EA045220B1 - Cot MODULATORS AND METHODS OF THEIR APPLICATION - Google Patents

Description

Field of technology

The present description relates generally to Cot modulators (Osaka type thyroid cancer).

State of the art

Cot protein (Osaka type thyroid cancer) is a serine/threonine kinase that is a member of the MAP kinase kinase kinase (MAP3K) family. It is also known as Tpl2 (tumor progression locus), MAP3K8 (mitogen-activated protein kinase kinase kinase 8), or EST (Ewing's sarcoma transformation factor). Cot has been identified by its oncogenic transforming activity in cells and has been shown to regulate oncogenic and inflammatory pathways.

Cot is known to participate in the MEK-ERK pathway and is required for the production of LPS-induced tumor necrosis factor-α (TNF-α). Cot has been shown to be involved in TNFa production and signaling. TNFa is a pro-inflammatory cytokine and plays an important role in inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), diabetes, sepsis, psoriasis, TNFa misexpression and transplant rejection.

In this regard, agents and methods that modulate Cot expression or activity may be useful in preventing or treating such diseases.

Short description

Provided herein are compounds that modulate the expression or activity of Cot. The description also suggests compositions, including pharmaceutical compositions. The compounds provided herein are suitable for the treatment of diseases, disorders or conditions mediated by Cot.

In one aspect, there is provided a compound having the structure of Formula III:

where R ¹ represents hydrogen, -OR ⁷ , -N(R ⁸ )(R ⁹ ), -C(O)-R ⁷ , -S(O)2-R ⁷ , -C^alkyl, C2-6alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one to four Z ¹ ;

R ⁴ represents heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is optionally substituted with one to four Z ⁴ ;

^R5 is hydrogen, halogen, -CN, -NO2, ^-OR7 , -N( ^R8 )( ^R9 ), -S(O) ^-R7 , -S(O) ^2R7 , -S(O )2N(R ⁷ )2, -C(O)R ⁷ , -OC(O)-R ⁷ , -C(O)OR ⁷ , -OC(O)OR ⁷ , -OC(O)N(R ¹⁰ )(R11), -C(O)N(R ⁷ )2, -N(R ⁷ )C(O)(R ⁷ ), C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁵ ;

R ⁶ is hydrogen, -C(O)-R ⁷ , -C(O)OR ⁷ , -C(O)N(R ⁷ ) ₂ , C _1-9 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁶ ;

each R ⁷ independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁷ ;

R ⁸ and R ⁹ are each independently hydrogen, -S(O)2R ¹⁰ , -C(O)-R ¹⁰ , -C(O)OR ¹⁰ , -C(O)N(R ¹⁰ )(R11 ), C1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to four Z ⁸ ;

R ¹⁰ and R ¹¹ are each independently hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl, where each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ^1b ;

- 1 045220 each Z ¹ , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ independently represents hydrogen, oxo, halogen, -NO ₂ , -N ₃ , -CN, thioxo, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C ₃ - ₁₅ cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)-R ¹² , -C(O) OR ¹² , -C(O)-N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )(R ¹⁴ ), -NiRAiRr -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -NR ¹² S(O )2N(R ¹³ )(R ¹⁴ ), -NR ¹² S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)-N(R ¹³ )(R ¹⁴ ), -P (O)(OR ¹² )2, -OP(O)(OR ¹² )2, -CH2P(O)(OR ¹² )2, -OCH2P(O)(OR ¹² )2, -C(O)OCH2P(O )(OR ¹² )2, -P(O)(R ¹² )(OR ¹² ), -OP(O)(R ¹² )(OR ¹² ), -CH2P(O)(R ¹² )(OR ¹² ), - OCH2P(O)(R ¹² )(OR ¹² ), -C(O)OCH2P(O)(R ¹² )(OR ¹² ), -P(O)(N(R ¹² )2)2, -OP(O )(N(R ¹² h)2, -CH2P(O)(N(R ¹² h)2, -OCH2P(O)(N(R ¹² h)2, -C(O)OCH2P(O)(N( R ¹² )2)2, -P(O)(N(R ¹² )2)(OR ¹² ), -OP(O)(N(R ¹² )2)(OR ¹² ), -CH2P(O)(N (R ¹² )2)(OR ¹² ), -OCH2P(O)(N(R ¹² )2)(OR ¹² ), -C(O)OCH2P(O)(N(R ¹² )2)(OR ¹² ) , -P(O)(R ¹² )(N(R ¹² )2), -OP(O)(R ¹² )(N(R ¹² )2), -CH2P(O)(R ¹² )(N(R ¹² )2), -OCH2P(O)(R ¹² )(N(R ¹² )2), -C(O)OCH2P(O)(R ¹² )(N(R ¹² )2), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O)2R ¹² or -S(O)2N(R ¹³ )(R ¹⁴ );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1a groups;

each Z ^1a independently represents oxo, halogen, thioxo, -NO2, -CN, -N ₃ , C _1-9 alkyl, C ₂ _ ₆ alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₁₅ cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)R ¹² , -C(O)OR ¹² , -C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )( R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , -N(R ¹² )-C(O)R ¹² , -N(R ¹² )C(O)O(R ¹² ), -N( R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -N(R ¹² )S(O)2-N(R ¹³ ) (R ¹⁴ ), -N(R ¹² )S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)OR ¹² , -OC(O)-N(R ¹³ )(R ¹⁴ ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(OhR ¹² or -S(O)2N(R ¹³ ) (R ¹⁴ );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups;

each R ¹² independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl, where any alkyl _, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups;

R ¹³ and R ¹⁴ are each independently hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C ₂ _ ₆ alkynyl, C ₃ _ ₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one four groups Z ^1b ; and each Z ^1b independently represents oxo, thioxo, hydroxy, halogen, -NO ₂ , -N ₃ , -CN, _{C 1-9} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C ₁ . ₉ alkyl), -O(C ₂ . ₆ alkenyl), -O(C ₂ . ₆ alkynyl), -O(C ₃ . ₁₅ cycloalkyl ), -O(C ₁ . ₈ haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH ₂ , -NH(C ₁ . ₉ alkyl), -NH(C ₂ . ₆ alkenyl), -NH(C ₂ . ₆ alkynyl), -NH(C ₃ . ₁₅ cycloalkyl), -NH(C ₁ . ₈ haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl ), -N(C ₁ . ₉ alkyl) ₂ , -N(C ₃ . ₁₅ cycloalkyl) ₂ , -N(C ₂ . ₆ αlkenyl) ₂ , -N(C ₂ . ₆ alkynyl) ₂ , -N(C _3.15 cycloalkyl) ₂ , -N(C _1.8 haloalkyl) _{2 ,} -N(aryl) ₂ , -N ₍ heteroaryl) ₂ , -N( _heterocyclyl ) ₂ , -N(C _1.9 αlkyl)(C _{2.6 alkenyl} ),

-LSH^alkyl) (C _2-6 alkynyl),

-N(C ₁ . ₉ αlkyl)(C ₃ . ₁₅ cycloalkyl),

-N(C ₁ . ₉ alkyl)(C ₁ . ₈ haloalkyl),

-N(C _1-9 alkyl)(aryl), -N(C _1-9 αlkyl)(heteroaryl), -N(C _1.9 αlkyl _{)(heterocyclyl), -C(O)(C 1.9 alkyl )} ),

-C(O)(C ₂ . ₆ alkenyl), -C(O)(C ₂ . ₆ alkynyl), -C(O)(C ₃ . ₁₅ cycloalkyl), -C(O)(C _1-8 haloalkyl) ), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C _1-9 alkyl), -C(O)O( _C2.6alkenyl ), _{-C(O)O(C2.6alkenyl ) ,}

-C(O)O(C ₃ . ₁₅ cycloalkyl),

-C(O)O(C ₁ . ₈ haloalkyl),

-C(O)O(aryl),

-C(O)O(heterocyclyl), _-C (O ₎ NH2, -C(O)NH( _C1.9alkyl ), -C(O)NH( _C2.6alkenyl ),

-C(O)NH(C ₃ . ₁₅ cycloalkyl), -C(O)NH(heterocyclyl), -C(O)N(C ₃ . ₁₅ cycloalkyl) ₂ , -C(O)N (heterocyclyl) ₂ , -NHC(O)(C ₃ - ₁₅ cycloalkyl), -NHC(O)(heterocyclyl),

-C(O)NH(C _1-8 haloalkyl), -C(O)NH(aryl),

-C(O)N(C _1-9 alkyl) ₂ , -C(O)N(C _2-6 alkenyl) ₂ ,

-C(O)N(C _1-8 haloalkyl) ₂ , -C(O)N(aryl) ₂ ,

-NHC(O)(C _1-9 alkyl), -NHC(O)(C _2-6 alkenyl),

-NHc(O)(C _1-8 haloalkyl), -NHC(O)(aryl),

-NHC(O)O(C _1-9 alkyl), -NнC(O)O(C ₂ . ₆ alkenyl),

-NHC(O)O(C ₃ . ₁₅ cycloalkyl), -NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl),

-C(O)O(heteroaryl), -C(O) _{NH ( C2-6alkynyl} ), -C(O)NH(heteroaryl), -C(O)N(C2.6alkynyl) ₂ ,

-C(O)N (heteroaryl) ₂ ,

-NHC(O)(C ₂ . ₆ alkynyl),

-NHC(O)(heteroaryl), -NHC(O)o(C _2-6 alkynyl), -NHC(O)O(heteroaryl),

-NHC(O)O(heterocyclyl), -NHC(O)NH(C _1-9 alkyl), -NHC(O)NH(C _2-6 alkenyl), -NHC(O)NH(C _2-6 alkynyl ),

-NHC(O)NH(C ₃ . ₁₅ cycloalkyl),

-NHC(O)NH(C ₁ . ₈ haloalkyl),

-NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C _1-9 αlkyl),

-NHC(O)NH(aryl), -S(C ₂ . ₆ αlkenyl),

-S(C ₂ . ₆ αlkynyl), -S(C ₃ . ₁₅ cycloalkyl), -S(C _1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl),

-NHS(O)(C _1-9 alkyl),

-S(O)(NH)(C ₁ . ₉ alkyl),

-S(O)(C _1-8 haloalkyl),

-N(C _1-9 alkyl)(S(O)(C _1-9 alkyl),

-S(O)(C _2- 6alkenyl),

-S(O)N(C _1-9 alkyl) ₂ ,

-S(O)(C _2- 6 alkynyl), -S(O)(C ₁ . ₉ alkyl),

-S(O)(C ₃ . ₁₅ cycloalkyl),

-S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O) ₂ (C _1-9 αlkyl),

-S(O) ₂ (C _2- 6alkenyl), -S(O) ₂ (C _2- 6αalkenyl), -S(O) ₂ (C ₃ . ₁₅ cycloalkyl), -S(O) ₂ (C _{1- 8} haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-9 alkyl) or - S(O) ₂ N(C _1-9 alkyl) ₂ ;

wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four halogens, _C1-9 alkyls, _C1-8 haloalkyls, -OH, -NH2, -NH( _C1-9 alkyl), -NH( _{C3- 15} cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl),

- 2 045220

-N(C _1-9 alkyl) ₂ , -N(C _3-15 cycloalkyl) ₂ , ^HC(O)(C _3-15 cycloalkyl), -NHC(O)(C _1-8 haloalkyl), ^HC (O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C _1-9 alkyl),

-NHc(o)0(c _2-6 alkynyl), -NНC(O)O(C _3-15 cycloalkyl), -NHc(O)O(Cl. ₈ haloalkyl), ^HC(O)O(aryl) , -NHC(o)o(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(o)NH(C _1-9 alkyl), -8(O)(NH)(C _1-9 alkyl) , -8(O) ₂ (C _1-9 alkyl), -8(O) ₂ (C _3-15 cycloalkyl), -8(O) ₂ (C _1-8 haloalkyl), -8(O) ₂ ( aryl), -8(O)2(heteroaryl), -8(O)2(heterocyclyl), -8(O) ₂ NH(C _1-9 alkyl), -8(O) ₂ N(C _1-9 alkyl) ₂ , -O(C _3-15 cycloalkyl), -O(C _1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl) or -O(C _1-9 alkyl) );

W, X and Y are each independently N or C;

n is 1, 2 or 3;

each aryl independently contains from 6 to 10 carbon atoms in the ring;

each heteroaryl independently contains from 1 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, 8 and O; and each heterocyclyl independently contains from 2 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, 8 and O;

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

According to another aspect, the description provides a pharmaceutical composition for the treatment of a disease or condition mediated by Osaka type (Cot) thyroid cancer, containing a compound as described (a compound of formula III) or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue, and a pharmaceutically acceptable carrier.

Detailed description

Definitions and general parameters.

The following description provides exemplary methods, parameters and the like. However, it should be understood that such description does not limit the scope of the present description, but is instead presented as a description of exemplary embodiments.

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.

A dash (-) that is not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH ₂ 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.

The prefix C _c- D indicates that the following group contains from and to v carbon atoms. For example, C _1-6 alkyl means that the alkyl group contains from 1 to 6 carbon atoms.

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. In addition, singular forms include references to the plural 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.

Alkyl refers to a straight or branched saturated hydrocarbon chain. As used herein, alkyl contains from 1 to 20 carbon atoms (i.e., _C1-20 alkyl), from 1 to 8 carbon atoms (i.e., _C1-8 alkyl), from 1 to 6 carbon atoms (i.e. i.e. C _1-6 alkyl) or 1 to 4 carbon atoms (i.e. C _1-4 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 (t 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 alkyl group containing at least one carbon-carbon double bond and containing from 2 to 20 carbon atoms (i.e. _C2-20 alkenyl), from 2 to 8 carbon atoms (i.e. _{C2- 8} alkenyl), 2 to 6 carbon atoms (i.e. C _2-6 alkenyl) or 2 to 4 carbon atoms (i.e. C 2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

Alkynyl refers to an alkyl group containing at least one carbon-carbon triple bond and containing from 2 to 20 carbon atoms (i.e. C _2-2 oalkynyl), from 2 to 8 carbon atoms (i.e. C _{2- 8} alkynyl), from 2 to 6 carbon atoms (i.e. C ₂ . ₆ αlkynyl) or from 2 to 4 carbon atoms (i.e. C ₂ . ₄ αlkynyl). 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.

Alkylthio belongs to the alkyl-S- group.

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, cyclohexylmethylcarbonyl and benzoyl.

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

Amidino refers to -C(NH)(NH2).

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 6 to 20 ring carbons (i.e., _C6.20 aryl), 6 to 12 ring carbons ( _i.e. , _C6.12 aryl) _, or 6 to 10 ring carbons carbon in _the ring (i.e. _C6.10aryl ). 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, the resulting ring system is heteroaryl. If one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl.

Azido refers to -N ₃ .

Carbamoyl refers to both the O-carbamoyl group, which belongs to the -OC(O)NR ^y R ^z group, and the N-carbamoyl group, which belongs to the -NR ^y C(O)OR ^z group, where R ^y and R ^z is independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl or heteroaryl; each of which may optionally be substituted.

Carboxyl refers to -C(O)OH.

A carboxylic acid ester refers to both -OC(O)R and -C(O)OR, where R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

Cyano or carbonitrile belongs to the -CN group.

Cycloalkyl refers to a saturated or partially unsaturated 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 to ₂₀ cycloalkyl), 3 to 12 ring carbon atoms (i.e., C ₃ to ₁₂ cycloalkyl), 3 to 10 ring carbon atoms carbon in the ring (i.e. _{C3_10} cycloalkyl), 3 to 8 carbon atoms in _the ring (i.e. _{C3_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.

Guanidino belongs to -NHC(NH)(NH2).

Hydrazino belongs to -NHNH2.

Imino refers to the group -C(NR)R, where each R is alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may optionally be substituted as defined herein.

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

- 4 045220 include difluoromethyl (-CHF2) and trifluoromethyl -(-CF ₃ ).

Heteroalkyl refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom group. The term heteroalkyl includes a straight or branched saturated chain containing carbon and heteroatoms. As an example, 1, 2 or 3 carbon atoms may be independently replaced by the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O) ₂ - and the like, where R is H, alkyl, aryl, cycloalkyl , heteroalkyl, heteroaryl or heterocyclyl, each of which may be optionally substituted. Examples of heteroalkyl groups include _-OCH3 , _-CH2OCH3 , _-SCH3 , _-CH2SCH3 , -NRCH3 and -CH2NRCH3, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl, each of which may be optionally substituted . As used herein, heteroalkyl includes 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

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., _C1.20 heteroaryl), from ₃ to _{12 ring carbon atoms (i.e., C3_12 heteroaryl} ), or from 3 to 8 carbon atoms in the ring (i.e. C ₃ _ ₈ heteroaryl); and 1 to 5 heteroatoms, 1 to 4 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. Examples of fused heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and umidazo[1,5 -a]nurudinil, where heteroaryl can be linked through any ring of the fused system. Any aromatic ring having one or more fused rings containing at least one heteroatom is considered a heteroaryl regardless of attachment to the rest of the molecule (ie, through any of the fused rings). Heteroaryl does not span or overlap with aryl as defined above.

Heterocyclyl refers to a saturated or unsaturated cyclic alkyl group with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term heterocyclyl includes heterocycloalkenyl groups (ie, a heterocyclyl group having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. The heterocyclyl may be a single ring or multiple rings, where the plurality of rings may be fused, bridged, or spiro-linked. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of attachment (ie, may be bonded through a carbon atom or a heteroatom). In addition, the term heterocyclyl embraces any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring regardless of attachment to the rest of the molecule. As used herein _{, heterocyclyl contains from 2 to 20 ring carbon atoms (i.e., C2.20 heterocyclyl), from 2 to 12 ring carbon atoms (i.e., C2.12 heterocyclyl ) ,} from 2 to 10 ring carbons carbon in the ring (i.e. C ₂ . ₁₀ heterocyclyl), from 2 to 8 carbon atoms in the ring (i.e. C ₂ . ₈ heterocyclyl), from 3 to 12 carbon atoms in the ring (i.e. C ₃ _ ₁₂ heterocyclyl), from 3 to 8 carbon atoms in the ring (i.e. C ₃ _ ₈ heterocyclyl), or from 3 to 6 carbon atoms in the ring (i.e. C ₃ - ₆ heterocyclyl); containing 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. The heterocyclyl may contain one or more oxo and/or thioxo groups. 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-membered heterocyclyl contains one or more additional rings, wherein one or more additional rings is a three- to ten-membered cycloalkyl or a three- to ten-membered heterocyclyl, wherein one atom of one or more additional rings is also an atom of a three-ten-membered heterocyclyl. Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 1-oxo-1,2,3,4tetrahydroisoquinolinyl, 1-oxo-1,2-dihydroisoquinolinyl, 4,5,6,7 -tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, heterocyclyl can be linked through any fused ring

- 5 045220 systems.

Hydroxy or hydroxyl refers to the -OH group. Hydroxyalkyl refers to a straight or branched alkyl group, as defined above, where one or more hydrogen atoms are replaced by hydroxyl.

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

Nitro belongs to the -NO2 group.

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

Alkylsulfonyl refers to the group -S(O)2R, where R represents alkyl.

Alkylsulfinyl refers to the group -S(O)R, where R represents alkyl. Thiocyanate -SCN.

Thiol refers to the group -SR, where R represents alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl or aryl.

Thioxo and thione belong to the (=S) or (S) group.

Some common alternative chemical names may 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 alkylenyl group, an arylene group or an arylenyl group, respectively. In addition, unless explicitly stated otherwise, when combinations of groups are referred to herein as a single moiety, for example, arylalkyl, the last mentioned group contains the atom at which the moiety is attached to the rest of the molecule.

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 refers to any one or more hydrogen atoms on the designated atom or group that may or may not be replaced by another group other than hydrogen.

Any formula or structure given herein is also intended to represent the unlabeled forms and isotopically labeled forms of the 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, ² H (deuterium, D), ³ H (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 ³ H, ¹³ C and ¹⁴ C. 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 assays distribution of tissue or substrate, or during radioactive treatment of patients.

The description also includes deuterated analogues of compounds of formula III in which 1 to n hydrogen atoms attached to the carbon atom are replaced by deuterium, where n represents 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 III 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.

Labeled or deuterium-substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) distribution, metabolism, and excretion (ADME) properties. 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 can generally 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 is understood that deuterium in this context is considered as a substituent in the compound of formula III.

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.

Pharmaceutically acceptable salts of the compounds described herein are also provided. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other materials that can be used to prepare a pharmaceutical composition suitable for pharmaceutical use in veterinary or human medicine.

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 salts or physiologically acceptable salts include, for example, inorganic acid salts and organic acid salts. In addition, when the compounds described herein are prepared as an acid addition salt, the free base can be prepared by making the acid salt solution alkaline. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, can be prepared by dissolving the free base in a suitable organic solvent and treating the solution with an acid in accordance with conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will recognize various synthetic techniques that can be used to prepare non-toxic pharmaceutically acceptable addition salts. 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, p-toluenesulfonic acid, salicylic acid and the like. Likewise, 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 (i.e. NH ₂ (alkyl)), dialkylamines (i.e. HN (alkyl) ₂ ), trialkylamines (i.e. N(alkyl) ₃ ), substituted alkylamines (i.e. NH ₂ (substituted alkyl)), di(substituted alkyl) amines (i.e. I^substituted alkyl) ₂ ), tri(substituted alkyl) amines (i.e. K(substituted alkyl) ₃ ), alkenyl amines (i.e. NH ₂ (alkenyl)), dialkenyl amines (i.e. HN (alkenyl) ₂ ), trialkenyl amines (i.e. N (alkenyl) ₃ ), substituted alkenyl amines (i.e. NH ₂ (substituted alkenyl)), di(substituted alkenyl) amines (i.e. HN (substituted alkenyl) ₂ ), tri(substituted alkenyl) amines (i.e. K(substituted alkenyl) ₃ , mono-, di-tricycloalkylamines (i.e. NH ₂ (cycloalkyl), HN(cycloalkyl) ₂ , N(cycloalkyl) ₃ ), mono-, di- and triarylamines (i.e. NH ₂ (aryl), HN(aryl) ₂ , N(aryl) ₃ ), 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.

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, carboxylic acid ester, cyano, guanidino, halogen, haloalkyl, haloalkoxy, 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 (for example, methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen atoms

- 7 045220 in 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. Unless otherwise indicated, when a group is described as optionally substituted, any substituents on the group are themselves unsubstituted. For example, in some embodiments, the term substituted alkyl refers to an alkyl group having one or more substituents, including hydroxyl, halogen, alkoxy, 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.

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. Unless any conventional vehicle or agent is incompatible with the active ingredient, its use in therapeutic compositions is contemplated. Additional active ingredients may also be included in the compositions.

List of abbreviations and abbreviations.

Abbreviation Meaning

°C Degree Celsius Ace Acetyl aq. Water ATP Adenosine triphosphate VOS Tert-butoxycarbonyl br widened B.S.A. Bovine serum albumin Cbz Carboxybenzyl C.O.D. Cyclooctadiene

- 8 045220

COPD Chronic obstructive pulmonary disease Cot Osaka type thyroid cancer Cp C,iclopentadienyl d Doublet DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethene DXM Dichloromethane dd Double doublet DEF N,N-diethylformamide DMF Dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene dt Doublet-triplet DTT Dithiothreitol ec ₅₀ Half-maximal effective concentration EGFR Epidermal growth factor receptor EKV equivalents ES/MS Electrospray mass spectrometry Et Ethyl FBS G Fetal bovine serum grams

HEPES 2-[4-(2-hydroxyethyl)piperazin-1yl]ethanesulfonic acid HPLC High Pressure Liquid Chromatography watch watch Hz Hertz IBD Inflammatory bowel disease i-pr J isopropyl Interaction constant (MHz)

- 9 045220

kg Kilogram LCMS Liquid chromatography-mass spectroscopy LPS Lipopolysaccharide M Molar m Multiplet M+ Mass peak M+H+ Mass peak plus hydrogen Me Methyl mg Milligram MHz Megahertz min Minute ml Milliliter mm Millimolar Millimole mmol MOPS 3-morpholinopropane-1-sulfonic acid MS Mass spectroscopy Ms Mezil nBu/Bu Butyl nl Nanoliter nm Nanometer NMR Nuclear magnetic resonance NP-40 Nonyl phenoxypolyethoxyethanol Ns Nozil Pd-C/ Pd/C Palladium on coal pg Pictogram Ph Phenyl PPTS Pyridinium p-toluenesulfonate PS Polystyrene p-TSOH/ pTSA p-toluene sulphate oxide

- 10 045220

Quartet

q.s.

RBF

Quantity sufficient to achieve the stated function

Round bottom flask

R.P.

Reverse phase

RPMI

Wednesday Roswell Park Memorial Institute ct

Room temperature

Singlet us.

saturated

TBAF

Tetra-n-butylammonium fluoride triplet

TBS tert-butyldimethylsilyl t-Bu

Tert-butyl

TS

Thiophene-2-carboxylate

TEA

Triethanolamine

Tf

Trifluoromethanesulfonyl

T.F.A.

Trifluoroacetic acid

THF

T ethrahydrofuran

Tr12

Tumor progression locus 2

TR-FRET

Ts

Time-resolved resonant fluorescence energy transfer

Tozil

Chemical shift (ppm) µl

Microliter µM Compound.

Micromolar

Provided herein are compounds that act as Cot modulators. In one aspect, there is provided a compound having the structure of Formula III:

where R ¹ represents hydrogen, -OR ⁷ , -N(R8)(R ⁹ ), -C(O)-R ⁷ , -S(O)2-R ⁷ , -C _1-9 alkyl, C _{2- 6} alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one to four Z ¹ ;

R ⁴ represents heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is non-4.

;

, halogen, -CN, -NO2, -OR ⁷ , -N(R ⁸ )(R ⁹ ), -S(O)-R ⁷ , -S(O)2R ⁷ ,

-C(O)OR ⁷ , -OC(O)OR ⁷ , -OC(O)N(R ¹⁰ )(R ¹¹ ), -C(O)N(R ⁷ )2, , C _2-6 alkynyl, C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, necessarily substituted with one to four Z

R ⁵ represents hydrogen, -S(O)2N(R ⁷ )2, -C(O)R ⁷ , -OC(O)-R ⁷ ,

-N(R ⁷ )C(O)(R ⁷ ), C _1-9 alkyl, C _2-6 alkenyl, aryl, heterocyclyl or heteroaryl;

where each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁵ ;

R ⁶ represents hydrogen, -C(O)-R ⁷ , -C(O)OR ⁷ , -C(O)N(R ⁷ ) ₂ , C _1-9 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁶ ;

- 11 045220 each R ⁷ independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl,

C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁷ ;

R ⁸ and R ⁹ are each independently hydrogen, -S(O)2R ¹⁰ , -C(O)-R ¹⁰ , -C(O)OR ¹⁰ , -C(O)N(R ¹⁰ )(R ¹¹ ), C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl;

wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to four Z ⁸ ;

R ¹⁰ and R ¹¹ are each independently hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl, where each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ^1b ;

each Z ¹ , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ independently represents hydrogen, oxo, halogen, -NO2, -N ₃ , -CN, thioxo, C _1-9 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)-R ¹² , -C(O)OR ¹² , - C(O)-N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , -N(R ¹² )C(O)R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ) , -NR ¹² S(O)2N(R ¹³ )(R ¹⁴ ), -NR ¹² S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)-N(R ¹³ ) (R ¹⁴ ), -P(O)(OR ¹² )2, -OP(O)(OR ¹² )2, -CH2P(O)(OR ¹² )2, -OCH2P(O)(OR ¹² )2, - C(O)OCH2P(O)(OR ¹² )2, -P(O)(R ¹² )(OR ¹² ), -OP(O)(R ¹² )(OR ¹² ), -CH2P(O)(R ¹² )(OR ¹² ), -OCH2P(O)(R ¹² )(OR ¹² ), -C(O)OCH2P(O)(R ¹² )(OR ¹² ), -P(O)(N(R ¹² )2 )2, -OP(O)(N(R ¹² h)2, -CH2P(O)(N(R ¹² h)2, -OCH2P(O)(N(R ¹² h)2, -C(O) OCH2P(O)(N(R ¹² )2)2, -P(O)(N(R ¹² )2)(OR ¹² ), -OP(O)(N(R ¹² )2)(OR ¹² ), -CH2P(O)(N(R ¹² )2)(OR ¹² ), -OCH2P(O)(N(R ¹² )2)(OR ¹² ), -C(O)OCH2P(O)(N(R ¹²⁾ )2)(OR ¹² ), -P(O)(R ¹² )(N(R ¹² )2), -OP(O)(R ¹² )(N(R ¹² )2), -CH2P(O)( R ¹² )(N(R ¹² )2), -OCH2P(O)(R ¹² )(N(R ¹² )2), -C(O)OCH2P(O)(R ¹² )(N(R ¹² )2 ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O)2R ¹² or -S(O)2N(R ¹³ )(R ¹⁴ );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1a groups;

each Z ^1a independently represents oxo, halogen, thioxo, -NO ₂ , -CN, -N ₃ , C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _{1- 8} haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)R ¹² , -C(O)OR ¹² , -C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹³ ) (R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , -N(R ¹² )-C(O)R ¹² , -N(R ¹² )C(O)O(R ¹² ), -N (R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -N(R ¹² )S(O)2-N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)OR ¹² , -OC(O)-N(R ¹³ )( R ¹⁴ ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(OhR ¹² or -S(O)2N(R ¹³ )(R ¹⁴ );

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups;

each R ¹² independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups;

R ¹³ and R ¹⁴ are each independently hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one four groups Z ^1b ; and each Z ^1b independently represents oxo, thioxo, hydroxy, halogen, -NO ₂ , -N ₃ , -CN, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C _1-9 alkyl), -O(C _2-6 alkenyl), -O(C _2-6 alkynyl), -O(C _3-15 cycloalkyl ), -O(C _1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl), -NH2, -NH(C _1-9 alkyl), -NH(C _2-6 alkenyl), -NH(C _2-6 alkynyl), -NH(C _3-15 cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl) , -N(C _1-9 alkyl) ₂ , -N(C _3-15 cycloalkyl) ₂ , -N(C _2-6 αlkenyl) ₂ , -N(C _2-6 alkynyl) ₂ , -N(C _{3 -15} cycloalkyl) ₂ , -N(C _1-8 haloalkyl) ₂ , -N(aryl) ₂ , -N(heteroaryl) ₂ , -N(heterocyclyl) ₂ , -N(C _1-9 αlkyl)(C _{2 -6} alkenyl),

-N(C _1-9 alkyl) (C _2-6 alkynyl),

-N(C _1-9 αlkyl)(C _3-15 cycloalkyl),

-N(C _1-9 alkyl)(C _1-8 haloalkyl),

-N(C _1-9 alkyl)(aryl), -N(C _1-9 alkyl) ₍ heteroaryl), -N(C _1.9 αlkyl)(heterocyclyl), -C(O)(C _1-9 alkyl) ),

-C(O)(C _2-6 αlkenyl), -C(O)(C _2-6 alkynyl), -C(O)(C _3-15 cycloalkyl), -C(O)(C _1-8 haloalkyl) ), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C _1-9 alkyl), -C(O)O( C _2-6 αlkenyl), -C(O)O(C _2-6 alkynyl),

-C(O)O(C _3-15 cycloalkyl),

-C(O)O(C _1-8 haloalkyl),

-C(O)O(aryl),

-C(O)O(heterocyclyl), -C(O)NH2, -C(O)NH(C _1-9 alkyl), -C(O)NH(C _2-6 alkenyl),

-C(O)NH(C _3-15 cycloalkyl), -C(O)NH(heterocyclyl), -C(O)N(C _3-15 cycloalkyl) ₂ , -C(O)N (heterocyclyl) ₂ , -NHC(O)(C _3-15 cycloalkyl), -NHC(O)(heterocyclyl),

-C(O)NH(C _1-8 haloalkyl), -C(O)NH(aryl),

-C(O)N(C _1-9 alkyl) ₂ , -C(O)N(C _2-6 alkenyl) ₂ ,

-C(O)N(C _1-8 haloalkyl) ₂ , -C(O)N(aryl) ₂ ,

-NHC(O)(C _1-9 alkyl), -NHC(O)(C _2-6 alkenyl),

-NHc(O)(C _1-8 haloalkyl), -NHC(O)(aryl),

-NHC(O)O(C _1-9 alkyl), -NHC(O)O(C ₂ .6αalkenyl),

-C(O)O(heteroaryl), -C(O)NH(C _2-6 alkynyl), -C(O)NH(heteroaryl), -C(O)N(C _2-6 alkynyl) ₂ ,

-C(O)N (heteroaryl) ₂ ,

-NHC(O)(C _2-6 alkynyl),

-NHC(O)(heteroaryl), -NHC(O)o(C _2-6 alkynyl),

- 12 045220

-NHC(O)O(C _3-15 cycloalkyl), -NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl),

-NHC(O)O(heterocyclyl), -NHC(O)NH(C _1-9 alkyl), -NHC(O)NH(C _2-6 alkenyl), -NHC(O)NH(C _2-6 alkynyl ),

-NHC(O)NH(C _3-15 cycloalkyl), -NHC(O)NH(C _1-8 haloalkyl), -NHC(O)NH(aryl),

-NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C _1-9 alkyl), -S(C _2-6 alkenyl),

-S(C _2-6 alkynyl), -S(C _3-15 cycloalkyl), -S(C _1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS (O)(C _1-9 alkyl), -N(C _1-9 alkyl)(S(O)(C _1-9 alkyl), -S(O)N(C _1-9 aaKua) ₂ , -S (O)(C _1-9 alkyl),

-S(O)(NH)(C _1-9 alkyl), -S(O)(C _2-6 alkenyl), -S(O)(C _2-6 alkynyl), -S(O)(C _{3 -15} cycloalkyl),

-S(O)(C _1-8 haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O) ₂ (C _{1- 9} alkyl), ^(O) ₂ (C _2-6 alkenyl), -S(O) ₂ (C _2-6 alkynyl), -S(O) ₂ (C _3-15 cycloalkyl), -S(O) ₂ (C _1-8 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _{1- 9} alkyl) or -S(O) ₂ N(C _1-9 alkyl) ₂ ;

wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four halogens, C _1-9 alkyls, C _1-8 haloalkyls, -OH, -NH2, -NH(C _1-9 alkyl), -NH(C _{3- 15} cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C _1-9 alkyl) ₂ , -N(C _3-15 cycloalkyl) ₂ , -NHC(O)(C _3-15 cycloalkyl), -NHC(O)(C _1-8 haloalkyl),

-NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C _1-9 alkyl),

-NHC(O)O(C _2-6 alkynyl), -NHC(O)O(C _3-15 cycloalkyl), -NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl ), NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C _1-9 alkyl), -S(O)(NH)(C _1-9 alkyl) , S(O) ₂ (C _1-9 alkyl), -S(O) ₂ (C _3-15 cycloalkyl), -S(O) ₂ (C _1-8 haloalkyl), -S(O) ₂ (aryl ), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-9 alkyl), -S(O) ₂ N(C _1-9 alkyl ) ₂ , -O(C _3-15 cycloalkyl), -O(C _1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl) or -O(C _1-9 alkyl) ;

W, X and Y are each independently N or C;

n is 1, 2 or 3;

each aryl independently contains from 6 to 10 carbon atoms in the ring;

each heteroaryl independently contains from 1 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, S and O; and each heterocyclyl independently contains from 2 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, S and O;

or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof.

In some embodiments, W is N, X is NZ ³ , and Y is CZ ³ .

In some embodiments, the compound of Formula III is represented by Formula VIIIA:

where Z ³ , R ¹ , R ⁴ , R ⁵ and R ⁶ are as defined herein, and Z ⁹ represents hydrogen, halogen, -CN, or -OR ¹² .

In some embodiments, R ⁶ is hydrogen.

In some embodiments, Z ³ is hydrogen or C _1-9 alkyl;

wherein said C _1-9 alkyl may be optionally substituted with one to four substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)OR ¹² , -N(R ¹³ )(R ¹⁴ ) , -N(R ¹³ )2(R ¹⁴ ) ⁺ , C1-9alkyl, _C6-10 aryl, heterocyclyl and heteroaryl.

In some embodiments, Z ³ is C _3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein said C _3-15 cycloalkyl or heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)OR ¹² , -N(R ¹³ )(R ¹⁴ ) , -N(R ¹³ )2(R ¹⁴ ) ⁺ , C1-9alkyl, _C1-8 haloalkyl, _C1-8 hydroxyalkyl, _C3-15 cycloalkyl, heterocyclyl and heteroaryl.

In some embodiments, Z ³ is hydrogen, C _1-9 alkyl, C _3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein said C _1-9 alkyl, C _3-15 cycloalkyl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of oxo, -CN, halogen, -OR ¹² , -C(O)OR ¹² , -C(O)-N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2 (R ¹⁴ ) ⁺ , C _1-9 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl;

Z ⁹ represents hydrogen;

R ¹ represents C _1-9 alkyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl;

wherein said C _1-9 alkyl, heterocyclyl, aryl or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² ,

- 13 045220

-S(O)2R ¹² , C ₁ . ₉ alkyl, ^^haloalkyl, heterocyclyl and aryl;

R ⁴ represents heterocyclyl or heteroaryl;

wherein said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ),

C ₁ . ₉ αlkyl, C ₁ . ₈ haloalkyl and heterocyclyl;

R ⁵ is -CN, halogen, -OR ⁷ or -S(O)2R ⁷ ;

R ⁶ represents hydrogen;

each R ⁷ is independently C ₁ . ₉ αlkyl;

where the specified C ₁ . ₉ alkyl may be optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, halogen, -O(C ₁ . ₉ alkyl) and aryl;

each R ¹² independently represents hydrogen, C ₁ . ₉ αlkyl or heterocyclyl;

where the specified C ₁ . _{The 9} alkyl may be optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, halogen, -O(C _{1 9} alkyl) and aryl.

In some embodiments, Z ³ is C3.15 cycloalkyl, optionally substituted with one to four substituents independently selected from the group consisting of -CN, halogen, -C(O)-N(R ¹³ )(R ¹⁴ ), C1. ₉ αlkyl, C ₁ . ₈ haloalkyl, C ₁ . ₈ hydroxyalkyl, C ₃ . ₁₅ cycloalkyl and heteroaryl.

In some embodiments, Z ³ is a heterocyclyl optionally substituted with one to four substituents independently selected from the group consisting of -OR ¹² , -C(O)OR ¹² , C ₁ . ₉ alkyl, C ₁ . ₈ haloalkyl, C ₁ . ₈ hydroxyalkyl and heterocyclyl.

In some embodiments, R ¹ is C1.9alkyl, C3.15cycloalkyl, heterocyclyl, aryl, or heteroaryl; and said C1.9αalkyl, C3.15cycloalkyl, heterocyclyl, aryl or heteroaryl may be optionally substituted with one to four substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , C1. ₉ alkyl and aryl.

In some embodiments, R ¹ is -OR ⁷ , C1.9αalkyl, C3.15cycloalkyl, heterocyclyl, aryl, or heteroaryl; and said C1.9 alkyl, heterocyclyl, aryl or heteroaryl may be optionally substituted with one to four substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , -S(O)2R ¹² , C1. ₉ αlkyl, C ₁ . ₉ haloalkyl, C ₃ . ₁₅ cycloalkyl, heterocyclyl and aryl, where the indicated C ₃ . ₁₅ cycloalkyl may be optionally substituted with one to four substituents independently selected from the group consisting of C ₁ . ₉ alkyl and C ₁ . ₉ haloalkyl.

In some embodiments, R ¹ is C1.9alkyl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , -S(O)2R ¹² , C3. ₁₅ cycloalkyl, heterocyclyl and aryl, where the indicated C ₃ . ₁₅ cycloalkyl or heterocyclyl may be optionally substituted with one to four substituents independently selected from the group consisting of C ₁ . ₉ alkyl and C ₁ . ₉ haloalkyl.

In some embodiments, R ¹ is C ₃ . ₁₅ cycloalkyl, heterocyclyl or heteroaryl;

wherein said heterocyclyl or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , C ₁ . ₉ alkyl and aryl.

In some embodiments, R ¹ is R ¹ is heterocyclyl or heteroaryl, wherein said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen and C ₁ . ₉ alkyl.

In some embodiments, R ¹ is aryl;

wherein said aryl may be optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , C ₁ . ₉ alkyl and aryl.

In some embodiments, R ¹ is aryl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OR ¹² and C ₁ . ₉ αlkyl.

In one embodiment, R ¹ is (1S,3S,5S,7S)-adamantan-2-yl, (R)-1-phenylethyl, (R)-1-phenylpropyl, (R)-1-phenylpropyl-1 ,2,2,3,3,3-d6, (R)-1-phenylpropyl-2,2,3,3,3-d5, (R)-2-cyano-1-phenylethyl, (R)-2 -hydroxy-1-phenylethyl, (R)-2-hydroxy-2-methyl-1-phenylpropyl, (R)-2methoxy-1-phenylethyl, (R)-3-piano-1-phenylpropyl, (R)-3 -fluoro-1-phenylpropyl, (R)-3-hydroxy-1phenylpropyl, (S)-1-phenylpropyl-2,2,3,3,3-d5, (S)-2-cyano-1-phenylethyl, ( S)-2-hydroxy-1-phenylethyl, (S)2-hydroxy-2-methyl-1-phenylpropyl, (S)-3-cyano-1-phenylpropyl, (S)-3-hydroxy-1-phenylpropyl, 1phenylpropyl-2,2,3,3,3-d5, 2-cyano-1-phenylethyl, 3,3-dimethyltetrahydro-2H-pyran-4-yl, 3,4-dichloro-2fluorophenyl, 3,4-difluorophenyl, 3-chloro-2,6-difluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-methoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-1- phenylpropyl, 5,6-difluoropyridin3-yl, 5-chloro-6-fluoropyridin-3-yl, 5-chloropyridin-3-yl, cycloheptyl, cyclohexyl, neopentyl, neopentyl-1,1-d2, (1-(difluoromethyl) cyclopropyl)methyl, (1-methylcyclobutyl)methyl, (1R,5S)-bicyclo[3.1.0]hexan-6-yl, (1R,5S,6r)-3-oxabicyclo[3.1.0]hexan-6-yl , (R)-2,2-dimethyltetrahydrofuran-3-yl,

- 14 045220 (R)-3,3-dimethylbutan-2-yl, (R)-3,3-dimethyltetrahydro-2H-niran-4-yl, (R)-cyclopropyl(phenyl)methyl, (S)-2 ,2-dimethyltetrahydrofuran-3-yl, (8)-3,3-dimethyltetrahydro-2H-pyran-4-yl, 2,2-dimethylpropyl1,1-d2, 2,2-dimethyltetrahydrofuran-3-yl, 2-cyano -2-methylpropyl, 2-methyl-2-phenylpropyl, 3-chloro-2,2-dimethylpropyl, 3-cyano-2,2-dimethylpropyl, 3-hydroxy-2,2-dimethylpropyl, tert-butoxy or tetrahydro-2H-pyran -4-il.

In one embodiment, R ¹ is (18,38,58,78)-adamantan-2-yl, (R)-1-phenylethyl, (R)-1-phenylpronyl, (R)-1-phenylpropyl-1 ,2,2,3,3,3-d6, (R)-1-phenylpropyl-2,2,3,3,3-d5, (R)-2-cyano-1-phenylethyl, (R)-2 -hydroxy-1-phenylethyl, (R)-2-hydroxy-2-methyl-1-phenylpropyl, (R)-2methoxy-1-phenylethyl, (R)-3-cyano-1-phenylpropyl, (R)-3 -fluoro-1-phenylpronyl, (R)-3-hydroxy-1-phenylpropyl, (S)-1-phenylpropyl-2,2,3,3,3-d5, (8)-2-cyano-1-phenylethyl, ( 8)-2-hydroxy-1-phenylethyl, (S)2-hydroxy-2-methyl-1-phenylpropyl, (8)-3-cyano-1-phenylpropyl, (8)-3-hydroxy-1-phenylpropyl, 1phenylpronyl-2,2,3,3,3-d5, 2-cyano-1-phenylethyl, 3,3-dimethyltetrahydro-2H-pyran-4-yl, 3,4-dichloro-2fluorophenyl, 3,4-difluorophenyl, 3-chloro-2,6-difluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-2-methoxyphenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methoxyphenyl, 3-chlorophenyl, 3-cyano-1- phenylpropyl, 5,6-difluoropyridin3-yl, 5-chloro-6-fluoropyridin-3-yl, 5-chloropyridin-3-yl, cycloheptyl, cyclohexyl, neopentyl, neopentyl-1,1-d2 or tetrahydro-2H-pyran- 4-il.

In another embodiment, R ¹ is (R)-1-phenylethyl, (R)-1phenylpropyl, 3,4-dichloro-2-fluorophenyl, 3-chloro-2-fluorophenyl, 3-chloro-4-fluorophenyl, 5. 6-difluoropyridin3-yl or neopentyl.

In one embodiment, R ⁴ is heterocyclyl or heteroaryl; and said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _{1 -9} alkyl, C _1-8 haloalkyl and heterocyclyl.

In some embodiments, R ⁴ is heteroaryl, optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl.

In some embodiments, R ⁴ is heterocyclyl, optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl.

In some embodiments, R ⁴ is an optionally substituted bicyclic heterocyclyl or an optionally substituted bicyclic heteroaryl.

In some embodiments, R ⁴ is an optionally substituted bicyclic heteroaryl.

R ⁴ represents

- 15 045220

where Z ⁴ is as defined herein and q is 0, 1, 2, 3 or 4.

In some embodiments, R ⁴ is

'where Z ⁴ is as defined herein and q is O, 1,2, 3 or 4.

In some embodiments, each Z ⁴ is independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl.

In some embodiments, each Z ⁴ is independently selected from the group consisting of -CN, halogen, -OR ¹² and C _1-9 alkyl.

In some embodiments, R ⁴ is an optionally substituted monocyclic heteroaryl. In some embodiments, R ⁴ is

^N ' where Z ⁴ is as defined herein and q is 0, 1, 2, 3, or 4. In some embodiments, R ⁴ is

- 16 045220

z ⁴

Z ⁴ is ' where Z ⁴ is as defined herein.

In some embodiments, Z ³ is

7 ^{4 N} 7 ⁴

OR ^ζ

In some embodiments, each Z ⁴ is independently selected from the group consisting of -CN, halogen, -OR ¹² and C1-9 alkyl. R ¹ is C1-9 alkyl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , C _1-9 alkyl and aryl. R ⁶ represents hydrogen. R ⁵ represents halogen or cyano.

According to one embodiment, R ⁴ is

- 17 045220

- 18 045220

- 19 045220

According to one embodiment, R ⁴ is

- 20 045220

- 21 045220

WW WW I

II σννν ww • ^/ “Y ^V JVVV jwv

I ww

X A X X- δό

WW ww ww ww ww I I I WW I WW οό уЯ $^b ζά сЯ — — -p — d5 o5. co o5 c6 co ώ5 th -У У °ΐ όδ

Ν Cl Cl Ν Ν Ν

According to one embodiment, R ⁴ is

- 22 045220

- 23 045220

, or .

According to one embodiment, R ⁴ is

- 24 045220

represents

In some embodiments, R ⁴ is

According to one implementation of R

- 25 045220

implementations R ⁵ represents hydrogen, halogen, -CN, -OR ⁷ ,

According to some options

C _1-9 alkyl, C _2-6 alkenyl,

-S(O)-R ⁷ , -S(O)2R ⁷ , -S(O)2N(R ⁷ ) ₂ , -C(O)R ⁷ , -C(O)N(R ⁷ ),,

C _2-6 alkynyl,

C _3-15 cyclodlkyl, aryl, heterocyclyl or heteroaryl; where each C _1-9 αlkyl, C _2-6 alkenyl, C _2-6 αlkynyl,

C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl may be optionally substituted with one to four Z ⁵ .

In some embodiments, R ⁵ is hydrogen, halogen, -CN, -C(O)R ⁷ or heteroaryl. In one embodiment, R ⁵ is -CN, halogen, or -OR ⁷ . In some embodiments, R ⁵ is hydrogen, halogen, -CN, -C(O)R ⁷ , -OR ⁷ , -S(O) ₂ R ⁷ or heteroaryl. In one embodiment, R ⁵ is a halo gene.

In some embodiments, R ⁵ is N-pyrazol-4-yl, 1-hydroxyethyl, 1-methyl-1H-pyrazol-4-yl, 4-(acetylamino)phenyl, 6-fluoropyridin-3-yl, methyl acetyl, bromo, chlorine, cyano, cyclopropyl, dimethylaminocarbonyl, ethynyl, fluorine, iodine, methoxy, methyl, hydroxyl, phenyl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl, acetyl, methylsulfonyl or trifluoromethyl. In one embodiment, R ⁵ is chlorine.

In general, specific compounds exemplified herein were named using ChemBioDraw Ultra. However, it should be understood that other names may be used to identify compounds of the same structure. In particular, compounds may also be named using other nomenclature systems and symbols generally accepted in the field of chemistry, including, for example, the Chemical Abstract Service (CAS) and the International Union of Pure and Applied Chemistry (IUPAC). Other compounds or radicals may be called by common names or by systematic or unsystematic names.

The compositions provided herein, which include a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, may include racemic mixtures or mixtures containing an enantiomeric excess of one enantiomer or individual

- 26 045220 diastereomers or diastereomeric mixtures. All such isomeric forms of said compounds are expressly included herein in the same manner as if each isomeric form had been specifically and individually identified.

Some embodiments provide a compound of formula III or VIIIA, wherein R ⁶ is

where each R ¹² independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C3 _- l ₅ cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups; and each Z ^1b independently represents oxo, thioxo, hydroxy, halogen, -NO ₂ , -N ₃ , -CN, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C _1-9 alkyl), -O(C _2-6 alkenyl), -O(C _2-6 alkynyl), -O(C _3-15 cycloalkyl ), -O(C _1-8 haloalkyl), -O(aryl), -O(heteroαrul), -O(heterocyclyl), -NH2, -NH(C _1-9 alkyl), -NH(C _2-6 alkenyl), -NH(C _2-6 alkynyl), -NH(C _3-15 cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl) , -N(C _1-9 alkyl) ₂ , -N(C _3-15 cycloalkyl) ₂ , -N(C _2-6 alkenyl) ₂ , -N(C _2-6 alkynyl) ₂ , -N(C _{3 -15} cycloalkyl) ₂ , -N(C _1-8 haloalkyl) ₂ , -N(αryl) ₂ , -N(heteroaryl) ₂ , -N(heterocyclyl) ₂ , -N(C _1-9 alkyl)(C _{3 -15} cycloalkyl), -N(C _1-9 alkyl)(C _2-6 alkenyl), -N(C _1-9 alkyl)(C _2-6 alkynyl), -N(C _1-9 alkyl)(C _3-15 cycloalkyl),

-N(C _1-9 alkyl)(C _1-8 haloalkyl), -N(C _1-9 alkyl)(aryl), -N(C _1-9 alkyl)(heteroaryl), -N(C _1-9 alkyl)(heterocyclyl), -C(O)(C _1-9 αlkyl), -C(O)(C _2-6 alkenyl), -C(O)(C _2-6 alkynyl), -C(O) (C _3-15 cycloalkyl), -C(O)(C _1-8 haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C (O)O(C _1-9 alkyl), -C(O)O(C _2-6 αlkenyl), -C(O)O(C _2-6 alkyl), -C(O)O(C _{3- 15} cycloalkyl), -C(O)O(C _1-8 haloalkyl), -C(O)O(aryl), -C(O)O(heteroaryl), -C(O)O(heterocyclyl), -C (O)NH ₂ , -C(O)NH(C _1-9 alkyl), -C(O)NH(C _2-6 alkenyl), -C(O)NH(C _2-6 alkynyl), -C (O)NH(C _3-15 cycloalkyl), -C(O)NH(C _1-8 haloalkyl), -C(O)NH(aryl), -C(O)NH(heteroaryl), -C(O )NH(heterocyclyl), -C(O)N(C _1-9 alkyl) ₂ ,

-C(O)N(C _3-15 cycloalkyl) ₂ , -C(O)N(C _2-6 alkenyl) ₂ , -C(O)N(C _2-6 alkunyl) ₂ , -C(O) N(C _3-15 cycloalkyl) ₂ ,

- 27 045220

-C(O)N(C _1-8 haloalkyl) ₂ ,

-C(O)N(aryl) ₂ ,

-NHC(O)(C _1-9 alkyl), -NHC(O)(C _2-6 alkenyl),

-NHc(o)(c _1-8 haloalkyl), -NHC(O)(aryl),

-NHC(O)O(C _1-9 alkyl), -NHC(O)O(C _2-6 alkenyl),

-C(O)N(heteroaryl) ₂ ,

-KNS(O)(C _2-6 alkynyl),

-NHC(O)(heteroaryl),

-NHC(O)O(C _2-6 alkynyl),

-C(O)N(heterocyclyl) ₂ ,

-NHC(O)(C _3-15 cycloalkyl),

-NHC(O)(heterocyclyl),

-NHC(O)O(C _3-15 cycloalkyl),

-NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH (C1-9alkyl), -NHC(O)NH(C2-6alkenyl), -NHC(O)NH(C2-6alkynyl), -KHC(O)KH(C3-15Cycloalkyl), -NHC(O)NH(C _1-8 haloalkyl), -NHC(O)NH(aryl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C _1-9 alkyl), - S(C _2-6 alkenyl), -S(C _2-6 alkynyl), -S(C _3-15 cycloalkyl), -S(C _1-8 haloalkyl), -8(aryl), -S(heteroαryl) , -S(heterocyclyl), -NHS(O)(C _1-9 alkyl), -N(C _1-9 alkyl)(S(O)(C _1-9 alkyl), -S(O)N(C _1-9 alkyl) ₂ , -S(O)(C _1-9 alkyl), -S(O)(NH)(C _1-9 alkyl), -S(O)(C _2-6 alkenyl), - S(O)(C _2-6 alkynyl), -S(O)(C _3-15 cycloalkyl), -S(O)(C _1-8 haloalkyl), -8(O)(aryl), -S( O)(heteroaryl), -S(O)(heterocyclyl), -S(O) ₂ (C _1-9 alkyl), -S(O) ₂ (C _2-6 alkenyl), -S(O) ₂ ( C _2-6 alkynyl), -S(O) ₂ (C _3-15 cycloalkyl), -S(O) ₂ (C _1-8 haloalkyl), -8(O)2(aryl), -S(O) ₂ (heteroaryl), -8(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-9 αlkyl) or -S(O) ₂ N(C _1-9 alkyl) ₂ ;

wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four halogens, C _1-9 alkyls, C _1-8 haloalkyls, -OH, -NH2, -NH(C _1-9 alkyl), -NH(C _{3- 15} cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N(C _1-9 alkyl) ₂ , -N(C _3-15 cycloalkyl) ₂ , -NHC(O)(C _3-15 cycloalkyl), -NHC(O)(C _1-8 haloalkyl),

-NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)O(C _1-9 alkyl), -NHC(O)O(C _{2 -6} alkynyl), -NHC(O)O(C _3-15 cycloalkyl), -NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O( heteroaryl), -NHC(o)o(heterocyclyl), -NHC(O)NH(C _1-9 alkyl), -S(O)(NH)(C _1-9 alkyl), S(O) ₂ (C _1-9 alkyl), -S(O) ₂ (C _3-15 cycloalkyl), -S(O) ₂ (C _1-8 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -8(O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-9 alkyl), -S(O) ₂ N(C _1-9 alkyl) ₂ , -O(C _{3 -15} cycloalkyl), -O(C _1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl) or -O(C _1-9 alkyl).

O.P<—OR ¹²

OR ¹²

In some embodiments, R6 is ^R12, independently as defined herein.

’ and everyone

ABOUT

In some embodiments, R6 is

R6 also includes all individual stereoisomers and mixtures thereof, including, but not limited to, chirality at the phosphorus atom, such as in the representative fragments above.

Therapeutic applications of the compounds.

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, i.e. causing regression of clinical symptoms (eg, improving disease status, providing partial or complete remission of a disease or condition, enhancing the effect of another drug, delaying disease progression, 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, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof means an amount sufficient to provide a treatment effect when administered to a subject to provide a therapeutic effect, such as improving symptoms.

- 28 045220 ptoms or slowing the progression of the 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 Cot 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 the activity of Cot or variants thereof refers to a decrease in the activity of Cot as a direct or indirect response to the presence of a compound of the present application relative to the activity of Cot in the absence of a compound of the present application. Cot inhibition refers to a decrease in Cot activity as a direct or indirect response to the presence of a compound described herein relative to Cot activity in the absence of a compound described herein.

The compounds and compositions described herein can be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal regimen and/or dosage for Cot 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 compounds and compositions described herein 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.

The compounds disclosed herein are suitable for the treatment of diseases or conditions mediated by Cot. Non-limiting examples of diseases or conditions mediated by Cot include, but are not limited to, cancer, diabetes and inflammatory diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, misregulated TNF expression and graft rejection.

In some embodiments, the Cot-mediated disease or condition is a solid tumor. In specific embodiments, the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatic cell cancer, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, cancer head and neck, melanoma, neuroendocrine cancers, central nervous system cancers, brain tumors (eg, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer.

In some embodiments, the Cot-mediated disease or condition is diabetes, which includes any metabolic disorder characterized by impaired insulin production and glucose tolerance. In some embodiments, diabetes includes type 1 and type 2 diabetes, gestational diabetes, prediabetes, insulin resistance, metabolic syndrome, impaired fasting glucose, and impaired glucose tolerance. Type 1 diabetes is also known as insulin-dependent diabetes mellitus (IDDM). Type 2 is also known as non-insulin dependent diabetes mellitus (NIDDM).

In some embodiments, the Cot-mediated disease or condition is an inflammatory disease or LPS-induced endotoxin shock. In some embodiments, the disease is an autoimmune disease. In certain specific embodiments, the autoimmune disease is systemic lupus erythematosus (SLE), myesthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), inflammatory bowel disease (IBD), sepsis, psoriasis, Sjögren's syndrome, autoimmune hemolytic anemia, asthma or chronic obstructive pulmonary disease (COPD), ankylosing spondylitis, acute gout and ankylosing spondylitis, reactive arthritis, single-joint arthritis, osteoarthritis, gouty arthritis, juvenile arthritis, juvenile rheumatoid arthritis with systemic onset, juvenile rheumatoid arthritis or psoriatic arthritis. In other embodiments, the disease is inflammation. In other embodiments, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

- 29 045220

In some embodiments, the disease or condition mediated by Cot is inflammatory bowel disease (IBD). As used herein, the term inflammatory bowel disease or IBD is a general term describing inflammatory diseases of the gastrointestinal tract, the most common forms of which are ulcerative colitis and Crohn's disease. Other forms of IBD that can be treated with the compounds, compositions and methods described herein include diversion colitis, ischemic colitis, infectious colitis, chemical colitis, microscopic colitis (including collagenous colitis and lymphocytic colitis), atypical colitis, pseudosembrane colitis, fulminant colitis, autistic enterocolitis, indeterminate colitis, Behçet's disease, gastroduodenal Crohn's disease CD, nausea, ileitis, ileocolitis, Crohn's disease (granulomatous colitis), irritable bowel syndrome, mucositis, radiation-induced enteritis, short bowel syndrome, celiac enteropathy, gastric ulcers, diverticulitis and chronic diarrhea.

Treatment or prevention of IBD also includes improving or reducing one or more IBD symptoms. As used herein, the term IBD symptoms refers to detected symptoms such as abdominal pain, diarrhea, rectal bleeding, weight loss, fever, loss of appetite and other more serious complications such as dehydration, anemia and exhaustion. A number of such symptoms can be analyzed quantitatively (eg, weight loss, fever, anemia, etc.). Some symptoms are easily determined by a blood test (such as anemia) or a test that detects the presence of blood (such as rectal bleeding). The term wherein said symptoms are reduced refers to a qualitative or quantitative reduction in detectable symptoms, including, but not limited to, a detectable effect on the rate of recovery from illness (eg, rate of weight gain). Diagnosis is usually determined by endoscopic observation of the mucosa and pathological examination of endoscopic biopsy specimens.

The course of IBD varies and is often associated with periods of intermittent remission and exacerbation of the disease. Various methods have been described to characterize disease activity and severity of IBD, as well as response to treatment in patients with IBD. Treatment in accordance with the present description is generally applicable to a subject having IBD of any level or degree of disease activity.

In some embodiments, the disease or condition treated by administration of a compound and composition described herein includes acute gout and ankylosing spondylitis, allergic disorders, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), amyotrophic lateral sclerosis and multiple sclerosis, atherosclerosis, bacterial infections , pain from bone cancer and pain due to endometriosis, BRAF-resistant melanoma, brain glioma or pituitary adenoma, burns, bursitis, anal cancer, endocrine cancer, kidney or ureter cancer (eg, renal cell carcinoma of the renal pelvis ), penile cancer, small intestinal cancer, thyroid cancer, urethral cancer, blood cancers such as acute myeloid leukemia, tongue cancers, cervical carcinoma, endometrial carcinoma, fallopian tube carcinoma, renal pelvis carcinoma, vaginal carcinoma or carcinoma vulva, chronic myeloid leukemia, chronic or acute leukemia, chronic pain, classic Bartter's syndrome, catarrhal conjunctivitis, coronary heart disease, cutaneous or intraocular melanoma, dermatitis, dysmenorrhea, eczema, endometriosis, familial adenomatous polyposis, fibromyalgia, fungal infections, gout, gynecological tumors, uterine sarcoma, fallopian tube carcinoma, headache, hemophilic arthropathy, Parkinson's disease, AIDS, herpes zoster, Hodgkin's disease, Huntington's syndrome, hyperprostaglandin E syndrome, influenza, iritis, juvenile arthritis, juvenile rheumatoid arthritis with systemic onset, juvenile rheumatoid arthritis , low back and neck pain, lymphocytic lymphomas, myofascial disorders, myositis, neuralgia, neurodegenerative disorders such as Alzheimer's disease, neuroinflammatory diseases, neuropathic pain, vulvar carcinoma, Parkinson's disease, childhood tumor, pulmonary fibrosis, rectal cancer, rhinitis, sarcoidosis, soft tissue sarcoma, scleritis, skin cancer, solid tumors in children, spinal axis tumors, dislocations and sprains, stomach cancer, stroke, subacute and chronic musculoskeletal pain syndromes such as bursitis, surgical or dental procedures, influenza-related symptoms or other viral infections, synovitis, toothache, ulcers, uterine cancer, uterine sarcomas, uveitis, vasculitis, viral infections, viral infections (eg, influenza) and wound healing.

Criteria suitable for assessing disease activity in patients with ulcerative colitis can be found, for example, in Truelove et al. (1955) Br Med J 2:1041-1048.) Using these criteria, disease activity can be characterized in a subject having IBD as moderate disease activity or severe disease activity. Subjects who do not meet all criteria for severe disease activity and who exceed the criteria for moderate disease activity are classified as having moderate disease activity.

Measures to determine the effectiveness of IBD treatment in clinical practice have been described and include, for example, the following: symptom control; closure of the fistula; necessary degree of cortico

- 30 045220 steroid therapy; and improving quality of life. Health-related quality of life (HRQL) can be assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ), which is widely used in clinical practice to assess the quality of life in a subject with IBD. (See Guyatt et al., 1989) Gastroenterology 96:804-810.) In some embodiments, the disease or condition is an immune-mediated liver injury, disease or condition. Tpl2 may mediate immune diseases or liver conditions. (Vyrla et al., The Journal of Immunology, 2016, 196; Perugorria et al., Hepatology, 2013;57:1238-1249)

In some embodiments, the disease or condition mediated by Cot is alcoholic hepatitis. Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver failure that develops in subjects with chronic and active alcohol abuse. (See Akriviadis E. et al., Ann Gastroenterol. 2016 AprJun; 29(2): 236-237). Alcoholic hepatitis can cause cirrhosis and fibrosis of liver cells. Glucocorticoids (eg, prednisolone) and phosphodiesterase inhibitors (eg, pentoxifylline) may be used to treat alcoholic hepatitis. The compounds described herein may be used as stand-alone treatments or in combination with current treatments for alcoholic hepatitis.

In some embodiments, the Cot-mediated disease or condition is systemic lupus erythematosus (SLE), lupus nephritis, lupus-related or other autoimmune disorder or symptom of SLE. Symptoms of systemic lupus erythematosus include joint pain, joint swelling, arthritis, fatigue, hair loss, mouth ulcers, swollen lymph nodes, sensitivity to sunlight, skin rashes, headaches, numbness, tingling, seizures, vision problems, personality changes, abdominal pain, nausea, vomiting, abnormal heart rhythm, coughing up blood and difficulty breathing, mottled skin color and Raynaud's phenomenon.

Improvements in any of the above response criteria are specifically provided by the methods of the present disclosure.

Pharmaceutical compositions and methods of administration.

The compounds provided herein are typically administered in the form of pharmaceutical compositions. Thus, also provided herein are pharmaceutical compositions that contain a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, and pharmaceutically acceptable carrier vehicles selected from carriers, adjuvants and excipients. 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.).

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 composition can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or in the form of 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, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, the active ingredient is typically diluted with an excipient and/or enclosed 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, the compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (solid or liquid), ointments containing, e.g. , up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions and sterile packaged powders

- 31 045220 kov.

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. The compositions may further include lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweetening agents; and flavors.

Compositions that include a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof, can be formulated to provide rapid, sustained, or sustained release of the active ingredient upon administration to a subject using procedures known in the art. level of technology. Controlled-release drug delivery systems 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. No. 3,845,770; 4326525; 4902514; and 5616345. Another formulation described herein utilizes 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 a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue. 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.

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 herein. In some embodiments, the compositions are administered by the oral or nasal route 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.

Dosing.

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 rate of excretion, 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, at 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. The daily dose of a compound of Formula III may be from about 1 mg to 4000 mg, about 2000 to 4000 mg/day, about 1 to 2000 mg/day, about 1 to 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.

When administered orally, the total daily dose for humans may be from 1 mg to 1000 mg, about 1000 to 2000 mg/day, about 10 to 500 mg/day, about 50 to 300 mg/day, about 75 to 200 mg /day or approximately 100 to 150 mg/day.

The compounds of this application or 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.

Synthesis of compounds of formula III.

The compounds can be prepared using the methods described herein and their usual modifications, which will be understood 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.

General synthesis.

Exemplary embodiments of the compounds described herein can be synthesized using the general reaction schemes described below. From the foregoing description it will be understood that the general schemes can be modified by replacing the starting materials with other substances having similar structures, obtaining products that will be 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 provided herein. In general, the compounds described herein are generally stable and can be isolated at room temperature and pressure.

Synthesis reaction parameters.

The compounds of the present disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that when typical or preferred process conditions are stated (i.e., reaction temperatures, times, reactant molar ratios, solvents, pressures, etc.), other process conditions may be used unless otherwise indicated. Optimal reaction conditions may vary depending on the specific reagents or solvent used, but such conditions can be determined by one skilled in the art using routine optimization procedures.

In addition, as will be appreciated by those skilled in the art, traditional protecting groups may be necessary to prevent undesirable reactions of certain functional groups. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups are well known in the art. For example, numerous protecting groups are described by T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York and references therein.

In addition, the compounds of the present disclosure may contain one or more chiral centers. Accordingly, if necessary, such compounds can be prepared or isolated in the form of pure stereoisomers, i.e. as individual enantiomers or diastereomers or as mixtures enriched in stereoisomers. All such stereoisomers (and enriched mixtures) are included within the scope of this specification unless otherwise indicated. Pure stereoisomers (or enriched mixtures) can be

- 33 045220 are prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolving agents, and the like.

The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures or obvious modifications thereof described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1 -5, and Supplemental (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

The term solvent generally refers 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, solvents are inert organic solvents and reactions can be carried out under an inert gas, preferably argon or nitrogen.

The term q.s. means adding an amount sufficient to achieve the stated function, for example, to bring the solution to the desired volume (i.e. 100%).

Compounds of formula III can be prepared by first preparing the substituted quinoline core, and optionally further modifying the core as necessary to obtain the substituents described herein.

Scheme 1 shows the preparation of a quinoline core to yield compounds of Formula 1 wherein m, R ⁵ and R ¹⁵ are as defined herein or are a functional group that can be converted thereto using standard reaction conditions.

Scheme 1

In Scheme 1, suitably substituted 1-a and 1-b are condensed in a suitable solvent (eg DMF, etc.) in the presence of a catalyst (eg Cs ₂ CO3, etc.) at elevated temperature (eg about 40 -50°C) providing 1-c. Compound 1-c is then converted to 1-d under thermal cyclization conditions (ie, approximately 250°C) or microwave conditions. Chlorination of 1-d to produce 1-e is achieved using a suitable chlorinating agent (e.g. POCl3, _SOCl2 , etc.) at elevated temperature (e.g. about 110-120°C) in the presence of a base (e.g. pyridine, dimethylaniline , diethylaniline, etc.) or catalyst (e.g. DMF, DEF, etc.) and in a suitable solvent (e.g. chlorobenzene, CH3CN, etc.) or solvent-free conditions (i.e. neat ).

Scheme 2 shows the synthesis of compounds of formula 2-c and 2-d, where m, R ¹ , R ² , R ⁵ and R ¹⁵ are as defined herein.

- 34 045220

Scheme 2

In Scheme 2, 1-e is reacted with a suitable amine under standard nucleophilic aromatic substitution conditions in the presence of a base (eg NEt3, etc.) and at elevated temperature (eg 150°C) to give 2-a. Compounds of formula III where R ⁵ and/or R ¹⁵ are cyano are prepared by reacting 2-a with a suitable cyanidating agent (eg CuCN, Zn(CN) ₂ etc.) in the presence of a catalyst (eg palladium, nickel, copper, etc.). Compounds 2-c and 2-d are then provided by reducing the nitro group of compounds 2-a or 2-b, respectively (using, for example, Fe, SnCl ₂ etc.).

Scheme 3 shows the synthesis of compounds of formula 3-d and 3-e, where R ⁴ is as defined herein.

Scheme 3

1.HC^CMgBr

H^O NaBD ₄ D^OH MnO^^ D^O ^{2 Ac} 2° '^H^OAc

R ⁴ R ⁴ R ⁴ R

3-a 3-b 3-c3-d

1.HC=CMgBr

2. Ac ₂ O ^^^^x^OAc

R ⁴

3In Scheme 3, deuterated 3-c is prepared by reduction of a suitably substituted aldehyde 3-a with a deuteride-containing reducing agent (e.g., NaBD4), followed by oxidation of 3-b to the corresponding aldehyde 3-c under standard oxidation conditions (e.g., MnO ₂ , Fe ₂ O ₃ , NiO, CuO, ZnO, ZrO ₂ , La ₂ O ₃ , Sm ₂ O ₃ , Eu ₂ O ₃ , Yb ₂ O ₃ , etc.). Compound 3-d is prepared in two steps by reacting 3-c with ethynyl Grignard followed by acylation of the resulting alcohol with acetic anhydride in the presence of a base (eg, pyridine, TEA, etc.). Compound 3-e is prepared in a similar two-step process by reacting suitably substituted aldehyde 3a with Grignard ethynyl, followed by acylation of the resulting alcohol with acetic anhydride.

Scheme 4 shows the synthesis of a suitably protected azide compound of formula 4-b, where Lg is a leaving group and Z ³ is as defined in the invention.

Scheme 4

Z ³ Z

II

_NH2N

4-a4-b

Z ³ Lg-XZ

OH LgN

4-c 4-d4-b

In Scheme 4, suitably substituted amine 4-a is treated with a diazo transfer agent (eg, imidazole-1-sulfonyl azide hydrochloride) to yield the corresponding 4b. Alternatively, 4-b can be prepared in two steps from alcohol 4-c by converting the hydroxyl moiety to a suitable leaving group (Lg) (e.g. TsO-, MsO-, NsO-, TfO-, etc.), followed by nucleophilic displacement by azide.

Scheme 5 shows the synthesis of intermediates of formula 5-c wherein R ⁵⁰ is alkyl and Z ³ is as defined herein.

- 35 045220

Scheme 5

In Scheme 5, suitably substituted triazole 5-b is prepared by reacting 4-b with 5a using standard 1,3-dipolar cycloaddition conditions. Acetal 5-b is converted to the corresponding aldehyde 5-c under standard carbonyl deprotection conditions (eg, aqueous acid).

Scheme 6 shows the general synthesis of typical compounds of formula III, where Z ³ , m, R ¹ , R ² , R ⁴ , R ⁵ and R ¹⁵ are as defined herein.

Scheme 6

In Scheme 6, compounds of formula 6-c can be prepared by N-alkylation of amine 2-d with 3-d (or 3-e) followed by cyclization with azide 4-b under standard 1,3-dipolar cycloaddition conditions. Resolution of isomers of Formula 6-a to give compounds of Formula 6-b can be accomplished using standard chiral separation/resolution techniques (eg, chiral chromatography, crystallization, etc.). Alternatively, compounds of formula 6-b can be prepared by enantioselective N-alkylation of 2-d with 3-d (or 3-e) using a chiral metal complex (eg, [Cu(CH ₃ CN) ₄ ]PF ₆ , CuOTf -benzene, Cu(OAc) ₂ or Cu(I)I, etc. with a chiral ligand). Suitable reaction conditions and examples of chiral ligands/complexes can be found in the literature (see, for example, Detz, et al. Angew. Chem. Int. Ed. 2008, 47, 3777-3780). Contacting compound 6-c with azide 4-b under standard 1,3-dipolar cycloaddition conditions affords compound 6-b. 6-c may or may not be isolated before adding compound 4-b.

Scheme 7 shows an alternative synthesis of compounds of formula III by formation of an imine and subsequent nucleophilic addition, Z ³ , m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ¹⁵ are as defined herein.

- 36 045220

Scheme 7

7th 7-f 7-g

In Scheme 7, amine 2-d is reacted with aldehyde 7-a to give the corresponding imine 7-b under standard conditions for the formation of imines. Compound 7-b is then reacted with Grignard reagent 7-c to give Formula III. Alternatively, 2-d can be reacted with aldehyde 7-d to give imine 7-e, which is then reacted with ethynyl Grignard to give 7-f. Compound 7-f can then be converted to compound 7-g under standard 1,3-dipolar cycloaddition conditions with 4-b as shown in Scheme 6. Additionally, resolution of isomers of formula III or compound 7-f can be accomplished using standard chiral separation/resolution conditions (eg, chiral chromatography, crystallization, etc.).

Scheme 8 shows another alternative synthesis of compounds of formula III, where m, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ¹⁵ are as defined herein.

Scheme 8

In Scheme 8, amine 2-d is reacted with appropriately substituted 8-a under nucleophilic substitution conditions, where Lg is a suitable leaving group such as a halide (e.g., fluorine, chlorine, bromine, iodine) or activated alcohol (e.g., AcO- , TsO-, TfO-, MsO-, etc.) in the presence of a base to obtain the compound of formula III. Alternatively, amine 2-d is reacted with ketone 8-b to give 8-c, which is then reduced to give the compound of formula III. Resolution of isomers of Formula III can be accomplished using standard chiral separation/resolution conditions (eg, chiral chromatography, crystallization, etc.).

- 37 045220

Examples

The following examples are included to demonstrate specific implementations of the description. It will be appreciated by those skilled in the art that the methods described in the following examples are methods that work well in the practical implementation of the description and, thus, can be considered as specific methods for its practical implementation. However, those skilled in the art should understand in light of the present disclosure that many changes may be made to the specific embodiments disclosed to achieve the same or a similar result without departing from the spirit and scope of the disclosure.

List of abbreviations and abbreviations.

Abbreviation Meaning °C Degree Celsius Ace Acetyl aq. Water ATP Adenosine triphosphate VOS Tert-butoxycarbonyl bg widened B.S.A. Bovine serum albumin Cbz Carboxybenzyl C.O.D. C,iclooctadiene COPD Chronic obstructive pulmonary disease Wed C,iclopentadienyl d Doublet DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE Dichloroethene DXM Dichloromethane dd Double doublet DEF N,N-diethylformamide DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide dppf 1,1'-bis(diphenylphosphino)ferrocene dt Doublet-triplet DTT Dithiothreitol EC so Half-maximal effective concentration

- 38 045220

EGFR Epidermal growth factor receptor eq equivalents ES/MS Electrospray mass spectrometry Et Ethyl FBS G Fetal bovine serum grams

HEPES 2-[4-(2-hydroxyethyl)piperazin-1yl]ethanesulfonic acid HPLC High Pressure Liquid Chromatography watch Watch Hz Hertz IBD Inflammatory bowel disease i-pr Isopropyl J Interaction constant (MHz) kg Kilogram LCMS Liquid chromatography-mass spectroscopy LPS Lipopolysaccharide m Molar m Multiplet M+ Mass peak M+H+ Mass peak plus hydrogen Me Methyl mg Milligram MHz Megahertz min Minute ml Milliliter mm Millimolar mmol Millimole MOPS 3-morpholinopropane-1-sulfonic acid MS Mass spectroscopy

- 39 045220

Ms Mezil nBu/Bu Butyl nl Nanoliter nm Nanometer NMR Nuclear magnetic resonance NP-40 Nonyl phenoxypolyethoxyethanol Ns Nozil Pd-C/ Pd/C Palladium on coal pg Pictogram Ph Phenyl PPTS Pyridinium p-toluenesulfonate PS Polystyrene

p-TSOH/ pTSA p-toluene sulphate oxide q Quartet q.s. Quantity sufficient to achieve the stated function RBF Round bottom flask R.P. Reverse phase RPMI Wednesday Roswell Park Memorial Institute KT Room temperature s Singlet us. Saturated t Triplet TBAF Tetra-n-butylammonium fluoride TBS Tert-butyldimethylsilyl t-Bu Tert-butyl TC Thiophene-2-carboxylate TEA Triethanolamine Tf Trifluoromethanesulfonyl T.F.A. Trifluoroacetic acid THF Tetrahydrofuran Tpl-2 Tumor progression locus 2 TR-FRET Time-resolved resonant fluorescence energy transfer Ts Tozil δ Chemical shift (ppm) µl Microliter µM Micromolar

Intermediate connections.

An example of the synthesis of a cyanoquinoline nucleus:

- 40 045220

A mixture of 2-chloro-4-nitroaniline (1 eq), (Z)-ethyl-2-cyano-3-ethoxyacrylate (1.3 eq) and Cs ₂ CO ₃ (1.3 eq) in DMF was heated at 45°C during the night. After cooling to room temperature, the mixture was poured into water. The resulting solid was filtered and washed with water and dried to obtain the title compound as a solid, which was used in the next step without further purification.

1H NMR (DMSO-d ₆ , 300 MHz): δ 11.28 (d, J=12.9 Hz, 1H), 8.84 (d, J=12.9 Hz, 1H), 8.42 (d , J=2.4 Hz, 1H), 8.26-8.22 (m, 1H), 8.02 (d, J=9.3 Hz, 1H), 4.27 (q, J=7, 2 Hz, 2H), 1.27 (t, J=7.2 Hz, 3H).

Synthesis of 8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile

A suspension of (Z)-ethyl-3-((2-chloro-4-nitrophenyl)amino)-2-cyanoacrylate in diphenyl ether under a nitrogen atmosphere was heated to boiling point in a sand bath to a heating mantle for 24 hours. After cooling to room temperature, the reaction mixture was poured into hexane and stirred for 2 hours. The mixture was filtered and the filter cake was washed with hexane twice to obtain the title compound as a brown solid.

1H NMR (DMSO- _d6 , 300 MHz): δ 12.86 (br s, 1H), 8.73-8.71 (m, 3H).

Synthesis of 4,8-dichloro-6-nitroquinoline-3-carbonitrile

A suspension of 8-chloro-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile and five drops of DMF in POCl ₃ was heated at 115°C overnight. The brown clear solution was cooled to room temperature and excess POCl ₃ was removed. The residue was dissolved in DCM and we were washed. NaHCO ₃ , saline and dried over Na ₂ SO ₄ . The solution was filtered and concentrated to obtain the crude product. The residue was triturated with hexane and EtOAc to give the title compound as a brown solid.

1H NMR (DMSO-d ₆ , 300 MHz): δ 9.50 (s, 1H), 8.98 (d, J=2.4 Hz, 1H), 8.89 (d, J=2.4 Hz , 1H).

Example alkynyl acetate ^\^OAc

F

1-(6-Fluoropyridin-3-yl)prop-2-yn-1-yl acetate: 6-fluoronicotinaldehyde (300 mg, 2.40 mmol) was dissolved in THF (15 ml) and brought to 0°C. Ethynylmagnesium bromide (0.5 M in THF, 5.76 mL, 2.88 mmol) was added slowly and the resulting solution was left stirring for 30 minutes. Acetic anhydride (0.45 mL, 4.80 mmol) was then added, the cold bath was removed and the reaction mixture was allowed to warm to room temperature for 2 hours. The reaction contents were quenched by adding saturated aqueous NH ₄ Cl (5 ml), poured into water (5 ml) and extracted with EtOAc (3x15 ml). The combined organic phase was washed with brine (10 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

1-(1-Oxo-1,2-dihydroisoquinolin-5-yl)prop-2-yn-1-yl acetate (200 mg, 0.83 mmol) was dissolved in DMF (2 ml) after which cesium carbonate (405 mg) was added , 1.2 mmol) and 2-iodopropane (211 mg, 1.2 mmol) and the resulting mixture was stirred at 25°C under ambient atmosphere overnight. The reaction mixture was poured into water (3 ml) and extracted with EtOAc (3x5 ml). The organic layer was dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (eluent: EtOAc/hexanes) to give the N-alkylated product. Note: The same alkylation protocol can be performed on the precursor 1-oxo-1,2-dihydroisoquinoline-5-carbaldehyde.

- 41 045220

Example of aldehydes for the synthesis of alkynyl acetate °yD

V

F

6-Fluoronicotinaldehyde-α-D: 6-fluoronicotinaldehyde (1.14 g, 9.11 mmol) was dissolved in MeOH (8 ml) at room temperature. NaBD4 (458 mg, 10.9 mmol) was then added in one portion and the reaction mixture was stirred for 20 minutes. The reaction mixture was carefully quenched with water (5 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine (5 mL), dried over MgSO ₄ and concentrated to give the crude alcohol, which was carried forward without further purification. The crude alcohol was redissolved in DCM (40 ml) and manganese(IV) oxide (19.9 g, 281 mmol) was added at room temperature. After 2 hours, the reaction mixture was filtered through a pad of celite, washing with DCM and EtOAc. The filtrate was then concentrated to obtain the desired product with approximately 95% deuterium inclusion.

I ⁰

2-Acetyl-3-oxoisoindoline-4-carbaldehyde: 3-oxoisoindoline-4-carbaldehyde (300 mg, 1.86 mmol) was dissolved in THF (5 ml) at room temperature. Acetic anhydride (0.53 mL, 5.59 mmol) and DMAP (45 mg, 0.37 mmol) were added and the reaction mixture was stirred overnight. The reaction contents were quenched by adding saturated aqueous NH ₄ Cl (3 ml), poured into water (3 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

tert-Butyl-(7-formylbenzo[b]thiazol-2-yl)carbamate

Ethyl 2-((tert-butoxycarbonyl)amino)benzo[b]thiazole-7-carboxylate: ethyl 2-aminobenzo[b]thiazole7-carboxylate (300 mg, 1.35 mmol), di-tert-butyl dicarbonate (0 .34 ml, 1.49 mmol) and DMAP (181 mg, 1.49 mmol) were dissolved in DCM (10 ml) and stirred at room temperature for 3 hours. The reaction mixture was then poured into water (10 ml) and extracted with DCM (2x20 ml). The combined organic extracts were dried over MgSO ₄ , concentrated and purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

tert-Butyl-(7-(hydroxymethyl)benzo[b]thiazol-2-yl)carbamate: ethyl 2-((tertbutoxycarbonyl)amino)benzo[b]thiazol-7-carboxylate (204 mg, 0.63 mmol) dissolved in THF (7 ml) and brought to 0°C. LiAlH ₄ (72 mg, 1.90 mmol) was added portionwise and the reaction mixture was left stirring for 90 minutes. The reaction mixture was carefully quenched at 0°C with water (5 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated to give the desired product, which was used without further purification.

tert-Butyl-(7-formylbenzo[b]thiazol-2-yl)carbamate: tert-butyl-(7-(hydroxymethyl)benzo[b]thiazol2-yl)carbamate (177 mg, 0.63 mmol) was dissolved in DCM (5 ml), after which Dess-Martin periodinane (321 mg, 0.76 mmol) was added at room temperature. After 30 minutes, the reaction was quenched by adding saturated aqueous Na ₂ SO ₃ (3 ml) and stirred vigorously for 5 minutes. The reaction mixture was then poured into saturated aqueous NaHCO ₃ (5 ml) and extracted with EtOAc (3x15 ml). The combined organic phase was washed with brine (5 ml), dried over MgSO ₄ and concentrated to give the desired aldehyde, which was used without further purification.

2-Methyl-1-oxoisoindolin-4-carbaldehyde: to a solution of 4-bromo-2-methylisoindolin-1-one (200 mg,

- 42 045220

0.89 mmol) in THF (3 ml), n-BuLi (0.78 ml, 1.95 mmol) was added to the solution at -78°C. In 30 minutes

DMF (0.273 mL, 3.57 mmol) was added to the solution. After 1 hour, the reaction mixture was heated. Diluted with EtOAc and washed with saline. The organic layer was dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography (eluent: EtOAc/hexanes) to obtain the product after lyophilization from water/MeCN.

1-Methyl-6-oxo-1,6-dihydropyridine-3-carbaldehyde: solution of 6-chloro-2-methylnicotinaldehyde (1.0 g, 6.43 mmol) in conc. HCl (3 ml), heated to 90°C overnight. Cool it and pour it into ice water (20 ml). Filtered and dried in vacuum. Used without further purification.

To a suspension of 6-oxo-1,6-dihydropyridine-3-carbaldehyde (300 mg, 2.19 mmol) in DMF, sodium hydride (96 mg, 2.4 mmol) was added to the suspension under ice bath conditions. Iodomethane (0.15 ml, 2.4 mmol) was added to the suspension. It was then stirred overnight. Diluted with EtOAc and washed with saline. The organic layer was dried and concentrated. Used without further purification.

3-Methyl-4-oxo-3,4-dihydroquinazoline-8-carbaldehyde: to a suspension of 3,8-dimethylquinazoline-4(3H)one (300 mg, 2 mmol) (prepared according to Organic and Biomolecular Chemistry, 2011, vol. 9, No. 17 pp. 6089 - 6099) and selenium dioxide (955 mg, 9 mmol) in 1,2-dichlorobenzene (1270 mg, 9 mmol) were heated to 170°C overnight. The organic layer was dried over MgSO ₄ , filtered, concentrated and purified by silica gel chromatography (eluent: EtOAc/hexanes) to give the title compound.

Example of amines

(2,2-dimethylpropyl-1,1-d2)amine HCl: LiAlD ₄ (252 mg, 6.02 mmol) was suspended in Et ₂ O (10 ml) at room temperature. Trimethylacetonitrile (0.67 mL, 6.02 mmol) was then added slowly as a solution in Et ₂ O (6 mL) while maintaining the temperature below reflux. After 30 minutes, the reaction mixture was quenched by careful, slow addition of water until gas evolution ceased. Then a saturated aqueous solution of Rochelle salt (50 ml) was added and the resulting solution was stirred vigorously for 2 hours. The phases were then separated and the aqueous extracted with Et ₂ O (3x30 ml). The combined organic phases were washed with brine (15 ml), dried over MgSO ₄ and filtered. HCl (1.0 M in ether, 15 ml, 15 mmol) was added to the product solution in ether, after which the newly formed HCl salt was collected by filtration.

(R)-1-phenylpropane-1-amine-d7

Auxiliary Ellman's condensation: (S)-(-)-2-methyl-2-propanesulfinamide (862 mg, 7.12 mmol) was dissolved in DCM (15 ml). PPTS (81 mg, 0.32 mmol), MgSO ₄ (3.89 g, 32.3 mmol) and benzaldehyde-d were then added and the resulting mixture was left stirring at room temperature for 4 hours. The reaction mixture was filtered through Celite, washed with DCM, concentrated and purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

Grignard formation and addition to sulfinimine: Ethyl bromide-d5 (1.00 g, 8.77 mmol) as a solution in dry THF (2 ml) was added to a suspension of magnesium turnings (426 mg, 17.5 mmol) in dry THF (7 ml) and stirred at room temperature for 2 hours. Heat and discoloration indicated successful formation of the Grignard reagent to produce approximately 1.0 M solution of EtMgBr-d5 in THF. EtMgBr-d5 (1.0 M in THF, 7.2 mL, 7.2 mmol) was added dropwise to the solution

- 43 045220 sulfinimine (752 mg, 3.58 mmol) in DCM (10 ml) at -78°C. After stirring for 3 hours at -78°C, the reaction mixture was allowed to warm to room temperature overnight. The reaction contents were quenched by adding saturated aqueous NH ₄ Cl (5 ml), poured into water (5 ml) and extracted with EtOAc (3x30 ml). The combined organic phases were washed with brine (15 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

Auxiliary removal: The starting material (451 mg, 1.84 mmol) was dissolved in MeOH (0.9 ml) at room temperature. HCl (4.0M in dioxane, 0.92 mL, 3.69 mmol) was added and the solution was stirred for 30 minutes. The reaction mixture was diluted with Et ₂ O (20 ml) and the resulting precipitate was collected by filtration to obtain the desired product as the HCl salt.

(1 R,2R)-2-((S)-amino(phenyl)methyl)cyclopropanecarbonitrile

2-Benzoylcyclopropanecarbonitrile: phenacyl chloride (10.0 g, 64.7 mmol) and DABCO (7.26 g, 64.7 mmol) were dissolved in THF (200 ml) and DMSO (50 ml) at room temperature and stirred for 30 minutes. Na ₂ CO ₃ (10.3 g, 97.0 mmol) and acrylonitrile (8.48 ml, 129.4 mmol) were then added and the resulting mixture was heated to 90°C overnight. The reaction contents were quenched by adding saturated aqueous NH ₄ Cl (40 ml), poured into water (20 ml) and extracted with EtOAc (3x150 ml). The combined organic phases were washed with brine (40 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to give trans-2-benzoylcyclopropanecarbonitrile (5.91 g, 53%) and cis-2-benzoylcyclopropanecarbonitrile separately and as racemic mixtures.

(R)-N-(((1S,2S)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide and (R)-N(((1R,2R)-2-cyanocyclopropyl)( phenyl)methylene)-2-methylpronan-2-sulfinamide: Racemic trans-2benzoylcyclopropanecarbonitrile (1.00 g, 5.84 mmol), (R)-(+)-2-methyl-2-propanesulfinamide (2.12 g, 17.5 mmol) and titanium(IV) ethoxide (7.35 ml, 35.1 mmol) were combined and heated to 85°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml) followed by dilution with water (5 ml) and left to stir for 30 minutes). The white precipitate was removed by filtration and the filtrate was washed with brine and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to give (R)-N(((1R,2R)-2-cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide and (R )-N-(((1S,2S)-2cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide in the form of pure enantiomers.

(R)-N-((S)-((1R,2R)-2-cyanocyclononyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide: (R)-N(((1R,2R)-2 -cyanocyclopropyl)(phenyl)methylene)-2-methylpropane-2-sulfinamide (250 mg, 0.91 mmol) was dissolved in THF and brought to -78°C. NaBH ₄ (70.0 mg, 1.85 mmol) was added in one portion and the reaction mixture was allowed to warm slowly to room temperature. Upon reaching room temperature, the reaction contents were quenched with water (2 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to give (R)-N-((R)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2 -sulfinamide (56 mg, 22%) and (R)-N-((S)-((1R,2R)-2-cyanocyclopropyl)(phenyl)methyl)-2-methylpropane-2-sulfinamide as pure enantiomers.

(1R,2R)-2-((S)-amino(phenyl)methyl)cyclopropanecarbonitrile: (R)-N-((S)-((1R,2R)-2cyanocyclopropyl)(phenyl)methyl)-2-methylpropane -2-sulfinamide (143 mg, 0.52 mmol) was dissolved in MeOH (0.5 ml) at room temperature. HCl (4.0M in dioxane, 0.26 mL, 1.04 mmol) was added and the solution was stirred for 30 minutes. The reaction mixture was diluted with Et ₂ O (20 ml) and the resulting precipitate was collected by filtration to obtain the desired product as the HCl salt.

3-Chloro-2-cyclopropoxyaniline

o h ₂ n

1-Chloro-2-cyclopropoxy-3-nitrobenzene: To a solution of NaH (60% dispersion in mineral oil, 319 mg, 7.98 mmol) in THF (10 ml), cyclopropyl alcohol (0.35 ml, 5.58 mmol). Through

- 44 045 220 minutes of stirring, 1-chloro-2-fluoro-3-nitrobenzene (700 mg, 3.99 mmol) was added and the resulting solution was heated to 75°C for 1 hour. The reaction mixture was cooled to room temperature, quenched with water (5 ml) and extracted with EtOAc (3x15 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by flash chromatography (eluent: EtOAc/hexanes) to obtain the desired product.

3-Chloro-2-cyclopropoxyaniline: 1-chloro-2-cyclopropoxy-3-nitrobenzene (420 mg, 1.97 mmol) was dissolved in EtOH (8 ml) at room temperature. Iron (549 mg, 9.83 mmol), CaCl ₂ (327 mg, 2.95 mmol) and water (1 ml) were then added and the resulting mixture was heated to 75°C for 3 hours. Solids were removed by filtration, washing with MeOH and EtOAc, the filtrate was concentrated, and then redissolved in EtOAc (100 ml). The organic phase was washed with saturated aqueous NaHCO ₃ (2x20 ml), brine (20 ml), dried over MgSO ₄ and concentrated to give the product, which was used without further purification.

Diazo transfer reaction and formation of azides

3-(Aminomethyl)oxetan-3-ol (50 mg, 0.49 mmol) was added to a suspension of 1-Himidazole-1-sulfonyl azide hydrochloride (129.5 mg, 0.62 mmol), potassium carbonate (136 mg, 0.99 mmol ) and copper(II) sulfate pentahydrate (12.3 mg, 0.049 mmol) in methanol (1.0 ml). The blue mixture was stirred at room temperature for 16 hours and used without treatment in click chemistry (Example 4). Reference: E. D. Goddard, et al., Org. Lett., 2007, p. 3797.

Piperidine triazolaldehyde

Benzyl 4-(tosyloxy)piperidine-1-carboxylate (2).

Benzyl 4-hydroxypiperidine-1-carboxylate (1) (17.2 g, 73.1 mmol) and p-toluenesulfonyl chloride (15.3 g, 80.4 mmol) were dissolved in pyridine (50 ml) and stirred at room temperature . After 23 h, the pyridine was removed under reduced pressure and the residue was dissolved in EtOAc (300 ml). The organic phase was washed with water (2x150 ml) and saturated ammonium chloride (100 ml), dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (eluent: ethyl acetate/hexanes). Fractions containing the product were combined and the solvent was removed under reduced pressure to give benzyl 4-(tosyloxy)piperidine-1-carboxylate (2).

Benzyl 4-azidopiperidine-1-carboxylate (3).

Sodium azide (2.48 g, 38.2 mmol) was added to a solution of benzyl 4-(tosyloxy)piperidine-1-carboxylate (2) (12.4 g, 31.8 mmol) in dimethylformamide (100 ml). The mixture was heated at 90°C for 30 minutes. The mixture was cooled and diluted with ethyl acetate (250 ml) and washed with water (2x15 ml), 5% aqueous lithium chloride solution (10 ml) and saline (10 ml). The organic phase was dried over sodium sulfate and concentrated (NOT to dryness) to obtain the desired substance. All substances were used in the next stage.

Benzyl 4-(4-(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (4).

Copper powder (2.0 g, 31.5 mmol) was added to a solution of benzyl 4-azidopiperidine-1-carboxylate (3) (8.2 g, 31.5 mmol) of 3,3-diethoxyprop-1-yne (4 .44 g, 34.6 mmol) and saturated copper (II) sulfate (8 ml) in tetrahydrofuran (100 ml). After 17 hours the mixture was filtered through a pad of celite. The solvent was removed under reduced pressure and the residue was diluted in ethyl acetate (200 ml). The organic phase was washed with brine (3x100 ml), dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography on silica gel (eluent: ethyl acetate/hexanes). Fractions containing

- 45 045220 the product was combined and the solvent was removed under reduced pressure to obtain benzyl 4-(4(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (4).

Benzyl 4-(4-formyl-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate (5).

Aqueous hydrochloric acid (1 M, 2.2 mL, 2.2 mmol) was added to a solution of benzyl 4-(4(diethoxymethyl)-1H-1,2,3-triazol-1-yl)piperudin-1-carboxylate ( 4) (429 mg, 1.1 mmol) in tetrahydrofuran (4 ml) and water (2 ml). The organic solvent was removed under reduced pressure. The aqueous mixture was diluted with acetonitrile (2 ml) and lyophilized.

tert-Butyl-3-formyl-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate / ^OH HATU, DIPEA, DMF / ^N ~° ⁰ MeONHMe HCI \ \ ⁰

BocN-%BocN^Z

N,N-Diisonropylethylamine (1.53 mL, 8.82 mmol) was added to a solution of 6-(tert-butoxycarbonyl)4,5,6,7-tetrahydrothieno[2,3-c]pyrudine-3-carboxylic acid (1 .00 g, 3.53 mmol) and N-[(dimethylamino)1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium hexafluorophosphate N-oxide (1, 62 g, 4.24 mmol) in dimethylformamide (15 ml). After 2 min, N,Odimethylhydroxylamine hydrochloride (413 mg, 4.24 mmol) was added. After 16 hours, the reaction mixture was diluted with ethyl acetate (75 ml) and washed with water (2x25 ml), saturated ammonium chloride (2x25 ml) and brine (25 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-100% ethyl acetate/hexanes). Fractions containing the product were combined and the solvent was removed under reduced pressure to give tert-butyl3-(methoxy(methyl)carbamoyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate.

A solution of diisobutylaluminum hydride in tetrahydrofuran (4.42 ml, 1.0 M, 4.42 mmol) was added dropwise to a solution of tert-butyl-3-(methoxy(methyl)carbamoyl)-4,7-dihydrothieno[2,3- c]pyridine-6(5H)carboxylate (1.03 g, 3.15 mmol) in tetrahydrofuran (20 ml) at -78°C under argon. After 5 hours at -78°C, the reaction was 40% complete. A solution of diisobutylaluminum hydride in tetrahydrofuran (3.15 ml, 1.0 M, 3.15 mmol) was added dropwise. After 30 min, the reaction mixture was quenched with saturated ammonium chloride (20 ml) at -78°C and allowed to warm to room temperature.

The organic phase was shaken with water (20 ml) and ethyl acetate (75 ml) (causing gel formation). Hydrochloric acid (2N, 5 ml) was added and the solid was removed by filtration through a pad of celite. The organic phase was washed with saturated sodium bicarbonate (25 ml) and brine (25 ml). The organic phase was dried over sodium sulfate and concentrated. The residue was subjected to flash chromatography (0-50% ethyl acetate/hexanes). Fractions containing the product were combined and the solvent was removed under reduced pressure to give tert-butyl-3-formyl-4,7-dihydrothieno[2,3c]pyridine-6(5H)-carboxylate.

Connection examples

Example 1, procedure 1.

8-Chloro-4-(neopentylamino)-6-nitroquinoline-3-carbonitrile: 4,8-dichloro-6-nitroquinoline-3carbonitrile (615 mg, 2.29 mmol), neopentylamine (220 mg, 0.25 mmol) and triethylamine (278 mg, 2.75 mmol) in isopropanol (4 ml) was heated under microwave conditions at 150°C for 45 minutes. The reaction mixture was cooled to room temperature. Water was added and the resulting precipitate was collected by filtration. The crude product was used in the next step without additional purification.

ES/MS 319.1 (M+H+).

Alternative reaction conditions for the above conversion: 4,8-dichloro-6-nitroquinoline-3carbonitrile (3000 mg, 11.2 mmol), neopentylamine (1073 mg, 12.3 mmol) and triethylamine (1246 mg, 12.3 mmol) to isopropanol (60 ml) was heated at 80°C for 4 hours. The reaction mixture was cooled to room temperature. The solvents were removed and the crude reaction product was purified by silica gel chromatography (eluent: EtOAc/hexanes) to give the product.

ES/MS(M+H+) 319.1.

6-Amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile: 8-chloro-4-(neopentylamino)-6nitroquinoline-3-carbonitrile (699 mg, 2.2 mmol), calcium chloride (483.6 mg, 3.28 mmol), iron powder (612.3 mg, 10.96 mmol) was heated in ethanol (22 ml)/water (2.2 ml) at 60°C for 1 hour. The reaction mixture was cooled to room temperatures and solids were removed by filtration. The solids were washed with EtOAc and the combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. As a result of filtering and evaporation of all volatile substances, the product was obtained.

ES/MS 289.1 (M+H+).

Alternative reduction conditions with stannous chloride: 8-chloro-4-(neopentylamino)-6nitroquinoline-3-carbonitrile (2,000 mg, 6.2 mmol) and stannous chloride (7079 mg, 31.3 mmol) were heated at 70°C for 4 hours. More stannous chloride (2832 mg, 12.6 mmol) was added. After 5 hours the reaction was complete. The reaction mixture was cooled to room temperature. Half of the ethanol was removed under reduced pressure. The mixture was added to NaHCO ₃ (200 ml) and diluted with EtOAc (500 ml). The organic phase was washed with brine (200 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure to obtain the desired substance.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.19 (s, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.29 (t, J=7.3 Hz, 1H), 7.18 (d, J=2.3 Hz, 1H), 5.74 (s, 2H), 3.66 (d, J=6.6 Hz, 2H), 0.96 (s, 9H).

ES/MS 289.1 (M+H+).

