHz, chloroform-d) δ 8.14 (s, 1H), 7.87 (s, 1H), 7.66 (s, 1H), 7.51 (d, J = 7.1 Hz , 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 0.04

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7.00 (s, 1H), 5.17 - 4.72 (m, 1H), 3.51 (d, J = 10.2 Hz, 2H), 2.80 - 2.60 (m, 2H) , 2.05 (d, J = 35.4 Hz, OH), 1.25 (s, 8H), 0.85 (d, J = 18.2 Hz, 1H), 0.07 (d, J = 4.3 Hz, 4H). 18 621.4 Ή NMR (400 MHz, DMSO-de) δ 9.34 (s, 1H), 8.85 (d, J = 1.7 Hz, 1H), 8.66 (s, 1H), 8.48 (s , 1H), 8.19 8.13 (m, 1H), 7.98 (s, 1H), 7.85 (d, J = 1.8 Hz, 1H), 7.57 - 7.48 (m , 2H), 7.20 (d, J = 8.2 Hz, 1H), 5.35 5.24 (m, 1H), 4.33 - 4.22 (m, 1H), 3.60 - 3 .49 (m, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.98 - 2.75 (m, 5H), 2.74 (d, J = 4.6 Hz, ZN), 2.31 (s, ZN), 1.84 (d, J = 14.2 Hz, 2H), 1.76 - 1.59 (m, 3H), 1.56 (d, J = 6 .5 Hz, 6H), 1.43 (t, J = 14.4 Hz, 1H), 1.31 (s, 6H). 0.4 19 697.5 Ή NMR (400 MHz, DMSO-de) δ 9.47 (d, J = 7.7 Hz, 1H), 8.83 (t, J = 1.8 Hz, ZN), 8.59 (s, 1H ), 7.98 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.52 (dd, J = 8.3, 2.4 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.11 (t, J = 57.3 Hz, 1H), 5.41 - 5 .29 (m, 1H), 4.32 (h, J = 8.5, 7.8 Hz, 1H), 3.58 - 3.45 (m, 1H), 3.39 (d, J = 11 .8 Hz, 2H), 2.99 - 2.74 (m, 5H), 2.31 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.76 - 1 .62 (m, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.46 - 1.37 (m, 1H), 1.31 (s, 6H), 1.11 - 1.03 (m, 2H), 0.96 - 0.88 (m, 2H). 0.3 20 670.4 'NMR (400 MHz, DMSO-de) δ 9.33 (s, 1H), 8.63 (t, J = 6.1 Hz, 1H), 8.53 (s, 1H), 7.87 (s , 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (s, 1H), 7.55 - 7.50 (m, 2H), 7.37 ( d, J = 7.7 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 6.23 - 5.92 (m, 1H), 5.34 - 5.23 (m , 1H), 4.25 (q, J = 8.3 Hz, 1H), 3.69 - 3.55 (m, 2H), 3.47 (q, J = 7.9 Hz, 1H), 3 .37 (d, J = 11.9 Hz, 2H), 2.98 - 2.69 (m, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.54 (d, J = 6.5 Hz, 8H), 1.27 (s, 6H). 0.05 21 684.4 Ή NMR (400 MHz, DMSO-de) δ 9.48 (s, 1H), 8.90 (d, J = 12.5 Hz, 1H), 8.62 (d, J = 6.2 Hz, 1H ), 8.52 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz , 1H), 7.57 - 7.49 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5 .97 (td, J = 56.2, 3.4 Hz, 1H), 5.35 (s, 1H), 4.43 - 4.18 (m, 2H), 3.54-3.31 (m , 3H), 2.84 (dp, J = 41.0, 11.3, 10.6 Hz, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.75 1.46 (m, 9H), 1.41 (t, J = 12.5 Hz, 1H), 1.27 (s, 6H), 1.14 (d, J = 7, 0 Hz, ZN). 0.05 21A (1 elutable peak) 684.4 Ή NMR (400 MHz, DMSO-de) δ 9.48 (s, 1H), 8.90 (d, J = 12.5 Hz, 1H), 8.62 (d, J = 6.2 Hz, 1H ), 8.52 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz , 1H), 7.57 - 7.49 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5 .97 (td, J = 0.07

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56.2, 3.4 Hz, 1H), 5.35 (s, 1H), 4.43 - 4.18 (m, 2H), 3.54-3.31 (t, ZN), 2.84 (dp, J = 41.0, 11.3, 10.6 Hz, 7H), 2.31 (s, ZN), 1.82 (d, J = 14.1 Hz, 2H), 1.75 1 .46 (t, 9H), 1.41 (t, J = 12.5 Hz, 1H), 1.27 (s, 6H), 1.14 (d, J = 7.0 Hz, ZN). 21B (2nd peak to be eluted) 684.4 Ή NMR (400 MHz, DMSO-46) δ 9.48 (s, 1H), 8.90 (d, J = 12.5 Hz, 1H), 8.62 (d, J = 6.2 Hz, 1H ), 8.52 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 0.9 Hz, 1H), 7.74 (dd, J = 7.8, 1.4 Hz , 1H), 7.57 - 7.49 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 5 .97 (td, J = 56.2, 3.4 Hz, 1H), 5.35 (s, 1H), 4.43 - 4.18 (m, 2H), 3.54-3.31 (m , 3H), 2.84 (dp, J = 41.0, 11.3, 10.6 Hz, 7H), 2.31 (s, 3H), 1.82 (d, J = 14.1 Hz, 2H), 1.75 1.46 (m, 9H), 1.41 (t, J = 12.5 Hz, 1H), 1.27 (s, 6H), 1.14 (d, J = 7, 0 Hz, ZN). 0.07 22 676.4 NMR (400 MHz, DMSO-46) δ 9.36 (s, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 8.23 (t, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 - 7.55 (m, 2H), 7.54 - 7 .46 (m, 2H), 7.17 (d, J = 8.3 Hz, 1H), 5.30 (q, J = 6.7 Hz, 1H), 4.26 (t, J = 8, 2 Hz, 1H), 4.03 (q, J = 5.7 Hz, 1H), 3.87 - 3.77 (m, 1H), 3.42 (dd, J = 39.1, 9.9 Hz, ZN), 3.27 - 3.16 (m, 2H), 2.92 (q, J = 9.8 Hz, 2H), 2.78 (d, J = 11.8 Hz, 4H), 2.30 (s, 3H), 1.87 - 1.47 (m, 15H), 1.39 (d, J = 13.0 Hz, 1H), 1.05 (t, J = 7.2 Hz , ZN). 0.07 23 702.4 NMR (400 MHz, DMSO-46) δ 9.44 (s, 1H), 8.86 (s, 1H), 8.58 - 8.52 (m, 1H), 8.50 (d, J = 7 .7 Hz, 1H), 7.89 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (d, J = 8.0 Hz, 2H ), 7.56 - 7.47 (m, 2H), 7.19 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.5 Hz, 1H), 4.30 (dq, J = 43.8, 8.2 Hz, 2H), 4.04 (p, J = 5.7 Hz, 2H), 3.83 (dt, J = 10.8, 5.0 Hz, 2H), 3.52 - 3.30 (m, 3H), 3.00 - 2.84 (m, 2H), 2.78 (td, J = 13.9, 12.7, 8.7 Hz, 5H), 2.29 (s, 3H), 2.16 (td, J = 8.3, 4.1 Hz, 2H), 1.93 (dq, J = 11.8, 9.4 Hz, 2H ), 1.87 - 1.48 (m, 15H), 1.41 (t, J= 12.3 Hz, 1H). 0.2 24 648.4 NMR (400 MHz, DMSO-46) δ 9.52 (s, 1H), 8.89 (s, 1H), 8.57 (s, 1H), 8.23 (t, J = 5.7 Hz, 1H), 7.87 (s, 1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (t, J = 1.8 Hz, 2H), 7, 49 (dd, J = 8.2, 2.4 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.6 Hz, 1H), 4.23 (p, J = 8.3 Hz, 1H), 3.48 (h, J = 8.4 Hz, 1H), 3, 36 (d, J = 11.7 Hz, 2H), 3.15 (q, J = 6.6 Hz, 2H), 2.95 - 2.70 (m, 7H), 2.31 (s, 3H ), 1.81 (d, J = 14.1 Hz, 2H), 1.56 (d, J = 6.5 Hz, 8H), 1.50 - 1.34 (m, 3H), 1.27 (s, 6H), 0.81 (t, J = 7.4 Hz, ZN). 0.08 25 684.4 NMR (400 MHz, DMSO-46) δ 9.52 (s, 1H), 9.00 (s, 1H), 8.62 (s, 1H), 8.39 (t, J = 5.7 Hz, 1H), 7.88(s, 0.07

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1H), 7.75 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 2H), 7.51 (dd, J = 8.2 , 2.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.08 (tt, J = 56 .5, 4.5 Hz, 1H), 5.36 (p, J = 6.5 Hz, 1H), 4.29 4.16 (m, 1H), 3.48 (h, J = 8.1 Hz, 1H), 3.42 - 3.29 (m, 4H), 2.95 - 2.70 (m, 6H), 2.32 (s, 3H), 2.04 (ttd, J = 18, 0, 7.0, 4.5 Hz, 2H), 1.82 (d, J = 14.1 Hz, 2H), 1.57 (d, J = 6.5 Hz, 8H), 1.41 ( dd, J = 14.7, 10.5 Hz, 1H), 1.27 (s, 6H). 26 646.4 Ή NMR (400 MHz, DMSO-46) δ 9.46 (s, 1H), 8.83 (s, 1H), 8.53 (s, 1H), 8.29 (d, J = 4.5 Hz , 1H), 7.88 (s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.57 (dd, J = 8.1, 1.9 Hz, 2H), 7.50 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 5.34 (p, J = 6.6 Hz, 1H), 4.35 - 4.22 (m, 1H), 3.52 (h, J = 8.3 Hz, 1H), 3.39 (d, J = 11.7 Hz, 2H), 2.99 - 2.75 (m, 7H), 2.31 (s, 3H), 1.84 (d, J = 14.0 Hz , 2H), 1.57 (d, J = 6.5 Hz, 9H), 1.43 (t, J = 12.5 Hz, 1H), 1.30 (s, 6H), 0.65 (td , J = 7.0, 4.7 Hz, 2H), 0.51 - 0.42 (m, 2H). 0.1 27 696.4 NMR (400 MHz, DMSO-de) δ 9.51 (s, 1H), 8.90 (d, J = 2.9 Hz, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 7.89 (s, 1H), 7.75 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 - 7.49 (m, 3H), 7.39 (d , J = 7.8 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.09 (t, J = 57.3 Hz, 1H), 5.36 (p, J = 6.6 Hz, 1H), 4.35 - 4.22 (m, 1H), 3.58 - 3.32 (m, 4H), 3.02 2.74 (m, 6H), 2.31 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.77 - 1.52 (m, 7H), 1.49 - 1.35 (m, 1H), 1, 30 (s, 7H), 1.11 - 1.04 (m, 2H), 0.88 (hept., J = 2.5 Hz, 2H). 0.07 28 684.4 Ή NMR (400 MHz, DMSO-46) δ 9.40 (d, J = 10.0 Hz, 1H), 8.76 (s, 1H), 8.67 (t, J = 6.4 Hz, 1H ), 8.55 (s, 1H), 7.89 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.61 - 7.48 (m, 3H), 7.38 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.32 (p, J = 6.5 Hz, 1H) , 4.25 (p, J = 8.3 Hz, 1H), 3.67 (td, J = 13.9, 6.3 Hz, 2H), 3.56 3.32 (m, 3H), 3 .00 - 2.72 (m, 6H), 2.33 (s, 3H), 1.84 (d, J = 14.2 Hz, 2H), 1.76 - 1.49 (m, 12H), 1.41 (q, J = 12.7, 11.4 Hz, 1H), 1.29 (s, 6H). 0.1 29 666.4 Ή NMR (400 MHz, DMSO-06) δ 9.47 (s, 1H), 8.85 (d, J = 15.6 Hz, 1H), 8.58 (d, J = 6.8 Hz, 1H ), 8.31 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 20.7, 9.2 Hz, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 5.44 - 5 .28 (m, 1H), 4.41 (d, J = 5.7 Hz, 1H), 4.27 (dt, J = 12.9, 5.8 Hz, 3H), 3.58 - 3, 31 (m, 3H), 2.99 - 2.71 (m, 7H), 2.32 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.77 - 1 .53 (m, 8H), 1.48 - 1.34 (m, 1H), 1.29 (s, 6H), 1.11 (d, J = 6.6 Hz, 3H). ο,ι

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thirty 666.4 Ή NMR (400 MHz, DMSO-ab) δ 9.55 (s, 1H), 9.01 8.92 (m, 1H), 8.66 - 8.61 (m, 1H), 8.32 (d , J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (ddd, J = 17.7, 7, 1, 1.8 Hz, ZN), 7.40 (d, J = 7.7 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 5.38 (p, J = 6.3, 5.9 Hz, 1H), 4.41 (dd, J = 5.6, 1.9 Hz, 1H), 4.35 - 4.22 (m, 3H), 3.58 - 3 .32 (m, 3H), 3.01 - 2.71 (m, 6H), 2.33 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.59 ( d, J = 6.6 Hz, 8H), 1.42 (ddt, J = 16.1, 12.5, 6.3 Hz, 1H), 1.29 (s, 6H), 1.11 (d , J = 6.7 Hz, ZN). 0D 31 684.4 Ή NMR (400 MHz, DMSOb) δ 9.49 (s, 1H), 8.87 (d, J = 13.8 Hz, 1H), 8.61 (d, J = 7.0 Hz, 2H), 7.89 (d, J = 1.0 Hz, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.56 (t, J = 9.4 Hz, ZN ), 7.39 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 5.35 (s, 1H), 4.60 (d, J = 4.5 Hz, 2H), 4.48 (d, J = 4.1 Hz, 2H), 4.26 (p, J = 8.3 Hz, 1H), 3.49 (q, J = 8 .1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.98 - 2.73 (m, 6H), 2.33 (s, 3H), 1.84 (d , J = 14.1 Hz, 2H), 1.77 - 1.49 (m, 8H), 1.49 - 1.36 (m, 1H), 1.29 (s, 6H). 0.08 32 738.4 Ή NMR (400 MHz, DMSOb) δ 9.48 (s, 1H), 8.84 (d, J = 12.2 Hz, 2H), 8.58 (s, 1H), 7.90 (s, 1H ), 7.76 (dd, J = 7.9, 1.4 Hz, 1H), 7.64 - 7.48 (m, 4H), 7.21 (d, J = 8.2 Hz, 1H) , 6.09 (t, J = 57.3 Hz, 1H), 5.35 (p, J = 6.7 Hz, 1H), 4.35 - 4.21 (m, 1H), 4.12 - 4.02 (m, 2H), 3.85 (dt, J = 10.9, 5.0 Hz, 2H), 3.56 - 3.34 (m, 3H), 2.96 (qd, J = 9.2, 2.6 Hz, 2H), 2.87 - 2.73 (m, 4H), 2.31 (s, 3H), 1.89 - 1.52 (m, 15H), 1.41 (d, J = 12.2 Hz, 1H), 1.10 - 1.04 (m, 2H), 0.89 (hept., J = 3.5, 2.7 Hz, 2H). 0.08 33 605.3 Ή NMR (400 MHz, methanolD4) δ 8.77 (d, J = 0.6 Hz, 1H), 7.89 (s, 1H), 7.67 (dd, J = 7.8, 1.5 Hz , 1H), 7.58 (dt, J = 2.5, 0.4 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.41 (dt, J = 8, 4, 0.6 Hz, 1H), 7.37 - 7.30 (m, 2H), 4.31 - 4.20 (m, 1H), 4.00 - 3.91 (m, 1H), 3 .72 3.63 (m, 1H), 3.53 (d, J = 12.2 Hz, 2H), 3.02 (qd, J = 9.0, 2.7 Hz, 2H), 2.88 (tdd, J = 12.4, 6.5, 3.3 Hz, ZN), 2.56 - 2.52 (m, ZN), 2.01 (d, J = 14.5 Hz, 2H), 1.88 (d, J = 13.3 Hz, 1H), 1.83 - 1.66 (m, 1H), 1.56 (qt, J = 12.8, 3.8 Hz, 1H), 1 .38 - 1.23 (m, 11H). 0.2 34 619.4 'NMR (400 MHz, methanolD4) δ 8.75 - 8.72 (m, 1H), 7.90 (d, J = 0.5 Hz, 1H), 7.67 (dd, J = 7.8, 1.5 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 - 7.31 (m, 2H), 4.32 - 4.20 (m, 1H), 3.92 (dq, J = 10.8, 3.6 Hz, 1H), 3.68 (p, J = 8.0 Hz, 1H), 3 .54 (d, J = 12.4 Hz, 2H), 3.03 (qd, J = 9.0, 2.7 Hz, 2H), 2.94 - 2.84 (m, 7H), 2, 49 (s, 3H), 2.01 (d, J = 14.6 Hz, 2H), 1.88 (d, J = 13.5 Hz, 1H), 1.75 (q, J = 13.8 , 13.3 Hz, 2H), 1.56 (qt, J = 13.4, 4.1 Hz, 1H), 0.6

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1.37 - 1.23 (w, IN). 35 680.4 'NMR (400 MHz, DMSO-de) δ 9.51 (s, 1H), 8.90 (d, J = 4.0 Hz, 1H), 8.47 (s, 1H), 8.21 (q , J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.68 (dd, J = 7.8, 1.4 Hz, 1H), 7.59 (dd, J = 14, 3, 8.0 Hz, 2H), 7.46 (d, J = 1.5 Hz, 1H), 7.22 (d, J = 12.0 Hz, 1H), 5.33 (p, J = 6.6 Hz, 1H), 4.16 (p, J = 8.3 Hz, 1H), 4.05 (dt, J = 11.5, 5.7 Hz, 2H), 3.84 (dt, J = 10.9, 5.1 Hz, 2H), 3.52 (h, J = 8.4 Hz, 1H), 3.39 (d, J = 11.7 Hz, 2H), 2.93 ( qd, J = 9.3, 2.7 Hz, 2H), 2.87 - 2.70 (m, 6H), 2.39 (s, 3H), 1.90 1.54 (m, 15H), 1.43 (ddt, J = 12.2, 7.4, 3.9 Hz, 1H). 0D 36 620.4 Ή NMR (400 MHz, methanol-dd) δ 8.84 (s, 1H), 8.41 (d, J = 2.9 Hz, 1H), 7.83 - 7.76 (m, 1H), 7 .73 (d, J = 1.4 Hz, 1H), 7.68 (d, J = 1.1 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 4.47 (q, J = 8.0 Hz, 1H), 4.19 (d , J = 27.5 Hz, 2H), 3.83 (s, OH), 3.71 (t, J = 8.0 Hz, 1H), 3.51 (d, J = 11.7 Hz, 1H ), 3.42 (d, J = 12.6 Hz, 1H), 3.02 (ddt, J = 52.7, 41.1, 10.9 Hz, 6H), 2.49 (s, 3H) , 2.01 - 1.67 (m, 3H), 1.53 - 1.36 (m, 10H). 0.1 37 620.4 Ή NMR (400 MHz, methanol-dd) δ 8.60 (d, J = 4.3 Hz, 1H), 8.46 (d, J = 2.4 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 1.4 Hz, 1H), 7.67 (s, 1H), 7.53 (dd, J = 8.3, 2.5 Hz , 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 4.47 (t, J = 8.1 Hz, 1H ), 4.22 (s, 1H), 4.10 (s, 1H), 3.72 (t, J = 7.8 Hz, 1H), 3.59 - 3.38 (m, 1H), 3 .14 (d, J = 8.5 Hz, 1H), 3.06 (d, J = 13.1 Hz, 4H), 2.91 (d, J = 11.4 Hz, OH), 2.49 (s, 3H), 2.01 1.65 (m, 3H), 1.42 (s, 12H). 0.1 38 646 'NMR (400 MHz, methanol-dd) δ 8.31 (s, 1H), 8.19 (s, 1H), 7.8d - 7.55 (m, dH), 7.37 (d, J= 7.8 Hz, 1H), 7.2d (d, J = 8.d Hz, 1H), d,d7 - d.36 (m, 1H), d,Od 3.95 (m, 1H), 3 .65 - 335 (m, 3H), 3.20 - 2.50 (m, 13H), 2.39 (s, 3H), 1.92 - 176 (s, 2H), 1.53 - 1.30 (m, 10H), 1.07 (s, 6H). 0.07 39 622.3 'NMR (dOO MHz, DMSO-de) δ 10.12 - 9.97 (m), 8.70, 8.d6, 8.15 (d, J = d.6 Hz), 7.88, 7, 78 (dd, J = 7.8, l,d Hz), 7.63 - 7.d7 (m), 7.39 (d, J = 7.7 Hz), 7.20 (d, J = 8 ,3 Hz), 5.30 (p, J = 6.5 Hz), d,d2 - d.21 (m), d.02 (d, J = 13.3 Hz), 3.75 - 3, 53 (m), 3.d0 (d, J = 12.2 Hz), 3.17 - 2.62 (m), 2.32, 1.56 (d, J = 6.5 Hz), 1, 30 (s, 6H). 0D 40 638.5 Ή NMR (dOO MHz, DMSO-de) δ 9.35 (d, J = 9.d Hz, 1H), 8.5d - 8.30 (m, 3H), 8.02 (d, J = 2, 7 Hz, 1H), 7.95 - 7.72 (m, 3H), 7.59 (d, J = 1.5 Hz, 1H), 7.d3 (dd, J = 21.6, 8.3 Hz, 2H), d,dO - d.23 (m, 1H), d.12 (p, J = 6.d Hz, 1H), 3.56 - 3.26 (m, 3H), 3.07 - 2.58 (m, 8H), 1.99 - 1.50 (m, 6H), l.d5 - 1.15 (m, 11H). 0D

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41 773.7 Ή NMR (400 MHz, DMSO-ab) δ 9.37 (s, 1H), 8.44 (s, 1H), 8.39 (q, J = 3.6, 3.0 Hz, 2H), 7 .97 (d, J = 2.6 Hz, 1H), 7.91 (dd, J = 8.8, 2.7 Hz, 1H), 7.86 (s, 1H), 7.80 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.47 ( d, J = 8.8 Hz, 1H), 4.40 - 4.28 (m, 1H), 4.13 (s, 1H), 4.04 - 3.81 (m, 2H), 3.41 (d, J = 11.8 Hz, 3H), 3.06 - 2.79 (m, 5H), 2.77 (d, J = 4.6 Hz, 3H), 2.13 (d, J = 6.9 Hz, 6H), 1.90 - 1.53 (m, 12H), 1.41 (d, J = 13.1 Hz, 1H), 1.24 (d, J = 7.5 Hz, 5H). 0.07 42 755.5 'NMR (400 MHz, chloroform-d) δ 7.95 (s, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 12.6 Hz, 2H ), 7.77 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 1.4 Hz, 1H), 7.56 (s, 1H), 7.22 (d, J = 8.3 Hz, 2H), 5.87 (d, J = 5.0 Hz, 1H), 5.00 (dt, J = 17.5, 6.4 Hz, 2H), 4.85 (dt , J = 9.5, 4.9 Hz, 2H), 4.39 (t, J = 8.7 Hz, 1H), 4.26 (d, J = 14.0 Hz, 1H), 4.18 - 4.01 (m, 1H), 3.86 (dd, J = 13.5, 8.9 Hz, 2H), 3.74 (s, 1H), 3.28 (d, J = 28.3 Hz, 2H), 3.00 (dd, J = 5.0, 1.5 Hz, 3H), 2.67 (dd, J = 17.8, 9.7 Hz, 5H), 2.45 (d , J = 1.3 Hz, 3H), 2.41 - 2.29 (m, 2H), 1.84 (d, J = 11.3 Hz, 3H), 1.65 (d, J = 9, 9 Hz, 2H), 1.42 (d, J = 7.6 Hz, 5H), 1.31-1.23 (m, 4H). 0.06 43 765.6 'NMR (400 MHz, DMSO-46) δ 9.82 (s, OH), 9.35 (s, 1H), 8.37 (s, 1H), 8.21 (s, 1H), 8.18 (d, J = 4.6 Hz, 1H), 7.89 (s, OH), 7.85 (d, J = 2.4 Hz, 1H), 7.83 7.77 (m, 2H), 7.76 (s, 1H), 7.64 - 7.55 (m, 2H), 7.21 (d, J = 8.3 Hz, 1H), 4.25 (t, J = 8.5 Hz , 1H), 4.19 4.06 (m, 1H), 4.02 - 3.70 (m, 6H), 3.68 - 3.55 (m, 1H), 3.23 (s, 1H) , 2.98 - 2.78 (m, 5H), 2.74 (dd, J = 4.7, 0.6 Hz, 3H), 2.69 - 2.64 (m, OH), 2.36 - 2.25 (m, 3H), 2.11 (d, J = 10.9 Hz, 7H), 1.93 (d, J = 11.4 Hz, 1H), 1.82 - 1.56 ( m, 8H), 1.36 (s, 1H), 1.25 (d, J = 8.0 Hz, 4H). 0.08 44 713.5 Ή NMR (400 MHz, DMSO-de) δ 8.30 (d, J = 0.4 Hz, 1H), 8.23 - 8.15 (m, 2H), 8.12 (d, J = 1, 5 Hz, 1H), 7.94 (dd, J = 8.3, 2.4 Hz, 1H), 7.87 - 7.81 (m, 2H), 7.77 (s, 1H), 7, 51 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 4.60 - 4.47 (m, 1H), 4.17 - 4.09 (m, 1H), 3.97 - 3.81 (m, 2H), 3.73 (q, J = 6.3 Hz, 2H), 3.06 2.93 (m, 1H), 2.77 (d, J = 4.6 Hz, 3H), 2.72 - 2.57 (m, 4H), 2.31 (s, 4H), 2.24 (d, J = 8.8 Hz, 1H) , 2.09 (d, J = 0.8 Hz, 3H), 1.88 - 1.72 (m, 2H), 1.73 - 1.55 (m, 5H), 1.55 - 1.29 (m, 3H), 1.30 - 1.23 (m, 4H), 1.22 1.17 (m, 2H). 0.2 45 648.5 Ή NMR (400 MHz, DMSO-de) δ 9.39 (d, J = 9.6 Hz, 1H), 8.68 (s, 1H), 8.47 (s, 1H), 8.14 (q , J = 4.5 Hz, 1H), 7.99 - 7.75 (m, 2H), 7.67 - 7.42 (m, 3H), 7.23 (dd, J = 37.4, 8 ,1 Hz, 2H), 5.28 (p, J = 6.5 Hz, 1H), 4.24 (t, J = 8.2 Hz, 1H), 3.56 - 3.25 (m, 3H ), 3.04 - 0D

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2.62 (m, 9H), 2.30 (s, ZN), 1.95 - 1.20 (m, 16H), 0.50 (t, J = 7.3 Hz, 6H). 46 703.5 Ή NMR (400 MHz, DMSO-ab) δ 9.38 (d, J = 9.8 Hz, 1H), 8.71 (s, 1H), 8.47 (s, 1H), 8.14 (q , J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.62 - 7.43 (m, 4H), 7.17 (d, J = 9.0 Hz, 1H), 5.28 (p, J = 6.5 Hz, 1H), 4.63 - 3.23 (m, 7H), 3, 08 - 2.62 (m, 10H), 2.30 (s, 3H), 2.07 (s, 3H), 1.91 - 1.28 (m, 16H). 0D 47 721.6 ^J H NMR (400 MHz, DMSO-de) δ 9.44 (s, 1H), 8.56 8.24 (m, 3H), 8.05 - 7.71 (m, 4H), 7.66 - 7.33 (m, 3H), 4.70 - 3.24 (m, 12H), 3.10 - 2.59 (m, 6H), 2.07 (s, 3H), 1.94 - 1, 12 (m, 14H). 0.2 48 717.6 NMR (400 MHz, DMSOZH) δ 9.35 (s, 1H), 8.67 (s, 1H), 8.43 (s, 1H), 8.14 (d, J = 4.7 Hz, 1H) , 7.89 (s, 1H), 7.75 (dd, J = 8.2, 1.4 Hz, 1H), 7.65 - 7.33 (m, 4H), 7.16 (d, J = 8.1 Hz, 1H), 5.08 (q, J = 6.6 Hz, 1H), 4.55 - 3.27 (m, 7H), 3.12 - 2.63 (m, 10H) , 2.29 (s, 3H), 2.07 (s, 3H), 1.96 - 1.50 (m, 14H), 1.41 (t, J = 12.9 Hz, 1H), 0, 76 (t, J = 7.3 Hz, ZN). 0D 49 689.5 U NMR (400 MHz, DMSO-de) δ 9.34 (s, 1H), 8.44 (d, J = 29.5 Hz, 2H), 8.14 (q, J = 4.5 Hz, 1H ), 7.92 7.73 (m, 2H), 7.69 - 7.42 (m, 4H), 7.18 (d, J = 8.3 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.26 (p, J = 8.2 Hz, 1H), 4.12 - 3.25 (m, 8H), 3.07 - 2.63 (m, 8H) , 2.30 (s, 3H), 2.07 (s, 3H), 1.93 - 1.50 (m, 10H), 1.38 (t, J = 7.2 Hz, ZN). 0D 50 717.6 SH NMR (400 MHz, DMSO-de) δ 9.44 (d, J = 10.1 Hz, 1H), 8.51 (s, 1H), 8.29 - 8.11 (m, 2H), 7 .95 - 7.73 (m, 4H), 7.67 - 7.45 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 5.05 - 4.00 (m , 6H), 3.91 - 3.27 (m, 11H), 3.04 2.66 (m, 7H), 2.30 (s, 3H), 2.03 - 1.09 (m, 11H) . 0.1 51 727.6 Ή NMR (400 MHz, DMSO-de) δ 9.38 (d, J = 9.8 Hz, 1H), 8.44 (s, 1H), 8.32 - 8.04 (m, 2H), 7 .98 - 7.73 (m, 4H), 7.74 - 7.51 (m, 2H), 7.21 (d, J = 8.4 Hz, 1H), 4.47 - 3.25 (m , 8H), 3.07 - 2.65 (m, 9H), 2.30 (s, 3H), 2.12 - 1.14 (m, 16H), 0.87 - 0.58 (m, 4H ). 0.1 52 729.6 Ή NMR (400 MHz, DMSO-de) δ 9.32 (s, 1H), 8.33 (s, 1H), 8.22 - 8.13 (m, 2H), 7.95 - 7.76 ( m, 4H), 7.71 - 7.48 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 4.32 (t, J = 8.1 Hz, 1H), 4.12 (d, J = 4.4 Hz, 1H), 3.84 (d, J = 33.9 Hz, ZN), 3.41 (s, ZN), 3.00 - 2.65 (m , 9H), 2.29 (s, 3H), 1.91 - 1.53 (m, 9H), 1.43 - 1.14 (m, 5H), 1.04 (dd, J = 11.3 , 6.6 Hz, 7H). 0.09 53 763.5 SH NMR (400 MHz, DMSO-de) δ 9.38 (d, J = 9.6 Hz, 1H), 8.67 (s, 1H), 8.49 - 8.34 (m, 1H), 8 .14 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.66 - 7.42 (m, 4H), 7.17 (d, J = 12.1 Hz, 1H), 5.38 - 5.14 (m, 1H), 4.33 - 3.93 0.08

