EA038715B1 - Bromodomain inhibitors - Google Patents

Abstract

The invention relates to substituted heterocyclic compounds of general formula (II), compositions comprising said compounds, and the use of said compounds and compositions for epigenetic regulation by inhibition of bromodomain-mediated recognition of acetyl lysine regions of proteins, such as histones. Said compositions and methods are useful for the treatment of cancer and neoplastic diseases.

Description

This patent application claims priority under the provisional patent application

US No. 61/893133, filed October 18, 2013, and US Provisional Patent Application No. 61/931467, filed January 24, 2014, the entire contents of which are incorporated herein by reference.

State of the art

There is a need in the art for an effective treatment for cancer and neoplastic diseases.

Summary of the invention

The present invention provides substituted heterocyclic compounds and pharmaceutical compositions containing said compounds. The claimed compounds and compositions are useful for epigenetic regulation by inhibiting bromodomain-mediated recognition of the acetyllysine regions of proteins such as histones. In addition, the compounds and compositions according to the invention are useful for the treatment of cancers such as midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, bladder cancer, lung cancer and / or melanoma, and the like. The substituted heterocyclic compounds described herein are based on isoquinolinones and related heterocyclic structures. These isoquinolinones and related heterocyclic structures are substituted at the 4-position by a group such as aryl, heteroaryl and the like, and also on the nitrogen atom of the isoquinolinone or related heterocyclic structure with a small alkyl group such as a methyl group.

One embodiment relates to a compound of formula (II) or a pharmaceutically acceptable salt thereof r ^a

° Formula (II) where R ² is C1-C4 alkyl optionally substituted with OH or F group, 3-4 membered cycloalkyl, methoxy, -SO2R ⁵ , oxetanyl, phenyl or 5-membered heteroaryl containing 1-2 heteroatoms selected from O or N; 3-4 membered cycloalkyl, CH2D, CHD2, or CD3;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , C ₁ -C ₄ alkyl, where each R ⁶¹ is phenyl optionally substituted with halogen;

R ⁶ is hydrogen, halogen, -OH, -CN, C ₁ -C ₄ -alkyl optionally substituted with halogen or ethynyl, cyclopropyl, amino, (C ₁ -C ₂ -alkyl) amino, di (C ₁ -C ₂ -alkyl) amino, 3-membered cyclopropyl (C ₁ -C ₄ -alkyl) amino, C ₁ -C ₂ -alkoxy optionally substituted with halogen, -S-methyl, 3-4-membered cycloalkyl-C ₁ -C ₄ - alkoxy, pyrrolidinyl, phenyl C ₁ -C ₄ alkyloxy, 5-membered heteroaryloxy containing 2 heteroatoms selected from N, phenoxy, C ₂ -C ₄ alkynyloxy, or —N (H) COC ₁ -C ₄ alkyl;

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen;

R ¹³ represents -YZ;

Y is selected from a bond, -CH ₂ - or -CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₂ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, C ₁ -C ₄ alkyl, or methoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, C ₁ -C ₄ alkyl, C ₁ -C ₂ alkoxy optionally substituted with halogen or ethynyl, phenoxy optionally substituted with halogen, phenyl C ₁ -C ₄ alkyloxy optionally substituted with methyl, halogen, CN or methoxy, cyclopropyl C ₁ -C ₄ alkyloxy, 4-membered heterocyclyloxy containing 1 heteroatom selected from O, or 6-membered heteroaryl-C ₁ - C ₄ -alkyloxy containing 1 heteroatom selected from N, or butynyloxy;

R ¹⁶ is hydrogen, halogen, —N (H) COX or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from C ₁ -C ₄ alkyl optionally substituted with halogen , phenyl, phenyl-C ₁ -C ₄ -alkyl, optionally substituted with a methoxy group, 5-6-membered cycloalkyl, optionally substituted with halogen or OH, 3-4-membered cycloalkyl-C ₁ -C ₄ -alkyl, C ₄ -C ₅ -alkynyl, optionally substituted with cyclopropyl, 3-4-membered cycloalkyl-C ₂ -C ₄ -alkynyl or 5-6 membered heterocyclyl containing 1 heteroatom selected from O;

1,038715 each R ^{21 is} independently selected from C _g C ₄ alkyl; and each R ^{22 is} independently selected from hydrogen, C ₁ -C ₄ alkyl, or oxetanyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen.

In one embodiment, the compound of formula (II) is represented by formula (IIa) r ^a ° formula (Pa) wherein R ² is CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD _2, or CD ₃ ;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen;

R ⁶ is hydrogen;

R ^a represents ^;

X2 is N or CR ¹² , where R ¹² is hydrogen;

R ¹³ represents -YZ;

Y is selected from a bond or —CH ₂ -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen;

X4 is N or CR ¹⁵ where R ¹⁵ is hydrogen;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S— or —NH— and X is selected from C ₁ -C ₄ alkyl or 3-membered cycloalkyl C ₁ -C ₄ -alkyl;

each R ^{21 is} independently selected from C ₁ -C ₄ alkyl; and each R ^{22 is} independently selected from hydrogen or C ₁ -C ₄ alkyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen.