(S)-8-chloro-6-(((1-cyclopronyl-1H-1,2,3-triazol-4-yl)(4-fluoro-3-pyridyl)methyl-d)amino)-4(neopentylamino )quinoline-3-carbonitrile: 6-amino-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile (75 mg, 0.26 mmol), CuI (3.6 mg, 0.019 mmol) and 2,6- bis((4S,5R)-4,5-diphenyl-4,5-dihydrooxazol-2yl)pyridine [oxazoline ligand] (9.9 mg, 0.019 mmol) was sonicated in MeOH (3.5 mL) for ~1 minutes. Alkynyl acetate (44.4 mg, 0.23 mmol) and di-isopropylethylamine (29.4 mg, 0.229 mmol) were added and the reaction mixture was stirred at room temperature overnight. tert-Butyl azide (45 mg, 0.454 mmol) was added and the reaction mixture was stirred for an additional 24 hours at room temperature. Solvents were removed in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

1H NMR (400 MHz, DMSO- _d6 ) δ 8.37 (m, 2H), 8.17 (s, 1H), 8.05 (m, 1H), 7.79 (brs, 1H), 7, 62 (d, J=2.2 Hz, 1H), 7.51 (br s, 1H), 7.15 (m, 2H), 4.03 (m, 1H), 3.44 (dd, J= 13.9 / 5.5 Hz, 1H), 1.59 (s, 9H), 0.88 (s, 9H).

ES/MS 522.2 (M+H+).

Example 2, procedure 2.

8-Chloro-6-(((8)-( 1 -isopropyl-1H-1,2,3-triazol-4-yl)(2-methylpyridin-3 -yl)methyl)amino)-4-((( R)-1 phenylpropyl)amino)quinoline-3-carbonitrile

(R)-8-chloro-6-nitro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile: 4,8-dichloro-6-nitroquinoline3-carbonitrile (200 mg, 0.75 mmol), ( R)-ethylbenzylamine (121 mg, 0.895 mmol) in isopropanol (3 ml) was heated in the microwave at 150°C for 45 minutes. The reaction mixture was cooled to room temperature. Water and EtOAc were added. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over sodium sulfate. As a result of filtering and evaporation of the solvents, a crude product was obtained, which was used in the next step without further purification.

- 47 045220

ES/MS 367.1 (M+H+).

6-Amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile: (R)-6-amino-8-chloro-4-((1phenylpropyl)amino)quinoline-3-carbonitrile ( 287 mg, 0.78 mmol), calcium chloride (172.6 mg, 1.17 mmol), iron powder (218.5 mg, 3.91 mmol) heated in ethanol (5 ml)/water (0.5 ml ) at 60°C for 1 hour. The reaction mixture was cooled to room temperature and solids were removed by filtration. The solids were washed with EtOAc and the combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. As a result of filtering and evaporation of all volatile substances, the product was obtained.

ES/MS 337.1 (M+H+).

8-Chloro-6-(((R)-1 -(2-methylpyridin-3-yl)prop-2-in-1 -yl)amino)-4-(((R)-1 phenylethyl)amino)quinoline -3-carbonitrile: CuI (2.0 mg, 0.01 mmol) and 2,6-bis((4S,5R)-4,5-diphenyl-4,5dihydrooxazol-2-yl)pyridine [oxazoline ligand] ( 6.9 mg, 0.013 mmol) were sonicated in MeOH (3.0 mL) for ~5 minutes. 1-(2-methylpyridin-3-yl)prop-2-yn-1-yl acetate (50 mg, 0.27 mmol) in MeOH (1 ml), (R)-6-amino-8-chloro-4- ((1-phenylpropyl)amino)quinoline-3-carbonitrile (75 mg, 0.223 mmol) and di-isopropylethylamine (34 mg, 0.27 mmol) were added and the reaction mixture was stirred at room temperature overnight. The crude reaction product was purified by silica gel chromatography (20% - 100% EtOAc in hexanes) to give the product.

ES/MS 465.99 (M+H+).

8-Chloro-6-(((S)-( 1 -isopropyl-1H-1,2,3-triazol-4-yl)(2-methylpyridin-3 -yl)methyl)amino)-4-((( R)-1 phenylpropyl)amino)quinoline-3-carbonitrile: 8-chloro-6-(((R)-1-(2-methylpyridin-3-yl)prop-2-yn-1yl)amino)-4- (((R)-1-phenylethyl)amino)quinoline-3-carbonitrile (45 mg, 0.10 mmol) was dissolved in THF (0.5 ml) at room temperature and copper(I) thiophenecarboxylate (5.7 mg) was added , 0.030 mmol). 2-azidopropane (10 mg, 0.120 mmol) was added and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was partitioned between aqueous sodium bicarbonate and EtOAc. The aqueous layer was extracted with EtOAc and the combined layers were washed with saturated sodium bicarbonate and dried over sodium sulfate. As a result of filtering and evaporation of solvents, a crude substance was obtained. The crude material was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

1H NMR (400 MHz, CD3OD) δ 8.61 (m, 1H), 8.37 (m, 1H), 8.29 (m, 1H), 8.05 (m, 1H), 7.73 (m , 1H), 7.60 (s, 1H), 7.32 (m, 5H), 7.14 (m, 1H), 6.46 (s, 1H), 5.64 (m, 1H), 4 .88 (m, 1H), 2.83 (s, 3H), 2.17 - 2.02 (m, 2H), 1.56 (d, 6H), 0.97 (m, 3H).

ES/MS 551.09 (M+H+).

Example 3, procedure 3.

8-Chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2,6-difluoropyridin-3-yl)methyl-d))amino)- 4(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile

8-Chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2,6-difluoropyridin-3-yl)methyl-d))amino)- 4(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile: CuI (2.0 mg, 0.01 mmol) and 2,6-6uc((4S,5R)-4,5diphenyl-4, 5-dihydrooxazol-2-yl)pyridine [oxazoline ligand] (4.6 mg, 0.009 mmol) was sonicated in MeOH (3.0 mL) for ~5 minutes. Add alkynyl acetate (79 mg, 0.37 mmol) in MeOH (1 ml), (R)-6-amino-8-chloro-4-((1-phenylpropyl)amino)quinoline-3-carbonitrile (50 mg, 0.148 mmol), and di-isopropylethylamine (23 mg, 0.18 mmol) and the reaction mixture was stirred at room temperature overnight. The crude reaction mixture was directly used in the next step.

ES/MS: 489.19 (M+H+).

Cyclopropyl azide (16 mg, 0.192 mmol) was added to the reaction mixture. After 1 hour at room temperature, the mixture was filtered and then purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

1H NMR (400 MHz, CD3OD) δ 8.43 (m, 1H), 8.05 (m, 1H), 8.01 (m, 1H), 7.64 (m, 1H), 7.42 - 7 .25 (m, 6H), 6.98 (m, 1H), 5.80 - 5.66 (m, 1H), 3.97 - 3.84 (m, 1H), 2.25 -2.01 (m, 2H), 1.28 - 1.11 (m, 4H), 1.01 (m, 3H).

ES/MS: 572.24 (M+H+).

- 48 045220

Example 4, procedure 4.

8-Chloro-6-(((S)-(1-((3-hydroxyoxetan-3-yl)methyl)-1H-1,2,3-triazol-4-yl)(pyridin-3yl)methyl)amino )-4-(((R)-1-phenylpropyl)amino)quinoline-3-carbonitrile: 8-chloro-4-((^)-1phenylpropyl)amino)-6-(((R)-1-(pyridine -3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile (20 mg, 0.046 mmol), copper powder (15 mg, 0.23 mmol), acetic acid (118 µl, 1. 8 mmol) and saturated aqueous copper (II) sulfate (0.1 ml) and THF (3 ml) were added to the stock solution of 3-(azidomethyl)oxetan-3ol (0.049 mmol). After 2 hours the reaction was complete and the volatiles were removed in vacuo. The crude material was partitioned between ethyl acetate (15 ml) and water. The organic layer was washed with saturated sodium bicarbonate, brine, dried over Na ₂ SO ₄ and concentrated after filtration. The residue was diluted in water (1 ml) and MeOH (1 ml) with 2 drops of TFA and subjected to RP-HPLC (eluent: water/MeCN * 0.1% TFA). Fractions containing the desired product were combined and lyophilized to obtain the desired compound.

¹ H NMR (400 MHz, DMSO) δ 8.84 (dd, J=14.0, 2.2 Hz, 1H), 8.64 - 8.52 (m, 1H), 8.23 (d, J =2.1 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.05 (d, J=6.7 Hz, 1H), 7.65 - 7.54 (m , 2H), 7.46 (d, J=9.5 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.38 - 7.31 (m, 2H), 7.28 - 7.21 (m, 2H), 7.21 - 7.15 (m, 3H), 6.48 (d, J=6.9 Hz, 1H), 5.48 (q, J=7.7 Hz , 1H), 4.68 (d, J=2.0 Hz, 2H), 4.50 (dd, J=6.2, 4.5 Hz, 3H), 4.41 (dd, J=6, 7, 3.4 Hz, 2H), 2.12 (dt, J=14.5, 7.4 Hz, 1H), 2.04 - 1.78 (m, 1H), 0.94 (t, J =7.3 Hz, 3H).

ES/MS 581.2 (M+H+).

Example 5, procedure 5.

(R)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((1-(2,5-dichlorothiophen-3-yl)prop-2-yn-1yl)amino) quinoline-3-carbonitrile: CuI (4.1 mg, 0.022 mmol) and 2,6-bis((4S,5R)-4,5-diphenyl-4,5dihydrooxazol-2-yl)pyridine [oxazoline ligand] (13 .5 mg, 0.026 mmol) were sonicated in MeOH (1 mL) for ~5 minutes. Additional MeOH (4 ml) was added. Alkynylacetate (150.7 mg, 0.61 mmol), 6-amino-8-chloro-4-((4-chloro-3-fluorophenyl)amino)quinoline-3carbonitrile (150 mg, 0.43 mmol) and di -isopropylethylamine (67 mg, 0.52 mmol) and the reaction mixture was stirred at -15°C for 4 days. Solvents were removed in vacuo. The crude reaction product was purified by silica gel chromatography (eluent: EtOAc/hexanes) to give the product.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 8.45 (s, 1H), 7.54 (dd, J=6.4, 2.4 Hz, 2H), 7.43 (t, J=9.0 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.30 (d, J=4.3 Hz, 1H), 7. 27 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 5.54 (dd, J=8.6, 2.2 Hz, 1H), 3.51 (d, J =2.2 Hz, 1H).

ES/MS 534.9 (M+H+).

(S)-tert-butyl-4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(2,5dichlorothiophen- 3-yl)methyl)-1H-1,2,3-triazol-1-yl)piperidin-1-carboxylate: (R)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6- ((1-(2,5-dichlorothiophen-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile (174 mg, 0.324 mmol) and N-Boc-nineridin-4-azide ( 73.4 mg, 0.324 mmol) was dissolved in THF (5 ml). Copper thiophenecarboxylate (6.2 mg, 0.032 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Volatiles were removed under reduced pressure and the residue was purified by silica gel chromatography (eluent: EtOAc/hexanes). Fractions containing the product were pooled and

- 49 045220 the solvent was removed under reduced pressure to obtain the product.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.16 (s, 1H), 7.60 (d, J=2.2 Hz, 1H), 7.40 7.33 (m, 2H), 7.27 (d, J=8.3 Hz, 1H), 7.14 (dd, J=7.1, 2.0 Hz, 2H), 7.10 (s, 1H), 5.96 (d, J=8.2 Hz, 1H), 4.72 4.59 (m, 1H), 4.01 (q, J=9, 1, 8.1 Hz, 3H), 2.86 (d, J=17.5 Hz, 2H), 1.96 (d, J=5.0 Hz, 3H), 1.77 (qd, J= 12.2, 4.4 Hz, 2H), 1.39 (s, 9H).

ES/MS 762.9 (M+H+).

Alternatively, the cycloaddition can be performed in a one-step mode using Cu(I) present from the N-alkylation.

^)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((2,5-dichlorothiophen-3-yl)(1-(piperidin-4-yl)-III, 2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile: (S)-tert-butyl-4-(4-(((8-chloro-4-((3-chloro-4fluorophenyl) amino)-3-cyanoquinolin-6-yl)amino)(2,5-dichlorothiophen-3-yl)methyl)-III-1,2,3-triazol-1yl)piperidine-1-carboxylate (157 mg, 0.206 mmol ) was suspended in DCM (0.5 ml). HCl in dioxane (5 ml; 4M) was added and the reaction mixture was stirred at room temperature for 30 minutes. Solvents were removed under reduced pressure. The residue was flash chromatographed (eluent: (20% MeOH in EtOAc)/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in EtOAc/aqueous saturated sodium bicarbonate solution. The organic layer was isolated and dried over sodium sulfate. Filtration and evaporation of the solvent in vacuo yielded the product.

1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.59 (d, J=2.1 Hz , 1H), 7.37 (t, J=8.9 Hz, 2H), 7.26 (d, J=8.1 Hz, 1H), 7.13 (d, J=10.0 Hz, 3H ), 5.96 (d, J=8.2 Hz, 1H), 4.48 (tt, J=11.8, 4.3 Hz, 1H), 3.75 - 3.62 (m, 1H) , 3.55 (s, 1H), 3.46 (dq, J=9.7, 5.2 Hz, 1H), 2.99 (d, J=12.2 Hz, 2H), 2.55 ( td, J=12.5, 2.4 Hz, 2H), 1.92 (dd, J=11.9, 3.7 Hz, 2H), 1.75 (t, J=12.0 Hz, 3H ).

ES/MS 662.1 (M+H+).

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((2,5-dichlorothiophen-3-yl)(1-(1-ethylpiperidin-4-yl) 1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3-carbonitrile: (S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)6-(( (2,5-dichlorothiophen-3-yl)(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)methyl)amino)quinoline-3carbonitrile (138 mg, 0.208 mmol) dissolved in THF (3 ml) and dichloroethane (3 ml). Acetaldehyde (91.8 mg, 2.08 mmol) and sodium triacetoxyborohydride (176 mg, 0.833 mmol) were added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. The crude material was filtered and volatiles were removed in vacuo and the crude material was purified by silica gel chromatography (eluent: MeOH (20%) in EtOAc/hexanes) to give the product.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.60 (d, J=2.3 Hz, 1H), 7.41 7.34 (m, 2H), 7.27 (d, J=8.2 Hz, 1H), 7.15 (dd, J=9.1, 3.3 Hz, 2H), 7.12 (s, 1H), 5.96 (d, J=8.1 Hz, 1H), 4.50 4.32 (m, 1H), 3.00 - 2.83 (m, 2H), 2.42 - 2.25 (m, 2H), 2.18 - 1.81 (m, 6H), 0.98 (t, J=7.2 Hz, 3H).

ES/MS 689.9 (M+H+).

Example 6, procedure 6.

Benzyl-4-(4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)(3pyridyl)methyl)- 1H-1,2 ,3-triazol-1-yl)piperidin-1-carboxylate: 6-amino-8-chloro-4-((4-chloro3-fluorophenyl)amino)quinoline-3-carbonitrile suspension (159 mg, 0.51 mmol) , aldehyde (176 mg, 0.51 mmol) and pTSA (9.6 mg, 0.05 mmol) in toluene (12 ml) were heated at boiling point (50 ml RBF equipped with a Hickman distillation head). After 4 hours, the solvent was removed under reduced pressure. The solid was dissolved in methyl THF and 3-pyridylmagnesium bromide (2.03 mmol; 8.1 ml 0.25-M

- 50 045220

Me-THF) was added dropwise at -10°C. After 130 minutes the reaction mixture was quenched for us. NH4C1 (3 ml).

The layers were separated and the aqueous phase was extracted with EtOAc (15 ml). The combined organic layers were washed with brine (5 ml), dried over sodium sulfate and concentrated. The residue was flash chromatographed on silica gel (eluent: EtOAc/hexanes). Fractions containing the product were combined and the solvent was removed to obtain the product.

8-Chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((1-(1-ethylpiperidin-4-yl)-III-1,2,3-triazol-4yl)(pyridine -3-yl)methyl)amino)quinoline-3-carbonitrile: benzyl-4-(4-(((8-chloro-4-((3-chloro-4fluorophenyl)amino)-3-cyanoquinolin-6-yl) amino)(pyridin-3-yl)methyl)-1H-1,2,3-triazol-1yl)piperidine-1-carboxylate (57 mg, 0.079 mmol), acetaldehyde (34.7 mg, 0.79 mmol) and Pd-C (25 mg, 10%) in EtOH (3 ml)/EtOAc (2 ml) was stirred under hydrogen atmosphere. After 43 h, the reaction mixture was filtered and volatiles were removed in vacuo and the crude material was purified by HPLC (eluent: water/MeCN 0.1% TFA) to give the product as the trifluoroacetate salt.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.41 (s, 1H), 8.74 (d, J=2.2 Hz, 1H), 8.54 (dd, J=5.0, 1 .5 Hz, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.67 (d, J=2 .2 Hz, 1H), 7.49 (tt, J=6.8, 3.7 Hz, 3H), 7.42 (t, J=9.0 Hz, 1H), 7.26 (d, J =2.5 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.20 (d, J=7.8 Hz, 2H), 4.79 - 4.69 (m, 1H) , 3.61 (d, J=12.4 Hz, 2H), 3.26 - 2.98 (m, 4H), 2.34 (d, J=13.9 Hz, 2H), 2.15 ( q, J=12.5, 11.6 Hz, 2H), 1.22 (t, J=7.3 Hz, 3H).

ES/MS: 616.1 (M+H+).

Compounds of the indicated sequence can be separated into the corresponding stereoisomers using appropriate means (eg, chiral stationary phase chromatography, crystallography) after performing C6 N-alkylation.

Removal of the protecting group in the absence of a reaction partner results in the corresponding non-alkylated amine derivatives.

Example 7, procedure 7.

C.I.

α

8-Chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((pyridin-2-yl(pyridin-3-yl)methyl)amino)quinoline-3carbonitrile: to a suspension of 6-amino-8 -chloro-4-((4-chloro-3-fluorophenyl)amino)quinoline-3-carbonitrile (50 mg, 0.144 mmol) and pyridin-2-yl(pyridin-3-yl)methanone (27 mg, 0.144 mmol) triethylamine (35 mg, 0.346 mmol) was added in DCM (1 ml), followed by TiCl ₄ in DCM (0.086 mmol/0.086 ml). The reaction mixture was stirred overnight at room temperature. It was diluted with MeOH (2 ml) and sodium borohydride (16 mg, 0.432 mmol) was added. The reaction mixture was stirred for 2 hours, then diluted with water and treated with 1 M NaOH until pH ~13 was reached. Solids were removed by filtration and washed with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The product was purified by silica gel chromatography (eluent: EtOAc/hexanes) to obtain the product after lyophilization from water/MeCN.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.66 (dd, J=2.4, 0.8 Hz, 1H), 8.56 (ddd, J=4 .9, 1.8, 0.9 Hz, 1H), 8.47 - 8.39 (m, 2H), 7.87 - 7.75 (m, 3H), 7.61 - 7.19 (m , 8H), 6.08 (d, J=8.7 Hz, 1H).

ES/MS: 515.1 (M+H+).

Example 8, procedure 8.

F

8-Chloro-4-((5,6-difluoropyridin-3-yl)amino)-6-nitroquinoline-3-carbonitrile: 4,8-dichloro-6nitroquinoline-3-carbonitrile (1.4 g, 5.22 mmol ), 2,6-difluoropyridin-3-amine (755 mg, 5.74 mmol) and pyridine hydrochloride (1.8 g, 15.6 mmol) in isopropanol (40 ml) were heated at 70°C overnight. The reaction mixture was cooled to room temperature. Water was added and the resulting precipitate was collected

- 51 045220 by filtering. The crude product was used in the next step without further purification. ES/MS 362.0 (M+H+).

6-Amino-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)quinoline-3-carbonitrile: Prepared from 8-chloro4-((5,6-difluoropyridin-3-yl)amino) -6-nitroquinoline-3-carbonitrile by step-2 of general procedure 1. ES/MS 332.0 (M+H+).

(S)-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)-6-((( 1 -isopropyl-1H-1,2,3-triazol-4-yl)(pyridine -3 yl)methyl)amino)quinoline-3-carbonitrile).

Prepared from 6-amino-8-chloro-4-((5,6-difluoropyridin-3-yl)amino)quinoline-3-carbonitrile via step-3 of general procedure 1. ES/MS 532.1 (M+H+) .

Example 9, procedure 9.

(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8 -dicarbonitrile (): DMF (2 ml) was added to (S)-6-((benzo[d]thiazol-7yl(1-cyclopropyl-III-1,2,3-triazol-4-yl)methyl)amino) -8-bromo-4-(neopentylamino)quinoline-3carbonitrile (38 mg, 0.064 mmol) and CuCN (41 mg, 0.46 mmol) in a microwave vial. The vial was heated to 200°C for 15 minutes in a microwave oven and allowed to cool to room temperature. The reaction mixture was poured into water (4 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

¹ H NMR (400 MHz, Methanol-04) δ 9.20 (s, 1H), 8.34 (s, 1H), 8.05 (dd, J=7.3, 1.9 Hz, 1H), 7.86 (d, J=2.5 Hz, 1H), 7.82 (s, 1H), 7.64 - 7.54 (m, 2H), 7.16 (d, J=2.6 Hz , 1H), 6.34 (s, 1H), 3.97 (d, J=13.7 Hz, 1H), 3.91 3.80 (m, 1H), 3.49 (d, J=13 .7 Hz, 1H), 1.23 - 1.07 (m, 4H), 0.81 (s, 9H). ES/MS 534.1 (M+H+).

Alternative introduction of 8-cyano group

6-Amino-4-(neopentylamino)quinoline-3,8-dicarbonitrile: Solid Zn(CN) ₂ (211 mg, 1.8 mmol) and Pd(PPh) ₄ (35 mg, 0.03 mmol) were added to the solution 6-amino-8-bromo-4-(neopentylamino)quinoline-3carbonitrile (500 mg, 1.5 mmol) in NMP (20 ml). The resulting mixture was degassed by bubbling argon gas for 5 min. The reaction vessel was sealed, then heated to 120°C for 16 hours. The reaction mixture was cooled, then loaded directly onto a silica gel column to obtain pure nitrile. ES/MS 280.3 (M+H+).

Further development of the final compound according to the procedures outlined in this document

Example 10, procedure 10.

(S)-6-((benzo[d]thiazol-6-yl(1H-1,2,3-triazol-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4fluorophenyl )amino)quinoline-3-carbonitrile: (R)-6-((1-(benzo[d]thiazol-6-yl)prop-2-yn-1-yl)amino)-8chloro-4-((3 α-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile (40.0 mg, 0.077 mmol) was dissolved in THF (2 ml). Cu(I)-thiophene-2-carboxylate (4.4 mg, 0.023 mmol) and azidomethyloxypivalate (0.018 ml, 0.12 mmol) were added and the resulting solution was stirred at room temperature for 30 minutes. The reaction contents were poured into saturated aqueous NaHCO ₃ (5 ml) and extracted with EtOAc (3x8 ml). The combined organic layers were washed with brine (5 ml), dried over MgSO ₄ and

- 52 045220 concentrated. The resulting crude residue was then dissolved in MeOH (2 ml). NaOH (1.0 M in water, 0.17 mL, 0.17 mmol) was added and the reaction mixture was left stirring at room temperature for 30 minutes. HCl (1.0 M in water, 0.17 mL, 0.17 mmol) was then added and the resulting solution was poured into water (5 mL) and extracted with EtOAc (3x8 mL). The combined organic layers were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The resulting crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 561.0 (M+H+).

Example 11, procedure 11.

8-Chloro-6-[[(S)-(1-cyclopropyltriazol-4-yl)-deutero-(6-fluoropyridin-3-yl)methyl]amino]-4-[[(1R)3-fluoro-1 -phenylpropyl]amino]quinoline-3-carbonitrile

F

^)-8-chloro-4-((3-hydroxy-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile: 4,8-dichloro-6nitroquinoline-3-carbonitrile (400 mg, 1.49 mmol) , (R)-3-amino-3-phenylpropan-1-ol (270.76 mg, 1.79 mmol) in isopropanol (1.5 ml) was heated under microwave conditions at 150°C for 45 minutes. The reaction mixture was cooled to room temperature. Water and Et ₂ O were added. The aqueous layer was extracted with Et ₂ O and the combined organic layers were dried over sodium sulfate. As a result of filtering and evaporation of the solvents, a crude product was obtained, which was used in the next step without further purification.

ES/MS 383.1 (M+H+).

(R)-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)-6-nitroquinoline-3-carbonitrile: (K)-8-chloro-4-((3hydroxy-1-phenylpropyl)amino )-6-nitroquinoline-3-carbonitrile (100 mg, 0.26 mmol) was treated with deoxofluor® (0.6 ml) at room temperature for 16 hours. The reaction mixture was cooled in an ice bath and carefully quenched with saturated sodium bicarbonate solution, then extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated to give the crude product (115 mg), which was used without further purification.

ES/MS 385.1 (M+H+).

(R)-6-amino-8-chloro-4-((3-fluoro-1-phenylpropyl)amino)quinoline-3-carbonitrile: (R)-8-chloro-4-((3fluoro-1-phenylpropyl) amino)-6-nitroquinoline-3-carbonitrile (115 mg, 0.3 mmol), calcium chloride dihydrate (66 mg, 0.45 mmol) and iron powder (83 mg, 1.49 mmol) were heated in ethanol (3 ml ) / water (0.3 ml) at 60°C for 12 hours. The reaction mixture was cooled to room temperature and solids were removed by filtration. The solids were washed with EtOAc and the combined organic layers were washed with aqueous sodium bicarbonate, brine and dried over sodium sulfate. As a result of filtering and evaporation of all volatile substances, the product was obtained.

ES/MS 355.0 (M+H+).

8-Chloro-6-(((S)-(1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4-fluorophenyl)methyl)amino)-4-(((R)-3 -fluoro-1phenylpropyl)amino)quinoline-3-carbonitrile: (R)-6-amino-8-chloro-4-((3-fluoro-1phenylpropyl)amino)quinoline-3-carbonitrile (50 mg, 0.14 mmol ), CuI (1.4 mg, 0.05 eq) and 2,6-6uc((4S,5R)4,5-diphenyl-4,5-dihydrooxazol-2-yl)pyridine [oxazoline ligand] (4, 4 mg, 0.06 eq) were sonicated in MeOH (2.0 mL) for ~1 minute. Alkynyl acetate (68 mg, 0.35 mmol) and diisopropylethylamine (22 mg, 0.17 mmol) were added and the reaction mixture was stirred overnight. Cyclopropyl azide (16 mg) was added and the reaction mixture was stirred for an additional 16 hours at room temperature. Solvents were removed in vacuo and the crude material was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 572.0 (M+H+).

- 53 045220

Example 12, procedure 12.

(S)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)-6-((indolin-4-yl(1-isopropyl-1H-1,2,3-triazol-4yl)methyl )amino)quinoline-3-carbonitrile: (S)-tert-butyl-4-(((8-chloro-4-((3-chloro-4-fluorophenyl)amino)-3cyanoquinolin-6-yl)amino)( 1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)indoline-1-carboxylate (45 mg, 0.065 mmol) was dissolved in DCM and trifluoroacetic acid and stirred at room temperature. After 30 minutes, the reaction mixture was concentrated to dryness and the residue was purified by HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 586.9 (M+H+).

Example 13, procedure 13.

(S)-6-((( 1-(1 -(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(2-ethylisoindolin-4yl)methyl)amino )-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile: (S)-6-(((1-(1-(tert-butyl)piperidin-4-yl)- Ш-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4fluorophenyl)amino)quinolin-3-carbonitrile (80, 0 mg, 0.12 mmol) was dissolved in MeOH (3 ml) and AcOH (1 ml) at room temperature. Acetaldehyde (0.066 mL, 1.17 mmol) and polymer-bound PS-CNBH3 (467 mg, 1.17 mmol) were then added and the reaction mixture was stirred at room temperature. After 1 hour, additional acetaldehyde (0.066 mL, 1.17 mmol) and polymer-bound PS-CNBH3 (467 mg, 1.17 mmol) were added. After 1 additional hour, PS-CNBH3 was removed by vacuum filtration and the filtrate was concentrated to dryness. The resulting crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 712.1 (M+H+).

Example 14, procedure 14.

(S)-6-((( 1-(1 -(tert-butyl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)(2-(oxetan-3 -yl) isoindolin-4yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile: (S)-6-(((1-(1-(tert-butyl) piperidin-4-yl)-III-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4fluorophenyl)amino)quinoline -3-carbonitrile (15 mg, 0.022 mmol) was dissolved in a 1:1 mixture of THF and DCE, after which oxetanone (0.007 ml, 0.11 mmol) and sodium triacetoxyborohydride (23.2 mg, 0.11 mmol) were added. After 1.5 hours, the reaction mixture was poured into saturated aqueous NaHCO ₃ and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO ₄ and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 740.0 (M+H+).

- 54 045220

Example 15, procedure 15.

(S)-6-((( 1 -(1 -(tert-butyl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)(2-(2-hydroxyacetyl)isoindolin4- yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile: (S)-6-(((1-(1-(tert-butyl)piperidine- 4-yl)-III-1,2,3-triazol-4-yl)(isoindolin-4-yl)methyl)amino)-8-chloro-4-((3-chloro-4fluorophenyl)amino)quinoline-3 -carbonitrile (10.0 mg, 0.015 mmol) was dissolved in DMF (1 ml) followed by glycolic acid (5.6 mg, 0.073 mmol), diisopropylethylamine (0.008 ml, 0.044 mmol) and HATU (7.1 mg, 0.022 ml ) was added at room temperature. The reaction mixture was stirred for 20 minutes, after which it was poured into water (4 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 742.1 (M+H+).

Example 16, procedure 16.

8-Chloro-6-(((S)-( 1-(1,1-difluoro-2-hydroxyethyl)- 1H-1,2,3-triazol-4-yl)(pyridin-3-yl)methyl) amino)4-(((R)-1 -phenylpropyl)amino)quinoline-3-carbonitrile.

Ethyl 2-azido-2,2-difluoroacetate (47 mg, 0.29 mmol) was added to a solution of 8-chloro-4-(((K)-1phenylpropyl)amino)-6-(((R)-1- (pyridin-3-yl)prop-2-yn-1-yl)amino)quinoline-3-carbonitrile (130 mg, 0.26 mmol) and copper(I) thiophene-2-carboxylate (4.9 mg, 0.026 mmol) in THF (2 ml). After 1 hour, the solvent was removed under reduced pressure. The residue was diluted in methanol (6 ml) and sodium borohydride (19.5 mg, 0.52 mmol) was added to the solution. After 1 hour, the reaction mixture was quenched with water and extracted with ethyl acetate (3x10 ml). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated. The residue was flash chromatographed (0-100% (20% methanol in ethyl acetate) and hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in methanol/water with two drops of trifluoroacetic acid and subjected to preparative HPLC, eluting with acetonitrile/water with 0.1% trifluoroacetic acid. Fractions containing the product were combined and lyophilized to give 8-chloro-6-(((8)-(1-(1,1difluoro-2-hydroxyethyl)-III-1,2,3-triazol-4-yl) (pyridin-3-yl)methyl)amino)-4-(((K)-1phenylpropyl)amino)quinoline-3-carbonitrile.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.92 - 8.83 (m, 1H), 8.67 (d, J=9.5 Hz, 1H), 8.65 - 8.58 ( m, 1H), 8.24 (d, J=3.3 Hz, 1H), 8.15 (d, J=7.7 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.52 (d, J=8.3 Hz, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.39 7.29 (m, 2H), 7.29 - 7, 16 (m, 6H), 6.54 (d, J=7.8 Hz, 1H), 5.47 (q, J=7.6 Hz, 1H), 4.32 (t, J=12.0 Hz, 2H), 2.11 (m, 1H), 2.04 - 1.83 (m, 1H), 0.93 (t, J=7.3 Hz, 3H).

ES/MS 575.1 (M+H ⁺ ).

- 55 045220

Example 17, procedure 17.

(S)-6-((( 1-(1 -(tert-butyl)piperidin-4-yl)- 1H-1,2,3-triazol-4-yl)(6-isopropoxypyridin-3 yl)methyl) amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

NaH (60% dispersion in mineral oil, 26.6 mg, 0.66 mmol) was added to /PrOH (2 ml) at 0°C for 20 minutes. (S)-6-((( 1 -(1 -(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(6-fluoropyridin-3yl)methyl)amino )-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile (22 mg, 0.033 mmol) in DMF (0.5 ml) was then added to the newly formed alkoxide. The ice bath was removed and the resulting solution was heated to 70°C for 1 hour. The reaction mixture was quenched with water (1 ml) and extracted with EtOAc (3x8 ml). The combined organic phases were then washed with brine (5 ml), dried over MgSO ₄ and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

Example 18, procedure 18.

(S)-6-((( 1 -(1 -(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(tetrahydro-2H-pyran-4yl)methyl )amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile

(S)-6-((( 1 -(1 -(tert-butyl)piperidin-4-yl)-1H-1,2,3-triazol-4-yl)(3,6-dihydro-2H-pyran -4yl)methyl)amino)-8-chloro-4-((3-chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile (20.0 mg, 0.023 mmol), 10% Pd/C (2.5 mg, 0.002 mmol) and EtOH (1.5 ml) were combined and H ₂ was bubbled through the reaction mixture for 5 minutes. The reaction mixture was left stirring overnight under 1 atm H ₂ after which it was filtered through celite, washing with EtOAc and EtOH. The filtrate was then concentrated and purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

Example 19, procedure 19.

(S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(3-oxoisoindolin-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8 - dicarbonitrile

(S)-6-(((2-acetyl-3-OkCOisoindolin-4-yl)(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline -3,8-Dicarbonitrile (34 mg, 0.059 mmol) was dissolved in MeOH (2 ml) at room temperature. NaOH (1.0 M aq, 0.30 mL, 0.30 mmol) was added and the reaction mixture was stirred for 30 minutes. HCl (1.0 M aq, 0.30 mL, 0.30 mmol) was added, after which the reaction mixture was poured into water (3 mL) and extracted with EtOAc (3x8 mL). The combined organic phases were washed with brine (5 mL). , dried over MgSO4 and concentrated.The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

- 56 045220

Example 20, procedure 20.

8-Chloro-4-(3-chloro-4-fluoroanilino)-6-[[(S)-[1-(1-ethylpiperidin-4-yl)triazol-4-yl]-(1,3-thiazol- 4yl)methyl]amino]quinoline-3-carbonitrile

The title compound was prepared with the following final step conditions: (S)-8chloro-4-((3-chloro-4-fluorophenyl)amino)-6-(((1-(piperidin-4-yl)-III-1 ,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)quinoline-3-carbonitrile (74.31 mg, 0.13 mmol) was dissolved in 1.20 ml of a 3:1 mixture of 2methyltetrahydrofuran: acetic acid and treated with acetaldehyde (10.52 μl, 0.19 mmol) and PSBH ₃ CN (cyanoborohydride on polystyrene, 58 mg, 2.28 mmol/g). The mixture was stirred overnight. Additional acetaldehyde and 0.1 ml methanol were added and the reaction was completed in one hour. The resin was filtered and the resulting filtrate was concentrated, dissolved in dichloromethane, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. Purification using RP-HPLC (eluent: water/MeCN *0.1% TFA) gave the product as the trifluoroacetate salt.

1H NMR (400 MHz, CD3OD) δ 9.02 (m, 1H), 8.46 (s, 1H), 8.01 (m, 1H), 7.68 (m, 1H), 7.60 (m , 1H), 7.52 (m, 1H), 7.33 (m, 4H), 6.31 (s, 1H), 3.75 (m, 2H), 3.25 - 3.13 (m, 3H), 2.45 (m, 2H), 2.36 (m, 2H), 2.25 - 2.01 (m, 2H), 1.37 (m, 3H),

ES/MS 622.0 (M+H+)

Example 21, procedure 21.

8-Chloro-4-(3 -chloro-4-fluoroanilino)-6-[ [(S)-( 1 -propan-2-yltriazol-4-yl)-[5-(pyrrolidin-1 carbonyl)pyridin-3 -yl]methyl]amino]quinoline-3-carbonitrile

O

Mixture of (S)-6-(((5-bromopyridin-3-yl)(1-isopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-8-chloro-4-(( 3chloro-4-fluorophenyl)amino)quinoline-3-carbonitrile (200 mg, 0.32 mmol), pyrrolidine (580.6 mg, 8.16 mmol) and dichloro-1,1-bis(diphenylphosphino)ferrocene palladium(P ) and dichloromethane (269.1 mg, 0.32 mmol) in DMF (1.2 ml) were degassed and purged twice with carbon monoxide, heated at 80°C for 5 hours. The solution was cooled and poured into water, then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The crude product was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

ES/MS 644.1 (M+H+)

Example 22, procedure 22.

6-(((S)-(6-fluoropyridin-3-yl)(1-methyl-1H-1,2,3-triazol-4-yl)methyl-d)amino)-4-(((R) -1phenylpropyl)amino)quinoline-3,8-dicarbonitrile: A 1.0 M solution of TBAF (0.38 mL, 0.38 mmol) in THF was added to a stirred solution of 6-(((R)-(6-fluoropyridine-3 -yl)(1-((trimethylsilyl)methyl)-1H-1,2,3triazol-4-yl)deuteromethyl)amino)-4-(((R)-1-phenylpropyl)amino)quinoline-3,8- dicarbonitrile (150 mg, 0.25 mmol) in THF (5 ml). The resulting solution was stirred for 2 hours and then concentrated to give the crude material. As a result of HPLC purification, the title compound was obtained.

Ή NMR (400 MHz, DMSO-06) δ 8.49 - 8.38 (m, 1H), 8.28 (d, J=5.1 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.84 (t, J=2.4 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.42 - 7.31 (m, 1H), 7.31 - 7 .15 (m, 4H), 5.49 (q, J=7.7 Hz, 1H), 4.04 (s, 3H), 3.20 - 3.11 (m, 1H), 2.20 - 2.05 (m, 1H), 2.05 - 1.85 (m, 1H), 1.63 - 1.50 (m, 1H), 1.37 - 1.20 (m, 1H), 0, 99 - 0.83 (m, 3H).

ES/MS 519.2 (M+H+).

Example 23, procedure 23.

The CuI (2.6 mg, 0.014 mmol) and ligand (8.7 mg, 0.017 mmol) were suspended in MeOH (1 ml) and sonicated under argon for 5 min. The remaining MeOH was added followed by acetate (70.3 mg, 0.36 mmol) and amine (80 mg, 0.27 mmol) and DIPEA (43 mg, 0.33 mmol) in that order at room temperature. After 14 h, the N-reactions were completed. Evaporation and purification on silica gel (eluent: EtOAc in hexanes) gave 95 mg of N-alkylated product. The substance was diluted in THF (2 ml). Stock solution of azide (1 ml/1 eq), Cu and CuSO ₄ was added. Stir at room temperature for 1 hour. Dilute with EtOAc, wash with NaHCO ₃ brine and dry over sodium sulfate. Filtration, evaporation and purification by RP-HPLC (eluent: water/MeCN *0.1 TFA) gave the product as the TFA salt.

1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.69 (d, J=2.3 Hz , 1H), 7.26 (d, J=2.3 Hz, 1H), 6.31 (s, 1H), 5.91 (t, J=54.8 Hz, 1H), 4.09 (d , J=13.9 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H), 2.56 (s, 3H), 1.50 (m, 4H), 1.05 (s , 9H).

Example 24, procedure 24.

Starting material (38 mg, 0.05 mmol), Zn (0.4 mg, 0.007 mmol), PddppfCl ₂ (0.8 mg, 0.001 mmol) and Zn(CN) ₂ (7.1 mg, 0.061 mmol) were combined in dimethylacetamide (1 ml) and degassed for 2 min. The mixture was heated in a microwave reactor at 200°C for 20 minutes. The mixture was filtered and purified by RP-HPLC. The product fractions were combined and lyophilized to obtain the desired compound as the TFA salt.

1H NMR (400 MHz, Methanol-d4) δ 8.78 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H), 7.83 (d, J=2.5 Hz , 1H), 7.44 (d, J=2.5 Hz, 1H), 6.32 (s, 1H), 5.92 (t, J=54.8 Hz, 1H), 3.96 (d , J=13.9 Hz, 1H), 3.80 (d, J=13.9 Hz, 1H), 2.56 (s, 3H), 1.50 (m, 4H), 1.02 (s , 9H).

Example 25, procedure 25.

Starting material (0.04 g, 0.06 mmol), Zn powder (0.006 g, 0.09 mmol), PddppfCl2 (0.009 g, 0.012

- 58045220 mmol) and Zn(CN)2 (0.021 g, 0.18 mmol) were combined in dimethylacetamide (0.7 ml) and degassed for min. The mixture was heated in a microwave reactor at 200°C for 15 minutes. The mixture was filtered and purified by RP-HPLC. The product fractions were combined and lyophilized to obtain the desired compound as the TFA salt.

1H NMR (400 MHz, Methanol-BD) δ 9.61 (s, 1H), 8.69 (d, J=6.1 Hz, 1H), 8.33 (s, 1H), 8.23 (s , 1H), 8.17 (d, J=7.6 Hz, 1H), 8.16 (d, J=6.1 Hz, 1H), 8.02 (d, J=7.6 Hz, 1H ), 7.83 (d, J=2.5 Hz, 1H), 7.02 (d, J=2.5 Hz, 1H), 6.91 (s, 1H), 3.82 (d, J =13.8 Hz, 1H), 3.42 (d, J=13.7 Hz, 1H), 1.79 - 1.55 (m, 4H), 0.62 (s, 9H).

Example 26, procedure 26.

K (S)-8-chloro-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(2-fluoropyridin-3-yl)methyl-d)amino)-4( Dimethylamine (2 M solution in MeOH, 0.9 ml) was added to neopentylamino)quinoline-3-carbonitrile (TFA salt, 24 mg, 0.04 mmol). The solution was heated to 100°C (external temperature, pW) for 8 hours. The resulting solution was concentrated, purified using preparative HPLC (Gemini column, 10-42% MeCN/H ₂ O/0.1% TFA) and lyophilized to obtain product in the form of the corresponding TFA salt.

1H NMR (400 MHz, Methanol^) δ 8.38 (s, 1H), 8.06 (dd, J=5.4, 1.8 Hz, 1H), 7.92 (s, 1H), 7, 81 (dd, J=7.6, 1.8 Hz, 1H), 7.49 (d, J=2.3 Hz, 1H), 7.06 (d, J=2.3 Hz, 1H), 7.02 (dd, J=7.6, 5.4 Hz, 1H), 4.10 (d, J=14.0 Hz, 1H), 3.78 (ddd, J=11.4, 7, 1, 4.2 Hz, 1H), 3.63 (d, J=14.0 Hz, 1H), 2.97 (s, 6H), 1.12 - 1.02 (m, 4H), 0, 91 (s, 9H).

Example 27, procedure 27.

Cu(I) iodide (16.5 mg, 0.09 mmol) and bis-oxazoline ligand (54.2 mg) were sonicated in MeOH (10 ml) for 5 minutes. The mixture was cooled to 0°C. A solution of alkynyl acetate (687 mg, 3.3 mmol) in MeOH (7 mL) was added followed by quinoline (500 mg, 1.73 mmol) and di-isopropylethylamine (268.5 mg, 2.08 mmol). Stirring at 0°C was continued. After consumption of the starting material, the reaction volume was reduced and the crude material was purified by silica gel chromatography (eluent: EtOAc in hexanes) to obtain the product.

1H NMR (400 MHz, Acetonitrile^) δ 8.34 (s, 1H), 8.14 (t, J=8.2 Hz, 1H), 7.43 (d, J=2.3 Hz, 1H) , 6.95 6.82 (m, 2H), 5.98 (t, J=6.4 Hz, 1H), 5.64 (dd, J=7.1, 2.2 Hz, 1H), 5 .52 (d, J=7.2 Hz, 1H), 3.81 (dd, J=13.4, 6.7 Hz, 1H), 3.67 (dd, J=13.4, 6.0 Hz, 1H), 2.88 (d, J=2.2 Hz, 1H), 2.56 (s, 3H), 2.23 (s, 1H), 1.01 (s, 9H).

ES/MS m/z: 436.2.

The alkyne starting material (1.6 g, 3.67 mmol) was dissolved in MeTHF (16 mL) and a solution of azide in MTBE (0.5 M, 7.34 mL) and copper(I) thiophene carboxylate (24 mg, 0. 18 mmol) and continued stirring at room temperature. After consumption of the starting material, the reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvents provided a crude material which was purified by silica gel chromatography (el. EtOAc in hexanes) to give the product.

1H NMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.93 (t, J=8.1 Hz, 1H), 7.41 (s, 1H), 7.35 (d , J=2.3 Hz, 1H), 6.80 (dd, J=8.4, 3.2 Hz, 1H), 6.25 (s, 1H), 5.93 (s, 1H), 5 .91 (t, J=56.0 Hz, 1H), 5.27 (s, 1H), 3.57 (m, 2H), 2.58 (s, 3H), 1.55 - 1.50 ( m, 4H), 0.94 (s, 9H).

ES/MS m/z: 569.6.

Example 28, procedure 28.

(S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3- 59 045220 yl) methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile

Copper(I) iodide (172.5 mg, 0.906 mmol) and iodine chloride (147 mg, 0.906 mmol) were added to a solution of (R)-8-chloro-6-((1-(6-fluoro-2-methylpyridinium- 3-yl)prop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3 carbonitrile (394 mg, 0.906 mmol), cyclopropyl azide (79.1 mg 0.906 mmol) and triethylamine (151.6 μl , 1.09 mmol) in tetrahydrofuran (15 ml). After 16 h, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with water (25 ml) and brine (25 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The material was mixed with ethyl acetate (5 ml) and the solid was isolated by filtration to give (S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H1,2,3-triazol-4-yl)() 6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3carbonitrile.

Example 29, procedure 29.

(S)-8-Chloro-6-(((1,5-diciclopropyl-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)-4 -(neopentylamino)quinoline-3-carbonitrile

1,4-Dioxane (4.0 ml) and water (0.5 ml) were added to (8)-8-Chloro-6-(((1-cyclopropyl-5-iodo-III-1,2,3triazol- 4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (100 mg, 0.155 mmol), cyclopropylboronic acid (20 mg, 0.223 mmol), tetrakis(triphenylphosphine)palladium(0) (35.8 mg, 0.031 mmol) and potassium carbonate (42.8 mg, 0.310 mmol) in a microwave vial. The reaction mixture was heated in a microwave reactor for 20 minutes at 130°C. The mixture was diluted with ethyl acetate (10 ml) and washed with saline (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0 - 100% ethyl acetate/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in methanol (1 ml) and water (0.5 ml) with 2 drops of trifluoroacetic acid and subjected to preparative HPLC. The pure fractions were combined and lyophilized to give (8)-8-Chloro-6-(((1,5-dicyclopropyl-III-1,2,3triazol-4-yl)(6-fluoro-2-methylpyridin-3- yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 30, procedure 30.

(S)-8-chloro-6-(((1-cyclopropyl-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino) -4-(neopentylamino)quinoline-3-carbonitrile

F

Acetonitrile (1.0 ml) and water (1.0 ml) were added to (S)-8-Chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3triazol-4-yl) (6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (50 mg, 0.078 mmol) and potassium fluoride (22.5 mg, 0.388 mmol) in a microwave vial . The vial was sealed and the reaction mixture was heated in a microwave reactor at 180°C for 12 minutes. The reaction mixture was diluted with ethyl acetate (10 ml) and washed with brine (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0 - 100% ethyl acetate/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in methanol (1 ml) and water (0.5 ml) with 2 drops of trifluoroacetic acid and subjected to preparative HPLC. Pure fractions

- 60 045220 were combined and lyophilized to give (S)-8-chloro-6-(((1-cyclopropyl-5-fluoro-1H-1,2,3triazol-4-yl)(6-fluoro-2-methylpyridine -3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 31, procedure 31.

(S)-8-chloro-6-(((1-cyclopropyl-5-methoxy-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino) -4-(neopentylamino)quinoline-3-carbonitrile

Sodium methoxide (26 μL, 0.119 mmol, 25% purity in THF) was added to a solution of (S)-8-chloro-6-(((1cyclopropyl-5-fluoro-III-1,2,3-triazol-4-yl )(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4(neopentylamino)quinoline-3-carbonitrile (42.6 mg, 0.079 mmol) in tetrahydrofuran (2.0 ml). The solution was heated at 90°C for 30 minutes and the reaction mixture was quenched with 2 drops of acetic acid. The solution was diluted with ethyl acetate (15 ml) and washed with saturated sodium bicarbonate (5 ml) and brine (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-100% ethyl acetate/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in methanol (1 ml) and water (0.5 ml) with 2 drops of trifluoroacetic acid and subjected to preparative HPLC. Pure fractions containing product were combined and lyophilized to give (S)-8-chloro-6-(((1-cyclopropyl-5-methoxy-1H-1,2,3-triazol-4-yl)(6- fluoro-2-methylpyridin-3yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile.

Example 32, procedure 32.

Aldehyde (223 mg, 1.4 mmol) was dissolved in acetonitrile (8 ml). Triethylamine (0.29 ml, 2.1 mmol) and DMAP (34 mg, 0.28 mmol) were added followed by Boc ₂ O (365 mg, 1.7 mmol) and the resulting mixture was stirred for 2 minutes. Once complete, the reaction contents were directly concentrated, then purified by silica gel chromatography (EtOAc in hexanes) to give the product.

The newly formed substance was diluted in THF (15 ml) and brought to 0°C. Ethynylmagnesium bromide (0.5M in THF, 3.7 ml, 1.8 mmol) was added dropwise and the resulting solution was stirred for 30 minutes, after which acetic anhydride (0.29 ml, 3.1 mmol) and the reaction contents were added left to warm to room temperature for 1 hour. The reaction mixture was quenched by adding saturated aqueous NH4Cl and extracted with EtOAc. The organic layers were washed with brine, dried over magnesium sulfate, filtered and concentrated to give crude propargyl acetate, which was used without further purification.

CuI (6.6 mg, 0.035 mmol) and ligand (22 mg, 0.042 mmol) were suspended in MeOH (5 mL) and sonicated under argon for 5 min. Acetate (136 mg, 0.42 mmol) as a solution in MeOH (2 mL), amine (100 mg, 0.35 mmol) and DIPEA (54 mg, 0.42 mmol) were added in that order at room temperature. After 2 hours, the reaction mixture was directly concentrated and purified on silica gel (EtOAc in hexanes) to give the alkylated product.

The substance was diluted in THF (2 ml). Azide stock solution (1 ml/1 eq), Cu and CuSO ₄ were added and the resulting mixture was stirred at room temperature for 30 minutes. Dilute with EtOAc, wash with water, brine and dry over magnesium sulfate. As a result of filtration and concentration, a crude product was obtained, which was then stirred in 1 ml of a 1:1 mixture

DCM:trifluoroacetic acid for 30 min. DCM and TFA were removed by rotary evaporation, after which the crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1 TFA) to give the product as the TFA salt.

Example 33, procedure 33.

F F

A solution of alkyne starting material (50 mg, 0.115 mmol) in deuterated methanol (CD3OD, 2 ml) was treated with a solution of azide in DCM (25% w/w, 80 mg, 0.138 mmol) and copper(I) thiophenecarboxylate (1 mg) at room temperature . After 1 hour, the reaction mixture was diluted with EtOAc and washed with aqueous sodium bicarbonate and dried over sodium sulfate. Filtration and evaporation of the solvents provided a crude product which was purified by reverse phase HPLC to obtain the pure product.

1H NMR (400 MHz, Acetonitrile^) δ 8.44 (s, 1H), 7.82 (t, J=8.2 Hz, 1H), 7.49 (d, J=2.3 Hz, 1H) , 6.84 (dd, J=8.4, 3.2 Hz, 1H), 6.78 (s, 1H), 6.17 (s, 1H), 3.83 (m, 2H), 1, 78 - 1.65 (m, 2H), 1.65 (m, 2H), 0.95 (s, 9H).

ES/MS m/z: 588.31.

Example 34, procedure 34.

Mixture of (S)-8-iodo-4-(neopentylamino)-6-((quinolin-5-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3triazol-4-yl)methyl) amino)quinoline-3-carbonitrile (61 mg, 0.09 mmol) and copper cyanide (23.53 mg, 0.26 mmol) in DMF (2 ml) were heated at 135°C in a microwave oven for 15 minutes. The solution was treated with Si-thiol, filtered and purified by reverse phase HPLC to give (S)-4(neopentylamino)-6-((quinolin-5-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H- 1,2,3-triazol-4yl)methyl)amino)quinoline-3,8-dicarbonitrile in the form of bis-trifluoroacetate salt.

1H NMR (400 MHz, Methanol-d ₄ ) δ 9.11 (s, 1H), 9.04 (d, J=8.7 Hz, 1H), 8.30 (s, 1H), 8.21 ( s, 1H), 8.18 8.10 (m, 1H), 7.99 - 7.90 (m, 1H), 7.90 - 7.82 (m, 2H), 7.80 (s, 1H ), 7.14 - 7.08 (m, 1H), 6.94 (s, 1H), 3.79 (d, J=13.8 Hz, 1H), 3.48 (d, J=13, 8 Hz, 1H), 1.75 - 1.56 (m, 4H), 0.66 (s, 9H).

ES/MS m/z: 596.35.

Example 35, procedure 35.

N-Ethyldiisopropylamine (15.47 µl, 0.09 mmol) was added to the mixture (8)-1-(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-6-yl)amino)( 6-fluoro-2-methylpyridin-3-yl)methyl)-1H-1,2,3-triazol-1yl)cyclopropane-1-carboxylic acid (25 mg, 0.044 mmol), 2-(7-aza-1Hbenzotriazole) hexafluorophosphate -1-yl)-1,1,3,3-tetramethyluronium (HATU), 99% (17.27 mg, 0.05 mmol) and 2 M dimethylamine solution (44.4 μl, 0.053 mmol) in dimethylformamide (1 ml). After 3 h, half of the solvent was removed under reduced pressure. The solution was diluted with methanol (0.75 ml), water (0.5 ml) and TFA (50 μl). This solution was subjected to preparative HPLC. Pure fractions containing the product were combined and lyophilized to obtain the desired compound. The lyophilized solid was diluted in methanol (0.5 ml) and passed through a carbonate resin with a methanol rinse (5 ml). The solvent was removed under reduced pressure and the residue was diluted in ACN (1 ml) and water (1 ml) with TFA (0.02 ml) and lyophilized to give (8)-1-(4-(((8-chloro-3 -cyano-4- 62 045220 (neopentylamino)quinolin-6-yl)amino)(6-fluoro-2-methylpyridin-3-yl)methyl)-III-1,2,3-triazol-1-yl)N, N-dimethylcyclopropane-1-carboxamide.

Example 36, procedure 36.

Solution of (S)-8-chloro-6-(((1-cyclopropyl-5-iodo-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino )-4-(neopentylamino)quinoline-3-carbonitrile (33 mg, 0.051 mmol), copper (I) cyanide (13.7 mg, 0.15 mmol) in dimethylformamide (1 ml) was heated in a microwave reactor at 200 C in for 20 minutes. The mixture was diluted with ethyl acetate (10 ml) and washed with 5% lithium chloride (2 x 5 ml) and saline (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-100% EtOAc/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in water (0.5 ml) and methanol (1 ml) with 2 drops of TFA and subjected to preparative HPLC. The pure fractions were combined and lyophilized to give (S)-8-chloro-6-(((5-cyano-1-cyclopropyl-1H1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin- 3-yl)methyl)amino)-4-(neopentylamino)quinoline-3carbonitrile.

Example 37 procedure 37.

A solution of tert-butyl-(8)-3-(((3-cyano-8-iodo-4-(neopentylamino)quinolin-6-yl)amino)(1cyclopropyl-1H-1,2,3-triazol-4- yl)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate (60.3 mg, 0.082 mmol), tetrakis(triphenylphosphine)palladium(0) (7.55 mg, 0 .01 mmol) and zinc cyanide (23.96 mg, 0.20 mmol) were degassed with argon for 10 minutes. The mixture was heated in a sealed vial at 100°C. After 36 h, the reaction mixture was diluted with ethyl acetate (20 ml) and washed with 5% lithium chloride (2x5 ml) and saline (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0-100% (20% methanol/ethyl acetate)/hexanes). Fractions containing the product were combined and the solvent was removed under reduced pressure to give tert-butyl-(S)-3-((1-cyclopropyl-1H-1,2,3-triazol-4-yl)((3,8- dicyano4-(neopentylamino)quinolin-6-yl)amino)methyl)-4,7-dihydrothieno[2,3-c]pyridine-6(5H)-carboxylate.

Zinc bromide (88.6 mg, 0.39 mmol) was added to a solution of tert-butyl-(S)-3-((1-cyclopropyl-1H1,2,3-triazol-4-yl)((3,8- Dicyano-4-(neopentylamino)quinolin-6-yl)amino)methyl)-4,7-dihydrothieno[2,3c]pyridine-6(5H)-carboxylate (50.2 mg, 0.079 mmol) in nitromethane (5 ml ). After 50 minutes, the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate (20 ml) and saturated sodium bicarbonate (10 ml). The resulting solid was removed by filtration. The organic phase was washed with saturated sodium bicarbonate (10 ml) and brine (10 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure to give (S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(4,5,6,7- tetrahydrothieno[2,3-c]pyridin-3yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile.

- 63 045220

3-Oxetanone (38.75 μL, 0.6 mmol) was added to the mixture (S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4yl)(4,5,6,7 -tetrahydrothieno[2,3-c]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8dicarbonitrile (32.5 mg, 0.060 mmol) and sodium triacetoxyborohydride (128.1 mg, 0. 60 mmol) in tetrahydrofuran (2 ml) dichloroethane (2 ml) and heated at 40°C for 16 hours. The mixture was diluted with ethyl acetate (10 ml) and washed with saturated sodium bicarbonate (2x5 ml) and brine (5 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was flash chromatographed (0 - 100% (20% methanol in ethyl acetate)/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in methanol (0.5 ml)/water (0.5 ml) with 2 drops of TFA and subjected to preparative HPLC (eluted with 0.100% acetonitrile in water with 0.05% trifluoroacetic acid). Pure fractions were pooled and lyophilized, (S)-6-(((1-cyclopropyl-1H-1,2,3-triazol-4-yl)(6-(oxetan-3-yl)-4,5,6 ,7tetrahydrothieno[2,3-c]pyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3,8-dicarbonitrile.

Example 38, procedure 38.

(S)-6-((benzo[d]thiazol-7-yl(1-cyclopropyl-1H-1,2,3-triazol-4-yl)methyl)amino)-4-(tertbutoxyamino)quinoline-3, 8-dicarbonitrile: to (S)-6-((benzo[d]thiazol-7-yl(1-cyclononyl-1H-1,2,3triazol-4-yl)methyl)amino)-4-(tert-butoxyamino )-8-iodoquinoline-3-carbonitrile (59 mg, 0.093 mmol) in N-methyl-2-πpyrrolidone (1 ml) was added zinc cyanide (27 mg, 0.232 mmol) and palladium tetrakistriphenylphosphine (9 mg, 0.007 mmol). The reaction mixture was degassed with nitrogen for 5 minutes, then stirred at 100°C overnight. The reaction mixture was then brought to room temperature and diluted with water and EtOAc. The aqueous layer was extracted again with EtOAc. The combined organics were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated to give the crude product, which was purified by HPLC (eluent: water/MeCN *0.1% TFA) to give the title product. ES/MS 536.20 (M+H+).

Example 39, procedure 39.

(S)-6-((benzo[d]thiazol-7-yl(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)8-( methylsulfonyl)-4-(neopentylamino)quinoline-3-carbonitrile: to (S)-6-((benzo[d]thiazol-7-yl(1-(1(trifluoromethyl)cyclopropyl)-1H-1,2,3 -triazol-4-yl)methyl)amino)-8-bromo-4-(neopentylamino)quinoline3-carbonitrile (31 mg, 0.047 mmol), (L)-proline (1.1 mg, 0.009 mmol), Cu(I )I (1 mg, 0.005 mmol), sodium methylsulfonate (5.8 mg, 0.057 mmol) and Cs ₂ CO ₃ (15 mg, 0.047 mmol) were added with DMSO (0.8 ml). The reaction mixture was placed under a nitrogen atmosphere and stirred at 110°C overnight. The reaction mixture was then brought to room temperature and diluted with water and EtOAc. The aqueous layer was extracted again with EtOAc. The combined organics were washed with water, brine, dried (Na ₂ SO ₄ ) and concentrated to give the crude product, which was purified by HPLC (eluent: water/MeCN *0.1% TFA) to give the title product. ES/MS 655.7 (M+H+).

- 64 045220

Example 40, procedure 40.

He

6-(((6-fluoro-2-methylpyridin-3-yl)(1-(1-(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4yl)methyl)amino)-8-(3 -Hydroxy-3-methylbut-1-in-1-yl)-4-(neopentylamino)quinoline-3-carbonitrile: 6(((6-fluoro-2-methylpyridin-3-yl)(1-(1-( trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)methyl)amino)8-iodo-4-(neopentylamino)quinoline-3-carbonitrile (30 mg, 0.044 mmol), copper iodide (0. 84 mg, 0.004 mg), and 2-methyl-3-butyn-2-ol (18.6 mg, 0.22 mmol) was dissolved in Me-THF. Bis(triphenylphosphine)palladium(P) dichloride (3.1 mg, 0.004 mmol) was then added to the mixture, followed by diethylamine (0.05 mL, 0.44 mmol). The reaction mixture was heated to 80°C for one hour, then diluted with EtOAc and brine, the organic layer was left, dried over sodium sulfate and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

Example 41, procedure 41.

F (S)-8-Chloro-6-((( 1-(1 -(difluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3 yl )methyl)amino)-5-fluoro-4-(neopentylamino)quinoline-3-carbonitrile: (S)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)-1H-1,2, 3-triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4(neopentylamino)quinoline-3-carbonitrile (100 mg, 0.18 mmol) was dissolved in ACN. Selectfluor (31.8 mg, 0.176 mmol) was added to the stirred mixture. The reaction was stopped after 20 minutes and diluted with EtOAc and water. The organic layer was dried over sodium sulfate and concentrated. The product was purified by silica gel chromatography (eluent: EtOAc/hexanes) to obtain the product after lyophilization from water/MeCN.

Example 42, procedure 42.

(S)-5-bromo-8-chloro-6-((( 1-(1 -(difluoromethyl)cyclopropyl)-5-fluoro-1H-1,2,3-triazol-4-yl)(6-fluoro -2methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: N-Bromosuccinimide (7.8 mg, 0.044 mmol) was added to a solution of (S)-8-chloro-6-(( (1-(1-(difluoromethyl)cyclopropyl)-5-fluoro-1H-1,2,3triazol-4-yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino )quinoline-3-carbonitrile (26 mg, 0.044 mmol) in acetonitrile (1 ml) at 0°C. After 24 hours at room temperature, trifluoroacetic acid (4 drops) was added and the mixture was diluted with water. The yellow solution was subjected to preparative HPLC. Fractions containing the product were combined and the solvent was removed under reduced pressure to give (S)-5-bromo-8-chloro-6-(((1-(1-(difluoromethyl)cyclopropyl)-5-fluoro-1H-1 ,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile as TFA salt.

Example 43, procedure 43.

ADMP, DBU

NH ₂ --------HCI MeCN

- 65 045220

1-Azidobicyclo[1.1.1]pentane: A solution of 2-azido-1,3-dimethylimidazolinium hexafluorophosphate (429 mg, 1.5 mmol) in acetonitrile (2 ml) was added to a solution of bicyclo[1.1.1]pentane-1-hydrochloride amine (150 mg, 1.25 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (420 mg, 4.2 mmol) in acetonitrile (3 ml) dropwise over 1 min. After 16 hours at rt, the reaction mixture was heated at 40°C for 3 hours. The reaction was assumed to be complete and the reaction mixture was used in the click reaction as is.

(S)-6-((( 1 -(bicyclo[1.1.1]pentan-1 -yl)- 1H-1,2,3-triazol-4-yl)(2-methyl-1-oxo-1, 2dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3-carbonitrile: 2Methyltetrahydrofuran (12 ml), copper powder (394 mg, 6.2 mmol) and (R)-8- chloro-6-((1-(2-methyl-1-oxo1,2-dihydroisoquinolin-5-yl)prop-2-in-1-yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (500 mg, 1.03 mmol) were combined. Saturated copper(II) sulfate (0.6 mL) was added followed by acetic acid (236 μL, 4.13 mmol). A solution of 1-azidobicyclo[1.1.1]pentane (137 mg, 1.25 mmol) in acetonitrile (5 ml - reaction mixture from step above) was added. After 1 hour, solids were removed by filtration. The mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride (50 ml). An emulsion with a light solid was formed. The solid was removed by filtration through celite. The organic phase was washed with saturated ammonium chloride (50 ml), saturated sodium bicarbonate (4x50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was subjected to flash chromatography (0 - 70% ethyl acetate/hexanes). Fractions containing product were combined and the solvent was removed under reduced pressure. The residue was diluted in acetonitrile (15 ml) and water (15 ml) and lyophilized to give (8)-6-(((1-(bicyclo[1.1.1]pentan-1-yl)-III-1,2, 3-triazol-4-yl)(2methyl-1-oxo-1,2-dihydroisoquinolin-5-yl)methyl)amino)-8-chloro-4-(neopentylamino)quinoline-3carbonitrile.

Example 44, procedure 44.

F (S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(4,5,6,7-tetrahydro-[1,2,3]triazolo[1,5- a]pyridin-3yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: A mixture of bromoalkane (54 mg, 0.09 mmol) in 4.4 ml of toluene was purged with argon for 45 minutes. It was heated to boiling point and then tris(trimethylsilyl)silane) (43.74 mg, 0.18 mmol) was added, followed by dropwise addition of 2,2'-azobisobutyronitrile, 98% (1.44 mg, 0.01 mmol ) in 0.44 ml of toluene. After 16 hours of reflux, another portion of silane was added and heating was continued for another 4 hours. The mixture was concentrated and purified by RP-HPLC to give the product as the trifluoroacetate salt.

Example 45, procedure 45.

(S)-8-chloro-6-(((6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3]oxazin-3-yl)(6- fluoro-2-methylpyridin-3yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile and (S)-8-chloro-6-(((6-fluoro-2-methylpyridin3 -yl)( 1 - (3-hydroxypropyl)-1 H-1,2,3-triazol-4-yl)methyl)amino)-4-(neopentylamino)quinoline-3 carbonitrile: (S)-8-chloro-6-(((5 -fluoro-1-(3-hydroxypropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3-yl)methyl)amino)-4-(neopentylamino)quinoline-3- carbonitrile (37 mg, 0.07 mmol, prepared as in Example 23) was dissolved in DMF and cooled in an ice bath. NaH was added to a 60% dispersion of sodium hydride in mineral oil (5.6 mg, 0.23 mmol) and the mixture was allowed to warm to room temperature. After 1 hour, the reaction was complete by UPLC-MS and the reaction mixture contained the dehalogenated uncyclized product. Purification by RP HPLC for 15 minutes yielded 10-49% of two products independently as the corresponding trifluoroacetate salts.

(S)-8-chloro-6-(((6,7-dihydro-5H-[1,2,3]triazolo[5,1-b] [1,3]oxazin-3-yl)(6- fluoro-2-methylpyridin-3yl)methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: ES/MS m/z: 535.34.

'and NMR (400 MHz, Acetonitrile-dz) δ 8.42 (s, 1H), 7.92 (m, 1H), 7.48 (s, 1H), 6.79 (m, 1H), 6, 70 (s, 1H), 5.97 (s, 1H), 4.35 (m, 4H), 3.90 (m, 1H), 3.68 (m, 1H), 2.50 (s, 3H ), 2.23 (m, 2H), 0.94 (s, 9H).

(S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(1-(3-hydroxypropyl)-1H-1,2,3-triazol-4yl)methyl)amino) -4-(neopentylamino)quinoline-3-carbonitrile: ES/MS m/z: 537.27.

'H NMR (400 MHz, Acetonitrile^) δ 8.41 (s, 1H), 7.84 (m, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 6.82 (m, 1H), 6.74 (m, 1H), 6.15 (m, 1H), 4.42 (m, 2H), 3.76 (m, 2H), 3.48 (m, 2H) , 2.51 (s, 3H), 1.98 (m, 2H), 0.94 (s, 9H).

Example 46, procedure 46.

(S)-6-(((6-fluoro-2-methylpyridin-3-yl)(1 -(1 -(trifluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4yl)methyl)amino)- 4-(neopentylamino)-8-(pyrimidin-5-yl)quinoline-3-carbonitrile: 6-(((6-fluoro-2methylpyridin-3 -yl)( 1-(1 -(trifluoromethyl)cyclopropyl)-1 H -1,2,3-triazol-4-yl)methyl)amino)-8-iodo-4(neopentylamino)quinoline-3-carbonitrile (20 mg, 0.03 mmol), potassium carbonate (0.03 ml, 0 .06 mmol) and pyrimidin-5-ylboronic acid (5.3 mg, 0.045 mmol) were dissolved in DME. Bis(triphenylphosphine)palladium(I) dichloride (1.0 mg, 0.002 mmol) was then added to the mixture. The reaction mixture was heated to 110°C in a microwave reactor for 5 minutes, then diluted with EtOAc and brine, the organic layer was saved, dried over sodium sulfate and concentrated. The crude residue was purified by RP-HPLC (eluent: water/MeCN *0.1% TFA) to give the product as the trifluoroacetate salt.

Example 47, procedure 47.

F (S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)(5-iodo-1-(1-methylcyclopropyl)-1H-1,2,3-triazol-4yl )methyl)amino)-4-(neopentylamino)quinolin-3-carbonitrile: to (K)-8-chloro-6-((1-(6-fluoro-2methylpyridin-3-yl)prop-2-yn-1 -yl)amino)-4-(neopentylamino)quinoline-3-carbonitrile (100 mg, 0.23 mmol) in MeTHF (2 ml) was added copper (I) iodide (4 mg, 0.02 mmol) and N-hydriodide iodomorpholine (95 mg, 0.28 mmol). The solution was stirred at room temperature for 5 hours. The resulting solution was filtered through carbonate resin and concentrated to give crude (S)-8-chloro-6-((1(6-fluoro-2-methylpyridin-3-yl)-3- iodoprop-2-yn-1-yl)amino)-4-(neopentylamino)quinoline-3carbonitrile.

To a solution of (S)-8-chloro-6-((1-(6-fluoro-2-methylpyridin-3-yl)-3-iodoprop-2-in-1-yl)amino)-4(neopentylamino)quinoline -3-carbonitrile in MeTHF (2 ml) was added triethylamine (0.05 ml, 0.36 mmol), copper (I) iodide (4 mg, 0.02 mmol) and 1-azido-1-methylcyclopropane (0.5 ml , 0.5 M in MTBE, 0.25 mmol).

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The resulting solution was stirred at room temperature for 3 days and then washed with aqueous bicarbonate. The aqueous layer was back-extracted with EtOAc (2x) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by reverse phase HPLC (10-60% MeCN/H ₂ O with 0.1% TFA) to give the product as the TFA salt. The product was dissolved in EtOAc and washed with aqueous bicarbonate. The aqueous layer was back-extracted with EtOAc (2x) and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by normal phase chromatography (10-50% EtOAc/CH ₂ Cl ₂ ) to give the product.

^1H NMR (400 MHz, Methanol^) δ 8.51 (d, J=1.1 Hz, 1H), 7.81 (t, J=8.1 Hz, 1H), 7.65 (d, J =2.3 Hz, 1H), 6.86 (dd, J=8.6, 2.7 Hz, 1H), 6.83 (d, J=2.3 Hz, 1H), 6.07 (s , 1H), 4.13 (d, J=13.9 Hz, 1H), 3.70 (d, J=13.9 Hz, 1H), 2.40 (s, 3H), 1.64 (s , 3H), 1.44 - 1.31 (m, 2H), 1.22 (t, J=2.0 Hz, 2H), 0.89 (s, 9H).

ES/MS: 659.255 (M+H+).

Example 48, procedure 48.

Cl Cl (S)-8-chloro-6-(((6-fluoro-2-methylpyridin-3-yl)( 1-(1 -(trifluoromethyl)cyclopropyl)-1H-1,2,3-triazol4-yl )methyl)(methyl)amino)-4-(neopentylamino)quinoline-3-carbonitrile: to a suspension of 6-amino-8-chloro-4(neopentylamino)quinoline-3-carbonitrile (1 g, 3.46 mmol) in H2O (35 ml) and H2SO4 (1.8 ml) at 0°C (external) 1.5 M aqueous NaNO ₂ (2.8 ml) was added dropwise. The resulting solution was stirred at 0°C for 1.5 h before adding potassium iodide (1.2 g, 7.23 mmol) in H ₂ O (15 ml). The resulting suspension was vigorously stirred at room temperature for 18 hours. The suspension was neutralized with NaOH (2 M), filtered and washed twice with H2O. The resulting filtrate was dissolved in EtOAc and washed with aqueous NaCl. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over MgSO ₄ and concentrated. The crude material was purified by SiCO ₂ chromatography (5-25-100% EtOAc/Hex, 20% MeOH/EtOAc wash) to obtain the desired product.

1H NMR (400 MHz, DMSO-d6) δ 8.82 (d, J=1.7 Hz, 1H), 8.55 (s, 1H), 8.25 (d, J=1.5 Hz, 1H ), 8.19 (t, J=7.0 Hz, 1H), 3.72 (d, J=6.8 Hz, 2H), 0.96 (s, 9H).

ES/MS: 400.428 (M+H+).

To a solution of (S,E)-2-methyl-N-(3-(trimethylsilyl)prop-2-yn-1-ylidene)propan-2-sulfinamide (0.5 g, 2.18 mmol) in THF (7 .5 ml) was added Cu(I) 2-thiophenecarboxylate (50 mg, 0.26 mmol), 2,6-lutidine (1.3 ml, 11.16 mmol) and cyclopropyl azide (17% in MTBE, 1 ml, 7 .82 mmol). The resulting solution was stirred at 40°C (external) for 18 hours and then diluted with EtOAc. The solution was washed with H2O and twice with aqueous NH ₄ Cl. The aqueous layers were back-extracted with EtOAc and the combined organic layers were dried over MgSO ₄ and concentrated. The crude residue was purified by SiO ₂ chromatography (15-50% EtOAc/CH ₂ Cl ₂ ) to obtain the desired product.

1H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J=1.2 Hz, 1H), 8.26 (s, 1H), 1.82 - 1.75 (m, 2H), 1 .72 (dt, J=8.0, 4.9 Hz, 2H), 1.26 (d, J=1.2 Hz, 9H).

ES/MS: 309.100 (M+H+).

A solution of n-butyllithium (2.5 M in hexanes, 1.25 ml) and the reaction mixture was stirred at -78°C for 1.5 hours. (S,E)-2-methyl-N-((1(1-(trifluoromethyl) Cyclopronyl)-1H-1,2,3-triazol-4-yl)methylene)propane-2-sulfinamide (200 mg, 0.65 mmol) in MeTHF (2 ml) and the resulting solution was warmed to room temperature for 2 hours. The reaction mixture was diluted with 50% NH ₄ Cl and extracted twice with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude material was purified by SiO ₂ chromatography (25-60% EtOAc (5% MeOH)/CH ₂ Cl ₂ ) to obtain the desired product as a single isomer.

1H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.81 (m, 1H), 7.52 (s, 1H), 6.81 (dd, J=8.5, 3.3 Hz, 1H), 5.93 (d, J=3.4 Hz, 1H), 4.41 (d, J=3.5 Hz, 1H), 2.55 (s, 3H), 1.74 -1, 59 (m, 4H), 1.24 (d, J=0.8 Hz, 9H).

ES/MS: 420.099 (M+H+).

Solution of (S)-N-((S)-(6-fluoro-2-methylpyridin-3-yl)( 1 -(1 -(trifluoromethyl)cyclopropyl)-1 H-1,2,3triazol-4-yl) Methyl)-2-methylpropane-2-sulfinamide (0.1 g, 0.25 mmol) in THF (3 ml) was cooled to 0°C. Sodium hydride (60% dispersion in mineral oil, 0.01 g, 0.29 mmol) was added and stirred for 30 min before iodomethane (0.02 mL, 0.32 mmol) was added.

The resulting solution was stirred at room temperature for 24 hours and diluted with EtOAc. The solution was washed with 50% NH ₄ Cl and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by SiO ₂ chromatography (20-50-60% EtOAc (5% MeOH)/CH ₂ Cl ₂ ) to obtain the desired product.

1H NMR (400 MHz, Chloroform-d) δ 7.95 (t, J=8.2 Hz, 1H), 7.78 (s, 1H), 6.83 (dd, J=8.5, 3, 3 Hz, 1H), 5.99 (s, 1H), 2.58 (s, 3H), 2.46 (s, 3H), 1.63 (d, J=62.7 Hz, 4H), 1 .17(s,9H).

ES/MS: 433.820 (M+H+).

To a solution of (S)-N-((S)-(6-fluoro-2-methylpyridin-3-yl)( 1-(1 -(trifluoromethyl)cyclopropyl)-1 H-1,2,3triazol-4-yl )methyl)-N,2-dimethylpropane-2-sulfinamide (0.07 g, 0.17 mmol) in MeOH (1 ml) was added 4M HCl in dioxane (0.45 ml). The resulting solution was stirred at room temperature for 2 hours and concentrated. The crude residue was diluted with EtOAc and washed with aqueous bicarbonate. The aqueous layer was back extracted with EtOAc and the combined organic layers were dried over Na ₂ SO ₄ and concentrated. The crude amine was dissolved in a 1:1 mixture of CH ₂ Cl ₂ and toluene and concentrated to dryness to obtain the desired product.

ES/MS: 329.872 (M+H+).

To a solution of (S)-1 -(6-fluoro-2-methylpyridin-3-yl)-N-methyl-1-(1-(1 -(trifluoromethyl)cyclopropyl)-1H1,2,3-triazol-4- yl)methanamine (0.05 g, 0.17 mmol) in toluene (3.5 ml) was added 8-chloro-6-iodo-4(neopentylamino)quinoline-3-carbonitrile (0.07 g, 0.17 mmol ), 2-(di-tert-butylphosphino)biphenyl (0.02 g, 0.07 mmol) and tris(dibenzylideneacetone) dipalladium (O) (0.03 g, 0.03 mmol). The suspension was degassed with argon for 5 min and potassium tert-butoxide, 95% (0.06 g, 0.5 mmol) was added. The resulting suspension was heated to 80°C (external) for 2 hours. The reaction mixture was then diluted with EtOAc and washed with aqueous bicarbonate. The aqueous layers were back-extracted and the resulting organic layers were concentrated. The crude oil was then purified by reverse phase HPLC (10-70% MeCN/H ₂ O with 0.1% TFA). The product was purified a second time using reverse phase HPLC (10-65% MeCN/H ₂ O with 0.1% TFA) to obtain the desired product as the TFA salt.

1H NMR (400 MHz, Methanol-d ₄ ) δ 8.55 (d, J=1.6 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J=2.6 Hz, 1H), 7.59 (t,

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J=8.1 Hz, 1H), 7.40 (d, J=2.6 Hz, 1H), 6.92 (dd, J=8.5, 2.8 Hz, 1H), 6.76 ( s, 1H), 4.09 (d, J=14.1 Hz, 1H), 3.96 (d, J=14.1 Hz, 1H), 2.97 (s, 3H), 2.35 ( s, 3H), 1.80 - 1.70 (m, 4H), 1.02 (d, J=3.2 Hz, 9H).

ES/MS: 601.367 (M+H+).

Example 49, procedure 49.

(S)-8-acetyl-6-((( 1-(1 -(difluoromethyl)cyclopropyl)-1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin3-yl)methyl )amino)-4-(neopentylamino)quinoline-3-carbonitrile

K (S)-6-((( 1-(1 -(difluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4-yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino )-8-iodo-4-(neopentylamino)quinoline-3-carbonitrile (37 mg, 0.056 mmol) and bis(triphenylphosphine)palladium(P) dichloride (5 mg, 0.006 mmol) in toluene (1 ml) was added tributyl(2ethoxyallyl )tin (23 mg, 0.062 mmol). The reaction mixture was purged with nitrogen and heated at 100°C overnight. After cooling to room temperature, 2N HCl (1 ml) was added and the mixture was stirred for 2 hours. The reaction mixture was diluted with water and extracted three times with EtOAc. The combined organics were washed with water and brine and dried (Na ₂ SO ₄ ). The filtrate was concentrated to give the crude material, which was purified twice by HPLC (eluent: water/MeCN *0.1% TFA) to give the product.

The following compounds were prepared in accordance with the examples and procedures described herein (and listed in Table 1 in the example/procedure), using suitable starting material(s) and appropriate protecting group chemistry as needed.

Table 1

Connect Structure Name Example procedure ES/MS m/z 1 \ „ A to Ta ^N aHo F (S)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methylb)amino)- 8 -chloro-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS 522.2 (M+H+) 2 8-chloro-6-(((8)-(1-isopropyl1H-1,2,3-triazol-4-yl)(2methylpyridine in-3 yl)methyl)amino)-4-(((I)-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 551.09 (M+H+) 3 D ( ¹ N h J _ 1 A A nA ci F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(2,6difluoropyrid in-3 -yl)methyl4)amino)-4-(((K)-1 phenylpropyl )amino)quinoline3-carbonitrile 2 ES/MS: 572.24 (M+H+)

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4 τ- .5. ώ сГ ' 8-chloro-6-(((8)-( 1 -((3 hydroxyoxetan-3-yl)methyl)1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((I)-1 phenylpropyl)amino)quinoline3-carbonitrile 4 ES/MS 581.1 (M + H+). 5 hb, Cl (\ ^CL A 'Af S-H. Ci Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2,5 dichlorothiophen-3-yl)( 1 -(1ethylpiperidin-4-yl)- 1H-1, 2,3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 688.9 (M + H+) 6 N-, Cl Q and D' DSD A ψ-Α N-D Cl 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(pyridin-3 yl) methyl)amino)quinoline-3 carbonitrile 6 7 ojAv ^ci 0 A 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((pyridin-2-yl(pyridin-4yl)methyl)amino)quinoline-3 carbonitrile 7 ES/MS 515.0 (M+H+) 8 / D-D 14 H %AA _f %ADrDD ^m D VA iD Cl (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1-isopropyl-1 Η-1,2,3 triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 532.1 (M+H+)

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9 7 nA L J Jf «Ν < ⁸ τί γ·^ ill Ν (8)-6-((benzo[b]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9a ES/MS 534.1 (M+H+) 10 Cl Η AU K n %AA ⁿ AaV JU (8)-6-((benzo[<1]thiazol-6-yl(1H1,2,3-triazol-4- yl)methyl)amino)-8-chloro-4-((3 - chlorine-4- fluorophenyl)amino)quinoline-3 carbonitrile 10 ES/MS 561.0 (M+H+) AND 4„A A AA N^J Cl F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl- <1)amino)-4-(((K)-3-fluoro-1 phenylpropyl)amino)quinoline3-carbonitrile AND 572 12 Cl N^ H ^N -1 N 1 <Ti) 1A VU Cl H (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6- ((ind olin-4-yl( 1 -isopropyl1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 586.9 (M+H+)

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13 V n ^Ν 1 Ν 1 l»eo Τ (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3 -triazol-4-yl)(2ETHILIZOINDOLINE-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 13 ES/MS 712.1 (M+H+) 14 η Λ ^Γ HELD °ΧΟ ά (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3 -triazol-4-yl)(2-(oxetan3 -yl)isoindolin-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 14 ES/MS 740.0 (M+H+) 15 0 _n d ^r _n Dod r ^N ' (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2-(2hydroxyacetyl)isoindolin-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 15 ES/MS 742.1 (M+H+)

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16 n ιΓΊ ^f V° τ ru? H ^H 'N-'V'' nU cX 8-chloro-6-(((8)-( 1-(1,1-difluoro2-hydroxyethyl)-1H-1,2,3triazol-4-yl)(pyridin-3yl)methyl)amino)-4- (((I)-1 phenylpropyl)amino)quinoline3-carbonitrile 16 ES/MS 575.1 (M + H+) 17 /A ^Cl H XXX J О t ⁿ Cl Y (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6isopropoxypyridin-3 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 17 ES/MS 702.0 (M+H+) 18 '/'l ^Cl \) <X- ^F 1ЛХ5 0%' (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(tetrahydro2H-pyran-4-yl)methyl)amino)8-chloro-4-((3-chloro-4fluorophenyl)amino) quinoline-3 carbonitrile 18 ES/MS 651.1 (M+H+) 19 4 H t Λ SX y ⁿ X YYj 40 FN (8)-6-((( 1 -cyclopropyl-1H1,2,3 -triazol-4-yl)(3 OXOISOINDOLIN-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 19 ES/MS 532.2 (M+H+)

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20 N-, Cl Q Η A ^F Sb S''IT Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(thiazol -4yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 622.0 (M+H+) 21 ^/- Β= \_ζ ..Ζ )=° ^>g 0 (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(5-(pyrrolidin-1carbonyl)pyr idin-3 yl)methyl)amino)quinoline-3 carbonitrile 21 ES/MS 644.1 (M+H+) 22 9Γ F ^N 6-(((8)-(6-fluoropyr idine-3 - yl)(1-methyl-1Η-1,2,3-triazol 4-yl)methyl-<1)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3,8-dicarbonitrile 22 ES/MS 519.2 (M+H+) 23 7 η t N'T, Η ^Nn VtY7 ΌΟ №%/ lb 4 ^Ν (8)-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(indolin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 12 ES/MS 518.2 (M+H+)

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24 4 n t FROM (8)-8-bromo-6-((( 1 -cyclopropyl1H-1,2,3-triazol-4yl)(indolin-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 12 ES/MS 571.1 (M+H+) 25 I Ψ k n ^H > _r ^J Ν'ΑBr (8)-6-((benzo[<1]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-8-bromo-4(neopentylamino)quinoline-3 carbonitrile 2 ES/MS 587.2 (M+H+) 26 O V _l Ϋ /g^ ζ (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2(oxetan-3 -yl)isoindolin-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 14 ES/MS 583.1 (M+H+) 27 4 Λ L J Ϊ N''g' ^M 'g''U''γ' ^h - ⁿ CO ά ^N (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(isoindolin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 12 ES/MS 527.0 (M+H+)

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28 H = J IP (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)( 1 -methyl-1 H- indazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 600.0 (M+H+) 29 / N^F N- H ^H ^ _N H- _F A n _l 1 X (Tit τ ^Ν ' W Cl Η (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((in olin-4-yl(1-isopropyl1H-1,2,3-triazol-4yl)methyl) amino)quinoline-3 carbonitrile 12 ES/MS 572.1 (M+H+) thirty n ΑΧ to Η %ΑΑ <10 ν / Η (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((in olin-4-yl(1 Η-1,2,3 triazol-4yl)methyl)amino) quinoline-3 carbonitrile 12 ES/MS 530.1 (M+H+) 31 ίΑ Q I χ (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((isoind olin-4-yl(1 Η-1,2,3 triazol-4yl)methyl)amino) quinoline-3 carbonitrile 12 ES/MS 530.0 (M+H+)

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32 CL 4 nV to h %AA _F ^N 1 N _l A Jk (8)-6-((benzo[<1]thiazol-7-yl( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)methyl)amino)-8chloro-4-( (5, 6-d iforopyridin-3 yl)amino)quinoline-3 carbonitrile 2 ES/MS 601.9 (M+H+) 33 -. %th (8)-6-((benzo[c1]thiazol-7-yl(1H1,2,3-triazol-4yl)methyl)amino)-8-chloro-4((5,6-d iforopyridin-3 yl) amino)quinoline-3 carbonitrile 10 ES/MS 545.9 (M+H+) 34 Cl rS' ^F krrV /0° (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(2-(oxetan-3 -yl) )-1,2,3,4tetrahydroisoquinolin-5yl)methyl)amino)quinoline-3 carbonitrile 13 ES/MS 657.3 (M+H+) 35 Q y to h %>i N 1 1 1 У Ν '^γ’γ-γ y-A kg Cl ok (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(2-(oxetan3-yl)-1,2,3,4- tetrahydroisoquinolin-5yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 13 ES/MS 754.2 (M+H+)

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36 T-X ή 4 3 -u n g / 1 χ 6-(((S)-( 1 -(tert-butyl)-1H1,2,3-triazol-4yl)(isoindolin-4yl)methyl)amino)-8-chloro-4(((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 12 ES/MS 591.2 (M+H+) 37 Cl n ^F vV' % n ^h - _n AJ ^Ν 1 Ν Y ^M t χ x g π-ν^ ϊι ^Ν (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6- ((isoind olin-4-yl( 1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 579.0 (M+H+) 38 1 1 X (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(2-methyl-3OXOIZOINDOLIN-4yl) methyl)amino)quinoline-3 carbonitrile 2 ES/MS 614.9 (M+H+) 39 3 ίΥ to Η %JU ^Ν ^^γΜγ^ ^Ν -W ά (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3 -triazol-4-yl)(2-methyl-3 OXOIZOINDOLINE-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 712.1 (M+H+)

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40 Cl. GK H ^Ν 1 Ν JK ^N X YVj -SP X (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(3-oxoisoindolin-4yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 601.0 (M+H+) 41 b iY ^N X Ν Γ Y 1ΧΎΤ - ^y od ά ^N (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3 -triazol-4-yl)(3 OXOISOINDOLINE-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 698.1 (M+H+) 42 Cl rV wr ^N H (8)-6-(((1H-benzo[c1]imidazol4-yl)( 1 -isopropyl-1 H-1,2,3 triazol-4-yl)methyl)amino)-8chloro-4-((3 -chlorine-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 586.0 (M+H+) 43 V hk _n AX HODH <.Y VM W ci (8)-6-((benzo[c1]thiazol-4-yl(1(1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)-8 -chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 700.5 (M+H+)

- 80 045220

44 Cl / r^V ^F N. H °> ww (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(2-(oxetan-3 yl) )isoindolin-4yl)methyl)amino)quinoline-3 carbonitrile 14 ES/MS 644.0 (M+H+) 45 Cl Ύ _H rV ^F X K ⁰ /-Jk LA·. J oXX) Cl rf (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2-(2hydroxyacetyl)isoindolin-4yl)( 1 -isopropyl-1 H-1,2,3 triazol- 4yl)methyl)amino)quinoline-3 carbonitrile 15 ES/MS 645.3 (M+H+) 46 Cl ^H ' n X K τΑ ^{1 0} - J'. oXX) X rf (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2-(2hydroxyacetyl)isoindolin-4yl)(1H-1,2,3-triazol-4yl)methyl) amino)quinoline-3 carbonitrile 15 ES/MS 603.0 (M+H+) 47 Cl to and X ^N ^XU>°> ww (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2(oxetan-3-yl)isoindolin-4yl)(1H-1,2,3-triazol-4yl )methyl)amino)quinoline-3 carbonitrile 14 ES/MS 601.1 (M+H+)

- 81 045220

48 Cl. Дт ^Η <Ό ά (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((isoind olin-4-yl(1 isopropyl-1 H-1,2,3-triazol-4yl)methyl)amino )quinoline-3 carbonitrile 12 ES/MS 587.0 (M+H+) 49 CI α η xУ уОУ ^Ν Χ XXX Α LE ^Cl ΑΧ (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2-ethyl1, 2,3,4-tetrahydroisoquinolin7-yl)( 1-isopropyl-1 H-1, 2,3 triazol-4yl)methyl)amino)quinoline-3 carbonitrile 13 ES/MS 628.9 (M+H+) 50 Cl A h ХУ ⁿ X2^XX> ⁿⁿ aOt A t ^N Ar ^Cl X'-X (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 Η-1,2,3-triazol-4yl)(1,2,3,4tetrahydroisoquinoline -7yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 601.1 (M+H+) 51 7 A ^l % lA (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(indolin-6yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 12 ES/MS 684.2 (M+H+)

- 82 045220

52 V Η 'Ν''* ³ < ^S A Τ'Κ W Cl (8)-6-((benzo[<1]thiazol-7-yl(1 (1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)- 8-chloro-4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 700.0 (M+H+) 53 Cl n ⁿ XZa>N—' (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2ethyl isoind olin-5-yl)( 1H1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 13 ES/MS 573.1 (M+H+) 54 Cl n rV ^F % H %Ad z- ^N CO ά ^N (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2ethylizoindolin-4-yl)( 1H1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 13 ES/MS 573.1 (M+H+) 55 Cl ⁿ A k Η ^Ν Χχν ^Ν Z y 4 (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((olin-5-yl isoind(1H-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 545.0 (M+H+)

- 83 045220

56 Cl n iV ^Η <ΙΠ « (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((olin-4-yl isoind( 1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 545.0 (M+H+) 57 Chu ΕΕ-Ζ /^=\ ) ^- νΛη _G U ^? (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4yl)(isoindolin-5- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 12 ES/MS 684.2 (M+H+) 58 b _y A ^F Y ^1, Ν—' (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2ethylizoinDOLIN-5 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 13 ES/MS 712.0 (M+H+)

- 84 045220

59 ^h <O ά ^Ν (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4yl)(isoindolin-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 12 ES/MS 684.0 (M+H+) 60 0 Λ ^ρ V Η Η JU ^Ν 1 Ν ϊ % <%Λ τ V=U a Η (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(indolin-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 12 ES/MS 684.2 (M+H+) 61 CI Ά η L ιΓ Η ^Η ' _Μ Ά> ^Ν 1 A l Ν' ¹ X IT J Α τ ^Ν Aj J ci s Χ·Ν (8)-6-((benzo[0]thiazol-6-yl(1isopropyl-1H-1,2,3-triazol-4yl)methyl)amino)-8-chloro-4-((3 chloro-4fluorophenyl) amino)quinoline-3 carbonitrile 2 ES/MS 603.0 (M+H+) 62 b χ ΐοχΧ χχ (8)-6-((benzo[<1]thiazol-5-yl( 1 (1-(tert-butyl)piperidin-4yl)- 1H-1,2,3-triazol-4yl)methyl)amino)- 8-chloro-4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 700.0 (M+H+)

- 85 045220

63 b a a (8)-6-((benzo[<1]thiazol-6-yl(1(1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)- 8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 700.0 (M+H+) 64 b A ^N 1 N 1 A AJ ¹ ci Vs (8)-6-((benzo[b]thiophen-5-yl(1 (1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)-8 -chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 698.9 (M+H+) 65 A Cl < \ An k h %aJ n 1 ό 7 йЯ ^Ν ΧΰΑ Hl T ^N nV ^Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(quinoline -7 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 666.1 (M+H+) 66 HA Τ' A s HA < ^s AT ^J N%> ill N (8)-6-((benzo[<1]thiazol-7-yl( 1 - (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9a ES/MS 602.2 (M+H+)

- 86 045220

67 νΣ η ^η Χ \γγγ ^Ν AO g No. '>' ill Ν (8)-6-((benzo[<1]thiazol-7-yl( 1 - (1-cyanocyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9a ES/MS 559.1 (M+H+) 68 am I _n ? ^Ν Λ^γγ> ^Λ Η'WX 8-chloro-4-(((R)-3 -cyano-1 phenylpropyl)amino)-6-(((8)(1 -cyclopropyl-1 Η-1,2,3 triazol-4-yl)(isoindoline -4yl)methyl)amino)quinoline-3 carbonitrile 12 ES/MS 600.0 (M+H+) 69 9 ^Τ) Q νΌχ ^{1 ct} 6-(((8)-benzo[<1]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-8-chloro-4(((R)- 3-cyano-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 616.1 (M+H+) 70 Η t Ό Η ^Η Ύ ν X Λ _Λ 1 ζ ^Ν ^ ΥαΟ- Η sX ΧΜ νοΥ] X Η Ν%> ^Br (8)-6-(((2-aminobenzo[<1]thiazol7-yl)( 1 -cyclopropyl-1 H-1,2,3 triazol-4-yl)methyl)amino)-8bromo-4(neopentylamino) quinoline-3 carbonitrile 12 ES/MS 602.1 (M+H+)

-87045220

72 I 9 γγχγ aA γΑ N-Y Cl F 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1 Η-1,2,3-triazol4-yl)(6-fluoro-2- methylpyridin3 -yl)methyl-(1)amino)quinoline3-carbonitrile 2 593.2 73 Yak Υ ΥΥΥ Ζ Z O V ² 8-chloro-6-(((2-chloropyridin-3 yl)( 1 -cyclopropyl-1 Η-1,2,3 triazol-4-yl)methyl-(1)amino)4-(((R) -3-cyano-1 phenylpropyl)amino)quinoline3-carbonitrile 2 595.1 74 I 9 "γΥγ" lA γΑ nY Cl 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((8)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(2methylpyride in-3 yl)methyl)amino)quinoline-3 carbonitrile 2 574.1 75 d 9 Λγχγ AVO νΥCI 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((8)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(pyridine -3 yl)methyl)amino)quinoline-3 carbonitrile 2 560.1

- 88 045220

76 I 1 l % (S)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(1OXOISOINDOLIN-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9a ES/MS 532.1 (M+H+) 77 I Ϋ s n ν Ν J Ν _Λ Λ μΎυυ -wr N (S)-6-((( 1 -cyclopropyl-1H1,2,3 -triazol-4-yl)(2-methyl-3 OXOISOINDOLINE-4- yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 9a ES/MS 546.2 (M+H+) 78 7 h t H H' Du (8)-8-bromo-6-((( 1 -cyclopropyl1 Η-1,2,3 -tri-azol-4-yl)(3 OXOIZOINDOLIN-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 2 ES/MS 585.1 (M+H+) 79 7 H t D JX a Ν'γ ^Ν γ%Α.ζ -SOUTH Ν (S)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4yl)(isoindolin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 12 ES/MS 518.6 (M+H+)

-89045220

80 V n Τ' ^Ν ΧγγΧ ^Ν Γ0 τ LA ^s| Τ (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3 - c]pyridin-3-yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 5 ES/MS 603.2 (M + H+) 81 \ „ τ Auy A<S Τ L' ^{s 01} Τ' (R)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3 - c]pyridin-3-yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 5 ES/MS 603.2 (M + H+) 82 ^/Ν ^· ίΧ ΚΟΑ ^{c Ν} τ 8-chloro-4-((3 -cyano-1 phenylpropyl)amino)-6-(((8)(1 -((1R, 5 S, 6g)-3 -(oxetan-3 -yl)3-azabicyclo [3.1,0]hexan-6yl)-1H-1,2,3-triazol-4-yl)(6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3c]pyridin-3 yl )methyl)amino)quinoline-3 carbonitrile 5 ES/MS 773.1 (M + H+)

- 90 045220

83 ar z 2 z 8-chloro-4-((3-cyano-1 phenylpropyl)amino)-6-(((K)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(6-(oxetan- 3 -yl)4,5,6,7-tetrahydrothieno[2,3c]pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 676.1 (M + H+) 84 Ox r 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((8)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(6 -(oxetan-3 -yl)4,5,6,7-tetrahydrothieno[2,3c]pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 676.1 (M + H+) 85 О H X° _H X Ν-, H A τ Cl F (8)-2-(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(6-fluoropyridin-3 yl)methyl-(1)-1 Η-1,2 ,3-triazol 1-yl)acetic acid 1 ES/MS 524.2 (M+H+) 86 О 7 HX NT ^H ΊΓ%'%:., ^Ν ΛγΑ>^< A MA Ny^ Cl F 8-chloro-4-(((K)-3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyr idin-3 yl )methyl-(1)amino)quinoline-3 carbonitrile 2 ES/MS 579.2 (M+H+)

- 91 045220

87 A LL A 8-chloro-4-(((8)-3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1 Η-1,2,3-triazol4-yl)(6-fluoropyridin-3 yl)methyl-c!)amino)quinoline-3 carbonitrile 2 ES/MS 579.2 (M+H+) 88 I _n 9 YES ^{N 1} YXy Cl F 8-chloro-4-(((8)-3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyr idin-3 yl )methyl-<1)amino)quinoline-3 carbonitrile 2 ES/MS 579.2 (M+H+) 89 O I Η X ν'ΑΧ ^{N 1} YXy A w N^JJ Cl F 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyr idin-3 yl )methyl-c!)amino)quinoline-3 carbonitrile 2 ES/MS 579.2 (M+H+) 90 ⁿ n AU Before 8-chloro-4-((3-cyano-1 phenylpropyl)amino)-6-(((8)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(6-(oxetan- 3 -yl)4,5,6,7-tetrahydrothieno[2,3c]pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 676.1 (M + H+)

- 92 045220

91 V n Y Υγ 04 A' 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6-(oxetan3-yl)-4,5,6,7tetrahydrothieno[2,3- c]pyridin-3-yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 5 ES/MS 603.2 (M + H+) 92 1 Ό? Avrr About ci F 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4-((3,3 - dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3 carbonitrile 1 ES/MS 548.2 (M+H+) 93 v -Ί k/ P g. ^H Ν CN Ν<0 CI F 8-chloro-4-((3-cyano-1 phenylpropyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyridin-3 yl)methyl-( 1)amino)quinoline-3 carbonitrile 2 ES/MS 579.2 (M+H+) 94 C.I. V η Α γΜ νΧ CI F (8)-8-chloro-4-((3-chloro-2methoxyphenyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyr idin-3 yl) methyl-c!)amino)quinoline-3 carbonitrile 8 ES/MS 576.1 (M+H+)

-93 045220

95 H ιφ α F 4-(((1 S,3S,5S,7S)-adamantan-2yl)amino)-8-chloro-6-(((S)-(lcyclopropyl-1H-1,2,3-triazol4-yl)( 6-fluoropyr idin-3 yl)methyl-(1)amino)quinoline-3 carbonitrile 1 ES/MS 570.2 (M+H+) 96 α 1 η «F And LG Ν<ΥCl (8)-8-chloro-4-((3-chloro-4methoxyphenyl)amino)-6-(((1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyr idin-3 yl) methyl-(1)amino)quinoline-3 carbonitrile 8 ES/MS 576.2 (M+H+) 97 I _n 9 AVrV D Y^ NyU 0-, F 6-(((8)-( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(6fluoropyridin-3 -yl)methyl<1)amino)-8-methoxy-4-(((K) -1phenylpropyl)amino)quinoline- 3-carbonitrile 2 ES/MS 550.1 (M+H+) 98 7 n X ,Ν^ Η ^H - _N - ^J A i ^n< Ny^ 0,. F (8)-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-8-methoxy-4- (neopentylamino)quinoline-3 carbonitrile 2 ES/MS 502.3 (M+H+)