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(m, 2H), 3.89 - 3.60 (m, 2H), 3.57 - 3.21 (m, 3H), 3.03 - 2.65 (m, 7H), 2.41 - 2 .18 (m, 5H), 1.90 - 1.47 (m, 16H), 1.38 (d, J = 13.2 Hz, 1H), 1.14 - 0.90 (m, 9H). 54 735.5 Ή NMR (400 MHz, DMSO-ab) δ 9.42 (d, J = 9.6 Hz, 1H), 8.58 (s, 1H), 8.39 (s, 1H), 8.15 (d , J = 7.9 Hz, 1H), 7.84 (s, 1H), 7.76 - 7.62 (m, 2H), 7.49 (d, J = 7.5 Hz, 2H), 7 .18 (d, J = 12.1 Hz, 1H), 4.63 (q, J = 7.1 Hz, 2H), 4.29 - 3.28 (m, 9H), 3.07 - 2, 62 (m, 5H), 2.35 (s, 3H), 2.06 (s, 3H), 1.95 - 1.23 (m, 14H), 1.07 (d, J = 6.5 Hz , 6H). 0.4 55 793.5 'NMR (400 MHz, DMSO-de) δ 9.35 (s, 1H), 8.66 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 7.8 Hz , 1H), 7.86 (s, 1H), 7.73 - 7.42 (m, 4H), 7.17 (d, J = 12.1 Hz, 1H), 5.27 (q, J = 6.7 Hz, 1H), 4.45 - 3.68 (m, 8H), 3.55 3.22 (m, 3H), 3.05 - 2.59 (m, 7H), 2.34 ( s, 3H), 1.91 1.44 (m, 15H), 1.35 (s, 5H), 1.07 (d, J = 6.6 Hz, 6H). 0.2 56 735.5 Ή NMR (400 MHz, DMSO-46) δ 9.40 (d, J = 9.8 Hz, 1H), 8.53 (s, 1H), 8.36 (s, 1H), 8.26 (t , J = 5.6 Hz, 1H), 7.84 (s, 1H), 7.75 - 7.60 (m, 2H), 7.54 - 7.41 (m, 2H), 7.18 ( d, J = 12.0 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.18 (p, J = 8.3 Hz, 1H), 3.96 - 3, 61 (m, 4H), 3.55 - 3.08 (m, 5H), 3.04 - 2.65 (m, 6H), 2.43 - 2.31 (m, 5H), 1.89 - 1.23 (m, 13H), 1.03 (dt, J = 9.5, 7.3 Hz, 6H). 0.3 57 606.4 Ή NMR (400 MHz, DMSO-46) δ 9.67 (d, J = 9.5 Hz, 1H), 9.01 (s, 1H), 8.62 - 8.40 (m, 1H), 8 .15 (q, J = 4.5 Hz, 1H), 7.71 (s, 1H), 7.59 - 7.47 (m, 2H), 7.31 (dd, J = 7.7, 1 .5 Hz, 1H), 7.18 (dt, J = 8.0, 0.7 Hz, 1H), 7.09 - 6.94 (m, 2H), 5.59 - 5.15 (m, 1H), 3.88 (p, J = 8.2 Hz, 1H), 3.51 - 3.29 (m, 3H), 3.12 (s, 2H), 2.84 - 2.68 (m , 5H), 2.57 - 2.44 (m, 3H), 2.40 - 2.25 (m, 5H), 1.83 (d, J = 14.2 Hz, 2H), 1.56 ( d, J = 6.5 Hz, 8H), 1.46 - 1.34 (m, 1H), 1.24 (s, 6H). 0.2 58a 701.6 1 'NMR (400 MHz, DMSOschb) δ 9.40 (s, 1H), 8.51 (s, 1H), 8.25 (s, 1H), 8.17 (q, J = 4.6 Hz, 1H ), 7.91 (d, J = 2.4 Hz, 1H), 7.85 - 7.77 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (p, J = 8.3 Hz, 1H), 4.20 - 4 ,12 (m, 1H), 3.89 (dd, J = 31.5, 7.9 Hz, 2H), 3.73 (dd, J = 11.9, 5.5 Hz, 2H), 3, 52 (q, J = 7.9 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.07 - 2.72 (m, 8H), 2.32 (s, 3H ), 2.12 - 2.06 (m, 4H), 1.89 - 1.54 (m, 8H), 1.32 - 1.23 (m, 3H). 0.1 58 604.3 Ή NMR (400 MHz, DMSO-46) δ 9.68 (d, J = 9.6 Hz, 1H), 8.62 (s, 1H), 8.31 - 7.98 (m, 2H), 7 .94 (d, J = 2.4 Hz, 1H), 7.81 (dd, J = 8.3, 2.4 Hz, 1H), 7.61 (s, 1H), 7.37 (dd, J = 7.7, 1.5 Hz, 1H), 7.29 - 6.97 (m, 3H), 4.17 (p, J = 5.3 Hz, 1H), 3.93 (p, J = 8.2 Hz, 0.6

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1H), 3.58 - 3.27 (m, ZH), 3.13 (s, 2H), 2.75 (d, J = 4.6 Hz, 5H), 2.61-2.51 (m , 2H), 2.41 - 2.21 (m, 4H), 1.93 - 1.00 (m, 17H). 59 763.4 Ή NMR (400 MHz, DMSO-de) δ 9.36 (d, J = 9.6 Hz, 1H), 8.70 (s, 1H), 8.41 (s, 1H), 7.89 (s , 1H), 7.87 (s, 1H), 7.72 - 7.62 (m, 1H), 7.57 - 7.44 (m, 3H), 7.17 (d, J = 12.1 Hz, 1H), 5.36 - 5.20 (m, 1H), 4.20 (p, J = 8.5 Hz, 1H), 3.91 - 3.80 (m, 2H), 3.79 - 3.63 (m, 2H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.02 - 2.84 ( m, 2H), 2.85 - 2.72 (m, 4H), 2.35 (s, 3H), 2.08 (s, 3H), 1.90 - 1.62 (m, 8H), 1 .62 - 1.54 (m, 7H), 1.47 - 1.35 (m, 1H), 1.33 (s, 9H). 0.3 60 749.4 ^NMR (400 MHz, DMSO-de) δ 9.31 (s, 1H), 8.62 (s, 1H), 8.38 (s, 1H), 8.27 (t, J = 5.6 Hz , 1H), 7.88 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.53 - 7 .49 (m, 2H), 7.19 (d, J = 12.0 Hz, 1H), 5.33 - 5.21 (m, 1H), 4.19 (p, J = 8.1 Hz, 1H), 3.93 3.65 (m, 4H), 3.51 (q, J = 8.0 Hz, 1H), 3.39 (d, J = 12.0 Hz, 2H), 3.22 (p, J = 7.1 Hz, 2H), 3.04 - 2.71 (m, 5H), 2.44 - 2.34 (m, 6H), 1.84 (d, J = 14.1 Hz, 2H), 1.80 - 1.53 (m, 13H), 1.48 - 1.34 (m, 1H), 1.08 - 1.01 (m, 6H). 0.2 61 743.4 ^NMR (400 MHz, DMSO-de) δ 9.50 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.20 (q, J = 4.4 Hz , 1H), 7.91 (s, 1H), 7.72 (d, J = 7.6 Hz, 1H), 7.61 (s, 1H), 7.51 (s, 1H), 7.19 (d, J = 12.1 Hz, 1H), 6.73 - 6.40 (m, 1H), 5.28 (p, J = 6.3 Hz, 1H), 4.20 (p, J = 8.4 Hz, 1H), 3.95 - 3.25 (m, 8H), 2.97 - 2.87 (m, 2H), 2.87 - 2.71 (m, 8H), 2.38 (s, 3H), 2.02 (s, 3H), 1.84 (d, J = 14.2 Hz, 2H), 1.76 - 1.55 (m, 10H), 1.48 - 1, 36 (m, 1H). 0.2 62 753.4 ^NMR (400 MHz, DMSO-de) δ 9.66 - 9.53 (m, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), 7.82 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (s, 1H), 7.58 - 7.44 (m, 2H), 7.18 (d, J = 8.4 Hz, 1H), 6.59 (t, J = 53.7 Hz, 2H), 5.32 (p, J = 6 .5 Hz, 1H), 4.28 (p, J = 8.4 Hz, 1H), 4.11 - 3.98 (m, 1H), 3.80 (s, 2H), 3.64 (s , 2H), 3.54 - 3.30 (m, 5H), 2.98 - 2.88 (m, 2H), 2.88 - 2.73 (m, 4H), 2.31 (s, 3H ), 2.26 - 1.89 (m, 4H), 1.84 (d, J = 14.1 Hz, 2H), 1.76 - 1.59 (m, 3H), 1.57 (d, J = 6.5 Hz, 6H), 1.48 - 1.35 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H). 0.1 63 642.4 Ή NMR (400 MHz, DMSO^b) δ 9.34 (s, 1H), 8.68 8.54 (m, 1H), 8.40 - 8.30 (m, 1H), 8.00 - 7 .88 (m, 1H), 7.81 - 7.74 (m, 1H), 7.62 - 7.50 (m, 3H), 7.48 7.31 (m, 2H), 6.16 - 5.69 (m, 1H), 5.27 - 5.22 (m, 1H), 4.23 (s, 2H), 2.99 - 2.63 (m, 6H), 2.47 - 2, 30 (m, 4H), 1.98 - 1.14 (m, 16H). 0.1

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64 745.4 Ή NMR (400 MHz, DMSSMb) δ 9.86 (s, 1H), 9.39 (s, 1H), 8.98 (s, 1H), 8.74 - 8.61 (m, 3H), 8 .00 (s, 1H), 7.76 - 7.66 (m, 1H), 7.50 - 7.30 (m, 1H), 6.06 (t, J = 56.9 Hz, 1H), 5.34 - 5.22 (m, 1H), 4.30 - 4.10 (m, 1H), 3.97 (s, 1H), 3.66 - 3.55 (m, 1H), 3, 40 - 3.35 (m, 1H), 3.30 - 3.21 (m, 1H), 2.95 (d, J = 8.1 Hz, 1H), 2.90 - 2.81 (m, 1H), 2.65 (d, J = 19.5 Hz, 1H), 2.29 (d, J = 2.2 Hz, 3H), 2.01 - 1.88 (m, 1H), 1, 74 (t, J = 12.2 Hz, 4H), 1.67 - 1.55 (m, 7H), 1.53 (d, J = 6.5 Hz, 1H), 1.39 (t, J = 8.1 Hz, 1H), 1.30 (s, 6H), 1.16 - 1.04 (m, 2H), 0.95 - 0.90 (m, 2H). 0D 65 714.4 ^NMR (400 MHz, DMSO-de) δ 9.42 (s, 1H), 8.84 (s, 1H), 8.75 (s, 1H), 8.45 (s, 1H), 7.85 (s, 1H), 7.68 7.60 (m, 2H), 7.46 (d, J = 1.5 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 12.1 Hz, 1H), 6.07 (t, J = 57.2 Hz, 1H), 5.30 (p, J = 6.6 Hz, 1H), 4, 20 (p, J = 8.4 Hz, 1H), 3.51 (p, J = 8.2 Hz, 1H), 3.40 (d, J = 11.9 Hz, 2H), 3.00 - 2.70 (m, 7H), 2.36 (s, 3H), 1.91 1.33 (m, 11H), 1.28 (s, 6H), 1.10 - 1.03 (m, 2H ), 0.88 (s, 2H). 0.1 66 726.4 ^NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 8.85 (d, J = 2.9 Hz, 1H), 8.69 (d, J = 3.6 Hz, 1H ), 8.42 (s, 1H), 7.83 (s, 1H), 7.68 - 7.54 (m, 2H), 7.47 - 7.31 (m, 2H), 7.22 ( d, J = 11.9 Hz, 1H), 6.07 (t, J = 57.1 Hz, 1H), 5.29 (p, J = 6.5 Hz, 1H), 4.22 - 4, 04 (m, 1H), 3.96 (s, 1H), 3.78 - 3.55 (m, 1H), 3.44 - 3.19 (m, 1H), 3.02 - 2.60 ( m, 6H), 2.36 (s, 3H), 1.98 (t, J = 13.8 Hz, 1H), 1.84 - 1.50 (m, 11H), 1.28 (s, 6H ), 1.07 (q, J = 5.0, 4.6 Hz, 2H), 0.89 (s, 3H). 0.09 67 715.4 Ή NMR (400 MHz, DMSO-de) δ 9.37 (d, J = 9.6 Hz, 1H), 8.86 (s, 1H), 8.74 - 8.65 (m, 2H), 8 .45 (s, 1H), 7.96 (s, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7 .22 (d, J = 12.0 Hz, 1H), 6.09 (t, J = 57.2 Hz, 1H), 5.35 - 5.24 (m, 1H), 4.32 - 4, 19 (m, 1H), 3.58 - 3.45 (m, 1H), 3.40 (d, J = 11.9 Hz, 2H), 2.97 2.75 (m, 6H), 2, 36 (s, 3H), 1.85 (d, J = 14.2 Hz, 2H), 1.76-1.61 (m, 3H), 1.59 (d, J = 6.5 Hz, 6H ), 1.42 (t, J = 12.6 Hz, 1H), 1.29 (s, 6H), 1.06 (t, J = 3.6 Hz, 2H), 0.92 (d, J = 6.0 Hz, 2H). 0.3 68 735.4 Ή NMR (400 MHz, DMSO-de) δ 11.20 - 10.66 (m, 1H), 9.82 - 9.48 (m, 1H), 8.68 (s, 1H), 8.39 ( s, 1H), 8.20 (d, J = 4.7 Hz, 1H), 8.02 - 7.12 (m, 6H), 5.29 (p, J = 6.5 Hz, 1H), 4.97 - 4.42 (m, 5H), 4.25 - 4.08 (m, 1H), 3.64 - 3.13 (m, 7H), 3.00 - 2.86 (m, 2H ), 2.86 2.71 (m, 7H), 2.45 - 1.77 (m, 9H), 1.78-1.51 (m, 9H), 1.51 - 1.34 (m, 1H). 0.2 69 749.4 ^NMR (400 MHz, DMSO-de) δ 10.90 - 10.64 (m, 1H), 9.60 - 9.40 (m, 1H), 8.60 (s, 1H), 8.42 - 8.35(m, 0.1

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1H), 8.28 (t, J = 5.6 Hz, 1H), 7.99 - 7.11 (m, 5H), 5.27 (p, J = 6.4 Hz, 1H), 4, 95 - 4.65 (m, 5H), 4.55 4.13 (m, 3H), 3.61 - 3.33 (m, 4H), 3.22 (p, J = 7.0 Hz, 3H ), 2.98 - 2.87 (m, 2H), 2.86 - 2.74 (m, 4H), 2.40 1.96 (m, 7H), 1.88 - 1.76 (m, 3H), 1.76 - 1.53 (m, 9H), 1.48 - 1.35 (m, 1H), 1.07 (t, J = 7.2 Hz, 3H). 70 769.4 Ή NMR (400 MHz, DMSOZhb) δ 8.68 (s, 1H), 8.39 (s, 1H), 8.21 (d, J = 4.6 Hz, 1H), 8.01 - 7.36 (m, 5H), 7.20 (d, J = 11.9 Hz, 2H), 5.29 (p, J = 6.4 Hz, 1H), 4.96 - 4.69 (m, 5H) , 4.18 (p, J = 8.6, 8.1 Hz, 1H), 3.94 - 3.03 (m, 9H), 3.03 - 2.82 (m, 3H), 2.80 - 2.65 (m, 4H), 2.60 - 2.44 (m, 1H, intersects with solvent), 2.38 (s, 3H), 2.43 - 1.69 (m, 5H), 1 .59 (d, J = 6.6 Hz, 6H). 0.7 71 739.4 'NMR (400 MHz, DMSO-de) δ 11.18 - 10.61 (m, 2H), 8.66 (s, 1H), 8.38 (s, 1H), 8.21 (d, J = 4.6 Hz, 1H), 8.02 - 7.10 (m, 6H), 5.64 - 5.39 (m, 1H), 5.28 (p, J = 6.7 Hz, 1H), 4.95 - 4.44 (m, 5H), 4.23 (s, 1H), 3.99 - 3.14 (m, 9H), 3.03 - 2.85 (m, 2H), 2, 83 - 2.71 (m, 5H), 2.45 - 1.72 (m, 9H), 1.59 (d, J = 6.5 Hz, 6H). 0D 72 739.4 Ή NMR (400 MHz, DMSOZhb) δ 11.21 - 10.64 (m, 2H), 8.65 (s, 1H), 8.37 (s, 1H), 8.21 (d, J = 4, 6 Hz, 1H), 8.01 - 7.07 (m, 6H), 5.51 (d, J = 53.0, 1H), 5.29 (p, J = 6.4 Hz, 1H), 4.86 - 4.46 (m, 5H), 4.31 - 4.16 (m, 1H), 3.97 - 3.15 (m, 9H), 2.95 (p, J = 9.6 Hz, 1H), 2.86 - 2.69 (m, 4H), 2.43 - 1.72 (m, 9H), 1.59 (d, J = 6.5 Hz, 6H). 0.2 73 745.5 Ή NMR (400 MHz, DMSOZhb) δ 11.23 - 10.72 (m, 1H), 9.83 - 9.53 (m, 1H), 8.71 (s, 1H), 8.51 (s, 1H), 8.12 (d, J = 7.9 Hz), 8.03 - 7.21 (m, 6H), 7.18 (d, J = 8.4 Hz, 1H), 5.32 ( p, J = 6.6 Hz, 1H), 4.95 - 4.40 (m, 5H), 4.28 (p, J = 8.4 Hz, 1H), 4.05 (hex, J = 6.8 Hz, 1H), 3.70 - 3.13 (m, 7H), 2.93 (q, J = 9.3 Hz, 2H), 2.87 - 2.74 (m, 4H), 2.40 - 1.50 (m, 19H), 1.50 - 1.32 (m, 1H), 1.10 (d, J = 6.6 Hz, 6H). 0.1 74 735.4 'NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 8.76 8.70 (m, 1H), 8.43 (s, 1H), 8.27 (t, J = 5 ,6 Hz, 1H), 7.87 (s, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7, 56 - 7.46 (m, 2H), 7.20 (d, J = 12.0 Hz, 1H), 5.36 - 5.20 (m, 1H), 4.17 (p, J = 8, 3 Hz, 1H), 3.93 - 3.79 (m, 2H), 3.77 - 3.66 (m, 2H), 3.51 (q, J = 8.1 Hz, 1H), 3, 39 (d, J = 11.7 Hz, 2H), 3.22 (p, J = 7.1 Hz, 2H), 3.03 - 2.71 (m, 6H), 2.38 (s, 3H ), 2.08 (s, 3H), 1.89 - 1.62 (m, 8H), 1.62 - 1.54 (m, 7H), 1.48 - 1.34 (m, 1H), 1.06 (t, J = 7.2, 3H). 0.2 75 763.4 Ή NMR (400 MHz, DMSO-de) δ 9.34 (s, 1H), 8.69 (s, 1H), 8.40 (s, 1H), 8.27 (t, J = 5.9 Hz , 1H), 7.86 (s, 0.2

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1H), 7.65 (d, J = 7.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.51 - 7.47 (m, 2H), 7. 18 (d, J = 12.1 Hz, 1H), 5.34 - 5.21 (m, 1H), 4.16 (p, J = 8.2 Hz, 1H), 3.93 3.76 ( m, 2H), 3.76 - 3.63 (m, 2H), 3.49 (q, J = 8.0 Hz, 1H), 3.38 (d, J = 11.7 Hz, 2H), 3.00 (t, J = 6.4 Hz, 2H), 2.97 - 2.81 (m, 2H), 2.81 - 2.71 (m, 3H), 2.35 (s, 3H) , 2.06 (s, 3H), 1.86 - 1.51 (m, 17H), 1.45 - 1.32 (m, 1H), 0.82 (d, J = 6.7 Hz, 6H ). 76 761.4 Ή NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 8.73 (s, 1H), 8.53 (d, J = 7.7 Hz, 1H), 8.44 (s , 1H), 7.88 (s, 1H), 7.71 - 7.64 (m, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.54.7.47 ( _m? 2H), 7.20 (d, J = 12.1 Hz, 1H), 5.30 (p, J = 6.5 Hz, 1H), 4.37 (hex, J = 8.1 Hz, 1H ), 4.18 (p, J = 8.6 Hz, 1H), 3.93 - 3.78 (m, 2H), 3.77 - 3.66 (m, 2H), 3.51 (q, J = 8.1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 3.02 - 2.72 (m, 6H), 2.36 (s, 3H), 2, 23 - 2.12 (m, 2H), 2.08 (s, 3H), 1.94 (p, J = 9.6 Hz, 2H), 1.88 1.53 (m, 16H), 1, 47 - 1.34 (m, 1H). 0.2 77 777.4 Ή NMR (400 MHz, DMSO-46) δ 9.92 (d, J = 8.9 Hz, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.14 (d , J = 7.9 Hz, 1H), 7.85 (s, 1H), 7.71 - 7.61 (m, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7 .44 (s, 1H), 7.18 (d, J = 12.2 Hz, 1H), 5.28 (p, J = 6.4 Hz, 1H), 4.17 - 3.98 (m, 2H), 3.96 (s, 2H), 3.93 - 3.80 (m, 4H), 3.79 - 3.66 (m, 4H), 3.59 3.46 (m, 1H), 3.07 - 2.81 (m, 4H), 2.34 (s, 3H), 2.21 2.05 (m, 7H), 1.87 - 1.73 (m, 2H), 1.69 (t, J = 5.9 Hz, 2H), 1.58 (d, J = 6.5 Hz, 6H), 1.09 (d, J = 6.5 Hz, 6H). 0.06 78 777.4 'H NMR (400 MHz, DMSO-46) δ 9.38 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.86 (s, 1H), 7.71 - 7.64 (m, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.47 (s, 1H), 7.19 (d, J = 12.1 Hz, 1H), 5.29 (p, J = 6.7 Hz, 1H), 4.52 (s, 2H), 4.14 (p, J = 8.4 Hz, 1H), 4.04 (hex, J = 6.7 Hz, 1H), 3.93 - 3.79 ( m, 2H), 3.79 - 3.57 (m, 3H), 3.38 (d, J = 11.9 Hz, 2H), 3.15 - 2.86 (m, 4H), 2.81 - 2.70 (m, 2H), 2.37 (s, 3H), 2.08 (s, 3H), 2.05 - 1.92 (m, 4H), 1.87 - 1.72 (m , 2H), 1.68 (t, J = 5.9 Hz, 2H), 1.59 (d, J = 6.5 Hz, 6H), 1.10 (d, J = 6.5 Hz, 6H ). 0.2 79 618.5 1 Ή NMR (400 MHz, DMSO-de) δ 9.36 (s, 1H), 8.42 (s, 1H), 8.23 (s, 1H), 8.19 (q, J = 4.6 Hz , 1H), 7.95 (d, J = 2.3 Hz, 1H), 7.85 - 7.78 (m, 2H), 7.78 (s, 1H), 7.63 (s, 1H) , 7.41 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.32 (p, J = 8.3 Hz, 1H), 4 .15 (s, 1H), 3.53 (q, J = 8.2 Hz, 2H), 3.40 (d, J = 11.8 Hz, 2H), 3.04 2.70 (m, 8H ), 2.31 (s, 3H), 1.83 (d, J = 14.0 Hz, 2H), 1.65 (dt, J = 40.1, 13.0 Hz, 4H), 1.29 (d, J = 19.6 Hz, JN). 0.2

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80 670.3 Ή NMR (400 MHz, methanol-d4) δ 9.25 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H), 7.75 (dd, J = 7.8, 1, 6 Hz, 1H), 7.69 (d, J = 2.5 Hz, 1H), 7.61 (s, 1H), 7.44 - 7.35 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 5.39 (q, J = 6.5 Hz, 1H), 4.39 (p, J = 8.2 Hz, 1H), 3.88 (p, J = 7.7 Hz, 1H), 3.35 (d, J = 13.4 Hz, 1H), 2.95 (t, J = 7.9 Hz, 4H), 2.91 - 2.85 (m, 3H), 2, 43 (s, 3H), 2.18 (d, J = 12.3 Hz, 4H), 2.07 - 1.84 (m, 2H), 1.80 - 1.66 (m, 8H), 1 .37(s,6H). 0.1 81 642.3 'NMR (400 MHz, methanol^4) δ 9.20 (s, 1H), 7.79 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7 .67 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7.44 - 7.36 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 5.38 (p, J = 6.6 Hz, 1H), 4.41 (p, J = 8.3 Hz, 1H), 3.83 (dt, J = 11.2, 5.6 Hz, 1H), 3.75 (q, J = 8.0 Hz, 1H), 3.17 - 2.95 (m, 4H), 2.95 - 2.83 (m , 7H), 2.44 (s, 3H), 1.72 (d, J = 6.6 Hz, 6H), 1.38 (s, 6H). 0.3 82 626.3 Ή NMR (400 MHz, methanol-d4) δ 9.07 (s, 1H), 7.80 - 7.74 (m, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7 .63 (d, J = 1.4 Hz, 1H), 7.43 - 7.36 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 5.35 (p, J = 6.4 Hz, 1H), 4.46 (p, J = 8.0 Hz, 1H), 3.81 (p, J = 7.6 Hz, 1H), 3.26 (s, 1H) , 3.09 2.91 (m, 4H), 2.89 (s, 3H), 2.43 (s, 3H), 1.71 (d, J = 6.6 Hz, 6H), 1.57 (s, 3H), 1.52 (s, 3H), 1.39 (s, 6H). 0.08 83 731.5 Ή NMR (400 MHz, DMSO-de) δ 9.40 (d, J = 9.1 Hz, 1H), 8.70 (s, 1H), 8.51 (s, 1H), 8.12 (d , J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7.63 (d, J = 1, 5 Hz, 1H), 7.56 - 7.45 (m, 3H), 7.18 (d, J = 8.2 Hz, 1H), 5.31 (p, J = 6.6 Hz, 1H) , 4.27 (q, J = 8.3 Hz, 1H), 4.05 (dq, J = 13.8, 6.9 Hz, 1H), 3.39 (d, J = 12.2 Hz, ZN), 3.02 - 2.73 (m, 5H), 2.31 (s, 3H), 2.08 (d, J = 3.7 Hz, 4H), 1.83 (t, J = 10 .5 Hz, 4H), 1.69 (t, J = 5.8 Hz, 2H), 1.59 - 1.54 (m, 7H), 1.31 (d, J = 6.6 Hz, 1H ), 1.10 (d, J = 6.6 Hz, 6H). 0.1 84 743.6 Ή NMR (400 MHz, DMCO-d6) δ 9.33 (s, 1H), 8.36 (s, 1H), 8.29 - 8.13 (m, 2H), 7.90 (d, J= 2.4 Hz, 1H), 7.88 - 7.79 (m, 3H), 7.66 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.22 ( d, J = 8.3 Hz, 1H), 4.34 (t, J = 8.1 Hz, 1H), 4.13 (s, 1H), 3.95 (s, 1H), 3.80 ( d, J = 10.1 Hz, 1H), 3.06 - 2.71 (m, 5H), 2.32 (d, J = 5.5 Hz, 4H), 1.84 (d, J = 13 .8 Hz, 9H), 1.76 - 1.54 (m, 7H), 1.45 (d, J = 19.3 Hz, 1H), 1.27 (d, J = 10.3 Hz, 5H ), 1.06 (t, J = 7.2 Hz, 4H). 0.2 85 757.4 Ή NMR (400 MHz, DMSO-de) δ 9.42 (d, J = 10.0 Hz, 1H), 8.45 (s, 1H), 8.25 (s, 1H), 8.19 (q , J = 4.5 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.86 - 7.79 (m, 3H), 7.66 - 7.61 (m, 2H), 4.88 (dd, J = 22.8, 5.8 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (q, J = 7.2 , 6.0 Hz, ο,ι