In one embodiment, X6 is CH. In one embodiment, X6 is N. In one embodiment, X5 is CR ⁵ . In one embodiment X5 is N. In one embodiment, R ⁵ represents hydrogen, halogen or C1-C4-alkyl. In one embodiment, R ⁶ is hydrogen, halogen, _{C 1} -C ₄ alkyl, or C _{1 -C 2} alkoxy. In one embodiment, Y is a bond. In one embodiment, Y is —CH ₂ -. In one embodiment, Z is —SO2R ²¹ . In one embodiment, Z is —N (R ²² ) SO2R ²¹ . In one embodiment, Z is —SO2N (R ²² ) 2. In one embodiment, Z is —N (R ²² ) SO2N (R ²² ) 2. In one embodiment, Z is —CON (R ²² ) 2. In one embodiment, Z is —N (R ²² ) CO2R ²¹ . In one embodiment, Z is —N (R ²² ) CON (R ²² ) 2. In one embodiment, R ²² is C1-C4 alkyl. In one embodiment, R ¹⁴ represents hydrogen, halogen or C1-C ₄ -alkyl. In one embodiment, X4 is CR ¹⁵ . In one embodiment, X3 is N. In one embodiment, X2 is N. In one embodiment, X2 and X3 are N and X4 is CH. In one embodiment, In one embodiment, W is —O—. In one embodiment, W is —NH—. In one embodiment, W is a bond. In one embodiment, X is C ₁ -C ₄ alkyl. In one embodiment, X is phenyl. In one embodiment, X is 3-4 membered cycloalkyl C ₁ -C ₄ alkyl. In one embodiment, W is —O— and X is C ₁ -C ₄ alkyl. In one embodiment, W is —O— and X is phenyl. In one embodiment, W is —O— and X is 3-4 membered cycloalkyl C ₁ -C ₄ alkyl. In one embodiment, W is a bond and X is C1-C4 alkyl. In one embodiment, W is a bond and X is phenyl. In one embodiment, W is a bond and X is a 3-4 membered cycloalkyl C ₁ -C ₄ alkyl. In one embodiment, R ⁶ is CD3.

In one embodiment, the compound, or a pharmaceutically acceptable salt thereof, is selected from:

N- [3 - (1,4-dimethyl-6-oxopyr-idin-3-yl) phenyl] methanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) phenyl] methanesulfonamide;

N- [3 - (1,4,5-trimethyl-6-oxopyr-idin-3-yl) phenyl] methanesulfonamide;

- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one;

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M- [4- (2,4-difluorophenoxy) -3- (1,4-dimethyl-6-oxopyridin-3yl) phenyl] methanesulfonamide a;

X- [4- (2,4-Difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3yl) phenyl] methanesulfonamide a;

M- [4- (2,4-difluorophenoxy) -3- (1,4,5-trimethyl-6-oxopyridin-3yl) phenyl] methanesulfonamide a;

-amino-1-methyl-5 - (3-methyl sulfonylphenyl) pyrazin-2-one;

-amino-5 - (3-ethylsulfonylphenyl) -1-methylpyrazin-2-one;

X- [5- (6-amino-4-methyl-5-oxopyrazin-2-yl) -2-methoxyphenyl] methanesulfonamide;

-amino-1-methyl-5 - (3-methyl sulfonylphenyl) pyridin-2-one;

-amino-5 - (3-ethylsulfonylphenyl) -1-methylpyridin-2-one;

N- [5 - (5-amino-1-methyl-6-oxopyr-idin-3-yl) -2-methoxyphenyl] methanesulfonamide a;

X- [2-methoxy-5- [1-methyl-5- (methylamino) -6-oxopyridin-3yl] phenyl] methanesulfonamide a;

X- [5- [5- (ethylamino) -1-methyl-6-oxopyridin-3-yl] -2methoxyphenyl] methanesulfonamide a;

M- [5- [5- (cyclopropylmethylamino) -1-methyl-6-oxopyridin-3-yl] -2methoxyphenyl] methanesulfonamide a;

X- [5- [5- (dimethylamino) -1-methyl-6-oxopyridin-3-yl] -2methoxyphenyl] methanesulfonamide a;

X- [5- [5- (diethylamino) -1-methyl-6-oxopyridin-3-yl] -2methoxyphenyl] methanesulfonamide a;

M- [3- (5-amino-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide;

3-amino-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2one;

4-ethoxy-3 - (1-methyl-6-oxopyr-idin-3-yl) benzene sulfonamide;

4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide;

5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2one;

- [2- (2,4-d Ifluorophenoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one;

- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one;

6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,4-dimethylpyridazin-3-one: 6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,5-dimethylpyridazin-3-one:

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M- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (trifluoromethyl) pyridin-3yl] phenyl] ethanesulfonamide;

N- [4- (2,4-difluorophenoxy) -3 - (4-fluoro-1-methyl-6-oxopyr-idin-3 yl) phenyl] ethanesulfonamide;

N- [3 - (5-cyclopropyl-1-methyl-6-oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide;