- 94 045220

99 \—/ _{ζ; _τ} (8)-6-(((6-fluoropyridin-3 yl)( 1 -methyl-1 Η-1,2,3 -triazol4-yl)methyl-b)amino)-4(neopentylamino)quinoline-3, 8dicarbonitrile 22 ES/MS 471.3 (M+H+) 100 4 nc kAv k' T ^N 4-(((R)-2-cyano-1 phenylethyl)amino)-6-(((8)-(1cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyridin-3 yl) methyl-b)amino)quinoline3,8-dicarbonitrile 1 ES/MS 556.2 (M+H+) 101 j T ^Ύ· ^πσ ω ζ-ζ k 8-chloro-6-(((1-cyclopropyl-1H- 1,2,3-triazol-4-yl)(4methylthiazol-5-yl)methyl- c1)amino)-4-(((K)-1 phenylpropyl)amino)quinoline- 3-carbonitrile 2 ES/MS: 556.2 (M+H+) 102 4„ t Λν J ϊ Ύ^ε γκ ACl 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(4methylthiazol-5-yl)methylb)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 508.3 (M+H+)

- 95 045220

103 4 Η X Ν' η ^Η TH xy Cl F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(2,6difluoropyrid in-3 -yl)methylb)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 524.3 (M+H+) 104 7 HY (S)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2fluoropyridin-3-yl)methylfamino)-4- (neopentylamino)quinoline-3 carbonitrile 2 ES/MS 506.4 (M+H+) 105 ι 9 Ν Η ^F Υ|1 Μ CI 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(2fluoropyridin-3-yl)methyl<1)amino)-4-(((K) -1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 554.2 (M+H+) 106 ι _Η 5χ ιΐιχχΧ ⁰ Τ IXI Α τ'^ Μ,!· ¹ CI F 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyld)aMHHo)-4-(((R)-1 phenylpropyl-2,2,3,3,3b5)amino)quinoline-3 carbonitrile 2 ES/MS 559.2 (M+H+)

- 96 045220

107 Ί 9 А n %v ^{Di ν} _ν 1?ν^Α> ^Ν ΧΙΑ X Α ι ^Ν ν D ci F 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4-(((8) -1 phenylpropyl-2,2,3,3,3b5)amino)quinoline-3 carbonitrile 2 ES/MS 559.2 (M+H+) 108 Η Idg^ ^{2 n} n1AyVa ⁿ Α τ' ^Ν nJ ci F 8-chloro-6-(((R)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4-(((K) -1 phenylpropyl-2,2,3,3,3d5)amino)quinoline-3 carbonitrile 2 ES/MS 559.1 (M+H+) 109 7 „ 9c. ^N > H 41% ² n^N^AlW A tA nD ci F 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyld)aMHHo)-4-(((R)-1 phenylpropyl-1,2,2,3,3,3b6)amino)quinoline-3 carbonitrile 2 ES/MS 560.2 (M+H+) 110 md> a W nA ci F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 -yl)methyld)aMHHo)-4-(((R)- 1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS: 568.2 (M+H+)

- 97 045220

111 4 „ t Ν' η ^H ΊΓ AwA Ά ψυ nA CI F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 -yl)methylb)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 520.3 (M+H+) 112 X Ϋ X1 XD% ^ν %· ^ν ΑΑkg A CI F (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methylb)amino)-4-((2,2dimethylpropyl-1 ,1b2)amino)quinoline-3 carbonitrile 2 ES/MS 508.3 (M+H+) FROM V У ΧΑ Ά yv nA- _f ^Cl 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(5-fluoro-2methylpyridin-3 -yl)methyls1)amino)-4-(((K)- 1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS: 568.2 (M+H+) 114 4 Η t у ух n^A _f ci 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(5-fluoro-2methylpyridin-3 -yl)methylb)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS 520.2 (M+H+)

-98045220

115 7 _H 9 _CD N ID' iAn A ι ^Ν yd ^ct g 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methylb)amino)-4-(( 1-phenylpropyl2,2 ,3,3,3 -b5)amino)quinoline-3 carbonitrile 2 ES/MS 559.3 (M+H+) 116 \ Η X O g (8)-6-((( 1 -cyclopropyl-1H1,2,3 -triazol-4-yl)(6fluoropyridin-3 -yl)methyl<1)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 1 ES/MS 597.2 (M+H+) 117 з „г Ν-, Н N 1 D 1 ϊ ' ^Ν αΌα A V ϊ Τ Ν 6-(((8)-( 1 -cyclopropyl-1H1,2,3 -triazol-4-yl)(6fluoropyridin-3 -yl)methyl<1)amino)-4-(((K)-1 - phenylpropyl)amino)quinoline3,8-dicarbonitrile 1 ES/MS 545.2 (M+H+) 118 x 9 Ν 1 D 1 ϊ ^Ν %Όν φ Α ^Ν F 6-(((8)-( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyld)amino)-8-chloro-4-((( R)-lphenylpropyl)amino)quinoline3-carbonitrile 3 ES/MS 570.3 (M+H+)

-99045220

119 V „ H J 'Srp.YYkA 0r F (S)-6-((( 1-cyclopropyl-1H1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methylb)amino)-8-fluoro-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS 490.2 (M+H+) 120 l „ A Lo 1 Jr About f F 6-(((S)-( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(6fluoropyridin-3 -yl)methylb)amino)-8-fluoro-4-(((K)-1 phenylpropyl)amino)quinoline3-carbonitrile 1 ES/MS 538.2 (M+H+) 121 d 0 DyDGx ⁰ ' D ψΑ NJ Cl F 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(6- fluoropyridin-3-yl)methyl- <1)amino)-4-(((K)-3 -hydroxy-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 570.1 (M+H+) 122 I c D W Cl Cl 8-chloro-6-(((6-chloro-2methylpyridin-3 -yl)( 1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl-b)amino)-4-(((K) -1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS: 584.3 (M+H+)

- 100045220

123 d Q Cl N 8-chloro-6-(((4-cyanothiophen-2yl)( 1 -cyclopropyl-1H-1,2,3 triazol-4-yl)methyl-(1)amino)4-(((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS: 566.0 (M+H+) 124 ^N-_D Η A' nA a 8-chloro-6-(((2-chloropyridin-3 yl)( 1 -cyclopropyl-1 Η-1,2,3 triazol-4-yl)methyl-(1)amino)4-(((R) -l- phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS: 570.5 (M+H+) 125 4„t N- η H V Yeah A W nA ci Cl 8-chloro-6-(((6-chloro-2methylpyrid in-3 -yl)( 1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl-c1)amino)-4(neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 536.9 (M+H+) 126 Λ _D H ¹ X A 8-chloro-6-(((2-chloropyridin-3 yl)( 1 -cyclopropyl-1 H-1,2,3 triazol-4-yl)methyl-(1)amino)4-(neopentylamino)quinoline- 3 carbonitrile 1 ES/MS: 522.4 (M+H+)

- 101 045220

127 Cl i Γώ ν Ίχ K ΐΑ Χχχτ Ο τ ^Ν CI F (8)-8-chloro-4-((3-chloro-2,6difluorophenyl)amino)-6-((( 1 cyclopropyl-1 H-1,2,3-triazol4-yl)(6-fluoropyr idin- 3 yl)methyl-(1)amino)quinoline-3 carbonitrile 2 ES/MS 582.2 (M+H+) 128 \ Η Η. νΙοΙ? Μ I11 7 Ο ^Ν N-^JI Cl F 8-chloro-4-(((8)-2-cyano-1 phenylethyl)amino)-6-(((8)-(1cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyridine -3 yl)methyl-(1)amino)quinoline-3 carbonitrile 2 ES/MS 565.1 (M+H+) 129 Y n k L □ i ? V Ill JA t ^N N<;JI Cl F 8-chloro-4-(((R)-2-cyano-1 phenylethyl)amino)-6-(((8)-(1cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoropyridine -3 yl)methyl-(1)amino)quinoline-3 carbonitrile 2 ES/MS 565.1 (M+H+) 130 i 9 ώ ci ^N 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl-<1)amino)-4-(((K)-3 hydroxy -1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 552.1 (M+H+)

- 102 045220

131 7„t UXX χ X (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2methylpyridine-3yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 501.2 (M+H+) 132 7J N-X Cl 8-chloro-6-(((1-cyclopropyl-1H- 1,2,3-triazol-4-yl)(2methylpyridin-3-yl)methyl- <1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 ES/MS: 502.16 (M+H+) 133 F •D /U to h YxJ/ iw %N Cl (8)-8-chloro-6-(((4-chloropyridin3 -yl)( 1 -cyclopropyl-1H-1,2,3triazol-4-yl)methyl)amino)-4((5,6-difluoropyr idin-3 yl)amino)quinoline-3 carbonitrile 1 ES/MS 563.9 (M+H+) 134 Q kkrk hQ Cl ^N F 8-chloro-6-(((8)-(6-fluoropyridin3 -yl)( 1 Η-1,2,3-triazol-4yl)methyl-c1)amino)-4-(((K)-1 phenylpropyl )amino)quinoline3-carbonitrile 10 ES/MS 514.1 (M+H+)

- 103 045220

135 ^Η ' Η Τ Ο α F (8)-8-chloro-6-(((6-fluoropyridin3-yl)( 1 H-1,2,3-triazol-4yl)methyl-c!)amino)-4(neopentylamino)quinoline-3 carbonitrile 10 ES/MS 466.1 (M+H+) 136 Cl Al H ^H JU ^N U J. I XX J t ⁿ Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((imidazo[1,5-a]pyridin-8yl( 1 -isopropyl-1 H-1,2,3 triazol- 4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 586.0 (M+H+) 137 b x V H N 1 Λ 1 A Άν γν s-^ Cl (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(5methylthiazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 664.1 (M+H+) 138 /^N Qψ ό X (8)-8-chloro-4- (neopentylamino)-b- ((pyridin-3 -yl( 1 -(pyridin-3 yl)-1H-1,2,3-triazol-4- yl)methyl-c1)amino)quinoline-3 carbonitrile 2 ES/MS 525.2 (M+H+)

- 104 045220

139 XH fr ^{F Ν} Ί1 η V 'N-YX'CI A γΜ ν'! ci F (8)-8-chloro-4-((5-chloro-6fluoropyridin-3-yl)amino)-6(((1-cyclopropyl-1 H-1,2,3 triazol-4-yl)(6- fluoropyridin3 -yl)methyl-(1)amino)quinoline3-carbonitrile 2 ES/MS 564.9 (M+H+) 140 Chn. х¥ Ν У J _АСА ^F χ TXT AA Ci F (S)-8 -chloro-6-((( 1 -cyclopropyl1H-1,2,3 -triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4-((5,6difluoropyride in-3 yl)amino)quinoline-3 carbonitrile 2 ES/MS 549.1 (M+H+) 141 aa A x—r /^\ (S)-8 -chloro-6-((( 1 -cyclopropyl1H-1,2,3 -triazol -4yl)(pyridin-3 -yl)methyl<1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 ES/MS 488.1 (M+H+) 142 \ HX n' 1 ^D । Ϊ y AoA «γ A F (S)-8 -chloro-6-((( 1 -cyclopropyl1H-1,2,3 -triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 ES/MS 506.1 (M+H+)

- 105 045220

143 X n χ¥ Α Υ,,ν α (8)-8-chloro-6-(((5- cyanopyridin-3-yl)(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl-b)amino)-4-((5,6difluoropyride in-3 - yl)amino)quinoline-3 carbonitrile 2 ES/MS 556.1 (M + H+) 144 7 9 γχΧΑ ΌΓ 8-chloro-6-(((1-cyclopropyl-1H- 1,2,3-triazol-4-yl)(2methylpyridin-3-yl)methyl- <1)amino)-4-(((K)-1 phenylpropyl)amino)quinoline- 3-carbonitrile 2 ES/MS: 550.1 (M+H+) 145 χ> ζ 8-chloro-6-(((2-methylpyridin-3yl)(1H-1,2,3-triazol-4yl)methyl-d)amino)-4-(((R)-1 phenylpropyl)amino)quinoline3- carbonitrile 10 ES/MS 510.0 (M+H+) 146 1 Αχ V Η ΧΑ-Ν Ν.χ I 1 01 τ τ χ χ Α τ ^Ν nL α Cl (8)-8-chloro-6-(((5-chloropyridin3 -yl)( 1 -cyclopropyl-1 H-1,2,3 triazol-4-yl)methyl)amino)-4((5,6- Difluoropyridine-Zyl)amino)quinoline-3 carbonitrile 1 ES/MS 564.0 (M+H+)

- 106 045220

147 F _n Ak k H ^h - _n JUn NI DI 1 νΑ ^ν υΑ/ Or 8-chloro-4-((5,6-difluoropyridin3-yl)amino)-6-(((2- methylpyride in-3 -yl)(1 Η-1,2,3 triazol-4-yl)methylb)amino)quinoline-3 carbonitrile 10 ES/MS 505.0 (M+H+) 148 th A ^F to H Ά|1 Ϊ ^Ν Cl 8-chloro-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(2- methylpyride in-3 -yl)methylb)amino)-4-((5,6- difluoropyride in-3 yl)amino)quinoline-3 carbonitrile 1 ES/MS 545.1 (M+H+) 149 I /V k n %Ау ^N _N lkYAV ^{N F} M Τ CI F (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2,6difluoropyrid in-3 yl)methyl)amino)-4-((5,6difluoropyride in-3 yl)amino)quinoline-3 carbonitrile 1 ES/MS 566.0 (M+H+) 150 7 rV cukv to to (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2methylpyridine in-3 yl)methyl)amino)-4-((5,6difluoropyride in- 3 yl)amino)quinoline-3 carbonitrile 1 ES/MS 543.9 (M+H+)

- 107 045220

151 _H TA CH N ^H ''nAA _f ^Ν ΧΛ ^F aw W ^Cl (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((2-fluoropyridin-3 -yl)( 1H1,2,3-triazol-4yl)methyl) amino)quinoline-3 carbonitrile 10 ES/MS 508.1 (M+H+) 152 F _H iV Ch and aАу AN 1 y ^N I it j AW ^N 1 CI Cl (8)-8-chloro-6-(((5-chloropyridin3-yl)( 1 Η-1,2,3-triazol-4yl)methyl)amino)-4-((5,6difluoropyridin-3 yl) amino)quinoline-3 carbonitrile 10 ES/MS 524.0 (M+H+) 153 F _H Ar Alw aw W Cl (8)-8-chloro-6-(((4-chloropyridin3-yl)( 1 Η-1,2,3-triazol-4yl)methyl)amino)-4-((5,6difluoropyrid in-3 yl) amino)quinoline-3 carbonitrile 10 ES/MS 524.0 (M+H+) 154 F and Ap 4 Η ^Η - _Ν ΛΤ ^N -1 N ΐ a H '/y'Vv Iw Cl F (8)-8-chloro-6-(((2,6difluoropyrid in-3-yl)( 1H1,2,3-triazol-4yl)methyl)amino)-4-((5,6difluoropyrid in-3-yl) amino)quinoline-3 carbonitrile 10 ES/MS 526.0 (M+H+)

- 108 045220

155 ¥ Ν-, Η ^Η Μ-Χ'' Χχχτ ό JY F 8-chloro-6-(((8)-(1-cyclopropyl1 Η-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)-4-(((K )-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 554.1 (M+H+) 156 η ΧΧ W U Ci (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((3,6-dihydro-2H-pyran-4yl)(1H-1,2,3-triazole -4yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 495.1 (M+H+) 157 Ct __/ Dt ν~ ^{n Ν} -·1 Ν Λ Υ ^Ν ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(pyrazolo[1,5 -a] pyridin-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 586.2 (M+H+) 158 Η χ¥ Ν—, Η Έ · ^ζ Ύ ^N '^nV ^N Ο ά ^Ν (S)-8 -chloro-6-((( 1 -cyclopropyl1H-1,2,3 -triazol -4yl)(pyrid in-3 -yl)methylb)amino)-4-((5,6difluoropyrid in-3 yl)amino)quinoline-3 carbonitrile 2 ES/MS 530.9 (M+H+)

- 109 045220

159 ι 0 Ν-, Η ΑγγΑ O <5 8-chloro-6-(((8)-(1-cyclopropyl1H-1,2,3-triazol-4yl)(pyridin-3-yl)methyl<1)amino)-4-(((K)- 1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 536.1 (M+H+) 160 Q ίΥ gk n %ΑΑ _Γ ^Ν 1 ν Α Υ ^{1 Ν} Υ 'η'Υ'Α Λ W NsY Ct (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1-phenyl-1H-1,2,3-triazol-4yl)(pyridin-3yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 565.9 (M+H+) 161 F and Ay KQy STROKE (8)-8-chloro-6-(((2-chloropyridin3-yl)( 1 Η-1,2,3-triazol-4yl)methyl)amino)-4-((5,6difluoropyrid in-3 yl) amino)quinoline-3 carbonitrile 10 ES/MS 524.0 (M+H+) 162 Q ίΎ Lo £ 3A ^F cKL l AX Λ X- A ct (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1-phenyl-1H-1,2,3-triazol-4yl)(pyrid in-3 - yl)methylb)amino)quinoline-3 carbonitrile 2 ES/MS 567.1 (M+H+)

- 110 045220

163 n AI F (8)-8-chloro-6-(((5,6difluoropyrid in-3-yl)( 1H1,2,3-triazol-4yl)methyl)amino)-4-((5,6difluoropyrid in-3-yl) amino)quinoline-3 carbonitrile 10 ES/MS 526.0 (M+H+) 164 Η ΑΥ AttV ^F ό Α (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((pyr idin-3 -yl(1H-1,2,3triazol-4-yl)methylph)amino) quinoline-3 carbonitrile 10 ES/MS 491.1 (M+H+) 165 / C ^r= kj (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1 -methyl-1 H-pyrazol-5 yl)(1H-1,2,3-triazole -4yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 493.1 (M+H+) 166 Η A/ to η %ΧΧ X ΙΑ I Ν< CI F (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((6-fluoropyridin-3 -yl)( 1H1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 508.0 (M+H+)

- 111 045220

167 n D A Η ^Η ' _Ν - ODuOD” ό ά ^Ν ' (8)-8-chloro-4- (neopentylamino)-b((pyridin-3-yl( 1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 447.2 (M+H+) 168 D Ν-, Η ^Η Α Yuchu O g (8)-8-chloro-4(neopentylamino)-6-((( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline -3 carbonitrile 1 ES/MS 503.2 (M+H+) 169 F ⁿ D ^r 4 Η %Α=> ^Ν AW Μ Ct Ct (8)-8-chloro-6-(((6-chloro-2methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4-yl)methyl)amino)-4((5,6 -difluoropyridine-Zyl)amino)quinoline-3 carbonitrile 10 ES/MS 538.1 (M+H+) 170 Η r ^N x ^F k n ΑΧ DodDod I ΙΑ J SA's γ Ν nA ci (R)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((4-methylthiazol-5-yl)(1H1,2,3-triazol-4yl)methyl)amino )quinoline-3 carbonitrile 10 ES/MS 510.0 (M+H+)

- 112 045220

171 "2 Ά]] χΑ ^ν χ θ ^[ 8-chloro-6-(((8)-(2methylpyridin-3-yl)( 1 (oxetan-3-yl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4(( (R)-lphenylethyl)amino)quinoline-3 carbonitrile 2 ES/MS 551.1 (M+H+) 172 0 F Μ α ^Ν (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((2-methylpyrid in-3 -yl)( 1 (oxetan-3 -yl)- 1H-1 ,2,3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 560.0 (M+H+) 173 F _Η Hell Μ α ^Ν (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((2-methylpyridin-3-yl)(1H1,2,3-triazol-4yl)methyl)amino )quinoline-3 carbonitrile 10 ES/MS 504.0 (M+H+) 174 $ 9 Ν-η Η SX Ο r ^N 8-chloro-6-(((8)-(1-((1K,58,b8)-3(oxetan-3-yl)-3 - azabicyclo[3.1,0]hexan-6-yl)1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3-carbonitrile 4 ES/MS 632.2 (M + H+)

- 113 045220

175 ^g _x chyu %\ 8-chloro-6-(((8)-(1-(cyanomethyl)1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((I)-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 534.1 (M + H+) 176 7 8-chloro-4-(((I)-1- phenylpropyl)amino)-6-(((8)pyrid in-3 -yl( 1 -(3 - (pyrrolidin-1 -yl)propyl)-1H1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 606.3 (M+H+) 177 4 9 N-, HA ^H n1 A Ϊ APT A | N Cl 8-chloro-6-(((8)-(1-(2-fluoroethyl)1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3-carbonitrile 1 ES/MS 541.2 (M+H+) 178 A' ^x A o \ zc 8-chloro-4-(((8)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)pyr idin-3 -yl(1H-1,2,3triazol-4yl)methyl)amino) quinoline-3 carbonitrile 10 ES/MS 511.1 (M+H+)

- 114045220

179 O ⁿ I k. μ Η, D__Ή ⁿ ν> (: Ν 1 I 1 ^νΛ ΪΪΎ Υ A W N. _; ,J ^Cl 8-xnop-4-(((R)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)pyr idin-3 -yl(1H-1,2,3triazol-4yl)methyl)amino) quinoline-3 carbonitrile 10 ES/MS 511.1 (M+H+) 180 ΑΑ ⁴ У ^с χ-ζ /=\ У .1. .= r^z ¹ 6-(((S)-(l-((lR,5S,6s)-3azabicyclo[3.1,0]hexan-6-yl)1H-1,2,3-triazol-4yl)(pyridin-3yl)methyl )amino)-8-chloro-4(((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 4 ES/MS 576.2 (M + H+) 181 \\\ Aw w AA _H A ^χ/ \ A X—Z /=\ g ^g 8-chloro-6-(((8)-( 1 -((S)-1 - fluoropropan-2-yl)-1H-1,2,3 triazol-4-yl)(pyridin-3 yl)methyl)amino)-4-((^)-1 phenylpropyl)amino)quinoline3-carbonitrile 4 ES/MS 555.1 (M + H+) 182 x 9 Λ A Ci 8-chloro-4-(((8)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)(1 -(oxetan-3 -yl)-1 Η-1,2,3 triazol- 4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.1 (M+H+)

- 115 045220

183 0\u 1 Η O Cl ^N 8-chloro-4-(((H)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)(1 -(oxetan-3 -yl)-1 H-1,2,3 triazol- 4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.1 (M+H+) 184 O 8-chloro-4-(((8)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)(1 -isopropyl-1H-1,2,3triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 553.1 (M+H+) 185 1" o X 8-chloro-4-(((I)-3 -hydroxy-1 phenylpropyl)amino)-6-(((8)(1 -isopropyl-1H-1,2,3triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 553.1 (M+H+) 186 /X-0 ⁷ X '1 ° = ¹ 1 X 8-chloro-4-(((8)-2-hydroxy-2methyl-1-phenylpropyl)amino)6-(((8)-pyr idin-3 -yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 525.1 (M+H+)

- 116 045220

187 V N nXX TIX I Ο T'N nY ci 8-chloro-4-(((8)-2-hydroxy-2methyl-1-phenylpropyl)amino)6-(((S)-( 1 -isopropyl-1H-1,2,3 triazol-4-yl) (pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.1 (M+H+) 188 ^h , Io· № nY ci 8-chloro-4-(((R)-2-hydroxy-2methyl-1-phenylpropyl)amino)6-(((S)-nnp idin-3 -yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 525.1 (M+H+) 189 F F F.1 H Χΐγ NI T >< ^N l Ox AT^ ^N Χ,Ν Cl (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1 -(2-fluoroethyl)-1 Η-1,2,3 triazol-4-yl) (pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 536.1 (M+H+) 190 X 9 Ν-, Η 'kX'' aoA 8-chloro-4-(((R)-lphenylpropyl)amino)-6-(((8)pyrid in-3 -yl( 1 -((R) -1,1,1trifluoropropan-2-yl)- 1H -1,2,3 triazol-4yl)methyl)amino)quinoline-3 carbonitrile 4 ES/MS 591.1 (M + H+)

- 117 045220

191 τ 0 -OH rf] nA ci 8-chloro-6-(((8)-(1-cyclopropyl1 H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3-carbonitrile 4 ES/MS 535.1 (M + H+) 192 l o -1A> About ci 6-(((8)-( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4- (((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 551.2 (M + H+) 193 v 9 Ν-^ Η ^Η >1'ν-' Κ1 ϊ α ^ν ΤΰΥ Ο 4 ^Ν 8-chloro-6-(((8)-(1-isopropyl- 1H-1,2,3 -triazole -4- silt)(pyridine in-3 - yl)methyl)amino)-4-(((R)-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 537.1 (M + H+) 194 „5, ^Ν —ι ^Η ΝΑ ΑγΑ Ο α 8-chloro-6-(((8)-(1-(oxetan-3yl)-1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((R)-1 phenylpropyl)amino)quinoline3-carbonitrile 2 ES/MS 551.1 (M + H+)

- 118045220

195 A A F N~, Η -νΉ, AVtV Α 4Ά Cl 8-chloro-4-(((E)-1phenylpropyl)amino)-6-(((8)pyridin-3-yl( 1 -(2,2,2trifluoroethyl)-1 Η-1,2,3 triazol- 4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 577.1 (M + H+) 196 n ^Cl 1 h A AW/ AW W Cl (8)-8-chloro-4-((3chlorophenyl)amino)-6-((( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)(pyridin-3 yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 543.1 (M+H+) 197 F nf nA N ΔΑ ^N jT YXa A w ⁿ N<J Cl 8-chloro-4-((5,6-difluoropyridin3 -yl)amino)-6-(((8)-(1 -((S)-1 fluoropropan-2-yl)- 1H-1,2, 3 triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 4 ES/MS 549.9 (M+H+) 198 A A (8)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4((5, 6-difluoropyr idin-3 yl)amino)quinoline-3 carbonitrile 8 ES/MS 546.2 (M+H+)

- 119 045220

199 rY FiU D dm N.^Cl (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6(((1 -(oxetan-3 -yl)-1 Η-1,2,3 triazol-4- yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 546.1 (M+H+) 200 D' ⁴ⁿ V rrV ^Ν nQ α ^Ν ” (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((pyridin-3 -yl( 1 -(3 (pyrrolidin-1 -yl)propyl)-1H1, 2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 601.2 (M+H+) 201 And G? ASA AWCl (8)-8-chloro-6-((( 1 -(oxetan-3 yl)-1H-1,2,3-triazol-4yl)(pyridin-3yl)methyl)amino)-4((tetrahydro-2H -pyran-4yl)amino)quinoline-3 carbonitrile 2 ES/MS 517.1 (M+H+) 202 Ύ Ul, ⁰ - Ί! A IIIJ A ^Cl 8-chloro-4-(((K)-2-hydroxy-2methyl-1-phenylpropyl)amino)6-(((8)-( 1 -isopropyl-1H-1,2,3 triazol-4-yl) (pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.2 (M+H+)

- 120 045220

203 z^'z^ ¹ Ya / 8-chloro-4-(((K)-2-methoxy-1 phenylethyl)amino)-6-(((8)pyr idin-3 -yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 511.0 (M+H+) 204 > 9 O 9 ^N 8-chloro-6-(((8)-(1-isopropyl1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((K)-2methoxy-1- phenylethyl)amino)quinoline-3 carbonitrile 2 ES/MS 553.3 (M+H+) 205 FF Xf < ⁿ ^< ^f n ⁿ tj Xx 1 ^{F N} χ YVj 0 Cl ^N 8-chloro-4-((5,6-difluoropyridin3-yl)amino)-6-(((8)-pyr idin-3 yl( 1 -((R)-1,1,1-trifluoropropan2-yl )-1 Η-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 4 ES/MS 585.9 (M+H+) 206 I h χΥ AVrV Ο ί* (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(pyridin-3yl)methyl)amino)-4-((5,6difluoropyrid in-3yl)amino )quinoline-3 carbonitrile 2 ES/MS 529.9 (M+H+)

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207 J ^Η Μ k n AtUH O Ji (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((pyr idin-3 -yl(1H-1,2,3triazol-4yl)methyl)amino)quinoline- 3 carbonitrile 10 ES/MS 490.1 (M+H+) 208 U I U -XLIZ A tA Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4((5,6-difluoropyridin-Zyl)amino) quinoline-3 carbonitrile 8 ES/MS 629.3 (M+H+) 209 F _F Xf f ⁿ A'ХХт ⁿ ' ⁿ VyyV nJ ci ' (8)-8-chloro-4-((5,6difluoropyrid in-3 -yl)amino)-6((pyrid in-3 -yl( 1-(2,2,2trifluoroethyl)-1 Η-1,2 ,3 triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 572.0 (M+H+) 210 o. 9 X Μγ=' to H %LU Λ U ci (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((3,6dihydro-2H-pyran-4-yl)( 1 (oxetan-3 -yl)- 1H-1,2,3triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 599.8 (M+H+)

- 122 045220

211 WITH! n W' K H ^N 1 _l 1 y ν-- _υ ^ ILLJ γΊ ^{< n} V Cl (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((3,6dihydro-2H-pyran-4-yl)( 1H1,2,3-triazol-4yl )methyl)amino)quinoline-3 carbonitrile 10 ES/MS 544.0 (M+H+) 212 3 0 Nn H ^H ir ^J 4 ^z AnV О ci 2-(4-((8)-((8-chloro-3-cyano-4(((R)-l- phenylpropyl)amino)quinolin6-yl)amino)(pyr idin-3 yl)methyl)-1 N-1,2,3-triazol-1 nn)-N,N - d eti l-N-methylethane1 -aminium 1 213 cAh A xx z=\ TA/ ,-.. 7 \ / ³ 8-chloro-6-(((8)-(1-cyclopentyl1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)-4-(((R)-1 phenylpropyl)amino)quinoline3-carbonitrile 1 ES/MS 563.2 (M+H+) 214 . 9 U Η ^H A n 1 । l y TV ^N ''^ X IT J N Ύ γ Η 'iO Cl 8-chloro-4-(((R)-2-hydroxy-lphenylethyl)amino)-6-(((8)oxazol-4-yl(1H-1,2,3-triazol4-yl)methyl)amino) quinoline-3 carbonitrile 10 ES/MS 487.1 (M+H+)

- 123 045220

215 . 9 ^Y > n ^N ''N'X' ^P _N Ν P J, I ^Η I XT J ^N 7 un U ci 8-chloro-4-(((8)-2-hydroxy-1 phenylethyl)amino)-6-(((8)oxazol-4-yl(1H-1,2,3-triazol4-yl)methyl)amino )quinoline-3 carbonitrile 10 ES/MS 487.0 (M+H+) 216 Cl n tv to h M.J. I I XT J Λ “N h=/ci (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-((( 1 methyl-1 H-pyrazol-5 -yl)( 1H1,2,3-triazol-4 - yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 542.0 (M+H+) 217 ex ? X Vx ^cl to H ^N XN 1 U M'UuU/ I XT J >A yN N ^J Cl (K)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((4methylthiazol-5 -yl)( 1 -(oxetan3 -yl)-1 Η-1,2, 3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 614.8 (M+H+) 218 . I'm O z o / X 8-chloro-4-(((8)-2-hydroxy-1 phenylethyl)amino)-6-(((8)-(2methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4yl )methyl)amino)quinoline-3 carbonitrile 10 ES/MS 511.1 (M+H+)

- 124 045220

219 " O ΊΟ α 8-chloro-4-(((K)-2-hydroxy-1phenylethyl)amino)-6-(((8)-(2methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 511.1 (M+H+) 220 CALX Α ^β γρ t-^ _z ^z 8-chloro-6-(((8)-(2- methylpyridine in-3 -yl)(1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 10 ES/MS 509.0 (M+H+) 222 Cl R J___-Cl H|C \u L 1 ΥτΎτ A A si (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3c]pyridine -3 -yl)(1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 655.4 (M + H+) 223 Cl < \ ^f A^ ^c| \ μι ΊΓ J N~~ H 41-44 ΑΜγΟΥ yA γΜ 9> ^{s Cl} ₀ A (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3 -triazol-4-yl)(6-(oxetan3-yl)-4,5,6 ,7tetrahydrothieno[2,3- c]pyridin-3-yl)methyl)amino)8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)quinoline-3 carbonitrile 5 ES/MS 794.3 (M + H+)

- 125 045220

224 Cl ⁿ A K n ^N .XaWW Χ)Γ (8)-8-chloro-4-((3chlorophenyl)amino)-6-(((2methylpyridin-3-yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 501.0 (M+H+) 225 Cl ίαΑ AW 'V Cl (8)-8-chloro-4-((3chlorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(2-methylpyridin-3yl)methyl)amino) quinoline-3 carbonitrile 1 ES/MS 543.1 (M+H+) 226 9l ^ci SL h _N u “Xbu/ AW nW θ' (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2methylpyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chlorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 640.1 (M+H+) 227 Cl S „ DN ^N >\W/' aw nW ci (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((2methylpyridin-3-yl)( 1 Η-1,2,3 triazol-4yl)methyl) amino)quinoline-3 carbonitrile 10 ES/MS 553.0 (M+H+)

- 126 045220

228 Ct _/ Al d r ^N (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(5-methylpyridin-3 yl )methyl)amino)quinoline-3 carbonitrile 1 ES/MS 561.1 (M+H+) 229 J D nA ci 8-chloro-6-(((8)-(2- methylpyride in-3 -yl)(1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(((R)-lphenylethyl)amino)quinoline-3 carbonitrile 10 ES/MS 495.0 (M+H+) 230 \=/ r—i X? = /\ / /=\ 4W 8-chloro-6-(((8)-(1-isopropyl1H-1,2,3-triazol-4-yl)(2methylpyride in-3 - yl)methyl)amino)-4-(((K)-1 phenylethyl)amino)quinoline-3 carbonitrile 2 ES/MS 537.1 (M+H+) 231 Q 2 A%v ΌΓ 6-(((8)-( 1-(1 -(tert-butyl)piperidin-4-yl)-1H1,2,3 -triazol-4-yl)(2methylpyridin-3 yl)methyl)amino)-8- chlorine-4(((R)-l- phenylethyl)amino)quinoline-3 carbonitrile 2 ES/MS 634.1 (M+H+)

- 127045220

232 Cl __, rA,ci gk h A-XX ODodd Ύγ γΧτ A Cl (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(2-methylpyridin- 3 yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 595.0 (M+H+) 233 a I ¹ Q OD. NH a _n AY xX γΧ' nJ ci (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2methylpyridin-3 - yl)methyl)amino)-8-chloro-4- ((3,4-dichloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 692.0 (M+H+) 234 Cl n AV' K h ^N XNAY NVVYV I XX J yA “ N N—Cl (C)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-(((4methylthiazol-5 -yl)( 1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 558.9 (M+H+) 235 Cl , rJci Ν' H И^ХХ ^Ν X ό AY νΥΥ<-\κΑ Τ XX J Ύδ γΝ N^ Cl (C)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(4-methylthiazol-5yl )methyl)amino)quinoline-3 carbonitrile 2 ES/MS 600.8 (M+H+)

- 128 045220

236 У X Cl v W ¹ I LA J A's Y ' Cl (R)-6-(((l-(l-(ipeT- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(4methylthiazol-5- yl)methyl)amino)-8-chloro-4- ((3,4-dichloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 697.9 (M+H+) 237 b 9 N~, H ^H N'k AV? ϊ L ^f NA ^{s Cl} T 6-(((8)-( 1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6-(oxetan3-yl)-4,5,6,7- tetrahydrothieno[2,3- c]pyridin-3-yl)methyl)amino)8-chloro-4-(((I)-1- phenylethyl)amino)quinoline-3 carbonitrile 5 ES/MS 736.2 (M + H+) 238 n 9 AO? LT ri 8-chloro-6-(((8)-(6-(oxetan-3yl)-4,5,6,7- tetrahydrothieno[2,3- c]pyridin-3-yl)(1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(((R)-l- phenylethyl)amino)quinoline-3 carbonitrile 10 ES/MS 597.1 (M + H+)

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239 a 9 Ν 1 ι _ ϊ X A Ta J Xs γ Ν rX Cl 8-chloro-6-(((R)-(1-isopropyl1H-1,2,3-triazol-4-yl)(4methylthiazol-5yl)methyl)amino)-4-(((R)-1 phenylethyl) amino)quinoline-3 carbonitrile 2 ES/MS 543.1 (M+H+) 240 j Σ'Σ'^^ί / IL Μ Hell _ζ _ _χ A 6-(((E)-(1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(4methylthiazol-5yl)methyl)amino)-8-chloro- 4(((R)-l- phenylethyl)amino)quinoline-3 carbonitrile 2 ES/MS 640.1 (M+H+) 241 Cl Q «Α ΐΧΧΧ /хЧ w ίΑ ^{ε Cl} A (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6-(oxetan- 3-yl)-4,5,6,7- tetrahydrothieno[2,3- c]pyridin-3-yl)methyl)amino)8-chloro-4-((3-chloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 5 ES/MS 760.1 (M + H+)

- 130045220

242 X N-, Cl QW ' n II J Ν' Η >G'G Ν.1 Ν _l Λ ^Ν ΥΥΤγ Αν γΎ' Ό-ί1 CI (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6-((oxazol4-yl( 1-(1 -(oxetan-3 yl)piperidin-4-yl)- 1H -1,2,3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 668.0 (M + H+) 243 ⁴ Α GO Η ν 1 > ι Α У s yw Cl 8-chloro-6-(((K)-(4-methylthiazol5 -yl)( 1 Η-1,2,3-triazol-4yl)methyl)amino)-4-(((K)-1 phenylethyl)amino )quinoline-3 carbonitrile 10 ES/MS 501.0 (M+H+) 244 z/ Z'Zx °V~\U (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((3,6dihydro-2H-pyran-4-yl)( 1 isopropyl-1 H-1,2,3 -triazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 551.9 (M+H+) 245 Cl A U y> D S' (8)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(2-methylpyridin-3 yl )methyl)amino)quinoline-3 carbonitrile 1 ES/MS 561.2 (M+H+)

- 131 045220

246 Cl F. X ^H Y 1\n 11 J (8)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6-(((6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3c]pyridin-3 -yl)(1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 621.5 (M + H+) 247 pw ^N W Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(2- methylpyride in-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 658.1 (M+H+) 248 Cl η Ύ “ΧΑγγΙΥ (8)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6-(((2methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino) quinoline-3 carbonitrile 10 ES/MS 519.2 (M+H+) 249 Cl ⁿ Xy ^f XX/ AW Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((5 methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino )quinoline-3 carbonitrile 1 ES/MS 519.0 (M+H+)

- 132 045220

250 9 A ^N 1 n Ν''γ- ^Ν ·^'4γ'<γ Ct (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(5methylpyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 658.1 (M+H+) 251 Cl n ^F A N 1 1 ΐ 4 X IA J As '^ N A Cl (C)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6-(((4methylthiazol-5-yl)( 1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 525.1 (M+H+) 252 Cl A ^F zS X h %XU N 1 Λ ? 4 χΑβ Xf N H Cl (H)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(4-methylthiazol-5yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 567.1 (M+H+) 253 Poison Ct NH - _n x5 M _l 1 4 ^Ν γγγγ γ''TG hA Cl (K)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(4methylthiazol-5- yl)methyl)amino)-8-chloro-4-((3 chloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 664.2 (M+H+)

- 133 045220

254 z. w X 4W %\ 8-chloro-4-(((R)-1phenylpropyl)amino)-6-(((8)pyridin-3-yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 495.2 (M+H+) 255 Νγ Η ^N DGCH AviV 0G 8-chloro-4-(((R)-1phenylethyl)amino)-6-(((8)pyridin-3-yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 481.2 (M+H+) 256 Cf R Λο n g Υ ' n k IJ 0 a ^lf (8)-8-chloro-4-((3,4-dichloro-2fluorophenyl)amino)-6- ((pyr idin-3 -yl( 1H-1,2,3- triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 539.1 (M+H+) 257 Cl r x H T || n L U N^, H wP o A (8)-8-chloro-4-((3-chloro-2fluorophenyl)amino)-6((pyr idin-3 -yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 505.1 (M+H+)

- 134 045220

258 Χ-Ζ /=x 6-(((8)-( 1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4(((R)-l- phenylpropyl)amino)quinoline3-carbonitrile 1 ES/MS 634.3 (M+H+) 259 X 2 10 N H-tJ-X _Ν 0Γ 6-(((8)-( 1-(1 -(tert-butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4(((R)-l- phenylethyl)amino)quinoline-3 carbonitrile 1 ES/MS 620.3 (M+H+) 260 X N-. Cl <7 and ΧγΥ A ΑΧ Ν0 Cl (8)-6-((( 1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4((3,4-dichloro-2- fluorophenyl)amino)quinoline-3 carbonitrile 8 ES/MS 678.1 (M + H+). 261 1 y ^f V Η Η AJ ^Ν _Ν ΑγγΑ ^Ν 4s τ^ν γ α (R)-6-(((l-(l-(TpeT- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2,4d have lthiazol-5 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 678.0 (M+H+)

- 135 045220

262 b A ^Ν 1 Ν 1 Α Ν γΤ' ^Ν ^>0 CI (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2,5dimethyloxazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 662.0 (M+H+) 263 9l ^Cl \) Al Η ^nAX ^Ν 1 Ν 1 Α Ά γΧ OL Cl (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(5methyloxazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 648.3 (M+H+) 264 9l ^ci ΐ) Al wX 0 A (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(3,6dihydro-2H-pyran-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 649.1 (M+H+)

- 136 045220

265 Yes ^x a xz o^. (R)-6-(((l-(l-(ipeT- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(4methyloxazol-5 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 648.2 (M+H+) 266 Cl n rV ^F A h ⁿ ' ⁿ VvyV A ⁿ A ci / (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1 H-imide azol-4-yl)( 1H1,2,3-triazol-4yl) methyl)amino)quinoline-3 carbonitrile 10 ES/MS 508.1 (M+H+) 267 9ts Cl V/ Ax N^, H ^N ^rrV ^N An AA N-^ Cl / (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(1-methyl1H-imide azol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 647.1 (M+H+)

- 137 045220

268 I γ AI A yV N' Cl / (K)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(1-methyl1H-pyrazol-3- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 647.0 (M+H+) 269 Cl A H H. _N U yA W kA ^CI A (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3c]pyridin-3 -yl)(1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 621.1 (M + H+) 270 Q[ ν h %X2 YyAU A A ( (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6-ethyl4,5,6,7-tetrahydrothieno[2,3c]pyridin-3-yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 593.1 (M + H+) 271 Cl ⁿ Ai η ⁿ _n A> _t JLy ⁿ rj] T^ ^N Ϋ Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6methylpyridine in-3 -yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino) quinoline-3 carbonitrile 10 ES/MS 519.0 (M+H+)

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272 Cl ⁿ Ar ^F A η ΊΟ ci ^N (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2methylpyridine-3-yl)( 1 Η-1,2,3 triazol-4yl)methyl)amino) quinoline-3 carbonitrile 1 ES/MS 519.0 (M+H+) 273 Cl BP h Xrrr A AA nJ ci (8)-(4-(((8-chloro-4-((3-chloro-4fluorophenyl)amino)-3 cyanoquinolin-6-yl)amino)(6methylpyridin-3 -yl)methyl)-1H1,2 ,3-triazol-1yl)methyl pivalate 10 ES/MS 633.1 (M+H+) 274 Cl A°l h ⁿ -DU ⁰ N 1 i । naas^a o A (8)-(4-(((8-chloro-4-((3-chloro-4fluorophenyl)amino)-3 cyanoquinolin-6-yl)amino)(2methylpyridine in-3 -yl)methyl)-1H1,2 ,3-triazol-1yl)methyl pivalate 10 ES/MS 633.0 (M+H+) 275 Cl At ^H [IT % H AAA nA X jn uulu LD w L> ^{s ci} H (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4,5,6,7tetrahydrothieno[2,3- c]pyridin-3-yl)(1 Η-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 565.1 (M + H+)

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276 Cl on the/ An γΑ A Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((thiazol4-yl(1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 511.0 (M+H+) 277 Cl ⁿ Ar ^F to Η As γν N=/ Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((thiazol5-yl(1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 511.1 (M+H+) 278 Cl Αχ xVrtA LA ^Cl ( (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6-ethyl4,5,6,7-tetrahydrothieno[2,3c]pyridin-3-yl)( 1 -(oxetan-3 yl)-1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 649.1 (M + H+). 279 Cl rV HA''A %ΑγΑγ- ^Ν <-AW LA ^Cl h' (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)(4, 5,6,7tetrahydrothieno[2,3с]pyridine-3 - yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 621.0 (M + H+)

- 140 045220

280 Cl Ay A ^HH 'N 'X ιφ a ^N (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(6-methylpyridin-3 yl) methyl)amino)quinoline-3 carbonitrile 1 ES/MS 561.2 (M+H+) 281 zf · Ay U? iz# ² (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6methylpyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 658.1 (M+H+) 282 Cl Ay % h %DD %YrrV Or (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(2-methylpyridin-3 yl) methyl)amino)quinoline-3 carbonitrile 1 ES/MS 561.2 (M+H+) 283 —C Cl 0 h /У ^VyY Ua (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2methylpyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 658.1 (M+H+)

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284 Ύ Ν-, Q ^N Xn_IyY Λ 'γ -,Γ rO Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4-((5chloropyridin-3 yl)amino)quinoline- 3 carbonitrile 8 ES/MS 629.2 (M + H+). 285 Q n y or (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4((3,4- difluorophenyl)amino)quinoline3-carbonitrile 8 ES/MS 628.2 (M+H+) 286 Y α q X Ν-, Η LG'-'' ό 1 (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8- chloro-4-((3 chloro-2fluorophenyl)amino)quinoline-3 carbonitrile 8 ES/MS 644.2 (M+H+) 287 ΟΧ Ά Χ-Ζ /=Χ X/ (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8- chloro-4(cyclohexyl amino)quinoline-3 carbonitrile 1 ES/MS 598.3 (M+H+)

- 142045220

288 Ъ «о Ν-, Η Ν'— ^Ν ΧϊΎΎ Ο α ^Ν (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4(cycloheptyl amino)quinoline-3 carbonitrile 1 ES/MS 612.3 (M+H+) 289 Ο ? 0 hX ^f ^VrrV VS A ^Ν A Cl Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6-chloro-4methylpyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 692.2 (M+H+) 290 -A Cl 0„A Ν-, H 'NO %Ugt¥ AΆ ACl A (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6methoxypyridin-3 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 674.2 (M+H+)

- 143 045220

291 A-Cl 0 to D' CIA 1 rMCl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2isopropoxypyridin-3 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 702.1 (M+H+) 292 X 9 ¹ 0 n D' A n^A _f ci F (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(5,6difluoropyrid in-3 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 680.2 (M+H+) 293 С[ 1 _F °XW W' (8)-6-(((5 -bromo-2-chloropyridin3 -yl)( 1 -isopropyl-1 H-1,2,3 triazol-4-yl)methyl)amino)-8chloro-4-((3 -chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 661.2 (M+H+) 294 Cl ./ D^-F A n _n JlJ A ιΐ ^ХХа I DA fV Ν% Cl Cl (8)-8-chloro-6-(((6-chloro-2methylpyrid in-3 -yl)( 1 isopropyl-1 H-1,2,3-triazol-4yl)methyl)amino)-4-(( 3-chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 595.6 (M+H+)

- 144 045220

295 CI / <W- ^F \ η Xa γ¥ nA ci Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2,6dichloropyridin-3-yl)( 1 isopropyl-1 H-1,2,3-triazol-4yl )methyl)amino)quinoline-3 carbonitrile 1 ES/MS 617.1 (M+H+) 296 Cl -YA^-f H ^C[ y4 v¥ Ct Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4,6dichloropyridin-3-yl)( 1 isopropyl-1 H-1,2,3-triazol- 4yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 617.1 (M+H+) 297 Cl / ^Af ^ν Ίι ^h A-Xy AW nA ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2chloropyridin-3-yl)( 1 isopropyl-1 H-1,2,3-triazol-4yl )methyl)amino)quinoline-3 carbonitrile 1 ES/MS 581.2 (M+H+) 298 Cl N^ Η '''DH ΑγνΥ Before TD A ci (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 Η-1,2,3-triazol-4yl)(oxazol-5yl)methyl)amino )quinoline-3 carbonitrile 2 ES/MS 537.1 (M+H+)

- 145 045220

299 _n a ΑγγΑ Ao A' ⁿ s =/ C1 (R)-6-(((l-(l-(ipeT- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(oxazol-5 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 634.1 (M+H+) 300 CI Q „ А AW Αν An ^z sA. ci N^\Q (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2morpholinothiazol-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 735.1 (M + H+) 301 Cl / Νγ H ^nAA An sA Cl N-\ Ή (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(2-morpholinothiazol-4yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 638.0 (M + H+) 302 Cl Aa \ i-i 11 J 1C H%-V An T S% Cl o <0 (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2morpholinothiazol-4-yl)( 1 (oxetan-3 -yl)- 1H-1,2,3triazol- 4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 652.0 (M + H+)

- 146 045220

303 Cl Ν' Η Uulu As A Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(thiazol-5yl)methyl)amino )quinoline-3 carbonitrile 2 ES/MS 553.0 (M+H+) 304 Cl y and %xY -nX χχχ Wct (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)( 1 -methyl-1 H- pyrazol-5 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 550.1 (M+H+) 305 A' Cl Vy .Α ¹⁷ Ν H %AY УгоУУ nA S^N^ N= Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(1-methyl- 1H-pyrazole-5- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 647.1 (M+H+) 306 Cl , AY ⁴ Ν' H ^N 'l NAA vA _s A ci (H)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(4-methylthiazol-5yl)methyl )amino)quinoline-3 carbonitrile 2 ES/MS 566.9 (M+H+)

- 147045220

307 X A -уГд 'YU' N=/ Cl (R)-6-(((l-(l-(ipeT- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(4- methylthiazole-5- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 664.0 (M+H+) 308 ,-., F ⁿ ΓΓ Y n %XAct ODodHd A YX nY ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((pyr idin-3 -yl(1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 10 ES/MS 505.1 (M+H+) 309 γγ \ / Xy ^f fa ( Υ-Χα ODDOD A W nY ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((pyr idin-3 -yl( 1 -(2,2,6,6tetramethylpiperidin-4-yl)1H-1, 2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 644.2 (M+H+) 310 Cl -D/ Ay Ν' H ^N-XX nA Άο Cl (8)-6-((( 1 -(tert-butyl)-1H- 1,2,3-triazol-4-yl)(oxazol-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 551.1 (M+H+)

- 148 045220

311 Cl , A< ^f N- H kTT ΛιΛρτ A ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)( 1 -methyl-1H-imidazole -5 yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 550.1 (M+H+) 312 Cl, I n £ F ry h Atta nA Ά ct (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1H-1,2,3-triazol-4yl)(oxazol-4yl)methyl)amino) quinoline-3 carbonitrile 2 ES/MS 537.0 (M+H+) 313 to y (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)(pyridin- 3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 505.1 (M+H+) 314 G N n U ktUU' A vA Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(1 (oxetan-3 -yl)piperidin-4yl)- 1H-1,2,3 - triazol -4yl)(pyridin-3yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 644.2 (M+H+)

- 149 045220

315 4 X HuU (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2chloropyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 680.1 (M+H+) 316 r-γ 1т ^N ^rrV ^N Αν V Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (pyridin-2-ylmethyl)- 1H-1,2,3 triazol-4-yl)(thiazol -4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 601.9 (M + H+) 317 nY ci g and A γγγ Α γΑ Cl Ν ^Ζ (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 - (pyridin-2-ylmethyl)-1H-1,2,3 triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 626.0 (M + H+) 318 A 4 X Λ V Ν'γΙγΧγ Ό γΑ NX CI C.I. (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6-chloro-2methylpyridin-3 yl)methyl)amino )-8-chloro-4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 692.2 (M+H+)

- 150045220

319 7 A/ ΐλΑΑ AW nA ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2chlor op pyr idin-3 -yl)( 1 -(oxetan3 -yl)-1 Η-1,2 ,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 595.0 (M+H+) 320 PI CH u xХDO NA _Br CI (8)-6-(((5 -bromo-2-chloropyridin3 -yl)( 1 -(oxetan-3 -yl)-1H1,2,3-triazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 675.0 (M+H+) 321 Cl Q Ay VH n 1 ό _l AA ^N jXYxT aS -a-nA Cl Cl (8)-8-chloro-6-(((6-chloro-2methylpyrid in-3 -yl)( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)methyl)amino) -4((3-chlorine-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 609.1 (M+H+) 322 CC Cl Q Ay у η %Ά АуЪ Aw nA Cl Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2,6dichloropyridin-3-yl)( 1 (oxetan-3-yl)- 1H-1,2 ,3triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 631.0 (M+H+)

- 151 045220

323 0·. Cl Ch Al S H ^ν-Ά d di OD Cl Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4,6dichloropyridin-3-yl)( 1 (oxetan-3-yl)- 1H-1,2 ,3triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 631.0 (M+H+) 324 A QA StyX NA _Br CI (8)-6-(((5-bromo-2-chloropyridin3-yl)(1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazole-4- yl)methyl)amino)-8-chloro-4-((3 - chlorine-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 758.1 (M+H+) 325 A N-1 Η ^η νΆΤ ^N 'l N 1 L STROKE ci Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2,6dichloropyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 714.2 (M+H+)

- 152045220

326 Ί QW ww VW ClCl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(4,6dichloropyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 714.1 (M+H+) 327 yO _ z J У (S)-6-(((5 -bromo-2-chloropyridin3 -yl)( 1 -(2-hydroxyethyl)-1H1,2,3-triazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 663.0 (M+H+) 328 l W ^N nMwV ^N VW rM ci Cl (8)-8-chloro-6-(((6-chloro-2methylpyridine in-3 -yl)( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazol-4-yl)methyl)amino)- 4((3-chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 1 ES/MS 597.0 (M+H+) 329 H ,-, ^Cl '% iV ⁷ VH %-M uvv w Cl Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2,6dichloropyridin-3-yl)( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 619.0 (M+H+)

- 153 045220

330 Μ Cl /V ^С| L w An ci ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4,6dichloropyridin-3-yl)( 1-(2hydroxyethyl)-1 Η-1,2,3 triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 619.0 (M+H+) 331 H-0 Cl _H h _v /d At/ ^c sA XM Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((2chloropyr idin-3-yl)( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazole -4- yl)methyl)amino)quinoline-3 carbonitrile 1 ES/MS 583.1 (M+H+) 332 CA ci A h x9 ^F As CT 2=/ s ¹ Ν' (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 -(2morph ol inoethyl)-1 Η-1,2,3 triazole -4- yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 648.1 (M + H+) 333 Cl ^H '° Aa A, h ΑγγΑ As уA 2=/ Cl N ^Z (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazol-4 - yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 579.0 (M + H+)

- 154045220

334 X gt At?? ¹ About ? ^N (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-b-((( 1 -(2(piperidin-1 -yl)ethyl)-1H1,2,3 -triazol-4- yl)(pyr idin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 616.2 (M+H+) 335 g J g A Poison (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2morph ol inoethyl)-1 Η-1,2,3 triazol-4-yl)(pyridine -3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 570.2 (M+H+) 336 d o' ν ^ν 1α._ΑΙ? ^{ν Cl N} jl TX? rjl T'' ^N Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-b-((( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazol-4-yl)(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 549.1 (M+H+) 337 Cl -о D/ LVrrV Xs γΑ Cl N ^Z (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 -(2methoxyethyl)-1 Η-1,2,3 triazol-4 - yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 593.0 (M + H+)

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338 Cl - Ό ^ρ Ν-η H A-LL As γ* Cl FT (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 isopropyl-1H-1,2,3-triazol-4yl)methyl) amino)quinoline-3 carbonitrile 2 ES/MS 577.0 (M + H+) 339 Ct 7 h A AUX> As γ? )= ¹ Cl IT (H)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1 -(oxetan3 -yl)-1 H-1,2,3 - triazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 591.0 (M + H+) 340 \ 0 o ^z / ¹ «rx ^F 'Xw ώ ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2-(2methoxyethoxy)ethyl)-1 Η-1,2,3 triazol-4-yl )(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 607.2 (M+H+) 341 H b 0 ? “rx ^F Nn H ^H N-AA _C | n L n AA ⁿ O i 'if A γΜ ^Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2-(2hydroxyethoxy)ethyl)-1 Η-1,2,3 triazol-4-yl )(pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 593.2 (M+H+)

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342 A a Α-γΥ N=/ Cl (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H- 1,2,3-triazol-4-yl)(1-methyl- 1 EI-imide azole-5- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 647.0 (M+H+) 343 Cl \ L У ^ν ' ^Ν Ί η ^η 7 ΝΎ ^Ν γγ4Υ ^Ν AT ^N nJ ci (R)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)quinoline-3 carbonitrile 6 344 ci and YES AD 04 A ( (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6-ethyl4,5,6,7-tetrahydrothieno[2,3c]pyridin-3-yl)( 1 -isopropyl1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 635.0 (M + H+) 345 Cl / Ay iy Η n.1 N ^AJ ^{N Г1} |' ЗрА yA γΜ L> ^{a с|} / (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(6-methyl-4,5 ,6,7tetrahydrothieno[2,3c]pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 620.9 (M + H+)

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346 Cl / Αχ N-. Η hi (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(4,5,6,7tetrahydrothieno [2,3c]pyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 606.9 (M + H+) 347 kA ^X XZ Γ=Σ '' (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(6fluoropyridin-3 - yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 662.1 (M+H+) 348 b to ΓΚ Η WAJ ^Ν 3 _γ ΑΑ NX vV X Cl (8)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(oxazol-4yl)methyl)amino)-8-chloro- 4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 634.1 (M+H+)

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349 Ε Τ Αχ (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(5chlorobenzo[b]thiophen-3yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 735.0 (M+H+) 350 γ ^CI χ χ° ^NN XjS^wXi ^{N ,κ} ΧίΧΧ Αν W A CI (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)-8-chloro-4((3,4- dichlorophenyl)amino)quinoline3-carbonitrile 2 ES/MS 665.9 (M+H+) 351 Ct\) a^f Ν- Η ^Η Ν·Χυ ^Ν 1 Ν 1 Α (8)-6-((benzo[b]thiophen-3 -yl(1 (1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)-8 -chloro-4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 699.7 (M+H+) 352 °η < ) CI ^νΝ γ rS ^F Ν-. Η Χν AChg S ^J Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2morph ol inoethyl)-1 Η-1,2,3 triazol-4-yl)(thiazol -4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 624.1 (M + H+)

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353 X A ww An Xn^ A ci (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 650.1 (M+H+) 354 b x A H H AJ N 1 1 7 ^N Τ'-γ'-γΎΑ' X LA J Ν Ά y ~N ΐ-S Cf (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (piper idin-4-yl)- 1H-1,2,3triazol-4-yl)(thiazol -4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 594.0 (M+H+) 355 -N Cl ? Η A Ν' H 'N-'-Y yy An γ" V Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2(dimethylamino)ethyl)- 1H-1,2,3 triazol-4-yl)( thiazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 581.9 (M + H+) 356 H o ^z Cl ? h A An γκ A Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2hydroxyethyl)-1 Η-1,2,3 triazol-4-yl)(thiazol-4yl )methyl)amino)quinoline-3 carbonitrile 2 ES/MS 555.0 (M + H+)

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357 Ay ^τ Ύ _/ 'Or ^Η (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 isopropyl-1 H-1,2,3-triazol-4yl)(thiazol-4yl)methyl)amino )quinoline-3 carbonitrile 2 ES/MS 553.0 (M + H+) 358 ο'CI ? Η Α ΧτΥ Αν γ—Α A CI (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(2methoxyethyl)-1 Η-1,2,3 triazol-4-yl)(thiazol-4yl )methyl)amino)quinoline-3 carbonitrile 2 ES/MS 569.0 (M + H+) 359 Η Η—Ν CI / Η Α Ν' Η •'Ν'Κ^ Ν.1 Α*Ν ^Ν τγ γγ ΥΝ γΆ S ^J Cf (8)-6-((( 1 -(2-aminoethyl)-1H1,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)-8-chloro-4-((3 - chlorine-4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 553.9 (M + H+) 360 ί Dxx (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 -(3 - (dimethylamino)propyl)-1H1,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 596.0 (M + H+)

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361 Cl A h D Ν-, H ''GG'-'Z An ODA M ci (S)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(thiazol-4yl)methyl)amino)-8-chloro-4-((3 chloro- 4- fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.0 (M + H+) 362 6 w Ν-, H 'ы'^Л-с! N 7 1 । .JJ A γΑ nS ^Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(pyridine -3 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 616.1 (M+H+) 363 z G OH YEAH PROGRESS (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (oxetan-3 -yl)- 1H-1,2,3triazol-4-yl)(thiazol- 4yl)methyl)amino)quinoline-3 carbonitrile 2 ES/MS 567.0 (M + H+) 364 Cl L O D O D _% n %Х7 AODOD An αα S- ¹ ' Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (cyanomethyl)- 1H-1,2,3triazol-4-yl)(thiazol-4yl)methyl) amino)quinoline-3 carbonitrile 2 ES/MS 550.0 (M + H+)

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365 z 1 f Z~f £V< z-x Х4 (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(5 - (trifluoromethyl)thiophen-2yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 689.1 (M + H+) 366 QH rx ^F A γΜ N^N Ct 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(pyrimide in-5 yl )methyl)amino)quinoline-3 carbonitrile 7 ES/MS 617.1 (M + H+). 367 QH rr ^F ΑγιΑ νΎ '''''Ν' M Ct 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(pyrimidin-2yl)methyl )amino)quinoline-3 carbonitrile 7 ES/MS 617.2 (M+H+) 368 WITH Q n .Of South Africa ό A (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(ethyl((1(1-ethylpiperide in-4-yl)-1H1,2,3-triazol-4-yl )(pyr idin-3 yl)methyl)amino)quinoline-3 carbonitrile 8 ES/MS 644.2 (M + H+).

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369 Ύ Ν-, Q Η rf γΑΤ Ο Cl ' ^J (8)-6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(pyr idin-3 yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 8 ES/MS 644.2 (M+H+) 370 j g 0 Ώ41 7 Υγ (K)-6-(((1-(1-(tert-butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(thiazol-5 yl)methyl)amino)-8-chloro -4-((3 chloro-4fluorophenyl)amino)quinoline-3 carbonitrile 2 ES/MS 650.1 (M+H+) 371 f Г0 Cl ( \ Av ^f Ν-, Η ^cl A l ^y Ϊ-S Ct (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4chlorothiophen-3-yl)( 1 -(1 ethylpiperidin-4-yl)- 1H-1,2, 3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 655.3 (M + H+). 372 LCl γγγ Α A y=/ CI h (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4cyanothiophen-2-yl)( 1-(1ethylpiperidin-4-yl)-1H-1,2,3triazole -4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 646.2 (M + H+)

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373 N~\ Cl Q and %xY n. 1 J. _l AA ^N As Y'N A Cl (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1propylpiperidin-4-yl)-1H1,2,3-triazol-4-yl)(thiazol -5 yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 636.1 (M+H+) 374 C Cl QHA YuY ⁿ xOa An γΎ M ci (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(ethyl(( 1 (1-ethylpiperide in-4-yl)-1H1,2,3-triazol-4-yl )(thiazol-4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 622.1 (M+H+) 375 H N-. Cl 9 η N 1 _l a A Mill As γΑ y Cl (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (piper idin-4-yl)- 1H-1,2,3triazol-4-yl)(thiazol -5yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 594.1 (M+H+) 376 Υ'Ά ALAa rj] nJ ci 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6- ((pyr idin-2-yl(pyr idin-3 yl)methyl)amino)quinoline-3 carbonitrile 7 ES/MS 515.1 (M+H+)

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377 w ^F oxa nA U i 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((di(pyridine-2- yl)methyl)amino)quinoline-3 carbonitrile 7 ES/MS 515.1 (M+H+) 378 X Cl A „ V n„1 J| _λ iv ^{N N} A As A ci (R)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(thiazol -5yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 621.9 (M+H+) 379 N-. Cl <\At AU A W Cn ci Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6chloropyridin-3-yl)( 1 -(1ethylpiperidin-4-yl)- 1H-1,2 ,3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 650.0 (M+H+) 380 YES (VC ω z-z (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(thiophene -2yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 620.9 (M+H+)

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381 N-, Cl 9 n A' ox? A τ'A ;=/ ci ci (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4chlorothiophen-2-yl)( 1 -(1ethylpiperidin-4-yl)- 1H-1,2,3triazole -4yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 654.9 (M + H+) 382 N-, Cl 0 H Υ As aA M ci Cl (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((5 chlorothiophen-2-yl)( 1 -(1ethylpiperidin-4-yl)- 1H-1,2, 3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 654.9 (M + H+) 383 H N-l Cl Q h i¥ A AL ίγΝ Cl Ct (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((6chloropyr idin-3-yl)( 1 (piper idin-4-yl)- 1H-1,2 ,3triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 624.0 (M+H+) 384 Na Cl Q „ γ FL H ΧΥυτ As T' W Cl tert-butyl-(K)-4-(4-(((8-chloro4-((3 -chloro-4fluorophenyl)amino)-3 cyanoquinoline-6- yl)amino)(thiazol-5-yl)methyl)1H-1,2,3-triazol-1yl)piperide in-1-carboxylate 5 ES/MS 694.0 (M+H+)

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385 Η A ci A „ jY Aw/ (As γ/ )=j Cl Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((4chlorothiophen-2-yl)(1(piperidin-4-yl)- 1H-1,2,3triazol- 4- yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 627.0 (M + H+) 386 H A ci A H jY As''A M ci Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((5chlorothiophen-2-yl)(1- (piperidin-4-yl)- 1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 3 ES/MS 628.9 (M + H+) 387 H A ci 9 H %VyyV ^cl Xs ΥΊΓ A Cl (I)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((3 chlorothiophen-2-yl)( 1 - (piper idin-4-yl)- 1H-1,2,3triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 626.9 (M + H+) 388 H A Cl X η γΥ Awa Ay yW \=/ Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (piper idin-4-yl)- 1H-1,2,3triazol-4-yl)(thiophene -2yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 593.0 (M+H+)

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389 X Cl X and A γχγ ^with J's γΑ Cl (C)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-(((3 chlorothiophen-2-yl)( 1 -(1ethylpiperidin-4-yl)- 1H-1,2, 3triazol-4yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 655.0 (M + H+) 390 ^0^.0 A Cl U and A krY A lyN Cl Cl tert-butyl-(8)-4-(4-(((8-chloro-4((3-chloro-4-fluorophenyl)amino)3-cyanoquinolin-6yl)amino)(6-chloropyr idin-3 yl) methyl)-1 Η-1,2,3-triazol-1 yl)piperide in-1-carboxylate 5 ES/MS 723.2 (M+H+) 391 Cl q h A Ν-, Η ΆΤ AS Y^A \=/Cl tert-butyl-(K)-4-(4-(((8-chloro4-((3 -chloro-4fluorophenyl)amino)-3 cyanoquinoline-6- yl)amino)(thiophen-2-yl)methyl)1H-1,2,3-triazol-1yl)piperide in-1-carboxylate 5 ES/MS 694.2 (M+H+) 392 N-, Cl Q h A γΥ AA ¹ S ^J Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)(thiophene -3yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 621.2 (M+H+)

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393 Η At Cl Q Η Α Avy ό Υ (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (piper idin-4-yl)- 1H-1,2,3triazol-4-yl)(thiophene -3yl)methyl)amino)quinoline-3 carbonitrile 5 ES/MS 593.2 (M+H+) 394 GN οι δ „Υ YAY Α τ·^ Cl tert-butyl-(8)-4-(4-(((8-chloro-4((3 -chloro-4-fluorophenyl)amino)3 -cyanoquinoline-6- yl)amino)(thiophen-3-yl)methyl)1H-1,2,3-triazol-1yl)piperide in-1-carboxylate 5 ES/MS 694.0 (M+H+) 395 Cl Ay k n γΧΐ ίγΐ γΑ νΥCI 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)quinoline-3 carbonitrile 6 396 Ν-, CI <> Αυ Η ^Η ' _Ν Ά AVrr Υν Υ^ίγ Ν-Ν CI / 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1-(1ethylpiperidin-4-yl)- 1H-1,2,3triazol-4-yl)( 1 -methyl-1H1 ,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 20 ES/MS 620.1 (M+H+)

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397 Η Ν—. Cl to „ jY XyA Xn γν N-NCl/ 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1H-1,2,3-triazol-4yl)( 1 -(piperide in-4-yl)-1H1 ,2,3-triazole-4- yl)methyl)amino)quinoline-3 carbonitrile 6 ES/MS 592.0 (M+H+) 398 γ Ddd N-N Cl / tert-butyl-4-(4-(((8-chloro-4-((3 chloro-4-fluorophenyl)amino)-3 cyanoquinolin-6-yl)amino)( 1 methyl-1H-1,2,3 -triazol-4yl)methyl)-1 Η-1,2,3-triazol-1 yl)piperide in-1-carboxylate 6 ES/MS 693.2 (M+H+) 399 X-d Cl 4 η N.X. 1 An uChg N-fJ Cl / 6-(((1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(1-methyl1H-1,2,3-triazol-4- yl)methyl)amino)-8-chloro-4-((3 chloro-4- fluorophenyl)amino)quinoline-3 carbonitrile 6 ES/MS 648.3 (M+H+) 400 9 ⁴ O X Cl ° Q „ Y Ο a ^N benzyl-(ZK)-3-(4-(((8-chloro-4((3-chloro-4-fluorophenyl)amino)3-cyanoquinolin-6yl)amino)(pyr idin-3 yl)methyl)-1 Η-1,2,3-triazol-1 yl)pyrrolid in-1-carboxylate 6

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401 K ci g „ mU Arir O X ^N 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6((pyridin-3-yl( 1 - ((R)pyrrolidin-3-yl)-1 Η-1,2,3 triazol- 4- yl)methyl)amino)quinoline-3 carbonitrile 6 402 Λ „ mУ О ^cin 8-chloro-4-((3-chloro-4φτopφenyl)amino)-6-(((l-((R)1 -ethylpyrrolidin-3 -yl)-1H1,2,3 -triazol-4-yl)( pyr idin-3 yl)methyl)amino)quinoline-3 carbonitrile 6 403 Cl Al\H Ji J XY OS ^N 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1 H-imide azol-4yl)(pyridin-3- yl)methyl)amino)quinoline-3 carbonitrile 6 ES/MS 518.1 (M + H+) 404 οΥίΡ) Ν-, 4 Cl Q „ A ΟϋΧ» Λ ψΑ nA ci benzyl-4-(4-(((8-chloro-4-((3chloro-4-fluorophenyl)amino)-3 cyanoquinolin-6yl)amino)(pyr idin-3 yl)methyl)-1 Η-1,2 ,3-triazol-1 yl)piperidine-1-carboxylate 6

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405 Η Ν-. CI CH n %Α ΑύΥΥ Ο a ^N 8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 (piper idin-4-yl)- 1H-1,2,3triazol-4-yl)(pyridin-3 yl) methyl)amino)quinoline-3 carbonitrile 6 406 Cl \ i Y ν' ^Ν Ί h A ΐΑ ^Ν γΑγ ^0Ν iW tU Cl (8)-8-chloro-4-((3-chloro-4fluorophenyl)amino)-6-((( 1 methyl-1H-1,2,3-triazol-4yl)(pyridin-3- yl)methyl)amino)quinoline-3 carbonitrile 6 407 O'<V< o p \=/ ζΛ oXO /=< °^ '° ¹ z (phosphonoxy)methyl-(8)(benzo[<1]thiazol-7-yl(1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)(3,8-dicyano- 4(neopentylamino)quinoline-bil)carbamate 408 0 1 l. u i Ά- An _h t AADу w A “ (8)-1-(4-(benzo[<1]thiazol-7yl((8-bromo-3-cyano-4(neopentylamino)quinolin-bil)amino)methyl)-1 Η-1,2,3 triazole -1-yl)cyclopropane-1 carboxamide 4 631

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409 K 1 /Dn 't n _n N J xA । ^N (S)-1 -(4-(benzo[<1]thiazol-7yl((3,8-dicyano-4- (neopentylamino)quinolin-bil)amino)methyl)-1 Η-1,2,3 triazol-1-yl)cyclopropan-1 carboxamide 9 577.10 410 7 nA A I t/LuAA nAP ill N (K)-6-((benzo[<1]thiazol-7-yl(1cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 534.20 411 i 0 % η ^N 1 Ν 1 Y A N% ill N 6-(((8)-benzo[<1]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-4-(((K)-1 phenylpropyl) amino)quinoline3,8-dicarbonitrile 9 582.10 412 A 9 ^Ν Χ.<ρΑΥ ^Ν γό । nAZ ||| N 6-(((8)-benzo[<1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3,8-dicarbonitrile 9 650.20

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413 . F O V0 ^F \ Ν / H Y vM nA ci F 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (i- (trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)methyl<1)amino)quinoline-3 carbonitrile 4 661.26 414 7 X AJA AI ⁴ si ^N 4-(((R)-3 -cyano-1 phenylpropyl)amino)-6-(((8)(1 -cyclopropyl-1 Η-1,2,3 triazol-4-yl)(6-(oxetan- 3 -yl)4,5,6,7-tetrahydrothieno[2,3c]pyridin-3 yl)methyl)amino)quinoline-3,8dicarbonitrile 37 667.30 415 A» „ Г H ^H - _N - (8)-6-((benzo[<1]thiazol-7-yl(1 (1-cyanocyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline -3 carbonitrile 4 568.30 416 β 1 l. U .n W 00 Ν η T W1AA FROM 0 (S)-1 -(4-(benzo[c1]thiazol-7yl((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)methyl)-1 Η-1,2,3 triazol- 1-yl)cyclopropane-1 carboxamide 4 586.50

- 175 045220

417 A У ^H Ν''W' (8)-6-((benzo[<1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 611.70 418 XA K H Τχχ f n-УУ ^Cl (8)-6-((benzo[<1]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 2 543.30 419 g ω s'у I ⁴ (8)-6-((benzo[<1]thiazol-7-yl(1 (1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)- 8-chloro-4(neopentylamino)quinoline-3 carbonitrile 2 642.30 420 y )I / (8)-6-((benzo[<1]thiazol-7-yl(1 (1-(tert-butyl)piperidin-4yl)-1H-1,2,3-triazol-4yl)methyl)amino)- 4- (neopentylamino)quinoline-3,8dicarbonitrile 9 633.20

- 176 045220

421 Y ^F A Νχ Η ^H OT w (8)-6-((benzo[c1]thiazol-7-yl( 1 (1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 593.40 422 XA k h N 1 L _l 1 Y ^N ΛίΊ S'A VOT ci (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(pyrazolo[1,5-a]pyridin-4yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 2 526.40 423 7 H t % ^H Ή- Aggl FROM FROM / (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)( 1 methyl-1H-indazol-4yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 2 540.30 424 Α η ψ OTCOT 00 ι ^Ν ν-^Ύ ||| Ν (8)-6-((benzo[c1]thiazol-7-yl( 1 (1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 584.30

- 177 045220

425 „θ 0 Q and Ά AVrV φ A F (8)-2-(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(6-fluoropyridin-3 yl)methyl-(1)-1 Η-1,2 ,3-triazol1-yl)-H- (methylsulfonyl)acetamide 1 600.99 426 1 l Gw A ⁷ (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2methyl-2H-indazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 2 540.30 427 Α Ψ i ⁿ A ^N 1 N Vw ¹ -Oo 1 N-OO ill N (8)-6-(((1-cyclopropyl-1H1,2,3-triazol-4-yl)(2methylbenzo[c1]thiazol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 548.20 428 7 A nA ' 1 Y ^N T VX J η-νΉι] i ^{n V} -O ill N 6-(((8)-( 1 -cyclopropyl-1H1,2,3-triazol-4yl)(isoindolin-4- yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3,8-dicarbonitrile 12 566.20

- 178 045220

429 A „ t Aw YEAR 1 ^rf J “ (8)-4-(neopentylamino)-6-(((6(oxetan-3-yl)-4,5,6,7tetrahydrothieno[2,3- c]pyridin-3-yl)(1 -(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3,8dicarbonitrile 37 662.40 430 w d Aj H'-v ill N (8)-6-(((2-methylbenzo[<1]thiazol7-yl)(1-(1- (trifluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 9 616.30 431 i h X'OCT aS W at Cl F 8-chloro-4-(((R)-3-cyano-1 phenylpropyl)amino)-6-(((8)(1-cyclopropyl-1 Η-1,2,3 triazol-4-yl)(6 -fluoro-2methylpyride in-3 yl)methyl)amino)quinoline-3 carbonitrile 23 592.12 432 OD H D l mind Cl F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 23 587.27

- 179045220

433 A G γ “ (8)-6-(((1-cyclopropyl-1H- 1,2,3-triazol-4-yl)(6-(oxetane- 3-yl)-4,5,6,7- tetrahydrothieno[2,3- c]pyridin-3-yl)methyl)amino)4-(neopentylamino)quinoline3,8-dicarbonitrile 37 594.20 434 Σ^'ω Η' ^^9 (k/ A (8)-6-((benzo[<1]thiazol-7-yl(1 (1-methylcyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-8-chloro-4(neopentylamino) quinoline-3 carbonitrile 4 557.40 435 to T— Σ /=\ /=?U4 \_-Z Σ ω , Σ L ' ^ζ * (8)-6-((benzo[<1]thiazol-7-yl( 1 - (1-methylcycloppropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 548.20 436 i„t Η-J w F (8)-8-chloro-6-(((2-chloro-6fluoropyridin-3-yl)( 1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-4(neopentylamino)quinoline- 3 carbonitrile 23 539.57

- 180 045220

437 \ H U A Ν _l Α Υ Qu 1 ^N (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 537.25 438 l n «.A A 0A0 vS γψ Cl F 8-chloro-4-(((H)-3-cyano-1 phenylpropyl)amino)-6-(((K)(1 -cyclopropyl-1 H-1,2,3 triazol-4-yl)(6 -fluoro-2methylpyride in-3 yl)methyl)amino)quinoline-3 carbonitrile 23 592.12 439 υυ and \| F _μ J hA ^H N γν (8)-6-((benzo[0]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-bromo-4(neopentylamino)quinoline-3 carbonitrile 1 655.05 440 . FA <1Д-Т Ύ γ ^Γ h ^h -- _n A-· A 1 _l ΐ γ ^N xt from Ύη yU nY ci F 8-chloro-6-(((8)-(6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4-(((I)-1 phenylpropyl)amino)quinoline3-carbonitrile 4 635.45

- 181 045220

441 V У А η ^H ' _n - Sa' n-AJ ill N (8)-6-((benzo[<1]thiazol-7-yl( 1 (1 -(fluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 566.30 442 poison y ^F H ^N D AL/ Si y (8)-6-((benzo[<1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8(methylsulfonyl)-4(neopentylamino)quinoline-3 carbonitrile 39 655.65 443 \„A N 1 J. 1 A SH A (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 537.15 444 A „ Ψ blow V ⁿ A ill N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)(pyrazolo[1,5-a]pyridin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 567.20

- 182 045220

445 Μ Hz n ^N M ^Ν 1 Ν A Α ^{Ν Η} ΟΟ Cl ^N (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(isoindolin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 12 577.20 446 7 nA ν· ^ν ι ϊ l ,- N-AyNy^ySyA _ν αΛ W V-nA ci (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(imidazo[1,5-a]pyridin-8yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 526.30 447 F Xf and Η T К1 i Ϊ a yS W NyV Cl F (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 569.60 448 7 „Ψ A ⁿ g ΜύΎΎ H (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(1Nindazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 2 526.30

- 183 045220

449 7 n U Λ ί ./ Τ'UD' jA 'G CA t ⁿ (8)-6-((benzo[<1]thiazol-4-yl(1cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 2 543.30 450 \„A N.I! 1 co A (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(quinolin-8yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 537.46 451 N-~ H ^H Y n,1 A AXXj ⁿ -E0 G Ν (8)-6-((isoindolin-4-yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 12 586.10 452 FF ty ^F T ⁰ N^, H %УУ ΥγΟΧ /т) । Ν- ^Λ ν ill N 6-(((8)-benzo[<1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-((3,3 - dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3,8dicarbonitrile 34 644.10

- 184045220

453 Α oA °\ /X / _ζ ^χ x A / A~ (8)-8-acetyl-6- ((benzo[<1]thiazol-7-yl(1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 14 619.48 454 I „ X N-. N A] A ^N ^ V ill FN (8)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 510.66 455 z/zW γ _z _ _x ⁴¹ yX XA (8)-6-((benzo[<1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-fluoro-4(neopentylamino)quinoline-3 carbonitrile 4 595.2 456 i X XH %- ⁰ XT N (8)-6-((benzo[<1]thiazol-7-yl(1 cyclopropyl-1H-1,2,3-triazol4-yl)methyl)amino)-4-(tertbutoxyamino)quinoline-3,8dicarbonitrile 38 536.20

- 185 045220

457 I Ψ Υ n Sr° CO g (8)-6-((benzo[<1]thiazol-7-yl(1 cyclopropyl-1 Η-1,2,3-triazol4-yl)methyl)amino)-4-(tertbutoxyamino)-8-iodoquinoline3- carbonitrile 1 637.10 458 9 „T Ν-! N ⁿ Y W (8)-6-((benzo[<1]thiazol-7-yl( 1 (1- (hydroxymethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 573.2 459 U) O tdA X (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)( 1 methyl-1H-benzo[c1]imide azol-7yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 2 540.2 460 X γ Ж Η ^Η γ Ν 1 0 ϊ Υ < ^S X j N'W ili Ν (8)-6-((benzo[<1]thiazol-7-yl( 1 (2,2,2-trifluoroethyl)-1 Η-1,2,3 triazol-4-yl)methyl)amino)-4 (neopentylamino)quinoline-3,8dicarbonitrile 9 576.1

- 186 045220

461 F. αλτ τ' NJ Η ^Η Ό ^ν Ά ν Α Α ίοίτχχ ΠίΊ ί ^Ν CHAR 0! (8)-8-chloro-4(neopentylamino)-b((quinolin-5 -yl(1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 23 605.10 462 F. ΧΎ τ' Ν% Η ^Η Ο ^ν Ά ν a α ΟαΧΧΤ CO Α (8)-8-chloro-6-((isoquinolin-5yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 605.19 463 ⁰ Η τΑ ⁿ I'-gg ⁿ nVay^ Co a (S)-1 -(4-(benzo[<1]thiazol-7yl((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)methyl)-1 Η-1,2,3 triazole -1-yl)cyclobutan-1 carboxamide 4 600.2 464 D-N guR T ΑυϋΑ Ct) W nA/ ||| N (8)-6-((benzo[<1]thiazol-7-yl( 1 (1-(pyridin-4- yl)cyclopropyl)-1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 34 611.1

- 187 045220

465 Y „ A Ν' Η W' Ν (8)-6-((benzo[<1]thiazol-7-yl( 1 (i- (hydroxymethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 564.2 466 to η Ο ^Ν 1 Λ ι Α Уу j Af JL IL wL Αγη W ^Ν ΑΑ ^{Ν С|} (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2,7naphthyridin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 538.3 467 I A Ν' Η ^Η Ά Ν.1 Ν Οη ^Ν ХХХдУ Οο ι ^Ν VA ill (8)-6-((( 1 -cyclopropyl-1H- 1,2,3-triazol-4-yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 528.13 468 X Α Ν' Η Ν.1 Ν usthU Αγη τ ^Ν nJJ I Ν (8)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 528.15

- 188045220

469 <Α ^ρ α У' ^{h H} 'N' w |j (8)-4-(neopentylamino)-6((quinolin-5 -yl(1-(1(trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4yl)methyl)amino)quinolin-3,8dicarbonitrile 34 596.35 470 4% h ^H 4 n 1 n _λ aa χιχχι AA i ^N |J (8)-6-((isoquinolin-5-yl(1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 596.27 471 Ύη AM A। Y N (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 578.24 472 And mA AQ ] ^N N'V ||| /NH (8)-6-((( 1 H-indazol-4-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3 -triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 585.2

- 189045220

473 Υ Ψ ψΓ F Ν (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)- 1 Η-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 34 560.2 474 VI Ά „ ±7 Ν', Η |Α-' OTOT ¹ Yj ρ νΆ- )|ι Ν 6-(((8)-benzo[c1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-(((K)-3,3 dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3,8dicarbonitrile 34 644.20 475 FF γΑ ^F Ό^ο Ν~, Η Άι ι “ νΆ- )|ι Ν 6-(((8)-benzo[c1]thiazol-7-yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-(((8)-3,3 dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3,8dicarbonitrile 34 644.20

- 190045220

476 J „ g Ν-, Η ''ij was yr F (8)-8-chloro-6-((( 1-(1cyanocyclopropyl)-1H-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 4 544.2 477 0 Η OD A A ^H u H. J Ν—, H PASSED All γΧ nJ ci F (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1yl)cyclopropan-1 carboxamide 4 562.3 478 0H < AP OD XyJ Χ|ΐ γΧ nA ci F (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1 -yl)cyclobutan1-carboxamide 4 576.3 479 An _h Y Νγ HA У]1 γΑ nJ ci F (8)-8-chloro-6-((( 1-(1cyanocyclobutyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 4 558.2

- 191 045220

480 X n ^N Y Wvrv YES nW ci F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1methylcyclopropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 4 533.3 481 W\Y from f (S)-1 -(4-(benzo[<1]thiazol-7yl((3-cyano-8-fluoro-4(neopentylamino)quinolin-bil)amino)methyl)-1 Η-1,2,3 triazole -1-yl)cyclobutan-1 carboxamide 4 584.20 482 H d Ah A Y dm nJ ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1 -(1 (hydroxymethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 23 549.18 483 X ψ N^ H YrXX ¢0 J ^N (8)-8-chloro-6-((( 1 -methyl- 1Hbenzo[<1]imidazol-7-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 608.5

- 192 045220

484 AA Ay < ^Ν χ) 1 ^N ” N-XP ill N (S)-6-((( 1 -methyl-1Hbenzo[<1]imidazol-7-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4- (neopentylamino)quinoline-3,8dicarbonitrile 34 599.3 485 <Y Y Al ΏΥ F (S)-6-(((l-(lcyanocyclopropyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyrid in-3 yl)methyl)amino)-8-fluoro-4 (neopentylamino)quinoline-3 carbonitrile 4 528.2 486 4U ^H h 4 TsH ρπ F (S)-1 -(4-(((3-cyano-8-fluoro-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1yl)cyclopropan-1 carboxamide 4 546.3 487 X Y 44 pr F (S)-1 -(4-(((3-cyano-8-fluoro-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1 -yl)cyclobutan1-carboxamide 4 560.3

- 193 045220

488 X n A Ανγγ kw F (8)-8-fluoro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1methylcyclopropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 4 517.3 489 L n t ήτ T _N (8)-6-(((1-(1- cyanocyclopropyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 535.2 490 qh A nA H ^H d ΆγγΥ VF ί ^N (8)-1-(4-(((3,8-dicyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1yl)cyclopropan-1 carboxamide 24 553.3 491 T—2 /=\ (8)-6-(((1-(1- cyanocyclobutyl)- 1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 549.3

- 194045220

492 Mr. yb Ayyv yr (8)-6-(((6-φτορ-2- methylpyride in-3 -yl)(1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 524.2 493 Z ^f ψ AQr AO W \ NN Cl 4 (8)-8-chloro-4(neopentylamino)-b((pyrazolo[1,5 -b]pyridazin-3 yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 4 595.3 494 0 H ψ 44 H ^H ' _N ·- 4 i (8)-1-(4-(((3,8-dicyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1 -yl)cyclobutan1-carboxamide 24 567.3 495 X ^F A 4 H Ук 44 Ύί γΑ n4 Cl F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)( 1 -(1 (fluoromethyl)cyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 27 551.30

- 195 045220

496 Y n T o Ou / (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1methyl-1H-indazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 590.5 497 Y + AAV -CO r ^N ' (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-2H-indazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 590.4 498 Y Ψ AHA ⁿ YI i ΑΎτύ X w ΎΥ ci (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-3-oxoisoind olin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 605.3 499 Y Ψ AAv CO A ^N ' (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4-yl)(1 methyl-1H-benzo[c1]imide azol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 590.3

- 196045220

500 Α γ yew Yes / Η (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1Nindazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 32 576.2 501 Α γ AW nA ci F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-((2,2dimethylpropyl-1,1b2)amino)quinoline-3 carbonitrile 4 571.3 502 F Ογ xw AW nA ci F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-((( 1 methylcyclobutyl)methyl)amino )quinoline-3-carbonitrile 4 581.3 503 A γ WS Vr I ^N (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1 -(1 (fluoromethyl)cyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 542.30

- 197045220

504 \ Η X Ύ ί Α Τ'^Ν< Τ|Ί ί ^Ν ΧΑΧ ά (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(isoquinolin-8yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 1 537.13 505 ACA XW nA ^Cl 8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2fluoropyridin-3-yl)methyl<1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 556.14 506 X y AO? λΨ nA CI (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(pyridin-3yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 537.08 507 α ο WnA CI 8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methylpyridin-3-yl)methyl<1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 552.18

- 198045220

508 A N A ACAa ¢0 th (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 587.11 510 A A D H ^hF bitches nA ci 8-chloro-6-(((2-chloropyr idin-3 yl)(1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)methyl<1)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 572.11 511 <1/ A \ ^F n 1 > N-. N CHG -' iXyOClo Vl] γΜ nW ci F 8-chloro-6-(((8)-( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-((2,2dimethyltetrahydrofuran-3yl)amino)quinoline-3 carbonitrile 23 597.25

- 199045220

512 <7 ^F λ Η XWy ϋ Υ F (8)-8-chloro-4-((3-cyano-2,2dimethylpropyl)amino)-6-((( 1 (1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 23 594.19 513 (8)-8-fluoro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 4 571.20 514 pr F (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-8-fluoro-4(neopentylamino)quinoline-3 carbonitrile 4 553.30

-200045220

515 N-Τ H X WwM N-W Cl F 8-chloro-6-(((8)-( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4-(((K)-2,2dimethyltetrahydrofuran-3yl)amino)quinoline-3 carbonitrile 23 597.24 516 <lX X° N-^H WwV ύί γΧ N-WCl F 8-chloro-6-(((8)-( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-(((8)-2,2dimethyltetrahydrofuran-3yl)amino)quinoline-3 carbonitrile 23 597.17 517 0 H YY o''U- WHW YyWiV A 'A ^N nJ ci F (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(6-fluoro-2methylpyridin-3 -yl)methyl)-1H1,2,3 -triazol-1yl)cyclopropane-1-carboxylic acid 4 563.1

- 201 045220

518 U Ψ AAA f A F (8)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6fluoropyridin-3-yl)methyl<1)amino)- 4- (neopentylamino)quinoline-3 carbonitrile 27 556.3 519 7 n U ΑτύΑ ΌΟ ά ηΆ ^Cl (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)( 1 - methyl-1 H-pyrrolo[2,3 - b]pyridin-4-yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 2 540.3 520 A (8)-8-chloro-6-((( 1 -methyl- 1Hbenzo[<1]imidazol-4-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 608.3 521 (8)-8-chloro-6-((( 1 -methyl- 1Nind azol-7-yl)( 1 -(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 608.3

- 202 045220

522 AND (8)-8-chloro-6-((( 1 -methyl- 1Hbenzo[(1] [1,2,3 ]triazol-7-yl)( 1 (i- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 609.3 523 <\ «A Έ/ατ Μ ] ^Ν N'U ill N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methyl-1H-benzo[b]imidazol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 34 581.2 524 I _H ψ ALu/ w 1 H (8)-8-chloro-6-(((3-methyl-1Nind azol-4-yl)( 1 -(1 - (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 608.4 525 A Τ' XQ> dau / (8)-8-chloro-6-((( 1 -methyl- 1Nind azol-4-yl)( 1 -(1methylcyclopropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 27 554.3

- 203 045220

526 ψΑ Ψ μ F μ II J HA Αν Ν (S)-6-((( 1 -methyl-1 H-indazol-7 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.5 527 ψΑ ψ Χ. F c H hA H A &w ν ΎΊ ] fX-x I N (S)-6-((( 1 -methyl-1H- benzo[<1] [1,2,3 ]triazol-7-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 600.5 528 F , W r nA h ^H k N L . 1 X Axxj ^Ν ΠΠ |A I H (S)-6-(((3 -methyl-1 H-indazol-4yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.3 529 to Τ' hU, H ^H ' _N ·'<Αγ CO V νΆζ ill / N (S)-6-((( 1 -methyl-1 H-indazol-4yl)( 1 -(1 -methylcyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 545.3

-204045220

530 \n X yA γ 'Ν'' νΥ α (S)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-8-chloro-4 (neopentylamino)quinoline-3 carbonitrile 1 535.4 531 γ GK Η χχ (8)-8-chloro-6-((( 1 -(1-fluoro-2 methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyride in- 3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 553.2 532 X Η t aaOD νχ %OD nJ ci F (8)-8-chloro-6-((( 1-(2,2difluoroethyl)-1H-1,2,3-triazol4-yl)(6-fluoro-2-methylpyridin3 -yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 4 543.2 533 A O N _l AY ^N Oqiyj ^Ν 1ί ' ^? ' f N AAA Cl (8)-8-chloro-6-((isoquinolin-8yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 605.36

- 205 045220

534 D O ^N "STROKE AIR STROKE s F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4-((3 hydroxy-2,2dimethylpropyl)amino)quinol n-3-carbonitrile 1 603.17 535 D ^r N %Dddd Oodg N (8)-6-((isoquinolin-8-yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.14 536 And at USOD SO OD (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 587.23 537 And xxD from OD' (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(isoquinolin-8yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 587.21

-206045220

538 A U XVW Whitefish (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)(pyrazolo[1,5-a]pyridin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 576.3 539 F Haa Aw ΫCl F 8-chloro-6-(((8)-( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-(((K)-3,3 dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3 carbonitrile 4 611.3 540 F W Wo -XWo Aw W ci F 8-chloro-6-(((8)-( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-(((8)-3,3 dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3 carbonitrile 4 611.2

-207045220

541 U t K n A Ν 1 1 X xc~ X) A ^Ν (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1,1,1trifluoro-2-methylpropan-2-yl)1H-1,2,3- triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 589.3 542 u n u HuU Ay (8)-8-chloro-6-(((1 -(1 - (difluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)(1 methyl-1H- benzo[<1][1,2,3]triazol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 591.7 543 % (S)-8 -chloro-6-((( 1 -methyl-1Nind azol-4-yl)( 1 -(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 608.5 544 I r> zz V m Wи CHI ^m A (8)-8-chloro-6-(((2-methyl-2Nind azol-4-yl)( 1 -(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 608.7

- 208 045220

545 A g /=\ . Ng (8)-8-chloro-6-((( 1-(1,1-difluoro2-methylpropan-2-yl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyride in-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 571.3 546 N ^N N G A 8-chloro-6-(((8)-(6-fluoro-2methylpyrid in-3 -yl)( 1-((8)-1fluoropropan-2-yl)- 1H-1,2,3 triazol-4 -yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 539.4 547 l«g X N nA γΑτ N^JCl F (8)-6-(((1-([1,1'- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(6-fluoro-2methylpyride in-3 - yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 559.6 548 A wA nA jH W Cl F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(3 (trifluoromethyl)oxetan-3-yl)1H-1,2,3-triazol-4yl )methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 603.4

-209045220

549 Y Q Yes ¹ (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl-5( 1)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 33 588.31 550 A „ C γγ ζύ γ· (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.28 551 γ WTv /DTL J On f ^N ||| N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.2 552 A ^f „ C <γΑγγ ^Ν CO AN (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(isoquinolin-8yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.19

-210045220

553 0 a „ A H A Y|1 TO nA ci F (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1 -ηπ)-N,Ndimethylcyclopropane-1 carboxamide 35 590.2 554 Sa γΜ nA ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1 -(1 (pyrrolidine-1 - carbonyl)cyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 35 616.2 555 lo „t AAA Sa t ⁿ nA ci F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (morpholine-4- carbonyl)cyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 35 632.3

-211 045220

556 Y Y Ου w Η (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(3methyl-1H-indazol-4 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 32 590.4 557 <O ^f ψ O H ^N '^ <O | ^N νΎτ ||| /N (S)-6-((( 1 -methyl-1 H-indazol-4yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.3 558 Υ γ yxxY nt nY ¹ III N (8)-6-(((2-methyl-2H-indazol-4yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.2 559 X y F μ H ? Να Η 'N Oy LyS i N-—T ill N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)- 1 Η-1,2,3-triazol-4-yl)( 1 methyl-1H- benzo[(1][1,2,3]triazol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 582.2

- 212 045220

560 X y AQy south (8)-8-chloro-4(neopentylamino)-b((pyrazolo[1,5-a]pyridin-4yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 4 594.3 561 0 Η A ⁿ Η ^Η Ά k 1 ν I α ^ν Οχ at CO g (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(isoquinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl)cyclopropane-1 carboxamide 4 580.2 562 0 Η λ)-ν Υ Ν- ^Η Η ^Η J ^Ν Χ ν /,lu Ut Co 00 Γ (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(isoquinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl)cyclobutane-1-carboxamide 4 594.2 563 4^» Η t ^n:n VtjV ⁿ OE ά (8)-8-chloro-6-(((1 -(1 cyanocyclopropyl)-1 Η-1,2,3 triazol-4-yl)(isoquinolin-5yl)methyl)amino)-4(neopentylamino)quinoline- 3 carbonitrile 4 562.1

- 213 045220

564 Π yQ G (8)-8-chloro-6-((isoquinolin-5yl(1-(1-methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 551.2 565 A 1 /X/ ^N Τ' ^H H ^H G NI _l 1 W Ν-'.,Λ.,ζΥίγ ΙΛ L Po r ^N HA S! (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(quinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl)cyclopropane-1 carboxamide 23 580.17 566 On . Υ/ ^Ν Τ' yes A' (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinolin-bil)amino)(quinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl)cyclobutane-1-carboxamide 23 594.21 567 ST·Π (8)-8-chloro-6-((( 1 -(1 cyanocyclopropyl)-1 Η-1,2,3 triazol-4-yl)(quinolin-5 yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 23 562.22

- 214 045220

568 A n X AAA ¢0 η (8)-8-chloro-6-((( 1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 23 551.25 569 U n Ν1 W XX U l op ^y N (S)-6-(((l-(l- (fluoromethyl)cyclopropyl)-1H1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 560.3 570 Α y Ν' Η ^Η ' _Ν ' аУ уУ ci (8)-8-chloro-6-(((2-methyl-2H- indazol-7-yl)( 1 -(1 - (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 608.2 571 A U AQa W r~^ Λ (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)- 1 H-1,2,3-tri-azol-4-yl)(3 methyl-1 H-indazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 581.2

-215 045220

572 A „ ψ AW Will N (8)-4-(neopentylamino)-6((pyrazolo[1,5-a]pyridin-4yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3,8dicarbonitrile 24 585.2 573 mA nA MD -N ] 1 ||| N (8)-6-(((2-methyl-2H-indazol-7yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.2 574 F F A d N A U H. J N*-/Hhr V/ V । F N (8)-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl-5<1)methyl )amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 579.17 575 К ^?l I /'7n τ' Υ,Ϋ Ύ Y' (S)-1-(4-(((3,8-dicyano-4(neopentylamino)quinolin-bil)amino)(quinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl) cyclopropane-1 carboxamide 24 571.18

- 216 045220

576 OD G I Sod O od od od N (8)-1-(4-(((3,8-dicyano-4(neopentylamino)quinolin-6yl)amino)(quinoline-5- yl)methyl)-1 Η-1,2,3-triazol-1 yl)cyclobutane-1-carboxamide 24 585.10 577 L! ^Ν Υ Η ^H --- _n 0 ν X > Stroke /D XXX 0ό t ^Ν (8)-6-(((1-(1cyanocyclopropyl)-1 Η-1,2,3 triazol-4-yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 553.12 578 D n %0 Add/ /OD XX X Οό I ^s (8)-6-(((1-(1- methylcyclopropyl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 542.17 579 od Г-S /=Ч 4 .n year*n 8-chloro-6-(((8)-(6-fluoro-2methylpyrid in-3 -yl)( 1 ((1 R,2 8)-2-fluorocyclopropyl)1H-1,2,3-triazol-4yl )methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 537.3

-217045220

580 Υ γ Η ^H ' _N -' Ο ό Y ΛΧΌα ΓΤί Τ (S)-6-(((l-(lcyanocyclopropyl)-1H-1,2,3 triazol-4-yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 553.2 581 Α Η Α * 1 ό , to Ll THu ODu τ ^Ν νΛΑ I Ν (8)-6-((isoquinolin-5-yl(1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 542.2 582 Ά η Ά OTytV pr F 8-chloro-4-(((I)-3,3- dimethylbutan-2-yl)amino)-6(((8)-(6-fluoro-2-methylpyridin3-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 23 601.25 583 A' n X XVyV yr F ^N 4-(((R)-3,3-dimethylbutan-2yl)amino)-6-(((8)-(6-fluoro-2methylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl) 1H-1,2,3-triazole-4- yl)methyl)amino)quinoline-3,8dicarbonitrile 25 592.30

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584 4 t Ay rj uU ΝγΙ Cl F (8)-8-chloro-6-(((1 -(1,1-difluoro2-hydroxyethyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyride in-3 yl)methyl) amino)-4(neopentylamino)quinoline-3 carbonitrile 4 559.3 585 BP vr T N (8)-4-(cyclohexylamino)-6(((6-fluoro-2-methylpyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 25 590.30 586 A X— s /=% V (S)-l -(4-(((3,8-dicyano-4(neopentylamino)quinolin-bil)amino)(isoquinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl) cyclopropane-1 carboxamide 24 571.3 587 0H <A «A N*—. Η N N.jl A .. i ..j JYXXj γΥ VV nYJ ill N (S)-1-(4-(((3,8-dicyano-4(neopentylamino)quinolin-bil)amino)(isoquinolin-5yl)methyl)-1 Η-1,2,3-triazol-1 yl) cyclobutane-1-carboxamide 24 585.2

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588 4 ^cf ₃ η AU Υ|1 γΑ Ν Υ CI F (8)-8-chloro-4- (cyclohexylamino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (i- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 599.32 589 X η X Λ- 0ώ ^l r (8)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 526.3 590 Υ Η X Λ Υ' (8)-6-((( 1-(1,1-difluoro-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyride in-3 yl) methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 562.2 591 X Η X Ν 1 Ν ζχ AX χγ V4 γν Α ιΐι F ^Ν (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1-(1,1,1trifluoro-2-methylpropan-2-yl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 580.2