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ZN), 4.20 - 4.13 (m, 1H), 3.78 (d, J = 9.0 Hz, 1H), 3.61 - 3.47 (m, 2H), 3.40 (d , J = 11.7 Hz, 2H), 3.18 (d, J = 13.6 Hz, 1H), 3.08 - 2.78 (m, 4H), 2.76 (d, J = 4, 6 Hz, 3H), 2.32 (s, 3H), 1.90 - 1.56 (m, 13H), 1.41 (d, J = 12.5 Hz, 1H), 1.27 (dq, J = 4.8, 2.4 Hz, 4H). 86 765.5 Ή NMR (400 MHz, DMSO-de) δ 9.39 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 8.30 (t, J = 5.4 Hz , 1H), 7.86 (s, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7 .52 - 7.46 (m, 2H), 7.18 (d, J = 12.1 Hz, 1H), 5.36 - 5.19 (m, 1H), 4.16 (t, J = 8 ,1 Hz, 1H), 3.94 - 3.76 (m, 1H), 3.71 (t, J = 6.8 Hz, 1H), 3.49 (q, J = 8.1 Hz, 1H ), 3.37 (tt, J = 10.1, 4.9 Hz, 7H), 3.18 (s, 3H), 3.05 - 2.68 (m, 9H), 2.36 (s, 3H), 2.06 (s, 3H), 1.92 - 1.50 (m, 12H), 1.41 (t, J = 12.7 Hz, 1H). 0.2 87 763.5 Ή NMR (400 MHz, DMSO-de) δ 9.49 (d, J = 9.7 Hz, 1H), 8.77 (s, 1H), 8.47 (s, 1H), 8.09 (d , J = 8.4 Hz, 1H), 7.88 (s, 1H), 7.64 (dd, J = 22.0, 8.0 Hz, 2H), 7.51 (d, J = 8, 5 Hz, 2H), 7.20 (d, J = 12.1 Hz, 1H), 5.32 (p, J = 6.6 Hz, 1H), 4.19 (p, J = 8.2 Hz , 1H), 3.86 (dq, J = 13.7, 7.2 Hz, 3H), 3.73 (dt, J = 17.1, 7.9 Hz, 2H), 3.53 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.02 - 2.73 (m, 6H), 2.37 (s, 3H), 2, 08 (s, 3H), 1.89 - 1.55 (m, 15H), 1.43 (p, J = 7.5 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H ), 0.83 (t, J = 7.4 Hz, 3H). 0.3 88 763.5 Ή NMR (400 MHz, DMCO-d6) δ 9.36 (s, 1H), 8.68 (s, 1H), 8.42 (s, 1H), 8.08 (d, J = 8.3 Hz , 1H), 7.88 (s, 1H), 7.64 (dd, J = 20.4, 8.3 Hz, 2H), 7.51 (dd, J = 4.6, 3.3 Hz, 2H), 7.19 (d, J = 12.1 Hz, 1H), 5.30 (q, J = 6.6 Hz, 1H), 4.20 (t, J = 8.1 Hz, 1H) , 3.86 (p, J = 7.6 Hz, 3H), 3.79 - 3.64 (m, 1H), 3.52 (q, J = 8.2 Hz, 1H), 3.40 ( d, J = 11.6 Hz, 2H), 3.03 - 2.74 (m, 7H), 2.37 (s, 3H), 2.08 (s, 3H), 1.91 - 1.53 (m, 15H), 1.43 (p, J = 7.1 Hz, 3H), 1.07 (t, J = 5.8 Hz, 3H), 0.82 (t, J = 7.4 Hz , 3H). 0.2 89 769.4 Ή NMR (400 MHz, DMCO-d6) δ 9.46 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.39 (d, J = 7.8 Hz , 1H), 7.94 (s, 1H), 7.69 (dd, J = 7.8, 1.4 Hz, 1H), 7.63 (dd, J = 10.6, 9.6 Hz, 2H), 7.53 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 5.29 (p, J - 6.6 Hz, 1H) , 4.20 (t, J - 8.2 Hz, 1H), 4.02 (dt, J = 7.5, 6.4 Hz, 1H), 3.94 - 3.81 (m, 1H), 3.73 (dq, J = 12.8, 6.2 Hz, 2H), 3.54 (q, J = 8.2 Hz, 1H), 3.41 (d, J = 11.8 Hz, 2H ), 2.95 (dq, J = 28.2, 9.8 Hz, 2H), 2.78 (dd, J = 13.2, 7.9 Hz, 4H), 2.08 (s, 3H) , 1.92 - 1.52 (m, 14H), 1.41 (d, J = 12.5 Hz, 1H), 1.11 (d, J = 6.6 Hz, 6H). 0.2 90 791.5 Ή NMR (400 MHz, DMSO-de) δ 9.44 (d, J = 9.8 Hz, 1H), 8.79 (s, 1H), 8.51 (s, 1H), 8.45 (s , 1H), 7.88 (s, 1H), 7.66 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 - 7.48 (m, 0.3

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ZN), 7.18 (d, J = 12.1 Hz, 1H), 5.39 - 5.24 (m, 1H), 4.19 (t, J = 8.0 Hz, 1H), 3, 95 - 3.80 (m, 1H), 3.80 3.64 (m, 2H), 3.51 (t, J = 8.1 Hz, 2H), 3.46 (s, 2H), 3, 39 (d, J = 11.7 Hz, ZN), 3.21 (s, ZN), 2.93 (dd, J = 25.6, 10.2 Hz, 1H), 2.79 (dd, J = 12.0, 7.1 Hz, 5H), 2.35 (d, J = 0.6 Hz, ZN), 2.08 (s, ZN), 1.92 - 1.64 (m, 5H) , 1.62 - 1.53 (m, 7H), 1.48 - 1.26 (m, 1H), 0.76 0.66 (m, 4H). 91 747.4 Ή NMR (400 MHz, DMSO-46) δ 9.47 (d, J = 9.1 Hz, 1H), 8.81 (s, 1H), 8.46 (s, 1H), 8.34 (d , J = 4.4 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (d, J = 8, 2 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 1.5 Hz, 1H), 7.20 (d, J = 12.1 Hz , 1H), 5.37 - 5.26 (m, 1H), 4.24 - 4.14 (m, 1H), 3.95 - 3.79 (m, 2H), 3.74 (q, J = 6.4 Hz, 2H), 3.53 (dt, J = 17.1, 7.6 Hz, 1H), 3.40 (d, J = 11.9 Hz, 2H), 3.00 - 2 .86 (m, 2H), 2.86 - 2.73 (m, 3H), 2.37 (s, 3H), 2.08 (s, 3H), 1.89 1.62 (m, 8H) , 1.60 (dd, J = 6.6, 1.3 Hz, 7H), 1.48 1.29 (m, 1H), 0.66 (td, J = 7.1, 4.8 Hz, 2H), 0.50 0.42 (m, 2H). 0D 92 721.4 1HNMR (400 MHz, flMCO-d6) δ 9.42 (d, J = 9.3 Hz, 1H), 8.72 (s, 1H), 8.45 - 8.37 (m, 1H), 8, 20 (q, J = 4.5 Hz, 1H), 7.88 (s, 1H), 7.67 (dd, J = 7.9, 1.5 Hz, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.20 (d, J = 12.2 Hz, 1H), 5.29 (p, J = 6.5 Hz , 1H), 4.23 - 4.11 (m, 2H), 3.95 - 3.79 (m, 1H), 3.77 - 3.66 (m, 2H), 3.51 (q, J = 8.0 Hz, 1H), 3.39 (d, J = 11.9 Hz, 2H), 2.91 (dt, J = 26.9, 10.2 Hz, 2H), 2.84 - 2 .75 (m, 6H), 2.73 (d, J = 4.6 Hz, ZN), 2.42 - 2.35 (m, ZN), 2.08 (s, ZN), 1.90 - 1.63 (m, 8H), 1.59 (d, J = 6.5 Hz, 6H). 0.08 93 739.6 1HNMR (400 MHz, flMCO-d6) δ 9.31 (s, 1H), 8.70 (d, J = 8.7 Hz, 1H), 8.45 (d, J = 4.7 Hz, 1H) , 8.39 (s, 1H), 8.34 (d, J = 2.9 Hz, 1H), 7.88 (s, 1H), 7.79 (dd, J = 7.9, 1.5 Hz, 1H), 7.65 (d, J = 11.1 Hz, 1H), 7.58 (d, J = 1.5 Hz, 1H), 7.53 (d, J = 7.8 Hz, 1H), 4.32 (t, J = 8.1 Hz, 1H), 4.15 - 4.03 (m, 1H), 4.02 - 3.79 (m, 1H), 3.79 - 3 .65 (m, 3H), 3.52 (s, 3H), 2.98 (dd, J = 26.5, 10.2 Hz, 2H), 2.83 (dd, J = 18.6, 9 .4 Hz, 4H), 2.77 (d, J = 4.7 Hz, ZN), 2.09 (s, ZN), 1.91-1.77 (m, ZN), 1.76 - 1 .55 (m, 5H), 1.40 (d, J = 12.8 Hz, 1H), 1.32 (d, J = 3.7 Hz, 2H), 1.24 (d, J = 5, 8 Hz, ZN). 0.2 94 729.5 1HNMR (400 MHz, flMCO-d6) δ 9.31 (s, 1H), 8.54 (s, 1H), 8.42 (s, 1H), 8.29 (d, J = 4.5 Hz, 1H), 7.91 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.58 - 7, 50 (m, 2H), 7.48 (dd, J= 8.1, 2.3 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 5.34 - 5.20 (m, OH), 4.30 (t, J = 8.0 Hz, 1H), 3.99 - 3.61 (m, 4H), 3.50 (d, J = 7.9 Hz, 2H) , 3.06 - 2.76 (m, 9H), 2.34 - 2.27 (m, 0.06

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ZN), 2.09 (s, ZN), 1.92 - 1.59 (m, JN), 1.60 - 1.51 (m, 6N), 0.65 (td, J = 7.1, 4.8 Hz, 2H), 0.52 - 0.40 (m, 2H). 95 719.5 1HNMR (400 MHz, DMSO-bb) δ 9.35 (d, J = 9.8 Hz, 1H), 8.64 (d, J = 8.5 Hz, 1H), 8.42 (s, 1H) , 8.23 (q, J = 4.5 Hz, 1H), 8.20 (d, J = 2.9 Hz, 1H), 7.83 (d, J = 3.1 Hz, 1H), 7 .80 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 1.5 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 12.4 Hz, 1H), 4.36 - 4.24 (m, 1H), 4.09 (dt, J = 7.1, 3.3 Hz, 1H), 3.97 - 3.63 (m, 5H), 3.52 (d, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 3.06 - 2.78 (m , 4H), 2.76 (d, J = 4.6 Hz, ZN), 2.35 (s, ZN), 2.09 (s, ZN), 1.94 - 1.53 (m, JN) , 1.40 (d, J = 12.2 Hz, 1H), 1.36 1.21 (m, 4H). 0.3 96 715.6 1HNMR (400 MHz, DMSO-ab) δ 9.30 (s, 1H), 8.36 (s, 1H), 8.19 - 8.13 (m, 2H), 7.88 - 7.83 (m , 2H), 7.80 (s, 1H), 7.66 (dd, J = 4.4, 1.8 Hz, 2H), 7.56 (d, J = 7.9 Hz, 1H), 4 .35 (t, J = 8.2 Hz, 1H), 4.19 - 4.07 (m, 1H), 3.99 - 3.79 (m, 3H), 3.62 (s, 2H), 3.40 (d, J = 12.5 Hz, 2H), 2.95 - 2.79 (m, 4H), 2.75 (d, J = 4.6 Hz, ZN), 2.30 (s , ZN), 2.18 (s, ZN), 2.09 (s, ZN), 1.94 1.77 (m, ZN), 1.66 (d, J = 47.7 Hz, 6H), 1.40 (d, J = 12.6 Hz, 1H), 1.32 - 1.21 (m, 4H). 0.2 97 705.3 1HNMR (400 MHz, DMSO-bb) δ 9.35 (s, 1H), 8.98 (dd, J = 8.1, 2.2 Hz, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.42 (d, J = 3.2 Hz, 1H), 8.31 (d, J = 2.8 Hz, 1H), 7.88 - 7.78 (m, 2H), 7.64 (d, J = 1.5 Hz, 1H), 7.59 (ddd, J = 8.5, 4.6, 2.2 Hz, 1H), 7.54 (d, J = 7, 9 Hz, 1H), 7.44 (dd, J = 11.0, 8.5 Hz, 1H), 4.36 (t, J = 8.2 Hz, 1H), 4.12 - 4.05 ( m, 1H), 3.98 - 3.68 (m, 2H), 3.37 (d, J = 12.4 Hz, 4H), 2.94 (dd, J = 30.4, 10.0 Hz , 2H), 2.82 (d, J = 4.5 Hz, 4H), 2.09 (s, 4H), 1.92 1.53 (m, 11H), 1.48 - 1.21 (m , 5H). 0.4 98 743.1 1HNMR (400 MHz, DMSO-ab) δ 9.41 (d, J = 9.6 Hz, 1H), 8.41 (s, 1H), 8.24 (s, 1H), 8.19 (q, J = 4.6 Hz, 1H), 7.89 - 7.81 (m, 3H), 7.80 (s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7, 60 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.14 ( dt, J = 6.6, 4.1 Hz, 1H), 3.92 (s, 5H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11 ,7 Hz, 2H), 3.04 - 2.94 (m, 2H), 2.92 2.79 (m, 2H), 2.76 (d, J = 4.6 Hz, ZN), 2, 32 (s, ZN), 1.91 - 1.53 (m, JN), 1.42 (t, J = 12.5 Hz, 1H), 1.26 (s, 13H). 0.09 99 763.4 1HNMR (400 MHz, DMSO-ab) δ 9.78 (s, 1H), 8.71 (s, 1H), 8.46 (s, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.89 (s, 1H), 7.60 (d, J = 85.2 Hz, ZN), 7.17 (d, J = 12.1 Hz, 1H), 5.37 - 5, 23 (m, 1H), 4.78 (dt, J = 23.7, 7.5 Hz, 4H), 4.24 - 3.93 (m, 2H), 3.43 (dd, J = 57, 4, 9.9 Hz, 0.2

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6H), 2.84 (dd, J = 47.9, 10.0 Hz, 6H), 2.35 (s, ZN), 2.32 - 1.92 (m, ZN), 1.86-1 .51 (m, JN), 1.40 (t, J = 12.4 Hz, 1H), 1.09 (d, J = 6.5 Hz, 5H). 100 777.4 1HNMR (400 MHz, flMCO-d6) δ 10.96 (d, J = 129.8 Hz, 2H), 8.89 (s, 1H), 8.55 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.97 - 7.38 (m, 5H), 7.19 (d, J = 12.0 Hz, 1H), 5.39 - 5.27 (m, 1H ), 4.78 (dt, J = 28.8, 7.4 Hz, 4H), 4.22 - 3.93 (m, 2H), 3.80 - 3.13 (m, 7H), 2, 97 2.62 (m, 3H), 2.37 (s, 3H), 2.05 - 1.69 (m, 2H), 1.59 (d, J = 6.5 Hz, 5H), 1, 16 (s, 3H), 1.13 - 0.99 (m, 8H). 0.3 101 624.4 1HNMR (400 MHz, flMCO-d6) δ 9.36 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.21 (q, J = 4.5 Hz, 1H), 7.83 (d, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.46 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.20 (d, J = 12.0 Hz, 1H), 4.62 (q, J = 7.2 Hz, 2H) , 4.17 (q, J = 8.2 Hz, 1H), 3.51 (q, J = 8.2 Hz, 1H), 3.38 (d, J = 11.7 Hz, 2H), 2 .91 (d, J = 10.0 Hz, 2H), 2.80 (m, 4H), 2.72 (d, J = 4.5 Hz, 3), 2.37 (s, 3H), 1 .83 (d, J = 14.0 Hz, 2H), 1.63 (m, 2H), 1.43 (t, J = 7.2 Hz, ZN), 1.27 (s, 6H). 0.2 102 605.4 1HNMR (400 MHz, flMCO-d6) δ 9.33 (s, 1H), 8.43 (m, 2H), 8.17 (d, J = 4.8 Hz, 1H), 7.86(s, 1H), 7.82 7.72 (m, 1H)), 7.69 - 7.50 (m, 3H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d , J = 8.3 Hz, 1H), 4.63 (q, J = 7.1 Hz, 2H), 4.27 (t, J = 8.1 Hz, 1H), 3.51 (q, J = 8.0 Hz, 1H), 3.45 - 3.33 (m, 2H), 3.00 - 2.88 (m, 1H), 2.88 - 2.76 (m, 3H), 2, 74 (d, J = 4.5 Hz, 2H), 2.31 (s, 3H), 1.84 (d, J = 14.1 Hz, 2H), 1.66 (dd, J = 41.6 , 13.1 Hz, 2H), 1.40 (t, J = 7.2 Hz, ZN), 1.30 (s, 6H). 0.09 103 606.4 1HNMR (400 MHz, flMCO-d6) δ 10.13 (s, 1H), 8.80 (s, 1H), 8.51 (s, 1H), 8.21 - 8.12 (m, 1H), 7.87 (s, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.65 - 7.47 (m, 4H), 7.39 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 5.38 - 5.27 (m, 1H), 4.38 - 4.25 (m, 1H), 3.73 3.60 (m, 1H), 3.54 - 3.46 (m, 1H), 3.07 - 2.88 (m, 2H), 2.85 - 2.71 (m, 6H) , 2.32 (s, 3H), 2.07 - 2.02 (m, 2H), 1.94 - 1.86 (m, 2H), 1.57 (d, J = 6.5 Hz, 6H ), 1.30 (s, 6H). 0.1 104 656.5 1HNMR (400 MHz, flMCO-d6) δ 10.41 (d, J = 45.7 Hz, 1H), 8.72 (s, 1H), 8.48 (s, 1H), 8.16 (q, J = 4.6 Hz, 1H), 7.87 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (dd, J = 14.2 , 1.9 Hz, 2H), 7.50 (dd, J = 8.2, 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d , J = 8.3 Hz, 1H), 5.30 (p, J = 6.5 Hz, 1H), 4.38 - 4.29 (m, 1H), 3.77 - 3.72 (m, 2H), 3.63 - 3.58 (m, 2H), 3.20 - 2.93 (m, 4H), 2.83 - 2.71 (m, 6H), 2.32 (s, 3H) , 2.14 - 2.07 (m, 1H), 1.90 - 1.85 (m, 1H), 1.56 (d, J = 6.5 Hz, 6H), 1.30 (s, 6H ). 0.2

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104 A (1st eluting peak) 656.3 1HNMR (400 MHz, DMSO-ab) δ 10.50 (d, J = 48.1 Hz, 1H), 8.91 (s, 1H), 8.55 (s, 1H), 8.21 - 8, 12 (m, 1H), 7.87 (d, J = 1.2 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.60 - 7.55 (m, 2H ), 7.51 (dd, J = 8.8, 2.1 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz , 1H), 6.43 - 5.97 (m, 1H), 5.41 - 5.29 (m, 1H), 4.38 4.29 (m, 1H), 3.75 (s, 2H) , 3.36 - 3.31 (m, 1H), 3.19 2.89 (m, 4H), 2.83 - 2.77 (m, 3H), 2.77 - 2.71 (m, 3H ), 2.33 (s, 3H), 2.17 - 2.05 (m, 1H), 1.91 - 1.86 (m, 1H), 1.58 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). 0.2 104B (2nd peak to be eluted) 656.3 1HNMR (400 MHz, DMSO+b) δ 10.50 (d, J = 47.4 Hz, 1H), 8.90 (s, 1H), 8.54 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.60 7.47 (m, 3H), 7.40 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.44 - 5.97 (m, 1H), 5.35 (p, J = 6.5 Hz, 1H), 4.38 - 4.29 (m, 1H), 3.75 (s, 2H), 3.61 (s, 2H), 3.20 - 2.89 (m, 4H ), 2.83 - 2.77 (m, 2H), 2.75 (d, J = 4.4 Hz, ZN), 2.33 (s, ZN), 2.14 - 2.07 (m, 1H), 1.91 1.86 (m, 1H), 1.58 (d, J = 6.4 Hz, 6H), 1.30 (s, 6H). 0.2 105 670.5 1HNMR (400 MHz, DMSO+b) δ 9.80 (s, 1H), 8.78 (s, 1H), 8.51 (s, 1H), 8.19 (d, J = 4.7 Hz, 1H), 7.91 (s, 1H), 7.81 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 (d, J = 1.4 Hz, 1H), 7, 60 - 7.50 (m, 2H), 7.42 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 6.28 - 5.96 (m, 1H), 5.40 - 5.28 (m, 1H), 4.38 - 4.24 (m, 1H), 3.64 - 3.57 (m, 1H), 3.52 - 3 .44 (m, 2H), 3.08 - 2.94 (m, 2H), 2.93 - 2.85 (m, 4H), 2.77 (d, J = 4.5 Hz, ZN), 2.35 (s, ZN), 2.03 - 1.95 (m, 1H), 1.93 - 1.85 (m, 1H), 1.74 1.66 (m, 1H), 1.60 (dd, J = 6.6, 1.5 Hz, 6H), 1.50 1.36 (m, 1H), 1.32 (s, 6H). 0.2 105A (1st eluting peak) 670.4 1HNMR (400 MHz, DMSODb) δ 9.91 (s, 1H), 8.96 (s, 1H), 8.57 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H) , 7.88 (s, 1H), 7.77 (dd, J = 7.7, 1.4 Hz, 1H), 7.59 - 7.48 (m, 3H), 7.40 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.09 (td, J = 55.6, 3.2 Hz, 1H), 5.42 - 5 .30 (m, 1H), 4.33 - 4.20 (m, 1H), 3.60 - 3.55 (m, OH), 3.44 (d, J = 11.4 Hz, 2H), 3.04 - 2.88 (m, 2H), 2.90 - 2.78 (m, 5H), 2.74 (d, J = 4.5 Hz, ZN), 2.41 - 2.36 ( m, 1H), 2.33 (s, 3H), 1.96 (d, J = 14.3 Hz, 1H), 1.86 (d, J = 12.8 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.58 (d, J = 6.8 Hz, 6H), 1.48 - 1.30 (m, 1H), 1.29 (s, 6H). 0.2 105V (2nd peak to be eluted) 670.4 1HNMR (400 MHz, DMSO+b) δ 9.70 (s, 1H), 8.72 (s, 1H), 8.47 (s, 1H), 8.15 (q, J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.78 (dd, J = 7.7, 1.3 Hz, 1H), 7.59 (s, 1H), 7.57 - 7.47 (m , 2H), 7.39 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H), 6.25 - 5.91 (m, 1H), 5 .36 - 5.24 (m, 1H), 4.33 - 4.22 (m, 1H), 3.61 - 3.54 (m, 1H), 3.49 - 3.41 (m, 2H) , 3.05 - 2.89 (m, 2H), 2.89 - 2.78 (m, 5H), 2.74 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN ), 1.96 (d, J = 0.09

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14.3 Hz, 1H), 1.86 (d, J = 12.7 Hz, 1H), 1.75 - 1.63 (m, 1H), 1.56 (d, J = 6.4 Hz, 6H), 1.47 - 1.33 (m, 1H), 1.30 (s, 6H). 106 638.5 1HNMR (400 MHz, DMSO-46) δ 9.86 (s, 1H), 8.85 (s, 1H), 8.53 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.76 (dd, J = 7.7, 1.4 Hz, 1H), 7.58 - 7.48 (m, 3H), 7.39 (d , J = 7.8 Hz, 1H), 7.19 (d, J = 8.2 Hz, 1H), 5.39 - 5.27 (m, 1H), 5.15 (d, J = 45, 4 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.70 - 3.47 (m, 1H), 3.41 - 3.10 (m, 2H), 3.04 - 2 .90 (m, 2H), 2.83 (d, J = 15.9 Hz, ZN), 2.73 (d, J = 4.5 Hz, ZN), 2.32 (s, ZN), 2 .03 1.94 (m, 1H), 1.91-1.76 (m, 2H), 1.74 - 1.66 (m, 1H), 1.57 (dd, J = 6.5, 1 .8 Hz, 6H), 1.29 (s, 6H). 0.07 107 656.4 1HNMR (400 MHz, DMSO-de) δ 9.84 (s, 1H), 8.76 (s, 1H), 8.41 (s, 1H), 8.20 (q, J = 4.6 Hz, 1H), 7.85 (s, 1H), 7.71 - 7.60 (m, 2H), 7.44 (s, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 12.0 Hz, 1H), 5.30 (p, J = 6.5 Hz, 1H), 5.17 (d, J = 45.0 Hz, 1H), 4, 22 - 4.13 (m, 1H), 3.68 - 3.54 (m, 2H), 3.43 - 3.13 (m, 2H), 3.03 2.90 (m, 3H), 2 .85 - 2.70 (m, 6H), 2.38 (s, 3H), 2.04 1.95 (m, 1H), 1.93 - 1.76 (m, 2H), 1.60 ( dd, J = 6.5, 2.0 Hz, 6H), 1.28 (s, 6H). 0.1 108 642.4 1HNMR (400 MHz, DMSO-de) δ 10.70 - 10.44 (m, 2H), 8.60 (s, 1H), 8.34 (s, 1H), 8.20 (d, J = 5 .6 Hz, 1H), 7.85 (s, 1H), 7.66 (dd, J = 12.9, 8.1 Hz, 2H), 7.47 (d, J = 7.9 Hz, 1H ), 7.36 (d, J = 7.8 Hz, 1H), 7.25 - 7.16 (m, 1H), 5.64 - 5.41 (m, 2H), 5.30 - 5, 22 (m, 1H), 4.28 - 4.23 (m, 1H), 3.91 - 3.53 (m, 4H), 3.30 - 3.25 (m, 1H), 2.98 - 2.93 (m, 3H), 2.76 - 2.70 (m, 3H), 2.37 (s, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.28 (s, 6H). 0.1 109 656.5 1HNMR (400 MHz, DMSO-de) δ 10.68 (s, 1H), 8.71 (s, 1H), 8.36 (s, 1H), 8.21 (d, J = 4.9 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J = 20.7, 8.0 Hz, 2H), 7.45 (s, 1H), 7.36 (d, J = 7 .8 Hz, 1H), 7.21 (d, J = 12.4 Hz, 1H), 5.61 - 5.56 (m, 1H), 5.48 - 5.43 (m, 1H), 5 .13 - 5.06 (m, 1H), 4.27 - 4.20 (m, 1H), 3.94 - 3.54 (m, 4H), 3.41 - 3.15 (m, 2H) , 3.01 - 2.88 (m, 2H), 2.73 (d, J = 4.5 Hz, ZN), 2.38 (s, ZN), 2.30 - 2.05 (m, 1H ), 2.00 1.84 (m, 2H), 1.60 (d, J = 6.6 Hz, ZN), 1.28 (s, 6H), 0.82 (t, J = 7.3 Hz, ZN). 0.3 110 684.5 1HNMR (400 MHz, DMSO-de) δ 9.83 (s, 1H), 8.74 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.85 (s, 1H), 7.64 (dd, J = 13.7, 7.9 Hz, 2H), 7.46 (s, 1H), 7.36 (d, J = 7 .7 Hz, 1H), 7.19 (d, J = 12.0 Hz, 1H), 5.31 (p, J = 6.7 Hz, 1H), 5.25 - 5.08 (m, 1H ), 4.22 4.15 (m, 1H), 4.10 - 3.97 (m, 1H), 3.68 - 3.54 (m, 1H), 3.39 (d, J = 12, 0 Hz, 1H), 3.34 - 3.26 (m, 1H), 0.2

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3.24 - 3.13 (m, 1H), 2.98 (q, J = 10.1 Hz, ZN), 2.80 (d, J = 16.7 Hz, ZN), 2.37 (s , ZN), 2.04 - 1.96 (m, 1H), 1.85 - 1.80 (m, 1H), 1.71 - 1.66 (m, 1H), 1.60 (d, J = 6.5 Hz, 6H), 1.28 (s, 6H), 1.10 (d, J = 6.5 Hz, 6H). 111 639.5 1HNMR (400 MHz, DMSO+b) δ 9.46 (d, J = 9.1 Hz, 1H), 8.77 (s, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.24 - 8.16 (m, 1H), 7.96 (s, 1H), 7.73 (s, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 11.9 Hz, 1H), 5.37 - 5.26 (m, 1H), 4.29 - 4.17 (m, 1H), 3.59 - 3.48 ( m, 1H), 3.39 (d, J = 11.9 Hz, 2H), 2.96 - 2.78 (m, 7H), 2.74 (d, J = 4.5 Hz, ZN), 2.39 (s, ZN), 1.85 (d, J = 14.2 Hz, 2H), 1.76-1.61 (m, 2H), 1.60 (d, J = 6.5 Hz , 6H), 1.48 1.38 (m, 1H), 1.29 (s, 6H). o, s 112 604.3 1HNMR (400 MHz, DMSO+b) δ 9.29 (s, 1H), 8.37 (s, 1H), 8.22 (s, 1H), 8.08 (d, J = 2.4 Hz, 1H), 7.86 7.68 (m, 4H), 7.63 (d, J = 1.5 Hz, 1H), 7.45 - 7.38 (m, 2H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (t, J = 8.1 Hz, 1H), 4.19-4.11 (m, 1H), 3.40 (d, J = 11.7 Hz, 2H), 3.01 2.74 (m, 7H), 2.36 (s, 3H), 1.83 (d, J = 14.2 Hz, 2H), 1.71 (d, J = 12.9 Hz, 1H), 1.60 (d, J = 13.5 Hz, 2H), 1.31 (s, 6H), 1.30 - 1.22 (m, 4H). 0.09 FROM 670.4 1HNMR (400 MHz, DMSO+b) δ 9.86 (s, 1H), 8.86 (s, 1H), 8.44 (s, 1H), 8.22 (q, J = 4.5 Hz, 1H), 7.86 (s, 1H), 7.67 (dd, J = 7.8, 1.4 Hz, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7, 43 (s, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.21 (d, J = 12.0 Hz, 1H), 5.24 - 5.08 (m, 2H ), 4.22 - 4.13 (m, 1H), 3.71 - 3.54 (m, 2H), 3.42 - 3.13 (m, 3H), 3.03 - 2.88 (m , 3H), 2.88 - 2.76 (m, 1H), 2.74 (d, J = 4.6 Hz, ZN), 2.41 - 2.36 (m, ZN), 2.09 - 1.80 (m, 4H), 1.71 (d, J = 14.4 Hz, 1H), 1.62 (d, J = 6.6 Hz, ZN), 1.28 (s, 6H), 0.83 (t, J = 7.4 Hz, ZN). OD 114 654.4 1HNMR (400 MHz, DMSO+b) δ 9.37 (d, J = 9.2 Hz, 1H), 8.68 (d, J = 6.1 Hz, 2H), 8.36 (q, J = 4.6 Hz, 1H), 7.95 (s, 1H), 7.77 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (ddd, J = 8.4, 4 ,6, 2.1 Hz, ZN), 7.46 - 7.36 (m, 2H), 5.08 (d, J = 6.7 Hz, 1H), 4.36 - 4.21 (m, 1H), 3.51 (q, J = 8.0 Hz, 1H), 3.42 (d, J = 11.3 Hz, 2H), 3.37 (s, 1H), 3.03 - 2, 88 (m, 2H), 2.88 - 2.78 (m, 2H), 2.75 (d, J = 4.6 Hz, ZN), 1.86 (ddd, J = 14.4, 10, 6, 4.5 Hz, 5H), 1.77 - 1.52 (m, 6H), 1.50 - 1.35 (m, 1H), 1.30 (s, 6H), 0.77 (t , J = 7.4 Hz, ZN). 0.05 115 668.3 1HNMR (400 MHz, DMSO+b) δ 9.33 (s, 1H), 8.68 (d, J = 19.1 Hz, 2H), 8.32 (d, J = 7.8 Hz, 1H) , 7.93 (s, 1H), 7.77 (dd, J = 7.8, 1.5 Hz, 1H), 7.61 - 7.57 (m, 2H), 7.55 (d, J = 2.7 Hz, 1H), 7.40 (dd, J = 14.7, 8.1 Hz, 2H), 5.36 - 5.22 (m, 1H), 4.28 (t, J = 8.1 Hz, 1H), 4.09 - 3.93 (m, 1H), 3.45 (dd, J = 38.2, 10.0 Hz, ZN), ο,ι

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3.02 - 2.86 (m, 2H), 2.88 - 2.72 (m, 4H), 1.84 (d, J = 14.1 Hz, 2H), 1.78 - 1.47 ( m, 8H), 1.40 (d, J = 12.2 Hz, 1H), 1.29 (s, 6H), 1.10 (d, J = 6.6 Hz, 6H). 116 682.5 1HNMR (400 MHz, DMSO-de) δ 9.50 (s, 1H), 8.77 (s, 1H), 8.45 (s, 1H), 8.31 (t, J = 5.4 Hz, 1H), 7.84 (s, 1H), 7.65 (dd, J = 7.8, 1.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7, 44 (d, J = 1.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 12.0 Hz, 1H), 5.38 - 5.23 (m, 1H), 4.15 (t, J = 8.2 Hz, 1H), 3.50 (q, J = 8.1 Hz, 1H), 3.44 - 3.30 (m , 6H), 3.18 (s, 3H), 2.97 - 2.69 (m, 6H), 2.36 (s, 3H), 1.89 - 1.52 (m, 11H), 1, 39 (d, J = 12.6 Hz, 1H), 1.26 (s, 6H). 0.2 117 686.4 1HNMR (400 MHz, DMSO-de) δ 9.35 (s, 1H), 8.64 (d, J = 18.0 Hz, 2H), 8.36 (d, J = 7.8 Hz, 1H) , 7.90 (d, J = 0.8 Hz, 1H), 7.66 (dd, J = 8.1, 5.9 Hz, 2H), 7.59 (d, J = 10.8 Hz, 1H), 7.45 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 5.34 - 5.16 (m, 1H), 4.18 (t, J = 8 .2 Hz, 1H), 4.00 (q, J = 6.8 Hz, 1H), 3.60 - 3.47 (m, 1H), 3.39 (d, J = 11.9 Hz, 2H ), 2.92 (q, J = 9.8, 9.2 Hz, 2H), 2.78 (d, J = 10.8 Hz, 3H), 1.83 (d, J = 14.1 Hz , 2H), 1.57 (d, J = 6.6 Hz, JN), 1.39 (d, J = 12.8 Hz, 1H), 1.26 (s, 6H), 1.09 (d , J = 6.6 Hz, 6H). 0.2 118 658.4 1HNMR (400 MHz, flMCO-d6) δ 9.31 (s, 1H), 8.60 (d, J = 12.1 Hz, 2H), 8.40 (d, J = 4.7 Hz, 1H) , 7.91 (s, 1H), 7.72 - 7.64 (m, 2H), 7.60 (d, J = 10.8 Hz, 1H), 7.44 (s, 1H), 7, 36 (d, J = 7.8 Hz, 1H), 5.30 - 5.14 (m, 1H), 4.18 (t, J = 8.2 Hz, 1H), 3.53 (t, J = 8.1 Hz, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.92 (q, J = 9.8 Hz, 2H), 2.84 - 2.70 (m , 7H), 1.83 (d, J = 14.0 Hz, 2H), 1.56 (d, J = 6.6 Hz, 8H), 1.40 (d, J = 12.5 Hz, 1H ), 1.27 (s, 5H). 0.09 119 640.3 1HNMR (400 MHz, DMSO-de) δ 9.39 (d, J = 9.2 Hz, 1H), 8.71 (d, J = 13.0 Hz, 2H), 8.38 (q, J = 4.5 Hz, 1H), 7.95 (s, 1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.60 (d, J = 7.8 Hz, 3H), 7.43 (dd, J = 17.8, 8.1 Hz, 3H), 5.34 - 5.21 (m, 1H), 4.29 (t, J = 7.9 Hz, 1H ), 3.52 (q, J = 8.2 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 2.93 (dt, J = 11.5, 8.9 Hz , 2H), 2.88 - 2.77 (m, 4H), 2.75 (d, J = 4.6 Hz, 3H), 1.85 (d, J = 14.1 Hz, 2H), 1 .62 (d, J = 13.9 Hz, 2H), 1.56 (d, J = 6.5 Hz, 6H), 1.43 (t, J = 12.1 Hz, 1H), 1.30 (s, 6H). 0.07 120 638.4 1HNMR (400 MHz, DMSO-de) δ 10.33 (d, J = 7.4 Hz, 1H), 8.74 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 4.7 Hz, 1H), 7.85 (s, 1H), 7.70 - 7.61 (m, 2H), 7.47 (d, J = 1.4 Hz, 1H), 7, 36 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 12.0 Hz, 1H), 5.36 - 5.22 (m, 1H), 4.34 - 4.19 (m, 1H), 3.86 (dt, J = 10.3, 5.3 Hz, 5H), 2.95 - 2.80 (m, 2H), 2.74 (d, J = 4.6 Hz, 3H), 2.67 (t, J = 8.7 Hz, 2H), 0.2

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2.39 (s, ZN), 1.60 (d, J = 6.5 Hz, 6H), 1.43 - 1.23 (m, 12H). 121 646.5 1HNMR (400 MHz, flMCO-d6) δ 10.41 (d, J = 7.4 Hz, 1H), 8.74 (s, 1H), 8.51 (s, 1H), 8.32 (d, J = 4.4 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.8, 1.4 Hz, 1H), 7.60 (dd, J = 16.0 , 1.9 Hz, 2H), 7.46 (dd, J = 8.3, 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.20 (d , J = 8.3 Hz, 1H), 5.41 - 5.25 (m, 1H), 4.40 (t, J = 8.3 Hz, 1H), 3.95 - 3.68 (m, 7H), 2.99 - 2.80 (m, 3H), 2.77 - 2.65 (m, 3H), 2.32 (s, 3H), 1.57 (d, J = 6.5 Hz , 6H), 1.44 1.20 (m, 18H), 0.66 (td, J = 7.0, 4.7 Hz, 2H), 0.52 0.42 (m, 2H). 0.1 122 620.5 1HNMR (400 MHz, flMCO-d6) δ 10.43 (d, J = 6.6 Hz, 1H), 8.78 (s, 1H), 8.52 (s, 1H), 8.18 (q, J = 4.6 Hz, 1H), 7.88 (s, 1H), 7.76 (dd, J = 7.7, 1.4 Hz, 1H), 7.61 (d, J = 1.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.2, 2.4 Hz, 1H), 7.39 (d, J = 7 .8 Hz, 1H), 7.21 (d, J = 8.3 Hz, 1H), 5.41 - 5.26 (m, 1H), 4.37 (t, J = 8.2 Hz, 1H ), 3.85 (t, J = 6.0 Hz, 5H), 2.97 - 2.83 (m, 2H), 2.79 - 2.61 (m, 5H), 2.33 (s, 3H), 1.57 (d, J = 6.5 Hz, 6H), 1.40 - 1.21 (m, 12H). 0.1 123 662.4 1HNMR (400 MHz, flMCO-d6) δ 9.45 (s, 1H), 8.51 (s, 1H), 8.16 (d, J = 4.7 Hz, 1H), 7.88 (d, J = 0.8 Hz, 1H), 7.76 (dd, J = 7.9, 1.5 Hz, 1H), 7.59 (d, J = 7.7 Hz, 2H), 7.51 ( q, J = 2.1 Hz, 2H), 7.21-7.17 (m, 1H), 5.31 (d, J = 9.3 Hz, 1H), 4.24 (p, J = 8 .4 Hz, 1H), 4.04 (dt, J = 11.3, 5.7 Hz, 2H), 3.83 (dt, J = 10.8, 5.0 Hz, 2H), 3.47 (p, J = 8.4 Hz, 1H), 3.36 (d, J = 11.7 Hz, 2H), 2.92 (q, J = 9.8 Hz, 2H), 2.85 - 2 .69 (m, 6H), 2.31 (s, 3H), 1.86 - 1.49 (m, 16H), 1.41 (t, J = 12.3 Hz, 1H). ο,ι 124 717.4 1HNMR (400 MHz, flMCO-d6) δ 9.44 (s, 1H), 8.82 (s, 1H), 8.54 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.88 (d, J = 0.7 Hz, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.61 7.55 (m, 2H) , 7.53 - 7.46 (m, 2H), 7.18 (d, J = 8.2 Hz, 1H), 5.33 (s, 1H), 4.26 (p, J = 8.3 Hz, 1H), 4.02 (tt, J = 9.2, 6.3 Hz, ZN), 3.83 (dt, J = 10.9, 5.1 Hz, 2H), 3.52 - 3 .31 (m, 3H), 2.92 (q, J = 10.0, 9.6 Hz, 2H), 2.78 (q, J = 10.6, 8.8 Hz, 4H), 2, 30 (s, 3H), 1.90 1.47 (m, 15H), 1.41 (t, J = 12.6 Hz, 1H), 1.08 (d, J = 6.6 Hz, 6H) . 0.2 125 708.4 1HNMR (400 MHz, DMSSMb) δ 9.50 (s, 1H), 8.87 (s, 1H), 8.50 (s, 1H), 8.15 (d, J = 7.9 Hz, 1H) , 7.85 (s, 1H), 7.65 (dd, J = 7.9, 1.4 Hz, 1H), 7.56 (dd, J = 8.0, 5.2 Hz, 2H), 7.46 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 12.1 Hz, 1H), 5.32 (p, J = 6.7 Hz, 1H), 4, 16 (p, J = 8.3 Hz, 1H), 4.03 (ddd, J = 13.5, 6.4, 4.6 Hz, ZN), 3.81 (dt, J = 10.9, 5.1 Hz, 2H), 3.50 (h, J = 8.5 Hz, 0.2

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1H), 3.38 (d, J = 11.7 Hz, 2H), 2.98 - 2.85 (m, 2H), 2.85 - 2.70 (m, 4H), 2.36 (s , 3H), 1.89 - 1.52 (m, 15H), 1.39 (q, J = 13.0, 12.6 Hz, 1H), 1.08 (d, J = 6.6 Hz, 6H). 126 646.4 1HNMR (400 MHz, CDC13) δ 8.16 (d, 1H), 7.87 (d, 1H), 7.73 (m, 1H), 7.63 (m, 3H), 7.51 (d, 1H), 7.41 (m, 1H), 7.16 (m, 1H), 6.49 (s, 1H), 6.24 (s, 1H), 4.40 (p, 1H), 4, 21 (m, 2H), 3.92 (m, 3H), 3.76 (m, 1H), 3.04 (d, 2H), 2.72 (m, 6H), 2.47 (m, 3H ), 1.84 (m, 10H), 1.52 (m, 3H), 1.32 (m, 5H). 0.07 127 660.5 1HNMR (400 MHz, DMSO) δ 9.41 (s, 1H), 8.43 (s, 1H), 8.23 (s, 1H), 8.19 (q, 1H), 7.91 (d, 1H), 7.80 (m, 4H), 7.61 (m, 2H), 7.21 (d, 1H), 4.31 (p, 1H), 4.08 (m, 3H), 3, 84 (m, 3H), 3.44 (m, 4H), 2.96 (m, 2H), 2.83 (m, 4H), 2.75 (d, 3H), 2.30 (s, 3H ), 1.71 (m, 12H), 1.40 (t, 1H), 1.26 (m, 5H). 0.1 128 634.5 1HNMR (400 MHz, DMSO-ab) δ 9.40 (a, J = 10.0 Hz, 1H), 8.73 (s, 1H), 8.46 (s, 1H), 8.14 (q, J = 4.5 Hz, 1H), 7.87 (s, 1H), 7.75 (aa, J = 7.8, 1.4 Hz, 1H), 7.60 - 7.27 (m, 4H ), 7.17 (a, J = 8.3 Hz, 1H), 5.10 (q, J = 6.6 Hz, 1H), 4.24 (p, J = 8.3 Hz, 1H), 3.42 (at, J = 47.2, 9.5 Hz, 4H), 3.03 - 2.63 (m, 10H), 2.30 (s, 3H), 2.04 - 1.11 ( m, 15H), 0.77 (t, J = 7.4 Hz, ZN). 0.1 129 749.4 1HNMR (400 MHz, DMSO-ab) δ 9.47 (s, 1H), 8.85 (s, 1H), 8.49 (s, 1H), 8.15 (a, J = 7.8 Hz, 1H), 7.86 (a, J = 0.9 Hz, 1H), 7.64 (aa, J = 7.9, 1.5 Hz, 1H), 7.56 (a, J = 8.2 Hz, 1H), 7.53 - 7.45 (m, 2H), 7.18 (a, J = 12.0 Hz, 1H), 5.38 - 5.25 (m, 1H), 4.16 (t, J = 8.1 Hz, 1H), 4.02 (aq, J = 13.6, 6.7 Hz, 1H), 3.93 - 3.76 (m, 1H), 3.70 ( p, J = 7.7, 7.1 Hz, 2H), 3.49 (p, J = 8.3 Hz, 1H), 3.38 (a, J = 11.7 Hz, 2H), 3, 00 - 2.71 (m, 7H), 2.35 (a, J = 0.8 Hz, ZN), 2.06 (s, ZN), 1.86 - 1.53 (m, 13H), 1 .40 (t, J = 12.5 Hz, 1H), 1.08 (a, J = 6.6 Hz, 6H). 0.2 130 717.6 2 1HNMR (400 MHz, DMSO-ab) δ 9.53 (a, J = 12.8 Hz, 1H), 8.88 (a, J = 9.8 Hz, 1H), 8.58 (a, J = 4.7 Hz, 1H), 8.25 (t, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.77 (a, J = 7.8 Hz, 1H), 7 .60 (s, 1H), 7.58 - 7.47 (m, 3H), 7.20 (a, J = 8.1 Hz, 1H), 5.34 (aq, J = 13.0, 6 ,8, 5.3 Hz, 1H), 4.26 (p, J = 8.3 Hz, 1H), 3.49 (q, J = 8.1 Hz, 1H), 3.38 (a, J = 11.6 Hz, 2H), 3.23 (p, J = 7.0 Hz, 2H), 3.02 - 2.72 (m, 7H), 2.32 (s, 3H), 2.08 (s, 3H), 1.90 - 1.76 (m, 4H), 1.76 - 1.63 (m, 3H), 1.57 (a, J = 6.4 Hz, 6H), 1, 50 - 1.35 (m, 1H), 1.06 (t, J = 7.2 Hz, ZN). 0D 131 747.5 4 1HNMR (400 MHz, DMSO-ab) δ 9.39 (a, J = 9.8 Hz, 1H), 8.75 (s, 1H), 8.53 (s, 1H), 8.27 (t, J = 5.4 Hz, 1H), 7.90 (s, 1H), 7.77 (aa, J = 7.9, 1.5 Hz, 1H), 0.2

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7.62 (d, J = 1.5 Hz, 1H), 7.57 - 7.46 (m, 3H), 7.19 (d, J = 8.3 Hz, 1H), 5.37 - 5 .26 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.39 (dt, J = 14.1, 5.3 Hz, 6H), 3.19 (s, 3H), 2.93 (dd, J = 25.7, 10.2 Hz, 1H), 2.81 (t, J = 9.7 Hz, 5H), 2.32 (s, 3H), 2, 09 (s, 4H), 1.88 - 1.76 (m, 3H), 1.75 - 1.61 (m, 3H), 1.57 (dd, J = 6.5, 1.5 Hz, 7H). 132 733.5 2 1HNMR (400 MHz, DMCO-d6) δ 9.43 (d, J = 10.1 Hz, 1H), 8.78 (d, J = 2.1 Hz, 1H), 8.53 (s, 1H) , 8.18 (t, J = 5.7 Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J = 7.9, 1.4 Hz, 1H), 7.60 ( d, J = 1.5 Hz, 1H), 7.57 - 7.45 (m, 3H), 7.20 (d, J = 8.2 Hz, 1H), 5.32 (p, J = 6 .5 Hz, 1H), 4.32 - 4.21 (m, 1H), 3.47 (t, J = 6.4 Hz, 2H), 3.38 (d, J = 11.7 Hz, 2H ), 3.29 (q, J = 6.2 Hz, 2H), 2.93 (dd, J = 25.1, 10.3 Hz, 2H), 2.81 (td, J = 10.4, 9.4, 5.5 Hz, 4H), 2.54 (s, OH), 2.33 (s, 3H), 2.08 (d, J = 3.7 Hz, 4H), 1.82 ( tt, J = 9.9, 4.8 Hz, 4H), 1.70 (q, J = 8.2, 6.2 Hz, 3H), 1.57 (d, J = 6.5 Hz, 8H ), 1.43 (dd, J = 14.7, 10.4 Hz, 1H). 0D 133 608.2 1HNMR (400 MHz, DMC0-d6) δ 8.78 (s, 1H), 8.49 (s, 1H), 7.84 (s, 1H), 7.77 - 7.67 (m, 3H), 7.64 (dd, J = 8.0, 2.1 Hz, 2H), 7.59 (d, J = 2.4 Hz, 1H), 7.41 7.35 (m, 2H), 7, 19 (d, J = 8.3 Hz, 1H), 4.69 (q, J = 7.2 Hz, 2H), 4.13 (dt, J = 22.5, 7.9 Hz, 2H), 2.77 2.61 (m, 3H), 2.35 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H), 1.28 (s, 6H), 1.15 ( d, J = 0.6 Hz, 1H), 1.10 (d, J = 0.6 Hz, 9H).; 1H NMR (400 MHz, DMSO-de) δ 9.09 (s, 1H), 8.96 (s, 1H), 7.70 (dd, J = 7.3, 2.3 Hz, 1H), 7 .66 (dt, J = 8.5, 2.5 Hz, 2H), 7.57 - 7.48 (m, 2H), 7.45 (d, J = 2.3 Hz, 1H), 7. 37 - 7.27 (m, 2H), 7.11 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.4, 2.3 Hz, 1H), 4.33 - 4.21 (m, 1H), 4.13 - 3.96 (m, 3H), 2.72 (dt, J = 9.6, 4.8 Hz, 4H), 2.27 (d, J = 2.4 Hz, 3H), 1.35 (d, J = 2.4 Hz, 6H), 1.10 (t, J = 2.3 Hz, 1H), 1.03 (d, J = 2 .5 Hz, 8H), 0.97 (td, J = 7.2, 2.3 Hz, 3H). 0.9 134 697.3 1HNMR (400 MHz, DMCO-d6) δ 9.42 (d, J = 9.2 Hz, 1H), 8.75 - 8.66 (m, 3H), 8.46 (s, 1H), 7, 96 (s, 1H), 7.76 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 12.0 Hz, 1H), 5, 37 - 5.25 (m, 1H), 4.54 (s, 1H), 4.42 (s, 1H), 4.31-4.18 (m, 1H), 3.58 - 3.45 ( m, 1H), 3.40 (d, J = 11.9 Hz, 2H), 2.97 - 2.74 (m, 6H), 2.36 (s, 3H), 1.85 (d, J = 14.2 Hz, 2H), 1.76 - 1.62 (m, 2H), 1.60 (d, J = 6.4 Hz, 6H), 1.48 - 1.37 (m, 1H) , 1.29 (s, 6H), 0.92 - 0.78 (m, 4H). 0.3 135 622.4 1HNMR (400 MHz, DMSO-de) δ 9.04 (s, 1H), 8.56 (s, 1H), 7.82 (s, 1H), 7.74 - 7.65 (m, 3H), 7.62 (d, J = 1.5 Hz, 1H), 7.58 (dd, J = 8.2, 2.4 Hz, 1H), 7.52 (d, J = 2.3 Hz, 1H ), 7.40 - 7.32 (m, 2H), 7.18 (d, J = 8.3 Hz, 1H), 5.37 (p, J = 6.5 Hz, 1H), 4.18 - 4.02 (m, 2H), 2.75 - 2.56 (m, 2H), 2.33 (s, 3H), 1.58 (d, J = 0.6

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6.5 Hz, 6H), 1.26 (s, 6H), 1.08 (s, 9H). 136 648.4 1HNMR (400 MHz, methanol-d4) δ 9.26 (s, 1H), 7.79 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7, 74 (d, J = 2.4 Hz, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4, 43 - 4.31 (m, 1H), 4.16 (p, J = 6.6 Hz, 1H), 3.63 (p, J = 8.1 Hz, 1H), 3.52 (d, J = 12.3 Hz, 2H), 3.05 (dt, J = 11.6, 8.9 Hz, 2H), 2.98 - 2.80 (m, 4H), 2.43 (s, 3H) , 2.00 (d, J = 14.5 Hz, 2H), 1.88 (d, J = 13.6 Hz, 1H), 1.73 (d, J = 6.5 Hz, 8H), 1 .57 (t, J = 12.9 Hz, 1H), 1.38 (s, 6H), 1.18 (d, J = 6.6 Hz, 6H). 0.1 137 664.4 1HNMR (400 MHz, methanol-44) δ 9.18 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 2.9 Hz, 1H), 7.75 (dd, J = 7.9, 1.5 Hz, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 1.6 Hz, 1H), 7.44 - 7, 35 (m, 2H), 7.29 (d, J = 8.4 Hz, 1H), 5.37 (p, J = 7.0 Hz, 1H), 4.36 (p, J = 8.0 Hz, 1H), 3.64 (p, J = 8.2 Hz, 1H), 3.51 (p, J = 3.9, 3.2 Hz, 6H), 3.25 (s, 3H), 3.03 (dt, J = 11.8, 9.2 Hz, 2H), 2.97 - 2.79 (m, 4H), 2.44 (d, J = 2.9 Hz, ZN), 2 .00 (d, J = 14.5 Hz, 2H), 1.87 (d, J = 13.0 Hz, 1H), 1.71 (dd, J = 7.0, 2.5 Hz, 8H) , 1.57 (t, J = 13.0 Hz, 1H), 1.37 (s, 6H). 0.1 138 634.4 1HNMR (400 MHz, methanol-44) δ 9.25 (s, 1H), 7.79 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7, 71 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.44 (dd, J = 8.2, 2.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 5.39 (p, J = 6.6 Hz, 1H), 4, 43 - 4.29 (m, 1H), 3.68 - 3.56 (m, 1H), 3.52 (d, J = 12.2 Hz, 2H), 3.37 (q, J = 7, 3 Hz, 2H), 3.05 (qd, J = 9.1, 2.8 Hz, 2H), 2.97 - 2.79 (m, 4H), 2.44 (s, 3H), 2, 00 (d, J = 14.2 Hz, 2H), 1.90 (s, 2H), 1.76 (m, 1H), 1.73 (d, J = 6.6 Hz, 6H), 1, 56 (q, J = 12.7 Hz, 1H), 1.38 (s, 6H), 1.16 (t, J = 7.2 Hz, ZN). 0.1 139 662.4 1HNMR (400 MHz, methanol-44) δ 9.30 (s, 1H), 7.81 - 7.78 (m, 2H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H ), 7.65 (d, J = 1.4 Hz, 1H), 7.43 (dd, J = 8.2, 2.4 Hz, 1H), 7.39 (d, J = 7.8 Hz , 1H), 7.30 (d, J = 8.3 Hz, 1H), 5.42 (p, J = 6.6 Hz, 1H), 4.34 (p, J = 8.1 Hz, 1H ), 3.62 (p, J = 8.1 Hz, 1H), 3.52 (d, J = 12.3 Hz, 2H), 3.16 (dd, J = 6.7, 4.8 Hz , 2H), 3.03 (qd, J = 9.2, 2.7 Hz, 2H), 2.97 2.79 (m, 4H), 2.44 (s, 3H), 2.04 - 1 .67 (m, 12H), 1.57 (t, J = 12.7 Hz, 1H), 1.38 (s, 6H), 0.88 (d, J = 6.7 Hz, 6H). 0.06 140 690.3 1HNMR (400 MHz, methanol-44) δ 8.83 (s, 1H), 7.88 (d, J = 2.8 Hz, 1H), 7.84 (s, 1H), 7.76 (dd, J = 7.8, 1.5 Hz, 1H), 7.64 (s, 1H), 7.53 (dd, J = 8.9, 2.8 Hz, 1H), 7D0 - 7.34 (m , 2H), 5.38 - 5.25 (m, 1H), 4.46 - 4.34 0.3

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(m, 1H), 3.67 - 3.48 (m, 3H), 3.15 - 3.02 (m, 2H), 2.98 - 2.71 (m, 7H), 2.05 - 1 .70 (m, 5H), 1.67 (d, J = 6.6 Hz, 6H), 1.60 - 1.51 (m, 1H), 1.37 (s, 6H). 141 674 1HNMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 7.90 (s, 1H), 7.83 - 7.69 (m, 2H), 7.64 (s, 2H), 7.51 (s, 1H), 7.37 - 7.32 (m, 1H), 5.28 - 5.12 (m, 1H), 4.31 4.22 (m, 1H), 3.74 - 3.48 (m, 1H), 2.86 (s, 3H), 2.75 2.55 (m, 4H), 2.50 - 2.30 (m, 4H), 1.71 - 1, 42 (m, 12H), 1.35 (s, 6H). 0.07 142 646 1HNMR (400 MHz, methanol-d4) δ 8.44 (s, 1H), 7.81 - 7.72 (m, 3H), 7.48 - 7.41 (m, 2H), 7.37 - 7 .28 (m, 1H), 7.00 (d, J = 8.5 Hz, 1H), 5.25 - 5.11 (m, 1H), 4.38 - 4.24 (m, 1H), 3.05 - 2.84 (m, 4H), 2.82 - 2.43 (m, 8H), 2.27 - 2.10 (m, 1H), 1.71 - 1.49 (m, 12H ), 1.35 (s, 6H), 0.99 - 0.85 (m, 2H), 0.78 - 0.61 (m, 2H). 0.2 143 634 1HNMR (400 MHz, methanol-d4) δ 9.15 (s, 1H), 7.82 - 7.75 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7, 64 (d, J = 1.5 Hz, 1H), 7.48 - 7.39 (m, 2H), 7.34 (d, J = 8.3 Hz, 1H), 5.42 - 5.33 (m, 1H), 4.44 - 4.34 (m, 1H), 3.73 3.62 (m, 1H), 3.58 - 3.48 (m, 2H), 3.18 - 3, 02 (m, 2H), 3.00 - 2.78 (m, 9H), 2.06 - 1.52 (m, 12H), 1.40 (s, 6H), 1.27 (t, J = 7.6 Hz, 3H). 0.06 144 732.4 1HNMR (400 MHz, methanol-d4) δ 8.98 (d, J = 3.1 Hz, 2H), 7.82 (s, 1H), 7.71 (td, J = 7.6, 1.6 Hz, 2H), 7.55 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 7.8 Hz, 1H), 5.93 (t, J = 57.1 Hz, 1H), 5.36 (p, J = 6.6 Hz, 1H), 4.37 (p, J = 8.4 Hz, 1H), 3.67 (p, J = 8.2 Hz, 1H) , 3.57 (d, J = 12.4 Hz, 2H), 3.18 - 3.06 (m, 2H), 3.00 2.82 (m, 4H), 2.40 (d, J = 2.3 Hz, 3H), 2.03 (d, J = 17.2 Hz, 2H), 1.91 (d, J = 13.1 Hz, 1H), 1.84 - 1.67 (m, 8H), 1.59 (t, J = 12.9 Hz, 1H), 1.40 (s, 6H), 1.21 - 1.12 (m, 2H), 1.00 - 0.89 (m , 2H). 0.07 145 744.4 1HNMR (400 MHz, DMSSMb) δ 9.91 - 9.31 (m, 1H), 8.96 (s, 1H), 8.70 - 8.56 (m, 2H), 7.88 (s, 1H ), 7.67 - 7.60 (m, 1H), 7.45 - 7.32 (m, 3H), 6.04 (t, J = 56.9 Hz, 1H), 5.27 (p, J = 6.6 Hz, 1H), 4.24 - 4.07 (m, 2H), 3.97 (s, 1H), 3.75 - 3.52 (m, 1H), 3.42 - 3 .20 (m, 1H), 3.07 - 2.72 (m, 5H), 2.71 - 2.60 (m, 1H), 2.29 (s, 3H), 2.02 - 1.87 (m, 1H), 1.84 - 1.48 (m, 10H), 1.46 1.34 (m, 1H), 1.28 (s, 6H), 1.15 - 1.01 (m, 2H), 0.93 0.85 (s, 2H). 0.07 146 747.4 1HNMR (400 MHz, DMSSMb) δ 9.36 (d, J = 9.2 Hz, 1H), 8.69 (s, 1H), 8.47 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.79 (dd, J = 7.9, 1.5 Hz, 1H), 7.62 (d, J = 1.5 Hz, 1H), 7.56 - 7.48 (m, 3H), 7.23 7.15 (m, 1H), 5.36 - 5.20 (m, 1H), 4.28 (t, J = 8 .3 Hz, 1H), 3.57 - 3.45 (m, 1H), 3.39 (d, J = 11.8 Hz, 2H), 2.94 (d, J = 10.3 Hz, 2H ), 2.82 (t, J = 9.8 Hz, 3H), 0.1