-220045220

592 F , K XA jut τχτ Ύη f ^N NA Cl F (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2-ethyl6-fluoropyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 583.25 593 <X ^F D M ^F H ^H U Ο ν _λ ΑΑ ^Ν waa -γ γ _Ν ' N^A ci F (8)-8-chloro-6-(((2-ethyl-6fluoropyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 23 601.42 594 χΐ X N-^ H 'Ν' ν X ^Xa ⁿ Mt TXT ^N rl [ N AM ci (8)-8-chloro-6-((( 1 -(1 - (fluoromethyl)cyclopropyl)-1H- 1,2,3-triazol-4yl)(isoquinolin-8yl)methyl)amino)-4(neopentylamino)quinoline-3 - carbonitrile 27 569.3 595 UXV VW nA F (8)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-8-methoxy-4(neopentylamino)quinoline-3 carbonitrile 4 583.20

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596 γ Ψ wYy™ AW F (S)-6-(((l-(lcyanocyclopropyl)-1H-1,2,3 triazol-4-yl)(6-fluoro-2methylpyride in-3 - yl)methyl)amino)-8-methoxy-4(neopentylamino)quinoline-3 carbonitrile 4 540.2 597 У γ ν 1 _Λ ί γ ^XXXI W γ V 'I' FN (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2-ethyl6-fluoropyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 574.23 598 FF y γ H ^H dn 1 _Λ ϊ γ ^XXX I Wy γ V 'I' FN (8)-6-(((2-ethyl-6-fluoropyridin3-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 592.39 599 kr „ “A Ay (8)-8-chloro-6-((imidazo[1,5- a]pyridin-8-yl( 1 -(1 - (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 594.1

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600 η γ Η ^N D k 1 ι _ l y nATzwPz /W lX X WO W Cl (8)-8-chloro-6-(((2-ethylpyridin3-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 583.3 601 II, ^F H vr (8)-6-(((1 -(2,6-difluorobenzyl)- 1H-1,2,3-triazol-4-yl)(6-fluoro- 2-methylpyr idin-3 - yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 596.3 602 A γ ,y ^H ^X N 1 1 1 У . T IJ J Wp Γ ^ν W ill N (8)-6-(((2-ethylpyrid in-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 574.2 603 IN (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methyl-1H-indazol-7yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 590.3

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604 Α Ϋ A H ν1 i N''YvwV ^Χ IX X Cl (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2ethylpyridin-3yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 565.2 605 A „ J TO/ w N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)- 1 H-1,2,3-triazol-4-yl)(1 methyl-1 H-indazol-7 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 581.2 606 Ά j WAX ^.X ХД X Ai f ^N M ill N (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2ethylpyridin-3yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 556.3

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607 Hu n WrrV γγ γΑ νΥ α F 4-(((lR,5S)- bicyclo[3.1.0]hexan-6yl)amino)-8-chloro-6-(((8)-(6fluoro-2-methylpyridin-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 597.26 608 O gr -^° U Η U ¹ Du/ Υγ γΑ N^J Cl F 4-(((lR,5S,6r)-3oxabicyclo[3.1,0]hexan-6yl)amino)-8-chloro-6-(((8)-(6fluoro-2-methylpyridin-3 -yl)( 1 (1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 599.20 609 \n Α <Υγ CO γ IkVill /Ν (8)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(1-methyl1H-indazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 531.4

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610 X g /=\ U Rk (8)-6-(((6-φτορ-2- methylpyride in-3 -yl)( 1 -(1 (hydroxymethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 540.3 611 <i About U · n m? Aw/ G) nA ci F 8-chloro-4-(((K)cyclopropyl(phenyl)methyl)amino)-6-(((8)-(6-fluoro-2methylpyridin-3-yl)( 1 -(1 (methyl trifluoro) cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 647.18 612 JcF, ώχ« yA γ? ΫCtF (8)-8-chloro-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4-((2-methyl- 2- phenylpropyl)amino)quinoline3-carbonitrile 1 649.23

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613 <ι 0 Oh oh T N 4-(((R)cyclopropyl(phenyl)methyl)amino)-6-(((8)-(6-fluoro-2methylpyridin-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H- 1,2,3-triazole-4- yl)methyl)amino)quinoline-3,8dicarbonitrile 25 638.33 614 / t us ¹⁷ “Huh? Ch (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4-((2-methyl- 2- phenylpropyl)amino)quinoline3,8-dicarbonitrile 25 640.30 615 o ΟΥ X yach (8)-4-((2-cyano-2- methylpropyl)amino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 25 589.3

-227045220

616 A ^f ϋ AV OQ o ^N F (8)-8-chloro-6-(((8fluoroisoquinolin-5 -yl)( 1 -(1(trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 27 623,747 617 A ^f X ΊΑ θφ A F (8)-8-chloro-6-(((8-fluoroquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 623.685 618 L ψ Ao χό X 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 635.4 619 AX NJ 1 _ X w Ν'·/ ^Ν Χ/'ό.-'οΥ A LA J 0G '* N N=/ Cf (K)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(4methylthiazol-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 557.4

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620 An Η./ ^N 1 and 14 A XfT Sl Cl (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(5methylthiazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 557.7 621 4 g /=\ Λ (S)-6-(((l-([l,r- bi(cyclopropane)]-1 -yl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 550.3 622 CH A RG T ^Ν 6-(((8)-(6-fluoro-2- methylpyride in-3 -yl)( 1 - ((1 R,2 8)-2-fluorocyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 528.3 623 V ^F Ϋ Г'У H ^H A ώ 'ρ 6-(((8)-(6-fluoro-2- methylpyride in-3 -yl)(1-((8)-1fluoropropan-2-yl)-1H-1,2,3 triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 530.3

-229045220

624 D-A A ΙΑ π Ν Duh νη A CI F (S)-1 -(4-(((8-chloro-3-cyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3 -triazol-1 -yl)-3,3 difluorocyclobutane-1 carboxylic acid 4 613.3 625 Α X— ζ /=\ Χζ ^g (8)-6-(((1-(1-fluoro-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl) amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 544.5 626 U ^r X ы F μ Η X WyyX Org (8)-6-(((8-fluoroisoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 614.453 627 ur X \ι F c Ηχ. Ζ Ν^. Η -Ν Λί - g' w ί (8)-6-(((8-fluoroquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 614.444

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628 Yang «A to 1 _l Ϊ γ JwOw Ou ά ^N (8)-8-chloro-6-((isoquinolin-4yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 605,604 629 △O o κι F LI H. J Ν—. Η Ν 9° (8)-8-chloro-4- (neopentylamino)-b((quinolin-3 -yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 27 605.197 630 A. ^χ_ Ο°> _w /Χ\ DsYa (K)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(4methyloxazol-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 541.3 631 A ^f y W g I ^N (8)-6-(((2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl) amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 626.2

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632 ϋΝΒ (8)-8-chloro-6-(((4methoxyquinolin-5 -yl)( 1 -(1(trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 4 635.3 633 i Y A ^CF 3 u n ⁿ - _n -kSyV g) % ^Ν nJ Cl F (8)-8-chloro-4-((2-cyano-2methylpropyl)amino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 598.34 634 VH £ ky pr ΐ ^N (8)-6-(((1 -(2,2-difluoroethyl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 534.4 635 k ^CF 3 'ΧΑγ All i N У Cl F (8)-8-chloro-4-((3-chloro-2,2dimethylpropyl)amino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 1 621.07

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636 OD n «OD dodod Vj odod nJ ci F (8)-8-chloro-4-(((1- (difluoromethyl)cyclopropyl)methyl)amino)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl) methyl)amino)quinoline-3 carbonitrile 1 621.06 637 Ha dD l odOD ^g V/ ^g (8)-4-((3 -chloro-2,2- dimethylpropyl)amino)-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 25 612.14 638 ONE LOT DOD T N (8)-4-(((1- (difluoromethyl)cyclopropyl)methyl)amino)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl) methyl)amino)quinoline-3,8dicarbonitrile 25 612.22

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639 H ⁿ L । ϊ X XX J f _N 0-^ Cf (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2,5dimethyloxazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 555.3 640 A ^f Τ' N-^ Η ^Η Ά Ki N Oxx ⁿ =/ q N (R)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(4methylthiazol-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.4 641 A~ ^x mH (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(5methylthiazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.4 642 /lHo X (S)-1 -(4-(((3,8-dicyano-4(neopentylamino)quinoline-bil)amino)(6-fluoro-2- methylpyride in-3 -yl)methyl)-1H1,2,3-triazol-1 -ηπ)-N,Ndimethylcyclopropane-1 carboxamide 24 581.2

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643 A "U" Τγ γΥ νΥ ci F (8)-8-chloro-6-(((1-cyclopropyl5-iodo-1H-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 28 645.50 644 Ο γ ΥΥ ζ-ζ V γ ^ζ \/% (8)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(3 (trifluoromethyl)oxetan-3-yl)1H-1,2,3-triazol-4yl)methyl)amino )-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 594.4 645 τ ψ Υ|1 Τ''' νΥ α F (8)-8-chloro-6-((( 1-(3,3difluorocyclobutyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 569.4 646 X ψ 10 Η ^H A ΥγΥ Τί τ ^Ν νΥ α F (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 545.7

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647 XJ nJ ΌΐΌο Xp α ^N F (8)-8-chloro-6-(((1-cyclopropyl5-methyl-1H-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 29 533.3 648 Hj - Xn ^; ^yvV ⁿ γΜ nJ ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(3 (hydroxymethyl)oxetan-3-yl)1H-1,2,3-triazol-4yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 565.4 649 d Ψ γγγ vr 1 (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)- 1H-1,2,3-triazol-4-yl)(6-fluoro- 2-methylpyr idin-3 - yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 536.3 650 I Ϋ k n ⁿ j ^ν νΑυϋ/ ^ν 'kA yV nW ci (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(2(dimethylamino)pyridin-3 yl)methyl-c!)amino)-4( neopentylamino)quinoline-3 carbonitrile 26 531.226

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651 'k, ^F n H, J fromAA OQ α ^Ν α (S)-8-xnop-6-(((8chloroisoquinolin-5 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 27 639,953 652 Μ Ϋ И Ηχ γΆ Η Ν ΑΑ> (Αί) Ατ ^ν ' nAA ¹ ci F (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroisoquinoline-5- yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 605.334 653 Μ Ϋ OTAA OOD F (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 605.337 654 k k ⁿ A AA G| l ¹ ^ nA ct F (8)-8-chloro-6-(((1-(2,6difluorobenzyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 1 605.3

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655 ^F W О „ X FU, Η ^Η Ύ Ουύτ / (8)-8-chloro-6-((( 1 -(2,6difluorobenzyl)- 1H-1,2,3triazol-4-yl)( 1 -methyl-1Nindazol-4-yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 1 626.2 656 ^F W η n X AAV Ar (8)-6-(((1 -(2,6-difluorobenzyl)1H-1,2,3-triazol-4-yl)( 1 methyl-1H-indazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 9 617.3 657 0 ^F У Η ^Η Ό Ν.1 Ν 1 γ ^Ν 0c χχτ V' C Τ Ν II Ν (R)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(4methyloxazol-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 532.4 658 ό (8)-8-chloro-6-((( 1 -methyl-1Hpyrrolo[2,3-b]pyridin-4yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 608.7

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658 Α Η Ϋ Asuu (S)-8 -chloro-6-((( 1 -methyl-1Hpyrrolo[2,3-b]pyridin-4yl)( 1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 608.7 659 F F A γ 1 1 Ά J To 1 1 ? guuAu JT (8)-8-chloro-6-(((4methylisoquinolin-5-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 2 619.51 660 FF A γ A 1 D yN ^N '\--N' _Y -'zzkP όΑ (8)-8-chloro-6-(((4methylquinolin-5 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 27 619.64 661 4 γ H ^N D WAL· L· r ί ~ (8)-6-(((1-( 1,1-difluoro-2hydroxyethyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino) -4- (neopentylamino)quinoline-3,8dicarbonitrile 24 550.2

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662 1% A Αγ ri nr ^N nJ ci F (8)-8-chloro-6-(((5-chloro-1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoro-2-methylpyridin3 -yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile thirty 553.4 663 A N A Cl F (8)-8-chloro-6-(((1-cyclopropyl5-fluoro-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile thirty 537.4 664 A „ Ψ TO I ^N AW 1 (8)-6-((( 1 -methyl-1Hpyrrolo[2,3-b]pyridin-4yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 599.5 665 dd h ^N A ν Λ x ^N О IT J nJ n=/ Cl (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methyl-1H-pyrazol-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 540.3

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666 DOD OD n. ^F h ⁿ X ^ν Λ ι Stroke D IX X nA γ^Ν N=/ Cf (S)-8 -chloro-6-((( 1 -methyl-1Hpyrazol-5 -yl)( 1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 558.4 667 FF /D A a ^H ^ir Odd \D XX J ODA f ^N ill N (8)-6-(((4-methylisoquinolin-5yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 610.41 668 X„ A D D/ odD XXX Oo 1 ^N w J (8)-6-(((4-methylquinolin-5yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 610.51

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669 'O' ⁰ SW nA ci F 6-(((S)-(l-([l,l'- bi(cyclopropane)] -1 -yl)-1H- 1,2,3-triazol-4-yl)(6-fluoro-2- methylpyride in-3 - yl)methyl)amino)-8-chloro-4(((R)-3,3-d imethyltetrahydro2H-pyran-4- yl)amino)quinoline-3 carbonitrile 4 601.3 670 aJs μ \| F „ H. J Of G N (S)-6-(((8-cyanoisoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 25 621,690 671 △x 9 \i F c FL J ^H Ν γ-,γ V i (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.477

-242045220

672 y X UuA CQ G (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.148 673 And AO>US Ια 7 PO t ^Ν W ill Ν (8)-6-((isoquinolin-4-yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.253 674 A γ Ν' Η ^Η Π ν.1 ό Tl W TXT Ϋ'Ν γ Ν °A II (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2,5dimethyloxazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 546.4 675 ^X Y M.A. A.W. Vill F N 6-(((S)-(l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(6-fluoro-2methylpyride in-3 - yl)methyl)amino)-4-(((K)-3,3 dimethyltetrahydro-2H-pyran4-yl)amino)quinoline-3,8dicarbonitrile 24 592.4

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676 ΑΧ W g (8)-8-chloro-4- (neopentylamino)-6-((( 1 -oxo1,2-dihydroisoquinolin-5yl)( 1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 4 621.3 677 Η ^Η Ά k! ν ΥΌΥ Ν^ Ζ Ν νΥ Ν (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methyl-1H-pyrazol-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 531.4 678 X Ν-^ Η ' _Ν -'ν'Λ Ν Τ X AG ID 7 years νΥ Ν (8)-6-((( 1 -methyl-1 H-pyrazol-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 549.2 679 D γ ν ^Ν X ^D ϊ ϊ G ^Ν ι ύχΧΧ JL X- Xs JJ ο Ύ ^Ν nA α χΧ (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(6(dimethylamino)pyridin-3 yl)methyl-c1)amino)-4-( (2,2dimethylpropyl-1,1b2)amino)quinoline-3 carbonitrile 26 533.309

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680 1% A Xwv rg (S)-6-(((5-chloro-1-cyclopropyl1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile thirty 544.2 681 А А XwV рг F ^N (S)-6-(((l -cyclopropyl-5-fluoro1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile thirty 528.1 682 XH D yiX·· Atyt on । NA/ ^Cl (S)-6-(((l-([l,l·- bi(cyclopropane)]-1 -yl)-1H1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 577.2 683 X ^f J H ^Н Х nI _l LA DPU OO ί ^Ν (8)-8-chloro-6-(((1 -(1,1-difluoro2-methylpropan-2-yl)-1H-1,2,3triazol-4-yl)(isoquinolin-5yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 589.2

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684 W «A ΧυύΥ οό ΙΑ (8)-8-chloro-6-((( 1 -(1 -φτορ-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(isoquinolin-5yl)methyl)amino) -4- (neopentylamino)quinoline-3 carbonitrile 4 571.6 685 7 ψ Η ^N D Wy Ο0Υ ^Ν (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4yl)(isoquinolin-5- yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 563.2 686 «'L □COo Αρ 1 ^Ν F (8)-8-chloro-6-(((5-cyano-1 cyclopropyl-1H-1,2,3-triazol4-yl)(6-fluoro-2-methylpyridin3 -yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 36 544.6 687 D ψ Χν C.I. (8)-8-chloro-6-(((2,6dimethylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile 23 583.307

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688 n Ϋ Al/ HA M ci (8)-8-chloro-6-(((2-fluoro-6methylpyrid in-3 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 23 587.622 689 X Y pW γ Ί (8)-6-(((2,6-dimethylpyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 574,505 690 d< (8)-6-(((2-fluoro-6- methylpyride in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578,467 691 S-Y Ύ (8)-6-(((1-([1,1'- bi(cyclopropane)] -1 -yl)-1H- 1,2,3-triazol-4-yl)(quinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 23 577.37

-247045220

692 Ύ - X Ν 1 Λ AC (D X Ου 1 ^Ν 8-chloro-6-(((8)-( 1 -((1 R,2 S)-2fluorocyclopropyl)- 1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4 - (neopentylamino)quinoline-3 carbonitrile 23 555.07 693 1 „ χ ν X 1 101 .-.X IX X date (8)-8-chloro-6-(((1 -(1,1-difluoro2-methylpropan-2-yl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 23 589.14 694 I „ χ AAV ΙΛ X Γϊί t MU S! (8)-8-chloro-6-(((1-(1-fluoro-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(quinolin-5 yl)methyl)amino )-4- (neopentylamino)quinoline-3 carbonitrile 23 571.11 695 and ¹ (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4yl)(quinolin-5- yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 23 563.36

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696 T n A to 1 _ 1 a AT XX X MO 1 ^N (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4-yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 568.31 697 \ X ' zy z ^T MM /Qn, Ζΐ \\ A (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4yl)(quinolin-5- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 554.30 698 △a ^f X κι I ⁷ u H. J ΓΆ H n u ° ” (8)-8-chloro-4- (neopentylamino)-b((quinolin-7-yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 27 605,770 699 △Α O \i ^F u n» J ΓΆ H n u ^c ' ^N (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-7yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 587,720

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700 ΛΑ- γ. (8)-4-(neopentylamino)-6-((( 1 oxo-1,2-dihydroisoquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 24 612.2 701 T „ o < X L A A aVu '\' S Υ Ν tA ci (R)-8-chloro-6-(((4-methylthiazol5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 575.4 702 1 „ nA Ν,, Η '-.γ n χ । _l 7 a Or xxj 'A Ts Ш N-=/ Cl (R)-6-(((l-([l,l·- bi(cyclopropane)] -1 -yl)-1H- 1,2,3-triazol-4-yl)(4- methylthiazole-5- yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 23 547.6 703 THU to X ^Xa ⁿ GGTHU On / « nOO iJ (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4yl)(isoquinoline-5- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 568.2

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704 Ο Ψ V Η ^Η _Ν νΛ ν Α Α ^Ν ν ο ίγ Υ Γ 6-(((S)-(l-((lS,2S)-2fluorocyclopropyl)-1H-1,2,3triazol-4-yl)(isoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 546.2 705 γ _Η y Y. _z y.4,j ΧΧΧΧΤ Oil Ο ^Ν ΥΤ ||| Ν (8)-6-((( 1-(1,1-difluoro-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(isoquinolin-5yl)methyl)amino)-4 - (neopentylamino)quinoline-3,8dicarbonitrile 24 580.2 706 У Ϋ Ν-^ Η ^Η ·- _Ν ·- Ο Ν χχχχχ nOJ j (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)- 1H-1,2,3-triazol-4yl)(isoquinolin-5yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 554.2 707 γ ψ Υι A and n. J Ν-Α n ΟύΎΥ Τ|] γΆ nJ ci F (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)-5 iodo-1H-1,2,3-triazol-4-yl)(6fluoro-2-methyl lpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 28 695.3

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708 V Ψ ν 1 _Λ ι γ X ΙΑ I JO 1 XX i (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-7yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.151 709 mI ^f γ И F μ Η, J Αν χρ Cl (8)-8-chloro-6-(((8-chloroquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 639.263 710 Ο ψ ζ ,ζγ Υ ί Ν (8)-6-(((8-cyanoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 25 621.265 711 I ι ^Η \ X ⁿ XLu^ _D Ohm τ DyOM Cl D 0 (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2- (methyl-io3)-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 43 596.32

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712 A od (8)-8-chloro-6-(((3cyanoisoquinolin-5 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 9 630.28 714 A GK Q ".A GK. Ag l from 0 (8)-6-((( 1-(1-(tert- butyl)piperidin-4-yl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5-yl)methyl)amino)-8-chloro-4(neopentylamino) quinoline-3 carbonitrile 1 666.65 715 a Chk U Η ⁿ k ^% ^GGYOD od γχ nA ci F (8)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyrid in-3 yl)methyl)amino)-8-chloro-4 ((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 589.34 716 7nt Awy A yV nA ci f (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 2 519.25

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717 4 4 (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2,6dimethylpyridin-3yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 564.16 718 4 U FL n ^Ν Χγνν ^Ν 4=] γΑ 4 Cf Cl (8)-8-chloro-6-(((6-chloro-2methylpyridine in-3 -yl)( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 2 585.60 719 f4f 1. -c 44 Y|1 4^ nJ ¹ ci F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 599.17 (M+H+) 720 nL h ^h A 44 41 Y* 4 ci F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1methylcyclopropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4( (3,3,3-trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile 2 587.1 (M+H+)

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721 od F A ⁿ od ODod Hoda ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 641.1 (M+H+) 722 G F oOD .-,/G ''OD A h ^N OD Oy Move n<J ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)- 1H-1,2,3-triazole-4- yl)methyl)amino)-4-((2-methyl- 2- (methylsulfonyl)propyl)amine o)quinoline-3-carbonitrile 2 651.22 (M+H+) 723 d 0 A ^f h N 1 I _l 1 OD ^N iOO nA ci F 8-chloro-6-(((8)-( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3- carbonitrile 2 617.21 (M+H+)

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724 Ο ψ 0γΙ> ^Ν ,ςό χ ^Ν 0 (8)-8-chloro-6-(((1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl )amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 671.2 (M+H+) 725 I n Ά„ ήπ F (8)-8-chloro-6-(((1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3-yl)methyl< 1)amino)-4-((2,2dimethylpropyl-1,1b2)amino)quinoline-3 carbonitrile 2 613 (M+H+) 726 χ I A.W. W I' 0 (8)-8-chloro-6-(((1 -(1 - (difluoromethyl)cyclopropyl)- 1 Η-1,2,3-triazol-4-yl)( 1 -oxo- 1,2-dihydroisoquinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 657.4 (M+H+)

- 256 045220

727 f fAf A L k 1 γ Ϊ a vS W nA ci F (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 2 621.95 (M+H+) 728 4 U D Hu (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1 Η-1,2,3-tri-azol-4-yl)(3 methyl-4-oxo-3,4dihydroquinazolin-8yl)methyl)amino)-8- chloro-4(neopentylamino)quinoline-3 carbonitrile 2 594.19 (M+H+) 729 A ⁿ 'Χ AAA Ώ A U (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6methoxy-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 581.44 (M+H+)

- 257 045220

730 F /\ k ^F HF ^F »XvJ> ,ςό and 0 (8)-8-chloro-6-(((1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl )amino)-4-((( 1 (trifluoromethyl)cyclobutyl)methyl)amino)quinoline-3 carbonitrile 2 683.41 (M+H+) 731 ,, F /Г \Ц W ^F y F I 4. J γΤ . ^N < ( ¹ NF .. TC TXT Ay T ^N GkT Cl F (8)-8-chloro-6-(((1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino )-4-((( 1 (trifluoromethyl)cyclobutyl)methyl)amino)quinoline-3 carbonitrile 2 635.12 (M+H+) 732 53 h N11 y pi-I ci 0 (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1,2dimethyl-6-oxo-1,6dihydropyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 581.15 (M+H+)

- 258 045220

733 / χχ X у/ ^Ω Μ / \ / ! ΥΓαΧ 4 χ- (8)-8-chloro-6-(((1-(1(difluoromethyl)cyclopropyl)- 1 Η-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-(((2,2,3,3 tetramethylcyclopropyl)methyl)amino)quinoline -3 carbonitrile 2 609.29 (M+H+) 734 J/ Η Χ γ-Αγτ ζότ ⁷ (8)-8-chloro-4(neopentylamino)-b((quinoxalin-5 -yl( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3 -triazol -4yl)methyl)amino)quinoline-3 carbonitrile 2 606.17 (M+H+) 735 (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1 Η-1,2,3-triazol-4-yl)(1 methyl-1H-indol-4- yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 2 566 (M+H+) 736 Cell Ψ k ^F η Υγγν ^Ν FROM A / (8)-8-chloro-6-(((1-(1- (difluoromethyl)cyclopropyl)1 H-1,2,3-triazol-4-yl)(1 methyl-1H-indol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 589.38 (M+H+)

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737 Η αΑ gut ^m X (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxoisoind olin-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 605.2 (M+H+) 738 \ « Η X Γ ' (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4yl)(thieno[2,3 -c]pyridin-3yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 2 543.20 739 Α Ϋ Aw Ή|1 γΧ ν') CI F (8)-4-((bicycle o[ 1.1.1]pentan-1ylmethyl)amino)-8-chloro-6-(((1 (1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)quinoline-3 carbonitrile 2 579.30 740 ^F γ Ν^. Η ^Η Μ WrrV аА γΧ ν') CI F (8)-4-((bicycle o[ 1.1.1]pentan-1ylmethyl)amino)-8-chloro-6-(((6fluoro-2-methylpyridin-3-yl)( 1 (1(trifluoromethyl)cyclopropyl )1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 2 597.30

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741 it no w \^= (8)-8-chloro-4(neopentylamino)-b((thieno[2,3 -c]pyridin-3-yl( 1 (i- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)quinoline-3 carbonitrile 2 611.20 742 F kXf < ⁿ w ^f Ν' H 'SAn ν X । _l l M ^Ν Χ'ό τη W Ν^Λ Cl F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4-((5,6difluoropyride in-3 yl)amino)quinoline-3 carbonitrile 2 612.10 743 Ao -Λ LO Ji ^N 0 (8)-8-chloro-6-(((2-(2,2- difluoroethyl)-1 -oxo-1,2dihydroisoquinolin-5 -yl)(1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 2 667.40

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744 V ψ уоД χό V ^Ν 0 (8)-8-chloro-6-(((1-(1(difluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl) methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 616.20 745 η 'Q τΗνγΑ ,ςό α 0 (S)-8 -chloro-6-((( 1 -cyclopropyl1H-1,2,3 -triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 2 567.40 746 Η Α A ct F (8)-8-chloro-6-(((1 -(1 - (difluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4-yl)(6-fluoro- 2-methylpyr idin-3 - yl)methyl)amino)-4-((3 - hydroxy-2,2- dimethylpropyl)amino)quinoli n-3-carbonitrile 2 585.30 747 Uy A /ΥΥ 1 \ (8)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5-yl)methyl)amino)- 8-chloro-4(neopentylamino)quinoline-3 carbonitrile 2 583.50

- 262 045220

748 And Η Τ AAA νΥ ci F 8-chloro-6-(((8)-( 1 -((lR,2R)-2(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin- 3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 548.30 749 9 γ A tG A CI F (8)-8-chloro-6-((( 1-(2,2difluoropropyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 557.32 (M+H+) 750 Τ Αν Α A CI F (8)-8-chloro-6-((( 1-(2,2difluorobutyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 571.77 (M+H+) 751 ΑΑ^ ^χ/ Λ FT / ^H (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-((1(trifluoromethyl)cyclopropyl)m ethyl)-1H-1,2,3-triazol-4yl )methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 601.47 (M+H+)

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752 F T H A A AV nX ci F (S)-8-chloro-6-((( 1-((1(difluoromethyl)cyclopropyl)methyl)-1 Η-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 583.42 (M+H+) 753 FF A ^F J AyVZ ύί N IJ Cl F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)( 1 -(1 (2,2,2- trifluoroethyl)cyclopropyl)1H-1,2,3 -triazol -4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 601.39 (M+H+) 754 H %Vrrv A|l γΎ nV ci F (8)-8-chloro-6-(((1 -(1 ethylcyclopropyl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile 4 547.5 (M+H+) 755 FF I ^z T A h ^H V AnY Yv nV ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)( 1-(3,3,3trifluoro-2,2-dimethylpropyl)1H-1,2,3 -triazole - 4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 603.43 (M+H+)

-264045220

756 X n Τ ΥΙΧΧΤ no r ^N (8)-8-chloro-6-((( 1-(1ethylcyclopropyl)-1H-1,2,3triazol-4-yl)(2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 595.1 (M+H+) 757 oD X n ⁿ o LAA ⁿ Ύι] γ ¹ ' ^N nA ci F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 isopropylcyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 4 561.40 758 H „ A UP ΏΓ F (8)-8-chloro-6-(((1-(2cyclopropylpropan-2-yl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 4 561.50 759 WWA ΏΓ F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(3 methyloxetan-3-yl)-1 Η-1,2,3 triazol-4-yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 549.20

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760 Υ I % Ψ Υγγ Ο ν 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)( 1-(3-methyloxetan-3-yl)1H-1,2,3-triazol-4yl )methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 597.20 761 Chan ν 1 ι 1 γ ^ν λΑΧζΑ ΥΊ γΎ νΥ CI F (8)-6-(((1-(1-(tert- butyl)cyclopropyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 575.40 762 o ^F У F Η ^Η Ύ %Vr?A ^N Υ1 γΆ νΥ CI F (8)-8-chloro-6-(((1-(1,3difluoropropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(6-fluoro-2methylpyride in-3 yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 557.37 763 Υ φ γ ^{Η Η} 'Ν'' ΟγγΥ Υ|] γΆ νΥ CI F (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(6-fluoro-2methylpyride in-3 - yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 613.30

-266045220

764 ^x T-g l aJO/ g (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)( 1-((1methylcyclopropyl)methyl)-1H1,2,3-triazol-4yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 4 547.40 765 Ό 190= Ε (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)( 1 -oxo1,2-dihydroisoquinolin-5yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 4 603.30 766 Т n ν Λ Ϊ I а ^N lМхт^ sA W nA ci F 8-chloro-6-(((18)-(6-fluoro-2methylpyrid in-3 -yl)( 1 (spiro[2.2] pentan-1 -yl)-1H1,2,3-triazol-4yl)methyl) amino)-4(neopentylamino)quinoline-3 carbonitrile 4 545.30 767 % h Ο,ΛγΛΑ/ LI UI - (8)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)( 1 methyl-1H-pyrrolo[2,3 - b]pyridin-4-yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 4 590.20

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768 Η I ,ο A “COLD Di g (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1 Η-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-8-chloro- 4-((3 hydroxy-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 609.23 769 4 APPROACH ^nQQ i ⁿ 0 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2-ethyl1-oxo-1,2- Dihydroisoquinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 607.30 770 D Ψ Ν Η ^N D ^Ν 1 Ν 4 L f OY'S τ'* όι 0 (8)-8-chloro-6-(((2-(2,2- difluoroethyl)-1-oxo-1,2dihydroisoquinolin-5-yl)(1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 684

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771 Ν Η У-- ^{1 Ν} 1 Ν 1 Υ g ^F ΑιίΊ γΧ 0 (8)-8-chloro-4- (neopentylamino)-6-((( 1 -oxo2-(2,2,2-trifluoroethyl)-1,2dihydroisoquinolin-5 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazole -4yl)methyl)amino)quinoline-3 carbonitrile 4 702.10 772 Α OTD _Ύ ίΟ J ^Ν 1 0 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2isopropyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-8-chloro-4 (neopentylamino)quinoline-3 carbonitrile 4 621.40 773 % Η A iddd otD τ H χ^νΑΑ ci 0 (8)-8-chloro-6-(((2-ethyl-1-oxo1,2-dihydroisoquinolin-5yl)( 1 -(1-methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4- (neopentylamino)quinoline-3 carbonitrile 4 595.30

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774 Υ Ψ Υ η Α UXyAY γΑ γΜ V ⁿ yV ^Cl 1 0 (8)-8-chloro-6-(((2-isopropyl-1oxo-1,2-dihydroisoquinolin5 -yl)( 1-(1 -methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 4 609.40 775 4 γ Αχ „with 0 (8)-8-chloro-6-((( 1 -(1 - (fluoromethyl)cyclopropyl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5 -yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 599.30 776 Α απ γγ €>° (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)( 1 -(1-methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 4 581.30 777 4ψ ΑΧ A £ 0 (8)-8-chloro-6-(((1-(1,3difluoropropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(2-methyl-1-oxo1,2- Dihydroisoquinolin-5yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 605.30

-270045220

778 F A Ψ 0 8-chloro-6-(((8)-( 1-((8)-1- fluoropropan-2-yl)-1H-1,2,3 triazol-4-yl)(2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 587.30 779 /A A BEFORE/ 0 (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5-yl)methyl)amino)-8-chloro-4 (neopentylamino)quinoline-3 carbonitrile 4 607.30 780 γ Ψ grandfather ,ςα γ 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 689.20

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781 Υ ψ 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)( 1-(1-methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 635.20 782 χ g ο Λ ' ^Η ' ⁴ (8)-8-chloro-6-(((2methoxypyridine in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 4 585.40 783 0ψ £0 0 0 (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5-yl)methyl)amino)-8-chloro-4 ((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 661.20

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784 U Ψ y ,ςό η 0 8-xnop-6-(((S)-(l-((S)-lφτορ propan-2-yl)-1 Η-1,2,3 triazol-4-yl)(2-methyl-1-oxo1 ,2-dihydroisoquinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 641.10 785 about 7 mTχρ η 0 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-8-chloro-4 ((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 4 647.20 786 Η Qο (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1 methyl-2-oxo-1,2- dihydroquinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 4 593.30

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787 7 n U WAv W Г' 0 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1 Η-1,2,3-triazol-4-yl)(1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-8-chloro-4( neopentylamino)quinoline-3 carbonitrile 4 579.20 788 O ^F _n Ψ ^Ν ύτχι νζϋ ο ^Ν F 0 (8)-8-chloro-6-(((2(difluoromethyl)-1 -oxo-1,2dihydroisoquinolin-5 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3 -triazole - 4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 4 671.50 789 ο Ν- Η ^Η ' _Ν - ^Ν X Ν _Λ Λ ζ ^Ν Λ X < aL A fn Τ ^Ν ₀ Α _ν Αο ^C| (S)-8-chloro-6-((( 1 -methyl-2-oxo1,2-d ihydroquinolin-5 -yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 4 635.40 790 4 Η I. X XXX mw ⁿ Cl 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)( 1 -methyl-1 H-1,2,3-triazol4-yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile 22 541.20

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791 n U mA mind F 8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -methyl1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 22 493.10 792 FF A A A XXX VT τ ^{ν N} V ^cf F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4-(((3 methyloxetan-3 yl)methyl)amino)quinoline-3 carbonitrile 23 601.34 793 y Ay A Hi nY Cf Cl (8)-8-chloro-6-(((6-chloropyridin3-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 589.39 794 A -U H IE yy^y A XXX UGU Y ^N N0 Cf Cl (8)-8-chloro-6-(((6-chloro-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 23 602.22

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795 L „ ψ Ay AW νΤ Ci (8)-8-chloro-6-(((6methylpyridine in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 23 569.27 796 WlpT А τ 0 (8)-8-chloro-6-(((1-cyclobutyl1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 581.21 797 A A H H γ tY. ^'Ά II IXI QU a (8)-8-chloro-6-((( 1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4-((3,3,3trifluoro -2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 23 605.14 798 y D-y A (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H- 1,2,3-triazol-4-yl)(quinolin-5yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 23 631.09

-276045220

799 U NN Ψ АХуу ¢0 ci ^; (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4- yl)(quinoline-5- yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 23 617.18 800 y z W Aure hmm oh 0 (8)-8-chloro-6-(((2-methyl-1-oxo1,2-dihydroisoquinoline-5- yl)( 1 -(1 -methylcyclobutyl)-1H1,2,3-triazol-4- yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 23 595.23 801 W n and A AAD α ^N 0 6-((( 1 S)-( 1 -(sec-butyl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5-yl)methyl)amino) -8-chloro-4(neopentylamino)quinoline-3 carbonitrile 23 583.28 802 'SI'L y, ?? ^gkDU ci 0 8-xnop-6-(((S)-(l-((S)-l- methoxypropan-2-yl)- 1H-1,2,3 triazol-4-yl)(2-methyl-1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 599.36

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803 T ^F Τ' Η ^N Π I 1 A J-yACY Yes 8-chloro-6-(((8)-(1-((8)-1- fluoropropan-2-yl)- 1H-1,2,3 triazol-4-yl)(quinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 23 557.28 804 /—F ₍ A η η ^X XX; Qu 4 ^N (8)-8-chloro-6-(((1-(1,3difluoropropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(quinolin-5 yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile 23 575.19 805 A-D Χ N ^F H ^H U n 1 I ia 'уУ^Ау X IT χ О w ⁿ na ^c| at (8)-8-chloro-6-(((6methoxypyridine in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 23 585.20 806 ,N, NA χ χ D HW nA 1 1 A ^N STROKE Γί x^n nJ ci (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1-(1-(5methyl-1,3,4-oxadiazol-2yl)cyclopropyl)-1 Η-1 ,2,3 triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 23 601.30

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807 ο— / Α САСх (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 584.40 808 4 Η t ^ν Ύ th X ,ζ χ χϊχτ fg Ο, ^Ν (S)-6-((( 1 -cyclopropyl-1H1,2,3-triazol-4-yl)(1methoxyisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 558.32 809 A n Ά ςύ ν χ ^Ν (S)-6-(((l -methoxyisoquinolin5 -yl)( 1 -(1 -methylcyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 572.32 810 Α Ψ AQ> ςύτ ^Ν ' °ο ^Ν (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 608.43

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811 tX χ ^N > Η πγ ^Ν 1 Ν 1 A JL 9. αΧ а όΟ γ (8)-6-(((2-methoxyquinolin-5yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 625.17 812 V ψ χοΟ Sig 0^ ^Ν (S)-6-(((l-methoxyisoquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 625.28 813 Υ Ψ ν 1 UU ^N 0$W (S)-6-(((8-fluoroquinolin-5yl)( 1 -(1-methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-((3,3,3trifluoro -2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 614.13 814 ο ρΧ (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 572.26

-280 045220

815 χν About (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3, 8-dicarbonitrile 24 650.48 816 f4f \ „ «j р О Υ ¹ g (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4-((3,3,3trifluoro-2, 2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 626.49 817 AVrV Ag and (S)-6-(((l-cyanoisoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 621.60

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818 od Ψ A n ^N '- _Y ''Vzl/L- X XXX Xj f ^N (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-7yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.15 819 l Φ A h ^H O ODODODE ςό/ g (S)-6-(((l -methoxyisoquinolin5 -yl)( 1 -(1 -methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-((3,3,3trifluoro- 2.2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 626.22 820 fXf R L STROKE ςύ od I. (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2, 2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 638.16

-282045220

821 γ φ nХ η ^η Ό ςόη I, ^Ν (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4-((3,3,3 trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 662.50 822 (8)-6-((imidazo[1,2-a]pyridin6-yl(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 584.11 823 Α „ «Α ν'Λ Ν Υ ΑΑ Τ ^Ν ODA I I ^Ν (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4-yl)(1methoxyisoquinolin-5- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 598.63 824 od ^r Ϋ ΓΚ Η ODA ODodokht ΟΟ OD lb I ^N 6-(((S)-( 1 -((S)-1 -fluoropropan-2yl)-1H-1,2,3-triazol-4-yl)(1methoxyisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.43

-283 045220

825 o ^F У ^F w ςό r A ^N (S)-6-(((l -(1,3-difluoropropan-2yl)-1H-1,2,3-triazol-4-yl)(1methoxyisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.67 826 ¹ wo r—/ — H ή A z (8)-6-(((6-cyanopyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 571.27 827 Ύ oo χψ Υ 'll (8)-6-((( 1 -(tert-butyl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4-((3 ,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 580.56 828 Η Ϋ Χυυ W γ i (8)-6-(((6-methylpyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 560.12

-284045220

829 A n ψ AW T IS (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2,6dimethylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 555.26 830 Α ψ O'W T I X J Yy γΥ Vill N w (8)-6-(((6-cyano-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 585.55 831 Ach Hu nV h ^h A f ^fn X\9v ⁿ w WW ill FN (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4-((( 1 (trifluoromethyl)cyclobutyl)methyl)amino)quinoline-3,8dicarbonitrile 24 626.37 (M+H+)

-285 045220

832 F fJ,F AHV N'l 1 1 У ^N xTxX у γ i (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4-((3,3,3- trifluoro-2,2- dimethylpropyl)amino)quinol n-3, 8-dicarbonitrile 24 614.2 (M+H+) 833 fYf t,. .J Toy Ух γ i (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4-((3,3,3- trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 590.5 (M+H+) 834 AΖ-Ζ d=\ Tz' 6-(((S)-( 1-((1 R,2R)-2(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro- 2-methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline-3,8- dicarbonitrile 24 560.31 (M+H+)

- 286 045220

835 у 9 iy Н Ν 1 1 j ^Ν ϊϊ γ 9 Ύιΐ । ^Ν V ιΐι F ^Ν 6-(((8)-(1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3, 8-dicarbonitrile 24 548.30 836 U y,U f 1' (S)-6-(((l -(2,2-difluoropropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.30 837 F ⁷ τ AAA γ i (S)-6-(((l -(2,2-difluorobutyl)- 1H-1,2,3-triazol-4-yl)(6-fluoro- 2-methylpyr idin-3 - yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 562.35 (M+H+) 838 y φ νΧ η ^η _ν »χγ> ,ςό y 8 ^Ν (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2 - dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 662.5 (M+H+)

-287 045220

839 XQa Ύυ γ¥ V ill Т ^N (8)-6-(((6-φτορ-2methylpyrid in-3 -yl)( 1-((1(trifluoromethyl)cyclopropyl)m ethyl)-1H-1,2,3-triazol-4yl)methyl)amino )-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 592.3 (M+H+) 840 _F y Α- Χ n ^Η J χΑγΧχ vS W ^N J ill Τ Ν (8)-6-(((1-((1- (difluoromethyl)cyclopropyl)methyl)-1 Η-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 574.35 (M+H+) 841 X ψ l γΧ yS W Ύ i (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-4-((3,3,3- trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 613 (M+H+)

-288 045220

842 F fXf Xt γ g (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3, 8-dicarbonitrile 24 629.7 (M+H+) 843 wH/Λ (8)-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- ((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 630.95 (M+H+) 844 A Ψ Η ^H -' _N - N'l 1 XY ||| N (8)-6-(((1 -methyl-2-oxo-1,2dihydropyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl) amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 575.53 (M+H+)

- 289 045220

845 <uΆ V H A N.I N A w γ Ί (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-(((2,2,3,3tetramethylcyclopropyl)methyl) amino)quinoline-3,8dicarbonitrile 24 600.4 (M+H+) 846 /vA )—Λ Y/7 X (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)(1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4((3,3,3-trifluoro-2,2dimethylpropyl)amino)quinolin -3,8-dicarbonitrile 24 578.2 (M+H+) 847 X n D yYyt yes γ / N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1methyl-1H-indol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 580.12 (M+H+) 848 Ά. X— Z /=\ (8)-4-((bicycle o[ 1.1.1]pentan-1ylmethyl)amino)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(1 (trifluoromethyl)cyclopropyl) 1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 24 588.20

-290045220

849 A z /=\ (8)-4-((bicycle ο[ 1.1.1] pentan-1 ylmethyl)amino)-6-((( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl )(6-fluoro2-methylpyridin-3 yl)methyl)amino)quinoline-3,8dicarbonitrile 24 570.20 850 Ά Δ (8)-6-(((1-(2- cyclopropylpropan-2-yl)-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 552.50 851 αΐ. ^η Ύ ^Ν χτχχ γ (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1 -(1 isopropylcyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 552.60 852 1 Η X рг (8)-6-(((6-fluoro-2methylpyridin-3-yl)( 1 -(3 methyloxetan-3-yl)-1 Η-1,2,3 triazol-4-yl)methyl)amino) -4(neopentylamino)quinoline-3,8dicarbonitrile 24 540.30

- 291 045220

853 ¢0 I 4 Ψ AQV ,φ Г 8 ^Ν (8)-6-(((2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl)( 1 -(3 methyloxetan-3-yl)-1 Η-1,2,3 triazol-4-yl )methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 588.20 854 Μ X yw ^Ν γ ill F ^Ν 6-(((8)-(5-fluoro-1-((8)-1fluoropropan-2-yl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridine in-3 yl) methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.20 855 DuA has an id (8)-4-(neopentylamino)-6((thieno[2,3 -c]pyr idin-3 -yl( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 24 602.10 856 V n X ADD 4 G (8)-6-(((1-cyclopropyl-1 Hl,2,3-τpiazol-4-yl)(thieno[2,3c]pyridin-3-yl)methyl)amino)4-(neopentylamino)quinoline3, 8-dicarbonitrile 24 534.30

- 292 045220

857 A χ Ν Τ 1 1 D γΛ..... Υ u (S)-6-((( 1,5-dicyclopropyl-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 550.29 858 ^,: Α Τ—2 6-(((8)-(5-fluoro-1-((8)-1fluoropropan-2-yl)- 1H-1,2,3 triazol-4-yl)(6-fluoro-2methylpyride in-3 yl)methyl)amino)-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 602.10 859 l j η Α Add Ρ Α I ^Ν (8)-6-(((1-cyclopropyl-5 methoxy-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 540.20 860 41 ί. Υ ^Ν ϊ ΐΥΤ V g (8)-6-(((1-(1-(tert-butyl)cyclopropyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 566.40

-293 045220

861 fXf 4. Ϋ L‘ -X· O G (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4-(( 3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 608.30 862 OD Ψ AD ώ ϊ’ ' (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4-((3, 3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 622.10 863 FyF A _F n NS Η * 1' (8)-6-(((5-fluoro-1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4-( (3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 596.20

-294045220

864 O Y Ογ ήυ (S)-6-(((l-cyclopropyl-5-fluoro1 Η-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4-(( 3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 582.10 865 Ο Ψ νΥ y α Υ ^ν V ν (S)-6-(((l-([l,l- bi(cyclopropane)] -1 -yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 568.10 866 ζ ' and γ Ν Τ-Ζ Λ Γ'·' ζ. (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1-((1methylcyclopropyl)methyl)-1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 538.30 867 Α ψ Υ ^{Η Η} 'Ν'' y (S)-6-(((l-([l,l’- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(6-fluoro-2methylpyride in-3 - yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 604.20

- 295 045220

868 Yu x—z /=\ (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 methoxy-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 566.20 869 v ^F T ^F Αν ήτ T Ν (8)-6-(((1-(1,3-difluoropropan-2yl)-1 Η-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl) amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.20 870 ν ϋ Ν N N-A ^Ν 1 Ν 1 X ·' ^F Ai'S T JcJU ill S ^N (8)-6-(((2-(2,2-difluoroethyl)-1oxo-1,2-dihydroisoquinolin5-yl)(1-(1- (difluoromethyl)cyclopropyl)- 1H-1,2,3 -triazole -4- yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 658.30 871 J ^F Ψ Av Yr o N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 607.10

- 296 045220

872 Λ Λ ^Ν iGxyG A γν M ill Τ Ν 6-(((18)-(6-φτορ-2methylpyrid in-3 -yl)( 1 (spiro[2.2] pentan-1 -yl)-1H1,2,3-triazol-4yl)methyl)amino)-4 - (neopentylamino)quinoline-3,8dicarbonitrile 24 535.20 873 AX 4 Η ^Η Ο A XXX CO ι ^Ν (8)-6-(((1-(1(difluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)( 1 methyl-1H-pyrrolo[2,3 - b]pyridin-4-yl)methyl)amino)4-(neopentylamino)quinoline3,8-dicarbonitrile 24 581.20 874 Α χ Ν Η %· ^{1 Ν} 1 Ν 1 Υ f ιΎίΊ ρΤΝγΛΥ |[| ^F V ν (8)-6-(((2-(2,2-difluoroethyl)-1oxo-1,2-dihydroisoquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 674.90 875 Α χ Ν Η %· ^{1 Ν} 1 Ν 1 Υ T'UU'V F ^F ίΤίΊ Τ™ ></χυ ιΐ ^F V ν (8)-4-(neopentylamino)-6-((( 1 oxo-2-(2,2,2-trifluoroethyl)-1,2dihydroisoquinolin-5 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H- 1,2,3-triazol-4yl)methyl)amino)quinoline-3,8dicarbonitrile 24 692.90

- 297 045220

876 Y ^f χ wx- D g 0 (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 594.30 877 QX ^x JXO H d )=o Г z у/ 6-(((S)-( 1 -((S)-1 -fluoropropan-2yl)-1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl) methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 578.30 878 9 kF <VrW ^N D X o N (S)-6-(((l-(l- (fluoromethyl)cyclopropyl)-1H1,2,3-triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5 -yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 590.20 879 A h st ,ςό r I ^N (8)-6-(((2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl)( 1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4 (neopentylamino)quinoline-3,8dicarbonitrile 24 572.20

-298 045220

880 0ψ ΑΟν W 0 (S)-6-(((l -(1,3-difluoropropan-2yl)-1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl) amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 596.20 881 Ψ AQy G (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5 -yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 598.20 882 At ψ <\·Μν horn 8 ^N (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(2-methyl-1 oxo-1,2-dihydroisoquinolin5 -yl)methyl)amino)-4-((3 ,3,3 trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 652.20

-299045220

883 tU ,ςο γ ^ν 8 ^Ν (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-4-((3 ,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 638.10 884 i n P wo' <O G (8)-6-(((2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl)( 1-(1methylcyclopropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4 ((3,3,3-trifluoro-2,2dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 626.20 885 A „ γ M.W. Mill Ν (8)-6-(((2-methoxypyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 576.30

- 300 045220

886 Α ⁵ ψ ,ςό g 8 ^Ν (8)-6-(((2-methyl-1-oxo-1,2dihydroisoquinolin-5-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl) amino)-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3, 8-dicarbonitrile 24 680.20 887 Oh yes Qо (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1 methyl-2-oxo-1,2dihydroquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 584.20 888 „ t odOD X» g 0 (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1-oxo1,2-dihydroisoquinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 570.10

- 301 045220

889 n Ψ Η J y U g F O (8)-6-(((2-(difluoromethyl)-1oxo-1,2-dihydroisoquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 662.20 890 р7у ² О хЭД С (8)-6-(((1 -methyl-2-oxo-1,2dihydroquinolin-5-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino )-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 626.20 891 ν and <\Оу ,ςο g about Ν (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2- Dihydroisoquinolin-5yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 584.20 892 m k t ^N T Ν' АуцА nn Г' ¹ 6-(((8)-( 1 -((S)-1 -fluoropropan-2yl)- 1H-1,2,3 -triazol -4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 548.28

- 302 045220

893 ^f X~ ^f ϊ a ά A 'N AO <4 ill (S)-6-(((l -(1,3-difluoropropan-2yl)-1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 566.30 894 Υ v ' y X/ H'-V And (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 632.07 895 fXf A kg ^Ν Τ1 ai ¹ N- -sz J'-x AA T IA J Od 1 ^N ill (S)-6-(((l-(lmethylcyclopropyl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4-((3,3,3trifluoro-2,2 - dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 596.11 896 I uU® 4 (S)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H- 1,2,3-triazol-4-yl)(quinoline-5- yl)methyl)amino)-4-((3,3,3- trifluoro-2,2- dimethylpropyl)amino)quinoli n-3,8-dicarbonitrile 24 622.08

- 303 045220

897 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4- yl)(quinoline-5- yl)methyl)amino)-4-((3,3,3- trifluoro-2,2- dimethylpropyl)amino)quinol n-3,8-dicarbonitrile 24 608.11 898 / g—Ar _/ (S)-6-((( 1-(1,1-difluoro-2methylpropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(quinolin-5yl)methyl)amino)-4 - (neopentylamino)quinoline-3,8dicarbonitrile 24 580.22 899 Ά yy / yy^z. ^~\yy 6-(((S)-(l-((lR,2S)-2fluorocyclopropyl)-1H-1,2,3triazol-4-yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 546.22 900 I W X z Lz X” G (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2methylquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 568.41

- 304 045220

901 X n Ψ l I a ΓγζΟ J (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(2(difluoromethyl)quinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 604.13 902 Ό * ζ (S)-6-(((l-(lmethylcyclopropyl)-1H-1,2,3triazol-4-yl)(2-methylquinolin5 -yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 556.29 903 Χχ Η ·ΧιθΙχ3 % A Ν (R)-6-(((l-([l,r- bi(cyclopropane)] -1 -yl)-1H1,2,3 -triazol-4-yl)(4- methylthiazol-5yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 538.20 904 V y 0x0 II N (R)-6-(((4-methylthiazol-5-yl)(l(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 566.20

- 305 045220

905 FF zA ^f Ϋ Ν—, Η Ύ...... J ^N (8)-6-(((6-methoxypyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 576.20 906 AY Xj G F N (8)-6-(((5-fluoro-1-methyl-1H1,2,3-triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 502.20 907 Ν Ά A A Ν—, Η Ύ Yr' F N (8)-6-(((6-fluoro-2methylpyridine in-3 -yl)( 1-(1-(5methyl-1,3,4-oxadiazol-2yl)cyclopropyl)-1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3,8dicarbonitrile 24 592.30 908 '. XH ^H -iX /g x N 6-(((6-fluoro-2-methylpyridin-3 yl)(5-methoxy-1 -methyl- 1H1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 24 514.30

- 306 045220

909 (S)-6-(((3-cyanoisoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 25 621.46 910 A τ NT' T g Ν (S)-6-(((8-cyanoquinolin-5 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 25 621.27 911 About γ \ι ν Ηχ J iW n Ή ΜϊΎΤ Ш Τ (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 27 593.45 912 ν η Η WyyV ςύ Μ (8)-8-chloro-6-(((1-cyclopropyl1H-1,2,3-triazol-4-yl)( 1 methoxyisoquinolin-5 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 567.24

- 307 045220

913 ASO went ci (8)-8-chloro-6-(((1- methoxyisoquinolin-5 -yl)(1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 581.30 914 Η U m F _u FL J φΓ (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)( 1 methoxyisoquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 617.30 915 A ^F У r0 ^F H ^H '- _H TY pX ψν ^N WX ct (8)-8-chloro-6-(((3- chlor isoquinolin-5 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 639.70 916 H ^f U y F u Fk / 4φφ Φ Y Cl (8)-8-chloro-6-(((1- chlor isoquinolin-5 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 639.98

- 308 045220

917 \n j of A F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 - yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 635.09 918 L f GL N YES ^s| F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 yl)methyl)amino)-4-( (3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 659.22 919 . f GL N ID ⁿ 'Wvwx ⁿ YES xDOD οι F (8)-8-chloro-6-(((8-fluoroquinolin5 -yl)( 1 -(1 -methylcyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4-((3, 3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile 27 623.24

- 309 045220

920 XA H ^N D dadai ςφ A F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1H-1,2,3-triazol-4-yl)(8fluoroquinolin-5 - yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 27 581.34 921 A ^r.1 F μ FL D Yes OQ A Cl (8)-8-chloro-6-(((8-chloroquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 639.26 922 △A ^f a Дьςό A (8)-8-chloro-6-(((5-fluoro-1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)( 1 methoxyisoquinolin-5 yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 27 653.66 923 Άκ J 9DL (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)-5 fluoro-1 Η-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 635.20

-310045220

924 lD ^r Ψ XuA (8)-8-chloro-6-(((5-iodo-1-(1(trifluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)( 1 methoxyisoquinolin-5 yl)methyl) amino)-4(neopentylamino)quinoline-3 carbonitrile 27 761.55 925 Y ¥ Μ U Η. J ΑνΥ Α (8)-8-chloro-6-(((1 -(1 - (difluoromethyl)cyclopropyl)-5 iodo-1 Η-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 743.10 926 Λ4± 0 η χό Α <ο (S)-6-(((l-([l,l'- bi(cyclopropane)] -1 -yl)-1H1,2,3-triazol-4-yl)(1methoxyisoquinolin-5- yl)methyl)amino)-8-chloro-4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 661.42 927 2 / ^χ/ ^Υο 00 (8)-8-chloro-6-(((1methoxyisoquinolin-5 -yl)( 1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)methyl)amino)-4((3,3, 3-trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile 27 635.42

- 311 045220

928 fIf D A J Η ^H A AAA φΓ ^N (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)1 Η-1,2,3-triazol-4-yl)(1 methoxyisoquinolin-5yl)methyl)amino)-8-chloro-4((3,3, 3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 647.40 929 △A γ m F _u K J AD ρό A ty (8)-8-chloro-6-(((1methoxyisoquinolin-5 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3 -triazol -4yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 27 635.90 930 △Λ A ΥγΑ/ - ₀ Ϋ0 9 (8)-8-chloro-6-(((2methoxyquinolin-5 -yl)( 1 -(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino) quinoline-3 carbonitrile 27 635.10 931 t. %t AAV A g su (S)-6-(((l-([l,l·- bi(cyclopropane)]-1 -yl)-1H1,2,3-triazol-4-yl)(1methoxyisoquinolin-5yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 27 607.63

- 312 045220

932 About OD s—x Hu /G\ / OD 8-chloro-6-(((8)-( 1 -((S)-1 fluoropropan-2-yl)-1H-1,2,3triazol-4-yl)(1methoxyisoquinolin-5yl)methyl)amino)- 4(neopentylamino)quinoline-3 carbonitrile 27 587.81 933 OD Ϋ ^F GK N 'J YA Si A 0' (8)-8-chloro-6-(((1-(1,3- difluoropropan-2-yl)-1 Η-1,2,3 triazol-4-yl)(1 methoxyisoquinolin-5 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 605.85 934 ku (8)-8-chloro-6-(((1 -(1 (difluoromethyl)cyclopropyl)1 Η-1,2,3-triazol-4-yl)( 1 methoxyisoquinolin-5yl)methyl)amino)-4- ((3,3,3trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 671.31 935 <OD A GK ^{F N N} A N.1 ^ay ⁿ «C An C1 (8)-8-chloro-6-((imidazo[1,2a]pyridin-6-yl( 1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 594.10

- 313 045220

936 A (S)-8 -chloro-6-((( 1 -methyl-2-oxo1,2-dihydropyridin-3 -yl)( 1 (1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 27 584.7 (M+H+) 937 FF /tZ~ ^F M-'Ν' Η ^Η Χ ^Ν ·1 Ν Λ P Х0Э (S)-8-chloro-6-(((3-fluoroquinolin5-yl)(1-(1- (trifluoromethyl)cyclopropyl)- 1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 27 623.12 938 y X Η Y Νg 1 I ^Ν yTyr οτύ ^C1 (8)-8-chloro-6-(((2-chloro-3methylpyridin-4-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 27 603.13 939 g y t wLja 0 (8)-6-(((1 -(bicyclo[2.2.2]octan1 -yl)- 1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl) methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 27 635.21

- 314 045220

940 F Up Thu n n I ''Ν' TX1XJ QO α (8)-8-chloro-6-((( 1-(1- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4-((3,3,3 trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile 27 641.10 941 γΤ Ψ k ^F η ^Η Ύ ΑΑΑ A U (8)-8-chloro-6-(((2methoxypyride in-4-yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4( neopentylamino)quinoline-3 carbonitrile 27 585.30 942 I ψ THAT/ nA Cf F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)-5 iodo-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl) methyl)amino)-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile 28 749.23 (M+H+); 748.25 (M+H+)

- 315 045220

943 o ψ Οι Ju K J NO Η Ν AUV γη γΑ nA ci F (S)-6-(((l-([l,l- bi(cyclopropane)] -1 -yl)-5 -iodo1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 - yl)methyl)amino)-8-chloro-4(neopentylamino)quinoline-3 carbonitrile 28 685.20 944 Ό "g Ό F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 iodo-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-8-chloro- 4(neopentylamino)quinoline-3 carbonitrile 28 671.10 945 And N A u H. J iw η -Ά wYV Y|] yA nJ ci F (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)-5 iodo-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 28 695.20 946 4% J n I ill -X Y U'9> F (8)-8-chloro-6-((( 1,5dicyclopropyl-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 29 EXP-15- AN3588

-316045220

947 n nV ci F (8)-8-chloro-6-(((5-fluoro-1-(1methylcyclopropyl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile thirty 551.64 948 '—' z—X A (8)-8-chloro-6-(((1 -(1 (difluoromethyl)cyclopropyl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl) methyl)amino)-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile thirty 641 (M+H+) 949 N—Z ^F H ^H '- _N aA Ύΐ τ nV ci F (S)-6-(((l-([l,l·- bi(cyclopropane)] -1 -yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-8-chloro-4( neopentylamino)quinoline-3 carbonitrile thirty 577.10 950 A 9 vC E χ vr) I ^N nV ci F 8-chloro-6-(((8)-(5-fluoro-1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl )methyl)amino)-4-(((I)-1 phenylpropyl)amino)quinoline3-carbonitrile thirty 653.40

- 317 045220

951 W and Xuja γτ F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-8-chloro- 4(neopentylamino)quinoline-3 carbonitrile thirty 563.40 952 χ 8-chloro-6-(((8)-(5-fluoro-1 -((S)-1 fluoropropan-2-yl)-1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyride in-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile thirty 557.30 953 F Ar , ^Ν „ ^Γ F Η XX , ^N Y Η %'A XWA W|1 T” nA ci F (8)-8-chloro-6-(((1 -(1 - (difluoromethyl)cyclopropyl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4-((5,6difluoropyridin-3 yl) amino)quinoline-3 carbonitrile thirty 630.10 954 X. X V r F ^N (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile thirty 554.40

- 318 045220

955 \=/ z—X y GL / A χ \v 8-chloro-6-(((8)-(5-fluoro-1 -((S)-1 fluoropropan-2-yl)- 1H-1,2,3 triazol-4-yl)(6-fluoro -2methylpyride in-3 yl)methyl)amino)-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3 -carbonitrile thirty 611.20 956 fO 4.-. -ί <Ma/ Si) γΟ nA ci F (8)-6-(((1- (bicyclo[1.1.1]pentan-1-yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-8-chloro- 4((3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile thirty 617.40 957 A ψ under Y|] 1 nA ci F (8)-6-(((1-([1,G- bi(cyclopropane)] -1 -yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-8-chloro-4( (3,3,3-trifluoro-2,2- dimethylpropyl)amino)quinol n-3-carbonitrile thirty 631.40

-319045220

958 F|F v О OrrV ^N ήπ F (8)-8-chloro-6-(((1-cyclopropyl5-fluoro-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)- 4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile thirty 591.10 959 FXF A _FH JN L H ^Μ Ύ Wy-tY Mil i ^nZ N IJ Cl F (8)-8-chloro-6-(((5-fluoro-1 -(1 methylcyclopropyl)- 1H-1,2,3triazol-4-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino )-4-((3,3,3trifluoro-2,2dimethylpropyl)amino)quinol n-3-carbonitrile thirty 605.20 960 M ^F Ϋ ^Kl z ^F LI H. J ΥΧγ ¹ Ύ|] Ίτ ⁿ NA Cl F (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile thirty 587.10

- 320 045220

961 Γ ψ γΙαΧν XT TXT ΑΎ|] T ^N _z r<Az ci 0 (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 fluoro-1H-1,2,3-triazol-4-yl)(2methyl-1-oxo-1,2dihydroisoquinolin-5yl)methyl)amino)-8 -chloro-4(neopentylamino)quinoline-3 carbonitrile thirty 611.30 962 T t ^h W GO ^N X TXT GO T ^N O Cl (8)-8-chloro-6-((( 1 -(1 - (difluoromethyl)cyclopropyl)-5 fluoro-1H-1,2,3-triazol-4yl)(quinolin-5yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile thirty 605.09 963 nW h w X χτ N<y Cl F (8)-8-chloro-6-(((5-fluoro-1-methyl1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile thirty 511.10 964 χ A hi Ύι H. J Xw X T N (8)-6-(((1-(1- (difluoromethyl)cyclopropyl)-5 methoxy-1H-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)quinoline-3,8dicarbonitrile 31 590.20

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965 A U KI H J Ν-γ Ή FT ΥγΥγ Y|1 уЯ nA ci F (8)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)-5 methoxy-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 31 599.30 966 A U Ush Ύη f ^N Cl (8)-8-chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)-5 methoxy-1 Η-1,2,3-triazol-4yl)(6-methoxy-2methylpyridin-3 yl) methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 31 611.20 967 Chu h Υ YY' yr F (8)-8-chloro-6-(((1-cyclopropyl5-methoxy-1H-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 31 549.28 968 J\J 'A h ^H J Aw/ U G F (S)-6-(((l- (bicyclo[1.1.1]pentan-1-yl)-5 methoxy-1 Η-1,2,3-triazol-4yl)(6-fluoro-2-methylpyridin-3 yl)methyl)amino)-8- chloro-4(neopentylamino)quinoline-3 carbonitrile 31 575.20

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969 Ν^- ⁰ Η ^H j AW F (8)-8-chloro-6-(((6-fluoro-2methylpyridine in-3 -yl)(5 methoxy-1 -methyl-1 Η-1,2,3 triazol-4-yl)methyl)amino) -4(neopentylamino)quinoline-3 carbonitrile 31 523.20 970 M H A vw A|1 nJ ci 8-chloro-6-(((5-methoxy-1 -methyl1H-1,2,3-triazol-4-yl)(6methoxy-2-methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline -3 carbonitrile 31 535.20 971 Ο Η Ά OtyYa w F 8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)(5 methoxy-1 -methyl-1 Η-1,2,3 triazol-4-yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 31 523.20 972 f· «J I H (8)-8-chloro-4(neopentylamino)-6-(((2(methyl trifluoro)-1Hbenzo[s!]imidazol-4-yl)( 1 -(1 (τpiφτopmethyl)cycloπpoπyl)1Н-1,2 ,3-triazol-4yl)methyl)amino)quinoline-3 carbonitrile 32 662.14

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973 h Λ 1 A ^and jlTXT aS nA Cl F (8)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl-5-c1)(6fluoro-2-methylpyridin-3 yl) methyl)amino)-4-((2,2dimethylpropyl-1,102)amino)quinoline-3 carbonitrile 33 572.36 (M+H+) 974 rT ^F ν γ NyO Η ^H YA XX? to x F (8)-8-chloro-6-(((5-cyano-1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl )methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 36 594.40 975 ^kl Xu H. J N—/ HD _r M UAW ^N A|1 I ^N lU Cl F (S)-5 -bromo-8 -chloro-6-((( 1 -(1 (difluoromethyl)cyclopropyl)-5 fluoro-1H-1,2,3-triazol-4-yl)(6fluoro-2-methylpyridine -3 yl)methyl)amino)-4- (neopentylamino)quinoline-3 carbonitrile 42 665.30

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976 A n / C) U F O (S)-6-(((l-(l- (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3 yl)methyl)amino)-4- (neopentylamino)-8(pyrimidin-5-yl)quinoline-3 carbonitrile 46 613.3 (M+H+) 977 H N X। γw Τη φν nJ ci F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)(5 -iodo-1 (1 -methylcyclopropyl)-1H1,2,3-triazol-4yl)methyl)amino )-4(neopentylamino)quinoline-3 carbonitrile 47 659.26 978 OyyV A 8-chloro-6-(((6-methoxy-2methylpyrid in-3 -yl)( 1 -(1 (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-4(neopentylamino )quinoline-3 carbonitrile 48 599.25 979 \--/ ^Q ~OXY Tu / GA (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3-yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)(methyl )amino)-4(neopentylamino)quinoline-3 carbonitrile 48 601.37

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980 F\Tsg NA N S V F H G Y Ni Y ^N 1 4'0 (8)-6-(((6-fluoro-2- methylpyride in-3 -yl)( 1-(1(trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4- yl)methyl)amino)-8-(3 -methyl-3 (methylsulfonyl)but-1 -in-1 yl)-4- (neopentylamino)quinoline-3 carbonitrile 40 697.29 981 F N-. Ν S V V F H 9 AW X lT/hl / (8)-8-acetyl-6-(((1 -(1 (difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-4- (neopentylamino)quinoline-3 carbonitrile 49 577.20 982 , F I-M N Ts NΎ V l F ,(. H Y Y N 6-(((6-fluoro-2-methylpyridin-3 yl)(1-(1- (trifluoromethyl)cyclopropyl)1H-1,2,3-triazol-4yl)methyl)amino)-8-(3hydroxy-3-methylbut-1-in-1yl)-4- (neopentylamino)quinoline-3 carbonitrile 40 635.29

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983 D _n Χ,A. Η _F ^г' Ν1 1 [ S Ν''' _γ 4. _γ 4,.Α./ ^? D xdX nA ci F (8)-8-chloro-6-((( 1-(1(difluoromethyl)cyclopropyl)1H-1,2,3-triazol-4-yl)(6-fluoro2-methylpyridin-3yl)methyl)amino )-5-fluoro-4(neopentylamino)quinoline-3 carbonitrile 41 587.45 984 O 1 nA tj' n I i _ χ A ν 'Α- Ύγγ vS dx nA ci F (8)-8-chloro-6-(((6-fluoro-2methylpyridin-3 -yl)(4,5,6,7tetrahydro-[1,2,3]triazolo[1,5a]pyridin-3 - yl)methyl)amino)4-(neopentylamino)quinoline-3 carbonitrile 44 534.22 985 cm αΦ PgtA A JM nA ci F (8)-8-chloro-6-(((6,7-dihydro-5H[1,2,3]triazolo[5,1- b][1,3]oxazin-3-yl)(6-fluoro-2methylpyridin-3 yl)methyl)amino)-4(neopentylamino)quinoline-3 carbonitrile 45 535.34 986 CM ^H -C PtSH AA F (8)-8-chloro-6-(((6-fluoro-2methylpyrid in-3 -yl)( 1 -(3 hydroxypropyl)- 1H-1,2,3triazol-4-yl)methyl)amino)-4 (neopentylamino)quinoline-3 carbonitrile 46 537.27 987 IZ /==\ ,h'· 8-chloro-6-(((8)-( 1-((1hydroxycyclobutyl)methyl)1H-1,2,3-triazol-4- silt)(pyridine in-3 - yl)methyl)amino)-4-(((K)-1 phenylpropyl)amino)quinoline3-carbonitrile

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Proton NMR data for selected compounds are shown in Table. 2.

table 2

Compound Ή-NMR 1 1HNMR (400 MHz, DMSSMb) δ 8.37 (m, 2H), 8.17 (s, 1H), 8.05 (m, 1H), 7.79 (brs, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.51 (br s, 1H), 7.15 (m, 2H), 4.03 (m, 1H), 3.44 (dd, J = 13.9 / 5.5 Hz, 1H), 1.59 (s, 9H), 0.88 (s, 9H). 2 1HNMR (400 MHz, CD3OD) δ 8.61 (m, 1H), 8.37 (m, 1H), 8.29 (m, 1H), 8.05 (m, 1H), 7.73 (m, 1H), 7.60 (s, 1H), 7.32 (m, 5H), 7.14 (m, 1H), 6.46 (s, 1H), 5.64 (m, 1H), 4, 88 (m, 1H), 2.83 (s, 3H), 2.17 - 2.02 (m, 2H), 1.56 (d, 6H), 0.97 (m, 3H). 3 1HNMR (400 MHz, CD3OD) δ 8.43 (m, 1H), 8.05 (m, 1H), 8.01 (m, 1H), 7.64 (m, 1H), 7.42 - 7, 25 (m, 6H), 6.98 (m, 1H), 5.80 - 5.66 (m, 1H), 3.97 - 3.84 (m, 1H), 2.25 - 2.01 ( m, 2H), 1.28 - 1.11 (m, 4H), 1.01 (m, 3H). 4 1H NMR (400 MHz, DMSSMb) δ 8.84 (dd, J = 14.0, 2.2 Hz, 1H), 8.64 - 8.52 (m, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 6.7 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.46 (d, J = 9.5 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.38 - 7.31 (m, 2H), 7.28 - 7 .21 (m, 2H), 7.21-7.15 (m, 3H), 6.48 (d, J = 6.9 Hz, 1H), 5.48 (q, J = 7.7 Hz, 1H), 5.35 (s, OH), 4.68 (d, J = 2.0 Hz, 2H), 4.50 (dd, J = 6.2, 4.5 Hz, 3H), 4, 41 (dd, J = 6.7, 3.4 Hz, 2H), 2.12 (dt, J = 14.5, 7.4 Hz, 1H), 2.04 - 1.78 (m, 1H) , 0.94 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.2 Hz, 1H). 5 1HNMR (400 MHz, DMSSMb) δ 9.41 (s, 1H), 8.47 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 2.3 Hz, 1H) , 7.41 - 7.34 (m, 2H), 7.27 (d, J = 8.2 Hz, 1H), 7.15 (dd, J = 9.1, 3.3 Hz, 2H), 7.12 (s, 1H), 5.96 (d, J = 8.1 Hz, 1H), 4.50-4.32 (m, 1H), 3.00 - 2.83 (m, 2H) , 2.42 - 2.25 (m, 2H), 2.18-1.81 (m, 6H), 0.98 (t, J = 7.2 Hz, 3H). 6 1H NMR (400 MHz, DMSSMb) δ 9.41 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.54 (dd, J = 5.0, 1.5 Hz , 1H), 8.41 (s, 1H), 8.13 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 2.2 Hz , 1H), 7.59 - 7.36 (m, 3H), 7.33 - 7.17 (m, 2H), 6.20 (d, J = 8.0 Hz, 1H), 4.83 - 4.67 (m, 1H), 3.61 (d, J = 12.4 Hz, 2H), 3.28 - 2.97 (m, 2H), 2.34 (d, J = 13.8 Hz , 2H), 2.17 (m, 2H), 1.22 (t, J = 7.3 Hz, 2H). 9 1H NMR (400 MHz, MeTaHon-d4) δ 9.20 (s, 1H), 8.34 (s, 1H), 8.05 (dd, J = 7.3, 1.9 Hz, 1H), 7 .86 (d, J = 2.5 Hz, 1H), 7.82 (s, 1H), 7.64 - 7.54 (m, 2H), 7.16 (d, J = 2.6 Hz, 1H), 6.34 (s, 1H), 3.97 (d, J = 13.7 Hz, 1H), 3.91 - 3.80 (m, 1H), 3.49 (d, J = 13 .7 Hz, 1H), 1.23 - 1.07 (m, 4H), 0.81 (s, 9H)

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16 1H NMR (400 MHz, DMSO-ab) δ 8.92 - 8.83 (m, 1H), 8.67 (d, J = 9.5 Hz, 1H), 8.65 - 8.58 (m, 1H), 8.24 (d, J = 3.3 Hz, 1H), 8.15 (d, J = 7.7 Hz, 1H), 7.64 - 7.56 (m, 2H), 7, 52 (d, J = 8.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.29 - 7.16 (m, 6H), 6.54 (d, J = 7.8 Hz, 1H), 5.47 (q, J = 7.6 Hz, 1H), 4.32 (t, J = 12.0 Hz , 2H), 2.11 (m, 1H), 2.04 - 1.83 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H). 20 1HNMR (400 MHz, CD3OD) δ 9.02 (m, 1H), 8.46 (s, 1H), 8.01 (m, 1H), 7.68 (m, 1H), 7.60 (m, 1H), 7.52 (m, 1H), 7.33 (m, 4H), 6.31 (s, 1H), 3.75 (m, 2H), 3.25 3.13 (m, 3H) , 2.45 (m, 2H), 2.36 (m, 2H), 2.25 - 2.01 (m, 2H), 1.37 (m, 3H), 22 1HNMR (400 MHz, DMSSMb) δ 8.49 - 8.38 (m, 1H), 8.28 (d, J = 5.1 Hz, 1H), 8.13 - 8.02 (m, 2H), 7.84 (t, J = 2.4 Hz, 1H), 7.65 - 7.52 (m, 2H), 7.42 - 7.31 (m, 1H), 7.31-7.15 ( m, 4H), 5.49 (q, J = 7.7 Hz, 1H), 4.04 (s, 3H), 3.20 - 3.11 (m, 1H), 2.20 - 2.05 (m, 1H), 2.05 - 1.85 (m, 1H), 1.63 - 1.50 (m, 1H), 1.37 - 1.20 (m, 1H), 0.99 - 0 .83 (m, 3H) 23 1HNMR (400 MHz, Methanol^4) δ 8.19 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 2.5 Hz, 1H), 7.43 - 7, 24 (m, 3H), 7.13 (d, J = 2.6 Hz, 1H), 6.05 (s, 1H), 3.86 - 3.63 (m, 4H), 3.56 (d , J = 13.9 Hz, 1H), 3.39 - 3.29 (m, 1H), 3.15 - 3.04 (m, 1H), 1.13 1.04 (m, 4H), 0 .83 (s, 9H) 25 1HNMR (400 MHz, Chloroform-d) δ 8.97 (s, 1H), 8.41 (s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.58 (t, J = 7.7 Hz, 1H), 7.15 (s, 1H), 6.50 (br s , 1H), 6.09 (br s, 1H), 3.67 (m, 1H), 3.59 (br s, 2H), 3.53 - 3.45 (m, 1H), 1.23 - 1.17 (m, 2H), 1.17 - 1.08 (m, 2H), 0.84 (s, 9H) 27 1HNMR (400 MHz, Methanol) δ 8.45 (s, 1H), 7.95 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 7.1, 1.7 Hz, 1H), 7.45 - 7.37 (m, 2H), 7.05 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.86 (d, J = 14.7 Hz, 1H), 4.57 (d, J = 1.7 Hz, 2H), 4.51 (d, J = 14.7 Hz, 1H), 4, 12 (d, J = 13.9 Hz, 1H), 3.94 - 3.84 (m, 1H), 3.73 (d, J = 13.9 Hz, 1H), 1.25 - 1.13 (m, 4H), 0.95 (s, 9H) 36 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.08 (s, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.58 - 7, 50 (m, 1H), 7.43 - 7.34 (m, 2H), 7.37 - 7.22 (m, 6H), 6.27 (s, 1H), 5.68 (t, J = 7.3 Hz, 1H), 4.92 (d, J = 14.4 Hz, 1H), 4.61 - 4.49 (m, 3H), 2.27 - 2.19 (m, 1H), 2.12 - 2.02 (m, 1H), 1.67 (s, 9H), 1.01 (t, J = 7.4 Hz, 2H) 61 1HNMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.49 (s, 1H), 8.18 (d, J = 1.7 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.64 (dd, J = 8.4, 1.8 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.39 - 7.30 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H), 6.22 (s, 1H), 4.79 (m, 1H), 1.52 (dd, J = 6.7, 2.3 Hz, 6H)

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62 1HNMR (400 MHz, Methanol-04) δ 9.26 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.84 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.47 (dd, J = 6 .5, 2.4 Hz, 1H), 7.35 - 7.21 (m, 3H), 6.24 (s, 1H), 4.89 - 4.71 (m, 1H), 3.79 ( d, J = 12.7 Hz, 2H), 3.20 (dd, J = 13.7, 10.8 Hz, 2H), 2.42 (m, 4H), 1.45 (s, 9H) 63 1HNMR (400 MHz, Methanol-44) δ 9.25 (s, 1H), 8.46 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.64 (dd, J = 8.6, 1.8 Hz, 1H), 7.47 (dd, J = 6.4, 2.5 Hz, 1H), 7.35 - 7.20 (m, 3H), 6.21 (s, 1H), 4.83 - 4.73 (m, 1H), 3.79 (d, J = 12.6 Hz, 2H), 3.26 - 3.15 (m, 2H), 2.48 - 2.35 (m, 4H ), 1.45 (s, 9H) 64 1H NMR (400 MHz, Methanol-44) δ 8.44 (s, 1H), 7.95 - 7.84 (m, 2H), 7.77 (s, 1H), 7.69 (d, J= 2.4 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.35 7.19 (m, 4H), 6 .14 (s, 1H), 4.83 - 4.68 (m, 1H), 3.78 (d, J = 12.5 Hz, 2H), 3.20 (t, J = 12.6 Hz, 2H), 2.52 - 2.30 (m, 4H), 1.45 (s, 9H) 72 1H NMR (400 MHz, Methanol-44) δ 8.43 (s, 1H), 7.92 (m, 1H), 7.85 - 7.72 (m, 1H), 7.60 (m, 1H) , 7.49 - 7.28 (m, 5H), 7.27 - 7.14 (m, 1H), 6.88 (m, 1H), 5.92 (m, 1H), 3.90 (m , 1H), 2.66 - 2.50 (m, 5H), 2.43 (m, 2H), 1.28 - 1.10 (m, 4H). 73 1HNMR (400 MHz, Methanol-44) δ 8.45 - 8.33 (m, 2H), 8.01 - 7.87 (m, 2H), 7.60 (m, 1H), 7.46 - 7 .27 (m, 6H), 7.25 (m, 1H), 5.98 - 5.86 (m, 1H), 3.92 (m, 1H), 2.67 - 2.33 (m, 4H ), 1.29 - 1.12 (m, 4H). 74 1HNMR (400 MHz, Methanol-44) δ 8.64 (m, 1H), 8.39 (m, 1H), 8.07 (s, 1H), 7.79 (m, 1H), 7.60 ( m, 1H), 7.41 - 7.29 (m, 6H), 6.46 (s, 1H), 5.86 (m, 1H), 3.93 (m, 1H), 2.63 (m , 2H), 2.43 (m, 2H), 1.29 - 1.13 (m, 4H). 75 1HNMR (400 MHz, Methanol-44) δ 8.83 (s, 1H), 8.70 (s, 1H), 8.43 (m, 1H), 8.38 - 8.28 (m, 1H), 8.03 (m, 1H), 7.78 (m, 1H), 7.70 - 7.62 (m, 1H), 7.49 - 7.29 (m, 5H), 6.43 (m, 1H), 6.00 - 5.89 (m, 1H), 2.66-1.98 (m, 4H), 1.25 - 1.13 (m, 4H).

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90 1HNMR (400 MHz, DMSO-C16) δ 8.21 (m, 1H), 8.09 (m, 1H), 7.60 (m, 1H), 7.55 - 7.48 (m, 1H), 7.41 - 7.33 (m, 3H), 7.31 (d, J = 5.0 Hz, 2H), 7.29 - 7.22 (m, 1H), 6.27 (d, J = 3.4 Hz, 1H), 5.66 (dd, J = 8.9, 5.5 Hz, 1H), 4.82 - 4.64 (m, 4H), 4.56 4.41 (m, 1H), 3.96 (qd, J = 7.2, 4.2 Hz, 1H), 3.00 (m, 1H), 2.82 (m, 1H), 2.62 (dd, J = 14 .7, 7.5 Hz, 2H), 2.40 (dt, J = 15.1, 7.4 Hz, OH), 2.31 (d, J = 5.7 Hz, OH), 2.29 -2.17(m, 1H), 1.16-1.11(m, 4H), 1.11(s, 1H). 91 1H NMR (400 MHz, DMSODb) δ 8.30 (s, 1H), 8.05 (s, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.43 (s, 1H ), 7.13 (s, 1H), 6.11 (s, 1H), 4.73 (dt, J = 8.0, 4.4 Hz, 4H), 4.59 4.45 (m, 1H ), 3.93 (tt, J = 7.6, 4.4 Hz, 1H), 3.00 (s, 1H), 2.77 (d, J = 15.6 Hz, 1H), 1.11 (td, J = 2.8, 1.7 Hz, 3H), 1.09 (t, J = 2.0 Hz, 1H), 0.89 (s, 9H). 92 1HNMR (400 MHz, DMSODb) δ 8.35 (m, 1H), 8.29 (m, 1H), 8.06 (m, 1H), 7.98 (m, 1H), 7.58 (m, 1H), 7.34 (m, 1H), 7.16 (m, 1H), 7.01 (m, 1H), 6.61 (m, 1H), 4.32 (tt, m, 1H), 3.93 (m, 2H), 3.40 (m, 2H), 3.06 (m, 1H), 2.02 - 1.67 (m, 1H), 1.20 - 1.02 (m, 4H), 0.91 m, 3H), 0.54 (m, 3H) 99 1H NMR (400 MHz, DMSSMb) δ 8.38 - 8.30 (m, 2H), 8.08 - 7.98 (m, 2H), 7.82 (d, J = 2.4 Hz, 1H) , 7.55 (t, J = 6.9 Hz, 2H), 7.41 (d, J = 2.5 Hz, 1H), 7.16 (dd, J = 8.5, 2.7 Hz, 1H), 4.02 (s, 4H), 3.42 (dd, J = 14.0, 5.5 Hz, 1H), 0.85 (s, 9H) 100 1H NMR (400 MHz, DMSODb) δ 8.45 (dd, J = 2.3, 1.1 Hz, 1H), 8.42 - 8.34 (m, 1H), 8.20 - 8.05 (m, 2H), 7.97 - 7.84 (m, 2H), 7.68 - 7.58 (m, 2H), 7.50 - 7.25 ( m, 5H), 7.23 - 7.12 (m, 1H), 6.05 - 5.90 (m, 1H), 4.03 - 3.92 (m, 1H), 3.42 - 3.17 ( m, 2H), 1.23 - 1.05 (m, 4H) 101 1H NMR (400 MHz, Methanol^4) δ 8.87 (d, J = 5.4 Hz, 1H), 8.47 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 6.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.50 - 7.27 (m, 6H), 5.78 (t, J = 7.2 Hz , 1H), 3.96 - 3.84 (m, 1H), 2.43 (s, 3H), 2.28 - 2.04 (m, 2H), 1.27 1.11 (m, 4H) , 1.02 (t, J = 7.3 Hz, 3H). 102 1HNMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.52 (s, 1H), 7.96 (s, 1H), 7.62 (m, 1H), 7.12 ( m, 1H), 4.03 (m 1H), 3.95 - 3.85 (m, 2H), 2.45 (s, 3H), 1.26 - 1.07 (m, 4H), 0. 99 (s, 9H).

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103 1HNMR (400 MHz, Methanol-<14) δ 8.50 (m, 1H), 8.11 - 7.98 (m, 2H), 7.65 (m, 1H), 7.11 - 7.04 ( m, 1H), 6.98 (m, 1H), 4.08 (m, 1H), 3.96 - 3.78 (m, 2H), 1.27 1.11 (m, 4H), 0. 97 (s, 9H). 106 1H NMR (400 MHz, Methanol-04) δ 8.40 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.01 (ddd, J = 8.5, 7, 5, 2.6 Hz, 1H), 7.93 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.39 - 7.23 (m, 6H), 7, 11 - 7.03 (m, 1H), 5.73 (s, 1H), 3.95 - 3.85 (m, 1H), 1.28 - 1.11 (m, 4H) 109 1H NMR (400 MHz, MethanolchM) δ 8.42 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 8.00 (ddd, J = 8.5, 7.5, 2.6 Hz, 1H), 7.93 (s, 1H), 7.64 (t, J = 2.1 Hz, 1H), 7.42 - 7.25 (m, 6H), 7.07 ( dd, J = 8.5, 2.6 Hz, 1H), 3.90 (m, 1H), 1.26 - 1.11 (m, 4H) BY 1H NMR (400 MHz, Methanol-04) δ 8.45 (m, 1H), 7.92 (m, 1H), 7.79 (m, 1H), 7.62 (m, 1H), 7.43 - 7.26 (m, 5H), 7.21 - 7.11 (m, 1H), 6.87 (m, 1H), 5.73 (m, 1H), 3.89 (m, 1H), 2.54 (s, 3H), 2.25-2.10 (m, 1H), 2.08 (m, 1H), 1.27-1.09 (m, 4H), 0.98 (m, 3H). 111 1HNMR (400 MHz, Methanol-04) δ 8.51 (s, 1H), 7.93 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 4.02 ( m, 1H), 3.94 - 3.83 (m, 2H), 2.51 (s, 3H), 1.25 - 1.10 (m, 4H), 0.94 (s, 9H). 112 1H NMR (400 MHz, Methanol-04) δ 8.48 (s, 1H), 8.30 (dt, J = 2.6, 0.8 Hz, 1H), 8.00 (ddd, J = 8, 5, 7.5, 2.6 Hz, 1H), 7.92 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.12 7.04 (m, 2H) , 3.89 (m, 1H), 1.25 - 1.10 (m, 4H), 0.97 (s, 9H) 116 1HNMR (400 MHz, DMSO-ab) δ 8.37 - 8.30 (m, 2H), 8.13 (s, 1H), 8.03 (td, J = 8.2, 2.6 Hz, 1H ), 7.82 (d, J = 2.3 Hz, 1H), 7.61 - 7.50 (m, 2H), 7.38 (d, J = 2.5 Hz, 1H), 7.19 -7.11 (m, 1H), 4.01-3.91 (m, 2H), 3.42 (dd, J= 14.0, 5.5 Hz, 1H), 1.19 - 1.04 (m, 4H), 0.85 (s, 9H)

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117 1H NMR (400 MHz, DMSO-ab) δ 8.53 - 8.38 (m, 1H), 8.28 (d, J = 5.7 Hz, 1H), 8.20 - 8.03 (m, 2H), 7.83 (t, J = 2.5 Hz, 1H), 7.63 - 7.52 (m, 3H), 7.42 - 7.14 (m, 6H), 5.54 - 5 .44 (m, 1H), 4.03 - 3.93 (m, 1H), 2.21 - 2.04 (m, 1H), 2.05 - 1.84 (m, 1H), 1.25 - 1.05 (m, 4H), 1.04 - 0.80 (m, 3H) 119 1HNMR (400 MHz, DMSOLb) δ 8.54 (s, 1H), 8.44 - 8.29 (m, 2H), 8.14 (s, 1H), 8.04 (td, J = 8.2 , 2.6 Hz, 1H), 7.72 (s, 1H), 7.43 - 7.26 (m, 2H), 7.21 - 7.12 (m, 1H), 7.08 (d, J = 2.2 Hz, 1H), 4.10 (dd, J = 14.0, 8.0 Hz, 1H), 4.01 - 3.90 (m, 1H), 3.59 - 3.49 (m, 1H), 1.19 - 1.04 (m, 4H), 0.89 (s, 9H) 120 1HNMR (400 MHz, DMSOLb) δ 8.48 - 8.38 (m, 1H), 8.37 - 8.30 (m, 1H), 8.18 8.03 (m, 2H), 7.76 ( d, J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.43 - 7.14 (m, 8H), 5.56 (q, J = 8.1 Hz, 1H), 4.03 - 3.92 (m, 1H), 2.23 - 2.05 (m, 1H), 1.98 (ddt, J = 20.7, 13.7, 7.0 Hz, 1H), 1.21 - 1.05 (m, 4H), 1.00 - 0.83 (m, 3H) 125 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.69 - 7.59 (m, 2H), 7.26 (m, 1H) , 6.85 (m, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.78 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.26 - 1.10 (m, 4H), 0.92 (s, 9H). 126 1HNMR (400 MHz, Methanol) δ 8.48 (s, 1H), 8.35 (dd, J = 4.8, 1.9 Hz, 1H), 7.96 (s, 1H), 7.88 ( dd, J = 7.7, 1.9 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.39 (m, 1H), 6.96 (d, J = 2 .3 Hz, 1H), 4.02 (m, 1H), 3.96 - 3.78 (m, 2H), 1.27 - 1.07 (m, 4H), 0.96 (s, 9H) . 131 1HNMR (400 MHz, Methanol-d4) δ 8.61 (m, 1H), 8.47 (s, 1H), 8.26 (m, 1H), 8.04 (s, 1H), 7.71 ( m, 1H), 7.62 (m, 1H), 6.96 (m, 1H), 6.33 (s, 1H), 4.03 - 3.83 (m, 3H), 2.73 (s , 3H), 1.27 - 1.12 (m, 4H), 0.93 (s, 9H). 132 1HNMR (400 MHz, Methanol^4) δ 8.62 (m, 1H), 8.48 (s, 1H), 8.28 (m, 1H), 8.05 (s, 1H), 7.73 ( m, 1H), 7.63 (d, J = 2.4 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 4.03 - 3.80 (m, 3H), 2.74 (s, 3H), 1.27 - 1.12 (m, 4H), 0.94 (s, 9H).

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142 1H NMR (400 MHz, Methanol-04) δ 8.51 (s, 1H), 8.30 (d, J = 2.5 Hz, 1H), 8.00 (ddd, J = 8.5, 7, 5, 2.6 Hz, 1H), 7.92 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H) , 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 4.13 (d, J = 14.0 Hz, 1H), 3.89 (m, 1H), 3.82 ( d, J = 14.0 Hz, 1H), 1.25 - 1.10 (m, 4H), 0.98 (s, 9H) 143 1HNMR (400 MHz, DMSO-yb) δ 9.52 (s, 1H), 8.93 (d, J = 2.1 Hz, 1H), 8.91 (d, J = 1.9 Hz, 1H) , 8.48 (s, 1H), 8.33 (t, J = 2.1 Hz, 1H), 8.14 (s, 1H), 7.99 (d, J = 12.5 Hz, 2H) , 7.67 (d, J = 2.3 Hz, 1H), 7.49 (s, 1H), 7.17 (d, J = 2.4 Hz, 1H), 4.00 - 3.89 ( m, 1H), 1.16 - 1.10 (m, 2H), 1.10 - 1.04 (m, 2H). 144 1HNMR (400 MHz, Methanol-d4) δ 8.61 (m, 1H), 8.38 (m, 1H), 8.29 (m, 1H), 8.04 (m, 1H), 7.71 ( m, 1H), 7.59 (m, 1H), 7.38 - 7.27 (m, 5H), 7.18 (m, 1H), 5.66 (m, 1H), 3.92 (m , 1H), 2.77 (s, 3H), 2.28 - 1.95 (m, 2H), 1.25 - 1.07 (m, 4H), 1.03 - 0.92 (m, 3H ). 155 1H NMR (400 MHz, MethanolD4) δ 8.43 (d, J = 1.0 Hz, 1H), 8.33 (d, J = 2.5 Hz, 1H), 8.00 (ddd, J = 8 ,5, 7.6, 2.6 Hz, 1H), 7.94 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.41 - 7.25 (m, 6H), 7.07 (ddd, J = 8.5, 2.7, 0.7 Hz, 1H), 5.77 (t, J = 7.2 Hz, 1H), 3.95 - 3.83 (m, 1H), 2.26-2.03 (m, 2H), 1.26 - 1.11 (m, 4H), 1.03 (t, J = 7.3 Hz, 3H) 174 1H NMR (400 MHz, DMSO-yb) δ 8.86 - 8.82 (m, 1H), 8.59 (dd, J = 5.0, 1.6 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 5.4 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.52 (dd, J = 8.0, 4.9 Hz, 1H), 7.37 (dt, J = 9.7, 3.8 Hz, 3H), 7.35 - 7.28 (m, 1H), 7.27 - 7.21 (m, 2H), 7.21 - 7.15 (m, 3H), 6.41 (t, J = 8.6 Hz, 1H), 5.46 (q, J = 7.7 Hz, 1H), 4.72 (t, J = 7.4 Hz, 2H) , 4.58 (dd, J = 7.8, 5.1 Hz, 2H), 4.42 - 4.29 (m, 1H), 4.17 (s, 1H), 3.77 (3, 1H ), 3.25 (m, 1H), 2.70 - 2.55 (m, 2H), 2.18 - 2.03 (m, 1H), 2.03 - 1.82 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).

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175 1H NMR (400 MHz, DMSOLb) δ 8.87 - 8.79 (m, 1H), 8.64 - 8.54 (m, 1H), 8.23 (s, 2H), 8.08 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.6 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.29 - 7.21 (m, 2H), 7.19 (dt, J = 4.5, 3.3 Hz, 2H), 6.49 (d, J = 7.8 Hz, 1H), 5.79 (d, J = 2.0 Hz, 2H), 5 .46 (q, J = 7.5 Hz, 1H), 5.35 (s, OH), 2.23 - 2.06 (m, 1H), 2.02 - 1.84 (m, 1H), 0.93 (t, J = 7.2 Hz, 3H). 176 1HNMR (400 MHz, DMSO-yb) δ 9.83 (s, 1H), 8.90 (s, 1H), 8.65 (s, 1H), 8.25 (s, 1H), 8.23 - 8.09 (m, 2H), 7.62 (dd, J = 3.7, 2.1 Hz, 2H), 7.47 (d, J = 8.6 Hz, 1H), 7.42 - 7 .33 (m, 2H), 7.30 - 7.16 (m, 4H), 6.50 (d, J = 6.5 Hz, 1H), 5.49 (q, J = 7.7 Hz, 1H), 5.43 - 5.32 (m, 1H), 4.46 (t, J = 7.0 Hz, 2H), 3.55 (m, 2H), 3.22 - 3.09 (m , 2H), 3.03 - 2.90 (m, 2H), 2.27 - 2.07 (m, 3H), 2.07 - 1.77 (m, 5H), 0.95 (t, J = 7.3 Hz, 3H) 177 1HNMR (400 MHz, DMSO-yb) δ 8.90 (s, 1H), 8.67 (s, 1H), 8.28 - 8.13 (m, 3H), 7.68 (s, 1H), 7.60 (dd, J = 4.8, 2.1 Hz, 1H), 7.56 - 7.43 (m, 2H), 7.40 - 7.28 (m, 2H), 7.28 - 7.12 (m, 5H), 6.50 (d, J = 5.9 Hz, 1H), 5.47 (q, J = 7.7 Hz, 1H), 4.86 (dd, J = 5 ,2, 4.1 Hz, 1H), 4.78-4.63 (m, 3H), 2.11 (dt, J= 13.6, 7.5 Hz, 1H), 1.91 (ddp, J = 20.8, 14.0, 7.3 Hz, 1H), 0.97 - 0.77 (m, 3H) 181 1H NMR (400 MHz, DMSO-yb) δ 8.88 (dd, J = 10.1, 2.1 Hz, 1H), 8.64 (ddd, J = 15.1, 5.2, 1.5 Hz, 1H), 8.25 (s, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.22 (s, 2H), 8.20 (s, 1H), 7, 66 (dd, J = 8.1, 5.2 Hz, 1H), 7.60 (dd, J = 4.5, 2.1 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.33 (s, 1H), 7.28 - 7.20 (m, 3H), 7, 18 (dt, J = 8.0, 1.8 Hz, 2H), 6.50 (d, J = 5.7 Hz, 1H), 5.48 (q, J = 7.6 Hz, 1H), 5.05 (dtd, J = 18.1, 7.0, 4.2 Hz, 1H), 4.83 - 4.72 (m, 1H), 4.72 - 4.59 (m, 1H), 2.21 - 2.06 (m, 1H), 2.04 - 1.85 (m, 1H), 1.49 (d, J = 8.0 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H). 189 1HNMR (400 MHz, DMSOLb) δ 9.61 (s, 1H), 8.80 (s, 3H), 8.49 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H) , 8.17 (s, 1H), 8.09 - 7.98 (m, 2H), 7.81 (s, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7, 65 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 6.33 (d, J = 6.4 Hz, 1H), 4.87 ( dd, J = 5.2, 4.0 Hz, 1H), 4.79 - 4.63 (m, 3H)

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190 1HNMR (400 MHz, DMSO-C16) δ 8.84 (dd, J = 14.0, 2.2 Hz, 1H), 8.64 - 8.52 (m, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 8.05 (d, J = 6.7 Hz, 1H), 7.65 - 7.54 (m , 2H), 7.46 (d, J = 9.5 Hz, 1H), 7.43 - 7.38 (m, 1H), 7.38 - 7.31 (m, 2H), 7.28 - 7.21 (m, 2H), 7.21-7.15 (m, 3H), 6.48 (d, J = 6.9 Hz, 1H), 5.48 (q, J = 7.7 Hz , 1H), 5.35 (s, OH), 4.68 (d, J = 2.0 Hz, 2H), 4.50 (dd, J = 6.2, 4.5 Hz, 3H), 4 .41 (dd, J = 6.7, 3.4 Hz, 2H), 2.12 (dt, J = 14.5, 7.4 Hz, 1H), 2.04 - 1.78 (m, 1H ), 0.94 (t, J = 7.3 Hz, 3H), 0.85 (t, J = 7.2 Hz, 1H). 191 1H NMR (400 MHz, DMSO^b) δ 8.88 (s, 1H), 8.67 (s, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.20 (d , J = 7.8 Hz, 1H), 8.17 (d, J = 6.2 Hz, 1H), 7.67 (dt, J = 7.5, 3.2 Hz, 1H), 7.59 (dd, J = 4.1, 2.1 Hz, 1H), 7.44 (t, J = 8.1 Hz, 2H), 7.40 - 7.30 (m, 1H), 7.29 ( d, J = 2.3 Hz, 1H), 7.26 - 7.20 (m, 2H), 7.20 - 7.13 (m, 3H), 6.45 (d, J = 4.9 Hz , 1H), 5.47 (q, J = 7.6 Hz, 1H), 4.03 - 3.92 (m, 1H), 2.18 - 2.02 (m, 1H), 2.02 1 .82 (m, 1H), 1.18-1.13 (m, 2H), 1.13 - 1.10 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). 192 1H NMR (400 MHz, DMSSMb) δ 8.89 (dd, J = 10.6, 2.1 Hz, 1H), 8.65 (ddd, J = 15.0, 5.2, 1.5 Hz, 1H), 8.24 (dd, J = 6.1, 3.6 Hz, 3H), 7.72 - 7.65 (m, 1H), 7.60 (dd, J = 4.3, 2, 1 Hz, 1H), 7.52 - 7.38 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.28 - 7.19 (m, 3H), 7, 16 (dq, J = 5.6, 1.6 Hz, 2H), 6.47 (m, 1H), 5.49 (q, J = 7.6 Hz, 1H), 5.35 (q, J = 7.5 Hz, OH), 2.11 (dq, J = 15.3, 7.6 Hz, 1H), 1.92 (ddq, J = 21.0, 14.1, 7.2 Hz, 1H), 1.59 (d, J = 1.0 Hz, 9H), 0.94 (t, J = 7.3 Hz, 3H). 193 1H NMR (400 MHz, DMSSMb) δ 8.87 (d, J = 11.9 Hz, 1H), 8.64 (d, J = 5.1 Hz, 1H), 8.23 (d, J = 2 .6 Hz, 1H), 8.21-8.13 (m, 2H), 7.63 (dd, J = 8.0, 5.1 Hz, 1H), 7.60 (dd, J = 4, 0, 2.2 Hz, 1H), 7.41 (dd, J = 15.7, 7.3 Hz, 2H), 7.38 - 7.33 (m, 1H), 7.33 - 7.27 (m, 1H), 7.27 - 7.20 (m, 2H), 7.20 - 7.14 (m, 2H), 6.48 (s, 1H), 5.48 (q, J = 7 .6 Hz, 1H), 4.80 (h, J = 6.7 Hz, 1H), 2.11 (dq, J = 14.8, 7.3 Hz, 1H), 2.00 1.85 ( m, 1H), 1.47 (d, J = 8.0 Hz, 6H), 0.94 (t, J = 7.3 Hz, 3H).