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2.73 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 1.89 - 1.67 (m, 9H), 1.62 (d, J = 13.3 Hz , 2H), 1.56 (d, J = 6.5 Hz, 6H), 1.47 (s, 1H), 1.42 (s, 1H), 1.37 (s, 6H), 1.30 (s, 1H). 147 733.4 1HNMR (400 MHz, flMCO-d6) δ 9.38 (s, 1H), 8.70 (s, 1H), 8.48 (s, 1H), 8.16 (q, J = 4.5 Hz, 1H), 7.90 (d, J = 2.6 Hz, 1H), 7.78 (dd, J = 7.9, 1.4 Hz, 1H), 7.65 7.56 (m, 2H) , 7.52 (d, J = 5.0 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 5.29 (q, J = 6.5 Hz, 1H), 4 .50 (q, J = 6.5 Hz, 1H), 4.28 (t, J = 8.2 Hz, 1H), 3.88 (s, 5H), 3.58 3.44 (m, 1H ), 3.39 (d, J = 12.0 Hz, ZN), 2.94 (dd, J = 20.1, 10.0 Hz, 2H), 2.81 (t, J = 9.7 Hz , ZN), 2.74 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 1.91-1.67 (m, 8H), 1.62 (d, J = 7.0 Hz, OH), 1.56 (d, J = 6.5 Hz, 6H), 1.49 1.35 (m, 1H), 1.31 (s, 1H), 1.24 (t , J = 7.1 Hz, ZN). 0.2 148 771.4 1HNMR (400 MHz, DMSO-de) δ 9.46 (d, J = 9.6 Hz, 1H), 8.80 (s, 1H), 8.52 (s, 1H), 8.17 (q, J = 4.5 Hz, 1H), 7.90 (s, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.63 - 7.56 (m, 2H ), 7.55 - 7.49 (m, 2H), 7.20 (d, J = 8.2 Hz, 1H), 5.41 - 5.26 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.99 - 3.69 (m, 4H), 3.50 (q, J = 8.1 Hz, 1H), 3.38 (d, J = 11.7 Hz, 2H), 3.03 - 2.77 (m, 7H), 2.74 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 2.13 (s, 6H ), 1.84 (d, J = 13.9 Hz, 2H), 1.70 (dd, J = 15.1, 9.6 Hz, 6H), 1.57 (d, J = 6.5 Hz , 6H), 1.42 (d, J = 12.7 Hz, 1H). 0.2 149 755.1 1HNMR (400 MHz, DMSO-de) δ 9.40 (d, J = 9.4 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.19 (q, J = 4.5 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.83 (td, J = 8.3, 1.9 Hz, 2H), 7.80 ( s, 1H), 7.65 (d, J = 1.5 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4.33 (t, J = 8.2 Hz, 1H), 4.20 - 4.10 (m, 1H), 3.59 3.46 (m, 2H), 3.40 (d, J = 12.0 Hz, 4H), 2.84 (dd, J = 25.7, 10.5 Hz, 4H), 2.76 (d, J = 4.6 Hz, ZN), 2.32 ( s, ZN), 2.02 - 1.90 (m, 1H), 1.89 - 1.53 (m, 13H), 1.41 (s, 5H), 1.27 (dq, J = 7, 1, 2.2 Hz, 5H). OD 150 741.4 1HNMR (400 MHz, DMSO-de) δ 9.56 (d, J = 9.8 Hz, 1H), 8.66 (s, 1H), 8.31 (s, 1H), 8.20 (q, J = 4.6 Hz, 1H), 7.91 - 7.78 (m, 4H), 7.68 - 7.58 (m, 2H), 7.24 (d, J - 8.2 Hz, 1H ), 4.32 (p, J - 8.3 Hz, 1H), 4.24 - 4.16 (m, 1H), 3.93 (s, 4H), 3.58 - 3.48 (m, 1H), 3.39 (d, J = 11.8 Hz, 2H), 3.06 - 2.92 (m, 2H), 2.93 2.79 (m, 2H), 2.76 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 1.71 (dq, J = 60.8, 13.8 Hz, 11H), 1.43 (t, J = 12.5 Hz, 1H), 1.29 (d, J = 3.9 Hz, 6H), 0.88 (d, J = 4.9 Hz, 2H), 0.62-0.51 (m, 2H). 0.1 151 731.5 5 1HNMR (400 MHz, DMSO-de) δ 8.43 (d, J = 2.6 Hz, 1H), 8.24 (s, 1H), 8.19 (q, J = 4.6 Hz, 1H) , 7.91 (dd, J = 10.9, 2.3 Hz, 1H), 7.82 (dd, J = 13.7, 5.0 Hz, 0.05

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ZN), 7.65 (s, 1H), 7.57 (d, J = 35.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.51 (q, J = 6.5 Hz, 1H), 4.33 (p, J = 8.2 Hz, 1H), 4.14 (td, J = 6.6, 3.2 Hz, 1H), 3.89 ( d, J = 21.1 Hz, 2H), 3.04 - 2.78 (m, 5H), 2.76 (d, J = 4.5 Hz, ZN), 2.32 (s, ZN), 1.84 (d, J = 14.5 Hz, ZN), 1.78 - 1.67 (m, 2H), 1.62 (d, J = 13.4 Hz, 2H), 1.48 - 1 .35 (m, 1H), 1.30 - 1.21 (m, 8H). 152 743.5 1HNMR (400 MHz, DMSO-46) δ 9.45 (d, J = 9.4 Hz, 1H), 8.85 (s, 1H), 8.54 (s, 1H), 8.17 (d, J = 4.7 Hz, 1H), 7.91 (s, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.60 (d, J = 7.7 Hz, 2H), 7.56 - 7.50 (m, 2H), 7.20 (d, J = 8.3 Hz, 1H), 5.41 - 5.27 (m, 1H), 4.27 (t, J = 8.2 Hz, 1H), 3.92 (s, 4H), 3.51 (q, J = 8.1 Hz, 1H), 3.38 (d, J = 11.8 Hz , 2H), 2.94 (q, J = 9.7 Hz, 2H), 2.80 (d, J = 11.1 Hz, 4H), 2.74 (d, J = 4.6 Hz, ZN ), 2.32 (s, ZN), 1.88 - 1.61 (m, 9H), 1.58 (d, J = 6.5 Hz, 6H), 1.42 (d, J = 12, 4 Hz, 1H), 1.28 (s, 3H), 0.93 - 0.83 (m, 2H), 0.61 - 0.54 (m, 2H). 0.2 153 743.4 1HNMR (400 MHz, DMSO-46) δ 9.50 (d, J = 9.5 Hz, 1H), 8.47 (s, 1H), 8.26 (s, 1H), 8.20 (q, J = 4.5 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.87 - 7.78 (m, 3H), 7.64 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.84 - 4.68 (m, 4H), 4.32 (t, J = 8.1 Hz, 1H), 4.25 - 4.12 (m, 2H), 4.07 3.92 (m, 1H), 3.86 - 3.71 (m , 1H), 3.71 - 3.59 (m, 1H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.9 Hz, 4H), 3 .07 - 2.79 (m, 2H), 2.76 (d, J = 4.6 Hz, 4H), 2.32 (s, 3H), 1.90 - 1.53 (m, 11H), 1.41 (d, J = 12.7 Hz, 1H), 1.27 (tt, J = 4.1, 2.1 Hz, 4H). 0D 154 771 1HNMR (400 MHz, DMSO-ab) δ 9.36 (d, J = 9.7 Hz, 1H), 8.41 (s, 1H), 8.23 (s, 1H), 8.19 (q, J = 4.5 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.83 (ddd, J = 7.6, 5.6, 2.0 Hz, 2H), 7.80 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8 .4 Hz, 1H), 4.32 (d, J = 8.1 Hz, 1H), 4.19 - 4.09 (m, 1H), 3.97 - 3.74 (m, 5H), 3 .52 (q, J = 8.1 Hz, 1H), 3.40 (d, J = 11.8 Hz, 2H), 2.86 (dt, J = 26.8, 12.9 Hz, 5H) , 2.76 (d, J = 4.6 Hz, ZN), 2.45 (d, J = 2.5 Hz, 6H), 2.32 (s, 3H), 1.89 - 1.55 ( m, 9H), 1.41 (d, J = 12.7 Hz, 1H), 1.27 (d, J = 8.6 Hz, 4H). 0.06 155 741.2 1HNMR (400 MHz, DMSO-46) δ 9.34 (s, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 8.18 (t, J = 4.7 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.85 - 7.80 (m, 2H), 7.80 (s, 1H), 7.65 (d, J = 1 .5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.24 - 7.20 (m, 1H), 4.33 (t, J = 8.2 Hz, 1H ), 4.19 4.08 (m, 1H), 3.83 (d, J = 44.5 Hz, 5H), 3.66 - 3.46 (m, 2H), 3.42 (dd, J = 17.4, 9.2 Hz, ZN), 3.09 - 2.79 (m, 5H), 2.76 (d, J = 4.6 Hz, ZN), 2.31 (s, ZN) , 2.29 2.05 (m, ZN), 1.99 - 1.54 (m, JN), 1.41 (d, J = 12.6 0.06

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Hz, 1H), 1.27 (d, J = 8.9 Hz, 5H). 156 753.6 1HNMR (400 MHz, DMSO) δ 9.34 (s, 1H), 8.39 (s, 1H), 8.23 (s, 1H), 8.18 (q, J = 4.5 Hz, 1H) , 7.89 (d, J = 2.3 Hz, 1H), 7.86 - 7.80 (m, 2H), 7.80 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.32 (q, J = 8.3 Hz, 1H), 4.17 - 4.10 (m, 1H), 4.05 - 3.71 (m, 6H), 3.52 (q, J = 8.1 Hz, 1H), 3.40 (d , J = 11.8 Hz, 2H), 3.08 - 2.79 (m, 5H), 2.76 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 2 .14 (s, 6H), 1.90 - 1.55 (m, 9H), 1.41 (d, J = 12.8 Hz, 1H), 1.27 (d, J = 8.9 Hz, 4H). 0.06 157 735 1HNMR (400 MHz, methanolD4) δ 8.98 (s, 1H), 7.80 (s, 1H), 7.77 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 ( s, 1H), 7.60 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.3, 2 .4 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.17 - 5.09 (m, 2H), 4.44 - 4.36 (m, 1H), 4 .12 3.99 (m, 3H), 3.91 - 3.52 (m, 4H), 3.18 - 2.93 (m, 6H), 2.87 (s, 3H), 2.41 ( s, 3H), 2.19 (s, 3H), 2.09 1.83 (m, 10H), 1.71-1.67 (m, 3H), 0.97 - 0.92 (m, 3H ). 0.2 158 765 1HNMR (400 MHz, methanolD4) δ 8.45 (s, 1H), 7.83 - 7.68 (m, 3H), 7.50 - 7.34 (m, 3H), 7.20 (d, J = 8.0 Hz, 1H), 5.03 - 4.93 (m, 1H), 4.38 - 4.26 (m, 1H), 4.09 - 3.77 (m, 4H), 3, 09 - 2.95 (m, 1H), 2.93 - 2.54 (m, 11H), 2.38 (s, 3H), 2.24 - 2.11 (m, 4H), 2.04 1 .76 (m, 7H), 1.62 (d, J = 6.7 Hz, ZN), 1.44 - 1.26 (m, 2H), 0.85 (t, J = 7.4 Hz, ZN). 0.2 159 715 1HNMR (400 MHz, methanolD4) δ 8.61 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7 .69 (s, 1H), 7.65 (s, 1H), 7.58 (dd, J = 8.2, 2.4 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 4.45 4.43 (m, 1H), 4.13 - 4.02 (m, 3H), 3.94 - 3, 81 (m, 3H), 3.75 -3.67 (m, 1H), 3.50 - 3.35 (m, 2H), 3.17 3.08 (m, 2H), 3.00 - 2 .92 (m, 3H), 2.89 (s, 3H), 2.41 (s, 3H), 2.20 (s, 3H), 1.98 - 1.83 (m, 6H), 1, 45 - 1.35 (m, 4H), 1.30 - 1.18 (m, 6H). 0D 160 757 1HNMR (400 MHz, methanolD4) δ 8.72 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7 .73 (d, J = 1.4 Hz, 1H), 7.66 (s, 1H), 7.59 - 7.50 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 4.67 - 4.59 (m, 1H), 4.22 4.14 (m, 1H), 4.12 - 4.06 (m, 1H), 4.02 - 3.96 (m , 1H), 3.94 - 3.68 (m, 4H), 3.38 - 3.34 (m, 1H), 3.24 3.17 (m, 2H), 3.08 - 3.00 ( m, 2H), 2.89 (s, 3H), 2.65 (d, J = 12.4 Hz, 2H), 2.41 (s, 3H), 2.20 (s, 3H), 2, 06 1.87 (m, 5H), 1.65 - 1.58 (m, 1H), 1.47 - 1.39 (m, 4H), 1.32 (d, J = 3.1 Hz, 6H ), 1.07 (s, 6H). 0.08 161 729 1HNMR (400 MHz, methanolD4) δ 8.24 (s, 1H), 7.99 (s, 1H), 7.85 - 7.73 (m, 3H), 7.59 (s, 1H), 7, 49 (d, J = 0.06

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7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.21 - 3.70 (m, 7H), 2.95 - 2.65 (m, 9H), 2.39 (s, 3H), 2.19 (s, 3H), 1.95 - 1.84 (m, 2H), 1.86 - 1, 79 (m, 2H), 1.70 - 1.60 (m, 2H), 1.42 - 1.25 (m, 6H), 1.00 0.85 (s, 6H). 162 721 1HNMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 7.84 - 7.74 (m, 2H), 7.69 (s, 1H), 7.60 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.36 (dd, J = 8.2, 2.3 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H ), 5.25 - 5.13 (m, 2H), 4.43 - 4.34 (m, 1H), 4.11 - 3.52 (m, 8H), 3.08 - 2.78 (m , 7H), 2.39 (s, 3H), 2.19 (s, 3H), 2.10-1.78 (m, 8H), 1.63 (d, J = 6.6 Hz, 6H) . θ,ι 163 764 1HNMR (400 MHz, methanol-d4) δ 8.22 (s, 1H), 7.93 - 7.81 (m, ZN), 7.76 (dd, J = 7.9, 1.5 Hz, 1H ), 7.60 (s, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.42 - 4.29 (m, 1H) 4.09 - 3.78 (m, 5H), 2.89 (s, 3H), 2.82 - 2.57 (m, 5H), 2.55 - 2.41 (m, 3H), 2.39 (s, 3H), 2.36 - 2.29 (m, 1H), 2.18 (s, 3H), 1.93 -1.86 (m, 2H), 1.85 - 1.78 (m, 2H), 1.74 - 1.46 (m, 4H), 1.40 1.26 (m, 4H), 1.17 - 1.04 (m, 2H). 0.1 164 751 1HNMR (400 MHz, methanol-d4) δ 8.82 (s, 1H), 7.80 - 7.73 (m, 2H), 7.69 -7.60 (m, 2H), 7.52 - 7 .47 (m, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.21 (m, 1H), 5.33 5.26 (m, 1H), 4.48 - 4.40 (m, 1H), 4.14 - 3.98 (m, 3H), 3.95 - 3.82 (m, 3H), 3.76 -3.44 (ms, 3H), 3, 25 3.10 (m, 3H), 2.95 - 2.85 (m, 5H), 2.41 (s, 34H), 2.19 (s, 3H), 1.96 - 1.88 (m , 2H), 1.87 - 1.80 (m, 2H), 1.76 - 1.63 (m, 8H). 0.2 165 716 1HNMR (400 MHz, methanol-d4) δ 9.23 (s, 1H), 7.83 - 7.72 (m, 2H), 7.64 (dd, J = 11.5, 1.9 Hz, 2H ), 7.50 (d, J = 7.9 Hz, 1H), 7.43 (dd, J = 8.2, 2.4 Hz, 1H), 7.29 (d, J = 8.3 Hz , 1H), 5.43 - 5.31 (m, 1H), 4.43 4.31 (m, 1H), 4.15 - 3.96 (m, 2H), 3.90 - 3.65 ( m, 4H), 3.46 - 3.32 (m, 3H), 3.17 - 3.02 (m, 2H), 3.00 2.80 (m, 5H), 2.43 (s, 3H ), 2.19 (s, 3H), 2.09 - 1.77 (m, 6H), 1.71 (d, J = 6.6 Hz, 6H), 1.24 (d, J = 20, 9 Hz, 6H). 0.1 166 727 1HNMR (400 MHz, methanol-d4) δ 8.25 (s, 1H), 8.11 (s, 1H), 7.78 (dd, J = 7.8, 1.5 Hz, 1H), 7, 74 - 7.59 (m, 3H), 7.49 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.45 -4.35 (m, 1H), 4.11 - 3.79 (m, 6H), 3.10 2.70 (m, 11H), 2.39 (s, 3H), 2.19 (s, 3H), 1 .94 - 1.80 (m, 6H), 1.39 - 1.30 (m, 4H), 0.60 - 0.48 (m, 4H). 0.1 167 763.5 7 1HNMR (400 MHz, flMCO-d6) δ 9.45 (s, 1H), 8.50 (s, 1H), 8.26 (s, 1H), 8.20 (q, J = 4.5 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.86 - 7.78 (m, 3H), 7.65 (s, 1H), 7.54 (d, J = 7 ,8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.33 (s, OH), 4.16 (q, J = 5.4 Hz, 1H), 3, 40 (d, J = 0.1

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12.6 Hz, 5H), 2.98 (q, J = 9.9, 9.4 Hz, 2H), 2.92 2.79 (m, 2H), 2.77 (d, J = 4, 5 Hz, ZN), 4.82 - 0.48 (m, 1H), 2.32 (s, ZN), 2.00 - 1.80 (m, 8H), 1.75 - 1.54 (m , 5H), 1.49 - 1.33 (m, 2H), 1.31 - 1.25 (m, 4H), 1.09 0.96 (m, 4H). 168 737.5 4 1HNMR (400 MHz, flMCO-d6) δ 9.41 (d, J = 9.4 Hz, 1H), 8.43 (s, 1H), 8.24 (s, 1H), 8.20 (q, J = 4.6 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.86 - 7.83 (m, 1H), 7.83 - 7.81 (m, 1H ), 7.81 (s, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 4.33 (t, J = 8.0Hz, 1H), 4.19 - 4.10 (m, 1H), 3.60 - 3.34 (m, 6H), 3.00 (s, 3H), 2.92 - 2.78 (m, 2H), 2.77 (d, J = 4.6 Hz, ZN), 2.32 (s, ZN), 2.00 - 1.79 (m, 5H), 1.67 (dd, J = 36.8, 13.3 Hz, ZN), 1.41 (d, J = 12.8 Hz, 1H), 1.27 ( dq, J = 5.6, 2.4 Hz, 5H). OD 169 733.4 1HNMR (400 MHz, methanol-44) δ 9.37 (d, J = 31.6 Hz, 1H), 7.83 (d, J = 3.1 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.64 - 7.60 (m, 3H), 7.51 (dd, J = 8.0, 3.9 Hz, 1H), 7.42 (s, 2H), 7.30 (d, J = 8.2 Hz, 1H), 5.23 (s, 1H), 4.34 (t, J = 8.4 Hz, 1H), 3.87 (s, 5H), 3.75 (d, J = 2.3 Hz, ZN), 3.68 - 3.45 (m, 4H), 3.07 (dq, J = 18.1, 9.8, 9.3 Hz, 2H), 2.87 (t, J = 5.9 Hz, 8H), 2.45 - 2.41 (m, 4H), 2.15 - 1.64 (m, 17H), 1.55 (q , J = 13.2 Hz, 2H), 0.98 (d, J = 9.2 Hz, ZN). 0.1 170 753 1HNMR (400 MHz, methanol-44) δ 8.44 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.72 - 7, 65 (m, 2H), 7.46 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 11.8 Hz, 1H), 5.26 - 5.18 (m, 1H ), 4.79 - 4.64 (m, 5H), 4.60 - 4.50 (m, 1H), 4.28 - 4.18 (m, 1H), 3.76 - 3.68 (m , 2H), 2.88 - 2.56 (m, 12H), 2.52 - 2.36 (m, 5H), 1.97 - 1.77 (m, 6H), 1.72 - 1.50 (m, 8H). 0.8 171 767 1HNMR (400 MHz, methanol-44) δ 9.16 (s, 1H), 8.01 - 7.71 (m, 3H), 7.58 (s, 1H), 7.51 - 7.34 (m , 1H), 7.16 (d, J = 11.5 Hz, 1H), 5.43 - 5.33 (m, 1H), 5.10 (d, J = 44.5 Hz, 1H), 5 .00 - 4.88 (m, 4H), 4.66 - 4.52 m, 1H), 4.38 - 4.25 (m, 1H), 3.81 - 3.33 (m, 10H), 3.19 - 2.85 (m, 5H), 2.46 (s, 3H), 2.41 - 1.85 (m, 8H), 1.81 - 1.66 (m, 6H), 1, 15 (t, J = 7.1 Hz, ZN). 0.2 172 781 1HNMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.82 - 7.76 (m, 2H), 7, 62 (s, 1H), 7.44 (s, 1H), 7.14 (d, J = 12.0 Hz, 1H), 5.31 (p, J = 6.3 Hz, 1H), 5, 10 (d, J = 44.8 Hz, 1H), 4.99 - 4.86 (m, 4H), 4.66 - 4.52 (m, 1H), 4.40 - 4.30 (m, 1H), 4.13 (p, J = 6.5 Hz, 1H), 3.82 - 3.66 (m, 4H), 3.58 - 3.42 (m, 3H), 3.18 - 3 .05 (m, 3H), 3.00 - 2.86 (m, 3H), 2.44 (s, 3H), 2.39 - 1.84 (m, 8H), 1.72 (d, J = 6.7, 6H), 1.16 (d, J = 6.7, 6H). 0.3 173 715.5 1HNMR (400 MHz, flMC0-d6) δ 10.74 (s, 1H), 9.50 0.08

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(s, 1H), 8.36 (s, 1H), 8.26 - 7.46 (m, 7H), 7.20 (d, J = 8.4 Hz, 1H), 4.78 (q, J = 7.6, 6.3 Hz, 4H), 4.59 - 3.99 (m, 3H), 3.43 (d, J = 9.1 Hz, 7H), 3.04 - 2.63 (m, 9H), 2.40 - 1.07 (m, 17H). 174 678.5 1HNMR (400 MHz, DMCO-d6) δ 9.42 (d, J = 9.1 Hz, 1H), 8.83 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 7.88 (s, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.7 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 5.40 - 5.28 (m, 1H), 4, 55 (s, 1H), 4.43 (s, 1H), 4.33 - 4.24 (m, 1H), 3.55 - 3.42 (m, 1H), 3.39 (d, J = 12.0 Hz, 2H), 2.99 - 2.73 (m, 6H), 2.30 (s, 3H), 1.84 (d, J = 14.0 Hz, 2H), 1.76 - 1.61 (m, 2H), 1.57 (d, J = 6.4 Hz, 6H), 1.48 - 1.33 (m, 2H), 1.30 (s, 6H), 0.90 - 0.84 (m, 2H), 0.83 - 0.77 (m, 2H). 0.09 175 638.4 1HNMR (400 MHz, DMSO+b) δ 9.36 (d, J = 9.7 Hz, 1H), 8.77 (s, 1H), 8.41 (s, 1H), 8.19 (q, J = 4.5 Hz, 1H), 7.84 (s, 1H), 7.65 (dd, J = 7.8, 1.4 Hz, 1H), 7.61 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 1.5 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.25 - 7.14 (m, 1H), 5.28 (p, J = 6.6 Hz, 1H), 4.15 (p, J = 8.3 Hz, 1H), 3.49 (p, J = 8.3 Hz, 1H), 3, 37 (d, J = 11.8 Hz, 2H), 2.90 (dt, J = 11.7, 8.9 Hz, 2H), 2.84 - 2.73 (m, 3H), 2.71 (d, J = 4.6 Hz, ZN), 2.36 (d, J = 0.6 Hz, ZN), 1.82 (d, J = 14.1 Hz, 2H), 1.76 - 1 .60 (m, 2H), 1.58 (d, J = 6.6 Hz, 6H), 1.47 - 1.33 (m, 1H), 1.26 (s, 6H). 0.1 176 666.4 1HNMR (400 MHz, DMSO+b) δ 9.38 (d, J = 9.5 Hz, 1H), 8.74 (s, 1H), 8.43 (s, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.83 (s, 1H), 7.65 (dd, J = 7.8, 1.5 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 12.1 Hz, 1H), 5.29 (p, J = 6.6 Hz, 1H), 4.17 (p, J = 8.3 Hz, 1H), 4.08 - 3.92 (m, 1H), 3.51 (h, J = 8.3 Hz, 1H), 3.38 (d, J = 11.9 Hz, 2H), 2.99 - 2.85 (m, 2H), 2.85 - 2.70 (m, 5H), 2.35 (d, J = 0.6 Hz, ZN ), 1.82 (d, J = 14.1 Hz, 2H), 1.58 (d, J = 6.6 Hz, 9H), 1.38 (q, J = 12.3 Hz, 1H), 1.26 (s, 6H), 1.07 (d, J = 6.6 Hz, 6H). 0.2 177 693.3 1HNMR (400 MHz, DMSO+b) δ 9.38 (d, J = 9.7 Hz, 1H), 8.75 (s, 1H), 8.43 (s, 1H), 8.20 (q, J = 4.5 Hz, 1H), 7.89 (s, 1H), 7.75 (dd, J = 7.9, 1.4 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 8.2 Hz, 1H), 7.45 (d, J = 1.4 Hz, 1H), 7.19 (d, J = 12.1 Hz, 1H), 5.27 (q, J = 6.5 Hz, 1H), 4.36 - 4.26 (m, 2H), 4.14 (q, J = 8.1 Hz, 2H), 4, 08 - 3.95 (m, 2H), 3.50 (q, J = 8.1 Hz, 1H), 3.37 (d, J = 11.6 Hz, 2H), 3.05 - 2.85 (m, 2H), 2.83 - 2.69 (m, 6H), 2.39 - 2.31 (m, 3H), 1.84 (m, 5H), 1.70 (d, J = 13 .0 Hz, 1H), 1.58 (m, 7H), 1.40 (d, J = 13.0 Hz, 1H). 0.4 178 707.4 1HNMR (400 MHz, DMSO+b) δ 9.33 (s, 1H), 8.69 0.3

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(s, 1H), 8.42 (s, 1H), 8.27 (t, J = 5.6 Hz, 1H), 7.89 (s, 1H), 7.74 (dd, J = 7, 9, 1.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.2 Hz, 1H), 7.47 (d, J = 1.4 Hz, 1H), 7.18 (d, J = 12.1 Hz, 1H), 5.28 (p, J = 6.6 Hz, 1H), 4.30 (d, J = 9, 2 Hz, 2H), 4.16 (p, J = 8.3 Hz, 1H), 4.07 - 3.96 (m, 2H), 3.50 (q, J = 8.1 Hz, 1H) , 3.37 (d, J = 11.8 Hz, 2H), 3.27 - 3.14 (m, 2H), 2.94 (dt, J = 27.9, 10.3 Hz, 2H), 2.85 - 2.68 (m, 4H), 2.36 (d, J = 0.6 Hz, ZN), 1.85 (s, 5H), 1.57 (m, 8H), 1.41 (t, J = 12.6 Hz, 1H), 1.05 (t, J = 7.2 Hz, ZN). 179 721.4 1HNMR (400 MHz, DMSO+b) δ 9.32 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.15 (d, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.74 (dd, J = 7.8, 1.4 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7, 55 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 1.4 Hz, 1H), 7.17 (d, J = 12.4 Hz, 1H), 5.39 - 5.12 (m, 1H), 4.31 (s, 2H), 4.17 (q, J = 8.2 Hz, 1H), 4.09 - 3.95 (m, 3H), 3.50 (q, J = 8.0 Hz, 1H), 3.38 (d, J = 11.5 Hz, 2H), 3.06 - 2.86 (m, 2H), 2.78 (dd, J = 13.9, 8.4 Hz, ZN), 2.39 - 2.33 (m, ZN), 1.85 (s, 5H), 1.57 (d, J = 6.5 Hz, 8H), 1.39 (d, J = 12.6 Hz, 1H), 1.08 (d, J = 6.6 Hz, 6H). 1.1 180 753 1HNMR (400 MHz, methanol^4) δ 8.46 (s, 1H), 8.08 (t, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.72 - 7, 66 (m, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 10.4 Hz, 1H), 5, 26 - 5.20 (m, 1H), 4.21-4.13 (m, 2H), 4.07 - 3.97 (m, 2H), 3.97 - 3.88 (m, 1H), 3.84 - 3.76 (m, 1H), 2.79 - 2.36 (m, 9H), 2.18 (s, 3H), 1.92 - 1.41 (m, 15H), 1, 23 (d, J = 6.8, 6H). 0.2 181 718 1HNMR (400 MHz, methanol-d4) δ 9.18 (s, 1H), 7.97 (s, 1H), 7.68 (dd, J = 7.9, 1.5 Hz, 1H), 7, 50 - 7.40 (m, 4H), 7.34 (dd, J = 8.3, 2.5 Hz, 1H), 5.42 - 5.30 (m, 1H), 4.33 - 4.217 ( m, 1H), 4.10 - 3.97 (m, 2H), 3.94 3.79 (m, 3H), 3.76 - 3.69 (m, 1H), 3.46 - 3.36 (m, 2H), 3.14 - 2.96 (m, 3H), 2.93 - 2.80 (m, 5H), 2.50 (s, 3H), 2.18 (s, 3H), 2.05 - 1.75 (m, 12H), 1.25 (d, J = 24.0 Hz, 6H). 0.2 182 642 1HNMR (400 MHz, methanol-d4) δ 8.52 (s, 1H), 8.23 (d, J = 6.7 Hz, 1H), 7.95 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.38 (dd, J = 7.5, 1.4 Hz, 1H), 7.18 (s, 1H), 6.12 (d, J = 12.3 Hz, 1H), 5.73 - 5.63 (m, 1H), 4.64 - 4.46 (m, 1H), 2.93 (s, 3H), 2.48 (m, 2H), 2 .12 (m, 2H), 1.79 (t, J = 7.1 Hz, 6H), 1.47 (d, J = 20.6 Hz, 6H), 1.35 - 1.11 (m, 8H), 0.92 - 0.83 (m, 2H).; 1HNMR (400 MHz, DMSO+b) δ 8.50 (s, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.93 - 7.76 (m, 3H), 7.60 (d, J = 7.9 Hz, 1H), 7.46 - 7.37 (m, 1H), 7.28 (d, J = 7.8 Hz, 1H), 5.27 - 5 .17 (m, 1H), 4.37 - 7.27 (m, 1H), 3.28 - 3.25 (m, 1H) 2.77 (d, J = 3.6 Hz, ZN), 2 .56 - 2.50 (m, 2H), 2.43 - 2.36 (m, 2H), 2.32 - 2.19 (m, 4H), 1.60 - 1.50 0.2