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194 1H NMR (400 MHz, DMSO^b) δ 8.93 - 8.83 (m, 1H), 8.64 (ddd, J = 14.7, 5.1, 1.5 Hz, 1H), 8, 36 (d, J = 7.0 Hz, 1H), 8.25 (d, J = 1.5 Hz, 1H), 8.23-8.16 (m, 1H), 7.65 (dd, J = 8.0, 5.1 Hz, 1H), 7.60 (dd, J = 4.0, 2.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7 .41 - 7.33 (m, 1H), 7.32 (d, J = 2.3 Hz, 1H), 7.29 - 7.20 (m, 2H), 7.20 - 7.14 (m , 2H), 6.51 (d, J = 5.6 Hz, 1H), 5.83 (tt, J = 7.6, 6.0 Hz, 1H), 5.52 - 5.44 (m, 1H), 4.99 (ddd, J = 7.7, 6.8, 0.8 Hz, 2H), 4.88 (m, 2H), 2.18 - 2.04 (m, 1H), 2 .04 - 1.84 (m, 1H), 0.93 (t, J = 7.2 Hz, 2H). 195 1H NMR (400 MHz, DMSSMb) δ 8.86 - 8.83 (m, 1H), 8.60 (dd, J = 5.0, 1.6 Hz, 1H), 8.26 - 8.21 ( m, 1H), 8.20 (s, 1H), 8.10 - 8.04 (m, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.56 (dd, J = 8.0, 5.0 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.37 - 7.31 ( m, 2H), 7.26 - 7.16 (m, 6H), 6.55 - 6.44 (m, 2H), 5.60 - 5.43 (m, 4H), 2.18 - 2, 03 (m, 1H), 2.03 - 1.83 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H). 212 1H NMR (400 MHz, DMSSMb) δ 8.46 (d, J = 27.8 Hz, 2H), 8.28 (d, J = 7.1 Hz, 2H), 7.78 - 7.08 (m , 6H), 6.79 (s, 4H), 5.59 - 5.33 (m, 1H), 4.92 (t, J = 6.8 Hz, 2H), 3.79 (t, J = 6.9 Hz, 2H), 3.68 - 3.56 (m, 1H), 3.49 - 3.27 (m, 4H), 3.22 - 3.06 (m, 1H), 2.99 (d, J = 2.4 Hz, 3H), 2.22 - 2.06 (m, 1H), 2.06 - 1.82 (m, 1H), 1.29 1.23 (m, 3H) , 1.17 (t, J = 7.1 Hz, 3H), 0.99 - 0.80 (m, 3H) 213 1HNMR (400 MHz, DMSSMb) δ 8.31 - 8.16 (m, ZH), 7.72 (s, 1H), 7.61 (dd, J = 4.6, 2.1 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.43 - 7.13 (m, 7H), 6.55 - 6.44 (m, 1H), 5.49 (q, J = 7.6 Hz, 1H), 5.04 - 4.92 (m, 1H), 2.24 - 2.05 (m, 3H), 2.05 - 1.60 (m, 8H), 1.29 - 1, 20 (m, 1H), 0.95 (t, J = 7.3 Hz, 3H) 223 1HNMR (400 MHz, DMSO-de) δ 9.52 (s, 1H), 9.18 (s, 1H), 8.44 (s, 1H), 8.07 (s, 1H), 7.68 ( d, J = 3.0 Hz, 1H), 7.62 - 7.50 (m, 1H), 7.47 - 7.19 (m, 3H), 6.10 (d, J = 8.1 Hz , 1H), 4.75 (m, 5H), 3.62 (m, 8H), 3.21 - 3.03 (m, 2H), 2.77 (m, 1H), 2.44 - 2, 13 (m, 4H), 1.46 - 1.15 (m, 9H).

- 337 045220

237 1H NMR (400 MHz, DMSO-C16) δ 9.21 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 7.60 (d , J = 2.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.40 (s, 2H), 7.38 - 7.11 (m, 4H), 6 .36 (d, J = 7.8 Hz, 1H), 5.81 - 5.70 (m, 1H), 4.90 - 4.78 (m, 1H), 4.70 (m, 4H), 3.68 (d, J = 12.3 Hz, ZN), 3.14 (d, J = 12.0 Hz, ZN), 2.44 - 2.24 (m, 5H), 1.68 (d , J = 6.7 Hz, ZN), 1.36 (s, 9H). 238 1H NMR (400 MHz, DMSOM) δ 8.23 (d, J = 2.3 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.63 (dd, J = 5 ,4, 2.1 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.55 (s, 1H), 7.41 (s, 1H), 7.34 - 7 .26 (m, 4H), 7.23 (ddd, J = 8.6, 5.2, 2.3 Hz, 2H), 6.38 (d, J = 6.3 Hz, 1H), 5, 76 (q, J = 7.1 Hz, 1H), 4.79 - 4.65 (m, 4H), 4.54 - 4.40 (m, 1H), 3.07 - 2.70 (m, 3H), 1.69 (d, J = 6.6 Hz, ZN). 241 1H NMR (400 MHz, DMSSMb) δ 9.44 (d, J = 4.9 Hz, 1H), 9.16 (s, 1H), 8.41 (s, 1H), 8.08 (s, 1H ), 7.67 (s, 1H), 7.51 (t, J = 7.5 Hz, 1H), 7.44 - 7.30 (m, 3H), 7.30 - 7.22 (m, 2H), 6.12 (d, J = 8.3 Hz, 1H), 4.92 (s, OH), 4.88 - 4.76 (m, 1H), 4.71 (s, 3H), 3.65 (d, J = 12.0 Hz, 2H), 3.23 - 3.06 (m, 2H), 2.82 (s, 1H), 2.43 - 2.30 (m, 2H) , 2.25 (d, J = 13.8 Hz, 2H), 1.35 (s, 9H). 253 1HNMR (400 MHz, Methanol) δ 8.87 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H) , 7.47 (t, J = 6.7 Hz, 1H), 7.35-7.18 (m, 3H), 6.34 (s, 1H), 4.84 - 4.76 (m, 1H ), 3.80 (d, J = 12.4 Hz, 2H), 3.27 - 3.16 (m, 2H), 2.53 - 2.36 (m, 4H), 2.42 (s, 3H), 1.46 (s, 9H) 258 1H NMR (400 MHz, DMSSMb) δ 9.17 (s, 1H), 8.88 (d, J = 11.8 Hz, 1H), 8.63 (d, J = 15.9 Hz, 1H), 8.37 - 8.05 (m, 3H), 7.68 - 7.10 (m, 10H), 6.49 (d, J = 7.0 Hz, 1H), 5.53 - 5.30 ( m, 1H), 4.95 - 4.74 (m, 1H), 3.69 (d, J = 11.8 Hz, 2H), 3.15 (q, J = 11.6 Hz, 2H), 2.46 - 2.20 (m, 4H), 2.14 (dt, J = 14.4, 7.4 Hz, 1H), 1.94 (tt, J = 13.8, 7.5 Hz, 1H), 1.37 (s, 9H), 1.10 - 0.76 (m, 3H) 264 1HNMR (400 MHz, Methanol^4) δ 8.47 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.59 - 7, 53 (m, 1H), 7.37 - 7.34 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 5.85 (s, 1H), 5.37 (s , 1H), 4.84 - 4.74 (m, 1H), 4.14 (s, 2H), 3.81 (d, J = 12.4 Hz, 2H), 3.77 (t, J = 5.6 Hz, 2H), 3.42 (s, 1H), 3.30 - 3.16 (m, 2H), 2.50 - 2.35 (m, 4H), 2.18 (d, J = 17.4 Hz, 1H), 2.06 (d, J = 17.5 Hz, 1H), 1.47 (s, 9H)

- 338 045220

275 1HNMR (400 MHz, DMSO-ab) δ 9.40 (s, 1H), 9.02 (d, J = 15.9 Hz, 2H), 8.40 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 6.6, 2.7 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.31 ( s, 1H), 7.29 (d, J = 2.3 Hz, 1H), 7.28 - 7.20 (m, 2H), 6.11 (d, J = 8.6 Hz, 1H), 4.31 (d, J = 5.2 Hz, 2H), 3.33 (s, 2H), 2.88 - 2.72 (m, 1H), 2.72 - 2.56 (m, 1H) . 279 1HNMR (400 MHz, DMSSMb) δ 9.41 (s, 1H), 9.03 (s, 2H), 8.40 (s, 1H), 8.21 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 6.5, 2.7 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.32 ( s, 1H), 7.30 (t, J = 1.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.22 (d, J = 9.6 Hz, 2H), 6.11 (d, J = 8.6 Hz, 1H), 5.81 (tt, J = 7.6, 6.0 Hz, 1H), 5.04 - 4.95 (m, 2H), 4 .86 (ddd, J = 6.8, 6.0, 0.7 Hz, 2H), 4.32 (m, 2H), 3.34 (m, 2H), 2.89 - 2.68 (m , 3H). 282 1HNMR (400 MHz, MeTaHon-d4) δ 8.66 (m, 1H), 8.49 (m, 2H), 8.09 (s, 1H), 7.87 (m, 1H), 7.68 ( m, 1H), 7.40 (m, 1H), 7.29 - 7.19 (m, 2H), 7.06 (m, 1H), 6.31 (s, 1H), 4.97 - 4 .86 (m, 1H), 2.69 (s, 3H), 1.56 (m, 6H). 283 1HNMR (400 MHz, MeTaHon-d4) δ 8.66 (m, 1H), 8.45 (m, 2H), 8.17 (s, 1H), 7.84 (m, 1H), 7.67 ( m, 1H), 7.39 (m, 1H), 7.38 - 7.19 (m, 2H), 7.09 (m, 1H), 6.34 (s, 1H), 4.97 - 4 .86 (m, 1H), 3.80 (m, 2H), 3.23 (m, 2H), 2.70 (s, 3H), 2.48 - 2.41 (m, 4H), 1, 46 (s, 9H). 301 1HNMR (400 MHz, DMSSMb) δ 9.65 (s, 1H), 8.46 (s, 1H), 8.05 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H) , 7.59 (dd, J = 6.6, 2.6 Hz, 1H), 7.50 (t, J = 9.0 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.34 (ddd, J = 8.8, 4.2, 2.6 Hz, 1H), 7.20 (d, J = 22.3 Hz, 1H), 6.78 (s, 1H ), 6.07 (s, 1H), 4.83 (p, J = 6.7 Hz, 1H), 3.70 (t, J = 4.7 Hz, 4H), 3.35 (dd, J = 6.1, 3.7 Hz, 4H), 1.49 (d, J = 8.0 Hz, 65H). 302 1HNMR (400 MHz, DMSSMb) δ 9.68 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H) , 7.60 (dd, J = 6.6, 2.6 Hz, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35 (ddd, J = 8.6, 4.3, 2.6 Hz, 1H), 6.80 (s, 1H), 6.12 (s, 1H), 5.94 - 5 .83 (m, 1H), 5.02 (t, J = 7.3 Hz, 2H), 4.92 (dt, J = 9.8, 6.6 Hz, 2H), 3.70 (t, J = 4.7 Hz, 4H), 3.35 (dd, J = 6.0, 3.7 Hz, 4H).

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306 1HNMR (400 MHz, MethanolU4) δ 8.89 (s, 1H), 8.54 (s, 1H), 7.96 (s, 1H), 7.67 (d, J = 2.4 Hz, 1H) , 7.63 - 7.55 (m, 1H), 7.40 - 7.30 (m, 3H), 6.35 (s, 1H), 4.83 (m, 1H), 2.40 (s , 3H), 1.54 (dd, J = 6.7, 0.7 Hz, 6H) 307 1HNMR (400 MHz, MethanolU4) δ 8.85 (s, 1H), 8.49 (s, 1H), 7.99 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H) , 7.47 (dd, J = 6.4, 2.5 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.23 (d, J = 2.4 Hz, 1H), 6.32 (s, 1H), 4.82 - 4.75 (m, 1H), 3.81 (d, J = 12.7 Hz, 2H), 3.32 3.17 (m, 2H), 2.51 - 2.38 (m, 4h), 2.40 (s, 3H), 1.46 (s, 9H) 308 1HNMR (400 MHz, DMSUB) δ 9.48 (s, 1H), 8.93 - 8.80 (m, 1H), 8.67 (dd, J = 5.2, 1.5 Hz, 1H), 8.44 (s, 1H), 8.24 (d, J = 8.1 Hz, 1H), 7.94 (s, 1H), 7.82 - 7.65 (m, 2H), 7.58 (d, J = 8.8 Hz, 1H), 7.53 (dd, J = 6.6, 2.6 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7 .34 - 7.24 (m, 2H), 6.32 (d, J = 7.4 Hz, 1H) 310 1HNMR (400 MHz, MethanolU4) δ 8.52 (s, 1H), 8.23 (s, 1H), 8.03 (s, 1H), 7.90 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.63 (dd, J = 6.6, 2.4 Hz, 1H), 7.46 - 7.34 (m, 3H), 6.11 (s, 1H ), 1.65 (s, 9H) 311 1HNMR (400 MHz, MethanolU4) δ 8.96 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H) , 7.45 (d, J = 6.7 Hz, 1H), 7.41 (s, 1H), 7.35 - 7.18 (m, 3H), 6.33 (s, 1H), 4, 89 - 4.80 (m, 1H), 3.84 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H) 312 1HNMR (400 MHz, MethanolU4) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.90 (s, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 6.4, 2.4 Hz, 1H), 7.43 - 7.33 (m, 3H), 6.11 (s, 1H ), 4.86 - 4.77 (m, 1H), 1.55 (d, J = 6.8 Hz, 6H) 316 1H NMR (400 MHz, DMSUB) δ 9.61 (s, 1H), 9.11 (d, J = 1.9 Hz, 1H), 8.59 8.55 (m, 1H), 8.45 ( s, 1H), 8.14 (s, 1H), 7.83 (td, J = 7.6, 1.8 Hz, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.65 - 7.59 (m, 1H), 7.57 - 7.44 (m, 2H), 7.43 - 7.32 ( m, 2H), 7.30 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H), 5.74 (s, 2H). 317 1HNMR (400 MHz, DMSUB) δ 9.53 (s, 1H), 8.56 (d, J = 5.0 Hz, 1H), 8.51 (d, J = 1.5 Hz, 1H), 8 .49 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 1.7 Hz, 1H), 7.85 (td, J = 7.8, 2.0 Hz, 1H) , 7.71 (d, J = 2.3 Hz, 1H), 7.67 - 7.56 (m, 2H), 7.54 - 7.43 (m, 3H), 7.43 - 7.29 (m, 3H), 6.50 (d, J = 8.0 Hz, 1H), 5.77 (d, J = 1.9 Hz, 2H).

- 340 045220

331 1HNMR (400 MHz, Methanol-d4) δ 8.55 (m, 1H), 8.35 (m, 1H), 7.92 (s, 1H), 7.89 (m, 1H), 7.68 ( m, 1H), 7.57 (m, 1H), 7.41 (m, 1H), 7.36 (m, 2H), 7.26 (m, 1H), 6.32 (s, 1H), 4.48 (m, 2H), 3.92 (m, 2H). 332 1HNMR (400 MHz, DMSO-C16) δ 8.50 (s, 1H), 8.48 (d, J = 1.1 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H) , 7.72 (d, J = 2.3 Hz, 1H), 7.57 (dd, J = 6.5, 2.7 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.41 (d, J = 1.3 Hz, 1H), 7.33 (dt, J = 7.6, 3.4 Hz, 1H), 6.49 (s, 1H), 4.84 (t , J = 6.7 Hz, 2H), 3.83 (s, 4H), 3.70 (t, J = 6.7 Hz, 2H), 3.24 (d, J = 37.5 Hz, 4H ). 333 1H NMR (400 MHz, DMSSMb) δ 9.51 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.48 (s, 1H), 8.14 (s, 1H ), 7.72 (d, J = 2.2 Hz, 1H), 7.60 (dd, J = 6.8, 2.8 Hz, 2H), 7.56 7.46 (m, 2H), 7.41 (s, 1H), 7.40 - 7.32 (m, 1H), 6.48 (d, J = 8.4 Hz, 1H), 4.45 (t, J = 5.3 Hz , 2H), 3.81 (t, J = 5.3 Hz, 2H). 334 1H NMR (400 MHz, DMSSMb) δ 9.43 (s, 1H), 8.67 (s, 1H), 8.48 (d, J = 4.7 Hz, 1H), 8.40 (s, 1H ), 7.98 (d, J = 0.5 Hz, 1H), 7.86 - 7.80 (m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 6.6, 2.6 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.41 - 7.36 (m, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.29 - 6.07 (m, 1H), 4.42 ( t, J = 6.3 Hz, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.29 (s, 4H), 1.48-1.21 (m, 6H) 336 1HNMR (400 MHz, DMSO-de) δ 9.42 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.46 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.02 (s, 1H), 7.88 - 7.80 (m, 1H), 7.68 (d, J = 2.2 Hz, 1H ), 7.53 (dd, J = 6.6, 2.7 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.44 (t, J = 9.0 Hz , 1H), 7.37 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 7.9, 4.4 Hz, 1H), 6.19 (d, J = 9.0 Hz, 1H), 5.09 - 4.99 (m, 1H), 4.38 (t, J = 5.3 Hz, 2H), 3.82-3.68 (m, 2H) 337 1H NMR (400 MHz, DMSO-de) δ 9.51 (s, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.48 (s, 1H), 8.13 (s , 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.65 - 7.58 (m, 2H), 7.53 - 7.45 (m, 2H), 7.43 ( d, J = 1.4 Hz, 1H), 7.34 (dt, J = 8.6, 3.4 Hz, 1H), 6.48 (d, J = 8.3 Hz, 1H), 4, 57 (t, J = 5.1 Hz, 2H), 3.76 (t, J = 5.1 Hz, 2H), 3.24 (s, 2H).

-341 045220

338 1H NMR (400 MHz, DMSOLb) δ 9.59 (s, 1H), 8.50 (d, J = 2.2 Hz, 2H), 8.22 (d, J = 1.6 Hz, 1H), 7.72 (d, J = 2.2 Hz, 1H), 7.61 (dt, J = 6.5, 3.9 Hz, 2H), 7.50 (dd, J = 9.8, 8, 2 Hz, 1H), 7.46 (dd, J = 4.2, 2.1 Hz, 2H), 7.35 (ddd, J = 8.6, 4.3, 2.5 Hz, 1H), 6.46 (q, J = 2.4 Hz, 1H), 4.86 (p, J = 6.7 Hz, 1H), 1.52 (d, J = 8.0 Hz, 6H). 339 1H NMR (400 MHz, DMSOLb) δ 9.53 (s, 1H), 8.50 (d, J = 1.4 Hz, 1H), 8.48 (s, 1H), 8.39 (s, 1H ), 7.71 (d, J = 2.2 Hz, 1H), 7.66 - 7.55 (m, 2H), 7.54 - 7.42 (m, 3H), 7.34 (ddd, J = 8.6, 4.1, 2.4 Hz, 1H), 6.49 (d, J = 7.9 Hz, 1H), 5.88 (tt, J = 7.3, 6.1 Hz , 1H), 5.03 (t, J = 7.3 Hz, 2H), 4.93 (q, J = 6.3 Hz, 2H). 340 1HNMR (400 MHz, DMSOLb) δ 9.42 (s, 1H), 8.71 - 8.64 (m, 1H), 8.47 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 7.99 (d, J = 0.5 Hz, 1H), 7.84 (dt, J = 7.9, 1.9 Hz, 1H), 7.68 (d , J = 2.2 Hz, 1H), 7.52 (dd, J = 6.6, 2.6 Hz, 1H), 7.50 - 7.41 (m, 2H), 7.38 (ddd, J = 7.9, 4.8, 0.8 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.27 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 6.18 (d, J = 8.9 Hz, 1H), 4.50 (t, J = 5.2 Hz, 2H), 3.77 (dd, J = 5, 6, 4.8 Hz, 2H), 3.53 - 3.41 (m, 2H), 3.36 - 3.24 (m, 2H), 3.13 (s, 3H) 342 1H NMR (400 MHz, MethanolL4) δ 8.97 (s, 1H), 8.45 (s, 1H), 8.26 (s, 1H), 7.64 (d, J = 2.4 Hz, 1H ), 7.51 - 7.39 (m, 2H), 7.39 - 7.25 (m, 3H), 6.36 (s, 1H), 4.92 4.85 (m, 1H), 3 .88 (s, 3H), 3.80 (d, J = 12.6 Hz, 2H), 3.29 - 3.18 (m, 2H), 2.47 (m, 4H), 1.46 ( s, 9H) 345 1H NMR (400 MHz, DMSOLb) δ 9.92 (s, 1H), 9.40 (d, J = 8.6 Hz, 1H), 8.40 (d, J = 3.4 Hz, 1H), 8.04 (d, J = 11.0 Hz, 1H), 7.66 (dd, J = 10.6, 2.2 Hz, 1H), 7.54 7.39 (m, 2H), 7, 34 (s, 1H), 7.31-7.18 (m, 3H), 6.08 (dd, J = 29.6, 8.6 Hz, 1H), 4.78 (p, J = 6, 7 Hz, 1H), 4.57 (d, J = 15.6 Hz, 1H), 4.27 (s, 1H), 3.62 (s, 1H), 3.27 (d, J = 12, 0 Hz, 1H), 2.93 (s, 1H), 2.86 (d, J = 4.4 Hz, 3H), 2.80 (s, 1H), 1.45 (d, J = 8, 0 Hz, 6H). 346 1H NMR (400 MHz, DMSOLb) δ 8.39 (s, 1H), 8.01 (s, 1H), 7.65 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 6.6, 2.7 Hz, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.31 (s, 1H), 7.28 7.21 (m, 2H), 6.05 (s, 1H), 4.76 (p, J = 6.7 Hz, 1H), 4.29 (s, 2H), 3.31 (dq, J = 22.6, 6.6 Hz , 2H), 2.87 - 2.74 (m, 1H), 2.75 - 2.62 (m, 1H), 1.43 (d, J = 8.0 Hz, 6H).

-342045220

347 1H NMR (400 MHz, Methanol-04) δ 8.45 (s, 1H), 8.28 (s, 1H), 8.02 (s, 1H), 7.96 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 (dd, J = 6.4, 2.5 Hz, 1H), 7.43 - 7.24 (m, 2H), 7.20 ( d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.6, 2.4 Hz, 1H), 6.15 (s, 1H), 4.79 (d, J = 11 .9 Hz, 1H), 3.80 (d, J = 12.6 Hz, 2H), 3.22 (t, J = 12.5 Hz, 2H), 2.55 - 2.32 (m, 4H ), 1.46 (s, 9H) 348 1H NMR (400 MHz, Methanol^4) δ 8.43 (s, 1H), 8.25 - 8.20 (m, 1H), 8.03 (s, 1H), 7.92 (s, 1H) , 7.63 (d, J = 2.3 Hz, 1H), 7.53 - 7.46 (m, 1H), 7.38 - 7.28 (m, 3H), 6.11 (s, 1H ), 4.84 - 4.73 (m, 1H), 3.81 (d, J = 12.1 Hz, 2H), 3.23 (t, J = 13.2 Hz, 2H), 2.51 -2.35 (m, 4H), 1.46 (s, 9H) 349 1H NMR (400 MHz, Methanol^) δ 8.44 (s, 1H), 7.95 - 7.85 (m, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7, 66 (d, J = 2.3 Hz, 1H), 7.59 (s, 1H), 7.43 (dd, J = 6.7, 2.3 Hz, 1H), 7.35 (dd, J = 8.6, 2.0 Hz, 1H), 7.31 - 7.18 (m, 3H), 6.38 (s, 1H), 4.82 - 4.69 (m, 1H), 3, 79 (d, J = 12.6 Hz, 2H), 3.20 (t, J = 12.5 Hz, 2H), 2.57 - 2.29 (m, 5H), 1.45 (s, 9H ) 350 1HNMR (400 MHz, Methanol^4) δ 9.01 (d, J = 1.9 Hz, 1H), 8.49 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.50 - 7.39 (m, 1H), 7.31 - 7.17 (m, 2H), 6 .27 (s, 1H), 4.83 - 4.74 (m, 1H), 3.80 (d, J = 12.5 Hz, 2H), 3.22 (t, J = 12.7 Hz, 2H), 2.74 - 2.14 (m, 4H), 1.46 (s, 9H) 351 1HNMR (400 MHz, Methanol^4) δ 8.48 (s, 1H), 7.95 - 7.86 (m, 2H), 7.75 - 7.65 (m, 2H), 7.55 - 7 .46 (m, 2H), 7.40 - 7.26 (m, 5H), 6.45 (s, 1H), 4.79 (m, 1H), 3.78 (d, J = 12.6 Hz, 2H), 3.25 - 3.14 (m, 2H), 2.47 - 2.31 (m, 4H), 1.45 (s, 9H) 352 1H NMR (400 MHz, DMSOM) δ 9.06 (q, J = 1.8 Hz, 1H), 8.39 (s, 1H), 8.08 (s, 1H), 7.69 (dd, J = 2.5, 1.2 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.56 - 7.51 (m, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.39 (t, J = 1.9 Hz, 1H), 7.28 (m, 1H), 6.36 (s, 1H), 4.76 (t, J = 6.8 Hz, 2H), 3.76 (m, 4H), 3.63 (t, J = 6.7 Hz, 2H), 3.17 (m, 4H).

- 343 045220

353 1HNMR (400 MHz, Methanol-d4) δ 9.02 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.38 - 7.30 (m, 3H), 6.32 (s, 1H), 4.79 (m , 1H), 3.80 (d, J = 12.6 Hz, 2H), 3.28 - 3.17 (m, 2H), 2.49 (d, J = 13.0 Hz, 2H), 2 .40 (d, J = 12.4 Hz, 2H), 1.46 (s, 9H) 354 1HNMR (400 MHz, Methanol-d4) δ 9.03 (d, J = 1.9 Hz, 1H), 8.46 (s, 1H), 7.97 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 5.7, 1.9 Hz, 1H), 7.37 - 7.30 (m, 3H), 6.31 (s, 1H), 4.86 - 4.80 (m, 1H), 3.60 - 3.50 (m, 2H), 3.22 (t, J = 11.0 Hz, 2H), 2.40 (d, J = 14.4 Hz, 2H), 2.34 - 2.24 (m, 2H) 355 1HNMR (400 MHz, DMSO16) δ 10.02 (s, 1H), 9.68 (s, 1H), 9.08 (s, 1H), 8.40 (s, 1H), 8.11 (s, 1H), 7.75 - 7.65 (m, 2H), 7.55 (dd, J = 6.6, 2.6 Hz, 1H), 7.51 - 7.39 (m, 2H), 7 ,30 (ddd, J = 8.8, 4.2, 2.6 Hz, 1H), 6.39 (s, 1H), 4.78 (t, J = 6.6 Hz, 2H), 3, 59 (dd, J = 7.9, 5.3 Hz, 2H), 2.77 (s, 7H). 356 1H NMR (400 MHz, DMSO-de) δ 9.52 (s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 7.96 (s , 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.55 (dd, J = 6.6, 2, 6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.29 (ddd, J = 8.8, 4.3, 2.7 Hz, 1H), 6.40 - 6.33 (m, 1H), 4.36 (t, J = 5.4 Hz, 3H), 3.73 (t, J = 5.4 Hz, 3H). 357 1H NMR (400 MHz, DMSO16) δ 9.54 (d, J = 2.1 Hz, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.39 (s, 1H), 8.01 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 6 .6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.28 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 6.33 (s, 1H), 4.77 (p, J = 6.7 Hz, 1H), 1.44 (d, J = 1.9 Hz, 3H), 1.43 (d, J = 1.9 Hz, 3H). 358 1H NMR (400 MHz, DMSO16) δ 9.52 (s, 1H), 9.05 (d, J = 1.9 Hz, 1H), 8.38 (s, 1H), 7.95 (s, 1H ), 7.69 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.54 (dd, J = 6.6, 2.6 Hz , 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.29 (ddd, J = 8.9, 4, 3, 2.7 Hz, 1H), 6.35 (s, 1H), 4.49 (t, J = 5.1 Hz, 2H), 3.68 (t, J = 5.2 Hz, 2H) , 3.18 (s, 4H).

-344045220

359 1H NMR (400 MHz, DMSO-46) δ 9.48 (s, 1H), 9.07 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.08 (s , 1H), 7.93 (s, 3H), 7.69 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.53 (dd , J = 6.6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.28 (ddd, J = 8.9, 4.3, 2.7 Hz, 2H), 6.37 (s, 1H), 4.56 (t, J = 6.3 Hz, 2H), 3.39 3 .25 (m, 2H). 360 1HNMR (400 MHz, DMSO-46) δ 9.47 (s, 1H), 9.37 (d, J = 10.0 Hz, 1H), 9.06 (d, J = 1.9 Hz, 1H) , 8.38 (s, 1H), 8.03 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H) , 7.52 (dd, J = 6.6, 2.6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.3 Hz, 1H), 7.37 - 7.25 (m, 2H), 6.35 (d, J = 7.3 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H), 3, 14 2.97 (m, 2H), 2.75 (s, 3H), 2.74 (s, 3H), 2.15 (p, J = 7.3 Hz, 2H). 361 1H NMR (400 MHz, DMSO-46) δ 9.59 (s, 1H), 9.04 (d, J = 1.9 Hz, 1H), 8.40 (s, 1H), 8.07 (s , 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.63 (dd, J = 2.1, 0.6 Hz, 1H), 7.55 (dd, J = 6, 6, 2.6 Hz, 1H), 7.45 (t, J = 9.0 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.29 (m, 1H) , 6.33 (s, 1H), 1.55 (s, 9H). 362 1H NMR (400 MHz, DMSO-46) δ 9.44 - 9.36 (m, 1H), 8.75 - 8.65 (m, 1H), 8.46 (dd, J = 4.8, 1 .6 Hz, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 7.92 - 7.80 (m, 1H), 7.68 (d, J = 2.3 Hz , 1H), 7.50 (dd, J = 6.6, 2.6 Hz, 1H), 7.49 - 7.40 (m, 2H), 7.37 (ddd, J = 7.9, 4 ,8, 0.8 Hz, 1H), 7.29 - 7.23 (m, 2H), 6.13 (d, J = 8.5 Hz, 1H), 4.53 - 4.37 (m, 1H), 2.92 (d, J = 10.6 Hz, 2H), 2.33 (t, J = 7.1 Hz, 2H), 2.09 - 1.86 (m, 6H), 1, 00 (t, J = 7.2 Hz, 3H). 363 1H NMR (400 MHz, DMSO-46) δ 9.51 (s, 1H), 9.06 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.20 (s , 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.54 (dd, J = 6.6, 2, 6 Hz, 1H), 7.44 (t, J = 9.0 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.28 (ddd, J = 8.9, 4.3, 2.7 Hz, 1H), 6.37 (s, 1H), 5.81 (tt, J = 7.6, 6.1 Hz, 1H), 4.96 (t, J = 7 .3 Hz, 2H), 4.85 (q, J = 6.6 Hz, 2H). 364 1H NMR (400 MHz, DMSO-46) δ 9.50 (s, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.38 (s, 1H), 8.16 (s , 1H), 7.68 (dd, J = 3.9, 2.1 Hz, 2H), 7.55 (dd, J = 6.7, 2.7 Hz, 1H), 7.49 - 7, 40 (m, 2H), 7.29 (ddd, J = 8.6, 4.3, 2.7 Hz, 1H), 6.39 (s, 1H), 5.77 (s, 2H).

- 345 045220

365 1HNMR (400 MHz, DMSOLb) δ 9.38 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H) , 7.57 - 7.49 (m, 3H), 7.45 - 7.37 (m, 2H), 7.26 (ddd, J = 8.8, 4.2, 2.6 Hz, 1H) , 7.16 (dt, J = 3.8, 1.1 Hz, 1H), 6.43 (d, J = 8.6 Hz, 1H), 4.53 -4.39 (m, 1H), 2.91 (d, J = 10.8 Hz, 2H), 2.33 (q, J = 6.9 Hz, 2H), 2.13 - 1.98 (m, 4H), 1.93 (dq , J = 11.7, 4.0, 3.5 Hz, 2H), 0.98 (t, J = 7.2 Hz, 3H). 369 1HNMR (400 MHz, DMSOLb) δ 9.40 (s, 1H), 8.70 (s, 1H), 8.56 - 8.30 (m, 2H), 8.14 (s, 1H), 7, 87 (dt, J = 8.0, 1.9 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.61 - 7.31 (m, 4H), 7.25 (qd, J = 4.1, 2.6 Hz, 2H), 6.12 (d, J = 8.4 Hz, 1H), 4.60 - 4.28 (m, 1H), 3.05 ( d, J = 10.9 Hz, 2H), 2.27 - 1.75 (m, 6H), 1.02 (s, 9H) 370 1H NMR (400 MHz, DMSOLb) δ 9.46 (s, 1H), 9.03 (d, J = 0.8 Hz, 1H), 8.95 (s, 1H), 8.44 (s, 1H ), 8.16 (s, 1H), 7.87 (t, J = 0.8 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.60 - 7.41 (m, 4H), 7.31 (dt, J = 8.8, 3.7 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.88 4.77 (m , 1H), 3.67 (d, J = 12.1 Hz, 2H), 3.20 - 3.09 (m, 2H), 2.39 (d, J = 13.8 Hz, 2H), 2 .25 (t, J = 12.8 Hz, 2H), 1.36 (s, 9H), 1.30 (s, 1H) 371 1HNMR (400 MHz, DMSOLb) δ 9.45 (s, 1H), 9.26 (s, 1H), 8.42 (s, 1H), 8.03 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.61 (d, J = 3.4 Hz, 1H), 7.48 - 7.42 (m, 2H), 7.39 (t, J = 9.0 Hz, 1H), 7.26 - 7.14 (m, 3H), 6.01 (d, J = 7.2 Hz, 1H), 4.72 (ddt, J = 11.8, 8.1, 4.3 Hz, 1H), 3.59 (d, J = 12.3 Hz, 2H), 3.24 - 2.97 (m, 4H), 2.35 - 2.28 (m, 2H), 2.26 - 2.06 (m, 2H), 1.22 (t, J = 7.3 Hz, 3H). 372 1H NMR (400 MHz, DMSOLb) δ 9.47 (s, 2H), 8.44 (d, J = 1.4 Hz, 1H), 8.43 (s, 1H), 8.17 (s, 1H ), 7.66 (d, J = 2.2 Hz, 1H), 7.58 - 7.47 (m, 2H), 7.47 - 7.37 (m, 4H), 7.27 (ddd, J = 8.9, 4.2, 2.7 Hz, 1H), 6.42 (d, J = 7.4 Hz, 1H), 4.77 (tt, J = 11.8, 4.1 Hz , 1H), 3.73 - 3.57 (m, 2H), 3.12 (tdd, J = 23.8, 18.1, 9.9 Hz, 4H), 2.42 - 2.28 (m , 2H), 2.28 - 2.12 (m, 2H), 1.23 (t, J = 7.2 Hz, 3H).

- 346 045220

373 1HNMR (400 MHz, DMSO-46) δ 9.53 (s, 3N), 9.03 (dd, J = 3.0, 0.8 Hz, 1H), 8.43 (s, 1H), 8, 20 (s, 2H), 7.88 (t, J = 0.8 Hz, 2H), 7.66 (d, J = 2.1 Hz, 2H), 7.61 - 7.42 (m, 8H ), 7.32 (ddd, J = 8.9, 5.6, 3.0 Hz, 2H), 6.54 (d, J = 8.4 Hz, 2H), 4.84 - 4.72 ( m, 2H), 3.63 (d, J = 12.3 Hz, 4H), 3.43 (s, 1H), 3.17 - 3.00 (m, 8H), 2.36 (d, J = 14.6 Hz, 4H), 2.23 (q, J = 12.8 Hz, 5H), 1.67 (ddt, J = 15.8, 11.1, 7.5 Hz, 4H), 0 .92 (td, J = 7.3, 5.5 Hz, 6H). 375 1H NMR (400 MHz, DMSO-ab) δ 9.46 (s, 1H), 9.02 (d, J = 0.8 Hz, 1H), 8.65 (s, 1H), 8.43 (s , 1H), 8.18 (s, 1H), 7.87 (t, J = 0.8 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.57 (dd , J = 6.6, 2.6 Hz, 1H), 7.52 - 7.40 (m, 3H), 7.35 - 7.26 (m, 1H), 6.51 (d, J = 8 .6 Hz, 1H), 4.86 - 4.76 (m, 1H), 3.41 (d, J = 13.0 Hz, 2H), 3.12 - 3.02 (m, 2H), 2 .28 (d, J = 13.5 Hz, 2H), 2.12 (d, J = 12.5 Hz, 2H) 381 1HNMR (400 MHz, DMSO-ab) δ 9.43 (s, 1H), 9.29 (s, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 7.66 ( d, J = 2.2 Hz, 1H), 7.52 (dd, J = 6.6, 2.6 Hz, 1H), 7.46 (t, J = 1.5 Hz, 1H), 7, 43 (t, J = 9.0 Hz, 2H), 7.39 (d, J = 2.4 Hz, 1H), 7.27 (ddd, J = 8.8, 4.2, 2.7 Hz , 1H), 7.04 - 6.97 (m, 1H), 6.35 (d, J = 8.3 Hz, 1H), 4.76 (tt, J = 11.9, 4.1 Hz, 1H), 3.62 (d, J = 12.4 Hz, 2H), 3.26 - 2.99 (m, 4H), 2.44 - 2.29 (m, 2H), 2.18 (ddt , J = 22.1, 13.3, 7.4 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). 382 1HNMR (400 MHz, DMSO-ab) δ 9.41 (s, 1H), 9.20 (s, 1H), 8.42 (s, 1H), 8.26 (s, OH), 8.13 ( s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.51 (dd, J = 6.6, 2.6 Hz, 1H), 7.48 7.37 (m, 4H), 7.26 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 6.90 (dd, J = 3.9, 0.9 Hz, 1H), 6.31 (d, J = 8.4 Hz, 1H), 4.84 - 4.66 (m, 1H), 3.62 (d, J = 12.7 Hz, 2H), 3.24 - 2.98 (m, 4H), 2.36 (d, J = 13.3 Hz, 2H), 2.17 (dd, J = 14.6, 11 .1 Hz, 2H), 1.23 (t, J = 7.3 Hz, 3H). 385 1HNMR (400 MHz, DMSO-ab) δ 9.42 (s, 1H), 8.64 (s, 1H), 8.42 (s, 2H), 8.12 (s, 1H), 7.65 ( 4, J = 2.2 Hz, 1H), 7.51 (44, J = 6.6, 2.6 Hz, 1H), 7.47 - 7.40 (m, 3H), 7.39 (4 , J = 2.4 Hz, 1H), 7.26 (444, J = 8.8, 4.2, 2.7 Hz, 1H), 7.00 (44, J = 1.6, 0.9 Hz, 1H), 6.35 (4, J = 8.4 Hz, 1H), 4.79 (tt, J = 11.0, 4.0 Hz, 1H), 3.39 (4, J = 13 .0 Hz, 2H), 3.06 (q, J = 11.9 Hz, 2H), 2.26 (4, J = 13.2 Hz, 2H), 2.19 - 2.01 (m, 2H ).

- 347 045220

386 1HNMR (400 MHz, DMSO-ab) δ 9.43 (s, 1H), 8.65 (s, 1H), 8.42 (s, 2H), 8.12 (s, 1H), 7.65 ( d, J = 2.2 Hz, 1H), 7.52 (dd, J = 6.6, 2.6 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.38 (d , J = 2.4 Hz, 1H), 7.26 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H) , 6.90 (dd, J = 3.8, 0.9 Hz, 1H), 6.31 (d, J = 8.1 Hz, 1H), 4.78 (ddt, J = 11.0, 8 ,1, 4.1 Hz, 1H), 3.39 (d, J = 12.7 Hz, 2H), 3.07 (q, J = 11.8 Hz, 2H), 2.26 (d, J = 13.4 Hz, 2H), 2.20 - 2.02 (m, 2H). 387 1HNMR (400 MHz, DMSO-yb) δ 9.43 (s, 1H), 8.61 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 18.2 Hz, 1H), 8.07 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 5.4 Hz, 1H), 7.44 - 7, 32 (m, 4H), 7.19 - 7.08 (m, 3H), 6.99 (d, J = 5.4 Hz, 1H), 6.22 (d, J = 7.2 Hz, 1H ), 4.76 (td, J = 11.2, 5.4 Hz, 1H), 3.37 (d, J = 13.4 Hz, 2H), 3.06 (t, J = 11.6 Hz , 2H), 2.22 (d, J = 13.7 Hz, 2H), 2.09 (t, J = 12.2 Hz, 2H). 389 1HNMR (400 MHz, DMSO-yb) δ 9.46 (s, 1H), 9.33 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.65 ( d, J = 2.2 Hz, 1H), 7.56 (dd, J = 5.3, 2.1 Hz, 1H), 7.42 - 7.33 (m, 4H), 7.13 (ddd , J = 8.7, 3.7, 2.3 Hz, 3H), 7.01 - 6.96 (m, 1H), 6.22 (d, J = 6.6 Hz, 1H), 4, 74 (ddt, J = 11.8, 8.2, 4.1 Hz, 1H), 3.60 (d, J = 12.3 Hz, 2H), 3.15 (qt, J = 11.5, 5.3 Hz, 3H), 3.04 (dd, J = 13.2, 10.0 Hz, 2H), 2.41 - 2.28 (m, 3H), 2.24 - 2.09 (m , 3H), 1.22 (t, J = 7.3 Hz, 3H). 400 1H NMR (400 MHz, DMSO-yb) δ 9.41 (s, 1H), 8.80 (s, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.41 (s , 1H), 8.25 - 8.06 (m, 2H), 7.74 - 7.57 (m, 2H), 7.56 - 7.14 (m, 8H), 6.86 (d, J = 6.5 Hz, 1H), 6.23 (d, J = 6.9 Hz, 1H), 5.25 (s, 1H), 5.04 (t, J = 9.8 Hz, 2H), 3.96 - 3.76 (m, 1H), 3.67 (d, J = 10.2 Hz, 1H), 3.59 - 3.37 (m, 2H), 2.47 2.21 (m , 2H). 401 1HNMR (400 MHz, DMSO-yb) δ 9.44 (s, 1H), 9.12 (brs, 2H), 8.74 (d, J = 2.2 Hz, 1H), 8.53 (dd, J = 4.9, 1.6 Hz, 1H), 8.41 (s, 1H), 8.21 (d, J = 6.3 Hz, 1H), 7.98 (d, J = 7.9 Hz, 1H), 7.66 (dd, J = 2.4, 1.3 Hz, 1H), 7.56 - 7.36 (m, 4H), 7.35 - 7.18 (m, 2H) , 6.24 (d, J = 8.2 Hz, 1H), 5.49 - 5.31 (m, 1H), 3.75 - 3.56 (m, 2H), 3.36 (t, J = 6.9 Hz, 2H), 2.48 (m, 1H), 2.36 - 2.19 (m, 1H).

- 348 045220

402 1H NMR (400 MHz, DMSO-C16) δ 10.01 (brs, 1H), 9.40 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.51 (dd , J = 5.0, 1.5 Hz, 1H), 8.41 (s, 1H), 8.21 (dd, J = 14.2, 7.1 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 2.1 Hz, 1H), 7.57 - 7.36 (m, 4H), 7.34 7.18 (m, 2H) , 6.21 (d, J = 8.0 Hz, 1H), 5.58 - 5.32 (m, 1H), 3.95 - 3.49 (m, 3H), 3.38-3.14 (m, 3H), 2.80-2.62 (m, 1H), 2.42-2.19 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H). 403 1HNMR (400 MHz, DMSSMb) δ 9.44 (s, 1H), 8.94 (s, 1H), 8.74 (dd, J = 2.3, 0.8 Hz, 1H), 8.62 ( dd, J = 4.9, 1.6 Hz, 1H), 8.44 (s, 1H), 7.97 (dt, J = 8.0, 1.9 Hz, 1H), 7.63 (d , J = 2.3 Hz, 1H), 7.56 (ddd, J = 8.0, 4.9, 0.8 Hz, 1H), 7.47 (dd, J = 6.6, 2.7 Hz, 2H), 7.44 - 7.38 (m, 2H), 7.26 (d, J = 2.4 Hz, 1H), 7.23 (ddd, J = 8.8, 4.2, 2.7 Hz, 1H), 6.13 (d, J = 7.9 Hz, 1H), 3.76 (s, 3H). 404 1HNMR (400 MHz, DMSSMb) δ 9.40 (s, 1H), 8.76 (s, 1H), 8.63 - 8.48 (m, 1H), 8.40 (s, 1H), 8, 16 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.61 - 7.13 (m, 10H ), 6.87 (s, 2H), 6.19 (d, J = 7.7 Hz, 1H), 5.07 (s, 2H), 4.71 (m, 1H), 4.07 (d , J = 13.1 Hz, 2H), 3.00 (m, 2H), 2.02 (d, J = 12.5 Hz, 2H), 1.92 - 1.66 (m, 2H). 405 1HNMR (400 MHz, DMSSMb) δ 9.46 (s, 1H), 8.81 - 8.64 (m, 2H), 8.54 (dd, J = 5.0, 1.6 Hz, 1H), 8.41 (s, 2H), 8.14 (s, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.58 - 7.36 (m, 4H), 7.32 - 7.16 (m, 2H), 6.22 (d, J = 7.9 Hz, 1H), 4.87 - 4.66 ( m, 1H), 3.38 (d, J = 12.9 Hz, 2H), 3.06 (q, J = 12.0 Hz, 2H), 2.33 2.18 (m, 2H), 2 .18-1.98 (m, 2H). 408 1HNMR (400 MHz, Methanol^4) δ 9.20 (s, 1H), 8.43 (s, 1H), 8.09 - 8.02 (m, 1H), 7.98 (s, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 7.2 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7. 01 (d, J = 2.4 Hz, 1H), 6.38 (s, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.53 (d, J = 13.9 Hz, 1H), 1.87 - 1.74 (m, 2H), 1.65 - 1.50 (m, 2H), 0.85 (s, 9H). 409 1HNMR (400 MHz, Methanol) δ 9.20 (s, 1H), 8.33 (s, 1H), 8.04 (d, J = 7.9 Hz, 1H), 8.00 (s, 1H) , 7.84 (d, J = 2.5 Hz, 1H), 7.68 (d, J = 7.3 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7 .15 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 4.00 (d, J = 13.7 Hz, 1H), 3.42 (d, J = 13, 7 Hz, 1H), 1.87 - 1.74 (m, 2H), 1.62 - 1.52 (m, 2H), 0.80 (s, 9H).

- 349 045220

410 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.35 (s, 1H), 8.04 (dd, J = 7.4, 1.8 Hz, 1H), 7 .87 (d, J = 2.5 Hz, 1H), 7.82 (s, 1H), 7.64 - 7.53 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 6.34 (s, 1H), 3.98 (d, J = 13.7 Hz, 1H), 3.97 - 3.80 (m, 1H), 3.50 (d, J = 13 .7 Hz, 1H), 1.23 - 1.07 (m, 4H), 0.81 (s, 9H). 411 1HNMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.23 (s, 1H), 8.10 - 8.03 (m, 1H), 7.86 (d, J = 2 .5 Hz, 1H), 7.83 (s, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.65 - 7.54 (m, 1H), 7.36 - 7 .29 (m, 1H), 7.21 - 7.11 (m, 2H), 6.92 (d, J = 6.8 Hz, 2H), 6.46 (s, 1H), 5.48 ( t, J = 7.1 Hz, 1H), 3.90 - 3.84 (m, 1H), 2.05 (dt, J = 14.4, 7.2 Hz, 1H), 1.84 (dt , J = 13.9, 7.1 Hz, 1H), 1.22 - 1.10 (m, 4H), 0.94 (t, J = 7.3 Hz, 3H). 412 1HNMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.07 (dd, J = 8.1, 1 .1 Hz, 1H), 7.88 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62 7.55 (m, 1H) , 7.38 - 7.30 (m, 2H), 7.23 - 7.10 (m, 2H), 6.96 - 6.89 (m, 2H), 6.53 (s, 1H), 5 .49 (t, J = 7.0 Hz, 1H), 2.06 (dt, J = 14.1, 7.1 Hz, 1H), 1.85 (dt, J = 14.1, 7.3 Hz, 1H), 1.75 - 1.62 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H). 413 1HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.21 (s, 1H), 8.05 (m, 1H), 7.81 (t, J = 8.1 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.44 - 7.29 (m, 5H), 7.24 (m, 1H), 6.97 - 6.85 (m , 2H), 5.95 (m, 1H), 3.47 (m, 1H), 2.67 - 2.41 (m, 7H), 1.80 (m, 4H). 414 1HNMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.99 (s, 1H), 7.73 (m, 1H), 7.57 (m, 1H), 7.42 ( s, 1H), 7.40 - 7.27 (m, 5H), 6.19 (s, 1H), 5.76 (dd, J = 8.6, 5.5 Hz, 1H), 4.90 (td, J = 7.6, 3.1 Hz, 2H), 4.78 (m, 2H), 4.55 - 4.35 (m, 5H), 3.92 (m, 1H), 2, 91 (m, 1H), 2.63 (m, 2H), 2.44 (m, 1H), 2.36 (m, 1H), 1.22 (m, 2H), 1.17 (m, 2H ). 415 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.14 (d, J = 0.6 Hz, 1H), 8.06 (dd, J = 7.4, 1.8 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.40 (s, 1H), 4.17 (d, J = 13.9 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 2.02 - 1.83 (m, 4H), 0.86 (s, 9H).

- 350 045220

416 1H NMR (400 MHz, Methanol-d4) δ 9.20 (s, 1H), 8.49 (s, 1H), 8.05 (dd, J = 8.0, 1.1 Hz, 1H), 7 .98 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 7.1 Hz, 1H), 7.59 (dd, J = 8, 1, 7.4 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.39 (s, 1H), 4.24 (d, J = 13.9 Hz, 1H) , 3.55 (d, J = 13.9 Hz, 1H), 1.88 - 1.74 (m, 2H), 1.65 - 1.50 (m, 2H), 0.86 (s, 9H ). 417 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.10 (s, 1H), 8.06 (dd, J = 7.3, 1 .9 Hz, 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.02 (d, J = 2.3 Hz, 1H ), 6.41 (s, 1H), 4.18(d, J = 13.8 Hz, 1H), 3.60 (d, J = 13.8 Hz, 1H), 1.79 - 1.59 (m, 4H), 0.86 (s, 9H). 418 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.05 (dd, J = 6.7, 2.5 Hz, 1H), 7 .80 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.63 - 7.54 (m, 2H), 6.99 (d, J = 2.4 Hz, 1H), 6.35 (s, 1H), 4.17 (d, J = 13.9 Hz, 1H), 3.86 (ddd, J = 11.4, 7.3, 4.0 Hz, 1H ), 3.60 (d, J = 13.8 Hz, 1H), 1.23 - 1.08 (m, 4H), 0.85 (s, 9H). 419 1HNMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.45 (s, 1H), 8.09 - 8.02 (m, 1H), 7.83 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 7.4 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.00 (d , J = 2.4 Hz, 1H), 6.39 (s, 1H), 4.77 (td, J = 11.4, 5.5 Hz, 1H), 4.18 (d, J = 13, 8 Hz, 1H), 3.79 (d, J = 12.6 Hz, 2H), 3.55 (d, J = 13.8 Hz, 1H), 3.20 (t, J = 12.0 Hz , 2H), 2.47 - 2.37 (m, 4H), 1.45 (s, 9H), 0.84 (s, 9H). 420 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.28 (s, 1H), 8.06 (dd, J = 7.7, 1.5 Hz, 1H), 7 .82 (d, J = 2.2 Hz, 2H), 7.67 - 7.55 (m, 2H), 7.15 (d, J = 2.5 Hz, 1H), 6.39 (d, J = 4.6 Hz, 1H), 4.79 - 4.71 (m, 1H), 3.90 (d, J = 13.7 Hz, 1H), 3.80 (d, J = 12.5 Hz, 2H), 3.43 (d, J = 13.7 Hz, 1H), 3.24 - 3.15 (m, 2H), 2.51 - 2.34 (m, 4H), 1.45 (s, 9H), 0.79 (s, 9H). 421 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.47 (s, 1H), 8.06 (dd, J = 7.5, 1.8 Hz, 1H), 7 .96 (s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.02 (d, J = 2.3 Hz, 1H), 6.40 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.18 (d, J = 13.9 Hz, 1H), 3.60 (d, J = 13.9 Hz, 1H), 1.54 - 1.46 (m, 4H), 0.86 (s, 9H).

- 351 045220

422 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 5.8 Hz, 2H), 7.95 (d, J = 2.4 Hz, 1H), 7.90 (s, 1H ), 7.68 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 7.0, 1.0 Hz, 1H), 7.00 (d, J = 2.3 Hz , 1H), 6.86 (t, J = 7.0 Hz, 1H), 6.61 (dd, J = 2.4, 0.9 Hz, 1H), 6.33 (s, 1H), 4 .10 (d, J = 13.9 Hz, 1H), 3.87 (tt, J = 7.5, 4.1 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H) , 1.24 - 1.08 (m, 4H), 0.83 (s, 9H). 423 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.09 (d, J = 0.9 Hz, 1H), 7.75 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.26 ( d, J = 7.0 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.43 (s, 1H), 4.15 (d, J = 13.9 Hz, 1H), 4.05 (s, 3H), 3.90 - 3.79 (m, 1H), 3.64 (d, J = 13.9 Hz, 1H), 1.22 1.06 (m, 4H), 0.84 (s, 9H). 424 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.35 (s, 1H), 8.05 (dd, J = 7.7, 1.6 Hz, 1H), 7 .97 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.66 - 7.54 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H), 6.39 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.99 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 1.51 - 1.48 (m, 4H), 0.82 (s, 9H). 425 1H NMR (400 MHz, DMSO-de) δ 8.40 - 8.35 (m, 2H), 8.08 (d, J = 0.8 Hz, 1H), 8.05 (dd, J = 8, 2, 2.6 Hz, 1H), 7.85 (s, 1H), 7.66 - 7.62 (m, 1H), 7.58 (s, 1H), 7.23 - 7.17 (m , 2H), 5.32 (s, 2H), 4.04 (dd, J = 14.1, 8.0 Hz, 1H), 3.48 (dd, J = 14.1, 5.6 Hz, 1H), 3.27 (d, J = 0.7 Hz, 3H), 0.88 (s, 9H). 426 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.76 (s, 1H), 7.69 (d, J = 2.2 Hz , 1H), 7.54 (dt, J = 8.6, 0.9 Hz, 1H), 7.25 (dd, J = 8.6, 6.9 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 6.32 (s, 1H), 4.17 (s, 3H), 4.15 (d, J = 14.7 Hz, 1H), 3.89 - 3.79 (m, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.21 - 1.05 (m, 4H ), 0.84 (s, 9H). 427 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 7.85 (dd, J = 6.2, 2.8 Hz, 2H), 7.80 (s, 1H), 7 .56 - 7.44 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.26 (s, 1H), 3.98 (d, J = 13.7 Hz, 1H), 3.91 - 3.81 (m, 1H), 3.47 (d, J = 13.7 Hz, 1H), 2.78 (s, 3H), 1.26 1.06 (m, 4H), 0.82 (s, 9H).

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428 1HNMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.99 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.63 - 7, 56 (m, 1H), 7.44 - 7.39 (m, 2H), 7.37 (d, J = 2.5 Hz, 1H), 7.34 (d, J = 4.4 Hz, 1H ), 7.31 - 7.21 (m, 2H), 7.15 (dd, J = 7.2, 2.5 Hz, 2H), 6.20 (s, 1H), 5.51 (t, J = 7.0 Hz, 1H), 4.62 - 4.48 (m, 4H), 3.94 - 3.88 (m, 1H), 2.20 - 1.89 (m, 2H), 1 .23 - 1.17 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H). 429 1HNMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 8.25 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 2.5 Hz, 1H), 6.15 (s, 1H), 4.91 (m, 2H), 4.80 (m, 2H), 4.62 - 4.46 (m, 2H), 4.39 (m, 1H), 3.86 (d, J = 13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 3.52 (s, 1H), 3.48 - 3.36 (m, 1H), 3.23 - 3.11 (m, 1H), 3.00 - 2.94 (m, 1H), 1, 78 (m, 2H), 1.68 (3, 2H), 0.98 (s, 9H). 430 1H NMR (400 MHz, Methanol-44) δ 8.34 (s, 1H), 8.09 (s, 1H), 7.86 (td, J = 3.3, 2.2 Hz, 2H), 7 .58 - 7.46 (m, 2H), 7.17 (d, J = 2.5 Hz, 1H), 6.33 (s, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.7 Hz, 1H), 2.77 (s, 3H), 1.79 - 1.57 (m, 4H), 0.83 (s, 9H). 431 1HNMR (400 MHz, Chloroform-d) δ 8.42 (s, 1H), 7.88 (m, 1H), 7.48 - 7.28 (m, 6H), 6.81 (m, 1H), 6.76 (s, 1H), 5.97 (s, 1H), 5.67 (m, 1H), 5.30 (s, 2H), 3.73 (m, 1H), 2.57 (s , 3H), 2.57 - 2.47 (m, 1H), 2.33 (m, 1H), 1.57 (s, 2H), 0.92 - 0.81 (m, 4H). 432 1HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.20 (s, 1H), 7.79 (m, 1H), 7.61 (m, 1H), 6.88 ( m, 2H), 6.24 (s, 1H), 3.88 (m, 2H), 3.62 (m, 2H), 2.51 (s, 3H), 1.86 - 1.56 (m , 4H), 0.92 (s, 9H). 433 1HNMR (400 MHz, Methanol) δ 8.30 (s, 1H), 7.96 (s, 1H), 7.71 (d, J = 2.5 Hz, 1H), 7.38 (s, 1H) , 7.31 (d, J = 2.5 Hz, 1H), 6.07 (s, 1H), 4.92 (m, 2H), 4.82 - 4.78 (m, 2H), 4, 64 - 4.47 (m, 2H), 4.40 (m, 1H), 3.90 (m, 1H), 3.85 (d, J = 14.1 Hz, 1H), 3.76 (d , J = 13.9 Hz, 1H), 3.52 (m, 1H), 3.42 (m, 1H), 3.16 - 3.13 (m, 1H), 3.02 - 2.88 ( m, 1H), 1.24 - 1.13 (m, 4H), 0.98 (s, 9H).

- 353 045220

434 1H NMR (400 MHz, Methanol-04) δ 9.21 (s, 1H), 8.46 (s, 1H), 8.05 (dd, J = 7.0, 2.2 Hz, 1H), 7 .87 (s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.64 - 7.54 (m, 2H), 6.98 (d, J = 2.3 Hz, 1H), 6.35 (s, 1H), 4.17 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H), 1.63 (s, 3H), 1.32 - 1.25 (m, 2H), 1.08 - 1.00 (m, 2H), 0.84 (s, 9H). 435 1H NMR (400 MHz, Methanol^4) δ 9.21 (s, 1H), 8.35 (s, 1H), 8.05 (dd, J = 7.5, 1.7 Hz, 1H), 7 .89 (s, 1H), 7.87 (d, J = 2.5 Hz, 1H), 7.65 - 7.54 (m, 2H), 7.16 (d, J = 2.5 Hz, 1H), 6.35 (s, 1H), 4.00 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 1.63 (s, 3H), 1.31-1.25 (m, 2H), 1.08 - 0.99 (m, 2H), 0.81 (s, 9H). 436 1H NMR (400 MHz, Methanol^4) δ 8.50 (s, 1H), 8.02 - 7.93 (m, 2H), 7.62 (m, 1H), 7.07 (m, 1H) , 6.96 (m, 1H), 6.31 (s, 1H), 4.12-3.98 (m, 1H), 3.95 - 3.80 (m, 1H), 3.39 (m , 1H), 1.29 - 1.10 (m, 2H), 1.03 (s, 2H), 0.97 (s, 9H). 4.94 - 4.85 (m, 4H), 4.87 (s, 21H), 437 1H NMR (400 MHz, Methanol^4) δ 9.01 (m, 1H), 8.83 (d, J = 8.6 Hz, 1H), 8.49 (s, 1H), 8.10 (d , J = 8.6 Hz, 1H), 7.90 - 7.81 (m, 2H), 7.81 - 7.65 (m, 4H), 6.92 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.86 (m, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.22 - 1.07 (m, 4H), 0.70 (s, 9H). 438 1H NMR (400 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.90 (m, 1H), 7.43 - 7.26 (m, 5H), 7.22 (m, 2H) , 6.78 (m, 1H), 6.61 (s, 1H), 6.00 (s, 1H), 5.69 (m, 1H), 5.30 (s, 2H), 3.75 ( m, 3.8 Hz, 1H), 2.65 (s, 3H), 2.64 - 2.49 (m, 1H) 2.44 (s, 2H), 2.33 (s, 1H), 0 .92-0.81 (m, 4H). 440 1HNMR (400 MHz, MeTaHon-d4) δ 8.45 (m, 1H), 8.21 (s, 1H), 7.82 (m, 1H), 7.64 (m, 1H), 7.40 - 7.25 (m, 5H), 7.13 (m, 1H), 6.93 - 6.83 (m, 1H), 6.37 (m, 1H), 5.79 - 5.64 (m, 1H), 2.53 (m, 3H), 2.23 - 2.09 (m, 1H), 2.07 (m, 1H), 1.81 - 1.64 (m, 4H), 1.04 -0.91 (m, 3H)

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441 1H NMR (400 MHz, DMSO-46) δ 9.32 (s, 1H), 8.30 (d, J = 1.5 Hz, 1H), 8.16 (s, 1H), 8.00 (dd , J = 8.1, 1.2 Hz, 1H), 7.92 (d, J = 2.3 Hz, 1H), 7.69 - 7.57 (m, 2H), 7.50 (td, J = 7.8, 1.5 Hz, 1H), 7.43 - 7.30 (m, 2H), 6.46 (d, J = 5.8 Hz, 1H), 4.72 (s, 1H ), 4.60 (s, 1H), 3.87 (dd, J = 13.8, 8.1 Hz, 1H), 3.34 (dd, J = 13.8, 5.0 Hz, 1H) , 1.41-1.27 (m, 4H), 0.75 (s, 9H). 443 1HNMR (400 MHz, Methanol-44) δ 9.75 (s, 1H), 8.59 (m, 1H), 8.46 (s, 1H), 8.26 m, 1H), 8.13 (m , 1H), 8.01 - 7.86 (m, 3H), 7.68 (m, 1H), 6.96 (m, 2H), 4.05 - 3.96 (m, 1H), 3, 87 (m, 1H), 3.63 (m, 1H), 1.37 (m, 1H), 1.21 - 1.07 (m, 4H), 0.72 (s, 9H). 444 1HNMR (400 MHz, Methanol) δ 8.50 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.29 (dt, J = 7.0, 1.0 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 6.64 (dd, J = 2.4, 0.9 Hz, 1H), 6.38 ( s, 1H), 5.93 (t, J = 54.8 Hz, 1H), 3.93 (d, J = 13.8 Hz, 1H), 3.54 (d, J = 13.7 Hz, 1H), 1.52 - 1.48 (m, 4H), 0.78 (s, 9H). 445 1HNMR (400 MHz, Methanol) δ 8.43 (s, 1H), 8.13 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.04 (d, J = 2.3 Hz, 1H), 6.12 (s, 1H), 5.94 ( t, J = 54.6 Hz, 1H), 4.92 (d, J = 14.6 Hz, 1H), 4.56 (s, 2H), 4.55 (d, J = 14.7 Hz, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 1.58 - 1.50 (m, 4H), 0. 96 (s, 9H). 446 1HNMR (400 MHz, Methanol) δ 9.13 (s, 1H), 8.46 (s, 1H), 8.39 (d, J = 7.1 Hz, 1H), 8.04 (s, 1H) , 7.80 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.20 (d, J = 6.9 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.98 (t, J = 7.0 Hz, 1H), 6.32 (s, 1H), 4.08 (d, J = 13.9 Hz, 1H), 3 .89 (ddd, J = 11.5, 7.4, 4.1 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 1.25 - 1.10 (m, 4H ), 0.87 (s, 9H). 447 1HNMR (400 MHz, Chloroform-d) δ 8.45 (s, 1H), 7.93 (t, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.35 (d, J = 2.3 Hz, 1H), 6.80 (dd, J = 8.4, 3.2 Hz, 1H), 6.25 (s, 1H), 5.93 (s, 1H), 5, 91 (t, J = 56.0 Hz, 1H), 5.27 (s, 1H), 3.57 (m, 2H), 2.58 (s, 3H), 1.55 1.50 (m, 4H), 0.94 (s, 9H).

- 355 045220

448 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.13 (s, 1H), 7.74 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 8.6, 7.0 Hz, 1H), 7.23 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.44 (s, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.90 - 3.79 (m, 1H), 3.69 - 3.60 (m, 1H), 1.22 - 1.06 (m, 4H), 0.84 (s, 9H). 449 1HNMR (400 MHz, Methanol) δ 9.29 (s, 1H), 8.44 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.89 (s, 1H) , 7.69 (s, 1H), 7.62 (d, J = 7.5 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.11 (s, 1H) , 6.93 (s, 1H), 4.04 (d, J = 13.8 Hz, 1H), 3.91 - 3.77 (m, 1H), 3.73 (d, J = 13.8 Hz, 1H), 1.24 - 1.00 (m, 4H), 0.87 (s, 8H). 450 1HNMR (400 MHz, Methanol-d4) δ 8.94 (dd, J = 4.3, 1.8 Hz, 1H), 8.47 (s, 1H), 8.37 (dd, J = 8.3 , 1.8 Hz, 1H), 7.93 (dd, J = 8.1, 1.4 Hz, 1H), 7.86 (dd, J = 7.2, 1.3 Hz, 1H), 7 .76 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.62 - 7.53 (m, 2H), 7.27 (s, 1H), 7.10 ( d, J = 2.2 Hz, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.86 - 3.70 (m, 2H), 1.19 - 1.04 (m , 4H), 0.80 (s, 9H). 451 1HNMR (400 MHz, Methanol-d4) δ 8.28 (s, 2H), 7.74 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 7.4 Hz, 1H) , 7.44 (t, J = 7.5 Hz, 1H), 7.40 (d, J = 7.3 Hz, 1H), 7.21 (d, J = 2.5 Hz, 1H), 6 .13 (s, 1H), 4.99 (d, J = 14.6 Hz, 1H), 4.59 (d, J = 14.8 Hz, 1H), 4.56 (s, 2H), 3 .97 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.8 Hz, 1H), 1.85 - 1.74 (m, 2H), 1.70 - 1, 61 (m, 2H), 0.93 (s, 9H). 452 1H NMR (400 MHz, Methanol-d4) δ 8.86 (d, J = 15.0 Hz, 2H), 8.01 (d, J = 11.5 Hz, 2H), 7.85 (s, 1H ), 7.77 - 7.64 (m, 3H), 7.56 (d, J = 2.5 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.34 - 7, 19 (m, 3H), 7.12 (d, J = 7.4 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 6.70 (d, J = 2.5 Hz, 1H), 6.12 (s, 1H), 6.07 (s, 1H), 4.58 - 4.42 (m, 3H), 4.20 (dd, J = 10.0, 5, 8 Hz, 1H), 4.02 (dd, J = 11.4, 4.5 Hz, 1H), 3.62 (dt, J = 15.5, 7.9 Hz, 2H), 3.20 - 3.07 (m, 2H), 3.02 (d, J = 11.6 Hz, 1H), 2.94 (p, J = 1.7 Hz, 14H), 2.89 2.81 (m, 1H), 2.75 (d, J = 11.6 Hz, 1H), 1.66 - 1.22 (m, 11H), 0.66 (s, 3H), 0.43 (s, 3H), 0.29 (s, 3H), -0.00 (s, 3H).

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453 1HNMR (400 MHz, DMSOLb) δ 9.36 (d, J = 1.3 Hz, 1H), 8.42 (s, 2H), 8.04 (dd, J = 8.0, 1.2 Hz, 1H), 7.80 (s, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.29 (s, 1H), 6.49 (d, J = 6.2 Hz, 1H), 3.97 (m, 2H), 2.69 (d, J = 1.3 Hz, 3H), 1.71 (d, J = 35.6 Hz, 4H), 0.79 (d, J = 1.3 Hz, 9H). 454 1H NMR (400 MHz, MethanolL4) δ 8.37 (s, 1H), 7.92 (s, 1H), 7.84 - 7.70 (m, 2H), 7.09 (m,lH), 6 .87 (m, 1H), 6.19 (s, 1H), 3.96 - 3.80 (m, 2H), 3.72 (m, 1H), 2.51 (s, 3H), 1, 34 - 0.94 (m, 4H), 0.89 (s, 9H). 455 1H NMR (400 MHz, DMSOLb) δ 9.32 (s, 1H), 8.35 (m, 2H), 8.00 (d, J = 8.0 Hz, 1H), 7.67 - 7.54 (m, 2H), 7.49 (t, J = 7.7 Hz, 1H), 7.35 (d, J = 12.8 Hz, 1H), 6.94 (s, 1H), 6.44 (d, J = 6.1 Hz, 1H), 3.89 (dd, J = 13.7, 7.8 Hz, 1H), 3.43 (dd, J = 13.7, 5.4 Hz, 1H), 1.72 (m, 2H), 1.64 (m, 2H), 0.77 (s, 9H). 456 1HNMR (400 MHz, DMSOLb) δ 11.05 (s, 1H), 9.34 (d, J = 1.4 Hz, 1H), 8.07 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.61 (s, 2H), 7.58 - 7.52 (m, 1H), 7.36 (s, 3H), 7.25 (s, 1H), 6, 01 (d, J= 13.4 Hz, 1H), 3.94 (s, 1H), 1.13 (s, 13H). 458 1H NMR (400 MHz, MethanolL4) δ 9.21 (s, 1H), 8.48 (s, 1H), 8.05 (dd, J = 7.9, 1.4 Hz, 1H), 7.86 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.60 (dt, J = 15.3, 7.3 Hz, 2H), 7.01 (d, J = 2.3 Hz, 1H), 6.37 (s, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.74 (d, J = 1.8 Hz, 2H), 3 .57 (d, J = 13.9 Hz, 1H), 1.34 - 1.25 (m, 2H), 1.21 - 1.13 (m, 2H), 0.86 (s, 9H). 459 1HNMR (400 MHz, MethanolL4) δ 9.18 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.82 (d, J = 8.3 Hz, 1H) , 7.65 (d, J = 2.2 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7 .01 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 4.22 (s, 3H), 3.95 - 3.85 (m, 1H), 3.89 ( s, 2H), 1.27 - 1.10 (m, 4H), 0.84 (s, 9H). 460 1H NMR (400 MHz, MethanolL4) δ 9.21 (s, 1H), 8.33 (s, 1H), 8.06 (dd, J = 7.6, 1.5 Hz, 1H), 7.90 (s, 1H), 7.88 (d, J = 2.5 Hz, 1H), 7.67 - 7.55 (m, 2H), 7.19 (d, J = 2.5 Hz, 1H) , 6.42 (s, 1H), 5.26 (qd, J = 8.7, 2.5 Hz, 2H), 3.99 (d, J = 13.7 Hz, 1H), 3.46 ( d, J = 13.7 Hz, 1H), 0.80 (s, 9H).

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461 1HNMR (400 MHz, Methanol-d4) δ 8.99 (s, 1H), 8.77 (m, 1H), 8.47 (s, 1H), 8.16 - 8.05 (m, 2H), 7.87 - 7.78 (m, 1H), 7.78 - 7.66 (m, 3H), 6.97 - 6.88 (m, 2H), 4.00 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.76 - 1.58 (m, 4H), 0.70 (s, 9H). 462 1HNMR (400 MHz, Methanol-d4) δ 8.48 m, 3H), 8.23 (m, 1H), 8.11 (m, 1H), 7.96 m, 1H), 7.63 (m, 1H), 7.50 (m, 1H), 7.43 (s, 1H), 7.27 m, 1H), 6.45 (s, 1H), 4.08 (d, J = 14.0 Hz , 1H), 3.83 (d, J = 14.0 Hz, 1H), 1.31 - 1.08 (m, 4H), 0.98 (s, 9H). 463 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.49 (s, 1H), 8.06 (dd, J = 8.0, 1.3 Hz, 1H), 7 .87 (s, 1H), 7.73 (d, J = 2.3 Hz, 1H), 7.67 - 7.54 (m, 2H), 7.02 (d, J = 2.3 Hz, 1H), 6.41 (s, 1H), 4.22 (d, J = 13.9 Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H), 2.98 - 2, 86 (m, 2H), 2.86 - 2.73 (m, 2H), 2.13 - 1.96 (m, 2H), 0.86 (s, 9H). 464 1HNMR (400 MHz, Methanol-d4) δ 9.22 (s, 1H), 8.59 (d, J = 6.0 Hz, 2H), 8.30 (s, 1H), 8.12 (s, 1H), 8.06 (dd, J = 8.1, 1.1 Hz, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.61 (dd, J = 8.1, 7.5 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 6 ,1 Hz, 2H), 6.45 (s, 1H), 3.94 (d, J = 13.7 Hz, 1H), 3.41 (d, J = 13.7 Hz, 1H), 2, 17-1.94 (m, 4H), 0.79 (s, 9H). 465 1H NMR (400 MHz, Methanol-d4) δ 9.21 (s, 1H), 8.34 (s, 1H), 8.08 - 8.01 (m, 1H), 7.88 (s, 1H) , 7.87 (d, J = 2.4 Hz, 1H), 7.67 - 7.62 (m, 1H), 7.62 - 7.55 (m, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 4.01 (d, J = 13.7 Hz, 1H), 3.74 (d, J = 1.9 Hz, 2H), 3.46 (d, J = 13.8 Hz, 1H), 1.32 - 1.27 (m, 2H), 1.22 - 1.14 (m, 2H), 0.81 (s, 9H) . 466 1HNMR (400 MHz, Methanol-d4) δ 9.60 (s, 1H), 9.53 (s, 1H), 8.76 (d, J = 6.1 Hz, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 8.01 (d, J = 6.2 Hz, 1H), 7.96 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.01 (d, J = 2.3 Hz, 1H), 6.76 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.96 - 3, 76 (m, 1H), 3.70 (d, J = 13.9 Hz, 1H), 1.24 - 1.11 (m, 4H), 0.76 (s, 9H).

- 358 045220

467 1HNMR (400 MHz, Acetonitril-d3) δ 9.08 (d, J = 4.6 Hz, 1H), 8.97 (d, J = 8.6 Hz, 1H), 8.36 (s, 1H) , 8.24 (d, J = 8.2 Hz, 1H), 7.87 (s, 1H), 7.83 - 7.70 (m, 2H), 7.65 (s, 1H), 6, 90 (d, J = 2.5 Hz, 1H), 6.77 (s, 1H), 5.74 (s, 1H), 3.65 (dd, J = 13.3, 6.8 Hz, 1H ), 3.48 (dd, J = 13.5, 5.3 Hz, 1H), 1.29 (s, 1H), 1.10 m, 4H), 0.68 (s, 9H). 468 1HNMR (400 MHz, Acetonitril-d3) δ 8.35 (s, 1H), 8.10 (s, 2H), 7.96 (s, 1H), 7.88 (s, 1H), 7.76 ( s, 1H), 6.94 (s, 1H), 6.88 (s, 1H), 5.93 (s, 1H), 3.84 - 3.71 (m, 2H), 3.39 (d , J = 13.9 Hz, 1H), 1.21 - 0.98 (m, 4H), 0.65 (s, 9H). 469 1HNMR (400 MHz, Methanol-d4) δ 9.11 (s, 1H), 9.04 (d, J = 8.7 Hz, 1H), 8.30 (s, 1H), 8.21 (s, 1H), 8.18 - 8.10 (m, 1H), 7.99 - 7.90 (m, 1H), 7.90 - 7.82 (m, 2H), 7.80 (s, 1H) , 7.14 - 7.08 (m, 1H), 6.94 (s, 1H), 3.79 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 1.75 - 1.56 (m, 4H), 0.66 (s, 9H). 470 1H NMR (400 MHz, Methanol-d4) δ 8.30 (d, J = 7.5 Hz, 2H), 8.19 (d, J = 8.0 Hz, 1H), 8.06 (t, J = 7.7 Hz, 1H), 8.00 (d, J = 7.3 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.15 (s, 1H), 7.00 (s, 1H), 3.82 (d, J =13.7 Hz, 1H), 3.48 (d, J =13.8 Hz, 1H), 1.82 - 1.53 (m , 4H), 0.68 (s, 9H). 471 1H NMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 8.20 (s, 1H), 7.84 - 7.74 (m, 3H), 7.11 - 7.06 ( m, 1H), 6.91 - 6.84 (m, 1H), 6.25 (s, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.80 - 1.65 (m, 4H), 0.88 (s, 9H). 472 1HNMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 8.16 (s, 1H), 8.04 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.40 - 7.31 (m, 1H), 7.26 (d, J = 7.1 Hz, 1H), 7, 18 (d, J = 2.5 Hz, 1H), 6.50 (s, 1H), 3.88 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.7 Hz, 1H), 1.79 - 1.54 (m, 4H), 0.79 (s, 9H). 473 1H NMR (400 MHz, MethanolO4) δ 8.36 (s, 1H), 8.05 (s, 1H), 7.84 - 7.75 (m, 2H), 7.10 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.24 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H) , 3.88 (d, J =13.8 Hz, 1H), 3.68 (d, J =13.8 Hz, 1H), 2.51 (s, 3H), 1.53 (s, 4H) , 0.89 (s, 9H).

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474 1HNMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 7.96 (s, 1H), 7.72 (s, 1H), 7.70 (d, 1H), 7.55 ( d, J = 2.6 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.25 (t, J = 7.7 Hz, 1H), 6.69 (d, J = 2.6 Hz, 1H), 6.09 (s, 1H), 3.96 (dd, J = 11.1, 4.9 Hz, 1H), 3.68 - 3.60 (m, 1H ), 3.23 - 3.12 (m, 1H), 3.03 (d, J = 11.5 Hz, 1H), 2.96 (p, J = 1.7 Hz, 21H), 2.77 (d, J = 11.5 Hz, 1H), 1.64 - 1.47 (m, 2H), 1.40 - 1.21 (m, 4H), 0.29 (s, 3H), 0, 00 (s, 3H). 475 1HNMR (400 MHz, Methanol-d4) δ 9.24 (s, 1H), 8.36 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.63 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 7.4 Hz, 1H) , 7.26 (d, J = 2.6 Hz, 1H), 6.48 (s, 1H), 4.56 - 4.47 (m, 1H), 3.95 (d, J = 11.4 Hz, 1H), 3.50 (d, J = 11.5 Hz, 2H), 3.22 (d, J = 11.7 Hz, 1H), 1.86 - 1.77 (m, 2H), 1.76 - 1.59 (m, 4H), 1.01 (s, 3H), 0.78 (s, 3H). 476 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.23 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.3, 2.8 Hz, 1H), 6.24 ( s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 2.04 - 1.97 (m, 2H), 1.97-1.91 (m, 2H), 0.94 (s, 9H). 477 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.7 Hz, 1H), 6.20 (s, 1H) , 4.11 (d, J = 13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.89 - 1.80 ( m, 2H), 1.66 - 1.59 (m, 2H), 0.94 (s, 9H). 478 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 7.95 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.23 ( s, 1H), 4.08 (d, J = 13.9 Hz, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.00 - 2.90 (m, 1H), 2.90 - 2.80 (m, 1H), 2.51 (s, 3H), 2.16 - 1.98 (m, 1H), 0.94 (s, 9H). 479 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.22 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.4, 2.8 Hz, 1H), 6.27 ( s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 3.09 - 2.95 (m, 3H), 2.53 (s, 3H), 2.33 (m, 1H), 2.24 - 2.10 (m, 1H), 0.94 (s, 9H).

- 360 045220

480 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.96 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 6.88 (d, J = 2.3 Hz, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.18 (s, 1H) , 4.01 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.66 (s, 3H) , 1.35-1.29 (m, 2H), 1.09 - 1.03 (m, 2H), 0.93 (s, 9H). 481 1HNMR (400 MHz, DMSO-de) δ 9.31 (s, 1H), 8.38 (s, 1H), 8.11 - 7.92 (m, 2H), 7.78 (s, 1H), 7.64 (dd, J = 12.6, 6.8 Hz, 2H), 7.55 - 7.28 (m, 4H), 6.95 (s, 1H), 6.43 (d, J = 5.8 Hz, 1H), 3.97 (dd, J = 13.4, 8.5 Hz, 1H), 3.38 (dd, J = 13.7, 5.2 Hz, 1H), 2, 90 - 2.71 (m, 2H), 2.73 - 2.57 (m, 2H), 1.87 (q, J = 8.3 Hz, 2H), 0.78 (s, 9H). 482 1H NMR (400 MHz, Acetonitril-d3) δ 8.45 (s, 1H), 7.85 (t, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.50 (d , J = 2.3 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.15 (s, 1H), 3.90 (dd, J = 13.5, 6.2 Hz, 1H), 3.81 (dd, J = 13.5, 5.6 Hz, 1H), 3.72 (s, 2H), 2.52 (s, 3H), 1.29 (s, 1H), 1.19 - 1.13 (m, 2H), 0.96 (s, 9H). 483 1HNMR (400 MHz, Methanol-d4) δ 9.13 (s, 1H), 8.49 (s, 1H), 8.25 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H) , 7.02 (d, J = 2.3 Hz, 1H), 6.89 (s, 1H), 4.22 (s, 3H), 3.89 (d, J = 2.5 Hz, 2H) , 1.82 - 1.66 (m, 4H), 0.85 (s, 9H). 484 1HNMR (400 MHz, Methanol^4) δ 9.29 (s, 1H), 8.31 (d, J = 0.6 Hz, 1H), 8.28 (s, 1H), 7.83 (d, J = 8.2 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.8 Hz, 1H), 7.20 (d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 4.27 (s, 3H), 3.72 (q, J = 13.9 Hz, 2H), 1.81 - 1.65 (m, 4H), 0.81 (s, 9H). 485 1HNMR (400 MHz, Methanol-d4) δ 8.56 (s, 1H), 8.23 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.32 (dd, J = 12.3, 2.2 Hz, 1H), 6.95 - 6.75 (m, 2H), 6.24 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H ), 3.87 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 2.04 - 1.88 (m, 4H), 0.95 (s, 9H).

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486 1HNMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.05 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.29 (dd, J = 12.5, 2.1 Hz, 1H), 6.92 - 6.82 (m, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.20 (s, 1H ), 4.10 (d, J = 13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.88 - 1.77 (m, 2H), 1.62 (td, J = 4.2, 1.9 Hz, 2H), 0.94 (s, 9H). 487 1HNMR (400 MHz, DMSO-de) δ 8.39 (s, 1H), 8.01 (s, 1H), 7.81 (m, 2H), 7.50 7.22 (m, 4H), 6 .92 (dd, J = 8.5, 3.0 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 6.22 (d, J = 6.1 Hz, 1H) , 3.94 (dd, J = 13.8, 8.0 Hz, 1H), 3.43 (dd, J = 13.7, 5.1 Hz, 1H), 2.88 - 2.74 (m , 1H), 2.68 (dd, J = 18.4, 8.4 Hz, 2H), 2.46 (s, 3H), 1.99 - 1.76 (m, 2H), 0.81 ( s, 9H). 488 1HNMR (400 MHz, DMSO-de) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.77 (t, J = 8.3 Hz, 1H), 7.65 (s, 1H), 7.38 (d, J = 7.1 Hz, 1H), 7.25 (d, J = 12.3 Hz, 1H), 6.91 (dd, J = 8.5, 3.0 Hz, 1H), 6.83 - 6.71 (m, 1H), 6.17 (d, J = 6.0 Hz, 1H), 3.95 - 3.82 (m, 1H), 3.45 (dd, J = 13.8, 5.2 Hz, 1H), 2.42 (s, 3H), 1.60 (s, 3H), 1.32 - 1.18 (m, 2H), 1, 06 - 0.94 (m, 2H), 0.80 (s, 9H). 489 1HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.23 (s, 1H), 7.83 - 7.75 (m, 2H), 7.10 (d, J = 2 .6 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.24 (s, 1H), 3.87 (d, J = 13.8 Hz, 1H ), 3.71 (d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 2.04 - 1.96 (m, 2H), 1.94 (m, 2H), 0 .90 (s, 9H). 490 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.07 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.85 (m, 1H), 6.20 (s, 1H), 3.94 (d, J = 13.8 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 1.83 (m, 2H), 1.62 (m, 2H), 0.89 (s, 9H). 491 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.23 (s, 1H), 7.86 - 7.76 (m, 2H), 7.11 (d, J= 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.27 (s, 1H), 3.86 (d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 3.10 - 2.91 (m, 3H), 2.54 (s, 3H), 2.33 (m, 1H), 2.21 - 2.12 (m, 1H), 0.90 (s, 9H).

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492 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.97 (s, 1H), 7.83 - 7.74 (m, 2H), 7.08 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.19 (s, 1H), 3.87 (d, J = 13.9 Hz, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.66 (s, 3H), 1.35 - 1.28 (m, 2H), 1.10 - 1.01 (m, 2H), 0.89 (s, 9H). 493 1HNMR (400 MHz, Methanol) δ 8.37 (dd, J = 4.5, 1.9 Hz, 1H), 8.21 (s, 1H), 8.20 (s, 1H), 8.17 ( dd, J = 9.1, 1.9 Hz, 1H), 7.99 (s, 1H), 7.53 (d, J = 2.4 Hz, 1H), 7.14 (dd, J = 9 ,1, 4.4 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.45 (s, 1H), 3.77 (d, J = 13.8 Hz, 1H ), 3.66 (d, J = 13.8 Hz, 1H), 1.78 - 1.61 (m, 4H), 0.87 (s, 9H). 494 1HNMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.96 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.10 (s, 1H), 6.91 - 6.81 (m, 1H), 6.23 (s, 1H), 3.93 (d, J = 13 .8 Hz, 1H), 3.67 (d, J = 13.8 Hz, 1H), 2.94 (m, 2H), 2.90 - 2.78 (m, 1H), 2.52 (s , 3H), 2.17-1.99 (m, 2H), 0.90 (s, 9H). 495 1HNMR (400 MHz, DMSSMb) δ 8.49 (s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H) , 7.67 (d, J = 2.1 Hz, 1H), 7.57 (s, 1H), 7.07 - 6.90 (m, 2H), 6.25 (s, 1H), 4, 75 (s, 1H), 4.62 (s, 1H), 3.99 (dd, J = 13.8, 7.9 Hz, 1H), 3.51 (dd, J = 13.8, 5, 3 Hz, 1H), 2.45 (s, 3H), 1.42 (dd, J - 8.2, 4.5 Hz, 2H), 1.33 (s, 2H), 0.82 (s, 9H).;1HNMR (400 MHz, DMSO-46) δ 8.33 (s, 1H), 8.13 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7, 61 (d, J = 2.2 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 7.4 Hz, 1H), 6.94 (dd, J = 8.5 , 3.0 Hz, 1H), 6.91 (s, 1H), 6.23 (d, J = 6.7 Hz, 1H), 4.75 (s, 1H), 4.63 (s, 1H ), 3.88 (dd, J = 13.8, 8.1 Hz, 1H), 3.40 (dd, J = 14.0, 4.8 Hz, 1H), 2.44 (s, 3H) , 1.42 (s, 2H), 1.33 (s, 2H), 0.79 (d, J = 1.1 Hz, 9H). 496 1HNMR (400 MHz, Methanol) δ 8.47 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 7.89 (s, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.56 - 7.49 (m, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.28 (d, J = 7 ,1 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.48 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4, 15 (d, J = 13.9 Hz, 1H), 4.05 (s, 3H), 3.64 (d, J = 13.9 Hz, 1H), 1.48 (d, J = 9.0 Hz, 4H), 0.85 (s, 9H).

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497 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.91 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.25 (dd, J = 8.5, 6.9 Hz, 1H), 7.20 (d, J = 6.6 Hz, 1H ), 7.04 (d,J = 2.3 Hz, 1H), 6.37 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.17 (s, 3H ), 4.16 (d, J = 13.8 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.52 - 1.45 (m, 4H), 0.85 (s, 9H). 498 1HNMR (400 MHz, Methanol^4) δ 8.47 (s, 1H), 7.96 (s, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.64 - 7, 59 (m, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.53 - 7.48 (m, 1H), 7.34 (d, J = 2.3 Hz, 1H ), 7.22 (s, 1H), 5.93 (t, J = 54.8 Hz, 1H), 4.49 (d, J = 3.6 Hz, 2H), 4.05 (d, J = 14.0 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 3.20 (s, 3H), 1.51 (s, 4H), 1.01 (s, 9H ). 499 1HNMR (400 MHz, Methanol-d4) δ 9.05 (s, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H) , 6.99 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.20 (s, 3H) , 3.86 (d, J = 1.7 Hz, 2H), 1.54 (s, 4H), 0.84 (s, 9H). 500 1HNMR (400 MHz, Methanol^4) δ 8.47 (s, 1H), 8.13 (d, J = 1.0 Hz, 1H), 7.88 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.35 (dd, J = 8.4, 7.0 Hz, 1H), 7.25 ( d, J = 7.0 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.49 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.15 (d, J = 13.9 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1.61 - 1.37 (m, 4H), 0. 86 (s, 9H). 501 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.05 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.23 ( s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 2.50 (s, 3H), 1.53 (s, 4H), 0.93 (s, 9H). 502 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.05 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.25 ( s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.12 (d, J = 14.2 Hz, 1H), 3.90 (d, J = 14.3 Hz, 1H), 2.50 (s, 3H), 2.03 - 1.90 (m, 1H), 1.76 - 1.66 (m, 3H), 1.54 (s, 4H), 1.19 (s, 3H).

- 364 045220

503 1HNMR (400 MHz, DMSO-C16) δ 8.33 (s, 1H), 8.14 (s, 1H), 7.87 - 7.74 (m, 2H), 7.49 - 7.38 (m , 2H), 7.20 (d, J = 2.5 Hz, 1H), 6.93 (dd, J = 8.3, 3.1 Hz, 1H), 6.24 (d, J = 7, 2 Hz, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 3.85 (dd, J = 13.8, 8.1 Hz, 1H), 3.40 (dd, J = 13.8, 5.1 Hz, 1H), 2.44 (s, 3H), 1.42 (s, 2H), 1.33 (s, 2H), 0.79 (s, 9H). 504 1HNMR (400 MHz, Acetonitril-d3) δ 10.01 (s, 1H), 8.60 (d, J = 6.3 Hz, 1H), 8.41 (s, 1H), 8.30 (d, J = 6.3 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 8.07 - 7.96 (m, 2H), 7.83 (s, 1H), 7, 58 (d, J = 2.2 Hz, 1H), 6.89 (s, 1H), 6.81 (d, J = 2.3 Hz, 1H), 3.95 - 3.75 (m, 2H ), 3.51 (d, J = 13.3 Hz, 1H), 1.17 - 1.07 (m, 4H), 0.69 (s, 9H). 505 1HNMR (400 MHz, Acetonitril-d3) δ 8.46 (s, 1H), 8.18 (m, 1H), 8.04 - 7.96 (m, 1H), 7.97 (s, 1H), 7.57 (d, J = 2.3 Hz, 1H), 7.33 - 7.22 (m, 2H), 6.96 (d, J = 2.3 Hz, 1H), 6.29 (s , 1H), 5.89 (t, J = 54.6 Hz, 1H), 3.98 (dd, J = 13.9, 6.3 Hz, 1H), 3.78 (dd, J = 13, 8, 5.3 Hz, 1H), 1.52 (d, J = 1.2 Hz, 4H), 0.97 (s, 9H). 506 1H NMR (400 MHz, Acetonitril-d3) δ 8.88 (s, 1H), 8.64 (d, J = 5.2 Hz, 1H), 8.42 (s, 1H), 8.25 (d , J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.70 - 7.62 (m, 1H), 7.55 (d, J = 2.3 Hz, 1H), 6 .98 (d, J = 2.3 Hz, 1H), 6.28 (s, 1H), 6.04 - 5.74 (m, 1H), 3.93 (m, 1H), 3.71 m , 1H), 1.52 (s, 4H), 0.96 (s, 9H). 507 1H NMR (400 MHz, Acetonitril-d3) δ 8.68 (dd, J = 5.8, 1.5 Hz, 1H), 8.46 (s, 1H), 8.41 (dd, J = 8, 1, 1.5 Hz, 1H), 7.97 (s, 1H), 7.74 (dd, J = 8.1, 5.8 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 7.38 (s, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.40 (s, 1H), 5.89 (t, J = 54.6 Hz, 1H), 3.95 - 3.79 (m, 2H), 2.79 (s, 3H), 1.53 (d, J = 2.8 Hz, 4H), 0.96 (s, 9H ). 508 1HNMR (400 MHz, Acetonitril-d3) δ 9.07 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.44 (m, 1H) , 8.27 - 8.20 (m, 1H), 7.92 - 7.81 (m, 3H), 7.76 (m, 1H), 7.56 (m, 1H), 6.85 - 6 .76 (m, 2H), 6.67 (s, 1H), 5.85 (t, J = 54.6 Hz, 1H), 3.81 (m, 1H), 3.60 (m, 1H) , 1.48 (m, 4H), 0.72 (s, 9H). 510 1HNMR (400 MHz, Acetonitrile^3) δ 8.43 (s, 1H), 8.36 (m, 1H), 7.94 (s, 1H), 7.97 - 7.90 (m, 1H), 7.51 (m, 1H), 7.36 (m, 1H), 6.80 (m, 1H), 3.82 (m, 1H), 1.52 (s, 4H), 0.98 (s , 9H).

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511 1H NMR (400 MHz, DMSO-C16) δ 8.35 (d, J = 1.2 Hz, 1H), 8.19 - 8.13 (m, 1H), 7.82 (dt, J = 15, 9, 8.2 Hz, 1H), 7.61 (dd, J = 26.8, 2.1 Hz, 1H), 7.43 - 7.28 (m, 1H), 7.09 (s, 1H ), 7.02 - 6.87 (m, 2H), 6.34 (dd, J = 25.4, 7.3 Hz, 1H), 6.29 - 5.98 (m, 1H), 4, 68 (d, J = 18.2 Hz, 1H), 3.92 (s, 1H), 3.78 (d, J = 6.9 Hz, 1H), 2.45 (s, 3H), 2, 50 (m, 2H), 1.50 (d, J = 4.5 Hz, 4H), 1.22 (d, J = 1.2 Hz, ZN), 1.14 (d, J = 1.2 Hz, ZN), 1.09 - 1.06 (m, ZN), 0.80 (s, ZN). 512 1HNMR (400 MHz, DMSO-de) δ 8.36 (s, 1H), 8.18 (s, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.63 (dd, J = 2.3, 1.0 Hz, 1H), 7.50 - 7.34 (m, 2H), 7.00 - 6.90 (m, 2H), 6.29 - 5.97 (m, 2H), 3.92 (dd, J = 14.0, 7.9 Hz, 1H), 3.59 (dd, J = 14.0, 4.9 Hz, 1H), 2.47 (s, 2H ), 2.45 (s, 3H), 1.51 (s, 4H), 0.90 (d, J = 8.0 Hz, 6H). 513 1H NMR (400 MHz, Methanol-d4) δ 8.56 (d, J = 1.9 Hz, 1H), 8.20 (d, J = 1.7 Hz, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.34 (ddd, J = 12.3, 2.3, 1.2 Hz, 1H), 6.95 - 6.77 (m, 2H), 6.25 ( s, 1H), 4.04 (dd, J = 13.9, 1.3 Hz, 1H), 3.87 (dd, J = 13.9, 2.1 Hz, 1H), 2.50 (s , 3H), 1.83 - 1.60 (m, 4H), 0.95 (d, J = 1.0 Hz, 9H). 514 1HNMR (400 MHz, Methanol^4) δ 8.53 (s, 1H), 8.05 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.32 (dd, J = 12.4, 2.2 Hz, 1H), 6.94 - 6.75 (m, 2H), 6.23 (s, 1H), 5.94 (t, J = 54.6 Hz, 1H ), 4.02 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.54 (s, 4H ), 0.94 (s, 9H). 517 1HNMR (400 MHz, Methanol^4) δ 8.50 (s, 1H), 8.03 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.89 - 6.84 (m, 1H), 6.21 (s, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3, 81 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.90 (m, 2H), 1.77 - 1.68 (m, 2H), 0.94 (s , 9H). 518 1H NMR (400 MHz, DMSOM) δ 8.39 - 8.30 (m, 2H), 8.26 (d, J = 1.1 Hz, 1H), 8.05 (td, J = 8.3, 2.5 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.47 (s, 1H), 7.20 - 7.12 (m, 2H), 6.29 - 5.94 (m, 1H), 4.00 (dd, J = 13.9, 8.0 Hz, 1H), 3.45 (dd, J = 13.8, 5.4 Hz, 1H), 1.51 ( s, 4H), 0.87 (d, J = 1.1 Hz, 9H).

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519 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.78 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.39 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.60 (d, J = 3.5 Hz, 1H), 6.44 (s, 1H), 4.12 (d, J = 13.8 Hz, 1H), 3 .86 (s, 3H), 3.60 (d, J = 13.8 Hz, 1H), 1.24 - 1.05 (m, 4H), 0.81 (s, 9H). 520 1HNMR (400 MHz, Methanol-d4) δ 8.88 (s, 1H), 8.47 (s, 1H), 8.12 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.61 - 7.47 (m, 2H), 7.15 (d, J = 2.3 Hz, 1H), 6, 65 (s, 1H), 4.15 (d, J = 13.9 Hz, 1H), 4.04 (s, 3H), 3.69 (d, J = 14.0 Hz, 1H), 1, 79 - 1.56 (m, 4H), 0.88 (s, 9H). 521 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.70 (d, J = 2.3 Hz , 1H), 7.69 - 7.63 (m, 1H), 7.37 (d, J = 6.9 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 7 .05 (dd, J = 8.4, 6.9 Hz, 1H), 6.64 (s, 1H), 4.22 (s, 3H), 4.15 (d, J = 13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 1.76 - 1.52 (m, 4H), 0.83 (s, 9H). 522 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.17 (s, 1H), 7.98 (dd, J = 5.3, 4.0 Hz, 1H), 7 .69 (d, J = 2.3 Hz, 1H), 7.39 - 7.31 (m, 2H), 6.97 (d, J = 2.4 Hz, 1H), 6.82 (s, 1H), 4.39 (s, 3H), 3.93 (d, J = 13.9 Hz, 1H), 3.78 (d, J = 13.9 Hz, 1H), 1.79 - 1, 63 (m, 4H), 0.78 (s, 9H). 523 1HNMR (400 MHz, Methanol-d4) δ 9.25 (s, 1H), 8.31 (s, 1H), 8.12 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H) , 7.18 (d, J = 2.5 Hz, 1H), 6.87 (s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.26 (s, 3H) , 3.71 (d, J = 1.2 Hz, 2H), 1.54 (s, 4H), 0.81 (s, 9H). 524 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.95 (s, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.3 Hz, 1H), 7.28 (dd, J = 8.4, 7.2 Hz, 1H), 6.97 (d, J = 7.1 Hz, 1H), 6.89 ( d, J = 2.3 Hz, 1H), 6.70 (s, 1H), 3.96 (d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 1.84 - 1.56 (m, 4H), 0.77 (s, 9H).

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525 1H NMR (400 MHz, DMSOLb) δ 8.35 (d, J = 1.4 Hz, 1H), 8.25 (d, J = 1.0 Hz, 1H), 8.07 (s, 1H), 7.80 (s, 1H), 7.68 (d, J = 2.1 Hz, 1H), 7.59 (s, 1H), 7.50 (dt, J = 7.7, 1.2 Hz , 1H), 7.34 - 7.23 (m, 2H), 7.14 (d, J = 2.2 Hz, 1H), 6.46 (s, 1H), 5.19 (s, 1H) , 3.98 (s, 3H), 3.40 (dd, J = 13.8, 5.3 Hz, 1H), 1.59 (s, 3H), 1.26 - 1.18 (m, 2H ), 1.04 - 0.96 (m, 2H), 0.81 (s, 9H). 526 1HNMR (400 MHz, MethanolL4) δ 8.33 (s, 1H), 8.24 (s, 1H), 8.00 (s, 1H), 7.84 (d, J = 2.5 Hz, 1H) , 7.70 - 7.63 (m, 1H), 7.38 (d, J = 6.9 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 7.05 ( dd, J = 8.4, 7.0 Hz, 1H), 6.62 (s, 1H), 4.22 (s, 3H), 3.94 (d, J = 13.8 Hz, 1H), 3.55 (d, J = 13.7 Hz, 1H), 1.72 - 1.58 (m, 4H), 0.78 (s, 9H). 527 1HNMR (400 MHz, MethanolL4) δ 8.35 (s, 1H), 8.17 (s, 1H), 7.97 (t, 1H), 7.82 (d, J = 2.5 Hz, 1H) , 7.36 (d, J = 4.8 Hz, 2H), 7.16 (d, J = 2.6 Hz, 1H), 6.83 (s, 1H), 4.41 (s, 3H) , 3.76 (d, J = 13.9 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1.78 - 1.62 (m, 4H), 0.74 ( s, 9H). 528 1HNMR (400 MHz, MethanolL4) δ 8.33 (s, 1H), 7.95 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 8.4, 7.2 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.70 (s, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.57 (d, J = 13.5 Hz, 1H) , 2.54 (s, 3H), 1.78 - 1.56 (m, 4H), 0.72 (s, 9H). 529 1H NMR (400 MHz, DMSOLb) δ 8.30 - 8.22 (m, 2H), 8.08 (d, J = 0.4 Hz, 1H), 7.88 (d, J = 2.3 Hz , 1H), 7.57 (s, 1H), 7.50 (ddd, J = 7.4, 1.9, 1.0 Hz, 1H), 7.43 7.34 (m, 2H), 7 .34 - 7.23 (m, 2H), 6.48 (s, 1H), 3.98 (s, 3H), 3.91 (dd, J = 13.8, 8.0 Hz, 1H), 3.35 (dd, J =13.8, 5.2 Hz, 1H), 1.59 (s, 3H), 1.27-1.18 (m, 2H), 1.05 - 0.96 ( m, 2H), 0.79 (s, 9H). 530 1HNMR (400 MHz, MethanolL4) δ 8.51 (s, 1H), 7.95 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.20 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.64 (s, 9H), 0.93 (s, 9H).