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(m, UN), 1.45 - 1.36 (m, 2H), 1.22 (s, 6H). 183 618.4 1HNMR (400 MHz, DMSO-de) δ 9.06 (s, 1H), 8.32 (s, 1H), 8.20 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.89 7.82 (m, 2H), 7.80 (s, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 4 46 - 4.37 (m, 1H), 3.29 - 3.17 (m, 2H), 3 .02 - 2.94 (m, 2H), 2.94 - 2.86 (m, 2H), 2.77 - 2.70 (m, 3H), 2.34 (s, 3H), 1.87 - 1.79 (m, 3H), 1.74 - 1.63 (m, 2H), 1.52 (s, 3H), 1.32 (s, 7H), 1.30 - 1.22 (m , 5H). 0.05 184 612.3 1HNMR (400 MHz, DMSOUB) δ 9.29 (d, J = 10.4 Hz, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.07 - 8.00 (m, 1H), 7.94 (s, 1H), 7.77 (q, J = 2.8, 2.3 Hz, 3H), 7.68 (dd, J = 8.2, 2.4 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 4.43 - 4 .30 (m, 1H), 4.21-4.11 (m, 1H), 3.40 (d, J = 11.9 Hz, 2H), 2.92 (t, J = 8.1 Hz, 4H), 2.87 - 2.73 (m, 2H), 2.36 (s, 3H), 1.88 - 1.51 (m, 6H), 1.41 (t, J = 12.6 Hz , 1H), 1.31-1.23 (m, 4H). 0.9 185 747.3 'NMR (400 MHz, DMSO-de) δ 9.13 (bs, 1H), 8.97 (s, 1H), 8.76 - 8.58 (m, 3H), 8.04 (s, 1H) , 7.72 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.38 - 5.15 ( m, 1H), 4.32 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.70 (m, 2H), 2.28 (s, 3H), 1.85 (m, 2H), 1.76 - 1.38 (m, 13H), 1.31 (s, 6H), 1.15 - 1.05 (m, 2H), 0.93 (m, 2H). 0.1 186 729.4 Ή NMR (400 MHz, DMSO-de) δ 9.09 (m, 1H), 8.80 (s, 1H), 8.73 - 8.60 (m, 3H), 8.03 (s, 1H) , 7.72 (s, 1H), 7.37 (d, J = 6.9 Hz, 1H), 5.32 - 5.17 (m, 1H), 4.49 (d, J = 52 Hz, 2H), 4.32 (m, 1H), 3.23 (m, 2H), 2.94 (m, 4H), 2.76 - 2.59 (m, 2H), 2.28 (s, 3H ), 1.85 (m, 2H), 1.69 (m, 13H), 1.31 (m, 6H), 0.86 (m, 4H). .07 187 791.4 Ή NMR (400 MHz, DMSO-de) δ 9.54 (bs, 1H), 8.97 (s, 2H), 8.70 (s, 1H), 8.66 (s, 1H), 8.03 (s, 1H), 7.73 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.06 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.32 (m, 2H), 4.14 (m, 1H), 3.47 (m, 1H), 3.30 (m, 1H), 3.15 (m, 2H) , 2.90 (m, 1H), 2.72 - 2.05 (m, 8H), 1.62 - 1.52 (m, 9H), 1.30 (s, 6H), 1.08 (m , 2H), 0.92 - 0.60 (m, 7H). 0.2 188 777.4 Ή NMR (400 MHz, DMSO-de) δ 9.19 (s, 1H), 8.98 (s, 1H), 8.71 (d, J = 8.0 Hz, 2H), 8.03 (s , 1H), 7.78 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.1 Hz, 1H), 5.38 - 5 .20 (m, 1H), 4.41 (m, 1H), 3.87 (m, 2H), 3.28 (m, 3H), 3.04 (m, 2H), 2.86 (m, 1H), 2.63 (m, 3H), 2.29 (s, 3H), 1.60 (m, 8H), 1.45 - 1.19 (m, 12H), 1.07 (m, 2H ), 0.93 (m, 2H). 0.4 189 775.4 'NMR (400 MHz, DMSO-de) δ 10.09 (m, 1H), 8.98 (s, 1H), 8.71 (s, 2H), 8.68 (s, 1H), 8.04 (s, 1H), 7.93 (d, J = 10.2 Hz, 1H), 7.43 (d, J = 6.9 Hz, 1H), 0.2

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6.07 (t, J = 57.0 Hz, 1H), 5.30 (m, 1H), 4.51 (m, 1H), 3.85 - 3.67 (m, 4H), 3.58 - 3.43 (m, 3H), 3.33 - 3.10 (m, 3H), 3.02 (m, 2H), 2.82 (m, 2H), 2.29 (s, 3H), 1.70-1.61 (m, 4H), 1.60 (m, 6H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 190 775.4 Ή NMR (400 MHz, DMSO-ab) δ 9.54 (bs, 1H), 8.98 (s, 1H), 8.69 (s, 2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.47 - 4.28 (m, 4H), 3.85 (m, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 ( m, 1H), 3.01 (m, 1H), 2.79 - 2.59 (m, 2H), 2.34 - 2.23 (m, 4H), 2.03 (m, 1H), 1 .89 - 1.68 (m, 3H), 1.62 (m, 9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 0.07 191 775.4 Ή NMR (400 MHz, flMCO-d6) δ 9.54 (bs, 1H), 8.98 (s, 1H), 8.69 (s, 2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.47 - 4.28 (m, 4H), 3.85 (m, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 ( m, 1H), 3.01 (m, 1H), 2.79 - 2.59 (m, 2H), 2.34 - 2.23 (m, 4H), 2.03 (m, 1H), 1 .89 - 1.68 (m, 3H), 1.62 (m, 9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 0.09 192 775.4 Ή NMR (400 MHz, DMSO-de) δ 9.54 (bs, 1H), 8.98 (s, 1H), 8.69 (s, 2H), 8.67 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.47 - 4.28 (m, 4H), 3.85 (m, 1H), 3.36 (m, 1H), 3.31 (m, 1H), 3.10 ( m, 1H), 3.01 (m, 1H), 2.79 - 2.59 (m, 2H), 2.34 - 2.23 (m, 4H), 2.03 (m, 1H), 1 .89 - 1.68 (m, 3H), 1.62 (m, 9H), 1.31 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 0.1 193 775.4 NMR (400 MHz, DMSO-de) δ 9.78 (m, 1H), 8.96 (s, 1H), 8.69 (d, J = 8.8 Hz, 2H), 8.64 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.42 (d, J = 6.9 Hz, 1H), 6.06 (t, J = 57.0 Hz, 1H), 5.27 (m, 1H), 4.36 (m, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 3.60 (m, 1H), 3, 34 (m, 1H), 3.27 3.12 (m, 2H), 3.01 - 2.89 (m, 2H), 2.65 (m, 2H), 2.28 (s, 3H), 1.65 - 1.50 (m, 9H), 1.31 (s, 6H), 1.11 - 1.04 (m, 2H), 0.96 - 0.86 (m, 3H), 0, 84 - 0.70 (m, 3H). 0.2 194 773.5 Ή NMR (400 MHz, DMSO-de) δ 9.03 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 10.3 Hz, 2H), 8.64 (s , 1H), 8.02 (s, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.06 (t, J = 56.8 Hz , 1H), 5.27 (m, 1H), 4.30 (m, 1H), 3.33 (m, 2H), 3.13 (m, 1H), 2.98 (m, 1H), 2 .81 (m, 1H), 2.67 (s, 3H), 2.31 (m, 2H), 2.08 (m, 1H), 1.90 (m, 3H), 1.65 - 1, 47 (m, 7H), 1.31 (m, 7H), 1.08 (m, 2H), 0.95 (m, 3H), 0.63 (m, 1H), 0.55 - 0.40 (m, 3H). 0.06

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195 765.4 Ή NMR (400 MHz, DMSO-ab) δ 9.14 (s, 1H), 8.92 (s, 1H), 8.75 (s, IH), 8.68 (s, 1H), 7.77 (s, IH), 7.63 (a, J = 8.1 Hz, 1H), 7.37 (a, J = 7.0 Hz, 1H), 6.02 (t, J = 56.9 Hz , 1H), 5.29 (m, 1H), 4.24 (m, 1H), 3.19 (m, 2H), 2.91 (s, 4H), 2.59 (m, 2H), 2 .26 (s, 3H), 1.83 1.36 (m, 15H), 1.31 (s, 6H), 1.07 (m, 2H), 0.89 (m, 2H). 0.07 196 765.4 'NMR (400 MHz, DMSO-ab) δ 9.46 (m, 1H), 8.97 (s, 1H), 8.70 (a, J = 5.8 Hz, 2H), 8.65 (s , 1H), 8.03 (s, 1H), 7.71 (s, 1H), 7.41 (a, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz , 1H), 5.34 - 5.26 (m, 1H), 5.19 (m, 1H), 4.33 (m, 1H), 3.59 - 3.43 (m, 1H), 3, 43 - 3.18 (m, 2H), 3.15 - 2.86 (m, 3H), 2.76 - 2.60 (m, 2H), 2.29 (s, 3H), 2.05 ( m, 14H), 1.31 (s, 6H), 1.12 - 1.02 (m, 2H), 0.93 (m, 2H). 0D 197 765 NMR (400 MHz, DMSO-ab) δ 9.54 (m, 1H), 8.97 (s, 1H), 8.81 - 8.49 (m, 3H), 8.04 (s, IH), 7.75 (s, 1H), 7.41 (m, 1H), 6.07 (t, J = 57.0 Hz, IH), 5.39 5.14 (m, 1H), 5.02 ( m, 1H), 4.33 (m, IH), 3.40 - 2.98 (m, 7H), 2.71 (m, 2H), 2.38 - 1.84 (m, 7H), 1 .65 1.43 (m, 9H), 1.30 (s, 6H), 1.00 (m, 4H). 0D 198 783.3 'NMR (400 MHz, DMSO-ab) δ 9.61 (bs, 1H), 9.17 (s, 1H), 8.94 (s, IH), 8.80 - 8.62 (m, 2H) , 8.10 (s, 1H), 7.70 (a, J = 1.9 Hz, 1H), 7.50 (aa, J = 7.5, 2.2 Hz, 1H), 6.04 ( t, J = 56.7 Hz, IH), 5.26 (m, 1H), 4.29 (m, IH), 3.93 - 3.76 (m, 3H), 3.39 - 3.19 (m, 4H), 2.99 (m, 2H), 2.72 (m, 2H), 2.05 (m, 2H), 1.71-1.49 (m, 10H), 1.31 ( s, 6H), 1.21-1.03 (m, 2H), 1.03 0.88 (m, 2H). 0.01 199 769.3 NMR (400 MHz, DMSO-ab) δ 9.93 (bs, 1H), 9.17 (s, 1H), 8.95 (s, IH), 8.72 (a, J = 1.7 Hz, 1H), 8.69 (s, 1H), 8.11 (s, 1H), 7.76 (a, J = 1.8 Hz, 1H), 7.51 (m, 1H), 6.05 ( t, J = 57.0 Hz, 1H), 5.26 (m, 1H), 4.38 (m, 1H), 4.03 (m, 2H), 3.70 (m, 2H), 3, 27 (m, 2H), 3.18 3.00 (m, 4H), 2.64 (m, 2H), 1.62 - 1.54 (m, 9H), 1.31 (s, 6H), 1.12 - 1.08 (m, 2H), 0.96 - 0.91 (m, 2H). 0.1 200 771.3 'NMR (400 MHz, DMSO-ab) δ 9.18 (s, 1H), 8.94 (s, 1H), 8.71 (s, IH), 8.69 (m, 2H), 8.11 (s, 1H), 7.97 (m, 1H), 7.54 (aa, J = 7.5, 2.1 Hz, 1H), 6.05 (t, J = 56.7 Hz, 1H) , 5.52 (m, 1H), 5.27 (m, 1H), 4.58 (m, 1H), 3.97 - 3.68 (m, 2H), 3.67 - 3.38 (m , 2H), 3.28 3.15 (m, 2H), 2.47 - 2.34 (m, 3H), 2.34 - 1.95 (m, 1H), 1.66 (m, 3H) , 1.59 (s, 6H), 1.31 (s, 6H), 1.12 1.07 (m, 2H), 0.96 - 0.90 (m, 2H). 0.1 201 785.3 NMR (400 MHz, DMSO-ab) δ 9.49 (m, 1H), 9.18 (s, 1H), 8.96 (s, IH), 8.73 (a, J = 1.7 Hz, 1H), 8.70 (s, iH), 8.10 (s, iH), 7.70 (a, j = 1.8 Hz, iH), 7.50 (aa, J = 7.5, 2 .0 Hz, IH), 6.05 (t, J = 56.8 Hz, IH), 5.32 - 0.2

- 398 045798

5.11 (m, 2H), 4.33 (m, 1H), 3.57 - 3.17 (m, 3H), 3.15 - 2.94 (m, 3H), 2.74 - 2, 57 (m, 2H), 2.05 - 1.64 (m, 4H), 1.59 (d, J = 6.5 Hz, 6H), 1.54 (s, 3H), 1.32 (s , 6H), 1.12 - 1.08 (m, 2H), 0.96 - 0.91 (m, 2H). 202 749.3 'NMR (400 MHz, DMCO-d6)δ 9.05 (m, 2H), 8.75 (s, 1H), 8.63 (d, J = 13.0 Hz, 2H), 8.07 (s , 1H), 7.74 (s, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.57 (d, J = 10.8 Hz, 1H), 6.07 (t , J = 57.0 Hz, 1H), 5.36 - 5.16 (m, 1H), 4.44.4D7 ( _m , 1H), 3.23 (m, 2H), 2.94 (m, 4H ), 2.67 (m, 2H), 1.86 (m, 2H), 1.67 - 1.24 (m, 19H), 1.08 (m, 2H), 0.92 (m, 2H) . 0D 203 793.3 'NMR (400 MHz, DMCO-d6)δ 9.14 (m, 2H), 8.95 (s, 1H), 8.76 - 8.62 (m, 2H), 8.09 (s, 1H) , 7.69 (d, J = 1.9 Hz, 1H), 7.51 (m, 1H), 6.04 (t, J = 56.7 Hz, 1H), 5.26 (m, 1H) , 4.30 (m, 1H), 3.41 - 3.23 (m, 2H), 3.14 (t, J = 10.4 Hz, 1H), 3.00 (m, 1H), 2, 84 (t, J = 10.4 Hz, 1H), 2.64 (m, 2H), 2.00 - 1.77 (m, 3H), 1.59 1.52 (m, 10H), 1, 31 (s, 6H), 1.17 - 1.03 (m, 2H), 0.95 (m, 3H), 0.65 - 0.57 (m, 1H), 0.49 (m, 3H) . 0.07 204 785.3 'NMR (400 MHz, DMC0-d6)δ 9.40 (s, 1H), 9.20 (d, J = 10.3 Hz, 1H), 8.96 (s, 1H), 8.78 - 8 .44 (m, 2H), 8.11 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.49 (m, 1H), 5.26 (m, 1H) , 4.32 (m, 1H), 3.23 (m, 2H), 3.01 2.74 (m, 4H), 2.67 (m, 2H), 1.97 - 1.20 (m, 23H), 1.14 (m, 2H). 0.2 205 779.3 'NMR (400 MHz, DMC0-d6) δ 10.15 (m, 1H), 9.17 (s, 1H), 8.92 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.11 (d, J = 2.7 Hz, 1H), 7.97 (s, 1H), 7.59 - 7.49 (m, 1H), 6.05 (t, J = 56.3 Hz, 1H), 5.26 (m, 1H), 4.63 4.52 (m, 1H), 3.72 (m, 2H), 3.33 (m, 4H), 3 .07 (m, 2H), 2.22 (m, 2H), 1.88 - 1.24 (m, 18H), 1.10 (m, 2H), 0.94 (m, 2H). 0D 206 771.4 'NMR (400 MHz, DMC0-d6) δ 9.17 (bs, 1H), 8.86 (s, 1H), 8.76 (s, 1H), 8.65 (s, 1H), 8.45 (s, 1H), 8.03 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.19 (d, J = 12.0 Hz, 1H), 6 .09 (t, J = 57.2 Hz, 1H), 5.29 (m, 1H), 4.33 (m, 1H), 4.11 (m, 1H), 3.98 - 3.88 ( m, 1H), 3.22 (m, 2H), 3.02 - 2.84 (m, 4H), 2.70 - 2.61 (m, 2H), 2.35 (m, 3H), 1 .85 - 1.35 (m, 21H), 1.07 (m, 2H), 0.92 (m, 2H). 0.07 207 767.3 'NMR (400 MHz, DMC0-d6) δ 9.14 (m, 2H), 8.89 (s, 1H), 8.63 (m, 2H), 8.04 (s, 1H), 7.64 (s, 1H), 7.43 (m, 1H), 5.98 (t, J = 56.8 Hz, 1H), 5.20 (m, 1H), 4.25 (m, 1H), 3 .16 (m, 2H), 2.96 - 2.77 (m, 4H), 2.62 (m, 2H), 1.78 - 1.45 (m, 15H), 1.24 (s, 6H ), 1.04 (m, 2H), 0.87 (m, 2H). 0.08 208 763.4 'NMR (400 MHz, DMSO-de) δ 9.61 (bs, 1H), 8.97 (s, 1H), 8.69 - 8.63 (m, 3H), 8.03 (d, J= 2.1 Hz, 1H), 0.09

- 399 045798

7.71 (s, 1H), 7.41 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 56.4 Hz, 1H), 5.35 - 5.21 (m , 1H), 4.40 - 4.22 (m, 1H), 3.30 (m, 8H), 2.99 (m, 2H), 2.74 (m, 5H), 2.31 (m, 3H), 2.16 - 1.94 (m, 2H), 1.66 - 1.50 (m, 8H), 1.31 (m, 4H), 1.08 (m, 2H), 0.93 (m, 2H). 209 759.4 Ή NMR (400 MHz, DMSOschb) δ 10.25 (bs, 1H), 8.98 (s, 1H), 8.74 - 8.64 (m, 3H), 8.05 (s, 1H), 7 .97 (s, 1H), 7.44 (d, J = 6.8 Hz, 1H), 6.07 (t, J = 57.1 Hz, 1H), 5.29 (m, 1H), 4 .57 (m, 1H), 3.77 - 3.49 (m, 2H), 3.32 (m, 4H), 3.21 - 2.93 (m, 2H), 2.43 (m, 2H ), 2.29 (m, 5H), 1.95 (m, 11H), 1.30 (s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 0.08 210 809.3 'NMR (400 MHz, DMSO-46) δ 9.14 (m, 2H), 8.94 (s, 1H), 8.77 (d, J = 1.7 Hz, 1H), 8.65 (s , 1H), 8.13 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.51 (dd, J = 7.5, 2.1 Hz, 1H), 6 .04 (t, J = 56.8 Hz, 1H), 5.25 (m, 1H), 4.32 (m, 1H), 4.11 (m, 2H), 3.94 (m, 2H) , 3.22 (m, 2H), 3.08 - 2.84 (m, 4H), 2.71 - 2.59 (m, 2H), 1.84 - 1.43 (m, 20H), 1 .18 - 1.03 (m, 2H), 0.93 (m, 2H). 0.08 211 749 'NMR (400 MHz, DMSOschb) δ 9.15 (bs, 1H), 9.01 (s, 1H), 8.92 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H ), 8.67 (s, 1H), 8.10 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.47 (m, 1H), 5.26 (m , 1H), 4.47 (d, J = 49.0 Hz, 2H), 4.32 (m, 1H), 3.23 (m, 2H), 2.95 (m, 4H), 2.67 (m, 2H), 1.85 (m, 2H), 1.81 - 1.38 (m, 13H), 1.31 (s, 6H), 0.95 0.75 (m, 4H). 0.1 212 757.4 'NMR (400 MHz, DMSO-46) δ 9.79 (bs, 1H), 8.87 (s, 1H), 8.77 (s, 1H), 8.69 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 12, 0 Hz, 1H), 6.10 (t, J = 57.3 Hz, 1H), 5.38 5.26 (m, 1H), 4.70 - 4.57 (m, 1H), 4.49 - 4.43 (m, 2H), 3.96 (m, 2H), 3.82 (m, 2H), 3.52 - 3.37 (m, 1H), 2.46 - 2.33 (m , 5H), 2.15 (m, 2H), 2.10 - 1.99 (m, 2H), 1.69 (s, 3H), 1.61 (d, J = 6.4 Hz, 6H) , 1.31 (s, 6H), 1.09 - 1.04 (m, 2H), 0.95 - 0.90 (m, 2H). 0.3 213 743.4 'NMR (400 MHz, DMSO-46) δ 8.98 (m, 1H), 8.86 (s, 1H), 8.73 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 8.01 (s, 1H), 7.71 (s, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 12, 1 Hz, 1H), 6.10 (t, J = 57.3 Hz, 1H), 5.29 (m, 1H), 4.21 (m, 1H), 3.28 (m, 2H), 2 .96 (m, 3H), 2.87 (m, 3H), 2.35 (s, 3H), 1.91 - 1.80 (m, 4H), 1.69 (m, 3H), 1, 59 (d, J = 6.4 Hz, 6H), 1.50 - 1.39 (m, 1H), 1.31 (s, 6H), 1.16 (m, 3H), 1.07 (m , 2H), 0.92 (m, 2H). 0.3

- 400 045798

214 733.4 Ή NMR (400 MHz, DMSOZhb) δ 9.23 (bs, 1H), 8.97 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 8.24 (s , 1H), 7.94 (s, 1H), 7.42 (s, 1H), 7.38 (d, J = 7.2 Hz, 1H), 6.08 (t, J = 57.0 Hz , 1H), 5.27 (m, 1H), 4.06 (m, 1H), 3.34 3.13 (m, 4H), 2.92 (m, 2H), 2.37 - 2.27 (m, 5H), 1.88 (m, 2H), 1.80 - 1.65 (m, 3H), 1.58 - 1.50 (m, 9H), 1.48 - 1.39 (m , 2H), 1.31 (s, 6H), 1.28 (m, 1H), 1.07 (m, 2H), 0.92 (m, 2H). 0D 215 731.4 Ή NMR (400 MHz, flMCO-d6) δ 10.12 (bs, 1H), 8.87 (s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.00 (d, J = 1.4 Hz, 1H), 7.78 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 11.9 Hz, 1H), 6.10 (t, J = 57.4 Hz, 1H), 5.39 - 5.27 (m, 1H), 4.44 - 4.31 ( m, 1H), 4.02 (m, 2H), 3.71 (m, 2H), 3.28 - 3.23 (m, 1H), 3.16 - 3.00 (m, 5H), 2 .69 - 2.59 (m, 2H), 2.36 (s, 3H), 1.64 - 1.54 (m, 9H), 1.30 (s, 6H), 1.10 - 1.05 (m, 2H), 0.95 - 0.90 (m, 2H). 0.1 216 729.4 Ή NMR (400 MHz, flMCO-d6) δ 9.12 (bs, 1H), 8.85 (s, 1H), 8.73 (s, 1H), 8.67 (d, J = 2.3 Hz , 1H), 8.45 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.74 (s, 1H), 7.65 7.58 (m, 1H), 7.19 (d, J = 11.6 Hz, 1H), 6.09 (t, J = 57.8 Hz, 1H), 5.34 - 5.25 (m, 1H), 4.36 - 4 .27 (m, 1H), 3.23 (m, 2H), 3.00 - 2.87 (m, 4H), 2.73 - 2.62 (m, 2H), 2.35 (s, 3H ), 1.85 (m, 2H), 1.75 - 1.63 (m, 3H), 1.62 - 1.04 (m, 16H), 1.09 - 1.04 (m, 2H), 0.94 0.89 (m, 2H). 0.1 217 721.3 Ή NMR (400 MHz, DMSSMb) δ 9.13 (m, 1H), 8.80 (d, J = 6.7 Hz, 1H), 8.76 - 8.64 (m, 3H), 8.03 (d, J = 2.3 Hz, 1H), 7.70 (s, 1H), 7.40 (d, J = 7.0 Hz, 1H), 6.39 - 5.29 (m, 2H) , 4.31 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.69 (m, 2H), 2.31 (s, 3H), 1.84 ( m, 2H), 1.69 (m, 3H), 1.59 (m, 6H), 1.51 (s, 3H), 1.44 (m, 1H), 1.30 (m, 5H). 0.06 218 715.4 'H NMR (400 MHz, flMCO-d6) δ 9.16 - 9.11 (m, 1H), 9.02 (s, 1H), 8.74 (s, 2H), 8.63 (s, 1H ), 8.11 8.01 (m, 2H), 7.77 - 7.63 (m, 3H), 7.49 (m, 1H), 7.44 - 7.34 (m, 1H), 6 .10 (t, J = 57.5 Hz, 1H), 5.37 - 5.26 (m, 1H), 4.32 - 4.21 (m, 1H), 3.18 (m, 2H), 2.96 2.84 (m, 4H), 2.58 (m, 2H), 1.85 (m, 2H), 1.73 - 1.62 (m, 3H), 1.60 (m, 6H ), 1.50 (s, 3H), 1.45 - 1.37 (m, 1H), 1.29 (s, 6H), 1.12 - 1.07 (m, 2H), 0.95 - 0.90 (m, 2H). 0.06 219 715.4 Ή NMR (400 MHz, flMCO-d6) δ 9.22 (bs, 1H), 8.85 (s, 1H), 8.64 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.67 - 7.53 (m, 2H), 7.46 (s, 1H), 7.17 (d, J = 12.1Hz, 1H ), 6.11 (t, J = 57.3 Hz, 1H), 5.32-5.22 (m, 1H), 4.10 - 4.03 (m, 1H), 3.34 - 3, 14 (m, 4H), 2.92 (m, 2H), 2.37 - 2.27 (m, 5H), 1.88 (m, 2H), 1.80 0.2

- 401 045798

- 1.65 (m, ZN), 1.58 (d, J = 6.5 Hz, 6H), 1.50 (s, ZN), 1.48 - 1.39 (m, 2H), 1, 31 (s, 6H), 1.28 (m, 1H), 1.07 (m, 2H), 0.92 (m, 2H). 220 699.4 Ή NMR (400 MHz, DMCO-d6) δ 9.16 - 9.03 (m, 1H), 8.76 - 8.56 (m, 3H), 8.27 (d, J = 7.5 Hz, 1H), 8.03 (s, 1H), 7.72 (s, 1H), 7.35 (d, J = 6.9 Hz, 1H), 5.27 (m, 1H), 4.31 ( m, 1H), 4.03 (m, 1H), 3.24 (m, 2H), 2.93 (m, 5H), 2.83 - 2.65 (m, 2H), 2.29 (s , 3H), 1.85 (d, J = 13.6 Hz, 2H), 1.69 (m, 3H), 1.64 - 1.30 (m, 15H), 1.12 (m, 6H) . 0.09 221 697.4 Ή NMR (400 MHz, DMCO-d6) δ 9.12 (s, 1H), 8.75 8.59 (m, 2H), 8.44 (d, J = 4.1 Hz, 1H), 8, 03 (s, 1H), 7.71 (s, 1H), 7.34 (d, J = 6.9 Hz, 1H), 5.39 - 5.15 (m, 1H), 4.46 - 4 .20 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.82 (m, 1H), 2.69 (m, 2H), 2.29 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.62 - 1.40 (m, 9H), 1.31 (m, 5H), 0.67 (m, 2H ), 0.58 - 0.43 (m, 2H). 0.07 222 685.4 Ή NMR (400 MHz, DMCO-d6) δ 9.21 (s, 1H), 8.71 (d, J = 3.5 Hz, ZN), 8.40 (d, J = 6.3 Hz, 1H ), 8.03 (d, J = 2.5 Hz, 1H), 7.70 (s, 1H), 7.36 (d, J = 7.0 Hz, 1H), 5.30 (m, 1H ), 3.31 - 3.10 (m, 4H), 2.93 (m, 4H), 2.69 (m, 2H), 2.30 (s, 3H), 1.84 (m, 2H) , 1.70 (m, 3H), 1.64 - 1.58 (m, 5H), 1.52 (m, 2H), 1.42 (m, 1H), 1.30 (m, 5H), 1.08 (m, 3H). 0.06 223 653.4 Ή NMR (400 MHz, DMSSMb) δ 9.30 (m, 1H), 8.78 (dd, J = 12.6, 2.4 Hz, 2H), 8.65 (s, 1H), 8.52 (d, J = 6.5 Hz, 1H), 8.11 - 8.01 (m, 2H), 7.70 - 7.64 (m, 2H), 7D4.7.34 ( _m , 1H), 5.40 - 5.28 (m, 1H), 4.32 - 4.19 (m, 1H), 3.35 - 3.22 (m, 1H), 3.16 (m, 2H), 2, 96 2.83 (m, 4H), 2.60 - 2.51 (m, 2H), 1.84 (m, 2H), 1.71 - 1.42 (m, 14H), 1.29 (s , 6H), 1.11 (m, 3H). 0.2 224 775.4 Ή NMR (400 MHz, DMCO-d6) δ 10.23 (bs, 1H), 9.93 (s, 1H), 8.98 (s, 1H), 8.67 (m, 3H), 8.04 (d, J = 12.1 Hz, 2H), 7.44 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.29 (m , 1H), 4.67 (m, 1H), 4.39 - 4.26 (m, 1H), 4.04 (m, 4H), 3.80 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.54 - 3.40 (m, 1H), 3.26 (m, 1H), 2.53 (m, 2H), 2.45 (m, 1H ), 2.17-1.24 (m, 18H), 1.08 (m, 2H), 0.93 (m, 2H). 0.06 225 779.3 ^NMR (400 MHz, DMSO-de) δ 9.17 - 9.11 (m, 2H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz, 1H), 6 .04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H) , 2.88 (m, 2H), 2.65 (m, 3H), 2.25 (s, 1H), 1.98 (m, 1H), 1.64-1.51 (m, 6H), 1.44 - 1.10 (m, 11H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 0.08

- 402 045798

226 781.3 Ή NMR (400 MHz, DMSO-de) δ 8.98 (s, 1H), 8.78 8.59 (m, 3H), 8.50 (s, 1H), 8.03 (d, J = 2 ,2 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5, 28 (m, 1H), 4.42 (m, 1H), 3.23 (m, 4H), 3.10 (m, 2H), 2.43 (m, 2H), 2.29 (s, 3H ), 1.79 - 1.55 (m, 14H), 1.52 - 1.40 (m, 1H), 1.32 (s, 6H), 1.08 (m, 2H), 0.93 ( m, 2H). 0.1 227 761.3 Ή NMR (400 MHz, DMSO-de) δ 9.13 (s, 1H), 9.01 (s, 1H), 8.92 (s, 1H), 8.73 (d, J = 1.8 Hz , 1H), 8.68 (s, 1H), 8.09 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.47 (dd, J = 7.5, 2.0 Hz, 1H), 5.26 (m, 1H), 4.48 (d, J = 52 Hz, 2H), 4.30 (m, 1H), 3.63 (m, 1H), 3 .10 - 2.95 (m, 2H), 2.95 - 2.79 (m, 2H), 2.73 - 2.57 (m, 2H), 2.35 - 2.16 (m, 1H) , 2.04 - 1.90 (m, 1H), 1.66 - 1.50 (m, 6H), 1.44 (s, 3H), 1.34 - 1.29 (m, 6H), 1 .22 (m, 1H), 1.15 1.04 (m, 1H), 0.91 (m, 2H), 0.88 - 0.70 (m, 3H), 0.63 (m, 1H) . 0.1 228 775.4 Ή NMR (400 MHz, DMSO-de) δ 9.09 (s, 1H), 8.97 (s, 1H), 8.69 (d, J = 10.5 Hz, 2H), 8.63 (s , 1H), 8.03 (s, 1H), 7.85 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 56.9 Hz , 1H), 5.38 - 5.15 (m, 1H), 4.57 (s, 2H), 4.49 (m, 1H), 3.32 (m, 2H), 3.27 - 3, 10 (m, 4H), 2.29 (s, 3H), 2.02 (m, 4H), 1.62 (m, 11H), 1.32 (s, 6H), 1.07 (m, 2H ), 0.93 (m, 2H). 0.3 229 761.4 'NMR (400 MHz, DMSO-46) δ 9.11 (s, 1H), 8.97 (s, 1H), 8.71 (s, 1H), 8.68 (s, 1H), 8.63 (d, J = 2.4 Hz, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.71 (s, 1H), 7.40 (d, J = 7.0 Hz , 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.36 - 5.13 (m, 1H), 4.28 (m, 1H), 3.23 (m, 2H) , 3.11 (m, 2H), 2.95 (m, 2H), 2.81 - 2.70 (m, 2H), 2.28 (m, 2H), 1.89 (m, 2H), 1.77 (m, 2H), 1.64 (m, 4H), 1.61 - 1.55 (m, 6H), 1.53 (m, 2H), 1.31 (s, 6H), 1 .08 (m, 2H), 0.92 (m, 2H). 0.08 230 773.4 Ή NMR (400 MHz, DMSO-de) δ 8.98 (s, 1H), 8.78 8.59 (m, 3H), 8.50 (s, 1H), 8.03 (d, J = 2 ,2 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5, 28 (m, 1H), 4.42 (m, 1H), 3.23 (m, 4H), 3.10 (m, 2H), 2.43 (s, 3H), 2.29 (s, 3H ), 1.79 (s, 4H), 1.70 (m, 1H), 1.65 - 1.55 (m, 9H), 1.52 - 1.40 (m, 1H), 1.32 ( s, 6H), 1.08 (m, 2H), 0.93 (m, 2H). 0.1

- 403 045798

231 759.4 Ή NMR (400 MHz, DMSO-ab) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5 .36 - 5.22 (m, 1H), 4.37 - 4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H ), 2.67 (m, 3H), 2.29 (s, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz, 6H), 1.44 (s , 3H), 1.31 - 1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 3H), 0.78 (m, 1H), 0.61 (m, 1H). 0D 232 759.4 Ή NMR (400 MHz, DMSO-de) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5 .36 - 5.22 (m, 1H), 4.37 - 4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H ), 2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz, 6H), 1.44 (s , 3H), 1.31 - 1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.61 (m, 1H). 0.09 233 759.4 Ή NMR (400 MHz, DMSO-de) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J = 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J = 6.9 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5 .36 - 5.22 (m, 1H), 4.37 - 4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H ), 2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (d, J = 6.3 Hz, 6H), 1.44 (s , 3H), 1.31 - 1.24 (m, 7H), 1.09 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.61 (m, 1H). 0.08 234 765.3 'NMR (400 MHz, DMSO-de) δ 9.58 (s, 1H), 9.17 (s, 1H), 8.91 (s, 1H), 8.69 (d, J = 1.7 Hz , 1H), 8.65 (s, 1H), 8.11 (s, 1H), 7.98 (d, J =1.8 Hz, 1H), 7.54 (dd, J = 7.5, 2.1 Hz, 1H), 6.05 (t, J = 56.8 Hz, 1H), 5.26 (m, 1H), 4.56 (m, 1H), 3.57 (m, 4H) , 3.25 (m, 2H), 2.43 2.35 (m, 2H), 1.84 (m, 2H), 1.65 (s, 3H), 1.59 (m, 7H), 1 .31 (s, 6H), 1.13 - 1.05 (m, 2H), 0.97 - 0.87 (m, 2H), 0.76 (m, 1H), 0.65 (m, 1H ). 0.3 235 728.4 Ή NMR (400 MHz, DMSSMb) δ 9.17 (m, 1H), 8.84 (d, J = 2.1 Hz, 1H), 8.75 (s, 1H), 8.44 (s, 1H ), 7.90 (d, J = 2.2 Hz, 1H), 7.71 - 7.60 (m, 2H), 7.45 (s, 1H), 7.36 (dd, J = 7, 9, 2.3 Hz, 1H), 7.16 (dd, J = 12.1, 2.3 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5.30 ( m, 1H), 4.38 - 4.19 (m, 1H), 3.22 (m, 2H), 2.94 (m, 4H), 2.64 (m, 2H), 2.34 (d , J = 2.2 Hz, 3H), 1.84 (m, 2H), 1.78 1.64 (m, 3H), 1.59 (m, 6H), 1.51 (s, 3H), 1.29 (s, 6H), 1.07 (m, 2H), 0.87 (m, 2H). 0.1 236 746.4 Ή NMR (400 MHz, DMSSMb) δ 9.13 (s, 1H), 8.95 (d, J = 2.6 Hz, 1H), 8.67 (s, 2H), 7.93 (d, J = 2.6 Hz, 1H), 7.60 (m, 2H), 7.46 - 7.34 (m, 4H), 6.07 (t, J = 57.0 Hz, 1H), 5.28 (m, 1H), 4.30 (m, 1H), 3.22 (d, J = 11.8 Hz, 3H), 2.93 (m, 5H), 2.68 (d, J = 8, 6 Hz, 3H), 0.07

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2.27 (s, ZN), 1.84 (d, J = 13.3 Hz, ZN), 1.78 - 1.36 (m, 14H), 1.29 (m, 7H), 1.07 (m, 3H), 0.89 (m, 3H). 237 732.4 Ή NMR (400 MHz, DMSO-46) δ 9.15 (s, 1H), 8.95 (s, 1H), 8.66 (d, J = 26.4 Hz, 2H), 7.76 (s , 1H), 7.39 (d, J = 6.9 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 4.1 Hz, 2H ), 6.06 (t, J = 57.0 Hz, 1H), 5.37 - 5.19 (m, 1H), 3.90 (m, 1H), 3.23 - 3.06 (m, 4H), 3.00 2.79 (m, 3H), 2.27 (d, J = 9.2 Hz, 6H), 1.94 - 1.35 (m, 17H), 1.26 (s, 6H), 1.08 (m, 2H), 0.89 (m, 3H). 0.3 238 714.4 Ή NMR (400 MHz, DMSO-de) δ 9.04 (bs, 1H), 8.99 (s, 1H), 8.64 (d, J = 2.6 Hz, 1H), 8.54 (s , 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H ), 7.62 (m, 1H), 7.43 (s, 1H), 7.35 (m, 2H), 6.08 (t, J = 57.3 Hz, 1H), 5.28 (m , 1H), 4.21 (m, 1H), 3.17 (m, 3H), 2.89 (m, 5H), 1.85 (m, 3H), 1.80 - 1.63 (m, 2H), 1.63 - 1.55 (m, 6H), 1.47 (m, 4H), 1.28 (s, 6H), 1.10 (m, 2H), 0.91 (m, 2H ). 0.02 239 684.4 Ή NMR (400 MHz, DMSO-de) δ 9.06 (m, 1H), 8.61 (s, 2H), 8.37 (m, 1H), 7.92 (d, J = 2.6 Hz , 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.48 - 7.33 (m, 3H), 5.26 (m, 1H), 4.30 (m, 1H) , 3.30 - 3.15 (m, 4H), 3.05 - 2.84 (m, 4H), 2.68 (m, 2H), 2.29 (s, 3H), 1.84 (m , 2H), 1.69 - 1.42 (m, 13H), 1.29 (s, 6H), 1.06 (m, 3H). 0.04 240 652.4 Ή NMR (400 MHz, DMSO-de) δ 9.12 (bs, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.49 (d, J = 5.5 Hz , 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 7.70 (d, J = 7.9 Hz, 1H ), 7.61 (m, 1H), 7.42 (s, 1H), 7.36 (m, 3H), 5.31 (m, 1H), 4.21 (m, 1H), 3.28 (m, 3H), 3.15 (m, 2H), 2.97 - 2.80 (m, 5H), 1.84 (m, 2H), 1.78 - 1.63 (m, 2H), 1.62 - 1.54 (m, 5H), 1.47 (m, 4H), 1.28 (s, 6H), 1.10 (m, 4H). 0.09 241 766.3 Ή NMR (400 MHz, DMSO-de) δ 9.12 (m, 2H), 8.69 (s, 1H), 8.00 (s, 1H), 7.66 (d, J = 7.8 Hz , 1H), 7.50 (d, J = 7.5, 2.0 Hz, 1H), 7.43 - 7.38 (m, 3), 6.02 (t, J = 56.8 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.23 (m, 2H), 2.98 (m, 4H), 2.63 (m, 2H), 1, 85 (m, 2H), 1.69 1.51 (m, 13H), 1.30 (s, 6H), 1.10 (m, J = 6.3 Hz, 2H), 0.90 (m, 2H). 0D 242 733.3 Ή NMR (400 MHz, DMSO-de) δ 9.20 (m, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.73 (d, J = 5.8 Hz , 2H), 8.09 (d, J = 2.0 Hz, 1H), 7.90 (d, J = 6.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H ), 6.08 (t, J = 57.1 Hz, 1H), 5.31 (m, 2H), 4.28 (m, 1H), 3.19 (m, 2H), 2.93 (m , 4H), 2.62 (m, 2H), 2.53 -2.44 (m, 2H), 1.85 - 1.19 (m, 18H), 1.11 (m, 2H), 0, 94 (m, 2H). 0.07 243 732.4 'H NMR (400 MHz, methanol-d4) δ 9.22 - 9.06 (m, 2H), 8.06 (d, J = 6.2 Hz, 1H), 7.93 (s, 1H), 7.77 7.46 (m, 3H), 7.40 (dd, J = 7.8, 2.4 Hz, 1H), 5.96 (t, J 0.05

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= 57.3 Hz, 1H), 5.41 (m, 1H), 4.49 - 4.35 (m, 1H), 3.38 (m, 3H), 3.04 (m, 5H), 2 .74 (m, 2H), 2.06 (m, 3H), 1.94 - 1.69 (m, 10H), 1.66 - 1.49 (m, 4H), 1.49 1.35 ( m, 9H), 1.18 (m, 2H), 0.98 (m, 3H). 244 752.3 Ή NMR (400 MHz, DMSO-de) δ 9.46 - 9.26 (m, 1H), 9.15 (s, 1H), 8.95 - 8.86 (m, 1H), 8.73 - 8.61 (m, 1H), 7.97 (s, 1H), 7.65 (m, 1H), 7.52 (m, 1H), 7.46 (s, 1H), 7.38 (d , J = 7.8 Hz, 1H), 6.02 (t, J = 56.7 Hz, 1H), 5.25 (m, 1H), 4.20 (m, 1H), 3.54 - 3 .34 (m, 3H), 3.04 - 2.92 (m, 2H), 2.89 - 2.72 (m, 4H), 1.85 (m, 2H), 1.78 - 1.53 (m, 9H), 1.49 - 1.36 (m, 1H), 1.29 (s, 6H), 1.13 - 1.06 (m, 2H), 0.95 - 0.86 (m , 2H). 0.05 245 753.3 'NMR (400 MHz, DMSO-de) δ 9.37 (s, 1H), 9.17 (s, 1H), 8.93 (s, 1H), 8.72 (d, J = 1.7 Hz , 1H), 8.67 (d, J = 1.2 Hz, 1H), 8.08 (s, 1H), 7.76 (d, J = 1.8 Hz, 1H), 7.54 (m , 1H), 6.04 (t, J = 56.7 Hz, 1H), 5.26 (m, 1H), 4.32-4.15 (m, 1H), 3.49 (m, 1H) , 3.41 (m, 2H), 3.00 - 2.89 (m, 2H), 2.89 - 2.76 (m, 4H), 1.85 (m, 2H), 1.76 - 1 .54 (m, 9H), 1.50 - 1.36 (m, 1H), 1.30 (s, 6H), 1.14 - 1.06 (m, 2H), 0.97 - 0.87 (m, 2H). 0D 246 733.3 Ή NMR (400 MHz, DMSO-de) δ 9.43 (d, J = 9.2 Hz, 1H), 8.98 (s, 1H), 8.70 (m, 3H), 8.01 (d , J = 1.6 Hz, 1H), 7.76 (s, 1H), 7.43 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H ), 5.30 (m, 1H), 4.40 - 4.05 (m, 1H), 3.45 (m, 3H), 2.88 (m, 6H), 2.30 (m, 3H) , 2.00 - 1.52 (m, 12H), 1.30 (m, 7H), 1.12 - 0.85 (m, 4H). 0.04 247 719.3 'NMR (400 MHz, DMSO-de) δ 8.87 (s, 1H), 8.61 (m, 2H), 8.56 (m, 1H), 8.15 (d, J = 1.8 Hz , 1H), 7.94 (s, 1H), 7.53 - 7.42 (m, 1H), 5.26 (m, 1H), 4.65 (m, 1H), 3.24 (m, 2H), 2.62 (m, 2H), 2.45 (m, 4H), 2.20 (m, 2H), 1.58 (m, 14H), 1.28 (s, 6H), 1, 18 (s, 3H), 1.09 (t, J = 7.2 Hz, ZN). 0.05 248 755.3 Ή NMR (400 MHz, DMSO-de) δ 9.01 (m, 1H), 8.92 (s, 1H), 8.66 - 8.55 (m, 2H), 8.14 (d, J= 1.8 Hz, 1H), 7.95 (s, 1H), 7.53 (m, 1H), 6.13 (tt, J = 55.6, 3.8 Hz, 1H), 5.25 ( m, 1H), 4.65 (m, 1H), 3.67 (m, 2H), 2.62 (m, 2H), 2.45 (m, 3H), 2.20 (m, 2H), 2.07 (s, 1H), 1.58 (m, 14H), 1.28 (s, 6H), 1.18 (s, 3H). 0.05 249 763.3 Ή NMR (400 MHz, DMSO-de) δ 9.08 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 8.73 (d, J = 1.7 Hz , 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.70 (d, J = 1.8 Hz, 1H), 7.47 (m, 1H), 5.25 (m, 1H), 4.47 (d, J = 49.0 Hz, 2H), 4.28 (m, 1H), 3.21 (m, 2H), 3.11 (m, 2H), 2 .96 (m, 2H), 2.77 2.68 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.64 (m, 4H), 1.58 (d, J = 6.6 Hz, 6H), 1.54 (s, 3H), 1.31 (s, 6H), 0.91 (m, 2H), 0.85 (m, 2H). 0.04 250 741.3 Ή NMR (400 MHz, DMSO-de) δ 9.19 (s, 1H), 9.02 (m, 2H), 8.85 - 8.58 (m, 2H), 8.11 (s, 1H) , 7.70 (d, J 0.1

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= 1.8 Hz, 1H), 7.49 (m, 1H), 6.39 - 5.91 (m, 1H), 5.27 (m, 1H), 4.31 (m, 1H), 3 .67 (m, 2H), 3.23 (m, 2H), 3.03 - 2.80 (m, 4H), 2.67 (m, 2H), 1.78 (m, 4H), 1, 65 - 1.49 (m, 8H), 1.49 - 1.36 (m, 3H), 1.31 (m, 5H). 251 717.3 Ή NMR (400 MHz, DMSO-ab) δ 8.87 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.56 (m , 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.29 - 3.17 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.17 (m, 2H), 2.12 - 2.01 (m, 2H), 1.89 (m, 1H), 1.67 (m, 1H), 1.58 (m, 6H), 1.27 (s, 6H), 1.16 - 0 .93 (m, 8H), 0.45 (m, 1H), 0.26 (m, 1H). 0.04 252 717.3 Ή NMR (400 MHz, DMSO-46) δ 8.87 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.56 (m , 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.29 - 3.17 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.17 (m, 2H), 2.12 - 2.01 (m, 2H), 1.89 (m, 1H), 1.67 (m, 1H), 1.58 (m, 6H), 1.27 (s, 6H), 1.16 - 0 .93 (m, 8H), 0.45 (m, 1H), 0.26 (m, 1H). 0.05 253 717.3 Ή NMR (400 MHz, DMSO-46) δ 8.87 (s, 1H), 8.63 (d, J = 1.6 Hz, 1H), 8.61 (s, 1H), 8.56 (m , 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.99 (s, 1H), 7.50 (m, 1H), 5.25 (m, 1H), 4.65 (m, 1H), 3.29 - 3.17 (m, 2H), 2.75 (m, 1H), 2.60 (m, 1H), 2.17 (m, 2H), 2.12 - 2.01 (m, 2H), 1.89 (m, 1H), 1.67 (m, 1H), 1.58 (m, 6H), 1.27 (s, 6H), 1.16 - 0 .93 (m, 8H), 0.45 (m, 1H), 0.26 (m, 1H). 0.05 254 731.3 Ή NMR (400 MHz, DMSO-46) δ 8.87 (s, 1H), 8.63 (d, J = 1.7 Hz, 1H), 8.60 (s, 1H), 8.45 (d , J = 7.8 Hz, 1H), 8.16 (d, J = 1.8 Hz, 1H), 7.98 (s, 1H), 7.50 (m, 1H), 5.26 (m , 1H), 4.65 (m, 1H), 4.10 - 3.93 (m, 1H), 2.75 (m, 1H), 2.60 (m, 1H), 2.50 (m, 1H), 2.22 - 2.12 (m, 2H), 2.07 (m, 3H), 1.89 (m, 1H), 1.66 (m, 1H), 1.58 (m, 6H ), 1.33 - 1.19 (m, 6H), 1.17 - 0.93 (m, 11H), 0.44 (m, 1H), 0.26 (m, 1H). 0.05 255 715.4 Ή NMR (400 MHz, DMSO-46) δ 9.17 (s, 1H), 8.74 (s, 1H), 8.70 (s, 1H), 8.35 (m, 1H), 7.77 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 6.9 Hz, 1H), 5.30 (m, 1H), 4.22 (m, 1H), 3.60 (m, 1H), 3.22 (m, 2H), 3.04 2.82 (m, 4H), 2.79 (m, 2H), 2.72 - 2 .49 (m, 3H), 2.27 (m, 3H), 2.25 - 2.18 (m, 1H), 1.96 (m, 1H), 1.59 (d, J = 6.5 Hz, 6H), 1.40 (s, 3H), 1.31 (s, 6H), 1.25-1.18 (m, 1H), 1.06 (t, J = 7.2 Hz, ZN ), 0.81 - 0.73 (m, 1H), 0.66 - 0.54 (m, 1H). 0D 256 753.3 Ή NMR (400 MHz, DMSO-46) δ 8.98 (s, 1H), 8.78 8.59 (m, ZN), 8.50 (s, 1H), 8.03 (d, J = 2 ,2 Hz, 1H), 7.82 (s, 1H), 7.42 (d, J = 7.0 Hz, 1H), 6.07 (t, J = 57.0 Hz, 1H), 5, 28 (p, J = 6.9 Hz, 1H), 4.42 (q, J = 8.1 Hz, 1H), 3.23 (t, J = 11.5 Hz, 4H), 3.10 ( t, J = 11.0 Hz, 0.05

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2H), 2.43 (s, ZN), 2.29 (s, ZN), 1.79 (s, 4H), 1.70 (d, J = 11.5 Hz, 1H), 1.65 - 1.55 (m, 9H), 1.52 - 1.40 (m, 1H), 1.32 (s, 6H), 1.08 (s, 2H), 0.93 (s, 2H). 257 761.3 W NMR (400 MHz, DMSOh/b) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J= 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J= 6.9 Hz, 1H), 6.07 5.22 (m, 2H), 4.37-4 .18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67 (m, 3H), 2.29 (m, 4H), 1.97 (m, 1H), 1.59 (m, 7H), 1.44 (m, 3H), 1.31 (s, 6H), 1.24 (m, 2H), 1, 09 (m, 3H), 0.93 - 0.78 (m, 4H), 0.61 (m, 1H). 0.1 258 761.3 Ή NMR (400 MHz, DMSO-b/ ₆ ) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J= 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J= 6.9 Hz, 1H), 6.07 5.22 (m, 2H), 4.37 -4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67 (m, 3H), 2.29 ( m, 4H), 1.97 (m, 1H), 1.59 (m, 7H), 1.44 (m, 3H), 1.31 (s, 6H), 1.24 (m, 2H), 1.09 (m, 3H), 0.93 - 0.78 (m, 4H), 0.61 (m, 1H). 0.09 259 761.3 Ή NMR (400 MHz, DMSO-g/b) δ 9.24 - 9.08 (m, 1H), 8.97 (s, 1H), 8.70 (m, 3H), 8.03 (d, J= 2.1 Hz, 1H), 7.70 (s, 1H), 7.41 (d, J= 6.9 Hz, 1H), 6.07 5.22 (m, 2H), 4.37 -4.18 (m, 1H), 3.63 (m, 1H), 3.01 (m, 2H), 2.88 (m, 2H), 2.67 (m, 3H), 2.29 ( m, 4H), 1.97 (m, 1H), 1.59 (m, 7H), 1.44 (m, 3H), 1.31 (s, 6H), 1.24 (m, 2H), 1.09 (m, 3H), 0.93 - 0.78 (m, 4H), 0.61 (m, 1H). 0.09 260 779.3 'NMR (400 MHz, DMSO-46) δ 9.17 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz , 1H), 6.04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.88 (m, 2H), 2.65 (m, 3H), 2.25 (m, 1H), 1.98 (m, 1H), 1.64 - 1.51 ( m, 6H), 1.44 (m, 2H), 1.31 (m, 5H), 1.24 (m, 1H), 1.10 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 0.08 261 779.3 'NMR (400 MHz, DMSO-46) δ 9.17 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J = 7.2 Hz , 1H), 6.04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H), 3.02 (m, 2H), 2.88 (m, 2H), 2.65 (m, 3H), 2.25 (m, 1H), 1.98 (m, 1H), 1.64 - 1.51 ( m, 6H), 1.44 (m, 2H), 1.31 (m, 5H), 1.24 (m, 1H), 1.10 (m, 3H), 0.93 (m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 0.09 262 779.3 'NMR (400 MHz, DMSO-46) δ 9.17 (s, 1H), 9.11 (s, 1H), 8.93 (s, 1H), 8.73 (s, 1H), 8.66 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.69 (s, 1H), 7.50 (d, J 0.1

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= 7.2 Hz, 1H), 6.04 (t, J = 56.6 Hz, 1H), 5.25 (m, 1H), 4.30 (m, 1H), 3.64 (m, 1H ), 3.02 (m, 2H), 2.88 (m, 2H), 2.65 (m, 3H), 2.25 (m, 1H), 1.98 (m, 1H), 1.64 - 1.51 (m, 6H), 1.44 (m, 2H), 1.31 (m, 5H), 1.24 (m, 1H), 1.10 (m, 3H), 0.93 ( m, 2H), 0.78 (m, 1H), 0.62 (m, 1H). 263 779.3 Ή NMR (400 MHz, DMSO-ab) δ 10.07 (bs, 1H), 9.18 (m, 2H), 8.93 (s, 1H), 8.75 - 8.62 (m, 2H) , 8.15 8.04 (m, 2H), 7.89 (d, J = 1.8 Hz, 1H), 7.53 (dd, J = 7.5, 2.1 Hz, 1H), 6 .05 (t, J = 56.9 Hz, 1H), 5.26 (m, 1H), 4.50 (m, 1H), 3.32 (m, 1H), 3.27 - 3.07 ( m, 4H), 2.72 (m, 1H), 1.92 - 1.68 (m, 5H), 1.69 - 1.53 (m, 9H), 1.43 (m, 1H), 1 .32 (d, J = 5.8 Hz, 6H), 1.10 (m, 2H), 0.94 (m, 3H). 0.05 264 763.3 Ή NMR (400 MHz, DMSO-46) δ 9.21 (m, 1H), 9.05 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.71 (s , 1H), 8.61 (s, 1H), 8.07 (s, 1H), 7.73 (d, J = 1.8 Hz, 1H), 7.62 (d, J = 8.2 Hz , 1H), 6.08 (t, J = 57.1 Hz, 1H), 5.28 (m, 1H), 4.33 (m, 1H), 3.22 (m, 2H), 2.98 - 2.85 (m, 4H), 2.65 (m, 2H), 2.34 (m, 3H), 1.84 (m, 2H), 1.75 - 1.62 (m, 3H), 1.59 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.49 1.39 (m, 1H), 1.31 (s, 6H), 1.10 - 1.05 (m, 2H), 0.95 0.89 (m, 2H). 0.2 265 717.3 Ή NMR (400 MHz, DMSO-46) δ 9.07 (s, 1H), 8.90 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.63 (d , J = 7.5 Hz, 2H), 8.10 (s, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.44 (m, 1H), 5.25 (m , 1H), 4.33 (m, 1H), 3.22 (s, 1H), 3.03 2.86 (m, 4H), 2.81 (m, 1H), 2.73 - 2.60 (m, 1H), 1.86 (m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.5 Hz, 6H), 1.52 (s, 3H), 1 .43 (m, 1H), 1.31 (s, 6H), 0.69 (m, 2H), 0.55 - 0.41 (m, 2H). 0.06 266 702.4 Ή NMR (400 MHz, DMSO-46) δ 9.03 (s, 1H), 8.66 (m, 1H), 8.61 (s, 1H), 8.42 - 8.38 (m, 1H) , 7.90 (s, 1H), 7.70 - 7.60 (m, 2H), 7.45 (d, J = 1.4 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.17 (d, J = 12.1 Hz, 1H), 6.09 (m, 1H), 5.27 (m, 1H), 4.27 (m, 1H), 3, 65 - 3.54 (m, 2H), 3.22 (m, 2H), 2.92 (m, 4H), 2.71 - 2.58 (m, 3H), 2.36 (s, 3H) , 1.84 (m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.29 (s, 6H). 0.06 267 719.3 Ή NMR (400 MHz, DMSO-46) δ 9.16 (s, 1H), 8.94 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.68 (d , J = 12.0 Hz, 1H), 8.47 (d, J = 7.7 Hz, 1H), 8.10 (s, 1H), 7.71 (m, 1H), 7.44 (m , 1H), 5.27 (m, 1H), 4.32 (m, 1H), 4.11 3.88 (m, 1H), 3.23 (m, 2H), 2.94 (m, 4H ), 2.67 (m, 2H), 1.85 (m, 2H), 1.70 (m, 3H), 1.59 (d, J = 6.5 Hz, 6H), 1.52 (s , 3H), 1.43 (m, 1H), 1.31 (s, 6H), 1.13 (d, J = 6.6 Hz, 6H). 0.1