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531 1HNMR (400 MHz, MethanolU4) δ 8.50 (s, 1H), 7.98 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.22 (s, 1H), 4.63 (d, J = 47.1 Hz, 2H), 4.03 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H) , 2.49 (s, 3H), 1.67 (s, 6H), 0.93 (s, 9H). 532 1HNMR (400 MHz, MethanolU4) δ 8.51 (s, 1H), 7.92 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.27 (tt, J = 56 Hz, J = 3.3 Hz, 1H), 6.25 (s, 1H), 4.95 - 4.86 (m, 2H), 4.04 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 0.94 (s, 9H). 533 1HNMR (400 MHz, AcetonitrileUS) δ 9.88 (s, 1H), 8.51 (s, 1H), 8.22 (m, 1H), 8.12 (s, 1H), 8.03 - 7, 92 (m, 1H), 7.87 (m, 3H), 7.46 (m, 1H), 6.95 (s, 1H), 6.62 (s, 1H), 6.22 (s, 1H ), 3.71 (s, 2H), 3.35 (m, 1H), 1.57 -1.45 (m, 4H), 0.50 (s, 9H). 534 1HNMR (400 MHz, AcetonitrileUS) δ 8.43 (s, 1H), 8.31 (s, 1H), 7.97 (s, 1H), 7.84 (m, 1H), 7.44 (m, 1H), 6.88 - 6.75 (m, 2H), 6.09 (s, 1H), 3.89 (m, 2H), 3.62 - 3.51 (m, 2H), 2.51 (s, 3H), 1.73 (s, 1H), 1.78 - 1.65 (m, 1H), 1.65 (s, 2H), 0.98 (s, 9H). 535 1H NMR (400 MHz, AcetonitrileUS) δ 10.37 (s, 1H), 8.56 (d, J = 6.5 Hz, 1H), 8.38 (d, J = 6.6 Hz, 1H), 8.18 - 8.06 (m, 1H), 8.08 - 7.97 (m, 3H), 7.92 (m, 1H), 7.74 (d, J = 2.4 Hz, 1H) , 7.53 (s, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.29 (s, 1H), 3.85 - 3.73 (m, 1H), 3, 27 (m, 1H), 1.77 - 1.60 (m, 3H), 1.56 - 1.47 (m, 1H), 0.42 (s, 9H). 536 1HNMR (400 MHz, AcetonitrileUS) δ 9.50 (s, 1H), 8.83 - 8.59 (m, 2H), 8.48 (d, J = 6.7 Hz, 1H), 8.31 - 8.08 (m, 3H), 7.87 - 7.66 (m, 2H), 7.50 (d, J = 2.1 Hz, 1H), 7.26 (s, 1H), 7.08 (d, J = 2.3 Hz, 1H), 6.69 (s, 1H), 5.73 (t, J = 54.5 Hz, 1H), 3.95 (dd, J = 13.8, 8.1 Hz, 1H), 3.55 (dd, J = 13.8, 5.1 Hz, 1H), 1.48 - 1.17 (m, 4H), 0.50 (s, 9H).

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537 1HNMR (400 MHz, Acetonitrile-03) δ 9.07 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 8.6 Hz, 1H), 8.44 (m, 1H) , 8.27 - 8.20 (m, 1H), 7.92 - 7.81 (m, 3H), 7.76 (m, 1H), 7.56 (m, 1H), 6.85 - 6 .76 (m, 2H), 6.67 (s, 1H), 5.85 (t, J = 54.6 Hz, 1H), 3.81 (m, 1H), 3.60 (m, 1H) , 1.48 (m, 4H), 0.72 (s, 9H). 538 1HNMR (400 MHz, Methanol) δ 8.51 (d, J = 7.0 Hz, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 2, 3 Hz, 1H), 6.86 (t, J = 7.0 Hz, 1H), 6.62 (dd, J = 2.5, 1.0 Hz, 1H), 6.38 (s, 1H) , 4.09 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 1.58 - 1.44 (m, 4H), 0.84 ( s, 9H). 539 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.03 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 6.89 - 6.82 (m, 1H), 6.75 (d, J = 2.2 Hz, 1H), 6.23 (s, 1H), 5, 96 (t, J = 54.7 Hz, 1H), 4.59 (dd, J = 11.5, 4.3 Hz, 1H), 4.09 - 4.01 (m, 1H), 3.58 - 3.46 (m, 2H), 3.21 (d, J = 11.7 Hz, 1H), 2.43 (s, 3H), 2.21 - 1.99 (m, 1H), 1, 94 (d, J = 13.1 Hz, 1H), 1.55 (s, 4H), 0.90 (s, 3H), 0.55 (s, 3H). 540 1H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 8.09 (s, 1H), 7.66 - 7.58 (m, 2H), 7.09 (d, J = 2.3 Hz, 1H), 6.94 - 6.86 (m, 1H), 6.34 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.76 ( dd, J = 11.7, 4.4 Hz, 1H), 4.06 (dd, J = 11.8, 4.7 Hz, 1H), 3.60 3.49 (m, 2H), 3, 25 (d, J = 11.7 Hz, 1H), 2.59 (s, 3H), 2.18 - 2.05 (m, 1H), 1.92 (d, J = 12.6 Hz, 1H ), 1.58 - 1.48 (m, 4H), 1.05 (s, 3H), 0.74 (s, 3H). 541 1HNMR (400 MHz, Methanol-d4) δ 8.21 (s, 1H), 8.19 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.22 ( s, 1H), 3.81 (d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.97 - 1.90 (m, 6H), 0.87 (s, 9H). 542 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.01 (s, 1H), 8.00 - 7.91 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.45 - 7.28 (m, 2H), 6.95 (d, J = 2.3 Hz, 1H), 6.80 (s, 1H), 5.93 ( t, J = 54.6 Hz, 1H), 4.38 (s, 3H), 3.95 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 1.61 - 1.42 (m, 4H), 0.77 (s, 9H).

- 370 045220

543 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.09 (d, J = 1.0 Hz, 1H), 8.01 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.27 ( d, J = 7.0 Hz, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.49 (s, 1H), 4.14 (d, J = 13.8 Hz, 1H), 4.05 (s, 3H), 3.64 (d, J = 13.9 Hz, 1H), 1.77 - 1.55 (m, 4H), 0.85 (s, 9H). 544 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.25 (s, 1H), 8.03 (s, 1H), 7.70 (d, J = 2.3 Hz , 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.6, 6.9 Hz, 1H), 7.19 (d, J = 6, 8 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.37 (s, 1H), 4.17 (s, 3H), 4.14 (d, J = 13, 8 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.74 - 1.59 (m, 4H), 0.84 (s, 9H). 545 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.05 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.7 Hz, 1H), 6.24 ( s, 1H), 6.12 (t, J = 56.0 Hz, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.76 (s, 6H), 0.94 (s, 9H). 546 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 7.94 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.23 ( s, 1H), 5.10 - 4.93 (m, 1H), 4.77 - 4.72 (m, 1H), 4.64 - 4.60 (m, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3.85 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 1.57 (d, J = 7.1, 3H), 0.94(s,9H). 547 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.02 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.20 ( s, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.55 ( m, 1H), 1.27 - 1.20 (m, 2H), 1.03 (m, 2H), 0.94 (s, 9H), 0.57 - 0.48 (m, 2H), 0 .37 - 0.30 (m, 2H). 548 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.27 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.5, 2.8 Hz, 1H), 6.30 ( s, 1H), 5.28 - 5.21 (m, 2H), 5.18 (d, J = 8.3 Hz, 2H), 4.03 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 14.0 Hz, 1H), 2.52 (s, 3H), 0.94 (s, 9H).

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549 1H NMR (400 MHz, Acetonitrile-43) δ 8.44 (s, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.49 (4, J = 2.3 Hz, 1H ), 6.84 (44, J = 8.4, 3.2 Hz, 1H), 6.78 (s, 1H), 6.17 (s, 1H), 3.83 (m, 2H), 1 .78 - 1.65 (m, 2H), 1.65 (m, 2H), 0.95 (s, 9H). 550 1HNMR (400 MHz, Acetonitrile-43) δ 9.14 - 9.06 (m, 2H), 8.37 (s, 1H), 8.32 8.25 (m, 1H), 8.00 - 7, 81 (m, 4H), 7.74 (4, J = 2.5 Hz, 1H), 6.91 (4, J = 2.5 Hz, 1H), 6.82 (s, 1H), 5, 85 (t, J = 54.6 Hz, 1H), 5.80 (s, 1H), 3.68 m, 1H), 3.48 (m, 1H), 1.53 - 1.43 (m, 4H), 0.69 (s, 9H). 551 1HNMR (400 MHz, Acetonitrile-43) δ 9.65 (m, 1H), 9.12 - 9.01 (m, 2H), 8.46 (s, 1H), 8.42 (m, 1H), 8.31 (s, 1H), 8.06 - 7.96 (m, 2H), 7.94 (m, 1H), 7.86 (s, 1H), 7.64 (m, 1H), 7 .50 (s, 1H), 7.23 (m, 1H), 6.88 (s, 1H), 5.83 (t, J = 54.6 Hz, 1H), 4.09 (m, 1H) , 3.64 (m, 1H), 1.53 - 1.32 (m, 4H), 0.58 (s, 9H). 552 1H NMR (400 MHz, Acetonitrile-43) δ 9.98 (s, 1H), 8.60 (4, J = 6.3 Hz, 1H), 8.38 - 8.29 (m, 2H), 8 .15 (4, J = 8.0 Hz, 1H), 8.09 - 7.98 (m, 3H), 7.76 (4, J = 2.5 Hz, 1H), 6.95 - 6, 88 (m, 2H), 6.30 (s, 1H), 5.88 (t, J = 54.6 Hz, 1H), 3.76 (m, 1H), 3.39 (m, 1H), 1.56 - 1.42 (m, 4H), 0.65 (m, 9H). 553 1HNMR (400 MHz, Methanol-44) δ 8.20 (s, 1H), 8.00 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.47 (4, J = 2.4 Hz, 1H), 6.86 (44, J = 8.5, 2.7 Hz, 1H), 6.73 (4, J = 2.4 Hz, 1H), 6.19 ( s, 1H), 3.82 (4, J = 13.7 Hz, 1H), 3.57 (4, J = 13.8 Hz, 1H), 2.93 (s, 6H), 2.51 ( s, 3H), 1.74 - 1.62 (m, 4H), 0.88 (s, 9H). 554 1HNMR (400 MHz, Methanol-44) δ 8.52 (s, 1H), 8.07 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.64 (4, J = 2.3 Hz, 1H), 6.95 (4, J = 2.3 Hz, 1H), 6.88 (44, J = 8.5, 2.7 Hz, 1H), 6.23 ( s, 1H), 4.09 (4, J = 13.9 Hz, 1H), 3.81 (4, J = 14.0 Hz, 1H), 3.39 (m, 2H), 3.08 ( m, 2H), 2.50 (s, 3H), 1.74 (m, 6H), 1.63 (m, 2H), 0.95 (s, 9H). 555 1HNMR (400 MHz, Methanol-44) δ 8.20 (s, 1H), 8.02 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.48 (4, J = 2.4 Hz, 1H), 6.87 (44, J = 8.5, 2.7 Hz, 1H), 6.77 (4, J = 2.4 Hz, 1H), 6.21 ( s, 1H), 3.84 (4, J = 13.7 Hz, 1H), 3.62 - 3.52 (m, 5H), 3.40 (m, 4H), 2.53 (s, 3H ), 1.77 - 1.67 (m, 2H), 1.65 (m, 2H), 0.89 (s, 9H).

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556 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.81 (s, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.49 - 7, 42 (m, 1H), 7.28 (dd, J = 8.4, 7.2 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.70 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.73 (d, J = 13.8 Hz, 1H), 2.52 (s, 3H), 1.50 (s, 4H), 0.77 (s, 9H). 557 1HNMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.11 (d, J = 1.0 Hz, 1H), 8.04 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.39 (dd, J = 8.5, 7.1 Hz, 1H), 7.29 ( d, J = 7.1 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.49 (s, 1H), 4.05 (s, 3H), 3.94 ( d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 1.76 - 1.58 (m, 4H), 0.79 (s, 9H). 558 1HNMR (400 MHz, Methanol^4) δ 8.36 (d, J = 0.6 Hz, 1H), 8.29 (s, 1H), 8.06 (s, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.26 (dd, J = 8.6, 6.9 Hz, 1H), 7.23 - 7.18 (m, 2H), 6.37 (s, 1H), 4.17 (s, 3H), 3.99 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 13, 7 Hz, 1H), 1.77 - 1.59 (m, 4H), 0.80 (s, 9H). 559 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.02 (s, 1H), 7.99 - 7.94 (m, 1H), 7.83 (d, J= 2.5 Hz, 1H), 7.40 - 7.33 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.81 (s, 1H), 5.93 ( t, J = 54.7 Hz, 1H), 4.40 (s, 3H), 3.77 (d, J = 13.9 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1.55 - 1.49 (m, 4H), 0.72 (s, 9H). 560 1HNMR (400 MHz, Methanol^4) δ 8.52 (d, J = 7.0 Hz, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.96 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.28 (dt, J = 7.0, 0.9 Hz, 1H), 7.03 ( d, J = 2.4 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 6.61 (dd, J = 2.4, 0.9 Hz, 1H), 6, 39 (s, 1H), 4.10 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 1.79 - 1.57 (m, 4H ), 0.83 (s, 9H). 561 1HNMR (400 MHz, Methanol^4) δ 9.64 (s, 1H), 8.56 (d, J = 6.6 Hz, 1H), 8.48 (s, 1H), 8.41 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 7.3 Hz, 1H), 8.07 (s, 1H) , 7.88 (dd, J = 8.3, 7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.87 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.59 (d, J = 13.9 Hz, 1H), 1.88 - 1, 75 (m, 2H), 1.64-1.52 (m, 2H), 0.72 (s, 9H).

- 373 045220

562 1HNMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.55 (d, J = 6.5 Hz, 1H), 8.46 (s, 1H), 8.38 - 8, 29 (m, 2H), 8.09 (d, J = 7.3 Hz, 1H), 7.96 (s, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7, 66 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.87 (s, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 2.99 - 2.86 (m, 1H), 2.81 (m,lH), 2.59 (m, 1H ), 2.40 - 2.24 (m, 1H), 2.18-1.95 (m, 2H), 0.72 (s, 9H). 563 1HNMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.56 (d, J = 6.5 Hz, 1H), 8.47 (s, 1H), 8.37 - 8, 29 (m, 2H), 8.23 (s, 1H), 8.06 (d, J = 7.3 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7, 67 (d, J = 2.3 Hz, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.89 (s, 1H), 3.98 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 2.01 - 1.94 (m, 2H), 1.94 - 1.83 (m, 2H), 0.73 (s, 9H). 564 1HNMR (400 MHz, Methanol-d4) δ 9.55 (s, 1H), 8.54 (d, J = 6.5 Hz, 1H), 8.45 (s, 1H), 8.28 (m, 2H), 8.03 (d, J = 7.3 Hz, 1H), 7.95 (s, 1H), 7.82 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.82 (s, 1H), 3.97 (d, J = 13.8 Hz, 1H) , 3.63 (d, J = 13.9 Hz, 1H), 1.63 (s, 3H), 1.29 (m, 2H), 1.08 - 1.01 (m, 2H), 0, 71 (s, 9H). 565 1HNMR (400 MHz, AcetonitrileM3) δ 9.13 - 8.99 (m, 2H), 8.43 (s, 1H), 8.31 8.24 (m, 1H), 7.97 - 7.87 ( m, 2H), 7.86 - 7.77 (m, 2H), 7.56 (m, 1H), 7.01 (s, 1H), 6.91 - 6.81 (m, 2H), 5 .97 (s, 1H), 5.66 (s, 1H), 3.88 (m, 1H), 3.60 (m, 1H), 1.94 (m, 1H) 1.73 (m, 1H ), 1.56 - 1.41 (m, 2H), 0.73 (s, 9H). 566 1H NMR (400 MHz, Acetonitril-d3) δ 9.14 - 9.05 (m, 2H), 8.44 (s, 1H), 8.29 (m, 1H), 7.98 - 7.76 ( m, 4H), 7.56 (m, 1H), 7.13 (s, 1H), 6.91 - 6.83 (m, 2H), 6.58 (s, 1H), 5.96 (s , 1H), 3.90 (m, 1H), 3.61 (m, 1H), 2.93 - 2.80 (m, 2H), 2.79 - 2.64 (m, 2H), 2, 12 - 1.96 (m, 2H), 0.73 (s, 9H). 567 1HNMR (400 MHz, Acetonitrile SW) δ 9.09 (dd, J = 4.8, 1.5 Hz, 1H), 8.96 (d, J = 8.5 Hz, 1H), 8.43 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.95 - 7.83 (m, 3H), 7.80 (dd, J = 8.7, 4.8 Hz, 1H ), 7.55 (d, J = 2.3 Hz, 1H), 6.93 (s, 1H), 6.87 - 6.79 (m, 2H), 6.42 (s, 1H), 3 .85 (dd, J = 13.7, 6.6 Hz, 1H), 3.63 (dd, J = 13.4, 5.1 Hz, 1H), 1.97 - 1.76 (m, 4H ), 0.73 (s, 9H).

- 374 045220

568 1HNMR (400 MHz, Acetonitrile-03) δ 9.09 (dd, J = 4.8, 1.5 Hz, 1H), 9.01 (d, J = 8.8 Hz, 1H), 8.43 ( s, 1H), 8.30 - 8.22 (m, 1H), 7.93 - 7.86 (m, 2H), 7.90 - 7.76 (m, 1H), 7.73 (s, 1H), 7.55 (d, J = 2.2 Hz, 1H), 6.89 (m, 1H), 6.80 (s, 2H), 3.84 (dd, J = 13.6, 6 .7 Hz, 1H), 3.61 (dd, J= 13.6, 5.0 Hz, 1H), 1.60 (s, 3H), 1.28-1.19 (m, 2H), 1 .05 - 0.98 (m, 2H), 0.72 (s, 9H). 569 1H NMR (400 MHz, DMSOLb) δ 9.44 (s, 1H), 8.57 (d, J = 6.0 Hz, 1H), 8.31 (s, 1H), 8.13 (d, J = 5.7 Hz, ZN), 7.89 - 7.83 (m, 2H), 7.69 (t, J = 7.7 Hz, 1H), 7.61 (d, J = 7.5 Hz , 1H), 7.31 - 7.19 (m, 2H), 6.90 (d, J = 7.3 Hz, 1H), 4.71 (s, 1H), 4.59 (s, 1H) , 3.70 (dd, J = 13.7, 7.6 Hz, 1H), 3.42 - 3.33 (m, 1H), 1.41 - 1.27 (m, 4H), 0.58 (s, 9H). 570 1H NMR (400 MHz, Methanol^4) δ 8.45 (s, 1H), 8.25 (s, 1H), 7.98 (s, 1H), 7.72 - 7.64 (m, 2H) , 7.37 (d, J = 6.9 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.63 (s, 1H), 4.22 (s, 3H), 4, 12 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.9 Hz, 1H), 1.80-1.50 (m, 2H), 1.28 (s, 2H ), 0.82 (s, 9H). 571 1HNMR (400 MHz, Methanol^4) δ 8.36 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.81 (s, 1H), 7.48 - 7, 41 (m, 1H), 7.29 (dd, J = 8.5, 7.1 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 7.1 Hz, 1H), 6.69 (s, 1H), 3.80 (d, J = 13.6 Hz, 1H), 3.58 (d, J = 13.6 Hz, 1H), 2.54 (s, 3H), 1.50 (d, J = 2.3 Hz, 4H), 0.72 (s, 9H). 572 1HNMR (400 MHz, Methanol^4) δ 8.51 (d, J = 7.0 Hz, 1H), 8.37 (s, 1H), 8.20 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.18 (d, J = 2.5 Hz, 1H), 6.87 (t, J = 7.0 Hz, 1H), 6.63 (dd, J = 2.5, 1.0 Hz, 1H), 6.39 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H), 1.79 - 1.57 (m, 4H), 0. 78 (s, 9H). 573 1HNMR (400 MHz, Methanol^4) δ 8.35 (s, 1H), 8.25 (s, 1H), 8.00 (s, 1H), 7.85 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 7.0 Hz, 1H), 7.26 (d, J = 2.5 Hz, 1H) , 7.05 (dd, J = 8.4, 7.0 Hz, 1H), 6.63 (s, 1H), 4.23 (s, 3H), 3.98 (d, J = 13.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.73 - 1.58 (m, 4H), 0.79 (s, 9H).

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574 1H NMR (400 MHz, Acetonitrile-a3) δ 8.41 (s, 1H), 7.81 (t, J = 8.2 Hz, 1H), 7.68 (d, J = 2.4 Hz, 1H ), 6.97 (d, J = 2.4 Hz, 1H), 6.84 (dd, J = 8.4, 3.1 Hz, 1H), 6.41 (s, 1H), 6.17 (s, 1H), 3.84 - 3.69 (m, 2H), 2.50 (s, 3H), 1.79 - 1.61 (m, 4H), 0.94 (s, 9H). 575 1HNMR (400 MHz, Acetonitril-d3) δ 9.27 - 9.20 (m, 1H), 9.17 - 9.10 (m, 1H), 8.40 - 8.29 (m, 2H), 8 .05 - 7.92 (m, 3H), 7.85 (s, 1H), 7.75 (d, J = 2.5 Hz, 1H), 6.93 (d, J = 2.5 Hz, 1H), 6.83 (s, 1H), 5.92 (s, 1H), 5.62 (s, 1H), 3.78 - 3.68 (m, 1H), 3.52 - 3.42 (m, 1H), 1.76 - 1.71 (m, 2H), 1.57 - 1.37 (m, 2H), 0.69 (s, 9H). 576 1HNMR (400 MHz, Chloroform-d) δ 8.91 (m, 1H), 8.55 (m, 1H), 8.33 (s, 1H), 8.08 (m, 1H), 7.70 ( m, 2H), 7.56 - 7.44 (m, 2H), 7.31 (s, 1H), 7.22 (s, 2H), 6.60 (m, 1H), 6.50 (m , 1H), 3.45 (m, 2H), 2.87-2.67 (m, 2H), 2.15 - 1.81 (m, 2H), 0.57 (s, 9H). 577 1HNMR (400 MHz, Acetonitrile^3) δ 9.14 - 9.03 (m, 2H), 8.37 (s, 1H), 8.30 (d, J = 8.3 Hz, 1H), 8, 00 - 7.84 (m, 4H), 7.73 (d, J = 2.4 Hz, 1H), 6.91 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H ), 5.82 (s, 1H), 3.68 (dd, J = 13.3, 6.7 Hz, 1H), 3.49 (dd, J = 13.4, 5.2 Hz, 1H) , 1.97 - 1.79 (m, 4H), 0.69 (s, 9H). 578 1H NMR (400 MHz, Acetonitril-d3) δ 9.18 - 9.08 (m, 2H), 8.33 (d, J = 22.8 Hz, 2H), 8.01 - 7.86 (m, 3H), 7.73 (t, J = 1.2 Hz, 2H), 6.90 (d, J = 2.5 Hz, 1H), 6.79 (s, 1H), 6.21 (s, 1H), 5.83 (s, 1H), 3.68 (dd, J = 13.3, 6.8 Hz, 1H), 3.48 (dd, J = 13.4, 5.0 Hz, 1H ), 1.60 (s, 3H), 1.25 (s, 2H), 1.05 - 0.98 (m, 2H), 0.68 (s, 9H). 579 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.94 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.22 ( s, 1H), 5.98 - 4.79 (m, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.95 - 3.81 (m, 2H), 2.50 (s, 3H), 2.02 - 1.89 (m, 1H), 1.67 - 1.55 (m, 1H), 0.93 (s, 9H).

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580 1HNMR (400 MHz, Methanol-04) δ 9.74 (s, 1H), 8.60 (d, J = 6.5 Hz, 1H), 8.53 (d, J = 6.8 Hz, 1H) , 8.43 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 8.29 (s, 1H), 8.20 (d, J = 7.4 Hz, 1H) , 7.95 (dd, J = 8.3, 7.4 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 6.91 (s, 1H), 3.79 (d, J = 13.8 Hz, 1H), 3.51 (d, J = 13.8 Hz, 1H), 2.05 1.94 (m, 2H), 1.94 - 1.86 (m, 2H), 0.69 (s, 9H). 581 1HNMR (400 MHz, Methanol-44) δ 9.73 (s, 1H), 8.59 (d, J = 6.7 Hz, 1H), 8.53 (d, J = 6.7 Hz, 1H) , 8.42 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.19 (d, J = 7.3 Hz, 1H), 8.04 (s, 1H) , 7.95 (dd, J = 8.3, 7.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.86 (s, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.50 (d, J = 13.8 Hz, 1H), 1.64 (s, 3H), 1.34 - 1.25 (m, 2H), 1.09 - 1.00 (m, 2H), 0.68 (s, 9H). 582 1H NMR (400 MHz, DMSO-46) δ 8.40 - 8.34 (m, 2H), 7.81 (t, J = 8.3 Hz, 1H), 7.68 - 7.62 (m, 1H), 7.43 (d, J = 7.0 Hz, 1H), 6.90 (dd, J = 8.4, 3.1 Hz, 1H), 6.77 (d, J = 2.4 Hz, 1H), 6.30 (dd, J = 21.8, 6.2 Hz, 1H), 4.48 - 4.20 (m, 1H), 2.39 (s, 3H), 1.83 - 1.59 (m, 4H), 1.26 (dd, J = 19.5, 6.6 Hz, 4H), 0.85 (s, 3H), 0.67 (s, 9H) 583 1HNMR (400 MHz, DMSO-46) δ 8.37 (dd, J = 14.4, 8.7 Hz, 2H), 7.89 (d, J = 2.3 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.52 (d, J = 7.0 Hz, 1H), 7.35 - 7.29 (m, 1H), 7.05 (d, J = 2.5 Hz , 1H), 6.93 - 6.83 (m, 2H), 6.70 (d, J = 10.5 Hz, OH), 6.28 (d, J = 6.5 Hz, 1H), 4 .24 (dd, J = 10.5, 6.6 Hz, 1H), 2.39 (s, 3H), 1.81 - 1.60 (m, 4H), 1.26 (dd, J = 17 ,3, 6.6 Hz, 4H), 0.85 (s, 3H), 0.67 (s, 9H). 584 1HNMR (400 MHz, Methanol-44) δ 8.53 (s, 1H), 8.33 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.31 ( s, 1H), 4.38 (ddd, J = 11.7, 10.7, 1.5 Hz, 2H), 4.00 (d, J = 14.0 Hz, 1H), 3.91 (d , J = 14.0 Hz, 1H), 2.53 (s, 3H), 0.95 (s, 9H). 585 1H NMR (400 MHz, DMSO-46) δ 8.35 (d, J = 9.9 Hz, 2H), 7.86 (t, J = 8.2 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1H), 7.49 - 7.32 (m, 2H), 7.24 (d, J = 8.5 Hz, 1H), 7.01 6.94 (m, 1H), 6.35 (d, J = 7.8 Hz, 1H), 4.17 (s, 1H), 2.06 (s, 1H), 1.89 (d, J = 12.0 Hz, 1H), 1.82 - 1.58 (m, 8H), 1.54 - 1.12 (m, 6H).

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586 1H NMR (400 MHz, Methanol-d4) δ 9.76 (s, 1H), 8.63 - 8.55 (m, 2H), 8.44 (d, J = 8.2 Hz, 1H), 8 .29 (m, 2H), 8.13 (s, 1H), 7.96 (dd, J = 8.3, 7.4 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 3.84 (d, J = 13.8 Hz, 1H), 3.44 (d, J = 13.8 Hz, 1H), 1.86 - 1.77 (m, 2H), 1.63 - 1.52 (m, 2H), 0.67 (s, 9H). 587 1H NMR (400 MHz, Methanol) δ 9.74 (s, 1H), 8.63 - 8.57 (m, 1H), 8.55 (m, 1H), 8.42 (d, J = 8, 3 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J = 7.3 Hz, 1H), 8.03 (s, 1H), 7.95 (dd, J = 8, 3, 7.4 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.13 (d, J = 2.5 Hz, 1H), 6.90 (s, 1H) , 3.82 (d, J = 13.8 Hz, 1H), 3.48 (d, J = 13.8 Hz, 1H), 2.93 (m, 2H), 2.81 (m, 2H) , 2.16 - 1.95 (m, 2H), 0.69 (s, 9H). 588 1H NMR (400 MHz, DMSOLb) δ 8.37 (s, 1H), 8.36 (s, 1H), 7.87 (t, J = 8.3 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.48 - 7.37 (m, 2H), 7.08 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 8.4, 3.0 Hz, 1H), 6.34 (d, J = 7.2 Hz, 1H), 4.20 (s, OH), 2.52 (s, 3H), 2.07 (d, J = 10.4 Hz, 1H), 1.89 (d, J = 12.1 Hz, 1H), 1.84 - 1.60 (m, 8H), 1.54 - 1.27 (m, 4H), 1.27-1.14 (m, 1H). 589 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.95 (s, 1H), 7.84 - 7.76 (m, 2H), 7.08 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.20 (s, 1H), 3.89 (d, J = 13.9 Hz, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.64 (s, 9H), 0.90 (s, 9H). 590 1H NMR (400 MHz, MethanolL4) δ 8.39 (s, 1H), 8.05 (s, 1H), 7.83 - 7.75 (m, 2H), 7.11 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 (s, 1H), 6.12 (t, J = 55.5 Hz, 1H) , 3.90 (d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.76 (d, J = 1.6 Hz, 6H), 0.90 (s, 9H). 591 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.21 (s, 1H), 7.83 - 7.75 (m, 2H), 7.11 (d, J= 2.5 Hz, 1H), 6.88 (dd, J = 8.4, 2.7 Hz, 1H), 6.25 (s, 1H), 3.89 (d, J = 13.9 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.94 (s, 6H), 0.90 (s, 9H). 592 1HNMR (400 MHz, Methanol^4) δ 8.48 (s, 1H), 8.05 (s, 1H), 7.76 (m, 1H), 7.60 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.86 (m, 1H), 6.30 (s, 1H), 5.92 (t, J = 54.6 Hz, 1H), 3.92 (m, 2H), 2.85 (dt, J = 15.3, 7.5 Hz, 2H), 1.53 (s, 4H), 1.15 (t, J = 7 .5 Hz, 3H), 0.94 (s, 9H).

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593 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.21 (s, 1H), 7.76 (s, OH), 7.61 (d, J = 2.3 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.86 (m, 1H), 6.31 (s, 1H), 3.93 (m, 2H), 2.94 - 2.70 (m, 2H), 1.84 - 1.54 (m, 4H), 1.15 (t, J = 7.5 Hz, 3H), 0.94 (s, 9H). 594 1H NMR (400 MHz, DMC0-d6) δ 9.76 (s, 1H), 8.61 (d, J = 6.0 Hz, 1H), 8.28 (s, 1H), 8.21 (s , 1H), 8.12 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.91 - 7.79 (m, 2H), 7.67 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J = 6.8 Hz, 1H), 6 .95 (s, 1H), 4.72 (s, 1H), 4.60 (s, 1H), 3.83 - 3.70 (m, 1H), 3.26 (dd, J = 13.7 , 4.9 Hz, 1H), 1.42 - 1.27 (m, 4H), 0.99 (s, 1H), 0.51 (s, 9H). 595 1HNMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.19 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.06 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.56 (d, J = 1.9 Hz, 1H), 6.26 ( s, 1H), 4.04 (m, 4H), 3.83 (d, J = 14.0 Hz, 1H), 2.51 (s, 3H), 1.83 - 1.60 (m, 4H ), 0.93 (s, 9H). 596 1HNMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.22 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 6.95 - 6.80 (m, 1H), 6.55 (d, J = 1.9 Hz, 1H), 6.25 (s, 1H), 4, 04 (m, 4H), 3.84 (d, J = 14.0 Hz, 1H), 2.52 (s, 3H), 2.08 - 1.84 (m, 4H), 0.93 (s , 9H). 597 1H NMR (400 MHz, Methanol^4) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.84 - 7.67 (m, 2H), 7.14 (d, J = 2.5 Hz, 1H), 6.86 (m, 1H), 6.30 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.90 - 3.68 ( m, 2H), 2.96 - 2.76 (m, 2H), 1.58 - 1.44 (m, 4H), 1.15 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H). 598 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.21 (s, 1H), 7.85 - 7.74 (m, 2H), 7.14 (d, J= 2.6 Hz, 1H), 6.86 (m, 1H), 6.31 (s, 1H), 3.78 (d, J = 2.6 Hz, 2H), 2.86 (m, 2H) , 1.84 - 1.54 (m, 4H), 1.15 (t, J = 7.5 Hz, 3H), 0.90 (s, 9H). 599 1H NMR (400 MHz, Methanol^4) δ 8.37 (s, 1H), 8.28 - 8.13 (m, 3H), 7.53 (d, J = 2.3 Hz, 1H), 7 .44 (s, 1H), 6.97 (d, J = 6.7 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.67 (t, J = 6, 9 Hz, 1H), 6.29 (s, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.46 (d, J = 13.6 Hz, 1H), 1.78 - 1.58 (m, 4H), 0.77 (s, 9H).

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600 1HNMR (400 MHz, Methanol-04) δ 8.69 (dd, J = 5.6, 1.6 Hz, 1H), 8.51 (s, 1H), 8.38 (s, 1H), 8, 34 (dd, J = 8.0, 1.5 Hz, 1H), 7.77 (dd, J = 8.1, 5.6 Hz, 1H), 7.64 (d, J = 2.3 Hz , 1H), 7.15 (d, J = 2.3 Hz, 1H), 6.50 (s, 1H), 3.96 (d, J = 1.8 Hz, 2H), 3.14 (q , J = 7.6 Hz, 2H), 1.82 - 1.60 (m, 4H), 1.21 (t, J = 7.6 Hz, 3H), 0.97 (s, 9H). 601 1HNMR (400 MHz, DMSO-46) δ 8.33 (s, 1H), 8.04 (s, 1H), 7.84 - 7.73 (m, 2H), 7.57 - 7.35 (m , 3H), 7.25 - 7.07 (m, 3H), 6.93 (dd, J = 8.4, 3.0 Hz, 1H), 6.25 (d, J = 7.0 Hz, 1H), 5.64 (s, 2H), 3.84 (dd, J = 13.8, 8.0 Hz, 1H), 3.40 (dd, J = 13.8, 5.3 Hz, 1H ), 2.44 (s, 3H), 0.79 (s, 9H). 602 1HNMR (400 MHz, Methanol-44) δ 8.70 (dd, J = 5.7, 1.5 Hz, 1H), 8.42 (d, J = 8.5 Hz, 1H), 8.39 ( s, 1H), 8.32 (s, 1H), 7.82 (dd, J = 8.1, 5.7 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.24 (d, J = 2.5 Hz, 1H), 6.48 (s, 1H), 3.77 (s, 2H), 3.17 (q, J = 7.6 Hz, 2H), 1.82 - 1.64 (m, 4H), 1.22 (t, J = 7.6 Hz, 3H), 0.92 (s, 9H). 603 1H NMR (400 MHz, MethanolD4) δ 8.48 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.75 (dd, J = 8.1, 1, 1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.19 (d, J = 7.2 Hz, 1H), 7.13 7.04 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.84 (s, 1H), 5.92 (t, J = 54.6 Hz, 1H), 4.17 (s, 3H), 3.87 (d, J = 2.9 Hz, 2H), 1.52 (s, 4H), 0.80 (s, 9H). 604 1HNMR (400 MHz, Methanol-44) δ 8.63 (dd, J = 5.5, 1.5 Hz, 1H), 8.48 (s, 1H), 8.21 (d, J = 5.4 Hz, 2H), 7.66 (dd, J = 8.0, 5.4 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.04 (d, J = 2 ,4 Hz, 1H), 6.44 (s, 1H), 5.93 (t, J = 54.4 Hz, 1H), 3.92 (d, J = 2.5 Hz, 2H), 3, 09 (q, J = 7.6 Hz, 2H), 1.57 - 1.51 (m, 4H), 1.19 (t, J = 7.6 Hz, 3H), 0.95 (s, 9H ). 605 1HNMR (400 MHz, Methanol-44) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.92 (s, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.75 (dd, J = 7.9, 1.0 Hz, 1H), 7.20 (d, J = 7.2 Hz, 1H), 7.17 (d, J = 2.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.84 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 4.19 ( s, 3H), 3.73 (s, 1H), 1.51 (s, 4H), 0.78 (s, 9H).

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606 1HNMR (400 MHz, Methanol-d4) δ 8.69 (dd, J = 5.7, 1.5 Hz, 1H), 8.47 - 8.40 (m, 1H), 8.32 (s, 1H ), 8.25 (s, 1H), 7.82 (dd, J = 8.1, 5.7 Hz, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 6.47 (s, 1H), 5.94 (t, J = 54.5 Hz, 1H), 3.84 - 3.70 (m, 2H) , 3.16 (q, J = 7.6 Hz, 2H), 1.61 - 1.51 (m, 4H), 1.22 (t, J = 7.6 Hz, 3H), 0.92 ( s, 9H). 607 1HNMR (400 MHz, DMSO-de) δ 8.39 (s, 1H), 8.34 (s, 1H), 8.04 (s, 1H), 7.86 7.79 (m, 1H), 7 .56 (d, J = 2.2 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.4, 3.1 Hz, 1H), 6.29 (d, J = 7.8 Hz, 1H), 2.82 (s, 1H), 2.49 (s, 3H) , 2.10(dt, J = 12.5,7.7 Hz, 2H), 1.79-1.65 (m, 5H), 1.64-1.54 (m, 1H), 1.50 (d, J = 2.4 Hz, 2H), 1.05 (m, J = 11.7 Hz, 1H). 608 1H NMR (400 MHz, DMSO-de) δ 8.38 (d, J = 4.0 Hz, 1H), 8.34 (d, J = 0.6 Hz, 1H), 8.07 (s, 1H ), 7.84 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 2.2 Hz, 1H), 7.42 - 7.16 (m, 1H), 7.12 (d, J = 2.4 Hz, 1H), 7.01 (dd, J = 8.4, 3.1 Hz, 1H), 6.28 (d, J = 7.9 Hz, 1H), 4 ,11 (t, J = 8.2 Hz, 2H), 3.68 (td, J = 8.7, 2.9 Hz, 2H), 2.89 - 2.82 (m, 1H), 2, 48 (s, 3H), 2.03 - 1.92 (m, 2H), 1.80 - 1.65 (m, 4H). 609 1H NMR (400 MHz, DMSO-de) δ 8.31 - 8.22 (m, 2H), 8.01 (s, 1H), 7.87 (d, J = 2.4 Hz, 1H), 7 .58 (d, J = 7.6 Hz, 1H), 7.51 (ddd, J = 7.0, 2.4, 1.0 Hz, 1H), 7.41 7.32 (m, 2H) , 7.33 - 7.23 (m, 2H), 6.48 (d, J = 6.9 Hz, 1H), 3.98 (s, 3H), 3.98 3.86 (m, 2H) , 3.34 (dd, J = 13.8, 5.2 Hz, 1H), 1.18 - 1.01 (m, 4H), 0.79 (s, 9H). 610 1HNMR (400 MHz, Methanol-d4) δ 8.33 (s, 1H), 7.93 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.94 - 6.77 (m, 1H), 6.19 (s, 1H), 3, 87 (d, J = 13.8 Hz, 1H), 3.77 (d, J = 4.5 Hz, 2H), 3.63 (d, J = 13.8 Hz, 1H), 2.51 ( s, 3H), 1.32 (m, 2H), 1.20 (s, 2H), 0.88 (s, 9H). 611 1HNMR (400 MHz, DMSO-de) δ 8.45 - 8.37 (m, 1H), 8.26 (d, J = 10.1 Hz, 1H), 8.02 - 7.83 (m, 2H ), 7.64 (t, J = 1.9 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.39 - 7.32 (m, 1H), 7.31 - 7, 16 (m, 3H), 7.10 (dd, J = 6.8, 2.9 Hz, 1H), 7.00 (dd, J = 8.4, 3.0 Hz, 1H), 6.47 (d, J = 7.3 Hz, 1H), 5.02 - 4.70 (m, 1H), 2.56 (d, J = 8.3 Hz, 3H), 1.81 1.65 (m , 5H), 1.39 (dt, J = 8.7, 4.7 Hz, 1H), 0.72 - 0.57 (m, 2H), 0.57 - 0.29 (m, 2H).

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612 1HNMR (400 MHz, DMSOLb) δ 8.41 (s, 1H), 8.20 (s, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.18 - 6.99 (m, 6H), 6.89 ( d, J = 2.3 Hz, 1H), 6.26 (d, J = 7.1 Hz, 1H), 4.29 (dd, J = 13.9, 8.3 Hz, 1H), 3, 64 (dd, J = 13.9, 5.1 Hz, 1H), 2.47 (s, 3H), 1.85 - 1.60 (m, 4H), 1.19 (d, J = 41, 4 Hz, 6H). 613 1H NMR (400 MHz, DMSOLb) δ 8.43 - 8.38 (m, 1H), 8.27 (d, J = 0.9 Hz, 1H), 7.96 - 7.79 (m, 3H) , 7.59 - 7.52 (m, 2H), 7.48 - 7.24 (m, 1H), 7.24 - 7.18 (m, 2H), 7.10 (dd, J = 6, 7, 3.0 Hz, 1H), 7.00 (dd, J = 8.4, 3.2 Hz, 1H), 6.47 (d, J = 7.9 Hz, 1H), 4.92 ( t, J = 8.1 Hz, 1H), 4.75 (t, J = 8.6 Hz, OH), 2.55 (d, J = 8.7 Hz, 3H), 1.83 - 1, 65 (m, 5H), 1.37 (td, J = 8.6, 8.2, 4.5 Hz, 1H), 0.76 - 0.28 (m, 3H). 614 1HNMR (400 MHz, DMSOLb) δ 8.42 (s, 1H), 8.19 (s, 1H), 7.88 - 7.79 (m, 2H), 7.49 (t, J = 7.0 Hz, 2H), 7.19 (d, J = 2.5 Hz, 1H), 7.17 - 6.97 (m, 6H), 6.29 (d, J = 6.6 Hz, 1H), 4.27 (dd, J = 14.0, 8.3 Hz, 1H), 3.63 (dd, J = 13.9, 5.1 Hz, 1H), 2.47 (s, 3H), 1 .83 - 1.63 (m, 4H), 1.19 (d, J = 42.4 Hz, 6H). 615 1H NMR (400 MHz, DMSOLb) δ 8.40 (d, J = 2.4 Hz, 2H), 7.99 (t, J = 7.1 Hz, 1H), 7.86 (d, J = 2 .3 Hz, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 6.98 (dd, J = 8.4, 3.0 Hz, 1H), 6.27 (d, J = 7.5 Hz, 1H), 4.19 (dd, J = 14 ,7, 7.6 Hz, 1H), 3.85 (dd, J = 14.7, 6.4 Hz, 1H), 2.46 (s, 3H), 1.81 - 1.63 (m, 4H), 1.29 (d, J = 18.6 Hz, 6H). 616 1HNMR (400 MHz, MethanolL4) δ 9.56 (s, 1H), 8.59 (d, J = 6.2 Hz, 1H), 8.48 (s, 1H), 8.14 (s, 1H) , 8.04 (d, J = 6.3 Hz, 1H), 7.84 (dd, J = 8.3, 5.4 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.44 - 7.35 (m, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.80 (s, 1H), 3.98 (d, J = 13 .9 Hz, 1H), 3.67 (d, J = 14.0 Hz, 1H), 1.77 - 1.55 (m, 3H), 0.73 (s, 10H). 617 1H NMR (400 MHz, MethanolL4) δ 8.94 (d, J = 4.3 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.48 (s, 1H), 8.10 (s, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.64 (ddd, J = 16.5, 8.5, 4.6 Hz, 2H), 6 .91 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.63 (d, J = 13, 9 Hz, 1H), 1.76 - 1.52 (m, 3H), 0.70 (s, 11H).

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618 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.38 - 8.31 (m, 1H), 8.06 (s, 1H), 7.73 (dd, J = 8.0, 1.0 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.41 (d, J = 7 ,7 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 4, 02 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.79 - 1.59 (m, 4H ), 0.78 (s, 9H). 619 1HNMR (400 MHz, Methanol-d4) δ 8.87 (s, 1H), 8.54 (s, 1H), 8.08 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.42 (s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.07 (d, J = 13.9 Hz, 1H), 3.91 (d, J = 14.0 Hz, 1H), 2.44 (s, 3H), 1.54 (m, 4H), 1.00 (s, 9H). 620 1H NMR (400 MHz, Methanol-d4) δ 8.79 (s, 1H), 8.49 (s, 1H), 8.00 (s, 1H), 7.69 (d, J = 2.3 Hz , 1H), 7.26 (d, J = 2.3 Hz, 1H), 6.31 (s, 1H), 5.91 (t, J = 54.8 Hz, 1H), 4.09 (d , J = 13.9 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 2.56 (s, 3H), 1.50 (m, 4H), 1.05 (s , 9H). 621 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.80 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.20 ( s, 1H), 3.87 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.54 ( m, 1H), 1.28 - 1.19 (m, 2H), 1.09 - 0.98 (m, 2H), 0.89 (s, 9H), 0.58 - 0.46 (m, 2H), 0.38-0.29 (m, 2H). 622 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.93 (s, 1H), 7.81 - 7.74 (m, 2H), 7.67 - 7.60 ( m, 1H), 7.56 (dd, J = 7.1, 3.3 Hz, 1H), 7.10 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8 .5, 2.7 Hz, 1H), 6.22 (s, 1H), 4.98 -4.78 (m, 1H), 3.92 - 3.83 (m, 2H), 3.74 ( d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 2.01 - 1.88 (m, 1H), 1.60 (m, 1H), 0.90 (s, 9H ). 623 1H NMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 7.94 (s, 1H), 7.82 - 7.75 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.23 (s, 1H), 5.01 (m, 1H), 4.76 - 4.71 (m, 1H), 4.66 - 4.60 (m, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.72 (d, J = 13.9 Hz , 1H), 2.51 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H), 0.90 (s, 9H).

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625 1H NMR (400 MHz, Methanol-04) δ 8.37 (s, 1H), 7.98 (s, 1H), 7.83 - 7.76 (m, 2H), 7.08 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.22 (s, 1H), 4.62 (d, J = 47.1 Hz, 2H), 3.88 (d, J = 13.8 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.67 (s, 6H), 0.89 (s, 9H). 626 1HNMR (400 MHz, Methanol-44) δ 9.66 (s, 1H), 8.62 (d, J = 6.4 Hz, 1H), 8.32 (s, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.19 (s, 1H), 7.96 (dd, J = 8.2, 5.2 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 9.8, 8.3 Hz, 1H), 7.11 (d, J = 2.5 Hz, 1H), 6.83 (s, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 13.7 Hz, 1H), 1.79 - 1.68 (m, 2H), 1.64 (t , J = 9.7 Hz, 2H), 0.69 (s, 10H). 627 1HNMR (400 MHz, Methanol-44) δ 8.95 (dd, J = 4.4, 1.4 Hz, 1H), 8.70-8.61 (m, 1H), 8.32 (s, 1H ), 8.12 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.66 (ddd, J = 13.4, 8.4, 4.5 Hz, 2H) , 7.48 (dd, J = 10.3, 8.2 Hz, 1H), 7.07 (d, J = 2.5 Hz, 1H), 6.82 (s, 1H), 3.78 ( d, J = 13.7 Hz, 1H), 3.48 (d, J = 13.7 Hz, 1H), 1.78 - 1.54 (m, 4H), 0.64 (s, 10H). 628 1HNMR (400 MHz, Methanol-44) δ 9.49 (s, 1H), 8.51 (s, 1H), 8.47 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 8.26 (s, 1H), 8.24 (d, J = 8.6 Hz, 1H), 8.02 (ddd, J = 8.5, 7.0, 1.3 Hz, 1H ), 7.90 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.94 (s, 1H), 3.93 (d, J = 13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 1 .78 - 1.58 (m, 4H), 0.73 (s, 9H). 629 1H NMR (400 MHz, Methanol-44) δ 9.36 (d, J = 2.2 Hz, 1H), 9.06 - 9.02 (m, 1H), 8.48 (d, J = 2, 1 Hz, 2H), 8.15 - 8.09 (m, 2H), 7.94 (ddd, J = 8.4, 6.9, 1.4 Hz, 2H), 7.77 - 7.71 (m, 2H), 7.52 (d, J = 2.3 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 4.05 (s, 2H), 3.80 (t, J = 6.3 Hz, 2H), 3.60 (t, J = 6.3 Hz, 2H), 1.78 - 1.63 (m, 1H), 1.10 (d, J = 2.1 Hz, 9H). 630 1H NMR (400 MHz, Methanol-44) δ 8.52 (s, 1H), 8.13 (m, 2H), 7.65 (d, J = 2.3 Hz, 1H), 7.30 (d , J = 2.3 Hz, 1H), 6.36 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.11 3.89 (m, 2H), 2, 15 (s, 3H), 1.53 (s, 4H), 1.04 (s, 9H).

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631 1HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 7.9 Hz, 1H), 8.34 (s, 1H), 8.08 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.77 - 7.69 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.89 - 6.81 (m, 1H), 6.60 (s, 1H), 3.83 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.54 (d, J = 13.7 Hz, 1H), 1.78 - 1.59 (m, 4H), 0.73 (s, 9H). 632 1HNMR (400 MHz, Methanol-d4) δ 9.03 (d, J = 6.7 Hz, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 8.13 - 7, 98 (m, 3H), 7.65 (d, J = 2.2 Hz, 1H), 7.50 (d, J = 6.7 Hz, 1H), 7.12 (s, 1H), 6, 77 (s, 1H), 4.09 (s, 3H), 4.06 (d, J = 14.0 Hz, 1H), 3.51 (d, J = 14.0 Hz, 1H), 1, 84 - 1.55 (m, 4H), 0.69 (s, 9H). 633 1H NMR (400 MHz, DMSO-de) δ 8.35 (d, J = 6.9 Hz, 2H), 7.92 (t, J = 7.0 Hz, 1H), 7.79 (t, J = 8.3 Hz, 1H), 7.60 (d, J = 2.2 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 2 .3 Hz, 1H), 6.99 - 6.92 (m, 1H), 6.24 (d, J = 7.0 Hz, 1H), 4.20 (dd, J = 14.7, 7, 6 Hz, 1H), 3.81 (dd, J = 14.7, 6.3 Hz, 1H), 2.44 (s, 3H), 1.77 - 1.62 (m, 4H), 1, 29 (s, 3H), 1.23 (s, 3H). 634 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.92 (s, 1H), 7.84 - 7.75 (m, 2H), 7.13 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.43 - 6.09 (m, 2H), 4.88 (ddd, J = 14 .9, 3.4, 1.1 Hz, 2H), 3.89 (d, J = 13.8 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.90 (s, 9H). 635 1H NMR (400 MHz, DMSO-de) δ 8.38 (d, J = 3.9 Hz, 2H), 7.80 (t, J = 8.3 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.40 (t, J = 8.2 Hz, 1H), 6.99 - 6.87 (m, 2H), 6.24 (d, J = 6.5 Hz , 1H), 3.97 (dd, J = 13.9, 8.1 Hz, 1H), 3.61 (dd, J = 13.9, 4.8 Hz, 1H), 3.52 - 3, 33 (m, 2H), 2.44 (s, 3H), 1.81 - 1.64 (m, 3H), 0.85 (d, J = 3.2 Hz, 6H). 636 1H NMR (400 MHz, flMCO-d6) δ 8.37 (d, J = 2.2 Hz, 2H), 7.81 (t, J = 8.3 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.49 - 7.35 (m, 2H), 7.02 - 6.90 (m, 2H), 6.26 (d, J = 7.0 Hz, 1H) , 5.73 (t, J = 56.1 Hz, 1H), 4.30 (dd, J = 14.6, 7.1 Hz, 1H), 3.85 (dd, J = 14.6, 4 .9 Hz, 1H), 2.48 (s, 3H), 1.80 - 1.62 (m, 3H), 0.81 - 0.62 (m, 4H).

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637 1H NMR (400 MHz, DMSO-C16) δ 8.39 (d, J = 7.2 Hz, 2H), 7.86 (d, J = 2.4 Hz, 1H), 7.80 (t, J = 8.2 Hz, 1H), 7.50 (d, J = 7.3 Hz, 1H), 7.19 (s, 1H), 6.99 - 6.90 (m, 1H), 6.25 (d, J = 7.3 Hz, 1H), 4.00 - 3.86 (m, 1H), 3.47 (d, J = 11.0 Hz, 3H), 2.44 (s, 3H) , 1.84 - 1.60 (m, 3H), 0.85 (d, J = 3.5 Hz, 6H). 638 1H NMR (400 MHz, DMCO-d6) δ 8.38 (s, 2H), 7.87 - 7.77 (m, 2H), 7.48 (d, J = 7.8 Hz, 1H), 7 .38 (t, J = 6.2 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 8.5, 3.0 Hz, 1H) , 6.28 (d, J = 7.3 Hz, 1H), 5.73 (t, J = 56.1 Hz, 1H), 4.31 - 4.22 (m, 1H), 3.84 ( dd, J = 14.6, 4.9 Hz, 1H), 2.48 (s, 3H), 1.83 - 1.59 (m, 4H), 0.80 - 0.62 (m, 4H) . 639 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.22 (s, 1H), 6.11 - 5.74 (m, 2H), 4.05 (d, J = 14.0 Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 2, 38 (s, 3H), 2.26 (s, 3H), 1.52 (s, 4H), 1.04 (s, 9H). 640 1HNMR (400 MHz, Methanol-d4) δ 8.92 (s, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 6.43 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.93 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 2.45 (s, 3H), 1.53 (m, 4H), 0.97 (s, 9H). 641 1HNMR (400 MHz, Methanol-d4) δ 8.78 (s, 1H), 8.37 (s, 1H), 8.02 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 6.32 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 3.96 (d, J = 13.9 Hz, 1H), 3.80 (d, J = 13.9 Hz, 1H), 2.56 (s, 3H), 1.50 (m, 4H), 1.02 (s, 9H). 642 1H NMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.01 (s, 1H), 7.85 - 7.74 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.23 (s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.95 (s, 6H), 2.50 (s, 3H), 1.68 (m, 2H), 1.66 ( m, 2H), 0.91 (s, 9H). 643 1HNMR (400 MHz, MethanolD4) δ 8.48 (s, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6 .90 - 6.83 (m, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.78 - 3.68 (m, 2H), 2.43 (s, 3H), 1.33 - 1.23 (m, 4H), 0.90 (s, 9H).

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644 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.26 (s, 1H), 7.85 - 7.76 (m, 2H), 7.12 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.6, 2.7 Hz, 1H), 6.30 (s, 1H), 5.24 (m, 2H), 5.18 ( m, 2H), 3.85 (d, J = 13.9 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 0.89 ( s, 9H). 645 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.97 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6.90 - 6.85 (m, 1H), 6.22 (s, 1H), 5, 08 (q, J = 6.7, 6.1 Hz, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.82 (d, J = 13.9 Hz, 1H), 3.29 - 3.16 (m, 4H), 2.51 (s, 3H), 0.93 (s, 9H). 646 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.91 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.89 (d, J = 2.2 Hz, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.20 (s, 1H) , 3.99 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.69 (s, 1H), 2.51 (s, 3H) , 2.37 (s, 6H), 0.92 (s, 9H). 647 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H) , 6.85 (dd, J = 8.6, 2.7 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.11 (s, 1H), 4.05 ( d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.9 Hz, 1H), 3.69 - 3.58 (m, 1H), 2.42 (s, 3H), 2.34 (s, 3H), 1.29 - 1.15 (m, 4H), 0.90 (s, 9H). 648 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.99 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 ( s, 1H), 5.08 (d, J = 7.1 Hz, 1H), 5.03 (d, J = 7.1 Hz, 1H), 4.84 - 4.82 (m, 12), 4.14 (s, 2H), 4.04 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 0.94(s,9H). 649 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.91 (s, 1H), 7.83 - 7.72 (m, 2H), 7.08 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.21 (s, 1H), 3.85 (d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 2.69 (s, 1H), 2.52 (s, 3H), 2.37 (s, 6H), 0.89 ( s, 9H).

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650 1HNMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 8.06 (dd, J = 5.4, 1.8 Hz, 1H), 7.92 (s, 1H), 7, 81 (dd, J = 7.6, 1.8 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 7.6, 5.4 Hz, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.78 (ddd, J = 11.4, 7, 1, 4.2 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 2.97 (s, 6H), 1.12 - 1.02 (m, 4H), 0, 91 (s, 9H). 651 1HNMR (400 MHz, Methanol-d4) δ 9.72 (s, 1H), 8.61 (d, J = 6.1 Hz, 1H), 8.50 (s, 1H), 8.18 (s, 1H), 8.09 (d, J = 6.1 Hz, 1H), 7.88 - 7.75 (m, 2H), 7.70 (dd, J = 7.9, 2.3 Hz, 1H ), 6.91 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.78 - 1.54 (m, 4H), 0.70 (s, 9H). 652 1HNMR (400 MHz, Methanol-d4) δ 9.56 (s, 1H), 8.59 (d, J = 6.2 Hz, 1H), 8.48 (s, 1H), 8.05 (d, J = 6.2 Hz, 1H), 8.01 (s, 1H), 7.84 (dd, J = 8.2, 5.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.39 (dd, J = 9.9, 8.2 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.79 (s, 1H), 5.91 (t, J = 54.6 Hz, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1, 50 (d, J = 4.1 Hz, 4H), 0.72 (s, 9H). 653 1H NMR (400 MHz, Methanol-d4) δ 8.94 (dd, J = 4.3, 1.4 Hz, 1H), 8.60 (dt, J = 8.9, 1.5 Hz, 1H) , 8.49 (s, 1H), 7.97 (s, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.64 (ddd, J = 18.1, 8.4 , 4.5 Hz, 2H), 7.47 (dd, J = 10.3, 8.2 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.80 (s , 1H), 5.90 (t, J = 54.7 Hz, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H ), 1.55 - 1.42 (m, 4H), 0.70 (s, 9H). 654 1H NMR (400 MHz, DMSO-de) δ 8.32 (s, 1H), 8.03 (s, 1H), 7.78 (t, J = 8.3 Hz, 1H), 7.61 - 7 .40 (m, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.23 - 7.13 (m, 2H), 6.98 - 6.89 (m, 1H), 6.24 (d, J = 6.8 Hz, 1H), 5.63 (s, 2H), 4.11 (s, 1H), 3.88 (dd, J = 13.8, 8.0 Hz , 1H), 3.40 (dd, J = 13.7, 5.2 Hz, 1H), 2.43 (s, 3H), 0.78 (s, 9H). 655 1H NMR (400 MHz, DMSO-de) δ 8.31 - 8.21 (m, 2H), 7.99 (s, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7 .55 - 7.46 (m, 2H), 7.34 - 7.23 (m, 3H), 7.22 - 7.11 (m, 3H), 6.49 (d, J = 6.8 Hz , 1H), 5.62 (s, 2H), 4.15 (s, 1H), 4.04 - 3.93 (m, 4H), 3.34 (dd, J = 13.8, 5.1 Hz, 1H), 0.80 (s, 9H).

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656 1H NMR (400 MHz, DMSO-ab) δ 8.30 - 8.20 (m, 2H), 8.00 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7 .61 (d, J = 7.7 Hz, 1H), 7.56 - 7.35 (m, 4H), 7.34 - 7.23 (m, 2H), 7.22 - 7.11 (m , 1H), 6.51 (d, J = 7.0 Hz, 1H), 5.62 (s, 2H), 4.13 (s, 1H), 3.98 (s, 3H), 3.99 - 3.88 (m, 1H), 3.32 (dd, J = 13.8, 5.1 Hz, 1H), 0.79 (s, 9H). 657 1H NMR (400 MHz, Methanol) δ 8.37 (s, 1H), 8.13 (m, 2H), 7.78 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 2.5 Hz, 1H), 6.36 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.86 (m, 2H), 2.16 (s, 3H ), 1.52 (m, 4H), 1.01 (s, 9H). 658 1HNMR (400 MHz, Methanolch14) δ 8.47 (s, 1H), 8.22 (d, J = 5.1 Hz, 1H), 8.05 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 3.6 Hz, 1H), 7.23 (d, J = 5.1 Hz, 1H), 6.98 (d, J = 2, 3 Hz, 1H), 6.59 (d, J = 3.6 Hz, 1H), 6.50 (s, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.86 (s, 3H), 3.60 (d, J = 13.9 Hz, 1H), 1.75 - 1.57 (m, 4H), 0.82 (s, 9H). 659 1HNMR (400 MHz, Methanolch14) δ 9.54 (s, 1H), 8.48 (s, 1H), 8.41 (d, J = 8.3 Hz, 2H), 8.18 (s, 1H) , 8.05 (d, J = 7.2 Hz, 1H), 7.87 (t, J = 7.8 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7 .16 (s, 1H), 6.98 (d, J = 2.3 Hz, 1H), 5.13 - 4.50 (m, 21H), 3.93 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.01 (s, 3H), 1.79 - 1.64 (m, 4H), 0.82 (s, 9H). 660 1H NMR (400 MHz, Methanolch14) δ 8.97 (d, J = 5.4 Hz, 1H), 8.48 (d, J = 8.4 Hz, 2H), 8.28 (s, 1H), 8.19 (d, J = 1.2 Hz, 2H), 7.85 (dd, J = 5.4, 1.0 Hz, 1H), 7.73 (d, J = 2.3 Hz, 1H ), 7.17 (d, J = 2.3 Hz, 1H), 6.47 (s, 1H), 4.95 - 4.81 (m, 3H), 4.11 (d, J = 14, 0 Hz, 1H), 3.72 (d, J = 14.0 Hz, 1H), 2.92 (d, J = 0.9 Hz, 3H), 1.81 - 1.64 (m, 4H) , 0.84 (s, 9H). 661 1H NMR (400 MHz, Methanolch14) δ 8.39 (s, 1H), 8.34 (s, 1H), 7.84 - 7.75 (m, 2H), 7.15 (d, J = 2, 5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.31 (s, 1H), 4.38 (t, J = 10.8, 2H), 3.86 (d, J = 13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 2.54 (s, 3H), 0.90 (s, 9H). 662 1HNMR (400 MHz, Methanol-44) δ 8.49 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H) , 6.87 (m, 2H), 6.17 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.79 (d, J = 13.9 Hz, 1H) , 3.72 (m, 1H), 2.47 (s, 3H), 1.34 - 1.18 (m, 3H), 0.92 (s, 9H).

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663 1HNMR (400 MHz, Methanol-04) δ 8.48 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H) , 6.94 - 6.83 (m, 2H), 6.17 (s, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.79 (d, J = 13.9 Hz, 1H), 3.71 - 3.63 (m, 1H), 2.51 (s, 3H), 1.32 - 1.17 (m, 4H), 0.93 (s, 9H). 664 1HNMR (400 MHz, Methanol) δ 8.34 (s, 1H), 8.27 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.46 (d, J = 3.6 Hz, 1H), 7.34 (d, J = 5.3 Hz, 1H), 7.15 (d, J = 2, 5 Hz, 1H), 6.70 (d, J = 3.6 Hz, 1H), 6.54 (s, 1H), 3.95 (d, J = 13.8 Hz, 1H), 3.89 (s, 3H), 3.47 (d, J = 13.7 Hz, 1H), 1.78 - 1.52 (m, 4H), 0.77 (s, 9H). 665 1HNMR (400 MHz, Methanol) δ 8.51 (s, 1H), 8.08 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.29 (s, 1H), 6.16 (d, J = 2.0 Hz, 1H), 5 .93 (t, J = 54.7 Hz, 1H), 4.08 - 3.90 (m, 2H), 3.85 (s, 3H), 1.54 (s, 4H), 1.02 ( s, 9H). 666 1HNMR (400 MHz, Methanol) δ 8.49 (s, 1H), 8.23 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.31 (s, 1H), 6.15 (d, J = 2.0 Hz, 1H), 3 .97 (q, J = 14.0 Hz, 2H), 3.85 (s, 3H), 1.84 - 1.60 (m, 4H), 1.01 (s, 9H). 667 1HNMR (400 MHz, Methanol) δ 9.61 (s, 1H), 8.44 (d, J = 6.7 Hz, 2H), 8.30 (s, 1H), 8.20 (s, 1H) , 8.13 (d, J = 6.5 Hz, 1H), 7.96 - 7.87 (m, 1H), 7.74 (d, J = 2.5 Hz, 1H), 7.16 ( s, 1H), 7.11 (d, J = 2.5 Hz, 1H), 3.74 (d, J = 13.8 Hz, 1H), 3.63 (d, J - 13.8 Hz, 1H), 3.04 (s, 3H), 1.74 (s, 2H), 1.66 (s, 2H), 0.76 (s, 9H). 668 1HNMR (400 MHz, Methanol-I4) δ 8.99 (d, J = 5.5 Hz, 1H), 8.53 (s, 1H), 8.35 8.15 (m, 4H), 7.90 (d, J = 5.6 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 2.5 Hz, 1H), 6.45 (s , 1H), 3.90 (t, J = 13.5 Hz, 1H), 3.52 (d, J = 13.9 Hz, 1H), 2.95 (s, 3H), 1.76 (s , 2H), 1.67 (s, 2H), 0.78 (s, 9H).

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669 1HNMR (400 MHz, Methanol-d4) δ 8.15 (s, 1H), 7.66 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 6.52 (dd, J = 8.5, 2.7 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.85 ( s, 1H), 4.20 (dd, J = 11.6, 4.3 Hz, 1H), 3.71 (dd, J = 11.8, 4.7 Hz, 1H), 3.26-3 .14 (m, 1H), 3.15 (d, J = 11.5 Hz, 1H), 2.86 (d, J = 11.7 Hz, 1H), 2.09 (s, 3H), 1 .82 - 1.66 (m, 1H), 1.59 (d, J = 13.2 Hz, 1H), 1.23 (ddd, J = 13.2, 8.2, 5.0 Hz, 1H ), 1.05 - 0.79 (m, 2H), 0.79 - 0.61 (m, 2H), 0.53 (s, 3H), 0.25 - 0.18 (m, 2H), 0.18 (s, 3H), 0.10 - -0.05 (m, 2H). 670 1HNMR (400 MHz, Methanol-d4) δ 9.61 (s, 1H), 8.69 (d, J = 6.1 Hz, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.16 (d, J = 6.1 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H) , 7.83 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.91 (s, 1H), 3.82 (d, J = 13.8 Hz, 1H), 3.42 (d, J = 13.7 Hz, 1H), 1.79 - 1.55 (m, 4H), 0.62 (s, 9H). 671 1HNMR (400 MHz, Methanol-d4) δ 8.95 (dd, J = 4.3, 1.4 Hz, 1H), 8.70 - 8.63 (m, 1H), 8.35 (s, 1H ), 7.99 (s, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.67 (ddd, J = 15.5, 8.4, 4.6 Hz, 2H) , 7.48 (dd, J = 10.3, 8.2 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.81 (s, 1H), 5.91 ( t, J = 54.7 Hz, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 1.55 - 1, 42 (m, 4H), 0.65 (s, 9H). 672 1HNMR (400 MHz, Methanol^4) δ 9.56 (s, 1H), 8.59 (d, J = 6.2 Hz, 1H), 8.29 (s, 1H), 8.11 (d, J = 6.2 Hz, 1H), 8.02 (s, 1H), 7.87 (dd, J = 8.2, 5.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 10.0, 8.2 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 6.79 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 3.76 (d, J = 13.7 Hz, 1H), 3.44 (s, 1H), 1.50 (d, J = 3 .2 Hz, 3H), 1.31 (t, J = 7.4 Hz, 1H), 0.65 (s, 9H). 673 1HNMR (400 MHz, Methanol-d4) δ 9.64 (s, 1H), 8.58 (s, 1H), 8.49 (d, J = 8.1 Hz, 1H), 8.38 - 8, 27 (m, 3H), 8.01 (d, J = 7.7 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.15 (d, J = 2.5 Hz, 1H), 6.98 (s, 1H), 3.74 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.9 Hz, 1H), 1.80 - 1.59 (m, 4H), 0.66 (s, 10H). 674 1HNMR (400 MHz, Methanol-d4) δ 8.39 (s, 1H), 8.06 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.42 (d, J = 2.5 Hz, 1H), 6.14 - 5.73 (m, 2H), 3.93 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.37 (s, 3H), 2.26 (s, 3H), 1.51 (m, 4H), 1.01 (s, 9H).

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675 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.99 (s, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.80 (d, J = 2.5 Hz, 1H), 6.90 (d, J = 2.5 Hz, 1H), 6.85 (dd, J = 8.4, 2.7 Hz, 1H), 6.19 ( s, 1H), 4.35 (dd, J = 11.1,4.9 Hz, 1H), 4.11-3.95 (m, 1H), 3.53 (td, J = 11.6, 3.3 Hz, 1H), 3.49 - 3.42 (m, 1H), 3.18 (d, J = 11.6 Hz, 1H), 2.44 (s, 3H), 2.04 - 1.84 (m, 2H), 1.57 (ddd, J = 13.2, 8.4, 5.0 Hz, 1H), 1.33 - 1.17 (m, 2H), 1.12 - 0.97 (m, 2H), 0.86 (s, 3H), 0.62 - 0.51 (m, 2H), 0.49 (s, 3H), 0.36 (dt, J = 6, 4, 4.8 Hz, 2H). 676 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.37 - 8.29 (m, 1H), 8.06 (s, 1H), 7.75 (dd, J= 7.6, 1.3 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H) , 4.05 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 1.79 - 1.55 (m, 4H), 0.80 ( s, 9H). 677 1HNMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.09 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.39 (m, 2H), 6.31 (s, 1H), 6.15 (d, J = 2.0 Hz, 1H), 5.94 (t, J = 54.7 Hz, 1H), 3.86 (d, J = 3.9 Hz, 4H), 1.53 (s, 4H), 0.98 (s, 9H). 678 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.22 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.38 (m, 2H), 6.32 (s, 1H), 6.14 (d, J = 2.0 Hz, 1H), 3.92 - 3.73 (m, 5H), 1.81 - 1.60 (m , 4H), 0.97 (s, 9H). 679 1H NMR (400 MHz, Methanol-d4) δ 8.17 (s, 1H), 8.09 (dd, J = 2.5, 0.7 Hz, 1H), 7.83 (s, 1H), 7 .57 (dd, J = 8.9, 2.5 Hz, 1H), 7.47 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 2.4 Hz, 1H) , 6.65 (dd, J = 8.9, 0.8 Hz, 1H), 3.93 - 3.81 (m, 1H), 3.04 (s, 6H), 2.03 (s, 1H ), 1.21 - 1.10 (m, 4H), 0.91 (s, 9H). 680 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H) , 7.06 (d, J = 2.5 Hz, 1H), 6.91 - 6.83 (m, 1H), 6.18 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.77 - 3.68 (m, 1H), 3.63 (d, J = 13.8 Hz, 1H), 2.47 (s, 3H), 1.31 - 1.21 (m, 4H), 0.88 (s, 9H).

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681 1HNMR (400 MHz, Methanol-04) δ 8.37 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H) , 7.09 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.18 (s, 1H), 3.90 ( d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.32 - 1.15 (m, 4H), 0.90(s,9H). 682 1HNMR (400 MHz, MeTaHon-d4) δ 9.01 (dd, J = 4.6, 1.4 Hz, 1H), 8.85 (d, J = 8.7 Hz, 1H), 8.48 ( s, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.90 - 7.82 (m, 1H), 7.81 - 7.73 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 1.56 - 1.44 (m, 1H), 1.24 1.13 (m , 2H), 0.99 (m, 2H), 0.70 (s, 9H), 0.53 - 0.42 (m, 2H), 0.29 (m, 2H). 683 1H NMR (400 MHz, Methanol^4) δ 8.99 (d, J = 4.4 Hz, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H ), 8.09 (d, J = 8.5 Hz, 1H), 7.99 (s, 1H), 7.88 - 7.81 (m, 1H), 7.78 - 7.70 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.89 (s, 1H), 6.09 (t, J = 55.6 Hz, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3.64 (d, J = 13.9 Hz, 1H), 1.77 1.67 (m , 6H), 0.71 (s, 9H). 684 1HNMR (400 MHz, MeTaHon-d4) δ 9.03 (dd, J = 4.7, 1.5 Hz, 1H), 8.88 (d, J = 8.7 Hz, 1H), 8.49 ( s, 1H), 8.11 (d, J = 8.6 Hz, 1H), 7.95 (s, 1H), 7.88 (dd, J = 8.5, 7.3 Hz, 1H), 7.82 - 7.75 (m, 2H), 7.69 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.89 (s , 1H), 4.60 (d, J = 47.1 Hz, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.64 (d, J = 13.9 Hz, 1H ), 1.64 (s, 6H), 0.71 (s, 9H). 685 1HNMR (400 MHz, MeTaHon-d4) δ 9.00 (dd, J = 4.6, 1.4 Hz, 1H), 8.81 (d, J = 8.7 Hz, 1H), 8.48 ( s, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.78 - 7.70 (m, 2H), 7.68 (d, J = 2.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.86 (s, 1H), 4.01 (d, J = 13.9 Hz , 1H), 3.62 (d, J = 13.9 Hz, 1H), 2.67 (s, 1H), 2.34 (s, 6H), 0.69 (s, 9H). 686 1HNMR (400 MHz, Methanol^4) δ 8.51 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H) , 6.98 (d, J = 2.3 Hz, 1H), 6.94 - 6.85 (m, 1H), 6.36 (s, 1H), 4.00 3.92 (m, 2H) , 3.89 (d, J = 14.0 Hz, 1H), 2.54 (s, 3H), 1.47 - 1.23 (m, 4H), 0.94 (s, 9H).

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687 1HNMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.37 (s, 1H), 8.27 (d, J = 8.2 Hz, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.38 (s, 1H) , 3.96 (d, J = 14.0 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 2.75 (s, 3H), 2.72 (s, 3H) , 1.84 - 1.74 (m, 2H), 1.70 (d, J = 13.9 Hz, 2H), 0.94 (s, 9H). 688 1HNMR (400 MHz, MethanolOT) δ 8.48 (s, 1H), 8.26 (s, 1H), 7.82 (dd, J = 10.0, 7.6 Hz, 1H), 7.66 ( d, J = 2.3 Hz, 1H), 7.17 (dd, J = 7.7, 1.5 Hz, 1H), 7.07 (d, J = 2.3 Hz, 1H), 6, 30 (s, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.78 (d, J = 14.0 Hz, 1H), 2.45 (s, 3H), 1, 81 - 1.71 (m, 2H), 1.72 - 1.62 (m, 2H), 0.96 (s, 9H). 689 1HNMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.36 (d, J = 8.3 Hz, 1H), 8.31 (s, 1H), 7.77 - 7, 66 (m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 6.39 (s, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3, 69 (d, J = 14.0 Hz, 1H), 2.78 (s, 3H), 2.74 (s, 3H), 1.83 - 1.74 (m, 2H), 1.71 (d , J = 14.7 Hz, 2H), 0.92 (s, 9H). 690 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.27 (s, 1H), 7.87 - 7.76 (m, 2H), 7.26 (dd, J= 2.5, 0.6 Hz, 1H), 7.16 (dd, J = 7.7, 1.5 Hz, 1H), 6.31 (s, 1H), 3.98 (d, J = 13 .9 Hz, 1H), 3.65 (d, J = 13.9 Hz, 1H), 2.45 (s, 3H), 1.80 - 1.71 (m, 2H), 1.71-1 .62 (m, 2H), 0.92 (s, 9H). 691 1HNMR (400 MHz, Methanol-d4) δ 9.37 (s, 1H), 8.28 (m, 1H), 8.20 (s, 1H), 8.14 - 8.05 (m, 2H), 7.87 - 7.75 (m, 2H), 7.60 (m, 1H), 7.40 (m, 1H), 6.69 (m, 1H), 6.58 (s, 1H), 3 .73 (m, 1H), 3.36 (m, 1H), 3.07 (s, 1H), 2.93 (s, 1H), 1.23 (m, 1H), 0.90 (m, 2H), 0.74 - 0.67 (m, 2H), 0.44 (s, 9H), 0.20 (m, 2H), 0.02 (m, 2H). 692 1HNMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.56 (m, 1H), 8.48 (s, 1H), 8.32 (m, 2H), 8.05 ( d, J = 7.3 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 6.97 (m, 1H), 6.88 (s, 1H), 3.98 (m, 1H), 3.94 - 3.76 (m, 1H), 3.68 (m, 1H), 2.01 - 1.88 (m, 1H), 1.61 (m, 1H), 0.74 (s, 9H). 693 1HNMR (400 MHz, Methanol^4) δ 9.54 (s, 1H), 8.54 (m, 1H), 8.46 (m, 1H), 8.28 (m, 2H), 8.08 - 7.98 (m, 2H), 7.86 - 7.78 (m, 1H), 7.67 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz , 1H), 6.88 (s, 1H), 6.10 (t, J = 55.6 Hz, 1H), 4.04 - 3.92 (m, 2H), 3.64 (m, 1H) , 1.73 (s, 6H), 0.71 (s, 9H).

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694 1HNMR (400 MHz, MethanolL4) δ 8.43 (s, 1H), 8.27 M, 1H), 8.00 (M, 2H), 7.80 (s, OH), 7.68 (s, 1H ), 6.89 (M, 2H), 4.98 - 4.78 (m, 26H), 4.73 - 4.63 (m, 2H), 4.57 (s, 1H), 3.96 ( d, J = 13.7 Hz, 1H), 3.62 (d, J = 13.7 Hz, 1H), 1.67 (s, 6H), 0.71 (s, 9H). 695 1HNMR (400 MHz, MethanolL4) δ 9.63 (s, 1H), 8.58 (d, J = 6.5 Hz, 1H), 8.49 (s, 1H), 8.36 (d, J = 6.7 Hz, 2H), 8.09 (m, 1H), 7.96 (s, 1H), 7.92 - 7.83 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (s, 1H), 4.06 - 3.96 (m, 1H), 3.67 (m, 1H ), 3.36 (s, 1H), 2.70 (s, 1H), 2.36 (s, 6H), 1.12 (s, 1H), 0.73 (s, 9H). 696 1HNMR (400 MHz, MethanolL4) δ 9.66 (s, 1H), 8.57 (d, J = 6.7 Hz, 1H), 8.45 (d, J = 6.7 Hz, 1H), 8 .36 (m, 1H), 8.28 (s, 1H), 8.14 (m, 1H), 8.07 (s, 1H), 7.90 (m, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.86 (s, 1H), 3.78 (d, J = 13.8 Hz, 1H) , 3.48 (d, J = 13.8 Hz, 1H), 1.20 (s, 2H), 1.00 (s, 2H), 0.67 (s, 9H), 0.53 - 0, 46 (m, 2H), 0.30 (d, J = 5.2 Hz, 2H). 697 1HNMR (400 MHz, MethanolL4) δ 9.66 (s, 1H), 8.57 (d, J = 6.6 Hz, 1H), 8.45 (d, J = 6.6 Hz, 1H), 8 .37 (m, 1H), 8.28 (s, 1H), 8.13 (m, 1H), 7.99 - 7.86 (m, 2H), 7.77 (d, J = 2.5 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 6.87 (s, 1H), 3.76 (d, J = 13.7 Hz, 1H), 3.49 ( d, J = 13.7 Hz, 1H), 2.68 (s, 1H), 2.35 (s, 6H), 0.66 (s, 9H). 698 1HNMR (400 MHz, MethanolL4) δ 8.90 (dd, J = 4.6, 1.6 Hz, 1H), 8.53 (d, J = 8.3 Hz, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 8.15 - 8.13 (m, 1H), 8.06 (d, J = 8.6 Hz, 1H), 7.81 - 7.76 (m , 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.65 (dd, J = 8.3, 4.5 Hz, 1H), 7.07 (d, J = 2, 3 Hz, 1H), 6.38 (s, 1H), 4.10 (d, J = 14.0 Hz, 1H), 3.63 (d, J = 14.0 Hz, 1H), 1.78 - 1.69 (m, 2H), 1.66 (s, 2H), 0.77 (s, 9H). 699 1HNMR (400 MHz, MethanolL4) δ 8.92 (dd, J = 4.7, 1.6 Hz, 1H), 8.61 - 8.56 (m, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 8.5, 1.7 Hz , 1H), 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.4, 4.6 Hz, 1H), 7.08 (d, J = 2, 3 Hz, 1H), 6.38 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.11 (d, J = 14.0 Hz, 1H), 3.64 (d, J = 14.0 Hz, 1H), 1.52 (d, J = 2.4 Hz, 4H), 0.78 (s, 9H).

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700 1HNMR (400 MHz, Methanol-d4) δ 8.32 (d, J = 7.6 Hz, 1H), 8.32 (s, 1H), 8.07 (s, 1H), 7.80 (d, J = 2.5 Hz, 1H), 7.76 (dd, J = 7.6, 1.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.22 ( d, J = 7.5 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.61 (s, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.53 (d, J = 13.6 Hz, 1H), 1.80 - 1.54 (m, 4H), 0. 74 (s, 9H). 701 1HNMR (400 MHz, Methanol-d4) δ 8.86 (s, 1H), 8.51 (s, 1H), 8.24 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.14 (d, J = 2.4 Hz, 1H), 6.42 (s, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.44 (s, 3H), 1.87 - 1.57 (m, 4H), 0.99 (s, 9H). 702 1HNMR (400 MHz, Methanol-d4) δ 8.85 (s, 1H), 8.50 (s, 1H), 8.06 (s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.11 (d, J = 2.3 Hz, 1H), 6.37 (s, 1H), 4.03 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.44 (s, 3H), 1.61 - 1.47 (m, 1H), 1.23 (d, J = 2.7 Hz, 2H), 0, 99 (m, 11H), 0.53 (dd, J = 8.1, 1.8 Hz, 2H), 0.40 - 0.27 (m, 2H). 703 1HNMR (400 MHz, Methanol-d4) δ 9.11 - 9.02 (m, 2H), 8.30 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8, 04 (s, 1H), 8.00 - 7.92 (m, 1H), 7.87 (m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.08 (d , J = 2.5 Hz, 1H), 6.88 (s, 1H), 3.80 (d, J = 13.7 Hz, 1H), 3.46 (d, J = 13.8 Hz, 1H ), 1.51 (m, 1H), 1.20 (m, 2H), 1.05 - 0.93 (m, 2H), 0.65 (s, 9H), 0.56 - 0.43 ( m, 2H), 0.30 (m, 2H). 704 1H NMR (400 MHz, Methanol-d4) δ 9.07 (d, J = 4.8 Hz, 1H), 9.01 (d, J = 8.7 Hz, 1H), 8.30 (s, 1H ), 8.12 (d, J = 8.5 Hz, 1H), 8.00 - 7.90 (m, 2H), 7.90 - 7.82 (m, 2H), 7.79 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.90 (s, 1H), 4.95 - 4.79 (m, 1H), 3, 86 (m, 1H), 3.78 (d, J = 13.7 Hz, 1H), 3.54 - 3.45 (m, 1H), 2.05 - 1.84 (m, 1H), 1 .68-1.51 (m, 1H), 0.66 (m, 9H) 705 1H NMR (400 MHz, Methanol-d4) δ 9.06 (d, J = 4.7 Hz, 1H), 8.99 (d, J = 8.6 Hz, 1H), 8.29 (s, 1H ), 8.11 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.98 - 7.87 (m, 1H), 7.87 - 7.73 (m, 3H), 7.09 (d, J = 2.6 Hz, 1H), 6.91 (s, 1H), 6.09 (t, J = 55.5 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 1.73 (s, 6H), 0.65 (s, 9H).

- 396 045220

706 1H NMR (400 MHz, Methanol-d4) δ 9.07 (d, J = 4.7 Hz, 1H), 9.03 (d, J = 8.9 Hz, 1H), 8.30 (s, 1H ), 8.12 (d, J = 8.5 Hz, 1H), 7.98 - 7.91 (m, 2H), 7.84 (m, 2H), 7.79 (d, J = 2, 5 Hz, 1H), 7.08 (d, J = 2.5 Hz, 1H), 6.89 (s, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3.46 (d, J = 13.7 Hz, 1H), 2.67 (s, 1H), 2.35 (s, 6H), 0.64 (s, 9H). 707 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H) , 6.90 - 6.81 (m, 2H), 6.14 - 5.81 (m, 2H), 4.12 (d, J = 13.9 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 2.41 (s, 3H), 1.70 (m, 2H), 1.62 (m, 2H), 0.90 (s, 9H). 708 1HNMR (400 MHz, Methanol-d4) δ 9.02 (dd, J = 5.0, 1.6 Hz, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.29 ( s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H ), 7.89 - 7.81 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.41 (s, 1H), 5.95 (t, J = 54, 6 Hz, 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.47 (d, J = 13.9 Hz, 1H), 1.54 (s, 4H), 0.72 (s, 9H). 709 1H NMR (400 MHz, Methanol-d4) δ 8.99 (dd, J = 4.3, 1.5 Hz, 1H), 8.60 (dd, J = 8.7, 1.5 Hz, 1H) , 8.50 (s, 1H), 8.12 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H) , 7.66 (dd, J = 8.7, 4.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.9 Hz, 1H), 1.76 - 1, 55 (m, 4H), 0.67 (s, 9H). 710 1H NMR (400 MHz, Methanol-d4) δ 9.05 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (dd, J = 8.8, 1.6 Hz, 1H) , 8.31 (s, 1H), 8.21 (d, J = 7.5 Hz, 2H), 7.84 - 7.79 (m, 2H), 7.69 (dd, J = 8.7 , 4.2 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 3.81 (d, J = 13.7 Hz, 1H), 3.37 (d, J = 13.7 Hz, 1H), 1.77 - 1.55 (m, 4H), 0.58 (s, 10H). 711 1H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 3.3 Hz, 1H), 8.35 (d, J = 7.9 Hz, 1H), 7.75 (t, J = 4.3 Hz, 2H), 7.65 (d, J = 3.3 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.40 (m, 1H), 6.83 (m, 2H), 6.56 (d, J = 3.2 Hz, 1H), 4.01 (m, 1H), 3.75 - 3.66 (m, 1H), 2.69 (d, J = 3.3 Hz, 1H), 2.36 (d, J = 3.3 Hz, 6H), 0.80 (s, 9H).

- 397 045220

712 1HNMR (400 MHz, Methanol-d4) δ 9.17 (s, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 8.09 (s, 1H), 7.88 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.68 - 7, 62 (m, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.78 (s, 1H), 3.73 (d, J = 13.6 Hz, 1H), 3, 54 - 3.44 (m, 3H), 1.76 - 1.58 (m, 3H), 0.64 (s, 9H). 714 1H NMR (400 MHz, Acetonitril-d3) δ 8.40 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.82 - 7.75 (m, 2H), 7 .53 (d, J = 2.2 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.81 (d, J = 7.6 Hz, 1H), 6.60 (s, 1H), 6.48 (s, 1H), 6.24 (s, 2H), 3.77 - 3.56 (m, 5H), 3.54 (s, 3H), 3.04 (m, 2H), 2.35 (s, 2H), 1.42 (s, 9H), 0.80 (s, 9H). 715 1HNMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 7.93 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.60 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.17 ( s, 1H), 4.30 (d, J = 15.0 Hz, 1H), 4.14 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.64 ( s, 9H), 1.12 (d, J = 2.2 Hz, 6H). 716 1HNMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 0.7 Hz, 1H), 7.91 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H) , 7.63 (d, J = 2.3 Hz, 1H), 6.94 - 6.84 (m, 2H), 6.18 (s, 1H), 4.02 (d, J = 13.9 Hz, 1H), 3.94 - 3.79 (m, 2H), 2.50 (s, 3H), 1.27 - 1.10 (m, 4H), 0.93 (s, 9H). 717 1HNMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 1.0 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.25 (s, 1H) , 7.68 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 2.3 Hz, 1H), 6 .38 (s, 1H), 5.94 (t, J = 54.5 Hz, 1H), 3.99 (d, J = 14.0 Hz, 1H), 3.84 (d, J = 14, 0 Hz, 1H), 2.75 (d, J = 7.7 Hz, 6H), 1.56 (s, 4H), 0.95 (d, J = 1.1 Hz, 9H). 718 1H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.06 (s, 1H), 7.71 - 7.58 (m, 2H), 7.26 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.20 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4 .04 (d, J = 13.9 Hz, 1H), 3.76 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.54 (d, J = 1, 1 Hz, 4H), 0.92 (s, 9H). 719 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.90 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.91 - 6.78 (m, 2H), 6.18 (s, 1H), 4.41 - 4.14 (m, 2H), 2.69 (s , 1H), 2.51 (s, 3H), 2.37 (s, 6H), 1.14 (d, J = 3.3 Hz, 6H).

- 398 045220

720 1HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.95 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.94 - 6.80 (m, 2H), 6.17 (s, 1H), 4.34 (d, J = 15.0 Hz, 1H), 4, 20 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.65 (s, 3H), 1.31 (d, J = 5.2 Hz, 2H), 1, 15 (d, J = 2.2 Hz, 6H), 1.09 - 1.00 (m, 2H). 721 1HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.18 (s, 1H), 7.76 (t, J = 8.2 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 6.95 - 6.74 (m, 2H), 6.22 (s, 1H), 4.29 (d, J = 14.9 Hz, 1H), 4, 13 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.84 - 1.59 (m, 4H), 1.13 (d, J = 2.1 Hz, 6H ). 722 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.20 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.93 - 6.77 (m, 1H), 6.62 (d, J = 2.3 Hz, 1H), 6.11 (s, 1H), 4, 53 - 4.20 (m, 2H), 3.04 (s, 3H), 2.46 (s, 3H), 1.87 - 1.57 (m, 4H), 1.48 (s, 3H) , 1.38 (s, 3H). 723 1H NMR (400 MHz, Methanol-d4) δ 8.43 (d, J = 3.3 Hz, 1H), 8.05 (d, J = 3.6 Hz, 1H), 7.81 (q, J = 8.0 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.46 - 7.21 (m, 5H), 7.14 (dd, J = 25.5, 2.3 Hz, 1H), 6.97 - 6.77 (m, 1H), 6.35 (d, J = 5.8 Hz, 1H), 5.94 (td, J = 54.7, 8 .7 Hz, 1H), 5.70 (dt, J = 20.5, 7.2 Hz, 1H), 2.53 (d, J = 5.7 Hz, 3H), 2.12 (dh, J = 29.2, 7.2 Hz, 2H), 1.53 (d, J = 6.7 Hz, 4H), 0.97 (dt, J = 14.5, 7.3 Hz, 3H). 724 1HNMR (400 MHz, Methanol^4) δ 8.50 (s, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.74 - 7, 61 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.94 6.74 (m, 2H) , 6.57 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.33 (d, J = 14.8 Hz, 1H), 4.06 (d, J = 14.8 Hz, 1H), 1.58 - 1.40 (m, 4H), 1.01 (d, J = 17.0 Hz, 6H). 725 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.85 - 7.70 (m, 2H), 7.04 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.21 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4.21 (d, J = 14.9 Hz, 1H), 4.05 (d, J = 14.9 Hz, 1H), 2.51 (s, 3H), 1.53 (t, J = 2.3 Hz, 4H), 1.10 (d, J = 2.4 Hz, 6H).

- 399 045220

726 1HNMR (400 MHz, Methanol-44) δ 8.52 (4, J = 1.3 Hz, 1H), 8.33 (4, J = 8.1 Hz, 1H), 7.92 (s, 1H) , 7.79 - 7.63 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.23 (4, J = 7.5 Hz, 1H), 6.85 ( 4, J = 2.2 Hz, 1H), 6.79 (4, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.36 (4, J = 14.8 Hz, 1H), 4.05 (4, J = 14.8 Hz, 1H), 1.50 (4, J = 5.1 Hz, 4H) , 1.01 (4, J = 10.6 Hz, 6H). 727 1HNMR (400 MHz, Methanol-44) δ 8.25 (s, 1H), 8.02 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.51 (4, J = 2.4 Hz, 1H), 6.86 (44, J = 8.5, 2.7 Hz, 1H), 6.71 (4, J = 2.4 Hz, 1H), 6.19 ( s, 1H), 5.95 (t, J = 54.8 Hz, 1H), 4.19 (4, J = 14.8 Hz, 1H), 3.99 (4, J = 14.8 Hz, 1H), 2.50 (s, 3H), 1.53 (q, J = 2.1 Hz, 4H), 1.07 (4, J = 2.3 Hz, 6H). 728 1HNMR (400 MHz, Methanol-44) δ 8.45 (s, 1H), 8.31 (s, 1H), 8.23 (44, J = 7.9, 1.5 Hz, 1H), 7, 92 - 7.86 (m, 1H), 7.77 (s, 1H), 7.66 (4, J = 2.2 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H ), 6.98 (4, J = 2.4 Hz, 2H), 4.03 (4, J = 13.8 Hz, 1H), 3.73 (4, J = 13.9 Hz, 1H), 3.59 (s, 3H), 2.66 (s, 1H), 2.34 (s, 6H), 0.86 (s, 9H). 729 1HNMR (400 MHz, Methanol-44) δ 8.49 (s, 1H), 7.96 (s, 1H), 7.62 (4, J = 2.3 Hz, 1H), 7.51 (4, J = 8.6 Hz, 1H), 6.93 (4, J = 2.3 Hz, 1H), 6.61 (4, J = 8.6 Hz, 1H), 6.17 (s, 1H) , 5.93 (t, J = 54.7 Hz, 1H), 4.00 (4, J = 13.9 Hz, 1H), 3.89 (s, 4H), 2.48 (s, 3H) , 1.52 (s, 4H), 0.94 (s, 9H). 730 1HNMR (400 MHz, Methanol-44) δ 8.47 (s, 1H), 8.33 (4, J = 8.1 Hz, 1H), 7.89 (s, 1H), 7.72 (44, J = 7.2, 1.2 Hz, 1H), 7.65 (4, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 ( 4, J = 7.6 Hz, 1H), 6.89 - 6.71 (m, 2H), 6.56 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.52 (4, J = 14.9 Hz, 1H), 4.09 (4, J = 14.8 Hz, 1H), 3.61 (s, 3H), 2.20 2.04 (m, 2H), 2.04 - 1.76 (m, 3H), 1.68 (4, J = 8.8 Hz, 1H), 1.50 (t, J = 3.8 Hz, 4H). 731 1HNMR (400 MHz, Methanol-44) δ 8.51 (s, 1H), 8.03 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.64 (4, J = 2.3 Hz, 1H), 6.94 - 6.74 (m, 2H), 6.21 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H), 4, 55 (4, J = 15.0 Hz, 1H), 4.28 (4, J = 15.0 Hz, 1H), 2.49 (s, 3H), 2.32 (444, J = 12.5 , 9.3, 6.6 Hz, 2H), 2.19 - 1.77 (m, 4H), 1.64 - 1.46 (m, 4H).

- 400 045220

732 1H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 12.2 Hz, 1H), 8.05 (s, 1H), 7.51 - 7.34 (m, 2H), 6 .79 (d, J = 2.4 Hz, 1H), 6.43 (dd, J = 15.8, 9.5 Hz, 1H), 6.08 (d, J = 9.5 Hz, 1H) , 3.80 (d, J = 13.8 Hz, 1H), 3.70 - 3.54 (m, 4H), 2.48 (s, 3H), 1.52 (s, 4H), 0, 90 (d, J = 2.4 Hz, 9H). 733 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 8.05 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.2 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 ( s, 1H), 5.94 (t, J = 54.6 Hz, 1H), 4.10 (dd, J = 14.6, 7.1 Hz, 1H), 3.97 (dd, J = 14 .6, 7.3 Hz, 1H), 2.50 (s, 3H), 1.54 (s, 4H), 1.11 (d, J = 3.7 Hz, 6H), 1.02 (d , J = 3.4 Hz, 6H), 0.79 (t, J = 7.2 Hz, 1H). 734 1H NMR (400 MHz, Methanol-d4) δ 8.92 (s, 2H), 8.45 (s, 1H), 8.21 - 8.02 (m, 2H), 7.97 - 7.88 ( m, 1H), 7.83 (dd, J = 8.4, 7.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.31 (s, 1H), 7.06 (d, J = 2.3 Hz, 1H), 3.99 (d, J = 13.8 Hz, 1H), 3.69 (d, J = 13.9 Hz, 1H), 1, 79 - 1.48 (m, 4H), 0.78 (s, 9H). 735 1H NMR (400 MHz, Methanol-d4) δ 8.12 (s, 1H), 7.60 (d, J = 3.1 Hz, 1H), 7.47 (dd, J = 7.2, 2, 3 Hz, 1H), 7.29 (dt, J = 7.9, 1.0 Hz, 1H), 7.22 - 7.03 (m, 3H), 6.65 - 6.49 (m, 2H ), 6.28 (s, 1H), 3.76 (s, 3H), 3.67 - 3.57 (m, 1H), 3.53 - 3.41 (m, 1H), 2.60 ( s, 1H), 2.29 (s, 6H), 0.73 (d, J = 1.4 Hz, 9H). 736 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 7.80 - 7.60 (m, 2H), 7.36 (p, J = 3.8 Hz, 1H), 7 .24 - 7.08 (m, 3H), 6.96 (d, J = 2.2 Hz, 1H), 6.54 (dd, J = 3.2, 0.9 Hz, 1H), 6, 39 (s, 1H), 5.90 (t, J = 54.8 Hz, 1H), 4.05 (d, J = 13.7 Hz, 1H), 3.80 (s, 3H), 3, 65 (d, J = 13.8 Hz, 1H), 1.58 - 1.35 (m, 4H), 0.84 (s, 9H). 737 1H NMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.04 (s, 1H), 7.80 - 7.57 (m, 3H), 7.50 (t, J= 7.6 Hz, 1H), 7.43 - 7.20 (m, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.21 (s, 1H), 5.94 ( t, J = 54.7 Hz, 1H), 4.69 (d, J = 18.0 Hz, 1H), 4.33 (d, J = 18.0 Hz, 1H), 4.13 (d, J = 13.8 Hz, 1H), 3.70 - 3.56 (m, 1H), 3.15 (s, 3H), 1.53 (d, J = 3.2 Hz, 4H), 0, 85 (s, 9H).

-401 045220

738 1HNMR (400 MHz, MethanolU4) δ 9.57 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.50 (s, 1H), 8.44 (d, J = 0.9 Hz, 1H), 8.24 (d, J = 6.4 Hz, 1H), 8.06 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7 .18 (d, J = 2.3 Hz, 1H), 6.61 (s, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.90 (tt, J = 7, 4, 4.0 Hz, 1H), 3.82 (d, J = 14.0 Hz, 1H), 1.24 - 1.13 (m, 4H), 0.88 (s, 9H). 739 1HNMR (400 MHz, MethanolU4) δ 8.49 (s, 1H), 8.06 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.4, 2.8 Hz, 1H), 6.25 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.12 (m, 2H), 2.52 (s, 1H), 2.51 (s, 3H), 1.80 ( s, 6H), 1.54 (s, 4H). 740 1HNMR (400 MHz, MethanolU4) δ 8.49 (s, 1H), 8.20 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 (s, 1H), 4.12 (s, 2H), 2.52 (s, 1H), 2.51 (s, 3H), 1.80 (s, 6H), 1.78 - 1.72 (m, 2H ), 1.72 - 1.65 (m, 2H). 741 1HNMR (400 MHz, MethanolU4) δ 9.52 (s, 1H), 8.56 (d, J = 6.3 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J = 1.0 Hz, 1H), 8.32 (s, 1H), 8.20 (d, J = 6.3 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 6.65 (s, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.80 (d, J = 14.0 Hz , 1H), 1.81 - 1.71 (m, 2H), 1.69 (m, 2H), 0.87 (s, 9H). 742 1HNMR (400 MHz, MethanolU4) δ 8.53 (s, 1H), 8.04 (s, 1H), 7.98 (t, J = 2.1 Hz, 1H), 7.87 - 7.75 ( m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.4, 2 .7 Hz, 1H), 6.17 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 2.45 (s, 3H), 1.53 (s, 4H). 743 1HNMR (400 MHz, MethanolD4) δ 8.48 (s, 1H), 8.35 (d, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7, 7 Hz, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.83 (d, J = 7.9 Hz, 1H), 6.60 (s, 1H), 6.23 (tt, J = 56.0, 4.1 Hz, 1H), 5.92 (t, J = 54.6 Hz, 1H), 4.56 - 4.43 (m, 1H), 4.44 - 4.28 (m, 1H), 4.04 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 1.62 1.38 (m, 4H), 0.78 (s, 9H).

- 402 045220

744 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.91 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 5 .92 (t, J = 54.7 Hz, 1H), 4.02 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.57 - 1.42 (m, 4H), 0.78 (s, 9H). 745 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.54 (s, 1H), 4 .04 (d, J = 13.8 Hz, 1H), 3.91 - 3.81 (m, 1H), 3.66 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.22 - 1.08 (m, 4H), 0.78 (s, 9H). 746 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 8.06 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.3, 2.8 Hz, 1H), 6.72 (d, J = 2.2 Hz, 1H), 6.09 ( s, 1H), 5.95 (t, J = 54.6 Hz, 1H), 4.09 - 3.95 (m, 2H), 3.65 - 3.53 (m, 2H), 2.49 (s, 3H), 1.54 (s, 4H), 1.01 (s, 3H), 0.98 (s, 3H). 747 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.39 - 8.28 (m, 1H), 7.80 (s, 1H), 7.73 (dd, J = 7 .5, 1.3 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.89 - 6.73 (m, 2H), 6.55 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.63 (m, 4H), 1.61 (s, 9H), 0.77 (s, 9H). 748 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.90 (s, 1H), 7.83 - 7.73 (m, 2H), 7.10 (d, J= 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J = 18.7 Hz, ZN), 0.89 (s, 9H). 749 1HNMR (400 MHz, Methanol-d4) δ 8.49 (d, J = 1.3 Hz, 1H), 7.90 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H) , 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 4.94 - 4.82 (m, 1H), 4.03 (d, J = 14.2 Hz, 1H), 3.81 (d, J = 14 .0 Hz, 1H), 2.50 (s, 3H), 1.66 (t, J = 18.7 Hz, ZN), 0.93 (s, 9H).