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268 720.4 Ή NMR (400 MHz, DMSO-ab) δ 9.10 (s, 1H), 8.79 (m, 1H), 8.67 (a, J = 9.0 Hz, 2H), 7.93 (s , 1H), 7.64 (m, 1H), 7.44 - 7.35 (m, 3H), 6.11 (m, 1H), 5.34 5.23 (m, 1H), 4.29 (m, 1H), 3.72 - 3.55 (m, 1H), 3.23 (m, 2H), 2.93 (m, 4H), 2.66 (m, 2H), 2.30 ( m, 3H), 1.84 (m, 2H), 1.74 - 1.36 (m, 13H), 1.29 (s, 6H). 0.03 269 739.3 'NMR (400 MHz, DMSO-ab) δ 9.04 (s, 1H), 8.82 8.70 (m, 2H), 8.64 (s, 1H), 7.77 (a, J = 1 .9 Hz, 1H), 7.62 (a, J = 8.1 Hz, 1H), 7.36 (a, J = 7.1 Hz, 1H), 6.36 - 5.82 (m, 1H ), 5.28 (m, 1H), 4.24 (m, 1H), 3.81 - 3.55 (m, 1H), 3.24 - 3.10 (m, 2H), 2.90 ( m, 3H), 2.59 (m, 2H), 2.38-2.19 (m, 3H), 1.93-1.81 (m, 2H), 1.68 (s, 3H), 1 .58 (a, J = 6.6 Hz, 6H), 1.48 (s, 3H), 1.41 (m, 1H), 1.31 (s, 6H). 0.07 270 749.3 'NMR (400 MHz, DMSO-ab) δ 9.10 (a, J = 8.3 Hz, 1H), 8.98 (s, 1H), 8.72 (s, 1H), 8.53 (m , 1H), 7.84 (a, J = 1.8 Hz, 1H), 7.61 (a, J = 8.2 Hz, 1H), 7.44 (m, 1H), 5.33 - 5 .22 (m, 1H), 4.31-4.18 (m, 1H), 3.40 3.17 (m, 4H), 3.11 (m, 1H), 3.04 - 2.90 ( m, 1H), 2.78 (m, 1H), 2.58 - 2.51 (m, 1H), 2.49 - 2.44 (m, 1H), 1.99 - 1.78 (m, 1H), 3H), 1.62 - 1.54 (m, 8H), 1.50 (s, 3H), 1.31 (s, 6H), 1.16 - 1.02 (m, 3H), 0.95 (m, 1H), 0.65 0.58 (m, 1H), 0.55 - 0.40 (m, 3H). ο,ι 271 703.4 'NMR (400 MHz, DMSO-ab) δ 9.06 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.35 (m, 1H), 7.76 (a, J = 2.0 Hz, 1H), 7.62 (a, J = 8.1 Hz, 1H), 7.34 (m, 1H), 5.28 (m, 1H), 4.23 (m, 1H), 3.22 (m, 4H), 2.98 - 2.81 (m, 4H), 2.71 - 2.57 (m, 2H), 2.27 (m, 3H), 1.84 (m, 2H), 1.68 (s, 3H), 1.58 (a, J = 6.6 Hz, 6H), 1.48 (s, 3H), 1.31 (s, 6H ), 1.06 (t, J = 7.2 Hz, ZN). 0.06 272 759.3 'NMR (400 MHz, DMSO-ab) δ 9.07 (s, 1H), 9.04 8.91 (m, 2H), 8.68 (s, 1H), 7.84 (a, J = 1 .8 Hz, 1H), 7.63 (a, J = 8.2 Hz, 1H), 7.46 (m, 1H), 6.10 (tt, J = 55.5, 3.6 Hz, 1H ), 5.26 (m, 1H), 4.24 (m, 1H), 3.66 (m, 2H), 3.19 (m, 2H), 2.91 (m, 4H), 1.84 (m, 2H), 1.66 (m, 4H), 1.58 (a, J = 6.6 Hz, 6H), 1.48 (m, 4H), 1.31 (s, 6H). 0.09 273 723.3 Ή NMR (400 MHz, DMSO-ab) δ 9.19 (s, 1H), 8.99 (s, 1H), 8.72 (s, 1H), 8.54 (m, 1H), 7.84 (a, J = 1.8 Hz, 1H), 7.63 (a, J = 8.2 Hz, 1H), 7.43 (m, 1H), 5.27 (m, 1H), 4.26 (m, 1H), 3.32 - 3.10 (m, 4H), 3.10 2.83 (m, 4H), 2.63 - 2.56 (m, 1H), 1.84 (m, 2H), 1.70 (m, 2H), 1.58 (m, 7H), 1.49 (m, 4H), 1.31 (s, 6H), 1.08 (t, J = 7.2 Hz, ZN). 0.07

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274 725.3 'NMR (400 MHz, DMSO-ab) δ 9.28 (m, 1H), 8.90 (m, 1H), 8.84 (s, 1H), 8.74 (s, 1H), 8.71 (s, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.60 (m, 1H), 6.15 (tt, J = 55.7, 3.8 Hz, 1H), 5.29 (m, 1H), 4.30 (m, 1H), 3.71 (m, 2H), 3.21 (m, 2H), 2.99 - 2.83 (m, 4H ), 2.64 (m, 2H), 1.84 (m, 2H), 1.75 - 1.65 (m, 3H), 1.60 (a, J = 6.5 Hz, 6H), 1 .50 (s, 3H), 1.45 - 1.36 (m, 1H), 1.30 (s, 6H). 0.04 275 738.3 Ή NMR (400 MHz, DMSO-ab) δ 9.05 - 8.92 (m, ZN), 8.66 (s, 1H), 8.01 (s, 1H), 7.65 (m, 1H) , 7.53 7.44 (m, 2H), 7.07 (a, J = 7.9 Hz, 1H), 6.11 (tt, J = 55.6, 3.7 Hz, 1H), 5 .25 (m, 1H), 4.38 (m, 1H), 3.21 (m, 2H), 3.05 - 2.82 (m, 5H), 2.75 - 2.61 (m, 2H ), 1.84 (m, 3H), 1.77 - 1.35 (m, 14H). 0.06 276 666.4 'NMR (400 MHz, DMSO-ab) δ 9.03 (s, 1H), 8.60 (s, 1H), 8.34 (s, 1H), 8.24 (m, 1H), 7.89 (s, 1H), 7.71 - 7.63 (m, 2H), 7.47 (a, J = 1.4 Hz, 1H), 7.36 (a, J = 7.8 Hz, 1H) , 7.14 (a, J = 12.2 Hz, 1H), 5.27 (m, 1H), 4.29 (m, 1H), 3.22 (m, 2H), 2.92 (m, 4H), 2.70 - 2.59 (m, 4H), 2.35 (m, 3H), 1.84 (m, 2H), 1.69 (t, J = 14.5 Hz, ZN), 1.58 (a, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.29 (s, 6H), 1.05 (t, J = 7.2 Hz, ZN). 0.06 277 765.3 'NMR (400 MHz, DMSO-ab) δ 9.05 (s, 1H), 8.81 8.73 (m, 2H), 8.66 (s, 1H), 7.76 (a, J = 2 .0 Hz, 1H), 7.59 (a, J = 8.2 Hz, 1H), 7.37 (m, 1H), 6.10 (tt, J = 55.8, 3.7 Hz, 1H ), 5.28 (m, 1H), 4.22 (m, 1H), 3.39 3.21 (m, 2H), 3.02 (m, 2H), 2.75 (m, 1H), 2.53 (m, 5H), 2.28 (m, 3H), 1.87 (m, 3H), 1.58 (m, 6H), 1.48 (s, 3H), 1.31 (a , J = 1.2 Hz, 6H), 0.95 (m, 1H), 0.61 (m, 1H), 0.54 - 0.36 (m, 3H). 0.07 278 689.4 'NMR (400 MHz, DMSO-ab) δ 9.24 (m, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.72 (s, 1H), 8.51 (m, 1H), 8.06 (s, 1H), 7.67 (s, 1H), 7.57 (m, 1H), 5.29 (m, 1H), 4.35 - 4.28 ( m, 1H), 3.28 (m, 2H), 3.21 (m, 2H), 2.96 (m, 2H), 2.89 (m, 2H), 2.64 (m, 2H), 1.84 (m, 2H), 1.70 (m, 4H), 1.60 (a, J = 6.5 Hz, 6H), 1.50 (s, 3H), 1.30 (s, 6H ), 1.11 (t, J = 7.2 Hz, ZN). 0.2 279 729.4 'NMR (400 MHz, DMSO-ab) δ 9.08 (m, 1H), 8.72 (s, 1H), 8.35 (m, 1H), 7.76 (a, J = 1.9 Hz , 1H), 7.60 (a, J = 8.2 Hz, 1H), 7.35 (a, J = 6.9 Hz, 1H), 5.29 (m, 1H), 4.22 (m , 1H), 3.38 - 3.14 (m, 3H), 3.13 - 3.04 (m, 1H), 2.95 (m, 1H), 2.77 (m, 1H), 2, 28 (m, 3H), 1.99 - 1.77 (m, 4H), 1.59 - 1.56 (m, 6H), 1.49 (s, 3H), 1.31 (s, 6H) , 1.06 (t, J = 7.1 Hz, ZN), 0.65 - 0.58 (m, 1H), 0.52 - 0.38 (m, 3H). 0.1 280 751.3 'NMR (400 MHz, DMSO-ab) δ 9.20 (m, 1H), 9.10 (s, 1H), 8.80 (s, 1H), 8.71 (s, 2H), 8.06 (s, 1H), 7.69 (s, 1H), 7.54 (m, 1H), 6.05 (t, J = 56.7 Hz, 1H), 5.28 (m, 1H), 4 .29 (m, 1H), 3.21 (m, 2H), 2.95 (m, 4H), 0.05

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2.65 (m, 2H), 1.85 (m, 2H), 1.77 - 1.64 (m, 4H), 1.60 (d, J = 6.7 Hz, 6H), 1.50 (s, ZH), 1.30 (s, 6H), 1.11 (m, 2H), 0.95 (m, 2H). 281 691.3 Ή NMR (400 MHz, DMSSMb) δ 9.04 (s, 1H), 8.89 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.64 (s, 1H ), 8.50 (d, J = 4.7 Hz, 1H), 8.10 (s, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.43 (d, J = 7.1 Hz, 1H), 5.25 (m, 1H), 4.40 - 4.22 (m, 1H), 3.23 (m, 2H), 2.95 (m, 4H), 2 .75 (m, 3H), 2.72 2.59 (m, 1H), 2.41 - 2.28 (m, 1H), 1.94 - 1.76 (m, 2H), 1.69 ( m, 3H), 1.59 (s, 3H), 1.52 (m, 4H), 1.31 (s, 6H). 0.07 282 767.3 'NMR (400 MHz, DMSO-de) δ 9.13 (m, 1H), 9.02 (m, 1H), 8.99 (s, 1H), 8.73 (d, J = 1.7 Hz , 1H), 8.70 (s, 1H), 8.10 (s, 1H), 7.67 (d, J = 1.8 Hz, 1H), 7.49 (m, 1H), 6.13 (tt, J = 55.6, 3.7 Hz, 1H), 5.27 (m, 1H), 4.29 (m, 1H), 3.67 (m, 2H), 3.39 - 3, 24 (m, 2H), 3.19 - 3.10 (m, 1H), 3.03 - 2.92 (m, 1H), 2.87 - 2.79 (m, 1H), 2.68 - 2.58 (m, 2H), 2.53 - 2.45 (m, 1H), 1.98 1.77 (m, 3H), 1.59 (m, 6H), 1.52 (s, 3H ), 1.31 (s, 6H), 0.96 (m, 1H), 0.66 - 0.59 (m, 1H), 0.54 - 0.40 (m, 3H). 0.1 283 731.3 'NMR (400 MHz, DMSO-de) δ 9.10 (m, 1H), 8.93 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.70 (s , 1H), 8.57 (m, 1H), 8.09 (s, 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.45 (m, 1H), 5.26 (m, 1H), 4.30 (m, 1H), 3.39 - 3.20 (m, 4H), 3.19 - 3.10 (m, 1H), 3.04 - 2.92 (m , 1H), 2.82 (m, 1H), 2.68 - 2.58 (m, 2H), 2.50 (m, 1H), 1.98 1.80 (m, 3H), 1.58 (m, 6H), 1.52 (s, 3H), 1.31 (s, 6H), 1.09 (t, J = 7.2 Hz, ZN), 0.99 - 0.91 (m, 1H), 0.66 - 0.59 (m, 1H), 0.54 - 0.41 (m, 3H). 0.09 284 747.4 'NMR (400 MHz, DMSO-de) δ 9.00 (s, 1H), 8.80 (m, 1H), 8.76 - 8.67 (m, 2H), 8.60 (s, 1H) , 8.03 (s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.40 (d, J = 7.1 Hz, 1H), 6.33 - 5.94 ( m, 1H), 5.27 (m, 1H), 4.40 - 4.16 (m, 1H), 3.76 - 3.57 (m, 1H), 3.22 - 3.07 (m, 1H), 1H), 2.98 (m, 1H), 2.81 (m, 1H), 2.72 - 2.59 (m, 2H), 2.32 (m, 3H), 1.90 (m, 4H ), 1.70 - 1.40 (m, 10H), 1.31 (s, 6H), 0.96 (m, 1H), 0.62 (m, 2H), 0.58 - 0.40 ( m, 2H). 0.1 285 711.4 ¹ H NMR (400 MHz, DMSSMb) δ 9.27 - 9.06 (m, 1H), 8.86 - 8.64 (m, 3H), 8.39 (m, 1H), 8.02 (s , 1H), 7.68 (d, J = 1.8 Hz, 1H), 7.37 (m, 1H), 5.76 (m, 1H), 5.30 (m, 1H), 4.29 (m, 1H), 3.43 - 3.19 (m, 4H), 3.15 (m, 1H), 2.99 (m, 1H), 2.83 (m, 1H), 2.65 ( m, 2H), 2.30 (m, 3H), 1.99 - 1.79 (m, 3H), 1.67 - 1.41 (m, 9H), 1.31 (s, 6H), 1 .08 (t, J = 7.2 Hz, ZN), 0.96 (m, 1H), 0.62 (m, 1H), 0.54 - 0.33 (m, 2H). 0.1

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286 705.3 Ή NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.92 (s, 1H), 8.74 (d, J = 1.7 Hz, 1H), 8.67 (s , 1H), 8.57 (m, 1H), 8.10 (d, J = 2.9 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.45 (m , 1H), 5.26 (m, 1H), 4.32 (m, 1H), 3.34 3.14 (m, 4H), 2.95 (m, 4H), 2.67 (m, 2H ), 1.85 (m, 2H), 1.69 (t, J = 13.8 Hz, 3H), 1.64 - 1.38 (m, 9H), 1.30 (m, 5H), 1 .09 (t, J = 7.2 Hz, 3H). 0.1 287 740.3 Ή NMR (400 MHz, DMSO-de) δ 9.13 (s, 1H), 9.00 (m, 1H), 8.94 (s, 1H), 8.66 (s, 1H), 8.00 (s, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 7.43 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 7, 8 Hz, 1H), 6.11 (tt, J = 55.6, 3.7 Hz, 1H), 5.31 - 5.20 (m, 1H), 4.35 - 4.25 (m, 1H ), 3.66 (m, 2H), 3.22 (m, 2H), 3.06 - 2.82 (m, 4H), 2.65 (m, 2H), 1.85 (m, 3H) , 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.51 (s, 3H), 1.29 (s, 6H). 0.08 288 704.3 'NMR (400 MHz, DMSO-de) δ 9.12 (s, 1H), 8.89 (s, 1H), 8.66 (s, 1H), 8.56 (m, 1H), 8.00 (s, 1H), 7.67 (m, 1H), 7.49 (m, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 7, 8 Hz, 1H), 5.25 (m, 1H), 4.29 (m, 1H), 3.23 (m, 4H), 3.06 - 2.83 (m, 5H), 2.64 ( m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.52 (s, 3H), 1, 29 (s, 6H), 1.07 (t, J = 7.2 Hz, 3H). 0.08 289 722.3 Ή NMR (400 MHz, DMSOUB) δ 9.13 (d, J = 10.2 Hz, 1H), 8.90 (m, 1H), 8.68 (d, J = 2.2 Hz, 2H), 7.97 (s, 1H), 7.68 (m, 2H), 7.56 (d, J = 10.9 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 6.09 (tt, J = 55.8, 3.8 Hz, 1H), 5.26 (m, 1H), 4.30 (m , 1H), 3.65 (m, 2H), 3.22 (m, 2H), 3.03 - 2.83 (m, 5H), 2.62 (m, 2H), 1.85 (m, 2H), 1.69 (m, 3H), 1.58 (d, J = 6.6 Hz, 6H), 1.52 (s, 3H), 1.29 (s, 6H). 0.07 290 686.3 'NMR (400 MHz, DMSO-de) δ 9.15 (d, J = 10.7 Hz, 1H), 8.68 (s, 1H), 8.63 (d, J = 1.8 Hz, 1H ), 8.46 (m, 1H), 7.97 (s, 1H), 7.73 - 7.67 (m, 2H), 7.53 (d, J = 10.9 Hz, 1H), 7 .46 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 5.26 (m, 1H), 4.29 (m, 1H), 3 .29 - 3.17 (m, 4H), 2.93 (m, 5H), 2.63 (m, 2H), 1.85 (m, 2H), 1.68 (m, 3H), 1, 58 (d, J = 6.6 Hz, 6H), 1.53 (s, 3H), 1.29 (s, 6H), 1.07 (t, J = 7.2 Hz, 3H). 0.07 291 785.3 Ή NMR (400 MHz, DMSOUB) δ 9.15 (s, 1H), 9.12 (s, 1H), 8.99 (s, 1H), 8.70 (s, 1H), 7.84 (s , 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 7.2 Hz, 1H), 6.00 (t, J = 56.7 Hz, 1H ), 5.27 (m, 1H), 4.25 (m, 1H), 3.19 (m, 2H), 2.92 (m, 4H), 2.60 - 2.53 (m, 2H) , 1.84 (m, 2H), 1.75 - 1.63 (m, 2H), 1.58 (d, J = 6.5 Hz, 6H), 1.48 (s, 3H), 1, 31 (s, 6H), 1.09 (m, 2H), 0.91 (m, 2H). 0.08 292 748.3 'NMR (400 MHz, DMSO-de) δ 9.06 (s, 1H), 8.98 (s, 1H), 8.87 (s, 1H), 8.63 (s, 1H), 8.00 (s, 1H), 7.66 (m, 1H), 7.49 (m, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.39 0.07

- 413 045798

(d, J = 7.8 Hz, 1H), 5.24 (m, 1H), 4.46 (t, 2H), 4.29 (t, 1H), 3.23 (d, J = 11, 6 Hz, 2H), 2.94 (t, 5H), 2.65 (t, 2H), 1.85 (t, 2H), 1.69 (t, ZN), 1.57 (d, J = 6.6 Hz, 6H), 1.51 (s, ZN), 1.30 (s, 6H), 0.97 - 0.74 (t, 4H). 293 730.3 Ή NMR (400 MHz, DMSOAB) δ 9.11 (s, 1H), 8.88 (s, 1H), 8.70 - 8.59 (m, 2H), 7.96 (s, 1H), 7 .69 (m, 2H), 7.52 (d, J = 10.8 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.38 (d, J = 7, 7 Hz, 1H), 5.26 (m, 1H), 4.47 (d, J = 49.1 Hz, 2H), 4.30 (m, 1H), 3.22 (m, 2H), 2 .93 (m, 5H), 2.63 (m, 2H), 1.85 (m, 2H), 1.69 (m, 2H), 1.58 (d, J = 6.5 Hz, 6H) , 1.53 (s, 3H), 1.43 (m, 1H), 1.29 (s, 6H), 0.89 (m, 2H), 0.80 (m, 2H). 0.05 294 748.3 ^NMR (400 MHz, DMSO-de) δ 9.07 (t, 2H), 8.69 - 8.58 (t, 2H), 7.97 (s, 1H), 7.73 - 7.66 ( t, 2H), 7.54 (d, J = 10.9 Hz, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.38 (d, J = 7.8 Hz, Sh), 6.04 (t, J = 57.0 Hz, Sh), 5.32 - 5.19 (t, 1H), 4.30 (t, 1H), 3.22 (t, ZN), 2.93 (t, 5H), 2.64 (t, 2H), 1.85 (t, 2H), 1.69 (t, 2H), 1.58 (d, J = 6.6 Hz, 6H ), 1.53 (s, ZN), 1.29 (s, 6H), 1.12 - 1.05 (t, 2H), 0.89 (t, 2H). 0.08 295 728.4 Ή NMR (400 MHz, DMSOAB) δ 9.02 (t, 1H), 8.85 (s, 1H), 8.77 (s, 1H), 8.50 (s, 1H), 7.82 (s , 1H), 7.67 (t, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.28 (d , J = 1.4 Hz, 1H), 7.19 (d, J = 11.9 Hz, 1H), 6.09 (t, J = 57.2 Hz, 1H), 5.31 (t, 1H ), 3.68 (t, 1H), 3.34 (t, 2H), 2.80 - 2.56 (t, 6H), 2.39 (s, ZN), 1.82 (t, 2H) , 1.70 (t, 1H), 1.60 (t, 6H), 1.56 - 1.48 (t, 1H), 1.45 (s, ZN), 1.37 (t, 1H), 1.32 - 1.16 (t, 8H), 1.12 - 1.05 (t, 2H), 0.90 (t, 2H). 0.1 296 766.3 Ή NMR (400 MHz, DMSO-de) δ 9.17 (s, 1H), 8.99 (d, J = 9.4 Hz, 1H), 8.90 (s, 1H), 8.61 (s , 1H), 7.95 (s, 1H), 7.68 (m, 1H), 7.45 - 7.34 (m, 2H), 7.27 (m, 1H), 6.03 (t, J = 56.7 Hz, 1H), 5.23 (m, 1H), 3.35 (m, 3H), 2.74 (m, 4H), 2.68 - 2.58 (m, 2H), 1.82 (m, 2H), 1.71 (m, 1H), 1.58 (m, 6H), 1.53 - 1.45 (m, 5H), 1.28 (s, 6H), 1 .24 (m, 1H), 1.15 - 1.07 (m, 2H), 0.93 (m, 2H). 0.1 297 767.3 'NMR (400 MHz, DMSO-46) δ 9.19 (s, 1H), 9.10 (d, J= 9.7 Hz, 1H), 8.94 (s, 1H), 8.79 (m , 1H), 8.65 (s, 1H), 8.10 (s, 1H), 7.51 (m, 1H), 7.45 - 7.38 (m, 1H), 6.05 (t, J= 56.7 Hz, 1H), 5.25 (m, 1H), 3.70 (m, 1H), 3.37 (m, 2H), 2.84 - 2.60 (m, 7H), 1.83 (m, 2H), 1.71 - 1.59 (m, 7H), 1.54 (m, 1H), 1.48 (s, 3H), 1.40 (m, 1H), 1 .30 (s, 6H), 1.16 - 1.08 (m, 2H), 0.95 (m, 2H). 0.2

All references, including publications, patents and patent documents, are incorporated herein by reference as if they were individually incorporated by reference. The present description contains references to various embodiments and techniques. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the present invention. It should be understood that the description is to be considered as an example of the claimed subject matter and not as limiting the appended claims to the specific embodiments illustrated.

Claims (33)

1. Compound of formula I R ^9d Formula I or a pharmaceutically acceptable salt thereof, - 414 045798 where: one of R ¹ and R ² is -OH, halogen or C1-6 alkyl, and the other of R ¹ and R ² is halogen or C _1-6 alkyl, or R ¹ and R ² together with the carbon atom to which they are attached form tetrahydropyran-4yl, cyclopropyl, azetidin-3-yl or piperidin-4-yl, wherein said azetidin-3-yl is optionally substituted with one acetyl or tert-butoxycarbonyl group and wherein said piperidin-4-yl is optionally substituted with one R ¹¹ ; R ¹¹ represents i) oxetan-3-yl, ii) -S(O) ₂ C _1-6 alkyl, iii) -S(O) ₂ C ₃ _ ₇ monocyclic cycloalkyl, iv) Ci. ₆ alkyl, optionally substituted with 1 or 2 halogens, or v) -C(O)R ²¹ ; R ²¹ is i) C _3-7 monocyclic cycloalkyl or bicyclo[1.1.1]pentyl, each of which is optionally substituted with 1-3 groups independently selected from -OH, halogen, or C _1-3 alkyl, ii) oxetan-3-yl, optionally substituted with 1-2 C _1-3 alkyl groups, iii) C _1-6 alkoxy, or iv) C _1-6 alkyl optionally substituted with 1-3 groups independently selected from -OH or halogen, each of R ³ and R ¹³ represents H, R ³ and R ¹³ together form =O; L ¹ represents cyclobut-1,3-diyl, optionally substituted with n groups selected from R ¹² where R ¹² represents C _1-3 alkyl; and n is 1 or 2; X represents -NR ¹⁵ R ¹⁶ where R ¹⁵ and R ¹⁶ independently represent i) H, ii) C3- ₇ monocyclic cycloalkyl, optionally substituted with 1-2 halogens, iii) tetrahydropyran-4-yl, optionally substituted with 1-3 C _1-3 alkyl groups, iv) -C(O)C _1-6 alkyl, v) C _1-6 alkyl, optionally substituted with 1-2 groups independently selected from a) -C _1-3 alkyl, b) -OH, c) halogen, or X is a 4-8 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1-2 heteroatoms independently selected from N and O, wherein said 4-8 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optional substituted with 1-4 R ¹⁸ ; each R ¹⁸ independently represents i) halogen, ii) -OH, iii) C _1-6 alkyl, optionally substituted with 1-2 halogen groups; X ¹ represents N or CR ¹⁷ ; R ⁴ represents H or halogen; R ⁵ , R ⁶ , and R ¹⁰ are each H; R ¹⁷ represents H; R ⁷ represents i) C| _-6 alkyl, or ii) _C3-7 monocyclic cycloalkyl; Z represents -O- or -NR ⁸ -; R ⁸ represents H; R ^{9 a} represents H or halogen; R ^9b represents H, halogen or C _1-6 alkyl; R ^9c is H, halogen, C _1-6 alkyl, C 3-7 monocyclic cycloalkyl, -CF3 or -OCF3; R ^9d represents COOH, -C(O)NH(R ¹⁹ ) ₂ , R ^9e represents H, R ¹⁹ is i) H, ii) C _1-6 alkyl, optionally substituted with 1-2 groups independently selected from -OH, halogen and C _1-3 alkoxy, iii) C _{3-7 monocyclic} cycloalkyl, optionally substituted with 1-2 groups selected of C _1-3 alkyl and C _1-3 alkoxy, wherein said C _1-3 alkyl is optionally substituted with 1-2 halogen or C _1-3 alkoxy groups. - 415 045798 2. A compound according to claim 1, characterized in that said compound has formula IIa: R ² _R Sd Formula Na or a pharmaceutically acceptable salt thereof; in which each R ¹² represents C _1-3 alkyl; and n is 0, 1 or 2. 3. A compound according to any one of claims 1, 2, characterized in that said compound has formula IIb: RSd Formula lib or a pharmaceutically acceptable salt thereof. 4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein ^R4 , ^R5 , ^R6 and ^R10 are H. 5. A compound according to any one of claims 1, 2 and 4, characterized in that said compound has formula III: R ² RSd Formula III or a pharmaceutically acceptable salt thereof; in which each R ¹² represents C _1-3 alkyl; and n is 0, 1 or 2. 6. A compound according to any one of claims 1 to 5, characterized in that said compound has formula IIIa: - 416 045798 Formula Illa or a pharmaceutically acceptable salt thereof. 7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R ³ and R ¹³ together form =O. 8. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein X ¹ represents CH. 9. A compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, where X ¹ represents N. 10. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R ¹² represents Cl _-2 αlkyl. 11. A compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, where Z represents NH. 12. A compound according to claim 1, characterized in that said compound has formula IV: Formula IV or a pharmaceutically acceptable salt thereof. 13. A compound according to claim 1, characterized in that said compound has formula IVa: ^9c R ^9d Formula IVa or a pharmaceutically acceptable salt thereof. 14. A compound according to claim 1, characterized in that said compound has formula IVb: - 417 045798 R.M. Formula IVb or a pharmaceutically acceptable salt thereof. 15. A compound according to claim 1, characterized in that said compound has formula IVc: Formula IVc or a pharmaceutically acceptable salt thereof. 16. A compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, where one of R ¹ and R ² is -OH, fluorine, methyl or ethyl and the other of R ¹ and R ² is fluorine, methyl or ethyl . 17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² are both fluorine, methyl or ethyl. 18. A compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein R ^9a , R ^9b and R ^9c independently represent H, -F, methyl or -Cl, R ^9d represents -C(O)N( R ¹⁹ ) ₂ , R ^9e represents H. 19. A compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein R ^9d is 0 W ^N^y ^{F Н} F is 20. A compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein R ^9a represents H or fluorine. 21. A compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein R ^9b represents H or methyl. 22. A compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein R ^9c represents methyl. 23. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ¹⁹ represents: i) H, ii) methyl, iii) ethyl, optionally substituted with 1 or 2 groups independently selected from -OH, fluorine and -OCH3, iv) n-propyl, optionally substituted with 1 or 2 groups independently selected from fluorine and -OCH3 , v) isopropyl, optionally substituted with 1 or 2 fluoro groups, vi) n-butyl, vii) isobutyl, optionally substituted with 1 or 2 fluoro groups, viii) sec-butyl, ix) tert-butyl, - 418 045798 x) cyclopropyl, optionally substituted with methyl, wherein said methyl is optionally substituted 1-2 fluoro groups, or xi) cyclobutyl. 24. A compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein R ⁷ is isopropyl, sec-butyl or cyclopropyl. 25. A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, where X is a 4-8 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from N and O, wherein said 4-8 membered monocyclic, fused bicyclic, bridged bicyclic or spirocyclic heterocyclyl is optionally substituted with 1-2 R ¹⁸ . 26. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X represents azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl, each of which is optionally substituted with 1-2 R ¹⁸ . 27. A compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, where X represents: stands for: each of which is optionally substituted with 1-2 R ¹⁸ . 28. A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, where X represents each of which is optionally substituted with 1-2 R ¹⁸ . 29. A pharmaceutical composition for treating cancer in a subject in need thereof, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient or carrier. 30. The pharmaceutical composition according to claim 29, further containing one or more additional therapeutic agents or a pharmaceutically acceptable salt thereof. 31. A method of inhibiting the activity of hematopoietic precursor kinase 1 (HPK1) in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims. 29, 30. 32. A method of increasing T cell activation in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 29, 30. 33. A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 29, 30.