-403 045220

750 1HNMR (400 MHz, Methanol-<14) δ 8.48 (s, 1H), 7.89 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.63 (d , J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 4.90 (dd, J = 13.7, 2.8 Hz, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.92 (td, J = 16.9, 8.3 Hz, 2H), 1.05 (t, J = 7.5 Hz, 3H), 0.93 (s, 9H). 751 1HNMR (400 MHz, Methanol-44) δ 8.50 (s, 1H), 7.92 (s, 1H), 7.74 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 ( s, 1H), 4.64 (d, J = 1.3 Hz, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.87 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.14 (s, 4H), 0.94 (s, 9H). 752 1HNMR (400 MHz, Methanol-44) δ 8.51 (s, 1H), 7.88 (s, 1H), 7.75 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.22 ( s, 1H), 5.59 (t, J = 56.0 Hz, 1H), 4.55 (s, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.86 ( d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 0.94 (s, 14H). 753 1HNMR (400 MHz, Methanol-44) δ 8.49 (s, 1H), 8.01 (s, 1H), 7.72 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 6.20 ( s, 1H), 3.99 (d, J = 14.0 Hz, 1H), 3.86 (d, J = 14.0 Hz, 1H), 2.86 (q, J = 10.3 Hz, 2H), 2.48 (s, 3H), 1.52 - 1.23 (m, 4H), 0.93 (s, 9H). 754 1HNMR (400 MHz, Methanol-44) δ 8.48 (s, 1H), 7.95 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.00 - 6.78 (m, 2H), 6.19 (s, 1H), 4.00 (d, J = 13.9 Hz, 1H), 3, 83 (d, J = 14.0 Hz, 1H), 2.49 (s, 3H), 1.92 - 1.74 (m, 2H), 1.31 - 1.17 (m, 2H), 1 .06 (d, J = 1.8 Hz, 2H), 0.93 (s, 9H), 0.82 (t, J = 7.4 Hz, 3H). 755 1HNMR (400 MHz, Methanol-44) δ 8.49 (s, 1H), 7.88 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.8 Hz, 1H), 6.23 ( s, 1H), 4.55 (s, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.49 ( s, 3H), 1.17 (d, J = 6.7 Hz, 6H), 0.94 (s, 9H).

- 404 045220

756 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.33 (d, J = 8.3 Hz, 1H), 7.80 (s, 1H), 7.76 - 7, 68 (m, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 6.88 - 6.75 (m, 2H), 6.54 (s, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.60 (s, 3H), 1.83 (q, J = 7.4 Hz, 2H), 1.21 (d, J = 5.5 Hz, 2H), 1.13 - 0.97 (m, 2H), 0.78 (d, J = 7.6 Hz, 12H). 757 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.91 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.93 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.21 ( s, 1H), 4.03 (d, J = 13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.65 ( p, J = 6.8 Hz, 1H), 1.24 - 1.15 (m, 2H), 1.15 - 1.08 (m, 2H), 0.94 (s, 9H), 0.93 - 0.87 (m, 6H). 758 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.97 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.90 - 6.87 (m, 1H), 6.87 - 6.85 (m, 1H), 6.20 (s, 1H), 4.02 (d , J = 13.9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.57 (s, 3H), 1.56 (s , 3H), 1.39 - 1.31 (m, 1H), 0.93 (s, 9H), 0.56 - 0.49 (m, 2H), 0.46 - 0.38 (m, 2H ). 759 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.07 (s, 1H), 7.80 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.95 - 6.84 (m, 2H), 6.24 (s, 1H), 5.09 (t, J = 6.3 Hz, 2H), 4, 75 (dd, J = 6.8, 2.3 Hz, 2H), 4.02 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.92 (s, 3H), 0.93 (s, 9H). 760 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.92 (s, 1H), 7.75 (dd, J = 7.5, 1.0 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 ( d, J = 7.7 Hz, 1H), 6.87 - 6.80 (m, 2H), 6.58 (s, 1H), 5.06 (dd, J = 6.8, 4.2 Hz , 2H), 4.76 - 4.69 (m, 2H), 4.02 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 3 .61 (s, 3H), 1.88 (s, 3H), 0.77 (s, 9H). 761 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.90 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.6, 2.8 Hz, 1H), 6.20 ( s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.28 ( m, 2H), 1.08 (m, 2H), 0.94 (s, 9H), 0.88 (s, 9H).

-405 045220

762 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.02 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.25 ( s, 1H), 5.39 - 5.21 (m, 1H), 5.05 - 4.91 (m, 2H), 4.84 (s, 2H), 4.02 (d, J = 13, 9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 0.93 (s, 9H). 763 1HNMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.00 (s, 1H), 7.76 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.88 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.18 (s, 1H) , 4.37(d, J = 15.0 Hz, 1H), 4.18 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.59 - 1.49 ( m, 1H), 1.30 - 1.19 (m, 2H), 1.15 (s, 3H), 1.15 (s, 3H), 1.08 - 0.96 (m, 2H), 0 .57 - 0.48 (m, 2H), 0.37 - 0.27 (m, 2H). 764 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.87 (s, 1H), 7.79 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.22 ( s, 1H), 4.23 (d, J = 3.1 Hz, 2H), 4.04 (d, J = 13.9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 0.96 (s, 3H), 0.93 (s, 9H), 0.71 - 0.66 (m, 2H), 0.43 (m, 2H ). 765 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.33 (d, J = 7.9 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 2.2 Hz, 1H), 6.81 (d, J = 7.5 Hz, 1H), 6.59 (s, 1H), 5 .92 (t, J = 54.7 Hz, 1H), 4.02 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.51 (s, 4H), 0.79 (s, 9H). 766 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.84 (s, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.19 (s, 1H), 4.21 - 4.14 (m, 1H), 4.02 (d, J = 14.0 Hz, 1H), 3.83 (d, J = 13.9 Hz , 1H), 2.49 (s, 3H), 1.75 - 1.67 (m, 2H), 1.17 - 1.12 (m, 1H), 1.06 - 0.95 (m, 1H) , 0.95 - 0.91 (m, 1H), 0.93 (s, 9H), 0.90 - 0.74 (m, 1H). 767 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.22 (d, J = 5.0 Hz, 1H), 7.94 (s, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 3.5 Hz, 1H), 7.25 (d, J = 5.2 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1H), 6.62 (d, J = 3.6 Hz, 1H), 6.50 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4 .14 (d, J = 13.8 Hz, 1H), 3.86 (s, 3H), 3.60 (d, J = 13.8 Hz, 1H), 1.56 - 1.39 (m, 4H), 0.82 (s, 9H).

- 406 045220

768 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.74 - 7, 67 (m, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.42 (s, 1H), 4.01 ( d, J = 13.3 Hz, 1H), 3.90 (d, J = 13.4 Hz, 1H), 3.61 (s, 3H), 3.48 (d, J = 10.5 Hz, 1H), 3.40 (d, J = 10.5 Hz, 1H), 2.68 (s, 1H), 2.35 (s, 6H), 0.91 (s, 3H), 0.81 ( s, 3H). 769 1HNMR (400 MHz, Methanol-d4) δ 8.44 (s, 1H), 8.33 (d, J = 8.2 Hz, 1H), 7.75 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.80 - 6.75 (m, 1H), 6.55 (s, 1H), 4.15 - 4.03 (m, 2H), 4.00 (d, J = 13.8 Hz, 1H), 3.59 (d, J = 13.7 Hz, 1H), 2.67 (s, 1H), 2.34 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H), 0.74 (s, 9H). 770 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.39 - 8.32 (m, 1H), 8.06 (s, 1H), 7.80 - 7.73 ( m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.39 - 6, 05 (m, 1H), 4.55 - 4.32 (m, 2H), 4.04 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H ), 1.75 - 1.56 (m, 4H), 0.78 (s, 9H). 771 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H), 7.81 - 7, 73 (m, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 5.03 - 4.84 (m, 1H), 4.81 - 4.66 (m, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.9 Hz , 1H), 1.84 - 1.53 (m, 4H), 0.78 (s, 9H). 772 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (d, J 8, l Hz, 1H), 7.75 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.46 (t, J = 7 .8 Hz, 1H), 6.87 (d, J = 7.9 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.56 (s, 1H), 5, 29 (p, J = 6.8 Hz, 1H), 4.04 (d, J = 13.7 Hz, 1H), 3.58 (d, J = 13.8 Hz, 1H), 2.67 ( s, 1H), 2.34 (s, 6H), 1.42 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.8 Hz, 3H), 0.73 ( s, 9H).

- 407 045220

773 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.37 - 8.30 (m, 1H), 7.82 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7, 6 Hz, 1H), 6.83 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.54 (s, 1H), 4.17 - 3.98 (m, 2H), 4.03 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 1.62 (s, 3H) , 1.36 (t, J = 7.1 Hz, 3H), 1.32 - 1.22 (m, 2H), 1.06 - 1.00 (m, 2H), 0.75 (s, 9H ). 774 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.38 - 8.30 (m, 1H), 7.81 (s, 1H), 7.73 (d, J= 7.3 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7, 8 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 6.54 (s, 1H), 5.36 - 5.22 (m, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.62 (s, 3H) , 1.42 (d, J = 6.9 Hz, 3H), 1.40 (d, J = 6.9 Hz, 3H), 1.32 - 1.25 (m, 2H), 1.07 - 0.99 (m, 2H), 0.73 (s, 9H). 775 1H NMR (400 MHz, Methanol-d4) δ 8.48 (d, J = 1.2 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 7.88 (s, 1H ), 7.73 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.57 (s, 1H), 4.59 (d, J = 48.4 Hz , 2H), 4.05 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.46 - 1 .29 (m, 4H), 0.77 (s, 9H). 776 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.33 (d, J = 8.1 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.85 - 6.77 (m, 2H), 6.54 (s, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.64 ( d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 1.62 (s, 3H), 1.30 - 1.26 (m, 2H), 1.07 - 1.01 (m, 2H), 0.76 (s, 9H). 777 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.77 - 7, 70 (m, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 5.24 ( t, J = 19.1 Hz, 1H), 5.02 - 4.91 (m, 2H), 4.87 - 4.69 (m, 2H), 4.05 (d, J = 13.8 Hz , 1H), 3.64 (d, J = 13.7 Hz, 1H), 3.61 (s, 3H), 0.77 (s, 9H).

- 408 045220

778 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 7.7 Hz, 1H), 6.58 (s, 1H), 5 .05 - 4.91 (m, 1H), 4.67 (d, J = 46.9 Hz, 1H), 4.66 (d, J = 47.0 Hz, 1H), 4.06 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 1.53 (dd, J = 7.1, 1.2 Hz, ZN), 0.77 (s, 9H). 779 1HNMR (400 MHz, Methanol) δ 8.18 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.58 (s, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 2.1 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7, 7 Hz, 1H), 6.55 - 6.48 (m, 2H), 6.25 (s, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.33 (d, J = 14.0 Hz, 1H), 3.31 (s, 3H), 1.26 - 1.17 (m, 1H), 0.98 - 0.81 (m, 2H), 0.79 - 0 .62 (m, 2H), 0.47 (s, 9H), 0.27 - 0.13 (m, 2H), 0.12 - -0.09 (m, 2H). 780 1HNMR (400 MHz, Methanol) δ 8.51 (s, 1H), 8.35 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.72 - 7.68 ( m, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 4.34 (d, J = 14.9 Hz, 1H), 4.07 (d, J = 14.9 Hz, 1H), 3.61 (s, 3H), 1.85 - 1.55 (m, 4H), 1, 02 (d, J = 16.4 Hz, 6H). 781 1HNMR (400 MHz, MethanolhI) δ 8.52 (s, 1H), 8.34 (d, J = 8.3 Hz, 1H), 7.84 (s, 1H), 7.72 - 7.67 ( m, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.80 (d, J = 7.5 Hz, 1H), 6.53 (s, 1H), 4.35 (d, J = 14.9 Hz, 1H), 4.07 (d, J = 14.9 Hz, 1H), 3.61 (s, 3H), 1.63 (s, 3H), 1.32 - 1, 25 (m, 2H), 1.06-1.01 (m, 5H), 0.99 (s, 3H). 782 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.14 (s, 1H), 8.12 (dd, J = 5.0, 1.9 Hz, 1H), 7 .68 (dd, J = 7.3, 1.9 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.3 Hz, 1H) , 6.95 (dd, J = 7.4, 5.0 Hz, 1H), 6.29 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.94 ( s, 3H), 3.85 (d, J = 13.9 Hz, 1H), 1.82 - 1.59 (m, 4H), 0.97 (s, 9H).

- 409 045220

783 1H NMR (400 MHz, MethanolM4) δ 8.18 (s, 1H), 8.08 - 8.00 (m, 1H), 7.57 (s, 1H), 7.46 - 7.38 (m, 1H), 7.35 (d, J = 2.3 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H) , 6.54 - 6.46 (m, 2H), 6.23 (s, 1H), 4.03 (d, J = 14.8 Hz, 1H), 3.71 (d, J = 14.9 Hz, 1H), 3.31 (s, 3H), 1.21 (ddd, J = 13.1, 8.1, 4.9 Hz, 1H), 0.97 - 0.79 (m, 2H) , 0.69 (d, J = 18.4 Hz, 6H), 0.71 - 0.68 (m, 2H), 0.25 - 0.15 (m, 2H), 0.01 (t, J = 5.0 Hz, 2H). 784 1HNMR (400 MHz, Methanol^4) δ 9.85 (s, 1H), 9.71 (d, J = 7.9 Hz, 1H), 9.17 (s, 1H), 9.07 (d, J = 7.5 Hz, 1H), 9.02 (s, 1H), 8.85 (t, J = 8.0 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H) , 8.18 (s, 2H), 7.93 (s, 1H), 6.46 - 6.27 (m, 1H), 6.03 (dd, J = 46.9, 5.4 Hz, 2H ), 5.70 (d, J = 14.8 Hz, 1H), 5.40 (d, J = 14.8 Hz, 1H), 4.98 (s, 3H), 2.90 (d, J = 7.0 Hz, ZN), 2.36 (d, J = 17.8 Hz, 6H). 785 1HNMR (400 MHz, Methanol^4) δ 9.84 (s, 1H), 9.70 (d, J = 8.3 Hz, 1H), 9.14 (s, 1H), 9.05 (d, J = 7.5 Hz, 1H), 9.00 (d, J = 2.2 Hz, 1H), 8.84 (t, J = 7.8 Hz, 1H), 8.78 (d, J = 7.6 Hz, 1H), 8.28 - 8.05 (m, 2H), 7.90 (s, 1H), 5.66 (d, J = 14.9 Hz, 1H), 5.41 ( d, J = 14.8 Hz, 1H), 4.97 (s, 3H), 4.03 (s, 1H), 3.71 (s, 6H), 2.36 (d, J = 18.1 Hz, 6H). 786 1HNMR (400 MHz, Methanol^4) δ 8.48 (s, 1H), 8.17 (d, J = 9.9 Hz, 1H), 7.78 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.40 - 7.33 (m, 1H), 6.83 (d, J = 2.3 Hz, 1H ), 6.71 (d, J = 9.9 Hz, 1H), 6.65 (s, 1H), 4.07 (d, J = 13.9 Hz, 1H), 3.77 (s, 3H ), 3.61 (d, J = 13.9 Hz, 1H), 2.67 (s, 1H), 2.35 (s, 6H), 0.77 (s, 9H). 787 1H NMR (400 MHz, Methanol^4) δ 8.46 (s, 1H), 8.32 (d, J = 8.1 Hz, 1H), 7.77 7.72 (m, 2H), 7, 65 (d, J = 2.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.5 Hz, 1H), 6.81 ( dd, J = 5.0, 2.6 Hz, 2H), 6.56 (s, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.63 (d, J = 13 .8 Hz, 1H), 2.67 (s, 1H), 2.35 (s, 6H), 0.77 (s, 9H). 788 1HNMR (400 MHz, Methanol^4) δ 8.49 (s, 1H), 8.36 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.91 (t, J = 60.1 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.62 (s, 1H), 4.07 (d, J = 13.8 Hz, 1H), 3.64 (d, J = 13.8 Hz, 1H), 1.85 -1, 51 (m, 4H), 0.79 (s, 9H).

- 410 045220

789 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.17 (d, J = 9.8 Hz, 1H), 8.08 (s, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.64 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.37 (dd, J = 5.5, 3.1 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 9.8 Hz, 1H), 6.70 (s, 1H), 4.08 ( d, J = 13.9 Hz, 1H), 3.78 (s, 3H), 3.61 (d, J = 13.8 Hz, 1H), 1.77 - 1.59 (m, 4H), 0.77(s,9H). 790 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.40 - 8.26 (m, 1H), 7.74 (dd, J = 7.6, 1.2 Hz, 1H ), 7.66 (d, J = 2.0 Hz, 2H), 7.47 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 6.88 - 6.75 (m, 2H), 6.54 (s, 1H), 4.03 (m, 4H), 3.71 - 3.55 (m, 4H), 0.77 (s, 9H). 791 1HNMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 7.89 - 7.70 (m, 2H), 7.48 (d, J = 2.4 Hz, 1H), 6, 86 (dd, J = 8.4, 2.7 Hz, 1H), 6.73 (d, J = 2.4 Hz, 1H), 6.16 (s, 1H), 4.07 (s, 3H ), 3.79 (d, J = 13.7 Hz, 1H), 3.59 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.86 (s, 9H ). 792 1HNMR (400 MHz, Methanol-d4) δ 8.50 (d, J = 1.0 Hz, 1H), 8.19 (s, 1H), 7.78 (t, J = 8.1 Hz, 1H) , 7.62 (d, J = 2.3 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 (s, 1H), 4.53 (dd, J = 12.1, 6.4 Hz, 2H), 4.43 (t, J = 6.1 Hz, 2H), 4, 12 (s, 2H), 2.50 (s, 3H), 1.81 - 1.56 (m, 4H), 1.39 (s, 3H). 793 1H NMR (400 MHz, MethanolT4) δ 8.47 (d, J = 3.1 Hz, 2H), 8.23 (s, 1H), 7.89 (dd, J = 8.3, 2.6 Hz , 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 2.3 Hz, 1H ), 6.20 (s, 1H), 4.15 (d, J = 14.0 Hz, 1H), 3.73 (d, J = 14.0 Hz, 1H), 1.80 - 1.72 (m, 2H), 1.69 (d, J = 9.1 Hz, 2H), 0.96 (s, 9H). 794 1H NMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.21 (s, 1H), 7.70 - 7.60 (m, 2H), 7.27 (d, J= 8.2 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.22 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3 .77 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.81 - 1.61 (m, 4H), 0.92 (s, 9H).

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795 1HNMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 2.2 Hz, 1H), 8.48 (s, 1H), 8.31 (s, 1H), 8.28 (dd, J = 8.3, 2.3 Hz, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.16 ( d, J = 2.3 Hz, 1H), 6.33 (s, 1H), 4.09 (d, J = 14.0 Hz, 1H), 3.81 (d, J = 14.0 Hz, 1H), 2.69 (s, 3H), 1.80 - 1.73 (m, 2H), 1.72 - 1.62 (m, 2H), 0.97 (s, 9H). 796 1H NMR (400 MHz, AcetonitrileIs) δ 8.39 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7 .7 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 6.46 (s, 1H), 5.07 - 4.98 (m , 1H), 3.77 - 3.69 (m, 1H), 3.62 (m, 1H), 3.54 (s, 3H), 2.54 - 2.44 (m, 4H), 1, 89 (m, 2H), 0.79 (s, 9H). 797 1H NMR (400 MHz, Methanol-d4) δ 9.03 (d, J = 4.5 Hz, 1H), 8.87 (d, J = 8.6 Hz, 1H), 8.45 (s, 1H ), 8.10 (d, J = 8.5 Hz, 1H), 7.95 - 7.83 (m, 2H), 7.82 - 7.73 (m, 2H), 7.66 (d, J = 2.3 Hz, 1H), 6.85 - 6.79 (m, 2H), 4.30 (d, J = 14.9 Hz, 1H), 3.93 (d, J = 14.9 Hz, 1H), 1.62 (s, 3H), 1.30 (d, J = 13.3 Hz, 2H), 1.03 (s, 2H), 0.94 (s, 3H), 0, 88 (s, 3H). 798 1H NMR (400 MHz, Methanol-d4) δ 9.02 (d, J = 4.9 Hz, 1H), 8.85 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H ), 8.09 (d, J = 8.6 Hz, 1H), 7.96 (s, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.81 - 7.72 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 6.86 - 6.79 (m, 2H), 4.31 (d, J = 14.8 Hz, 1H) , 3.91 (d, J = 14.9 Hz, 1H), 1.18 (s, 2H), 0.99 (s, 2H), 0.94 (s, 3H), 0.88 (s, 3H), 0.49 (d, J = 7.5 Hz, 2H), 0.29 (d, J = 5.1 Hz, 2H). 799 1H NMR (400 MHz, Methanol-d4) δ 9.05 (d, J = 4.6 Hz, 1H), 8.92 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H ), 8.12 (d, J = 8.6 Hz, 1H), 7.94 - 7.85 (m, 2H), 7.85 - 7.76 (m, 2H), 7.67 (d, J = 2.3 Hz, 1H), 6.88 - 6.81 (m, 2H), 4.31 (d, J = 14.9 Hz, 1H), 3.96 (d, J = 14.9 Hz, 1H), 2.67 (s, 1H), 2.34 (s, 6H), 0.95 (s, 3H), 0.90 (s, 3H). 800 (1HNMR (400 MHz, Acetonitrile^3) δ 8.38 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 7.5 Hz, 1H ), 7.65 (s, 1H), 7.52 (d, J = 2.2 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 7.7 Hz, 1H), 6.58 (s, 1H), 6.46 (s, 1H), 3.77 - 3.67 (m, 1H), 3.61 (m, 1H), 3.54 (s, 3H), 2.68 (d, J = 10.2 Hz, 2H), 2.5, (m, 2H), 2.27 (s, 2H), 1.69 (s, 3H), 0.78 (s, 9H).

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801 1H NMR (400 MHz, Acetonitrile-a3) δ 8.40 (s, 1H), 8.31 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H ), 7.56 (dd, J = 21.4, 1.8 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.7 Hz , 1H), 6.81 - 6.74 (m, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 3.84 3.68 (m, 1H), 3.63 (m, 1H), 3.54 (s, 3H), 1.86 - 1.78 (m, 2H), 1.46 (dd, J = 6.8, 3.3 Hz, 3H), 0, 79 (d, J = 1.1 Hz, 9H), 0.78 - 0.69 (m, 3H). 802 1H NMR (400 MHz, Acetonitril-d3) δ 8.39 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.83 - 7.76 (m, 1H), 7 .63 (s, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.31 (d, J = 7, 7 Hz, 1H), 6.81 (d, J = 7.8 Hz, 1H), 6.61 (s, 1H), 6.47 (s, 1H), 6.24 (s, 1H), 4 .79 (m, 1H), 3.76 (m, 1H), 3.71 - 3.53 (m, 3H), 3.54 (s, 3H), 3.20 (s, 3H), 1, 45 (d, J = 6.9 Hz, 3H), 0.80 (s, 9H). 803 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 4.6 Hz, 1H), 8.78 (d, J = 8.6 Hz, 1H), 8.46 (s, 1H ), 8.08 (d, J = 8.4 Hz, 1H), 7.89 - 7.79 (m, 2H), 7.79 - 7.65 (m, 3H), 6.95 - 6, 85 (m, 2H), 4.96 (dd, J = 12.2, 5.9 Hz, 1H), 4.71 (d, J = 5.4 Hz, 1H), 4.60 (d, J = 5.4 Hz, 1H), 4.00 (d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 1.52 (dd, J = 7 ,1, 1.3 Hz, 3H), 0.69 (s, 9H). 804 1H NMR (400 MHz, Methanol-d4) δ 8.98 (d, J = 4.5 Hz, 1H), 8.78 (d, J = 8.7 Hz, 1H), 8.46 (s, 1H ), 8.09 (d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.88 - 7.79 (m, 1H), 7.79 - 7.66 (m, 3H), 6.96 - 6.88 (m, 2H), 5.22 (s, 1H), 4.99 - 4.84 (m, 3H), 4.84 - 4.73 (m, 1H) , 4.00 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 13.8 Hz, 1H), 0.69 (s, 9H). 805 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.22 (s, 1H), 8.13 (s, 1H), 7.74 (dd, J = 8.7, 2 .5 Hz, 1H), 7.65 (d, J = 2.1 Hz, 1H), 7.10 (s, 1H), 6.81 (d, J = 8.7 Hz, 1H), 6, 10 (s, 1H), 4.12 (d, J = 14.0 Hz, 1H), 3.89 (s, 3H), 3.79 (d, J = 14.0 Hz, 1H), 1, 83 - 1.56 (m, 4H), 0.98 (s, 9H). 806 1HNMR (400 MHz, Methanol-d4) δ 8.54 (s, 1H), 8.20 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.7, 2.8 Hz, 1H), 6.25 ( s, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 2.46 ( s, 3H), 2.06 - 1.93 (m, 4H), 0.94 (s, 9H).

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807 1HNMR (400 MHz, Methanol-d4) δ 8.27 (s, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 6.2 Hz, 1H) , 7.75 (d, J = 2.5 Hz, 1H), 7.72 (s, 2H), 7.51 (d, J = 7.8 Hz, 1H), 7.49 - 7.42 ( m, 2H), 6.93 (d, J = 2.5 Hz, 1H), 6.66 (s, 1H), 4.09 (s, 3H), 3.71 (d, J = 13.5 Hz, 1H), 3.44 (d, J = 13.6 Hz, 1H), 2.30 (s, 6H), 0.61 (s, 9H). 808 1H NMR (400 MHz, Methanol-d4) δ 8.28 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.95 (dd, J = 6.3, 1, 4 Hz, 1H), 7.77 - 7.70 (m, 4H), 7.53 - 7.44 (m, 2H), 6.94 (d, J = 2.4 Hz, 1H), 6, 64 (s, 1H), 4.09 (d, J = 1.4 Hz, 3H), 3.85 - 3.77 (m, OH), 3.72 (d, J = 13.4 Hz, 1H ), 3.45 (d, J = 13.2 Hz, 1H), 1.16 - 1.04 (m, 4H), 0.62 (d, J = 1.4 Hz, 9H). 809 1HNMR (400 MHz, Methanol^4) δ 8.26 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 6.3 Hz, 1H) , 7.79 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.73 (s, 1H), 7.54 - 7.43 (m, 2H), 6, 92 (d, J = 2.5 Hz, 1H), 6.64 (s, 1H), 4.09 (d, J = 1.0 Hz, 3H), 3.71 (d, J = 13.4 Hz, 1H), 3.44 (d, J = 13.8 Hz, 1H), 1.58 (s, 3H), 1.24 (s, 3H), 1.01 - 0.96 (m, 2H ), 0.61 (d, J= 1.0 Hz, 8H). 810 1H NMR (400 MHz, Methanol^4) δ 8.29 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.98 - 7.93 (m, 1H), 7.87 (s, 1H), 7.79 - 7.76 (m, 1H), 7.74 (d, J = 7.3 Hz, 1H), 7.54 - 7, 44 (m, 3H), 6.98 (d, J = 2.5 Hz, 1H), 6.69 (s, 1H), 5.88 (t, J = 55.0 Hz, 1H), 4, 09 (d, J = 1.2 Hz, 3H), 3.75 (d, J = 13.6 Hz, 1H), 3.47 (d, J = 13.5 Hz, 1H), 1.46 ( d, J = 1.2 Hz, 2H), 0.63 (d, J = 1.1 Hz, JN). 811 1HNMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 9.2 Hz, 1H), 8.36 (s, 1H), 8.04 (s, 1H), 7.82 (s, 1H), 7.82 (d, J = 10.3 Hz, 1H), 7.59 (t, J = 8.5, 7.4 Hz, 1H), 7.43 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 2.5 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 6.78 (s, 1H), 4.06 ( d, J = 0.6 Hz, 3H), 3.83 (d, J = 13.7 Hz, 1H), 3.55 (d, J = 13.7 Hz, 1H), 1.76 - 1, 56 (m, 5H), 0.69 (s, 9H). 812 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 8.07 (s, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.83 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.58 - 7.51 ( m, 1H), 7.49 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.75 (s, 1H), 4.13 ( s, 3H), 3.82 (d, J = 13.7 Hz, 1H), 3.52 (d, J = 13.7 Hz, 1H), 1.77 - 1.55 (m, 4H), 0.66(s,9H).

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814 1HNMR (400 MHz, MethanolL4) δ 8.95 (dd, J = 4.4, 1.4 Hz, 1H), 8.67 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H), 7.86 (s, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.7, 4.3 Hz, 1H), 7, 64 (dd, J = 8.2, 4.8 Hz, 1H), 7.48 (dd, J = 10.3, 8.2 Hz, 1H), 7.06 (d, J = 2.5 Hz , 1H), 6.78 (s, 1H), 3.82 (d, J = 13.7 Hz, 1H), 3.49 (d, J = 13.8 Hz, 1H), 2.66 (s , 1H), 2.34 (s, 6H), 0.64 (s, 9H). 815 1H NMR (400 MHz, Methanol-d4) δ 8.96 (d, J = 4.3 Hz, 1H), 8.68 (d, J = 8.8 Hz, 1H), 8.35 (s, 1H ), 7.99 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.71 (dd, J = 8.7, 4.4 Hz, 1H), 7.63 (dd, J = 8.2, 4.8 Hz, 1H), 7.50 (dd, J = 10.0, 8.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.78 (s, 1H), 5.91 (t, J = 54.7 Hz, 1H), 4.16 (d, J = 14.8 Hz, 1H), 3.86 (d, J = 14.8 Hz, 1H), 1.49 (d, J = 5.4 Hz, 4H), 0.90 (s, 3H), 0.85 (s, 3H). 816 1H NMR (400 MHz, MethanolL4) δ 8.95 (d, J = 4.3 Hz, 1H), 8.66 (d, J = 8.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 8.8, 4.3 Hz, 1H), 7.61 (dd , J = 8.2, 4.8 Hz, 1H), 7.52 - 7.44 (m, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.75 (s, 1H), 4.14 (d, J = 14.8 Hz, 1H), 3.85 (d, J = 14.8 Hz, 1H), 2.66 (s, 1H), 2.34 (s, 6H), 2.02 (s, 1H), 0.88 (s, 3H), 0.83 (s, 3H). 817 1H NMR (400 MHz, Methanol-d4) δ 8.67 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H ), 8.29 (s, 1H), 8.16 (s, 1H), 7.98 (d, J = 7.2 Hz, 1H), 7.89 - 7.83 (m, 1H), 7 .82 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.88 (s, 1H), 3.80 (d, J = 13, 7 Hz, 1H), 3.43 (d, J = 13.7 Hz, 1H), 1.76 - 1.56 (m, 4H), 0.62 (s, 9H). 818 1HNMR (400 MHz, MethanolL4) δ 9.02 (dd, J = 5.0, 1.6 Hz, 1H), 8.84 (d, J = 8.3 Hz, 1H), 8.29 (s, 1H), 8.22 (s, 1H), 8.19 (s, 1H), 8.12 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.89 - 7.81 (m, 2H), 7.22 (d, J = 2.5 Hz, 1H), 6.41 (s, 1H), 5.95 (t, J = 54.6 Hz , 1H), 3.91 (d, J = 13.9 Hz, 1H), 3.47 (d, J = 13.9 Hz, 1H), 1.54 (s, 4H), 0.72 (s , 9H). 819 1HNMR (400 MHz, MethanolL4) δ 8.32 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 6.2 Hz, 1H), 7 .83 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.73 (d, J = 7.2 Hz, 1H), 7.53 (t, J = 7, 9 Hz, 1H), 7.48 (d, J = 6.3 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.66 (s, 1H), 4.12 (d, J = 14.8 Hz, 1H), 4.12 (s, 3H), 3.85 (d, J = 14.7 Hz, 1H), 1.62 (s, 3H), 1.27 (d, J = 5.6 Hz, 2H), 1.07 - 0.99 (m, 2H), 0.84 (d, J = 13.7 Hz, 6H).

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820 1HNMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.26 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.78 (d, J = 2.4 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.48 (d, J = 6.2 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.67 (s, 1H), 4 .10 (d, J = 12.8 Hz, 4H), 3.86 (d, J = 14.6 Hz, 1H), 2.66 (s, 1H), 2.34 (s, 6H), 0 .84 (d, J = 14.2 Hz, 6H). 821 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H) , 7.91 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.73 (dd, J = 7.4, 1.2 Hz, 1H), 7.58 - 7.51 (m, 1H), 7.48 (d, J = 6.3 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.71 (s, 1H), 5.92 (t, J = 54.8 Hz, 1H), 4.13 (s, 4H), 3.89 (d, J = 14.7 Hz, 1H), 1.49 (d, J = 3 .5 Hz, 4H), 0.87 (d, J = 12.6 Hz, 6H). 822 1HNMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.38 (s, 1H), 8.30 (s, 1H), 8.18 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 2.0 Hz, OH), 7.96 (s, 1H), 7.96 - 7, 91 (m, 1H), 7.80 (d, J = 2.6 Hz, 1H), 7.28 (d, J = 2.5 Hz, 1H), 6.31 (s, 1H), 3, 90 (d, J = 14.0 Hz, 1H), 3.57 (d, J = 14.0 Hz, 1H), 1.78 (s, 2H), 1.68 (s, 2H), 0. 83 (s, 10H). 823 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.86 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.69 (s, 1H), 4 .12 (s, 3H), 3.81 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 1.49 (ddd, J = 13, 2, 8.4, 5.0 Hz, 1H), 1.25 - 1.14 (m, 2H), 1.02 - 0.94 (m, 2H), 0.66 (s, 9H), 0 .52 - 0.42 (m, 2H), 0.28 (q, J = 5.3 Hz, 2H). 824 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 6.2 Hz, 1H) , 7.82 (d, J = 2.4 Hz, 1H), 7.79 (s, 1H), 7.77 (d, J = 7.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 6.3 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.72 (s, 1H), 5 .03 - 4.90 (m, 1H), 4.71 (d, J = 5.4 Hz, 1H), 4.59 (d, J = 5.4 Hz, 1H), 4.12 (s, 3H), 3.81 (d, J = 13.7 Hz, 1H), 3.51 (d, J = 13.7 Hz, 1H), 1.51 (dd, J = 7.0, 1.3 Hz, 3H), 0.66 (s, 9H), 0.09 (s, 1H).

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825 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H) , 7.87 (s, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.58 (d, J = 7.1 Hz, OH), 7.54 (dd, J = 8.3, 7.3 Hz, 1H), 7.50 (d, J = 6.3 Hz, 1H ), 7.03 (d, J = 2.5 Hz, 1H), 6.75 (s, 1H), 5.29 - 5.14 (m, 1H), 4.98 - 4.86 (m, 2H) , 4.83 - 4.74 (m, 1H), 4.68 (s, OH), 4.30 (s, OH), 4.12 (s, 3H), 3.81 (d, J = 13, 6 Hz, 1H), 3.51 (d, J = 13.7 Hz, 1H), 0.66 (s, 9H). 826 1HNMR (400 MHz, Methanol) δ 8.83 (d, J = 2.2 Hz, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 8.07 (dd, J = 8.1, 2.3 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.21 (d, J = 2.6 Hz, 1H), 6.29 (s, 1H), 4.00 (d, J = 14.0 Hz, 1H), 3.57 (d, J = 14.0 Hz, 1H) , 1.80 - 1.72 (m, 2H), 1.69 (d, J = 9.2 Hz, 2H), 0.90 (s, 9H). 827 1H NMR (400 MHz, Methanol) δ 8.41 (s, 1H), 7.96 (s, 1H), 7.82 - 7.71 (m, 2H), 7.04 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 4.25 (d, J = 15.0 Hz, 1H) , 4.08 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.64 (s, 9H), 1.10 (d, J = 1.9 Hz, 6H) . 828 1HNMR (400 MHz, Methanol-d4) δ 8.79 (d, J = 2.1 Hz, 1H), 8.48 (dd, J = 8.4, 2.2 Hz, 1H), 8.37 ( s, 1H), 8.31 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.76 (dd, J = 2.6, 1.2 Hz, 1H), 7.32 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 3.96 - 3.81 (m, 1H), 3.66 (d, J = 13.9 Hz , 1H), 2.75 (s, 3H), 1.82 - 1.74 (m, 2H), 1.69 (d, J = 5.5 Hz, 2H), 1.07 (s, 2H) , 0.94 (s, 9H). 829 1H NMR (400 MHz, Methanol^4) δ 8.37 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 15.4 Hz, 2H), 7.76 - 7.64 (m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 6.37 (s, 1H), 5.95 (t, J = 54.5 Hz, 1H), 3.85 (d, J = 13.9 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.76 (d, J = 12.5 Hz, 6H), 1.56 (d , J = 2.5 Hz, 4H), 0.92 (s, 9H). 830 1HNMR (400 MHz, Methanol-d4) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 6.29 (s, 1H) , 3.89 (d, J = 13.8 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 2.59 (s, 3H), 1.80 - 1.63 ( m, 4H), 0.86 (s, 9H).

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831 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.82 - 7.70 (m, 2H), 7.01 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.20 (s, 1H), 5.95 (t, J = 54.8 Hz, 1H), 4.42 (d, J = 14.9 Hz, 1H), 4.15 (d, J = 14.9 Hz, 1H), 2.49 (s, 3H), 2.41 - 2, 20 (m, 2H), 2.15-1.79 (m, 3H), 1.53 (s, 5H). 832 1H NMR (400 MHz, Methanol) δ 8.37 (s, 1H), 8.05 (s, 1H), 7.85 - 7.68 (m, 2H), 7.05 (d, J = 2, 5 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.22 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H) , 5.48 (s, 1H), 4.22 (d, J = 14.9 Hz, 1H), 4.06 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H) , 1.52 (t, J = 1.7 Hz, 4H), 1.10 (d, J = 2.5 Hz, 6H). 833 1HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.90 (s, 1H), 7.82 - 7.68 (m, 2H), 7.02 (d, J = 2 .5 Hz, 1H), 6.86 (dd, J = 8.6, 2.7 Hz, 1H), 6.18 (s, 1H), 4.25 - 4.00 (m, 2H), 2 .68 (s, 1H), 2.51 (s, 3H), 2.37 (s, 6H), 1.09 (d, J = 3.3 Hz, 6H). 834 1H NMR (400 MHz, MethanolA δ 8.35 (s, 1H), 7.97 (s, 1H), 7.84 - 7.68 (m, 2H), 7.07 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.20 (s, 1H), 5.98 (tt, J = 56.8, 3.4 Hz , 1H), 4.17 (dt, J = 8.2, 4.0 Hz, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.69 (d, J = 13, 8 Hz, 1H), 2.52 (s, 3H), 2.26 (ddq, J = 10.8, 7.4, 3.8 Hz, 1H), 1.66 (q, J = 10.4 , 8.7 Hz, 1H), 1.52 - 1.43 (m, 1H), 0.89 (s, 9H). 835 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.90 (s, 1H), 7.83 - 7.73 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J = 18.7 Hz, 3H), 0.89 (s, 9H). 836 1H NMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.90 (s, 1H), 7.83 - 7.73 (m, 2H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.25 (s, 1H), 3.88 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H), 1.65 (t, J = 18.7 Hz, 3H), 0.89 (s, 9H). 837 1H NMR (400 MHz, MethanolA δ 8.37 (s, 1H), 7.90 (s, 1H), 7.84 - 7.75 (m, 2H), 7.18 - 7.08 (m, 1H ), 6.88 (dd, J = 8.4, 2.8 Hz, 1H), 6.25 (s, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 2.01 - 1.77 (m, 2H), 1.05 (t, J = 7.5 Hz, 3H) , 0.89 (s, 9H).

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838 1H NMR (400 MHz, DMSO-C16) δ 8.35 (s, 1H), 8.18 (d, J = 7.9 Hz, 1H), 8.09 (s, 1H), 7.84 (d , J = 2.3 Hz, 1H), 7.69 - 7.58 (m, 1H), 7.58 - 7.37 (m, 4H), 7.24 (s, 1H), 6.72 ( d, J = 7.7 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 6.08 (t, J = 54.1 Hz, 1H), 4.07 (dd, J = 14.7, 7.6 Hz, 1H), 3.86 (dd, J = 14.6, 6.1 Hz, 1H), 3.48 (s, 3H), 1.45 (t, J = 4.4 Hz, 4H), 0.88 (d, J = 18.4 Hz, 6H). 839 1H NMR (400 MHz, Methanol) δ 8.37 (s, 1H), 7.92 (s, 1H), 7.86 - 7.67 (m, 2H), 7.13 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.24 (s, 1H), 4.64 (d, J = 1.1 Hz, 2H) , 3.86 (d, J = 13.8 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 1.13 (s, 4H) , 0.90 (s, 9H). 840 1H NMR (400 MHz, Methanol) δ 8.36 (s, 1H), 7.88 (s, 1H), 7.82 - 7.68 (m, 2H), 7.11 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.22 (s, 1H), 5.59 (t, J = 56.0 Hz, 1H) , 4.55 (s, 2H), 3.86 (d, J = 13.8 Hz, 1H), 3.71 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H) , 0.90 (s, 14H). 841 1H NMR (400 MHz, Methanol) δ 8.37 (s, 1H), 8.04 (s, 1H), 7.85 - 7.70 (m, 2H), 7.04 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.21 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H) , 4.21 (d, J = 14.9 Hz, 1H), 4.05 (d, J = 14.9 Hz, 1H), 2.51 (s, 3H), 1.53 (t, J = 2.3 Hz, 4H), 1.10 (d, J = 2.4 Hz, 6H). 842 1H NMR (400 MHz, MethanolC4) δ 8.33 (d, J = 6.9 Hz, 2H), 7.94 (s, 1H), 7.85 7.64 (m, 2H), 7.49 ( t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 2.4 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.58 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 4.15 (d, J = 14.7 Hz, 1H) , 3.91 (d, J = 14.8 Hz, 1H), 1.50 (s, 4H), 0.94 (d, J = 11.1 Hz, 6H). 843 1H NMR (400 MHz, Methanol) δ 8.35 (s, 1H), 8.19 (s, 1H), 7.87 - 7.66 (m, 2H), 7.04 (d, J = 2, 5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.23 (s, 1H), 4.19 (d, J = 14.9 Hz, 1H) , 4.04 (d, J = 14.9 Hz, 1H), 2.51 (s, 3H), 1.81 - 1.59 (m, 4H), 1.09 (d, J = 1.9 Hz, 6H).

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844 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.21 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.66 (dt, J = 6.5, 2.1 Hz, 2H), 7.25 (d, J = 2.5 Hz, 1H), 6.38 (t, J = 6.9 Hz, 1H), 6.18 ( s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.64 (d, J = 13.9 Hz, 1H), 3.59 (s, 3H), 1.81 - 1.54 (m, 4H), 0.96 (s, 9H). 845 1HNMR (400 MHz, Methanol-d4) δ 8.41 (s, 1H), 8.06 (s, 1H), 7.84 - 7.66 (m, 2H), 7.23 (d, J = 2 .5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.27 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H ), 3.99 (dd, J = 14.4, 7.2 Hz, 1H), 3.86 (dd, J = 14.4, 7.4 Hz, 1H), 2.50 (s, 3H) , 1.53 (s, 4H), 1.09 (d, J = 3.9 Hz, 6H), 1.00 (d, J = 1.7 Hz, 6H), 0.73 (d, J = 7.3 Hz, 1H). 846 1HNMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.96 (s, 1H), 7.83 - 7.65 (m, 2H), 7.01 (d, J = 2 .5 Hz, 1H), 6.86 (dd, J = 8.4, 2.8 Hz, 1H), 6.16 (s, 1H), 4.20 (d, J = 14.9 Hz, 1H ), 4.07 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.65 (s, 3H), 1.41 - 1.24 (m, 2H), 1 .07 (dd, J = 17.4, 1.8 Hz, 8H). 847 1H NMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 7.88 - 7.64 (m, 2H), 7.35 (dt, J = 7.5, 3.7 Hz, 1H), 7.27 - 6.97 (m, 4H), 6.57 (dd, J = 3.2, 0.9 Hz, 1H), 6.38 (s, 1H), 5.90 (t , J = 54.8 Hz, 1H), 5.48 (s, 1H), 3.96 - 3.69 (m, 4H), 3.53 (d, J = 13.5 Hz, 1H), 1 .61-1.32 (m, 4H), 0.79 (s, 9H). 848 1HNMR (400 MHz, Methanol^4) δ 8.36 (s, 1H), 8.20 (s, 1H), 7.81 - 7.72 (m, 2H), 7.22 (d, J = 2 .5 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 (s, 1H), 4.04 - 3.91 (m, 2H), 2 .52 (s, 3H), 2.49 (s, 1H), 1.74 (m, 8H), 1.69 (d, J = 8.0 Hz, 2H). 849 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.06 (s, 1H), 7.83 - 7.71 (m, 2H), 7.22 (d, J = 2 .5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.25 (s, 1H), 5.94 (t, J = 54.7 Hz, 1H ), 3.97 (m, 2H), 2.52 (s, 3H), 2.49 (s, 1H), 1.74 (s, 6H), 1.53 (s, 4H). 850 1H NMR (400 MHz, Methanol-d4) δ 8.38 (d, J = 0.8 Hz, 1H), 8.00 (s, 1H), 7.85 7.77 (m, 2H), 7, 10 (d, J = 2.5 Hz, 1H), 6.89 (dd, J = 8.4, 2.7 Hz, 1H), 6.22 (s, 1H), 3.90 (d, J = 13.8 Hz, 1H), 3.71 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.58 (s, 3H), 1.57 (s, 3H ), 1.43 - 1.31 (m, 1H), 0.91 (s, 9H), 0.58 - 0.48 (m, 2H), 0.47 - 0.37 (m, 2H).

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851 1HNMR (400 MHz, Methanol-d4) δ 8.38 (s, 1H), 7.91 (s, 1H), 7.83 - 7.75 (m, 2H), 7.11 (d, J = 2 .5 Hz, 1H), 6.89 (dd, J = 8.5, 2.8 Hz, 1H), 6.22 (s, 1H), 3.88 (d, J = 13.9 Hz, 1H ), 3.73 (d, J = 13.9 Hz, 1H), 2.52 (s, 3H), 1.66 (p, J = 6.9 Hz, 1H), 1.28 - 1.16 (m, 2H), 1.17 - 1.04 (m, 2H), 0.97 - 0.85 (m, 15H). 852 1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 8.07 (s, 1H), 7.85 - 7.75 (m, 2H), 7.12 - 7.06 ( m, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 (s, 1H), 5.10 (t, J = 6.5 Hz, 2H), 4.75 (dd, J = 6.9, 2.0 Hz, 2H), 3.86 (d, J = 13.8 Hz, 1H), 3.70 (d, J = 13.8 Hz, 1H ), 2.52 (s, 3H), 1.92 (s, 3H), 0.89 (s, 9H). 853 1HNMR (400 MHz, Methanol-d4) δ 8.37 - 8.29 (m, 2H), 7.95 (s, 1H), 7.81 - 7.73 (m, 2H), 7.53 - 7 .38 (m, 2H), 6.99 (d, J = 2.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 6.58 (s, 1H), 5 .07 (dd, J = 6.9, 3.0 Hz, 2H), 4.72 (d, J = 6.9 Hz, 2H), 3.80 (d, J = 13.6 Hz, 1H) , 3.61 (s, 3H), 3.52 (d, J = 13.6 Hz, 1H), 1.89 (s, 3H), 0.72 (s, 9H). 854 1H NMR (400 MHz, Methanol-d4) δ 8.36 (d, J = 1.4 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 6.92 - 6.85 (m, 1H), 6.22 (s, 1H), 4.81 - 4.55 (m, 3H), 3.92 (d, J = 13.9 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 2.50 (s, 3H) , 1.58 (d, 3H), 0.89 (s, 9H). 855 1HNMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.59 (d, J = 6.4 Hz, 1H), 8.47 (s, 1H), 8.34 (s, 1H), 8.33 - 8.30 (m, 2H), 7.79 (d, J = 2.5 Hz, 1H), 7.30 (d, J = 2.5 Hz, 1H), 6, 66 (s, 1H), 3.83 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 1.81 - 1.72 (m, 2H ), 1.72-1.61 (m, 2H), 0.82 (s, 9H). 856 1HNMR (400 MHz, Methanol-d4) δ 9.59 (s, 1H), 8.58 (d, J = 6.4 Hz, 1H), 8.46 (s, 1H), 8.33 - 8, 27 (m, 2H), 8.06 (s, 1H), 7.77 (d, J = 2.5 Hz, 1H), 7.27 (d, J = 2.6 Hz, 1H), 6, 59 (d, J = 1.0 Hz, 1H), 3.97 - 3.87 (m, 1H), 3.82 (d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.9 Hz, 1H), 1.29 - 1.12 (m, 4H), 0.81 (s, 9H).

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857 1HNMR (400 MHz, Methanol-44) δ 8.39 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.78 (4, J = 2.5 Hz, 1H) , 6.96 (4, J = 2.5 Hz, 1H), 6.83 (44, J = 8.5, 2.6 Hz, 1H), 6.09 (s, 1H), 4.03 ( 4, J = 13.8 Hz, 1H), 3.84 (tt, J = 7.4, 3.9 Hz, 1H), 3.51 (4, J = 13.8 Hz, 1H), 2, 38 (s, 3H), 1.87 (tt, J = 8.5, 5.4 Hz, 1H), 1.34 - 1.26 (m, 2H), 1.26 - 1.19 (m, 2H), 1.07 (444, J = 8.5, 3.4, 1.6 Hz, 2H), 0.98 - 0.90 (m, 1H), 0.85 (s, 9H), 0 .83 - 0.76 (m, 1H). 858 1HNMR (400 MHz, Methanol-44) δ 8.37 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.78 (4, J = 2.5 Hz, 1H) , 7.05 (4, J = 2.6 Hz, 1H), 6.88 (44, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 4.89 ( s, 1H), 4.80 - 4.69 (m, 1H), 4.69 - 4.56 (m, 1H), 4.25 (4, J = 14.8 Hz, 1H), 3.99 (4, J =14.9 Hz, 1H), 2.50 (s, 3H), 1.61-1.54 (m, 3H), 1.10 (s, 3H), 1.09 (s, 3H). 859 1HNMR (400 MHz, Methanol-44) δ 8.35 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.78 (4, J = 2.5 Hz, 1H) , 7.00 (4, J = 2.5 Hz, 1H), 6.86 (44, J = 8.5, 2.7 Hz, 1H), 6.13 (s, 1H), 3.97 ( 4, J = 13.8 Hz, 1H), 3.93 (s, 3H), 3.68 - 3.61 (m, 1H), 3.53 (4, J = 13.8 Hz, 1H), 2.45 (s, 3H), 1.29-1.21 (m, 2H), 1.21 - 1.13 (m, 2H), 0.87 (s, 9H). 860 1H NMR (400 MHz, Methanol-44) δ 8.36 (s, 1H), 7.90 (s, 1H), 7.83 - 7.70 (m, 2H), 7.10 (4, J= 2.5 Hz, 1H), 6.87 (44, J = 8.5, 2.7 Hz, 1H), 6.21 (s, 1H), 3.85 (4, J = 13.9 Hz, 1H), 3.71 (4, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.32 - 1.22 (m, 2H), 1.12 - 1.02 (m , 2H), 0.90 (s, 9H), 0.88 (s, 9H). 861 1HNMR (400 MHz, Methanol-44) δ 8.38 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.77 (4, J = 2.5 Hz, 1H) , 7.04 (4, J = 2.5 Hz, 1H), 6.87 (44, J = 8.5, 2.7 Hz, 1H), 6.16 (s, 1H), 4.23 ( 4, J = 14.9 Hz, 1H), 4.03 (4, J = 14.9 Hz, 1H), 2.72 (s, 1H), 2.51 (s, 3H), 2.43 ( s, 6H), 1.11 (s, 3H), 1.10 (s, 3H). 862 1HNMR (400 MHz, Methanol-44) δ 8.37 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.78 (4, J = 2.5 Hz, 1H) , 7.03 (4, J = 2.5 Hz, 1H), 6.87 (44, J = 8.5, 2.7 Hz, 1H), 6.16 (s, 1H), 4.28 ( 4, J = 14.9 Hz, 1H), 3.97 (4, J = 14.9 Hz, 1H), 2.49 (s, 3H), 1.54 - 1.44 (m, 1H), 1.28 - 1.18 (m, 2H), 1.10 (s, 4H), 1.10 - 1.05 (m, 5H), 0.57 - 0.45 (m, 2H), 0, 36 - 0.25 (m, 2H).

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863 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H) , 7.01 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.3, 2.7 Hz, 1H), 6.15 (s, 1H), 4.26 ( d, J = 14.9 Hz, 1H), 3.97 (d, J = 14.9 Hz, 1H), 2.49 (s, 3H), 1.60 (s, 3H), 1.41 - 1.28 (m, 2H), 1.14 - 1.05 (m, 6H). 864 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H) , 7.02 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.15 (s, 1H), 4.23 ( d, J = 14.8 Hz, 1H), 4.00 (d, J = 14.9 Hz, 1H), 3.72 - 3.58 (m, 1H), 2.51 (s, 3H), 1.31 - 1.15 (m, 3H), 1.10 (s, 3H), 1.09 (s, 3H). 865 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H) , 7.08 (d, J = 2.6 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.19 (s, 1H), 3.90 ( d, J = 13.8 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 2.50 (s, 3H), 1.54 - 1.42 (m, 1H), 1.27 - 1.22 (m, 2H), 1.10 - 1.05 (m, 2H), 0.89 (s, 9H), 0.52 - 0.47 (m, 2H), 0. 34 - 0.28 (m, 2H). 866 1HNMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.87 (s, 1H), 7.84 - 7.76 (m, 2H), 7.10 (d, J = 2 .5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.23 (s, 1H), 4.23 (m, 2H), 3.86 (s , 1H), 3.68 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.96 (s, 3H), 0.90 (s, 9H), 0.68 (s, 2H), 0.43 (s, 2H). 867 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.00 (s, 1H), 7.83 - 7.72 (m, 2H), 7.02 (d, J= 2.5 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 6.18 (s, 1H), 4.22 (d, J = 14.9 Hz, 1H), 4.03 (d, J = 14.9 Hz, 1H), 2.50 (s, 3H), 1.62 - 1.47 (m, 1H), 1.32 - 1.17 (m , 2H), 1.10 (s, 3H), 1.09 (s, 3H), 1.06 - 0.97 (m, 2H), 0.58 - 0.46 (m, 2H), 0, 38 - 0.28 (m, 2H). 868 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H) , 6.99 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.4, 2.7 Hz, 1H), 6.14 (s, 1H), 3.96 ( d, J = 13.8 Hz, 1H), 3.91 (s, 3H), 3.51 (d, J = 13.8 Hz, 1H), 2.69 (s, 1H), 2.44 ( s, 3H), 2.43 (s, 6H), 0.86 (s, 9H).

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869 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 8.02 (s, 1H), 7.85 - 7.74 (m, 2H), 7.11 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.8 Hz, 1H), 6.26 (s, 1H), 5.37 5.17 (m, 1H), 5 .05 - 4.90 (m, 2H), 4.84 (m, 2H), 3.89 (d, J = 13.8 Hz, 1H), 3.69 (d, J = 13.8 Hz, 1H), 2.51 (s, 3H), 0.89 (s, 9H). 870 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.34 (d, 1H), 7.94 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H) , 7.03 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.60 (s, 1H), 6.25 (tt, J = 56.0, 4.1 Hz, 1H), 5.92 (t, J = 54.7 Hz, 1H), 4.58 - 4.30 (m, 2H), 3.85 (d, J = 13 .7 Hz, 1H), 3.52 (d, J = 13.7 Hz, 1H), 1.53 - 1.47 (m, 4H), 0.73 (s, 9H). 871 1HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 8.2 Hz, 1H), 8.30 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5 .92 (t, J = 54.8 Hz, 1H), 3.79 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.50 (d, J = 13, 6 Hz, 1H), 1.50 (s, 4H), 0.72 (s, 9H). 872 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 7.84 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.76 (d, J = 2.3 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.6, 2.7 Hz, 1H), 6.19 ( s, 1H), 4.17 (dd, J = 7.0, 3.4 Hz, 1H), 3.84 (d, J = 14.0 Hz, 1H), 3.68 (d, J = 14 .0 Hz, 1H), 2.51 (s, 3H), 1.70 (q, J = 6.0 Hz, 2H), 1.20 - 1.09 (m, 1H), 1.06 - 0 .90 (m, 2H), 0.88 (s, 9H), 0.87 - 0.76 (m, 1H). 873 1HNMR (400 MHz, Methanol-d4) δ 8.31 (s, 1H), 8.25 (d, J = 5.2 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 3.6 Hz, 1H), 7.31 (d, J = 5.2 Hz, 1H), 7.12 (d, J = 2.5 Hz, 1H), 6.68 (d, J = 3.6 Hz, 1H), 6.51 (s, 1H), 5.92 (t, J = 54.7 Hz, 1H), 3 .90 (d, J = 13.7 Hz, 1H), 3.88 (s, 3H), 3.45 (d, J = 13.7 Hz, 1H), 1.50 (br s, 4H), 0.76(s,9H). 874 1HNMR (400 MHz, Methanol-d4) δ 8.34 (d, J = 8.0 Hz, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 2.6 Hz, 1H), 6.85 (d, J = 7.9 Hz, 1H), 6.62 (s, 1H), 6 .42 - 6.06 (m, 1H), 4.55 - 4.33 (m, 2H), 3.85 (d, J = 13.7 Hz, 1H), 3.53 (d, J = 13 .6 Hz, 1H), 1.75 - 1.59 (m, 4H), 0.73 (s, 9H).

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875 1HNMR (400 MHz, Methanol-d4) δ 8.35 (d, J = 8.0 Hz, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.81 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.03 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.62 (s, 1H), 5 .02 - 4.91 (m, 1H), 4.81 - 4.65 (m, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13 .8 Hz, 1H), 1.78 - 1.61 (m, 4H), 0.71 (s, 9H). 876 1HNMR (400 MHz, Methanol) δ 8.32 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 7.92 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7, 5 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.93 (t, J = 54.7 Hz, 1H), 3.81 (d, J = 13.6 Hz, 1H), 3.51 (d, J = 13.6 Hz, 1H), 1.50 (s , 4H), 0.73 (s, 9H). 877 1HNMR (400 MHz, Methanol) δ 8.34 (d, J = 8.1 Hz, 1H), 8.31 (s, 1H), 7.82 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7, 6 Hz, 1H), 6.99 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 7.8 Hz, 1H), 6.58 (s, 1H), 5.05 - 4.91 (m, 1H), 4.67 (d, J = 46.9 Hz, 1H), 4.66 (d, J = 46.9 Hz, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.50 (d, J = 13.6 Hz, 1H), 1.56 - 1.49 (m, 3H), 0.71 ( s, 9H). 878 1H NMR (400 MHz, Methanol-d4) δ 8.36 - 8.30 (m, 2H), 7.89 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7 .75 (d, J = 7.5 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 6.57 (s, 1H), 4.59 (d, J = 48.6 Hz, 2H), 3.84 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H), 3.52 (d, J = 13.6 Hz, 1H), 1.53 - 1.26 (m, 4H) , 0.72 (s, 9H). 879 1H NMR (400 MHz, Methanol-d4) δ 8.36 - 8.29 (m, 2H), 7.85 (s, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7 .74 (d, J = 7.6 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.85 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 3.81 (d, J = 13.7 Hz , 1H), 3.61 (d, J = 1.2 Hz, ZN), 3.51 (d, J = 13.7 Hz, 1H), 1.63 (s, 3H), 1.36 - 1 .22 (m, 2H), 1.09 - 0.96 (m, 2H), 0.71 (s, 9H).

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880 1H NMR (400 MHz, Methanol-d4) δ 8.37 - 8.30 (m, 2H), 7.89 (s, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7 .75 (d, J = 7.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.86 (d, J = 7.7 Hz, 1H), 6.61 (s, 1H), 5.26 - 5.21 (m, 1H) , 5.03 - 4.92 (m, 2H), 4.86 - 4.76 (m, 2H), 3.86 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H ), 3.52 (d, J = 13.7 Hz, 1H), 0.72 (s, 9H). 881 1H NMR (400 MHz, Methanol-d4) δ 8.07 - 8.00 (m, 2H), 7.60 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7 .45 (d, J = 7.5 Hz, 1H), 7.18 (t, J = 7.8 Hz, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.56 (d, J = 7.8 Hz, 1H), 6.26 (s, 1H), 3.56 (d, J = 13.5 Hz, 1H), 3.31 (d, J= 1.3 Hz, 3H), 3.23 (d, J = 13.6 Hz, 1H), 1.25 - 1.16 (m, 1H), 0.95 - 0.83 ( m, 2H), 0.75 - 0.65 (m, 2H), 0.43 (s, 9H), 0.24 - 0.14 (m, 2H), 0.05 - 0.06 (m, 2H). 882 1HNMR (400 MHz, Methanol-d4) δ 8.05 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H), 7.51 (d, J = 2.4 Hz, 1H) , 7.47 - 7.40 (m, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.7 Hz, 1H), 6.69 ( d, J = 2.5 Hz, 1H), 6.56 (d, J = 7.6 Hz, 1H), 6.25 (s, 1H), 3.89 (d, J = 14.7 Hz, 1H), 3.64 (d, J = 14.7 Hz, 1H), 3.33 (s, 3H), 1.30 - 1.16 (m, 1H), 0.96 0.88 (m, 2H), 0.75 - 0.68 (m, 2H), 0.69 (s, 3H), 0.64 (s, 3H), 0.21 (ddd, J = 8.2, 6.1, 4.5 Hz, 2H), 0.08 - -0.02 (m, 2H). 883 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.34 (d, J = 8.2 Hz, 1H), 7.79 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.54 (s, 1H), 4 .13 (d, J = 14.8 Hz, 1H), 3.94 (d, J = 14.8 Hz, 1H), 3.61 (s, 3H), 2.67 (s, 1H), 2 .35 (s, 6H), 0.94 (d, J = 19.8 Hz, 6H). 884 1HNMR (400 MHz, Methanol-d4) δ 8.34 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 6.96 (d, J = 2.5 Hz, 1H), 6.83 (d, J = 7.4 Hz, 1H), 6.52 (s, 1H), 4 .15 (d, J = 14.7 Hz, 1H), 3.93 (d, J = 14.7 Hz, 1H), 3.61 (s, 3H), 1.63 (s, 3H), 1 .36 - 1.24 (m, 2H), 1.07 - 1.01 (m, 2H), 0.94 (d, J = 19.6 Hz, 6H).

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885 1HNMR (400 MHz, Methanol-d4) δ 8.40 (s, 1H), 8.14 (s, 1H), 8.11 (dd, J = 5.1, 1.9 Hz, 1H), 7, 82 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.3, 1.8 Hz, 1H), 7.25 (d, J = 2.5 Hz, 1H), 6.95 (dd, J = 7.4, 5.0 Hz, 1H), 6.29 (s, 1H), 3.94 (d, J = 13.9 Hz, 1H), 3.94 (s , 3H), 3.74 (d, J = 13.9 Hz, 1H), 1.83 - 1.57 (m, 4H), 0.94 (s, 9H). 886 1HNMR (400 MHz, Methanol-d4) δ 8.25 (d, J = 7.3 Hz, 2H), 7.98 (s, 1H), 7.69 (d, J = 2.5 Hz, 1H) , 7.64 - 7.57 (m, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H), 6.91 ( d, J = 2.5 Hz, 1H), 6.74 (d, J = 7.7 Hz, 1H), 6.49 (s, 1H), 4.05 (d, J = 14.7 Hz, 1H), 3.85 (d, J = 14.7 Hz, 1H), 3.52 (s, 3H), 1.73 - 1.49 (m, 4H), 0.88 (s, 3H), 0.84(s, 3H). 887 1HNMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H), 8.12 (d, J = 9.9 Hz, 1H), 7.71 (s, 1H), 7.70 (d, J = 2.5 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.30 (q, J = 4.8 Hz, 1H), 6.89 (d, J = 2.5 Hz, 1H), 6.62 (d, J = 9.9 Hz, 1H), 6.57 (s, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3.68 ( s, 3H), 3.37 (d, J = 13.7 Hz, 1H), 2.58 (s, 1H), 2.26 (s, 6H), 0.61 (s, 9H). 888 1H NMR (400 MHz, Methanol-d4) δ 8.23 (s, 1H), 8.22 (d, J = 8.0 Hz, 1H), 7.71 7.68 (m, 2H), 7, 66 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.13 (d, J = 7.5 Hz, 1H), 6.87 ( d, J = 2.5 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.47 (s, 1H), 3.72 (d, J = 13.6 Hz, 1H), 3.41 (d, J = 13.6 Hz, 1H), 2.58 (s, 1H), 2.26 (s, 6H), 0.63 (s, 9H). 889 1H NMR (400 MHz, Methanol-d4) δ 8.39 - 8.33 (m, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.91 (t, J = 60.0 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.54 (t, J = 7.8 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 2.5 Hz, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.62 (s, 1H), 3.86 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.7 Hz, 1H), 1.85 - 1.55 (m, 4H), 0.73 (s, 9H). 890 1HNMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 8.12 (d, J = 9.9 Hz, 1H), 8.00 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H), 7.53 (d, J = 4.4 Hz, 2H), 7.30 (t, J = 4.3 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 10.1 Hz, 1H), 6.61 (s, 1H), 3.79 (d, J = 13.7 Hz, 1H), 3 .68 (s, 3H), 3.37 (d, J = 13.7 Hz, 1H), 1.74 - 1.45 (m, 4H), 0.62 (s, 9H).

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891 1H NMR (400 MHz, Methanol-d4) δ 8.37 - 8.30 (m, 2H), 7.79 (d, J = 1.9 Hz, 2H), 7.76 - 7.67 (m, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.42 (d, J = 7.7 Hz, 1H), 6.97 (d, J = 2.5 Hz, 1H) , 6.85 (d, J = 7.6 Hz, 1H), 6.56 (s, 1H), 3.82 (d, J = 13.6 Hz, 1H), 3.61 (s, 3H) , 3.52 (d, J = 13.7 Hz, 1H), 2.67 (s, 1H), 2.35 (d, J = 1.1 Hz, 6H), 0.71 (s, 9H) . 892 1H NMR (400 MHz, Methanol-d4) δ 9.09 - 8.97 (m, 2H), 8.29 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7 .97 - 7.88 (m, 2H), 7.88 - 7.76 (m, 3H), 7.09 (d, J = 2.4 Hz, 1H), 6.90 (s, 1H), 4.72 (d, J = 5.5 Hz, 1H), 4.60 (d, J = 5.8 Hz, 1H), 3.78 (d, J = 13.8 Hz, 1H), 3, 46 (d, J = 13.8 Hz, 1H), 1.53 (d, J = 7.4 Hz, 3H), 0.65 (s, 9H). 893 1H NMR (400 MHz, Methanol-d4) δ 9.12 - 9.04 (m, 2H), 8.29 (s, 1H), 8.14 (d, J = 8.5 Hz, 1H), 8 .03 (s, 1H), 8.00 - 7.91 (m, 1H), 7.87 (m, 2H), 7.80 (d, J = 2.5 Hz, 1H), 7.11 ( d, J = 2.5 Hz, 1H), 6.94 (s, 1H), 5.00 - 4.74 (m, 4H), 3.80 (d, J = 13.8 Hz, 1H), 3.47 (d, J = 13.8 Hz, 1H), 0.66 (s, 9H). 894 1HNMR (400 MHz, Acetonitril-d3) δ 9.15 - 9.07 (m, 2H), 8.41 (s, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8, 02 - 7.81 (m, 4H), 7.76 (d, J = 2.4 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.81 (s, 1H ), 6.25 (s, 1H), 5.90 (s, 2H), 5.85 (t, J = 54.6 Hz, 1H), 4.09 (dd, J = 14.7, 7, 4 Hz, 1H), 3.86 (dd, J = 14.7, 5.8 Hz, 1H), 1.51 - 1.43 (m, 4H), 0.94 (d, J = 21.8 Hz, 6H). 895 1H NMR (400 MHz, Acetonitril-d3) δ 9.13 (t, J = 7.7 Hz, 2H), 8.41 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H ), 8.02 - 7.87 (m, 3H), 7.78 - 7.70 (m, 2H), 6.85 (s, 1H), 6.77 (s, 1H), 5.88 ( s, 1H), 4.10 (dd, J = 14.5, 7.2 Hz, 1H), 3.91 - 3.81 (m, 1H), 1.60 (s, 3H), 1.25 (s, 2H), 1.01 (d, J = 1.9 Hz, 4H), 0.93 (d, J = 22.7 Hz, 6H). 896 1H NMR (400 MHz, Acetonitril-d3) δ 9.11 (s, 1H), 9.01 (d, J = 8.6 Hz, 1H), 8.39 (s, 1H), 8.26 (d , J = 8.0 Hz, 1H), 7.89 (s, 1H), 7.82 (d, J = 9.0 Hz, 2H), 7.74 (s, 1H), 6.85 (s , 1H), 5.88 (s, 1H), 4.09 (dd, J = 14.6, 7.3 Hz, 1H), 3.85 (dd, J = 14.6, 5.7 Hz, 1H), 3.01 (s, 1H), 2.87 (s, 1H), 2.01 (s, 1H), 1.16 (d, J = 4.5 Hz, 2H), 0.95 ( s, 5H), 0.90 (s, 3H), 0.47 (dd, J = 7.4, 5.7 Hz, 2H), 0.26 (d, J = 5.4 Hz, 2H).

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897 1HNMR (400 MHz, Acetonitrile-a3) δ 9.09 (dd, J = 14.8, 6.8 Hz, 2H), 8.40 (s, 1H), 8.29 (d, J = 8.2 Hz, 1H), 7.99 - 7.83 (m, 3H), 7.75 (d, J = 2.4 Hz, 1H), 7.65 (s, 1H), 6.87 (s, 1H ), 6.78 (s, 1H), 5.89 (s, 1H), 4.08 (dd, J = 14.7, 7.2 Hz, 1H), 3.87 (dd, J = 14, 7, 5.8 Hz, 1H), 2.66 (s, 1H), 2.32 (s, 6H), 0.93 (d, J = 21.2 Hz, 6H). 898 1H NMR (400 MHz, Acetonitrile^) δ 9.61 (s, 1H), 8.60 (d, J = 6.7 Hz, 1H), 8.49 (d, J = 6.7 Hz, 1H) , 8.38 - 8.33 (m, 2H), 8.19 (d, J = 7.3 Hz, 1H), 7.92 - 7.86 (m, 1H), 7.86 (s, 1H ), 7.74 (d, J = 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.06 (t, J = 55.5 Hz, 1H), 5.80 (s, 1H), 3.68 (m, 1H), 3.47 (m, 1H), 1.70 (m, 6H), 0.68 (s ,9H). 899 1HNMR (400 MHz, AcetonitrileLZ) δ 9.13 - 9.06 (m, 2H), 8.37 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.00 - 7.89 (m, 2H), 7.87 (dd, J = 8.7, 5.1 Hz, 1H), 7.74 (d, J = 2.4 Hz, 2H), 6.91 (d , J = 2.5 Hz, 1H), 6.82 (s, 1H), 5.79 (s, 1H), 4.86 (ddd, J = 64.1, 8.9, 5.4 Hz, 1H), 3.78 (dt, J = 10.2, 5.4 Hz, 1H), 3.68 (dd, J = 13.4, 6.6 Hz, 1H), 3.48 (dd, J = 13.4, 5.0 Hz, 1H), 1.94 - 1.79 (m, 1H), 1.64 - 1.49 (m, 1H), 0.69 (s, 9H). 900 1HNMR (400 MHz, Acetonitrile^3) δ 9.16 (d, J = 8.9 Hz, 1H), 8.35 (d, J = 7.5 Hz, 2H), 8.03 - 7.90 ( m, 2H), 7.82 (d, J = 8.9 Hz, 1H), 7.75 - 7.69 (m, 2H), 6.98 (d, J = 2.4 Hz, 1H), 6.81 (s, 1H), 6.26 (s, 1H), 6.00 (s, 1H), 3.70 (dd, J = 13.5, 6.1 Hz, 1H), 3.52 (dd, J = 13.7, 4.6 Hz, 1H), 3.00 (s, 4H), 2.67 (s, 1H), 2.33 (s, 6H), 0.72 (s, 9H). 901 1HNMR (400 MHz, Acetonitrile^3) δ 9.06 (d, J = 4.8 Hz, 1H), 8.94 (d, J = 8.9 Hz, 1H), 8.42 (s, 1H) , 8.30 - 8.16 (m, 1H), 7.89 - 7.83 (m, 2H), 7.77 (dd, J = 8.7, 4.7 Hz, 2H), 7.68 - 7.60 (m, 1H), 7.59 (s, 1H), 7.38 (t, J = 52.2 Hz, 1H), 6.96 (s, 1H), 6.94 - 6, 87 (m, 1H), 6.23 (s, 1H), 5.74 (s, 1H), 3.80 - 3.27 (m, 2H), 2.31 (d, J = 6.4 Hz , 6H), 1.03 (s, 1H), 0.56 (s, 9H).

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902 1HNMR (400 MHz, Acetonitril-d3) δ 9.14 - 9.07 (m, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 8, 00 - 7.90 (m, 2H), 7.80 (d, J = 8.9 Hz, 1H), 7.76 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H ), 6.92 (d, J = 2.5 Hz, 1H), 6.76 (s, 1H), 6.20 (s, 1H), 5.83 (s, 1H), 3.70 (dd , J = 13.3, 7.0 Hz, 1H), 3.50 (dd, J = 13.4, 5.3 Hz, 1H), 2.99 (s, ZN), 1.61 (s, ZN), 1.25 (s, 2H), 1.06 - 0.99 (m, 2H), 0.72 (s, 9H). 903 1HNMR (400 MHz, Methanol-d4) δ 8.89 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 6.38 (s, 1H), 3.89 (d, J = 13.8 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 2.46 (s, 3H), 1.62 - 1.48 (m, 1H), 1.23 (m, 2H), 1.03 (m, 2H), 0.96 (s, 9H), 0.53 (dd, J = 8.3, 1.8 Hz, 2H), 0.40 - 0.27 (m, 2H). 904 1HNMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 7.79 (d, J = 2.5 Hz, 1H), 7.35 (d, J = 2.5 Hz, 1H), 6.44 (s, 1H), 3.92 (d, J = 13.9 Hz, 1H), 3.77 (d, J = 13.9 Hz, 1H), 2.46 (s, 3H), 1.82 - 1.63 (m, 4H), 0.96 (s, 9H). 905 1HNMR (400 MHz, Methanol-d4) δ 8.30 (s, 1H), 8.23 (d, J = 2.5 Hz, 1H), 8.14 (s, 1H), 7.75 (m, 2H), 7.24 (d, J = 2.5 Hz, 1H), 6.81 (d, J = 8.6 Hz, 1H), 6.10 (s, 1H), 4.01 - 3, 84 (m, 4H), 3.64 (d, J = 13.9 Hz, 1H), 1.79 - 1.59 (m, 4H), 0.93 (s, 9H). 906 1HNMR (400 MHz, MethanolOT) δ 8.27 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7 .05 (d, J = 2.5 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.18 (s, 1H), 3.95 (d, J = 1.2 Hz, ZN), 3.84 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.7 Hz, 1H), 2.52 (s, 3H) , 0.87 (s, 9H). 907 1HNMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 8.20 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 2.5 Hz, 1H), 7.10 (d, J = 2.5 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.24 ( s, 1H), 3.92 (d, J = 13.8 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 2.53 (s, 3H), 2.45 ( s, 3H), 2.00 (d, J = 3.8 Hz, 4H), 0.89 (s, 9H). 908 1HNMR (400 MHz, Methanol^4) δ 8.32 (s, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.5 Hz, 1H) , 7.00 (d, J = 2.5 Hz, 1H), 6.86 (dd, J = 8.6, 2.6 Hz, 1H), 6.15 (s, 1H), 4.04 - 3.83 (m, 7H), 3.50 (d, J = 13.8 Hz, 1H), 2.45 (s, 3H), 0.86 (s, 9H).

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909 1HNMR (400 MHz, MethanolL4) δ 9.40 (d, J = 0.9 Hz, 1H), 8.59 (s, 1H), 8.30 (s, 1H), 8.21 (d, J = 8.7 Hz, 1H), 8.20 (s, 1H), 8.02 (d, J = 7.3 Hz, 1H), 7.85 (t, J = 7.8 Hz, 1H), 7 .82 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 6.86 (s, 1H), 3.79 (d, J = 13, 7 Hz, 1H), 3.51 - 3.44 (m, 1H), 3.34 (s, 2H), 1.77 - 1.59 (m, 4H), 0.65 (s, 9H). 910 1H NMR (400 MHz, MethanolL4) δ 9.05 (dd, J = 4.2, 1.5 Hz, 1H), 8.67 (dd, J = 8.8, 1.6 Hz, 1H), 8 .31 (s, 1H), 8.21 (d, J = 7.5 Hz, 2H), 7.84 - 7.79 (m, 2H), 7.69 (dd, J = 8.7, 4 ,2 Hz, 1H), 6.99 (d, J = 2.5 Hz, 1H), 6.92 (s, 1H), 3.81 (d, J = 13.7 Hz, 1H), 3, 37 (d, J = 13.7 Hz, 1H), 1.77 - 1.55 (m, 4H), 0.58 (s, 10H). 911 1H NMR (400 MHz, Methanol-d4) δ 8.43 (s, 1H), 8.23 (s, 1H), 7.95 (s, 1H), 7.70 (s, 2H), 7.62 (s, 1H), 7.49 (s, 1H), 7.42 (s, 1H), 6.80 (s, 1H), 6.66 (s, 1H), 4.08 (d, J= 5.0 Hz, 4H), 2.62 (s, 1H), 2.30 (s, 8H), 0.67 (s, 9H). 912 1H NMR (400 MHz, Methanol-d4) δ 8.39 (d, J = 1.4 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 6.2 Hz, 1H), 7.71 (d, J = 5.7 Hz, 2H), 7.60 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.43 (d, J = 6.3 Hz, 1H), 6.77 (s, 1H), 6.63 (s, 1H), 4.08 (t, J = 0.9 Hz, 3H), 3.90 (d, J = 13.9 Hz, 1H), 3.57 (d, J = 13.8 Hz, 1H), 1.18-0.99 (m, 5H), 0.66 (d , J = 1.0 Hz, JN). 913 1H NMR (400 MHz, MethanolL4) δ 8.39 (d, J = 1.2 Hz, 1H), 8.23 (d, J = 8.3 Hz, 1H), 7.95 (dd, J = 6 .2, 1.0 Hz, 1H), 7.77 (d, J = 0.9 Hz, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62 - 7.59 (m, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 6.3 Hz, 1H), 6.76 (d, J = 2.3 Hz , 1H), 6.64 (s, 1H), 4.08 (d, J = 1.1 Hz, 3H), 3.90 (d, J = 13.5 Hz, 1H), 3.57 (d , J = 13.8 Hz, 1H), 1.58 (d, J = 0.7 Hz, 3H), 1.28-1.19 (m, 2H), 1.03-0.93 (m, 2H), 0.66 (d, J = 1.1 Hz, 9H). 914 1HNMR (400 MHz, MethanolL4) δ 8.41 (d, J = 1.9 Hz, 1H), 8.27 - 8.20 (m, 1H), 7.96 (dd, J = 6.2, 1 .8 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 7.3 Hz, 1H), 7.62 (dd, J = 2.6, 1.6 Hz, 1H ), 7.54 - 7.46 (m, 1H), 7.43 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.69 (s, 1H), 5.87 (t, J = 54.7 Hz, 1H), 4.09 (d, J = 1.9 Hz, 3H), 3.92 (d, J = 14.2 Hz , 1H), 3.60 (d, J = 13.4 Hz, 1H), 1.46 (s, 3H), 0.68 (d, J = 1.7 Hz, JH).

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915 1HNMR (400 MHz, MethanolU4) δ 9.18 (s, 1H), 8.45 (s, 1H), 8.15 (s, 1H), 8.12 (s, 1H), 8.03 (s, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.70 - 7.61 (m, 2H), 6, 90 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 3.95 (d, J = 13.8 Hz, 1H), 3.68 (d, J = 13.8 Hz, 1H), 1.78 - 1.56 (m, 4H), 0.73 (s, 9H). 916 1HNMR (400 MHz, MethanolU4) δ 8.45 (s, 1H), 8.41 (d, J = 8.5 Hz, 1H), 8.27 (d, J = 6.0 Hz, 1H), 8 .11 (s, 1H), 7.96 (d, J = 6.1 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.74 (dd, J = 8.5, 7 .3 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 6.83 (d, J = 2.9 Hz, 2H), 3.99 (d, J = 13.8 Hz, 1H), 3.56 (d, J = 13.8 Hz, 1H), 3.34 (s, 1H), 1.77 - 1.54 (m, 4H), 0.67 (s, 10H ). 918 1H NMR (400 MHz, MethanolD4) δ 8.94 (d, J = 4.4 Hz, 1H), 8.59 (d, J = 8.7 Hz, 1H), 8.51 (s, 1H), 7.97 (s, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.68 - 7.64 (m, 1H), 7.59 (dd, J = 8.2, 4.9 Hz, 1H), 7.51 - 7.42 (m, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 5.91 ( t, J = 54.7 Hz, 1H), 4.32 (d, J = 14.9 Hz, 1H), 3.99 (d, J = 14.9 Hz, 1H), 1.49 (s, 3H), 0.95 (s, 3H), 0.92 (s, 3H). 919 1H NMR (400 MHz, MethanolD4) δ 8.94 (d, J = 4.2 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 7.88 (s, 1H), 7.69 - 7.63 (m, 2H), 7.59 (dd, J = 8.2, 4.9 Hz, 1H), 7.49 - 7.42 ( m, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.72 (s, 1H), 4.32 (d, J = 14.9 Hz, 1H), 3.97 ( d, J = 14.9 Hz, 1H), 1.61 (s, 3H), 1.32 - 1.23 (m, 2H), 1.03 (s, 2H), 0.93 (s, 3H ), 0.90 (s, 3H). 920 1H NMR (400 MHz, MethanolU4) δ 8.94 (d, J = 4.2 Hz, 1H), 8.59 (d, J = 8.8 Hz, 1H), 8.49 (s, 1H), 7.82 (s, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.65 (d, J = 4.4 Hz, 1H), 7.61 (dd, J = 8 ,2, 4.9 Hz, 1H), 7.52 - 7.40 (m, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 4.01 (d, J = 13.9 Hz, 1H), 3.61 (d, J = 13.9 Hz, 1H), 2.66 (s, 1H), 2.33 (s, 6H), 0.68 (s, 9H) . 921 1H NMR (400 MHz, MethanolU4) δ 8.99 (dd, J = 4.3, 1.5 Hz, 1H), 8.60 (dd, J = 8.7, 1.5 Hz, 1H), 8 .50 (s, 1H), 8.12 (s, 1H), 7.87 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 2.3 Hz, 1H), 7 .66 (dd, J = 8.7, 4.3 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H) , 6.83 (s, 1H), 4.03 (d, J = 13.8 Hz, 1H), 3.58 (d, J = 13.9 Hz, 1H), 1.76 - 1.55 ( m, 4H), 0.67 (s, 9H).

- 432 045220

922 1HNMR (400 MHz, Methanol-04) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 6.2 Hz, 1H) , 7.81 (d, J = 7.3 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.2 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.75 (s, 1H), 4.12 (s, 3H), 3.97 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.83 - 1.62 (m, 5H), 0. 72 (s, 10H). 923 1HNMR (400 MHz, Methanol-44) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.01 (d, J = 6.2 Hz, 1H) , 7.80 (d, J = 7.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.54 (t, J = 7.8 Hz, 1H), 7 .45 (d, J = 6.3 Hz, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.73 (s, 1H), 5.85 (t, J = 54, 2 Hz, 1H), 4.12 (s, 3H), 3.98 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.61 -1.47 (m, 4H), 0.73 (s, 8H), 0.70 (s, 1H). 924 1HNMR (400 MHz, Methanol-44) δ 8.25 (d, J = 8.4 Hz, 1H), 8.18 (s, 1H), 7.96 (d, J = 6.3 Hz, 1H) , 7.85 (d, J = 7.3 Hz, 1H), 7.56 (s, OH), 7.53 (q, J = 2.8 Hz, 2H), 7.38 (d, J = 6.3 Hz, 1H), 6.63 (s, 1H), 6.58 (s, 1H), 4.11 (s, 3H), 3.70 (d, J = 13.5 Hz, 1H) , 3.38 (d, J = 13.5 Hz, 1H), 2.98 (s, 1H), 2.85 (d, J = 0.8 Hz, 1H), 1.89 (s, 2H) , 1.74 (s, 2H), 1.28 (s, 1H), 0.96 - 0.84 (m, OH), 0.61 (s, 9H). 925 1HNMR (400 MHz, Methanol-44) δ 8.25 (d, J - 8.3 Hz, 1H), 8.19 (s, 1H), 7.96 (d, J = 6.2 Hz, 1H) , 7.85 (d, J = 7.5 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.39 (d, J = 6.2 Hz, 1H), 6.62 ( s, 1H), 6.57 (s, 1H), 5.99 (t, J = 55.0 Hz, 1H), 4.11 (s, 3H), 3.71 (d, J = 13.4 Hz, 1H), 3.38 (d, J = 13.4 Hz, 1H), 1.68 (s, 2H), 1.58 (s, 2H), 1.28 (s, 1H), 0, 62 (s, 9H). 926 1HNMR (400 MHz, Methanol-44) δ 8.29 (s, 1H), 8.01 (d, J = 8.3 Hz, 1H), 7.72 (d, J = 6.2 Hz, 1H) , 7.60 (s, 1H), 7.45 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H), 7.30 - 7.24 ( m, 1H), 7.17 (d, J = 6.3 Hz, 1H), 6.60 (d, J = 2.3 Hz, 1H), 6.42 (s, 1H), 4.12 ( d, J = 14.8 Hz, 1H), 3.85 (s, 3H), 3.75 (d, J = 14.9 Hz, 1H), 1.23 (ddd, J = 13.2, 8 ,3, 5.0 Hz, 1H), 0.96 - 0.87 (m, 2H), 0.75 - 0.70 (m, 2H), 0.67 (d, J = 8.3 Hz, 6H), 0.25 - 0.17 (m, 2H), 0.02 (dt, J = 5.7, 4.5 Hz, 2H).

- 433 045220

927 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.81 (s, 1H), 7.71 (dd, J = 7.3, 1.2 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.56 - 7.50 (m, 1H), 7.44 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.66 (s, 1H), 4.32 (d, J = 14.8 Hz, 1H), 4.12 (s, 3H), 4.01 (d, J = 14.8 Hz, 1H), 1.61 (s, 3H), 1.27 (d, J = 4.9 Hz, 2H), 1.05 - 1.00 (m, 2H), 0.93 (d, J = 9.1 Hz, 6H). 928 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.3 Hz, 1H) , 7.75 (s, 1H), 7.70 (d, J = 7.4 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.56 - 7.49 ( m, 1H), 7.44 (dd, J = 6.3, 0.9 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.68 (s, 1H), 4.30 (d, J = 14.8 Hz, 1H), 4.12 (s, 3H), 4.02 (d, J = 14.8 Hz, 1H), 2.66 (s, 1H), 2.34 (s, 6H), 0.93 (d, J = 10.0 Hz, 6H). 929 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 8.28 (d, J = 8.3 Hz, 1H), 8.04 (s, 1H), 7.99 (d, J = 6.2 Hz, 1H), 7.78 - 7.72 (m, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.2 , 7.4 Hz, 1H), 7.49 - 7.42 (m, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.75 (s, 1H), 4.12 (s, 3H), 3.98 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.8 Hz, 1H), 1.76 - 1.54 (m, 4H) , 0.72 (s, 9H). 930 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.39 - 8.32 (m, 1H), 8.01 (s, 1H), 7.82 (d, J= 8.4 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.62 - 7.55 (m, 1H), 7.42 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 9.2 Hz, 1H), 6.92 (d, J = 2.3 Hz, 1H), 6.77 (s, 1H), 4.05 (s, 3H), 4.00 (d, J = 13.9 Hz, 1H), 3.67 (d, J = 13.8 Hz, 1H), 1.77 - 1.55 (m, 4H), 0. 74 (s, 9H). 931 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.84 (s, 1H), 7.75 (dd, J = 7.3, 1.1 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 7.53 ( dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.2 Hz, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6, 69 (s, 1H), 4.12 (s, 3H), 4.01 (d, J = 13.8 Hz, 1H), 3.63 (d, J = 13.8 Hz, 1H), 1, 49 (ddd, J = 13.2, 8.3, 5.0 Hz, 1H), 1.23 - 1.13 (m, 2H), 1.03 - 0.94 (m, 2H), 0, 71 (s, 9H), 0.52 - 0.44 (m, 2H), 0.32 - 0.25 (m, 2H).

-434045220

932 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.78 (s, 1H), 7.76 - 7.72 (m, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 8.4 , 7.3 Hz, 1H), 7.45 (dd, J = 6.3, 0.9 Hz, 1H), 6.88 (d, J = 2.3 Hz, 1H), 6.72 (s , 1H), 5.03 - 4.90 (m, 1H), 4.71 (d, J = 5.4 Hz, 1H), 4.62 - 4.56 (m, 1H), 4.12 ( s, 3H), 4.01 (d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 1.51 (dd, J = 7.1, 1 .3 Hz, 3H), 0.72 (s, 9H). 933 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 8.28 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.85 (s, 1H), 7.75 (d, J = 7.2 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.4, 7.3 Hz, 1H), 7.46 (dd, J = 6.3, 0.9 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 6, 75 (s, 1H), 5.31 - 5.12 (m, 1H), 4.99 - 4.86 (m, 2H), 4.83 - 4.71 (m, 2H), 4.01 ( d, J = 13.8 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 0.72 (s, 11H). 934 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.27 (d, J = 8.3 Hz, 1H), 7.99 (d, J = 6.2 Hz, 1H) , 7.89 (s, 1H), 7.71 (dd, J = 7.3, 1.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.53 ( dd, J = 8.3, 7.4 Hz, 1H), 7.45 (d, J = 6.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6, 71 (s, 1H), 5.91 (t, J = 54.8 Hz, 1H), 4.28 (d, J = 14.7 Hz, 1H), 4.12 (s, 3H), 4, 00 (d, J = 14.7 Hz, 1H), 2.02 (s, 1H), 1.49 (d, J = 4.5 Hz, 4H), 0.92 (d, J = 10.6 Hz, 6H). 935 1HNMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.39 (s, 1H), 8.36 (s, 1H), 8.18 (d, J = 2.1 Hz, 1H), 8.04 (t, J = 2.2 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 9.4 Hz, 1H) , 7.66 (d, J = 2.3 Hz, 1H), 7.10 (d, J = 2.3 Hz, 1H), 6.33 (s, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.75 - 3.61 (m, 1H), 2.03 (s, 1H), 1.82 - 1.73 (m, 2H), 1.68 (s, 2H ), 1.10 (s, OH), 0.87 (s, 9H). 936 1H NMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 8.20 (s, 1H), 7.79 - 7.58 (m, 3H), 7.08 (d, J = 2.3 Hz, 1H), 6.39 (t, J = 6.9 Hz, 1H), 6.19 (s, 1H), 4.17 (d, J = 14.0 Hz, 1H), 3 .77 (d, J = 14.0 Hz, 1H), 3.59 (s, 3H), 1.81 - 1.57 (m, 4H), 0.99 (s, 9H). 937 1HNMR (400 MHz, Methanol-d4) δ 8.88 (d, 1H), 8.45 (s, 1H), 8.25 (dd, 1H), 8.11 (s, 1H), 8.10 - 8.02 (m, 1H), 7.73 - 7.66 (m, 3H), 6.90 (d, 1H), 6.76 (s, 1H), 4.02 3.93 (m, 1H ), 3.63 (d, 1H), 1.77 - 1.56 (m, 4H), 0.71 (s, 9H).

- 435 045220

938 1HNMR (400 MHz, Chloroform-d) δ 8.99 - 8.81 (m, 1H), 8.23 (d, 1H), 8.14 (s, 1H), 7.66 - 7.58 (m , 1H), 7.43 (d, 1H), 7.39 - 7.28 (m, 2H), 6.34 (s, 1H), 6.08 (s, 1H), 4.00 (d, 1H), 3.64 (d, 1H), 2.47 (d, 3H), 1.80 - 1.61 (m, 4H), 0.91 (d, 9H). 939 1H NMR (400 MHz, Acetonitrile-43) δ 8.44 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H ), 7.63 (s, 1H), 7.54 (s, 1H), 7.44 (t, J = 7.8 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H ), 6.78 (d, J = 7.7 Hz, 2H), 6.66 (s, 1H), 6.46 (s, 1H), 3.84 (dd, J = 13.5, 5, 9 Hz, 1H), 3.68 (dd, J = 13.2, 4.7 Hz, 1H), 3.54 (s, 3H), 2.08 - 1.99 (m, 6H), 1, 79 (m, 6H), 1.72 (m, 1H), 0.81 (s, 9H). 940 1H NMR (400 MHz, Methanol-44) δ 9.06 (d, J = 4.7 Hz, 1H), 8.93 (d, J = 8.7 Hz, 1H), 8.48 (s, 1H ), 8.16 - 8.08 (m, 1H), 8.02 (s, 1H), 7.95 - 7.86 (m, 1H), 7.81 (t, J = 7.3 Hz, 2H), 7.68 (d, J = 2.3 Hz, 1H), 6.91 - 6.84 (m, 2H), 5.91 (t, J = 54.7 Hz, 1H), 4, 32 (d, J = 15.0 Hz, 1H), 3.96 (d, J = 14.9 Hz, 1H), 1.50 (s, 4H), 0.96 (s, 3H), 0. 91 (s, 3H). 941 1H NMR (400 MHz, Methanol-44) δ 8.48 (s, 1H), 8.13 (m, 2H), 7.68 (d, J = 2.1 Hz, 1H), 7.05 (s , 2H), 6.91 (s, 1H), 6.10 (s, 1H), 4.22 (d, J = 13.9 Hz, 1H), 3.88 s, 3H), 3.68 ( d, J = 13.9 Hz, 1H), 1.72 (d, J = 31.5 Hz, 4H), 0.97 (d, J = 1.0 Hz, 9H). 942 1H NMR (400 MHz, Methanol-44) δ 8.49 (d, J = 1.3 Hz, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.64 (dd, J = 2.3, 1.1 Hz, 1H), 6.97 - 6.82 (m, 1H), 6.77 (d, J = 2.3 Hz, 1H), 6.17 - 5.79 ( m, 2H), 4.44 (d, J = 15.0 Hz, 1H), 4.01 (d, J = 14.9 Hz, 1H), 2.40 (s, 3H), 1.78 - 1.56 (m, 4H), 1.10 (d, J = 3.3 Hz, 6H). 943 1HNMR (400 MHz, Methanol-44) δ 8.50 (s, 1H), 7.82 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H) , 6.86 (dd, J = 12.6, 2.6 Hz, 2H), 6.08 (s, 1H), 4.12 (d, J = 13.9 Hz, 1H), 3.69 ( d, J = 13.9 Hz, 1H), 2.40 (s, 3H), 1.66 - 1.55 (m, 1H), 1.35 - 1.25 (m, 2H), 1.22 - 1.13 (m, 2H), 0.90 (s, 9H), 0.55 - 0.46 (m, 2H), 0.43 - 0.32 (m, 2H). 944 1HNMR (400 MHz, Methanol-44) δ 8.23 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H) , 6.93 - 6.82 (m, 1H), 6.67 (d, J = 2.4 Hz, 1H), 6.03 (s, 1H), 3.88 (d, J = 13.7 Hz, 1H), 3.50 (d, J = 13.6 Hz, 1H), 2.73 (s, 1H), 2.61 (s, 6H), 2.42 (s, 3H), 0, 85 (s, 9H).

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945 1HNMR (400 MHz, Methanol-d4) δ 8.26 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.53 (d, J = 2.4 Hz, 1H) , 6.86 (dd, J = 8.5, 2.6 Hz, 1H), 6.71 (s, 1H), 6.17-5.81 (m, 2H), 3.95 (d, J = 13.8 Hz, 1H), 3.49 (d, J = 13.7 Hz, 1H), 2.39 (s, 3H), 1.69 (m, 2H), 1.65 - 1.56 (m, 2H), 0.85 (s, 9H). 946 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H) , 6.83 (d, J = 6.3 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.08 (s, 1H), 4.14 (d, J = 13.8 Hz, 1H), 3.89 - 3.80 (m, 1H), 3.60 (d, J = 13.8 Hz, 1H), 2.37 (s, 3H), 1.91- 1.83 (m, 1H), 1.35 - 1.26 (m, 2H), 1.27 - 1.19 (m, 2H), 1.07 (dd, J = 8.7, 2.9 Hz, 2H), 0.91 (s, 1H), 0.87 (s, 9H), 0.84 - 0.77 (m, 1H). 947 1HNMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.2 Hz, 1H) , 6.88 (q, J = 3.1 Hz, 2H), 6.17 (s, 1H), 4.05 (d, J = 13.9 Hz, 1H), 3.75 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.60 (s, 3H), 1.36 - 1.30 (m, 2H), 1.15 1.07 (m, 2H) , 0.92 (s, 9H). 948 1H NMR (400 MHz, Methanol-d4) δ 8.23 (d, J = 1.2 Hz, 1H), 7.88 (t, J = 8.1 Hz, 1H), 7.51 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 6.17 (s , 1H), 5.90 (t, J = 54.3 Hz, 1H), 4.23 (d, J = 14.8 Hz, 1H), 3.92 (d, J = 14.8 Hz, 1H ), 2.49 (s, 3H), 1.66 - 1.43 (m, 4H), 1.07 (d, J = 5.3 Hz, 6H). 949 1HNMR (400 MHz, MethanolM4) δ 8.46 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 6 .88 (dd, J = 8.1, 2.5 Hz, 2H), 6.18 (s, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.74 (d, J = 13.9 Hz, 1H), 2.49 (s, 3H), 1.55 - 1.42 (m, 1H), 1.28 - 1.20 (m, 2H), 1.11 - 1 .03 (m, 2H), 0.92 (s, 10H), 0.57 - 0.46 (m, 2H), 0.35 - 0.28 (m, 2H). 950 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H) , 7.42 - 7.26 (m, 5H), 7.16 (d, J = 2.3 Hz, 1H), 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.36 (s, 1H), 5.78 (t, J = 7.2 Hz, 1H), 2.52 (s, 3H), 2.14 (m, 2H), 1.81 (m, 2H ), 1.74 (m, 2H), 1.02 (t, J = 7.3 Hz, 3H).

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951 1H NMR (400 MHz, Methanol-d4) δ 8.52 (d, J = 0.8 Hz, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.65 (dd, J = 2.3, 0.8 Hz, 1H), 6.94 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.4, 2.8 Hz, 1H), 6 .19 (s, 1H), 4.06 (d, J = 13.9 Hz, 1H), 3.83 (d, J = 13.9 Hz, 1H), 2.75 (s, 1H), 2 .52 (s, 3H), 2.45 (s, 6H), 0.96 (s, 9H). 952 1H NMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 0.9 Hz, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.66 (dd, J = 2.3, 0.9 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.90 (dd, J = 8.6, 2.8 Hz, 1H), 6 .23 (s, 1H), 4.98 - 4.87 (m, OH), 4.82 - 4.58 (m, 2H), 4.14 - 4.02 (m, 1H), 3.81 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.66 - 1.55 (m, 3H), 0.95 (d, J = 0.9 Hz, 9H) . 953 1HNMR (400 MHz, Methanol-d4) δ 8.52 (s, 1H), 7.92 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.78 - 7, 72 (m, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.89 (dd, J = 8.5 , 2.8 Hz, 1H), 6.12 (s, 1H), 5.88 (t, J = 54.2 Hz, 1H), 2.45 (s, 3H), 1.56 (m, 4H ). 954 1H NMR (400 MHz, Methanol-d4) δ 8.37 (d, J = 1.5 Hz, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.4 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.18 (s, 1H), 3.90 (d, J = 13.9 Hz, 1H), 3.65 (d, J = 13.8 Hz, 1H), 2.73 (s, 1H), 2.51 (s, 3H), 2.43 (s, 6H), 0.89 (s, 9H). 955 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H) , 6.88 (dd, J = 9.0, 2.6 Hz, 2H), 6.19 (s, 1H), 4.99 - 4.88 (m, OH), 4.80 - 4.68 (m, 1H), 4.68 - 4.52 (m, 1H), 4.37 (d, J = 14.9 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H) , 2.49 (s, 3H), 1.59 (d, J = 1.4 Hz, 2H), 1.57 (d, J = 1.4 Hz, 1H), 1.15 (s, 3H) , 1.14 (s, 3H). 956 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.83 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H) , 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 6.15 (s, 1H), 4.34( d, J = 15.0 Hz, 1H), 4.16 (d, J = 15.0 Hz, 1H), 2.72 (s, 1H), 2.51 (s, 3H), 2.43 ( s, 6H), 1.15 (s, 3H), 1.15 (s, 3H).

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957 1HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H) , 6.89 (d, J = 2.8 Hz, 1H), 6.86 (d, J = 2.2 Hz, 2H), 6.17 (s, 1H), 4.41 (d, J = 15.0 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.55 - 1.44 (m, 1H), 1.30 - 1.19 (m, 2H), 1.16 (s, 3H), 1.15 (s, 3H), 1.08 (m, 2H), 0.58 - 0.45 (m, 2H), 0 .38-0.28 (m, 2H). 958 1HNMR (400 MHz, Methanol-d4) δ 8.48 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H) , 6.87 (dd, J = 8.4, 2.8 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.15 (s, 1H), 4.34( d, J = 15.0 Hz, 1H), 4.13 (d, J = 15.0 Hz, 1H), 3.71 - 3.60 (m, 1H), 2.50 (s, 3H), 1.31 - 1.16 (m, 3H), 1.15 (s, 4H), 1.14 (s, 3H). 959 1HNMR (400 MHz, Methanol-d4) δ 8.51 (s, 1H), 7.84 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H) , 6.87 (dd, J = 8.5, 2.8 Hz, 1H), 6.84 (d, J = 2.3 Hz, 1H), 6.15 (s, 1H), 4.39( d, J = 15.0 Hz, 1H), 4.12 (d, J = 15.0 Hz, 1H), 2.49 (s, 3H), 1.60 (s, 3H), 1.40 - 1.29 (m, 2H), 1.15 (s, 3H), 1.14 (s, 3H), 1.12 - 1.06 (m, 2H). 960 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.87 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H) , 6.94 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.4, 2.8 Hz, 1H), 6.22 (s, 1H), 5.88 ( t, J = 54.2 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.79 (d, J = 14.0 Hz, 1H), 2.50 (s, 3H), 1.58 (m, 4H), 0.94 (s, 9H). 961 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 8.34 (dd, J = 8.1, 1.2 Hz, 1H), 7.81 - 7.74 (m, 1H ), 7.64 (d, J = 2.3 Hz, 1H), 7.48 (t, J = 7.8 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H), 6.83 (s, 1H), 6.82 (d, J = 4.5 Hz, 1H), 6.54 (s, 1H), 4.01 (d, J = 13.8 Hz, 1H), 3.62 (d, J = 13.8 Hz, 1H), 3.61 (s, 3H), 2.71 (s, 1H), 2.41 (s, 6H), 0.76 (s, 9H ). 962 1HNMR (400 MHz, AcetonitrileS3) δ 8.99 - 8.93 (m, 1H), 8.80 (d, J = 8.7 Hz, 1H), 8.31 (s, 1H), 8.12 ( d, J = 7.5 Hz, 1H), 7.83 - 7.72 (m, 2H), 7.66 (dd, J = 8.7, 4.7 Hz, 1H), 7.44 (d , J = 2.2 Hz, 1H), 6.69 (d, J = 3.0 Hz, 2H), 6.60 (s, 1H), 6.30 (s, 1H), 5.69 (t , J = 54.1 Hz, 1H), 3.71 (dd, J = 13.5, 6.6 Hz, 1H), 3.47 (dd, J = 13.5, 4.7 Hz, 1H) , 1.88 - 1.82 (m, 3H), 1.43 (m, 4H), 0.60 (s, 9H).

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963 1HNMR (400 MHz, Methanol-d4) δ 8.22 (s, 1H), 7.89 (t, J = 8.1 Hz, 1H), 7.49 (d, J = 2.3 Hz, 1H) , 6.86 (dd, J = 8.5, 2.7 Hz, 1H), 6.74 (d, J = 2.4 Hz, 1H), 6.15 (s, 1H), 3.94 ( d, J = 1.2 Hz, 3H), 3.84 (d, J = 13.7 Hz, 1H), 3.56 (d, J = 13.7 Hz, 1H), 2.51 (s, 3H), 0.87 (s, 9H). 964 1HNMR (400 MHz, Methanol4) δ 8.33 (s, 1H), 7.89 (t, J = 8.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 6 .98 (d, J = 2.5 Hz, 1H), 6.91 - 6.81 (m, 1H), 6.18 (s, 1H), 5.96 (t, J = 55.1 Hz, 1H), 4.06 (s, 3H), 3.99 (d, J = 13.7 Hz, 1H), 3.45 (d, J = 13.8 Hz, 1H), 2.42 (s, 3H), 1.54 (m, 2H), 1.50 (m, 2H), 0.85 (s, 9H). 965 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H) , 6.85 (m, 2H), 6.18 (s, 1H), 5.95 (t, J = 55.0 Hz, 1H), 4.17 (d, J = 13.9 Hz, 1H) , 4.03 (s, 3H), 3.64 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H), 1.60 - 1.53 (m, 2H), 1, 53 - 1.44 (m, 2H), 0.91 (s, 9H). 966 1HNMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.62 (d, J = 8.6 Hz, 1H) , 6.89 (d, J = 2.3 Hz, 1H), 6.63 (d, J = 8.6 Hz, 1H), 6.14 (s, 1H), 5.94 (t, J = 55.0 Hz, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.97 (s, 3H), 3.90 (s, 3H), 3.73 (d, J = 13.9 Hz, 1H), 2.43 (s, 3H), 1.61 - 1.52 (m, 2H), 1.52 - 1.42 (m, 2H), 0.93 (s, 9H ). 967 1HNMR (400 MHz, Methanol^4) δ 8.48 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H) , 6.86 (dd, J = 8.4, 2.7 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.12 (s, 1H), 4.11 ( d, J = 13.9 Hz, 1H), 3.91 (s, 3H), 3.69 (d, J = 13.9 Hz, 1H), 3.66 - 3.61 (m, 1H), 2.45 (s, 3H), 1.31 - 1.20 (m, 1H), 1.20 - 1.12 (m, 2H), 0.91 (s, 9H). 968 1HNMR (400 MHz, Methanol-d4) δ 8.49 (s, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H) , 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 6.13 (s, 1H), 4.11 ( d, J = 13.8 Hz, 1H), 3.88 (s, 3H), 3.69 (d, J = 13.9 Hz, 1H), 2.70 (s, 1H), 2.44 ( s, 3H), 2.43 (s, 6H), 0.91 (s, 9H). 969 1HNMR (400 MHz, Methanol-d4) δ 8.20 (s, 1H), 7.90 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 2.3 Hz, 1H) , 6.85 (dd, J = 8.4, 3.0 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 6.12 (s, 1H), 3.97 - 3.84 (m, 7H), 3.43 (d, J = 13.7 Hz, 1H), 2.44 (s, 3H), 0.84 (s, 9H).

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970 1H NMR (400 MHz, Methanol-c14) δ 8.50 (s, 1H), 7.71 - 7.53 (m, 2H), 6.86 (d, J = 2.3 Hz, 1H), 6 .62 (d, J = 8.5 Hz, 1H), 4.07 (d, J = 13.8 Hz, 1H), 3.88 (m, 7H), 3.81 (s, 3H), 2 .45 (s, 3H), 0.93 (s, 9H). 971 1HNMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 7.86 (t, J = 8.1 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H) , 6.86 (dd, J = 8.5, 2.8 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.14 (s, 1H), 4.10 ( d, J = 13.9 Hz, 1H), 3.88 (m, 6H), 3.66 (d, J = 13.8 Hz, 1H), 2.45 (s, 3H), 0.90 ( s, 9H). 972 1HNMR (400 MHz, Methanol-d4) δ 8.42 (s, 1H), 8.03 (s, 1H), 7.69 (d, 1H), 7.61 (d, 1H), 7.49 - 7.38 (m, 2H), 7.07 (s, 1H), 6.75 (s, 1H), 4.06 (d, 1H), 3.67 (d, 1H), 2.85 - 2 .74 (m, 1H), 1.74 - 1.57 (m, 4H), 0.83 (s, 9H). 973 1HNMR (400 MHz, DMSO-de) δ 8.23 (s, 1H), 7.78 (t, J = 8.3 Hz, 1H), 7.57 (d, J = 2.4 Hz, 1H) , 6.98 - 6.75 (m, 2H), 6.27 - 5.84 (m, 2H), 2.42 (s, 3H), 1.47 (d, J = 3.4 Hz, 4H ), 0.76 (s, 9H). 974 1HNMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.77 (t, J = 8.1 Hz, 1H), 7.68 (d, J = 2.3 Hz, 1H) , 7.04 (d, J = 2.3 Hz, 1H), 6.91 (dd, J = 8.5, 2.8 Hz, 1H), 6.43 (s, 1H), 5.92 ( t, J = 53.7 Hz, 1H), 3.95 (s, 2H), 2.54 (s, 3H), 1.81 - 1.62 (m, 4H), 0.95 (s, 9H ). 975 1HNMR (400 MHz, DMSO-de) δ 8.41 (s, 1H), 7.91 (t, J = 8.3 Hz, 1H), 7.73 (t, J = 5.5 Hz, 1H) , 7.49 (s, 1H), 7.00 (dd, J = 8.5, 3.1 Hz, 1H), 6.47 (s, 2H), 6.06 (t, J = 53.4 Hz, 1H), 3.61 (d, J = 5.5 Hz, 2H), 2.50 (s, 3H), 1.56 (m, 4H), 1.05 (s, 9H). 976 1HNMR (400 MHz, Methanol-d4) δ 9.31 (s, 1H), 8.94 (s, 2H), 8.38 (s, 1H), 8.06 (s, 1H), 7.82 ( t, J = 8.1 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 8.5, 2.7 Hz, 1H), 6.29 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.04 (d, J = 13.9 Hz, 1H), 3.84 (d, J = 13.9 Hz, 1H), 2.51 (s, 3H), 1.53 (s, 4H), 0.95 (s, 9H). 977 1HNMR (400 MHz, Methanol-d4) δ 8.51 (d, J = 1.1 Hz, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 6.86 (dd, J = 8.6, 2.7 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.07 (s, 1H), 4.13 (d, J = 13.9 Hz, 1H), 3.70 (d, J = 13.9 Hz, 1H), 2.40 (s, 3H), 1.64 (s, 3H), 1.44 - 1.31 (m, 2H), 1.22 (t, J = 2.0 Hz, 2H), 0.89 (s, 9H).

- 441 045220

978 1HNMR (400 MHz, Methanol-04) δ 8.47 (s, 1H), 8.11 (s, 1H), 7.62 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.5 Hz, 1H), 6.96 - 6.89 (m, 1H), 6.60 (d, J = 8.6 Hz, 1H), 6.19 (s, 1H), 3, 98 (d, J = 13.9 Hz, 1H), 3.88 (d, J = 6.4 Hz, 4H), 2.48 (s, 3H), 1.73 (d, J = 5.6 Hz, 2H), 1.66 (s, 2H), 0.94 (s, 9H). 979 1HNMR (400 MHz, Methanol-44) δ 8.55 (d, J = 1.6 Hz, 1H), 8.32 (s, 1H), 7.88 (d, J = 2.6 Hz, 1H) , 7.59 (t, J = 8.1 Hz, 1H), 7.40 (d, J = 2.6 Hz, 1H), 6.92 (dd, J = 8.5, 2.8 Hz, 1H), 6.76 (s, 1H), 4.09 (d, J = 14.1 Hz, 1H), 3.96 (d, J = 14.1 Hz, 1H), 2.97 (s, 3H), 2.35 (s, 3H), 1.80 - 1.70 (m, 4H), 1.02 (d, J = 3.2 Hz, 9H). 980 1HNMR (400 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.91 (t, 1H), 7.48 (s, 1H), 7.33 (d, 1H), 6.79 ( dd, 1H), 6.40 (s, 1H), 5.94 (s, 1H), 5.20 (s, 1H), 3.56 (t, 2H), 3.33 (s, 3H), 2.59 (s, 3H), 1.79 (d, 6H), 1.77 - 1.70 (m, 1H), 1.68 - 1.50 (m, 4H) 0.94 (s, 9H ). 981 1HNMR (400 MHz, Methanol) δ 8.56 (s, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.08 (s, 1H), 7.81 (t, J = 8.1 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 6.88 (dd, J = 8.5, 2.7 Hz, 1H), 6.29 (s, 1H), 5.93 (t, J = 54.6 Hz, 1H), 4.05 (d, J = 14.0 Hz, 1H), 3.87 (d, J = 14.0 Hz, 1H) , 2.77 (s, 3H), 2.52 (s, 3H), 1.54 (s, 4H), 0.94 (s, 9H). 982 1HNMR (400 MHz, Chloroform-d) δ 10.32 (s, 1H), 9.20 (s, 1H), 8.3O - 8.20 (m, 1H), 8.13 (s, 1H), 7.90 (t, 1H), 7.19 (s, 1H), 6.82 - 6.65 (m, 2H), 6.24 (s, 1H), 4.17 - 4.02 (m, 2H), 2.64 (s, 3H), 1.78 (s, 3H), 1.77 (s, 3H), 1.72 - 1.63 (m, 4H), 1.09 (s, 9H ). 983 1HNMR (400 MHz, DMSO16) δ 8.73 (s, 1H), 8.17 (t, 1H), 8.01 (s, 1H), 7.98 7.93 (m, 1H); 7.06 (dd, 1H), 6.70 (s, 1H),6.52 - 6.43 (m, 1H), 6.09 (t, 1H), 3.67 (qd, 2H), 2 .43 (s, 3H), 1.52-1.40 (m, 4H), 0.95 (s, 9H). 984 1HNMR (400 MHz, Methanol-44) δ 8.47 (s, 1H), 7.85 (s, 1H), 7.77 (m, 1H), 7.62 (s, 1H), 6.87 ( m, 2H), 6.20 (s, 1H), 4.38 (t, J = 7.4 Hz, 2H), 4.01 (d, J = 13.9 Hz, 1H), 3.80 ( d, J = 13.7 Hz, 1H), 2.50 (m, 5H), 1.89 - 1.80 (m, 2H), 1.29 (m, 2H), 0.92 (s, 11H ). 985 1HNMR (400 MHz, Acetonitrile yl-43) δ 8.41 (s, 1H), 7.84 (m, 1H), 7.66 (m, 1H), 7.48 (m, 1H), 6.82 (m, 1H), 6.74 (m, 1H), 6.15 (m, 1H), 4.42 (m, 2H), 3.76 (m, 2H), 3.48 (m, 2H) , 2.51 (s, 3H), 1.98 (m, 2H), 0.94 (s, 9H). 986 1HNMR (400 MHz, Acetonitrile-43) δ 8.42 (s, 1H), 7.92 (m, 1H), 7.48 (s, 1H), 6.79 (m, 1H), 6.70 ( s, 1H), 5.97 (s, 1H), 4.35 (m, 4H), 3.90 (m, 1H), 3.68 (m, 1H), 2.50 (s, 3H), 2.23 (m, 2H), 0.94 (s, 9H).

Biological analyses.

The following examples from Examples 40-42 describe biological assays for measuring the activity of certain test compounds against TNFa, Cot (also known as Tpl2) and EGFR. As summarized in table. 3, the tested compounds are effective inhibitors of Cot.

Example 40 Cellular analysis of TNFa in Cot monocytes.

Cryopreserved human monocytes (Stem Cell Technologies) were thawed, diluted in RPMI with Glutamax (10 mM HEPES, 1X Pen-Strep, 55 μM β-mercaptoethanol, 1 mM sodium pyruvate) containing 10% FBS, to 0.125 X 10 ^L 6 cells/ ml and reconstituted at 37°C for 2 hours. The cell suspension was then seeded at a density of 5000 cells/well onto black Greiner 384-well plates with a clear bottom. The plates were preloaded with test compounds and serially

- 442 045220 was diluted in DMSO, where 200 nL/well was delivered using an Echo 550 acoustic liquid dispenser (Labcyte®) to a final DMSO concentration of 0.5%. Cells plated were treated with the compound for 1 hour at 37°C. Cells were then stimulated with 50 pg/ml LPS (Sigma), excluding the outer columns of the plate used for control wells with unstimulated cells. Cells were incubated for another 4 h at 37°C. Cells were then isolated from the medium and a 5 μl sample was taken and analyzed for total TNFa using the TR-FRET Human TNFa Detection System (CisBio). This system uses two labeled antibodies (cryptate and XL665) that bind to two different epitopes of the TNFa molecule and produce a FRET signal proportional to the concentration of TNFa in the sample. Detection antibodies were mixed 50:50 and 5 μl was dispensed into each well. The plates were covered with a transparent sealing film and incubated at room temperature overnight. The following morning plates were read using a Multisabeled Envision 2103 reader (PerkinElmer) with FRET excitation/emission/emission at 340 nm/615 nm/665 nm, respectively. Fluorescence intensities at emission wavelengths of 615 nm and 665 nm were expressed as the ratio (665 nm/615 nm). The percentage of control was calculated as follows:

/% Control = 100 X (Sample Ratio - 0% Stimulation Ratio)/(100% Stimulation Ratio 0% Stimulation Ratio) where unstimulated cells (0% stimulation) were the negative control and stimulated cells (100% stimulation) were used as the positive control control.

Example 41: High-throughput biochemical analysis.

Human Cot enzyme activity was measured using KinEASE (Cisbio), a time-resolved fluorescence resonance energy transfer (TR-FRET) enzyme-linked immunosorbent assay. In this assay, Cot catalyzes the phosphorylation of an XL665-labeled peptide substrate. A europium-conjugated phosphotyrosine-specific antibody binds the resulting phosphorylated peptide. Phosphorylated peptide formation is quantified by TR-FRET with europium as donor and XL665 as acceptor in a two-step endpoint assay. Purified recombinant human Cot catalytic domain (30–397 amino acids) was purchased from Carna Biosciences. Briefly, test compounds, serially diluted in DMSO, were plated into low-volume white 384-well Proxy plates using an Echo 550 acoustic liquid dispenser (Labcyte®). Cot enzyme and substrates were spread onto assay plates using a Multi-Flo (Bio-Tek Instruments). A standard 5 µl reaction mixture contained 400 µM ATP, 1 µM STK3 peptide, 5 nM Cot in reaction buffer (10 mM MOPS, pH 7.0, 0.02% _NaN3 , 0.5 mg/ml BSA, 10 mM MgOAc, 1 mM DTT, 0.025% NP-40, 1.5% glycerol) and 0.1% DMSO. After 2.5 hours of incubation at room temperature, 5 μl of stop and detection solution (1:200 solution of europium cryptate-labeled antiphosphorylated peptide antibody and 125 nM streptavidin-XL665 label in 50 mM Hepes pH 7.0 detection buffer containing sufficient amount of EDTA). The plate was then incubated for an additional 120 min at room temperature and read using a Multisabeled Envision 2103 reader (PerkinElmer) with FRET excitation/emission/emission at 340 nm/615 nm/665 nm, respectively. Fluorescence intensities at emission wavelengths of 615 nm and 665 nm were expressed as the ratio (665 nm/615 nm). The percentage of inhibition was calculated as follows:

% inhibition = 100 x (Sample Ratio - %Inhibition Ratio)/(ιοο% Inhibition Ratio 0% Inhibition Ratio) where 0.1% DMSO (0% inhibition) was the negative control and 100 µM Comparative Example 1 (100% inhibition) used as a positive control.

Example 42: High Throughput Biochemical Assay for EGFR.

EGFR activity was measured using KinEASE (Cisbio), a time-resolved fluorescence resonance energy transfer (TR-FRET) enzyme-linked immunosorbent assay. In this assay, EGFR catalyzes the phosphorylation of a universal substrate tyrosine kinase tagged with XL665. A europium-conjugated phosphotyrosine-specific antibody binds the resulting phosphorylated peptide. Phosphorylated peptide formation is quantified by TR-FRET with europium as donor and XL665 as acceptor. The analysis was carried out in two main stages. The first step is a kinase reaction step, and the second step is a detection step with TR-FRET reagents. Briefly, test compounds, serially diluted 1:3 in DMSO, were delivered and loaded into low-volume Corning white non-binding 384-well plates using an Echo 550 acoustic liquid dispenser (Labcyte®). EGFR enzyme (human EGFR, cytoplasmic domain [669-1210] from Carna Biosciences Cat. No. 08-115) and TK substrate-biotin substrates (included in the Cisbio HTRF KinEASE-TK Kit Cat. No. 62TK0PEJ) were dispensed onto assay plates using Multi-Flo (Bio-Tek Instruments). A standard 10 μL reaction mixture contained 6 μM ATP (lXKm) or 12 μM ATP (2XKm), 1 μM biotinylated peptide, 0.3 nM EGFR (for 1XKm ATP) or 0.1 nM EGFR (for 2XKm ATP) in reaction buffer ( 10 mM MOPs, pH 7.0, 1.5% glycerol, 0.5 mg/ml BSA, 10 mM Mg-acetate, 1 mM DTT, 0.025% NP-40). After 60 minutes

- 443 045220 bation at room temperature, add 10 μl of stop and detection solution (1:400 solution of antiphosphorylated peptide antibody labeled with europium cryptate and 125 nM streptavidin-XL665 label in 50 mM Hepes detection buffer pH 7.0 containing sufficient EDTA). The plate was then incubated for 60 minutes at room temperature and read using a Multisabeled Envision 2103 reader (PerkinElmer) with FRET excitation/emission/emission at 340 nm/615 nm/665 nm, respectively. Fluorescence intensities at emission wavelengths 615 nm and 665 nm were expressed as the ratio (665 nm/615 nm). The percentage of inhibition was calculated as follows:

% Inhibition = 100 x (Ratio sample - Ratio o% Inhibition) / (Ratio 00% Inhibition ^_ Ratio 0% Inhibition) where 0.05% DMSO (0% inhibition) was the negative control and 100 μM Staurosporine and Gefitinib (100% inhibition) was used as a positive control.

As shown in table. 3, the compounds of formula III are inhibitors of Cot (Osaka type thyroid cancer).

Table 3

Conn. ICso HTRF (nM) ECso TNF (nM) 1 8 218 2 2 89 3 8 314 4 2 497 5 9 258 7 380 >1000 8 7 302 9 1 20 10 21 283 AND 4 154 12 27 214 13 eleven 765 14 7 196 15 2 545 16 2 115 17 53 1388 18 28 399 19 2 156 20 2 69 21 14 2035 22 2 89 23 4 69 24 12 185 25 2 57 26 6 113 27 2 62 28 12 195 29 17 498 thirty 34 1322 31 5 5069

- 444 045220

32 7 546 33 eleven 630 34 8 112 35 9 166 36 3 67 37 16 2638 38 25 952 39 AND 295 40 6 249 41 8 137 42 135 1926 43 33 915 44 9 129 45 2 178 46 3 1102 47 25 1068 48 2 87 49 118 16684 50 70 3534 51 55 1556 52 4 88 53 81 4018 54 AND 652 55 58 10816 56 6 2521 57 60 5990 58 72 2982

- 445 045220

59 2 892 60 12 131 61 eleven 238 62 10 216 63 5 257 64 42 2652 65 6 538 66 3 53 67 1 32 68 1 51 69 2 33 70 19 804 72 1 eleven 73 2 33 74 1 14 75 2 79 76 1 981 77 3 154 78 3 332 79 1 203 80 1 23 81 400 >1000 82 2 151 83 942 1000 84 1 10 85 4 >1000 86 2 37

- 446 045220

87 25 590 88 1161 >1000 89 520 >1000 90 1 18 91 2 52 92 6 65 93 7 74 94 2 130 95 10 445 96 AND 173 97 20 358 98 49 821 99 3 143 100 3 142 101 5 348 102 3 461 103 3 133 104 1 99 105 3 144 106 2 76 107 182 >10000 108 913 >10000 109 2 54 110 2 56 111 2 77 112 2 61 FROM 13 253

- 447 045220

114 10 233 115 5 119 116 3 144 117 3 94 118 6 150 119 4 99 120 5 137 121 7 171 122 6 240 123 6 193 124 8 376 125 3 78 126 3 146 127 16 194 128 698 >10000 129 2 81 130 6 147 131 2 49 132 4 97 133 25 978 134 6 197 135 23 660 136 10 291 137 15 235 138 3 141 139 2 92 140 3 183

- 448 045220

141 2 121 142 2 66 143 16 898 144 2 77 145 4 221 146 10 370 147 12 1139 148 5 174 149 8 381 150 4 154 151 8 1305 152 10 904 153 44 3759 154 26 1667 155 2 79 156 8 1191 157 5 127 159 2 95 160 AND 484 161 12 1668 162 7 429 163 67 4142 164 5 1802 165 9 2368 166 6 1425 167 4 506 168 6 394

- 449 045220

169 14 1217 170 6 1262 171 10 320 172 10 832 173 7 1112 174 2 54 175 3 73 176 2 31 177 2 79 178 7 931 179 265 >10000 180 1 104 181 2 92 182 13 1041 183 357 >10000 184 8 387 185 305 9745 186 118 6618 187 67 2114 188 >10000 >10000 189 8 1061 190 9 238 191 2 104 192 3 186 193 2 107 194 2 111 195 4 132

- 450 045220

196 6 668 197 9 599 198 17 982 199 9 2522 200 7 558 201 56 5595 202 >10000 >10000 203 6923 9089 204 8513 >10000 205 72 2048 206 3 211 207 5 931 208 12 465 209 23 941 210 10 424 211 16 544 212 44 9151 213 3 103 214 >10000 >10000 215 258 >10000 216 38 1187 217 12 264 218 26 2711 219 4449 >10000 220 4 348 222 19 739 223 7 94

- 451 045220

224 12 2628 225 10 1488 226 8 880 227 44 6419 228 18 2307 229 12 1467 230 9 252 231 8 230 232 15 346 233 8 114 234 21 504 235 17 370 236 9 172 237 1 29 238 3 901 239 16 928 240 16 631 241 2 32 242 143 5801 243 41 9492 244 4 328 245 2 125 246 6 652 247 2 102 248 4 398 249 12 332 250 5 127

- 452 045220

251 5 347 252 6 119 253 4 66 254 3 230 255 10 766 256 16 341 257 6 212 258 2 33 259 6 158 260 6 126 261 14 344 262 AND 130 263 13 242 264 2 70 265 14 426 266 37 28752 267 thirty 5120 268 12 234 269 6 326 270 4 666 271 9 826 272 5 297 273 51 1564 274 12 370 275 7 2334 276 6 789 277 7 923

- 453 045220

278 3 269 279 3 457 280 16 811 281 13 575 282 3 87 283 3 50 284 14 1305 285 8 219 286 4 121 287 20 373 288 26 1058 289 37 837 290 12 185 291 35 478 292 17 327 294 9 166 295 23 565 296 80 1104 297 9 200 298 39 1503 299 18 739 300 7 165 301 14 414 302 10 472 303 14 868 304 6 234 305 3 84

- 454 045220

306 6 202 307 4 60 308 4 286 309 8 181 310 40 2342 312 13 1235 313 5 373 314 15 302 315 4 132 316 6 298 317 16 251 318 8 271 319 5 165 321 10 212 322 33 369 323 86 666 325 20 650 326 34 3753 328 4 272 331 3 173 334 4 82 335 10 405 339 13 1010 340 8 328 341 6 843 342 38 6094 344 3 151

- 455 045220

345 3 73 346 3 208 347 4 278 348 13 444 349 41 718 350 26 4511 351 10 744 352 12 565 353 4 184 354 3 983 355 5 194 357 5 235 358 3 130 359 3 729 360 4 151 361 13 746 362 1 46 363 4 257 364 7 241 366 5 336 367 13 338 368 649 6296 369 3 89 370 8 232 371 2 173 372 2 81 373 3 81

- 456 045220

374 37 480 375 4 1511 376 182 >1000 377 398 >1000 378 2 168 379 6 179 380 14 609 381 7 303 382 14 768 389 AND 328 395 4 403 9 290 405 2 1044 406 3 102 6 2 293 32 311 thirty 320 60 324 10 327 15 329 14 330 59 332 65 333 3 336 2 337 16 338 13

-457 045220

343 504 356 2 365 38 384 153 385 14 386 36 387 18 388 10 390 343 391 282 392 3 393 5 394 147 396 43 397 46 398 435 399 58 400 119 401 10 402 19 404 232 408 1 88 409 1 559 410 from 1000 411 5 76 412 7 157 413 4 44

-458 045220

414 1 35 415 3 67 416 2 124 417 9 218 418 2 45 419 3 49 420 2 25 421 4 100 422 2 57 423 3 71 424 2 37 425 7 1000 426 2 95 427 2 41 428 1 69 429 2 56 430 5 214 431 1 21 432 6 89 433 1 65 434 2 61 435 1 24 436 5 289 437 2 82 438 473 1000 439 13 299 440 7 171

- 459 045220

441 2 26 442 56 2686 443 1 19 444 2 33 445 2 71 446 3 156 447 2 40 448 2 44 449 19 407 450 20 356 451 3 138 452 4 73 453 9 184 454 2 32 455 29 222 456 51 1000 457 315 1000 458 4 87 459 3 50 460 5 156 461 17 154 462 162 8766 463 2 63 464 1 16 465 2 155 466 28 926 467 2 47

- 460 045220

468 1 18 469 4 69 470 2 46 471 3 45 472 4 78 473 2 26 474 2 26 475 20 258 476 3 71 477 2 185 478 1 77 479 5 78 480 2 60 481 6 391 482 3 86 483 7 108 484 3 73 485 3 29 486 3 991 487 1 245 488 3 79 489 2 129 490 1 1000 491 3 40 492 2 21 493 31 1000 494 1 444

- 461 045220

495 3 50 496 6 467 497 6 379 498 19 689 499 3 97 500 8 321 501 3 55 502 6 206 503 2 45 504 1 38 505 5 277 506 8 528 507 2 87 508 4 96 510 5 222 511 6 133 512 10 418 513 9 154 514 4 77 515 199 1000 516 2 34 517 3 1000 518 7 207 519 3 158 520 123 926 521 27 256 522 5 52

-462045220

523 2 63 524 12 77 525 4 164 526 5 73 527 3 78 528 3 60 529 2 50 530 3 70 531 3 70 532 3 78 533 3 96 534 20 394 535 2 47 536 3 51 537 2 75 538 5 109 539 1 12 540 50 760 541 6 180 542 2 40 543 13 422 544 8 210 545 4 108 546 2 42 547 2 33 548 8 124 549 4 68

- 463 045220

550 2 29 551 2 27 552 2 26 553 3 64 554 5 151 555 7 208 556 8 120 557 5 117 558 3 72 559 2 42 560 AND 287 561 2 433 562 2 231 563 2 63 564 3 69 565 2 306 566 2 190 567 2 66 568 5 170 569 7 171 570 184 1000 571 2 77 572 4 79 573 66 751 574 4 86 575 1 974 576 1 433

- 464 045220

577 1 49 578 2 32 579 2 24 580 2 84 581 2 32 582 14 184 583 4 121 584 2 53 585 37 838 586 2 1000 587 1 489 588 55 629 589 2 34 590 3 57 591 5 106 592 5 78 593 8 298 594 2 33 595 209 1000 596 79 826 597 3 150 598 5 198 599 13 316 600 5 FROM 601 4 32 602 3 69 603 7 107

- 465 045220

604 3 71 605 3 thirty 606 2 27 607 21 225 608 42 314 609 2 46 610 2 199 611 20 229 612 AND 171 613 13 144 614 9 154 615 33 588 616 12 104 617 9 77 618 3 37 619 7 189 620 102 1000 621 1 12 622 1 24 623 1 27 624 AND 1000 625 2 26 626 5 35 627 4 46 628 450 1000 629 181 1000 630 68 1000

- 466 045220

631 2 32 632 380 1000 633 28 267 634 2 43 635 3 60 636 69 720 637 3 85 638 58 858 639 58 806 640 3 65 641 55 811 642 5 182 643 5 1000 644 7 88 645 AND 66 646 3 40 647 3 133 648 3 114 649 2 14 650 179 1000 651 14 135 652 4 40 653 4 37 654 3 36 655 12 104 656 4 86 657 37 806

- 467 045220

658 29 374 659 41 279 660 43 839 661 2 103 662 6 335 663 3 62 664 12 154 665 6 198 666 13 246 667 10 71 668 13 408 669 1 7 670 5 102 671 2 32 672 2 22 673 142 808 674 22 301 675 1 7 676 6 112 677 4 133 678 5 131 679 13 710 680 3 98 681 2 26 682 7 66 683 35 283 684 14 101

- 468 045220

685 4 39 686 4 77 687 15 178 688 thirty 437 689 9 81 690 21 250 691 6 66 692 3 38 693 15 141 694 7 84 695 3 39 696 2 14 697 1 AND 698 27 684 699 12 386 700 2 179 701 10 147 702 4 188 703 2 22 704 1 23 705 6 61 706 2 14 707 16 230 708 6 176 709 17 187 710 5 148 711 2 32

- 469 045220

714 6 57 715 3 91 716 2 54 717 8 100 718 9 112 719 2 24 720 2 35 721 6 109 722 43 403 723 4 84 724 3 44 725 3 56 726 4 127 727 3 48 728 7 154 729 5 108 730 10 89 731 AND 179 732 And 779 733 42 835 734 41 313 735 47 478 736 117 645 737 3 91 738 2 40 739 21 254 740 45 311

- 470 045220

741 6 120 742 17 199 743 5 116 744 3 33 745 2 28 746 13 178 747 4 36 748 5 47 749 6 66 750 AND 194 751 15 230 752 5 57 753 5 59 754 3 31 755 25 365 756 3 26 757 5 60 758 4 50 759 2 42 760 2 58 761 6 69 762 3 50 763 3 40 764 4 46 765 4 131 766 2 thirty 767 18 209

- 471 045220

768 6 86 769 2 28 770 4 108 771 4 293 772 2 33 773 2 35 774 2 40 775 3 27 776 2 24 777 5 46 778 4 thirty 779 3 26 780 5 52 781 2 22 782 23 177 783 2 23 784 3 51 785 2 23 786 5 47 787 2 65 788 23 208 789 13 156 790 5 82 791 22 242 792 89 843 793 35 782 794 15 130

-472 045220

795 34 530 796 2 31 797 3 77 798 7 90 799 4 46 800 2 25 801 3 31 802 4 36 803 7 97 804 9 137 805 28 778 806 3 28 807 3 31 808 3 29 809 3 32 810 4 54 811 AND 333 812 5 68 813 2 24 814 2 16 815 3 39 816 1 23 817 10 116 818 6 176 819 2 28 820 3 33 821 3 60

- 473 045220

822 10 687 823 4 53 824 5 59 825 7 FROM 826 51 1000 827 2 38 828 22 253 829 4 66 830 16 384 831 8 202 832 2 44 833 2 22 834 5 68 835 4 53 836 4 52 837 7 121 838 3 84 839 6 94 840 4 52 841 2 41 842 3 563 843 4 104 844 13 417 845 20 1000 846 2 17 847 31 296 848 31 247

- 474 045220

849 16 261 850 6 65 851 3 21 852 2 58 853 1 98 854 4 17 855 2 53 856 1 29 857 4 180 858 7 44 859 2 53 860 3 31 861 7 40 862 8 49 863 2 35 864 2 37 865 4 23 866 2 18 867 3 27 868 2 70 869 2 37 870 2 169 871 1 32 872 1 15 873 5 97 874 3 73 875 2 166

-475 045220

876 2 385 877 2 34 878 2 31 879 1 13 880 3 80 881 2 13 882 2 18 883 1 13 884 1 19 885 10 132 886 3 thirty 887 3 33 888 2 165 889 9 104 890 6 68 891 1 12 892 2 44 893 4 99 894 3 54 895 3 41 896 3 thirty 897 2 18 898 5 56 899 2 29 900 3 thirty 901 484 1000 902 3 36

- 476 045220

903 3 36 904 5 78 905 15 212 906 4 39 907 4 51 908 12 238 909 8 116 910 5 148 911 7 85 912 6 78 913 6 86 914 9 116 915 44 324 916 13 269 917 3 31 918 3 42 919 2 49 920 3 28 921 17 187 922 AND 225 923 16 258 926 13 174 927 6 124 928 6 99 929 AND 157 930 33 504 931 10 134

- 477 045220

932 14 205 933 29 247 934 7 81 935 24 424 936 18 287 937 23 277 938 26 223 939 18 104 940 7 86 941 64 804 945 17 142 946 5 153 947 3 39 948 5 99 949 4 34 950 17 260 951 9 61 952 4 36 953 36 353 954 7 16 955 6 50 956 7 44 957 5 54 958 2 56 959 3 41 960 7 55 961 3 48

- 478 045220

962 13 135 963 4 51 964 3 105 965 4 78 966 15 191 967 2 94 968 2 94 969 8 258 970 34 722 971 eleven 301 972 1817 1000 973 3 34 974 AND 60 975 1231 1000 976 21 276 978 9 303 979 244 1000 980 1000 1000 981 4 20 982 1000 1000 983 9644 1000 984 10 169 985 13 126 986 5 141

Data in table. 4 and 5 show that the compounds described herein are effective inhibitors of Osaka-type thyroid cancer kinase (Cot). In addition, the claimed compounds are not significant EGFR ligands.

Table 4

Compound Connection structure IC50/EC50 [nM] EGFR (1C ₅ o) [nM] Comparative example 1 ζ ^ν Ά ^С| Q od K Xx- Ch -y N CI 4/310 357 Comparative example 2 /A CI Q D ^r Αγά- -у N CI 62/NA N.A. 362 /OD CI 7 D' Og 1/46 3984

- 479 045220

Table 5

Compound Connection structure IC50/EC50 [nM] EGFR (IC50) [nM] Comparative example 3 CI ' A ^F id y^ N CI 67/>10000 >10000 Comparative example 4 CI ¹ D' PuD y^GT Cl > 10000/Na >10000 395 Cl k n A vU Cl 4/ΝΑ ΝΑ 406 Cl ' U ^F ό and 3 / 102 >10000

Claims (29)

1. Compound of formula III: where R ¹ represents hydrogen, -OR ⁷ , -N(R ⁸ )(R ⁹ ), -C(O)-R ⁷ , -S(O)2-R ⁷ , -C _1-9 alkyl, C _{2 -6} alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one to four Z ¹ ; R ⁴ represents heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is optionally substituted with one to four Z ⁴ ; ^R5 is hydrogen, halogen, -CN, -NO2, ^-OR7 , -N( ^R8 )( ^R9 ), -S(O) ^-R7 , -S(O) ^2R7 , -S(O )2N(R ⁷ )2, -C(O)R ⁷ , -OC(O)-R ⁷ , -C(O)OR ⁷ , -OC(O)OR ⁷ , -OC(O)N(R ¹⁰ )(R ¹¹ ), -C(O)N(R ⁷ )2, -N(R ⁷ )C(O)(R ⁷ ), C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-9 alkylthio, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁵ ; R ⁶ is hydrogen, -C(O)-R ⁷ , -C(O)OR ⁷ , -C(O)N(R ⁷ ) ₂ , C _1-9 alkyl, C _2-6 alkenyl, C _{2- 6} alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁶ ; each R ⁷ independently represents hydrogen, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl; wherein each C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl is optionally substituted with one to four Z ⁷ ; R ⁸ and R ⁹ are each independently hydrogen, -S(O)2R ¹⁰ , -C(O)-R ¹⁰ , -C(O)OR ¹⁰ , -C(O)N(R ¹⁰ )(R ¹¹ ), C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl or heteroaryl; - 480 045220 where each is C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, C ₃ . ₁₅ cycloalkyl, aryl, heterocyclyl or heteroaryl is optionally substituted with one to four Z ⁸ ; R ¹⁰ and R ¹¹ are each independently hydrogen, C ₁ . ₉ αlkyl, C ₂ . ₆ alkenyl, _C2 . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₅ cycloalkyl, aryl, heterocyclyl or heteroaryl, where each C ₁ . ₉ alkyl, C ₂ . ₆ αlkenyl, C ₂ . ₆ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₁₅ cycloalkyl, aryl, heterocyclyl and heteroaryl are optionally substituted with one to four Z ^1b ; each Z ¹ , Z ³ , Z ⁴ , Z ⁵ , Z ⁶ , Z ⁷ and Z ⁸ independently represents hydrogen, oxo, halogen, -NO ₂ , -N ₃ , -CN, thioxo, C _1-9 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-15 cycloalkyl, C _1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)-R ¹² , -C(O)OR ¹² , -C(O)-N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , -N(R ¹² )C(O) R ¹² , -N(R ¹² )C(O)OR ¹² , -N(R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -NR ¹² S(O)2N(R ¹³ )(R ¹⁴ ), -NR ¹² S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)-N(R ¹³ )(R ¹⁴ ), -P(O)(OR ¹² )2, -OP(O)(OR ¹² )2, -CH2P(O)(OR ¹² )2, -OCH2P(O)(OR ¹² )2, -C(O)OCH2P(O)(OR ¹² )2, -P(O)(R ¹² )(OR ¹² ), -OP(O)(R ¹² )(OR ¹² ), -CH2P(O)(R ¹² )(OR ¹² ), -OCH2P(O)(R ¹² )(OR ¹² ), -C(O)OCH2P(O)(R ¹² )(OR ¹² ), -P(O)(N(R ¹² ) 2)2, -OP(O)(N(R ¹² )2)2, -CH2P(O)(N(R ¹² )2)2, -OCH2P(O)(N(R ¹² )2)2, - C(O)OCH2P(O)(N(R ¹² )2)2, -P(O)(N(R ¹² )2)(OR ¹² ), -OP(O)(N(R ¹² )2)( OR ¹² ), -CH2P(O)(N(R ¹² )2)(OR ¹² ), -OCH2P(O)(N(R ¹² )2)(OR ¹² ), -C(O)OCH2P(O)( N(R ¹² )2)(OR ¹² ), -P(O)(R ¹² )(N(R ¹² )2), -OP(O)(R ¹² )(N(R ¹² )2), -CH2P (O)(R ¹² )(N(R ¹² )2), -OCH2P(O)(R ¹² )(N(R ¹² )2), -C(O)OCH2P(O)(R ¹² )(N( R ¹² )2), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O)2R ¹² or -S(O) 2N(R ¹³ )(R ¹⁴ ); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1a groups; each Z ^1a independently represents oxo, halogen, thioxo, -NO ₂ , -CN, -N ₃ , C ₁ . ₉ alkyl, C ₂ . ₆ αlkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₅ cycloalkyl, C ₁ . ₈ haloalkyl, aryl, heteroaryl, heterocyclyl, -OR ¹² , -C(O)R ¹² , -C(O)OR ¹² , -C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹³ ) (R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , -N(R ¹² )-C(O)R ¹² , -N(R ¹² )C(O)O(R ¹² ), -N (R ¹² )C(O)N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -N(R ¹² )S(O)2-N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2O(R ¹² ), -OC(O)R ¹² , -OC(O)OR ¹² , -OC(O)-N(R ¹³ )( R ¹⁴ ), -Si(R ¹² )3, -SR ¹² , -S(O)R ¹² , -S(O)(NH)R ¹² , -S(O)2R ¹² or -S(O)2N( R ¹³ )(R ¹⁴ ); wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups; each R ¹² independently represents hydrogen, C ₁ . ₉ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αlkynyl, C ₃ . ₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl, wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups; R ¹³ and R ¹⁴ are each independently hydrogen, C ₁ . ₉ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ αlkynyl, C ₃ . ₁₅ cycloalkyl, aryl, heteroaryl or heterocyclyl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z ^1b groups, or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one four groups Z ^1b ; and each Z ^1b is independently oxo, thioxo, hydroxy, halogen, -NO ₂ , -N ₃ , -CN, C ₁ . ₉ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₅ cycloalkyl, C ₁ . ₈ haloalkyl, aryl, heteroaryl, heterocyclyl, -O(C ₁ . ₉ alkyl), -O(C ₂ . ₆ alkenyl), -O(C ₂ . ₆ alkynyl), -O(C ₃ . ₁₅ cycloalkyl), - O( _{C1.8haloalkyl} ), -O(aryl), -O(heteroaryl), -O _{( heterocyclyl} ), -NH2, -NH( _C1.9alkyl ) _, -NH( _C2.6alkenyl ), -NH(C ₂ . ₆ alkynyl), -NH(C ₃ . ₁₅ cycloalkyl), -NH(C ₁ . ₈ haloalkyl), -NH(aryl), -NH(heteroaryl), -NH(heterocyclyl), -N (C ₁ . ₉ alkyl) ₂ , -N(C ₃ . ₁₅ cycloalkyl) ₂ , -N(C ₂ . ₆ αlkenyl) ₂ , -N(C ₂ . ₆ alkynyl) ₂ , -N(C ₃ . ₁₅ cycloalkyl ) ₂ , -N(C ₁ . ₈ haloalkyl) ₂ , -N(aryl) ₂ , -N(heteroaryl) ₂ , -N(heterocyclyl) ₂ , -N(C ₁ . ₉ αlkyl)(C ₂ . ₆ alkenyl ), -N(C ₁ . ₉ alkyl)(C ₂ . ₆ alkynyl), -N(C ₁ . ₉ alkyl)(C ₃ . ₁₅ cycloalkyl), -N(C ₁ . ₉ alkyl)(C ₁ . ₈ haloalkyl), -N(C ₁ . ₉ alkyl)(aryl), -N(C ₁ . ₉ αlkyl)(heteroaryl), -N(C ₁ . ₉ αlkyl)(heterocyclyl), -C(O)(C ₁ . ₉ alkyl) ), -C(O)(C ₂ . ₆ αlkenyl), -C(O)(C ₂ . ₆ alkynyl), -C(O)(C ₃ . ₁₅ cycloalkyl), -C(O)(C ₁ . ₈ haloalkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), -C(O)O(C ₁ . ₉ alkyl), -C(O) O(C ₂ . ₆ αlkenyl), -C(O)O(C ₂ . ₆ alkynyl), -C(O)O(C ₃ . ₁₅ cycloalkyl), -C(O)O(C ₁ . ₈ haloalkyl), -C(O)O(aryl), -C(O)O(heterocyclyl), _-C (O ₎ NH2, -C(O)NH( _C1.9alkyl ), -C(O)NH( _C2.6alkenyl ), -C(O)NH(C ₃ . ₁₅ cycloalkyl), -C(O)NH(heterocyclyl), -C(O)N(C ₃ . ₁₅ cycloalkyl) ₂ , -C(O)N (heterocyclyl) ₂ , -NHC(O)(C ₃ _ ₁₅ cycloalkyl), -NHC(O)(heterocyclyl), -C(O)NH(C _1-8 haloalkyl), -C(O)NH(aryl), -C(O)N(C _1-9 alkyl) ₂ , -C(O)N(C _2-6 alkenyl) ₂ , -C(O)N(C _1-8 haloalkyl) ₂ , -C(O)N(aryl) ₂ , -NHC(O)(C _1-9 alkyl), -NHC(O)(C _2-6 alkenyl), -NHc(O)(C _1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)O(C _1-9 alkyl), -NHC(O)O(C _2-6 alkenyl), -NHC(O)O(C ₃ . ₁₅ cycloalkyl), -NHC(O)O(C _1-8 haloalkyl), -NHC(O)O(aryl), -C(O)O(heteroaryl), , -C(O)NH(C ₂ . ₆ alkynyl), -C(O)NH(heteroaryl), -C(O)N(C _2-6 alkynyl) ₂ , -C(O)N (heteroaryl) ₂ , -NHC(O)(C _2-6 alkynyl), -NHC(O)(heteroaryl), -NHC(O)o(C _2-6 alkynyl), -NHC( O)O(heteroaryl), -NHC(O)O(heterocyclyl), -NHC(O)NH(C _1-9 alkyl), -NHC(O)NH(C _2-6 alkenyl), -NHC(O)NH(C _2-6 alkynyl ), -NHC(O)NH(C ₃ . ₁₅ cycloalkyl), -NHC(O)NH(C _1-8 haloalkyl), -NHC(O)NH(heteroaryl), -NHC(O)NH(heterocyclyl), -SH, -S(C _1-9 alkyl), -NHC(O)NH(aryl), -S(C _2-6 alkenyl), -S(C _2-6 alkynyl), -S(C ₃ . ₁₅ cycloalkyl), -S(C _1-8 haloalkyl), -S(aryl), -S(heteroaryl), -S(heterocyclyl), -NHS(O)(C _1-9 alkyl), -S(O)(NH)(C ₁ . ₉ alkyl), -N(C _1-9 alkyl)(S(O)(C _1-9 alkyl), -S(O)(C _2-6 alkenyl), -S(O)N(C _1-9 alkyl) ₂ , -S(O)( _{C 2-6} alkyl), -S(O)(C _1.9 alkyl), -S(O)(C ₃ . ₁₅ cycloalkyl), - 481 045220 -S(O)(C ₁ . ₈ haloalkyl), -S(O)(aryl), -S(O)(heteroaryl), -S(O)(heterocyclyl), -S(O) ₂ (C ₁ . ₉ αlkyl), -S(O) ₂ (C _2- 6alkenyl), -S(O) ₂ (C ₂ . ₆ αlkynyl), -S(O) ₂ (C ₃ . ₁₅ cycloalkyl), -S(O) ₂ (C _{1 8} haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S(O) ₂ (heterocyclyl), -S(O) ₂ NH(C ₁ . ₉ alkyl) or -S(O) ₂ N(C ₁ . ₉ alkyl) ₂ ; wherein any alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four halogens, C ₁ . ₉ αalkyls, C ₁ . ₈ haloalkyl, -OH, -NH ₂ , -NH(C ₁ . ₉ alkyl), -MH(C ₃ . ₁₅ cycloalkyl), -NH(C _1-8 haloalkyl), -NH(aryl), -NH(heteroaryl ), -NH(heterocyclyl), -N(C _1-9 alkyl) ₂ , -N(C ₃ . ₁₅ cycloalkyl) ₂ , -NHC(O)(C ₃ . ₁₅ cycloalkyl), -NHC(O)(C _1-8 haloalkyl), -NHC(O)(aryl), -NHC(O)(heteroaryl), -NHC(O)(heterocyclyl), -NHC(O)o(C _1-9 alkyl), -NHC(O)O(C _2-6 alkynyl), -NHc(o )0(C ₃ . ₁₅ cycloalkyl), -NнC(O)0(C _1-8 haloalkyl), -NHC(O)O(aryl), -NHC(O)O(heteroaryl), -NHC(o)o (heterocyclyl), -NнC(0)NH(C _1-9 alkyl), -S(O)(NH)(Cl. ₉ αlkyl), S(o) ₂ (C _1-9 alkyl), -S(O) ₂ (C ₃ . ₁₅ cycloalkyl), -S(O) ₂ (C _1-8 haloalkyl), -S(O) ₂ (aryl), -S(O) ₂ (heteroaryl), -S (O) ₂ (heterocyclyl), -S(O) ₂ NH(C _1-9 alkyl), -S(O) ₂ N(C _1-9 alkyl) ₂ , -O(C ₃ . ₁₅ cycloalkyl), - O(C _1-8 haloalkyl), -O(aryl), -O(heteroaryl), -O(heterocyclyl) or -O(C _1-9 alkyl); W, X and Y are each independently N or C; n is 1, 2 or 3; each aryl independently contains from 6 to 10 carbon atoms in the ring; each heteroaryl independently contains from 1 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, S and O; and each heterocyclyl independently contains from 2 to 20 ring carbon atoms and from 1 to 5 ring heteroatoms independently selected from N, S and O; or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. 2. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁵ represents hydrogen, halogen, -CN, -OR ⁷ , -S(O)-R ⁷ , - S(O)2R ⁷ , -S(O)2N(R ⁷ )2, -C(O)R ⁷ , -C(O)N(R ⁷ ) ₂ , C ₁ . ₉ αlkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₅ cycloalkyl, aryl, heterocyclyl or heteroaryl; where each C ₁ . ₉ alkyl, C ₂ . ₆ alkenyl, C ₂ . ₆ alkynyl, C ₃ . ₁₅ cycloalkyl, aryl, heterocyclyl and heteroaryl may be optionally substituted with one to four Z ⁵ . 3. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁵ represents hydrogen, halogen, -CN, -C(O)R ⁷ , -OR ⁷ , -S (O)2R ⁷ or heteroaryl. 4. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁶ represents hydrogen. 5. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ¹ is -OR ⁷ , -C ₁ . ₉ αlkyl, C ₃ . ₁₅ cycloalkyl, heterocyclyl, aryl or heteroaryl; and the specified C ₁ . ₉ αlkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one to four substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , -S(O)2R ¹² , C ₁ . ₉ alkyl, C ₁ . ₉ haloalkyl, C ₃ . ₁₅ cycloalkyl, heterocyclyl and aryl, where the indicated C ₃ . ₁₅ cycloalkyl is optionally substituted with one to four substituents independently selected from the group consisting of C ₁ . ₉ alkyl and C ₁ . ₉ haloalkyl. 6. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ¹ represents -C1.9αalkyl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , -S(O)2R ¹² , C3. ₁₅ cycloalkyl, heterocyclyl and aryl, where the indicated C ₃ . ₁₅ cycloalkyl or heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of C ₁ . ₉ alkyl and C ₁ . ₉ haloalkyl. 7. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ¹ is C ₃ . ₁₅ cycloalkyl, heterocyclyl, or heteroaryl; wherein said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , C ₁ . ₉ alkyl and aryl. 8. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue, characterized in that R ¹ represents heterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen and C ₁ . ₉ alkyl. 9. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ¹ is aryl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -CN, -OR ¹² , C ₁ . ₉ alkyl and aryl. 10. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoiso- - 482 045220 mer or deuterated analogue, characterized in that R ¹ is aryl, optionally substituted with one to three substituents independently selected from the group consisting of halogen, -OR ¹² and C ₁ . ₉ alkyl. 11. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that W is N, X is NZ ³ and Y is CZ ³ . 12. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ³ represents hydrogen or C1.9 alkyl, optionally substituted with one to four substituents independently selected from the group consisting of - CN, halogen, -OR ¹² , -C(O)OR ¹² , -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , Aralkyl, heterocyclyl, C6-10 aryl and heteroaryl. 13. A compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ³ represents C3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl, and said C3-15 cycloalkyl or heterocyclyl is optionally substituted with one- four substituents independently selected from the group consisting of CN, halogen, -OR ¹² , -C(O)OR ¹² , -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , C _1-9 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _3-15 cycloalkyl, heterocyclyl and heteroaryl. 14. A compound according to claim 1, having formula VIIIA: Z ³ R ⁵ VIIIA or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, wherein Z ³ , R ¹ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1 and Z ⁹ represents hydrogen, halogen , -CN or -OR ¹² . 15. The compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ³ represents hydrogen, C _1-9 αlkyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said C _1-9 alkyl, C _3-15 cycloalkyl or heterocyclyl is optionally substituted with one to four substituents independently selected from the group consisting of oxo, -CN, halogen, -OR ¹² , -C(O)OR ¹² , -C(O )-N(R ¹³ )(R ¹⁴ ), -N(R ¹² )S(O)2(R ¹² ), -N(R ¹³ )(R ¹⁴ ), -N(R ¹³ )2(R ¹⁴ ) ⁺ , ^alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _3-15 cycloalkyl, aryl, heterocyclyl and heteroaryl; Z ⁹ represents hydrogen; R ¹ represents C _1-9 alkyl, C _3-15 cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein said _C1-9 alkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, CN, ^OR12 , -S(O) ^2R12 , C1-9alkyl, P-ualoalkyl, heterocyclyl and aryl; R ⁴ represents heterocyclyl or heteroaryl; wherein said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _{1 -9} alkyl, C _1-8 haloalkyl and heterocyclyl; R ⁵ is -CN, halogen, -OR ⁷ or -S(O) ₂ R ⁷ ; R ⁶ represents hydrogen; each R ⁷ independently represents C _1-9 αlkyl; wherein said C _1-9 alkyl is optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, halogen, -O(C _1-9 alkyl) and aryl; and each R ¹² independently represents hydrogen, C _1-9 alkyl or heterocyclyl; wherein said C _1-9 alkyl is optionally substituted with one to three substituents independently selected from the group consisting of hydroxyl, halogen, -O(C _1-9 alkyl) and aryl. 16. The compound according to claim 15 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ³ represents C3-15 cycloalkyl, optionally substituted with one to four substituents independently selected from the group consisting of -CN, halogen, -C(O)-N(R ¹³ )(R ¹⁴ ), C1-9 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _3-15 cycloalkylα and heteroaryl. 17. The compound according to claim 15 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ³ is a heterocyclyl optionally substituted with one to four substituents independently selected from the group consisting of -OR ¹² , - C(O)OR ¹² , C _1-9 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl and heterocyclyl. 18. A compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoiso- - 483 045220 mers or a deuterated analogue, characterized in that R ⁵ represents cyano or halogen. 19. The compound according to claim 14 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁶ represents hydrogen. 20. The compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue, characterized in that R ⁴ represents heterocyclyl or heteroaryl; and said heterocyclyl or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _{1 -9} alkyl, C _1-8 haloalkyl and heterocyclyl. 21. The compound according to claim 20 or its pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue, characterized in that R ⁴ represents heteroaryl, optionally substituted with one to three substituents independently selected from the group consisting of CN, halogen, - OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl. 22. The compound according to claim 20 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁴ represents heterocyclyl, optionally substituted with one to three substituents independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl. 23. The compound according to claim 20 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁴ represents and q is 0, 1, 2, 3 or 4. 24. The compound according to claim 20 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁴ represents - 484 045220 σνυν jvw I ΑγΝ X AHA ^{or N} ' and q represents 0, 1, 2, 3 or 4. 25. The compound according to claim 24 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁴ represents 26. The compound according to claim 23 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that Z ⁴ is independently selected from the group consisting of -CN, halogen, -OR ¹² , -C(O)-R ¹² , -N(R ¹³ )(R ¹⁴ ), C _1-9 alkyl, C _1-8 haloalkyl and heterocyclyl. 27. The compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, characterized in that R ⁴ represents - 485 045220 - 486 045220 28. Connection selected from: - 487 045220 Connection number Connection structure 1 X „ A γΥ F 2 0 ,Α Η w 3 AnD SY nJ ct F 4 ^H 7 > 9 AA Connection number Connection structure 501 F 0 Η ^Η 'Η'Ύ' jY nW ct F 502 F x^ ^F cw Ya nW ct F 503 VJ N-^ H ^H '- _N - w...... 504 0 - 488 045220 5 <Ν' Cl ( \ Λγ Ν' Η γΎ Cl 505 A _n y JW D ⁿ Y nA Cl 6 Ν' Cl Q n xU 506 A y L ¹ ' n ^H - _N .-' Uy nA ^C1 7 γ 507 A _n u L Π N ' I 'N' ^ fj nA ^C1 8 A and XI Ух 508 A ^f y .Νχ N ^H -X SA' 9 t Η Η J w Ν - 489 045220 10 Cl У „ «X jY' An 510 А У iw U ci and h „ А ЛгУ NyJ Cl F 511 <1 Г Ao γΆ _H Г ) Η -H'~- ^z F 12 Cl j^f AH ALJ LA H 512 ^F Aa. μ ''N N_ H ^P A J·?;..... F 13 Q A /A 513 X J F 14 0 A A 514 S H V St F -490 045220 15 X „D' TA N 'f/U XY 515 G0 ^F n TtsKHU DuU F 16 fA 9 Α Η Xw 516 <ι£ Until 10 N Sr U DuU F 17 u - f At An ci O., 517 0 n A „ y 0 Η ^Η Ύ Ad F 18 u n Y' 518 A U n2 ^f η Ά Qu F 19 I'm at YES N 519 7 nU Y N SY M -491 045220 20 Y C! Q n/U Tu X ci 520 AY .N'T! H ^H AA' / 21 Cl / J.zh A n ?υΆ ^ν VnV^.n ci 521 Y ΛΚ η ^H k A' 22. A Ν-, H ^M - _N V'' JoZ 522 A Ν-, Η ^Η Ύ A..... 23 4 „Т A' 4 ^N 523 tJ ^F Ψ N-^ Η V A* N 24 4 H t N-, H ^H 'N' ^J AP' 4 524 Y ^F A .Ν') H ^H A / H - 492 045220 25 I Ϋ k n If' 525 X h A If' / 26 9 ht ., A' 526 <W ^F Ϋ κι F _Ν HL J ^F W ^H tj W' N 27 H t N't, H ^H ^ _N >-IF' 527 F . m^FI · H. J ^F W ^H tj If' N 28 Cl / I/ Λ H 1 G IF' / 528 F . \F _u Η. I Ν/ HN^ If' / N H 29 r ^N y ^F W' H 529 H ^H ''N^ If'' ! N - 493 045220 thirty n rV k n 'YT Η 530 'a 31 Η <V Λ 1 WT/f -T* 531 ΗAv 32 Λ η ίΥ VΗΥΥ JT 532 T H Y N-τ, Η yT F 33 Η <ν ,к η И?-..... 533 A ^{F h H} n·^ ^Ν 'Λ l _L l w IGAT ^N ΥίΊ f ^N 34 Cl / Ay ^f A u li T Η tTxU 534 A A ⁿ Ν-, H ^H _N Wr nW ci F - 494 045220 35 At θΧ 535 A; „ Ν-, Η V W' N 36 n 0 S n ^N nA· . U; A 536 A ^F y U n nJ ^Ν X Ν _Λ ϊα /X IJJ Mn Τ ^{Ν Ν} ΆΑΤ ^S! 37 Cl n Μα Νγ H ^H - _N AJ An' 537 A ^F u U n ^Η ·Ή ^Ν X Ν _Λ Λ α ^ν .-X ΙΑ Τ ^N H|=1 ^'- Ν AUD ^ci 38 Cl Η HA ^F 538 А У Η ^Η Ά χχ Ν' ^Ν Ή ^C! 39 C 4. , V' π 539 F Νγ Η ^H ' ^v fAN Xu hJ ci F -495 045220 40 Cl / X\ _Y x ^F N'T. H SA 540 F yA ^F 4ύ YH UD nY ci F 41 N-'n ci 4 _{Ί ?} 541 A - A ^N iAZ 42 Cl X hx H 542 Z ^f y -A ^H w...... 43 У A VH НшАУ Ύ' 543 Z ^f у .A h ^H A УА / 44 Cl z H %A? Y 544 Z y A h A _n J 44' - 496 045220 45 Cl X n χΫ W n ΆΧ .W 545 A A ua 46 CI Η ίΥ W ^Η 'Ν 546 -А У уА 47 C.I. X η %-У CM'· 547 ^A F 48 Cl at A.F. % Η %ΛΧ γν 548 °A y yA F 49 Cl A n A W' 549 <Y ^F y UA nA ct F - 497 045220 50 Ci A h A ^F ya 550 A y γ Η ^Η _Ν · XX Ν 51 VH ^N 1 ό 1 γΝ .M 551 sD y Xr' Ν 52 U. -L Μ ¹ ' 552 p ^F L Υ Η ^Η Α Ν 53 Cl ⁿ Ay ^F k h yr 553 Α η U F 54 Cl to h ^H - _N '0'Lg' 554 Μ Α F - 498 045220 55 Cl H if/ ¹³ AH yy h' 555 Fo od AH ^{P O} D F 56 Cl ⁿ Y AH YEAR 556 O ^f C Α H ^N Y JH 57 U L H 557 W ^F Ψ nA ^{N N} TG / N 58 ^Cl Q „ O XSAJ 558 W ^F Ψ N ^FHH 'N' y _? y N 59 7.. .y A' 559 D Ψ \| F I. H. J H ODOD w N -499 045220 60 χ. -A YA Η 560 A a Ν ^H A “Move VaS “ 61 α/ ^N -| η AA Ά 561 0 H Y ⁿ and OD NA JOCTXX nCU a 62 PART N 1 L 1 FOR A 562 0 H Mj H _H HJ OD N . .... X >- ^N Α,ΐχι “Si a 63 H A OT N %A Ν L 1 । _; -,Ν Ύ А 563 А» „ J Ν' H -rj-F ODodHd OD1 tk ^ν Ύ ^χ Ύ ^ct 64 Q a Ν' Η ^νΑ NI 0 1 L A- ¹ 564 % n A OD Ν ODCHOD nCu - 500 045220 65 Cl ( / H kAF yy 565 V ^H /A/ n \lz N-^ ^H H ^H T uh 66 A ^F H ^H V Ax N 566 / ^N I Cr ^N A ^H H yr 67 Τ' to Η A» N 567 Y ^N xT T AH ^H Y 68 I 0 H U-U-U. XX 568 £69H? ⁿ yh CHA-'U YH..... 569 Ti h SA' N - 501 045220 70 nA Ν-, Η ^Η Ύ 570 Α Τ Η Ύ ΥΥ' 571 D γ Η ^N D Ag Η ^w 72 A 9 ΑΧ' Νγ CI F 572 D u n- n ^Η Α U'U' VM ill N 73 A A ν/ CI 573 A ^f y Y η Ύ w N 74 A φ Ν--, Η ^η - _ν .Ύ'-. WA ν/ CI 574 FF zAf yes \| ,0 u H _X J Ν-γ Η N Ax - 502 045220 75 $ 0 YES Cl 575 K Λν ^Ν Dх ^Η Η ^Η _Ν ·- Α' Ν 76 У H t Η - _Ν ·'Α' 576 ΑΑ 1 qA α S ^Н Η ^H - _N - ^J A Ν 77 4 ψ ν-. ϊ ^Η Χ -Ά Ν 577 / ^Ν Χ to X Α Ν 78 7 Ψ κι η Η _χ D 578 η Υ Α' Ν 79 Y Η t Α' Ν 579 Λ and X Yes F -503 045220 80 / „U Ν', Η 'Ν' ΕΪ 580 y ^N t Η ^Η Ή YM 81 Yr Μ 581 \ « Α S;r' Ν 82 ^/Ν ^· Τα ^ϊΥγ Α 582 Τζ ³ η Ή' F 83 X Π Η Ν M/CN YJUyWn _ l y AL A LGU τ ^Ν ^nY~ ^{S Cl} OJ 583 Τζ ³ η Х?г 84 h _n 9 nA K ήΛ 584 4 y Ν' Η ^N X Tw F - 504 045220 85 0 Η V Η t Ν^, Η WX nV ci F 585 A ^cf ₃ (A vL h ^h 'n-'A У'Х 86 О 9 Η T Ν-, Η ΎνΧ Ν 1 D J. j ^Ν ρΆ F 586 0 H Xx n ^z V AY h %J A' Ν 87 , „9 Ν-, Η -ζχ Ν 1 Di 1 ζΝ Ν ρΥΫ F 587 ⁰ / ^H /jv A a' ^h η V ^N T n ,- AJ ^N JJTXT Av t ^N nA i|| N 88. „ .9 ν ^ν V К VV ^{N Ν ;} TCA nJ c f 588 Av [A n-^ h WVJ Tw ^N F 89 O Y N T n A K ^{N ;} ТХу AW nJ ci f 589 V - A Ja?' - 505 045220 90 χγ 590 A %y UA 91 5 „ U 0 n 44 591 U H %У UT 92 I A? Qyy F 592 F . κι F _u Η. T GD Η N Dx D Cl F 93 X У 'Ά ^{n N} X?CN N _s 1 D J. I yA F 593 F . χΧΉ H^· Κ|Χ _N H. T N0 Η N Hr D Cl F 94 Cl D Di X 0 ^N 0 nA cif 594 0 ^{n H} U jocixH ^N ^Til f ^{N cf} - 506 045220 95 Τγ Η Αγ' F 595 Α γ Ά νΥ c< F 96 C.I. 1 Η „V γ- 596 < « Υ Uw nA 0^ F 97 ι 9 ^{Η Η} Ν'Μ' Ν |1 D ι [ A γΫ F 597 XV Η ^H Y Ar 98 7 „Ψ ^Ν Υ Η ^Η Ύ YES F 598 FF A ^F t Ar 99 ' Η S Ν—, Η ^Μ Ύ ГГ 599 T h X Г??' - 507 045220 100 1 X N-l Η ''N'aA TU..... 600 U u A n ^H V UCH? nXci 101 i _n 9 UCHU N=/ Cl 601 w nV h ^H ---9^ y A 102 I „ U ^Ν Ίι n ^H Ύ V Cl 602 U Ν^ Η ^Η - _Ν 4 9 l Ν 103 i „ y AD У ^N Ν LuУ nA ci F 603 А У &?A 104 7 H t N? dJ T 604 А У A h ^H - _N 4 aCw nX ci - 508 045220 105 ν 9 kn ST 605 . ^N -T1 H ^H _N z ST' N 106 y h9w In F 606 L S' ssS N 107 I 9 WTiW' F 607 G h F 108 ^-η H ^H -nXz ^CD Lkut 9 ci ' F 608 O G'R V ⁽ 'F l 1 \ ³ H / X .π Ν~ _ί H 'DkrT AG F 109 7 „ ?o _CD lib D w F 609 V „ st ST' / N - 509 045220 110 X 9 γΥ nW ci F 610 Η D' A 111 i „ y γγ F 611 ο 0 ν ^{CF 3} I lch ^ν ί ^{η 1} γΥ ^Ν F 112 X Υ Ν ^Ν Jl ^D tij XA ya F 612 Α Υ ⁵ γΥ F FROM ^Ν~^ η Η ν-Α ^C1 613 ο Q ν ^{CF 3} I l. ^ν ί ^{η 1} Α 114 9 _D Η Η Υ γΥ nWw 614 Α, Υθ Ν-, Η XX - 510 045220 115 y 9 kn Vz ^CLF ND 1 I F 615 1 A H-CF, X H ^H ' _N ' yr 116 y „ to avg 616 py- ^F Ψ \i F ц HJ γΎ H ”N yr F 117 N-. N _N 'W' Y Y' 617 Y? Ϋ\| F |_| H. JH "N yr F 118 р 9 А Η ^1-4 ^- У'Г F 618 k ^F У Ye' 0 119 I. „ to Ay F 619 Y H У Wr №/ Ci - 511 045220 120 °X X— z /=\ uti di 620 wow 1S zl Cl 121 γ 0 DU F 621 By H I'schV Yp' 122 γ 9 b 0I UD. fromU nW ci ci 622 W H X Y'p 123 y o n-^ _D HY/V Ν' 623 w ^F Y Υγ' 124 o HZ _Y ДхУ nX ci 624 Уу Ψ nJ'S ^H _r r 944 F - 512 045220 125 i „ Νγ p ⁿ Ά Ν.Χ se Cl 625 A „ U Νγ H ^N -A UA 126 ADH ^H X χΧ nA ci 626 X ^F Ϋ \| F |_| N J rW N Gt UA 127 Cl /U Νγ HW yw F 627 X ^F Ϋ \i F q N J fW N Gt ya..... 128 i Q χχ F 628 X ^F Ϋ У1 fli _ 1 A UuuhU CO a 129 I'm F A I vA ΧΑ/ F F 629 △Х T F u h J N-—N Gh - 513 045220 130 k Η kW/ Ν Η DI 1 ΧΆ 630 A5 ^F h 'nA Aw n=/ Ci 131 Α η D Aw mD Cl 631 D y ^Ν τ H ^H tr w...... 132 „X Η ^Η - _Ν - Aw mD Cl 632 A „X w 133 F i L/ .γ Η ΗγΜ ΑΑΧ 633 i yes Ά-ύ 't \ ⁵ ts 1 Ν-' Η ^Π Ύ Ax F 134 0 Kn wX- HA F 634 A η X XA - 514 045220 135 n U X'U D fl | / F 635 i 'Ή'α \ ό Ts Ν' Η ^Π _Ν > kw F 136 Cl / Av ^f Ν' H 'NX SF' 636 „ F Ν-, Η ^И _ы > F Τη F 137 k _H w Ύ S ^J Cl 637 YL- ^CF 3 W^cf Ν' H ^H X i? ^y 138 WN Q ψ Ν' H ^N P Ν. П D 1 I ^N У У 638 „ F Ν-, H У _ы > F YES 139 h n AT Ν' _n n ^Ν 1 ^D ы 1 П уу F 639 ογ ci - 515 045220 140 Λ. -,Τ A>' F 640 Y ^f l Ν-_ Η Lug ν—' Ts Ν 141 U? V uch 641 A Η ^N U Ul Ν 142 V „ J Ul F 642 V „ У Η ^Μ ·' _Ν > у 143 9 H /у χΎ Α~ ^{Ν CI} 643 9 γ Μ JU Η. J Ν-Χ Η Ή 9l F 144 i 9 Α Η ^N schH' Ν 4 DI [ L...... 644 L _n u A - 516 045220 145 2 k n u s N/J Cl 645 Y Ν/ H ^H VF 146 I L/ to H V^N KhrU ΆθΙ 646 I I Ν/H F 147 F n W'' ^F Ύννν» 647 AW F 148 with X "-, h %A> χχχ 648 H o' < η hJ A;w F 149 I A ^f to HW N B I ] W F 649 I Ψ W' - 517 045220 150 I ή k n %-M χΑ 650 I T' Sucker 1 I nY ci 151 Η f 651 u ^f T \| F |_| H. J γΎ H ”N Sy Cl 152 F ⁿ iV U Η dA 652 Μ T \| F |_| H. JH "N Sy F 153 F n A< ^F u n dA 653 AX \i F c H D H ”N %”' F 154 F n Ay ΥΪ-Αα DM F 654 F-ZS y ^F η Πγφ' 9m F - 518 045220 155 h 9 Ν' N ^H 'W'V YU...... F 655 mOT Η Η t Ν' Η Α _ν > YOT / 156 n OD Ν' n AfAA 656 genus Ο Η t Ν' Η AD YOT /Ν 157 α Dod Ν' Η SOT 657 y? A Ν' Η ^Η Χ Move and - ⁷ II Ν 158 s η χΥ 'STROKE 658 Α , ^Ν Κ1 ^{Η Η} ^Ν^ γγ Ν'—FROM ^U 159 φ o Ν' Η IуА -.уу- 658 i^ ^F L OT ^{n Hl} N'''OT' ^Cf - 519 045220 160 Q γυ A 659 F F 4T LU u FL J 161 F ^H A h 660 FF H ^f y Yes 162 Q No. VH N.DL TA 661 4 T 10 H ^H ~U Y'A 163 n iV a h A..... F 662 F 164 h tV α η ^ιΑΑ N T D I | 0 T'A 663 s„ y Nm F - 520 045220 165 n rV ^F _Ν Α ϊ ^Ην η UoU A C1 664 Z ^f y AH ^Η Ά UD Υγ ill / Ν 166 ^Η rV Α η A _n -XA _f DA' F 665 XX n %χ ΧΧτ nA ci 167 Η У Α Η ^Η - _Μ ' W CI 666 DuU ψ a ^f η ^η Ά nA et 168 γ ιγ Η ^Η Ά Χν 667 FF V ^F y &'D' Ν 169 F Η V ΖγΜ Ct 668 FF V ^F X A ^{H Hi} rr xZ N - 521 045220 170 n YES Ν ^Ν Ί ϊ ^Ην η mm A CI 669 υΜ μ° Mxu A Ci F 171 yr 670 w ^f m F _u Η.. J Η 'hr &У Ν 172 0 F A n MM 671 Μ Ϋ \ι F c Η J fW Η ”Ν ί"... 173 F and D ⁷ A η γΤα ΜγΧ 672 Μ Ϋ \ι F |_| N. J fW Η ”Ν 174 $ 9 o Ν- _ί η ^H I|-V Mm 673 y .у ^Η Ν - 522 045220 175 ζ. ·2 N.J-Cl 674 D ψ dd C N 176 Soda Q ( H 1 Ns H ud 675 ζ \7 zy ν 4rL d 177 h 9 S Η A· 'H' ^H Ody Cl 676 D ^Рр У SHW .FOD' 0 178 , 9 Dod 677 od y Dod mc N 179 , 9 A H ODOD-lOD N 2 1 1 /1 Dod 678 OD ΙΑ N ODf Xd N -523 045220 180 9 9 Ν-, Η ^Н > _Г А уА 679 У γ νΥ D λ 9 Α 7ΧΑ νΜ CI Α 181 ~Α 0 Ν-. Η ^Η -νΎ' V Μ 680 Α ^{α Η} If' 182 q.....U ^g ' 681 Α 183 by 9 kn uA-A Ύ 682 X Η X Ν'Χ Ν AsthA SA A 184 ζ 9 kA 683 A T— Ζ /=\ )AA A> Q - 524 045220 185 w 9 AH VA koY 684 AT N-. H ^H - _N -' Ш 2a 186 HQ 0-H A h M \ TU 685 q γ N-^ H ^H '- _N z ^N 'XN ϋό i 187 V h hV\ 686 Y p ⁿ Τ' A* F 188 H ^< Q oH ,Ν^ HJ \ 99^ 687 t V ^HH ''N^ TchT 189 F F _F 1 K, _H kv Xx A Cl 688 T V ^HH ''N'' T\v nV ci -525 045220 190 Τ 9 Ν-. Η ^H > _r W ΤΤ 689 W Η ^Η Π 9Α 191 ν 9 Π, η ΤιΉ Gw 690 Α g 9Α 192 π 9 N-. Η Τ...... 691 A L η ^N -T Τ 193 y 9 Η ^Η γΤ ST' 692 Α 194 ή. -Λ td 693 Α - 526 045220 195 X n X ^F N-d n 694 £ „ x ,Ν^ N ^N A SA 196 X N A AU 695 h t U n ^N T 197 F to FA Ν-, N ^(AD: Tttt 696 I n I Yag' 198 A n /T ΤΥ 697 s i AT ^ΙΊ Ν 199 T fY Ν-, Η · _Ν ·Ύ'τ 698 △T ^f γ \| F Н J Ν-—Η hr £α - 527 045220 200 Ω τ' _F YES 699 A Υ Υι F u Η. J γΑ Η hr Α' 201 CL / „ ο Υ Η 'Ν'-'-·- Α 700 Y ^f χ ,Ν^ Η Ύ ..Α.....' 0 202 ν Α γ Η n-y \ Υ' 701 D η X Yes Ν=/CI 203, 9 J Η ^Η Χ Yes 702 Yes ν=/ ά 204 -/ 9 γ η ^Η Α Yes 703 Χ Ν X Α' - 528 045220 205 F F ;y n f X-,H here 206 ^ν ΤΎ 207 >LJ ^{7 H} w (yh ^H >r'U ΤχΤ 208 Q _H fY N<QJ Cl 209 F _F Xf r ^N v ^F _n ⁿ y 7 ^Hn 'h ^f w - 529 045220 210 4w Ν', H AX 211 Cl H ^f yV' to H AX 212 1. .2 ΎΥ' 704 X Ψ η ^Η -Ύ &Ύ Ν 213 To . Y уУ ·' 705 to „U ;w Ν 214 „ o K n da ΐ-ο Cl 706 y A Ν-^ Η ^Η '· _Ν ζ Χγ - 530045220 215. 9 n ^Η 'ν·'Α χΧ ΐ-0 Cl 707 X x Xi J u H. J NW Η N F 216 Cl n X ^e ' u n χΧ nN ci 708 А У AH ^H A ΐ / 217 9 W А h %V xX A Cl 709 X ^F X \| F |_| FL JH 'hr UA Cl 218 -. 9 Ν'- Η χΧ 710 X x A h ^H X a' N 219 -. 9 AHT _N J,, _z o χΧ 711 Ϋ η η X ^Ν Τ N 1 A .p'A ΟψΝγΛΑ Cl D 0 - 531 045220 220 " 9 A N S-U Ar' nV ci 712 AT V <V 222 Cl R Xil n G g ' n K IJ y°r 714 ~9 Q f ut YA 0 223 Cl QA yr...... _o p 715 A Ch-D A η M w nA ci F 224 Cl to h TV nV ^Cl 716 7 h У XX Jj AY ^N AA Cl F 225 Cl Ή η У A 717 A ^F H u у уу·· - 532 045220 226 To-, & Λ Η THAT 718 ATU ΝγΙ CI ΟΙ 227 Ct n ^f yV A Η ΤΤ 719 fAf χ. J γη F 228 CI Τ rS^ ^F 720 У У Ν' Η Aw nF ci F 229 ·ί Ν' Η Ъ:оУ Ν<Α CI 721 Α ψ Ν' Η ^Η -Ά Tw F 230 > 2 Ν' Η ^Η νΜ Μ' 722 F _F YL- fx/ ^F Π Ν' Η ^Η '- _Ν -· Tw F - 533 045220 231 ^g <. .я w 723 AQ y ^F n 'ήΎ ΤΑ nW CI F 232 Cl ₂ рШ^С1 У Η γΧΤ χΑ 724 у ψ y ^F Η ^Η Μ >/...... 0 233 4 I ¹ Q Μγ u n dA 725 D-S η X χΑ νΥ CI F 234 Cl n ΤΫ' u n ΑΧ Ν=/CI 726 A 0 235 C.I. / ΚΑΐΙ u n χΑ ΥCI 727 F fYf Μ „ τ χΑ nW CI F - 534 045220 236 X 9 ¹ x n W ¹ LU Ν=/ Cl 728 'a ^{n n} L y 237 4 . Υ TA ri 729 Υτ at 238 _c 2 A n X ri 730 . F/\XL? rO ^F A ^f n iL p ^F j?ri 0 239 l 9 A n XX LlH A SE 731 F A <A/\Jf mF m FL J P~F LrU r<J Ci F 240 Ch 2 L\L N=/Cl 732 ChH H “U taken into account” 0 - 535 045220 241 Ay Cl Q IS H ' GG A W' 733 u chu nJ n ^h Q ft F 242 Q Cl Q y N~. H --nAI SW oz/ Cl 734 wk / \__/ ^x si X— Z /=\ 243 У H w C Cl 735 В У Х _? y-/ 244 Cl ./ yL,-F Ν^ H WAS QnT 736 d t nJ n ⁿ D νΤ W TSKhDT GA t ^Ν Cl / 245 Cl and ^F Y kn W- ¹ ' 737 D U y ^F n ^H U - 536 045220 246 Cl sD 4 Η Ί Ν-. Η ST..... ft 738 V„J AND 247 GA 739 T $ H ^H - _N -- Gw F 248 Cl n A K H %AV 'USU nW ^Cl 740 Y <> ty ^{h H} -N^ Gw ^N F 249 Cl ⁿ Gy ^F kh AG 741 A ^f g TTXj /=Υη ( Ν- V _z Js Cl 250 I „ and GA ,W Ct 742 F ..% H ^H 'N''G'T ν . 1 J. | YN Gw nA ci F - 537 045220 251 Cl n OD K Η Ά" 252 LL Z—f Z od τ-ζ dot ODg ζ ' / ' ^ζ 253 OTA OD Τ-Ζ ^ζ W' ZOD OTP 254. ? Ν Η ^Η γ\/ υΥ nOT ^Cl 255 • l FH 743 A _Η γ Α η ^Η Ύ ,ΫΑ' 0 744 OD Ψ Α η ^Η Ά 0 745 X η Α _ν 5 OT' 0 746 Η Move Nyj Ci F 747 y γ Ν' Η Ay Yes' 0 - 538 045220 256 Cl to X Cl n YY \ and to II Ν-, H γγ 748 Y „ J yY F 257 Cl RA H YA X' nW ci 749 9 γ 0 h ^H W yY nW ci F 258 A. .I γΥ 750 X H t γχ F 259 4. I am γΥ 751 t. n F 260 X rw Cl A „W N~. H 752 F ^F X η -Υ Yw F - 539 045220 261 9 „ A TA Α α 753 F F t Ν-, H WW Ta F 262 9 „ A Ta Jo Cl 754 GA H A' F 263 9 n A TA 755 FF .9 ^h T N-_ H ^H z _n 7 F 264 /.. ..fr A 756 X h Y A..... 265 9 n A Ta W Cl 757 dT y Ν-, H H-V Ta F - 540 045220 266 Cl _H Ag k n k H / 758 F 267 ACl/ 759 Ay F 268 b „ J? fY Cl / 760 Pb 1 J r k i ^N A U??' 0 269 Cl L G h fY H ^N ZHA Ύ 761 ¥ h U 'Z F 270 C! v h mу pr ( 762 ¥ F H Ay F - 541 045220 271 Cl to „ w ΜνΥ ψΧ 763 γ ψ χχ F 272 Cl kn ΑΧ 764 k „у Ν- Η ^Μ Ύ ud F 273 Cl 765 X ψ ύ η 0 274 Cl D n ⁿ DU ⁰ Ν 1 ' ι Ύ' 766 ^<4 % n DU nF ci F 275 C1 Λτ ^Η ίΐ Ί \ Η 1 ,J Ν-, Η Ν'''OT' ιϊ 767 rf.: - 542 045220 276 Cl H liV AH xx 768 Η 1 Ό y „y A ^HH Y Y?:'..... 277 Cl n J a H XX nW ci 769 7 A A ^H AA' 0 278 Ct T Ж ' HUN Νγ H Ρ/ ^ύ ...... 770 AH U lUA 0 279 Cl and l N~- H AV TA h' 771 A „ y ^N YH ^N --gA lUA 0 280 Cl ij Hi ⁿ χχ 772 7 N.U ΤΑ' 1 s - 543 045220 281 YES 773 A to X ^Ν ~η ^Η 'Ν' .....ul 0 282 Cl Dt X n A.W. 774 A nH Ν/ N γ 10 283 -С Cl Cl .-V Μ Η ί J Ν~Γι Η a AW 775 Η W ^r ' 0 284 A 0 n l Ν', Η ήν-ΎγΙ Aw 776 X » A W' 0 285 I n l Aw 777 bi 0 - 544 045220 286 b. ci Q Ν-, H 778 F T T A H 0 287 „ i TvY 779 cT ψ ^N > η Xy A?' ¹⁰ 288 γΥ 780 I T y η Ύ .AX' 0 289 A Cl 0 h A ^F Cl 781 y η Ύ .AX' 0 290 I- Cl A _f to w Cl 782 I p A h ^H Y Tw nA ci - 545 045220 291 A- Cl J Ϋ P / ? zN vW 1 nJ ci 783 4 Ψ 0 h ^H J v 0 292 U ci 0 k xU 0 / zN w dD _r a F 784 0 H ^0 Y ³ ? ³ ' 0 293 CI Ή h у·»' ^N M _Br Cf 785 i 9 0 H ^0 Yes' 0 294 Cl yT Cl 786 i J Μ ³ ' 1 295 C[ z Hell 0 h ΧΉ nJ ci Cl 787 I Λ Yes...... 0 - 546 045220 296 Cl __/A.F Ν' H MAA γη Cl 788 T Ψ Ν' Η Μ ci F 0 297 Cl Uda nF G' 789 T ^f y Ν' H ^H _N - JYY..... 1 298 Cl 'U A/ P h MAA γτ ^Cl 790 k « A .γη 0 299 k _Η and P Cl 791 ' h У Ν' H YA F 300 A Ν'Cl U K %Α ΜCl NnQ 792 ut ° tku NyJ Cl F - 547 045220 301 Cl / A h M Cl N-h %0 793 SHU Cl Cl 302 Cl D A \ h 11 J N~. H '0'^ sj Cl Ny VO 794 X ^F Ψ IS HJ ШУ NyJ Cl Cl 303 Cl n·^ h χΡΧ ddu N=i ^Cl 795 304 Cl γ h %хУ yes WCI 796 tA >0' 0 305 b „ A yes N=/ Cl 797 A A η η A n ^N j] 1 χ Y - 548 045220 306 Cl .. Al kA Ύ Cl 798 ύ ^λ Y ^N X Jj 1 y ^N 307 k „ kA ' _N =/ Cl 799 4 hhA ^N kn l A yp 308 F ^H rY \ h LL A i AA kA 800 0 309 H, YA kA 801 4 Y W' 0 310 Cl A h ^h ''n9i kA M ct 802 AIA kv 0 - 549 045220 311 Cl Χτ H ^H 'H'T TU ^Cl 803 / ^F ~T Ж 312 Cl , ,X,F ¥ H to Г ^N > H Tk M Ct 804 'IT 313 У A JH ^H 'n'A:i Ta 805 χν Τ' nV η ^η Ύ 909 314 S I D' w nA ci 806 09 ν A η V ΤΑ 315 ~T Q J Y η %O Ά 807 Χ?'' - 550 045220 316 nW ci >=/ Ay M.A. 808 I don't Hell'· 317 A Cl U Η γΤΐ dA Ν' 809 .·i 318 Du 0 u mCh V h Chn Ag A CI CI 810 A ψ u n ⁿ A mind.....' 319 A MA nW Cl 811 A ^f t MM 320 & A U n /AJ Ύ ^N W _Br ci 812 A ψ ,un ⁿ A mm - 551 045220 321 Cl Q Dod ΙΑ Η OD-AM d U Ct Cl 813 U F rw H ODE' 322 CA Cl Q DOD A η ^H - _N A9 NJ 1 । JI w nA ci Cl 814 Λα h ^H > _r w 323 Cl D Dod A Η ^Ν-ΧΦ DX Cl 815 J Ψ N~. HM _N J /r 324 Q ζ· ^Ζ ζΛτ Z=< \=/ UCH-z D 816 FJF D hj FU'·' 325 9 W AH ^H H'' ^J N, l| Λ 1 >N wx yD ci Cl 817 X y ^N > ^HH ''N'Sy.....' - 552 045220 326 A 9 Μ l s γ4 ρΜ CI 818 Α u i ⁿ A w..... 327 mA 819 l ψ Νγ Η ^Η Α w 328 y α l n uXX νΜ ci Cl 820 fXf q A UD 329 y „ A Cl 821 ζΥ Ψ n2 ^F Η ^H L YES 330 .. ci D Am A, H uLD M Cl 822 A ^f u u n ⁿ A TA - 553 045220 331 H- _o Cl FU M A A U w nA ci 823 332 <A About Cl A A _F A h jfj Ν-, H VT yv G/ 824 at 333 Cl ° Xf X 825 y ^F X ^F A h AJ SA ⁵ ' A ^N 334 Q «— A _H χΥ A 'Ха 826 C^ ^r У Ν 335 A ri А _n dGT A 'Xci sx 827 l Y ^f A h A _n J 9x - 554 045220 336 Η o' /»rf Y Ύςα AX 828 I 337 Cl -° A/ Ν-, H У-кУ AX N ^Z 829 Yakh 338 Cl / Lt ax GG 830 D uy Ν 339 Ct AX A 831 <lJ A ^f ax 340\0 o ? H rf ⁿ 7 ? ax 832 F fIf AX - 555 045220 341 Η b 0 / Η A Xv 833 fXf \ . J 342 X η v _N x ci 834 L Y _N U Z ^r ' 343 Cl \ G T ^HH i X x xA XA t ^N N<V Cl 835 g 9 N A-A/ yr 344 Cl A η YES' ( 836 U n t A Fl A...... 345 Cl / J^F A h %AJ DA' / 837 9 ⁷ ht yr - 556 045220 346 Cl / Add Ν' Η FROM 838 L ψ nA η ^h - _n -' YES 347 H A N C 1 j -N STROKE CI F 839 X t Ν' Η ^Η ΉStroke 348 X _no STROKE M CI 840 Α n Stroke 349 H i d? · ¹ 841 Α Ψ Ν' Η ^N A Move 350 Q „ A STROKE V a 842 G fXf Y ^F τ Ν' n ΑΑ /FROM..... - 557 045220 351 Ct Vy at H jJ 843 >.. -7 XY 352 О 9 N 1 F У H V4 ХТу S ^J Cl 844 XJ ud N 353 9 _n a W Cl 845 <u ^F X γ h ^h Q Ufi 354 H W Cl M Cl 846 l F u Η ^Η |Γ By 355 -n' Cl Ϊ H U U N uU duu W Cl 847 Hw/N - 558 045220 356 Η o' Cl / n G GA W α 848 A ^f ϋ Η γ W..... 357 Cl / Ν-, H ^H ''N'W GA S ^J Cl 849 τ Ϋ H 7 F 358 o'Cl / HG GA JCl 850 A G Ν-, H Ж tu 359 H Η—N Cl / η G ga W Cl 851 ^χ/ 1 A_.Z 2 ^Z A ^z 360 \ N— ( ^Cl / A/ ^f N~. HY _n GI gA U Cl 852 X . -.+ TT - 559 045220 361 Cl gp' 853 ι Α Τ 362 " "AND 854 Жр Λ γτ 363 Ct XA ^F 855 Υ Η У γρ 364 Cl FROM ΙίΥ AC s-ϊ Cl 856 SiF 365 Ά ci QHP ^F 857 Ul J - 560 045220 366 U N n A AAAA TrU N^.NCl 858 Z—X Χτχ AT/Λ y ’ 367 У Ν »A ^F A У V4a WqA ' ^N A 859 X° H tX PA 368 У Q „ A A > a-aa Tn 860 aH iw aWM aXz s ^/ A ^H 369 U N-. QHA Tv 861 fAf 1-. -7 H ^y 370 y „ AX hY Cl 862 Α Ψ nA η ^h -- _n -Tyv - 561 045220 371 I q n 4/ TA 863 ^F 0 ^F u _F H y 0 ^Γ Η U y 372 L Cl y n L 0 Η n-Ά U 864 V / JAS / \__/ ¹ x—g /=\ 44^ 373 L Cl У „ A ^f у 865 Hf η Ή У ^у 374 Cl < ) JaA ^F |-| Ji J Hr A ci 866 g nU 0 Η y..... 375 H 0 Cl < 2.-44 ¹⁷ 0 H V-XX Ή μΜ C[ 867 А Ф 0 Η ^Η -- _Ν - уу - 562 045220 376 A 868 U.K Νρ N Ar A..... 377 У A 869 n · ^ρ A F to Н ^Η Ύ 'У/...... 378 to Cl u n dU Ν—, Η ау 870 F А n Ϋ _F А? pWnJJ ι 0 379 A Cl 1 / Ag k n ^h - _n aJ АУ An ci ci 871 AA Ν-, Η .γ..... 380 X Cl U Η Ϋ AU 872 Ύ?” - 563 045220 381 k n D αχ Cl 873 1:,:/Ν 382 k Cl Ν-, Η ^Η 'Ν УУ АΧ <31 874 У „ у Хн А 383 Η Ν—. CI to η Y kA D-I CI Ct 875 Η У τ dХ ΑγΟ ΐ 0 384 Cl g nda Ν' Η γΎ χΑ F CI 876 X a oud 0 385 Η Ν-, CI to η yes Ν' Η τΎΖ ΑΧ C.I. 877 F Η good luck - 564045220 386 Η N-, Cl Υ η Ν' Η SW ΥΤ C.I. 878 "U" Ν' Η Μη..... 387 Η Ν' CI Ρ Η Α τγ 879 A » A YA 388 Η Ν' CI ^ν ΤΥ 880 T? ^y 389 b. bΠΥ 881 Y Ϋ d? ^at 390 ''ογ ^Cl τΥ Wn ci Cl 882 γ Ψ Ν' H Y'? ⁵ ' - 565 045220 391 Cl Q _n D ODU 883 Y F YES 392 b y Ν' Η γΑ OK'·' 884 FyF „from YES' 393 Η Ν' CI Q „ U Ν' Η Α ΪΑ 885 Stroke N 394 CI Q „ Α ODE Cl 886 A ^f Ψ Ν' N A _n J YES 395 Cl Dod Ν' Η PROGRESS 887 7 A YES 1 N - 566 045220 396 N-, Cl q „ γ N~- H Y—' — MU N-NCl/ 888 X „t MM' ABOUT 397 H A Cl Q „ l¥ A NN Cl / 889 Α χ У Η %'.у?.....' F 0 ^N 398 lH ? 0 „ Ϋ OU NN Cl / 890 A ^f t ⁿ y Η ^Η Ύ w...... 1 N 399 JyCl M „ yU N-tJCl/ 891 r y h Mt..... 400 9 ⁴ O Y _ Cl ° \ and G di 892 Ύ y / u ^ΙΊ N - 567 045220 401 n ^S| 893 ^f Ά ^Ρ Ψ N ^N 1 1 X Ζ· ^Ν Α Α ¹ Ν 402 -0 CI У „ ДрУ 894 By ^1Ί Ν 403 ct Ya\n LT tw n ΡΧ 895 Υ ^ΙΝ Ν 404 W Cl У к хУ yes” 896 А ¹⁴ Ν 405 Η 0 Cl Q and _Г ,*У yes” 897 у Α Α ^ΙΊ Ν - 568 045220 406 Cl jy\i T n ^N 1 Η X 898 s? Ν 407 o?OH U ? ψ L1T AY SA N 899 T U l..... 408 ft i a U .η Ά- XHT HJ SA ¹ ' 900 X Η Η X y 409 U< ⁿ l y ^hh w y N 901 Ch ¹¹ tX .y 410 ε η T U Ν 902 S.....A, X - 569 045220 411 A 9 У H ^H z _r V W N 903 zQ у n^ h yyy N 412 У 9 У ^{H Η} 'νΆ' sw N 904 /У у У Η πχ W у Ц N 413. FA nJ η ^H ''N%-^y W U Cl F 905 yT Ν^ Η 414 x _H 9 nY £ A Yp 906 nW n ^H r9 γχ 415 У HY N^ h - _n z W 907 Д-В у ΥΥ' - 570 045220 416 o 1 /\ C .n Ρζ A n Τ Α' 908 N-V Η Χ0 Α..... 417 Υ Υ Η — Η α 909 V Ψ Α..... Ν 418 χΑ to η V Α 910 Ο τ Α Ν 419 Ρ Η Υ Α 911 ο Ϋ hL H Ik J IV Η Ν 900 τ ^Ν ^ Up. 420 Ν- Η '9 J®·’..... Ν 912 Ya n X A - 571 045220 421 Τ Ψ Η Τ-- ⁷ 913 Hf H ST ¹ ' 422 I to That WnW ci 914 A to M F u H. J Η Ν' st..... A 423 7 _H Y UZH / 915 A ^f to Y?y· 424 L ψ F* Ν 916 A ^f to ^\i F and FL J W ^H 'N sr..... Cl 425 „ t 0 SW Α ^ν ά Q n sJ Dt F 917 f/f 1 h ST' F - 572 045220 426 4 „ У Ν/ Η ^Η Ύ 918 If ψ F Η γν F 427 A Ϋ ^ν η ^η Ά IF' Ν 919 V Η HV JF' F 428 I'm Ν/ Η 'Ν-'Χ-'' W' Ν 920 q A Ν/ Η И^М^ w F 429 Α Η У ^ν ί ^{η η} Ά W' 921 W ^f Ϋ \| F II K J hW H TJ IF' Cl 430 w ψ ьр η Ά IF' Ν 922 W ^f X M u H. J NA H hr w...... F - 573 045220 431 i n u n ^Η 'Ν ^ζ ν·.. W nA c f 923 △Д Y EF _μ HJ NY H hr SA..... o _x 432 <YY TH ^H ' _N ·Tw nJ ci F 924 W ^f γ mu H. J NY Η M As..... 433 \h Y >A 925 ζγ Y M U H. J NY^ Η Ν' Ax..... 434 G „ J N^H 926 Λ4 A Ν-, H to AX' A 435 I „T Ax' N 927 l A Ν-, H Xj AX' A - 574 045220 436 i „ u A n Ά Ή F 928 ^F A ^F q Μ Να Ν 437 Y n ⁿ X n1 Waa ⁿ jXxxt Qu « ^N 929 AA ^F X μ F u Η. J Η Ν' ΝΑ 438 I n 2l XtU νΧ CI F 930 △l f gA η η-Α ΑΑ 439 IT 931 Un ΝΑ Α 440 τν „9, XX nA Ct F 932 TUYA' Α - 575 045220 441 <A a nL Η ada Ν 933 w ⁷ A F to H ud A 442 A ^f ψ N' ^F η ^η _ν - Uda 934 yes f nF h ^h 4 Uda* 443 W 935 <A ^f yes nL ^F H I-D A»X N-U 444 Д Ψ ΑΧ w ill N 936 F ^F h «У AX Cl 445 X a H ^N D yes 937 F ^f y U-yes - 576 045220 446 7 n U RA ¹ 938 uU Ψ Ν Η A UU..... 447F. F _and H. J ΓΎ Η 'Ν Αα A Cl F 939 X 1 ^N \U Ut' 0 448 7 n У yr J Η 940 F Jf Жр VT ^nN ? ν Λ A yr 449 7 „U yr 941 yX ^F A 5r· 450 W 942 F - 577 045220 451 T y Ν-, Η ήζ Ν 943 γ τ ^I M JUAJ Ν—Ζ Η Ν ^Υ F 452 FF W ^F τ ⁰ Ν' Η ^νΑΖ Α»' Ν 944 WA F 453 Y ^f ψ ΫΑ 945 i ^F У ki z ^[ U H. J H YZ F 454 I "U" Ν' Η ^Υ 946 and d F 455 F \ <Mf γ ΫΥ 947 Tf ^F H nN^ Ν 1] I [ 'N Yr? NyJ Cl F - 578 045220 456 Η 'Ν' ⁰ kF Ν 948 v to UA 457 I to Υ η ^Η _Ν -° SY 949 A _F ha NW Η ^A F 458 Η ο to Η 9 Η Ύ JCH' 950 Λ.?. ^A F 459 i ukn A kF ¹ ' 951 XY k^A F 460 U „k W' N 952 A X ^A F - 579 045220 461F. <1Д 'Ή ri ^F uh J V 953 F rV N0 ^F H ^tsAr Πχτ F 462 F , <LAf τ' A h ^H z0 Μ ν _Λ Α A Dt oj Ou a 954 I o N0 ^F h nU YES 463 0 H Ty v M...... 955 X Ψ Nm ^N F 464 A ^N X h U N 956 fXf 1-. -7 U A F 465 4 _H y 0 H XX' N 957 Ο Ф N0 ^F h ^il - _N ' YAM F - 580 045220 466 J A k n Μ y ^Cl 958 fX-f Μ/ h ^H A F 467 ν η α W Ν 959 fX-f A F H A iw Η Ύ F 468 Τ Α W' Ν 960 M ^F A n ^ ^f h ^h -' _N -- F 469 M ^f k A n W yy 961 k A yz h ^h A w 0 470 xk A YA N 962 Ik - 581 045220 471 N ^F H dd 963 kA h Y _n X ?OD F 472 X - -A / N H 964 OD U ;ά° ΐ ^H X d F 473 d X ΙΑ. H I/ η..... 965 ODl U d- F 474 S _: A ^F w ΙΑ. H ^Low -|Dx A»' N 966 ODA U / ^Ν Ύ° ΐ ^H>F d 475 V 1 W ^F D ⁰ H ^N' XX Y ^t »' N 967 Chz n dd F -582 045220 476 _Y DΗ a X» Α 968 7 s ¹ j D F οι γ F Cl 477 0 Η Η γ 0 969 Y-°H% --+. X F Cl D C F ;i 478 0 Η Αα ν γ У γ 970 Ny ⁰ H j. --+. :/ γ F Ct AC ,,ο :i 479 Η γ γ F 971 N-y° H Ύ -+. si* Μ F Cl Y C F ;i 480 χ „ χ F γ Ct 972 W H pPyPHOH X A Cl - 583 045220 481 уь X N N-»H _μ AJ N-~ η Η Ν y 973 Ύ η A Ai Ύ> ChY nA α F 482 Η ϋ Α ί Ύ „ LU N? CI F 974 Ψ 9l F 483 γ ψ JА 975 9 ^f χ ^14 F ы AJ МА F 484 ο9 η X GU Η YH' Ν 976 9 ^f h 9h9 F Wn 485 <Α=ν 'Α- Χ η ^Η Α Ν fl ι [ εχ F 977 9g ^{1 n h} i9 YA L Cl F - 584 045220 - 585 045220 491 Α TUN ^N I 983 A h XWVF lT 9A F 492 i and X l 984 o । ^η Ά у/ YJ' ν. χ i? Y ^Γ'ίΊ'ϊ mD DM nW ci F 493 X ψ ^N YH ^H Y y NN Ct 985 \Ψ Cha Ν% Cl F 494 0 Η /Μ ψ Х. ^Н Н ^H Y /% 986 η» X А' F 495 U Τ mA F 987 ^but sd Hmm - 586 045220 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or deuterated analogue thereof. 29. A pharmaceutical composition for the treatment of a disease or condition mediated by Osaka type (Cot) thyroid cancer, comprising a compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers or deuterated analogue thereof, and a pharmaceutically acceptable carrier.