N- {4- (2,4-difluorophenoxy) -3 - [1 - ( ² Hs) methyl-6-oxopyr-idin-3 yl] phenyl} ethanesulfonamide;

- [5 - (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3dimethylpyridin-2-one;

- [5 - (2,4-d ifluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -3-methoxy-1 methylpyridin-2-one;

- [5 - (2,4-d ifluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3dimethylpyridin-2-one;

- [5 - (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1,3-d-immethylpyridin2-one;

- [5 - (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3-methoxy-1 methylpyridin-2-one;

N- [5 - (cyclopropylmethoxy) -4- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimidin-2yl] methanesulfonamide a;

N- [5 - (cyclopropylmethoxy) -4- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimidin-2-yl] N-ethyl methanesulfonamide a;

N- [5 - (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimid in-2yl] methanesulfonamide a;

T4- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide a;

M- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide;

N- [5 - (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimide in-2yl] ethanesulfonamide;

[4- (cyclopropylmethoxy) -3 - (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] sulfamate;

M- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] Mmethylmethanesulfonamide;

M- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] -M- (oxetane-3yl) methanesulfonamide;

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- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1 - (cyclopropylmethyl) -3 methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3 -methyl-1 - (2methylpropyl) pyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1 - (2-methoxyethyl) -3 methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3 -methyl-1 - (oxetan-3 ylmethyl) pyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3-methyl-1- (1,3-oxazol-4ylmethyl) pyridin-2-one;

T \ T- [3- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide;

N- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] methanesulfonamide;

N- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4difluorophenoxy) pyrimidin-2-yl] ethanesulfonamide;

- (cyclopropylmethyl) -5 - [4- (2,4-difluorophenoxy) -1 - (methyl sulfonylmethyl) -6oxopyridin-3-yl] -3-methylpyridin-2-one;

1-cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3methylpyridin-2-one;

M- [4- (2,4-difluorophenoxy) -3- (5-fluoro-1-methyl-6-oxopyridin-3yl) phenyl] methanesulfonamide;

3-chloro-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one;

3-chloro-5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1-methylpyridin-2one;

- [2- (2,4-difluorophenoxy) -5 - (methanesulfonylmethyl) phenyl] -3 - ⁽² Hg) methyl-1--metil1,2 digidropir Idin-2-one;

N- [4- (2,4-difluorophenoxy) -3 - [5 - ( ² Hs) methyl-1-methyl-6-oxo-1,6-dihydropyrid in-3 yl] phenyl] methanesulfonamide;

N- [4- (2,4-difluorophenoxy) -3 - [5 - ( ² Hs) methyl-1-methyl-6-oxo-1,6-dihydropyrid in-3 yl] phenyl] ethane-1 -sulfonamide ;

N- [3 - (5-cyclopropyl-1-methyl-6-oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide;

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3-cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1methylpyridin-2-one;

K- [4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3yl) phenyl] methanesulfonamide a;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3-pyrrolidin-1 ylpyridin-2-one;

N- [4- (2,4-difluorophenoxy) -3 - (5-ethynyl-1-methyl-6-oxopyr-idin-3 yl) phenyl] ethanesulfonamide;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-ethynyl-1-methylpyr-idin-2 one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3-ethynyl-1-methylpyridin-2one;

N- [4- (2,4-difluorophenoxy) -3 - (5-ethynyl-1-methyl-6-oxopyr-idin-3 yl) phenyl] methanesulfonamide;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3 - (difluoromethoxy) -1 methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1 -methyl-3 - (2,2,2trifluoroethoxy) pyridin-2-one;

M- [3- [5- (difluoromethoxy) -1-methyl-6-oxopyridin-3-yl] -4- (2,4 difluorophenoxy) phenyl] ethanesulfonamide;

M- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (2,2,2-trifluoroethoxy) pyridin-3yl] phenyl] ethanesulfonamide;

- (difluoromethoxy) -5 - [2- (2,4-difluorophenoxy) -5 - (ethylsulfonylmethyl) phenyl] -1 methylpyridin-2-one;

- [2- (2,4-difluorophenoxy) -5 - (ethylsulfonylmethyl) phenyl] -1-methyl-3 - (2,2,2trifluoroethoxy) pyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1 -methyl-3 - (1-methylpyrazol-4yl) oxypyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1 -methyl-3 - (1-propan-2ylpyrazol-4-yl) oxypyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1 -methyl-3-phenoxypyridin-2one;

M- [4- (1-butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidine-2yl] methanesulfonamide;

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1C- [4- (1-butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidin-2yl] ethanesulfonamide;

N- [4- [l- (cyclobutylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4difluorophenoxy) pyrimidin-2-yl] methanesulfonamide;

K- [4- [1- (cyclobutylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4difluorophenoxy) pyrimidin-2-yl] ethanesulfonamide;

- (5-ethyl-2-methylsulfonylpyrimidin-4-yl) -1,3-dimethylpyridin-2-one;

1,3-dimethyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1,3-d-immethylpyridin-2-one;

N- [4- (1,5-dimethyl-6-oxopyr-idin-3-yl) -5-ethylpyrimidin-2-yl] ethanesulfonamide a;

N- [4- (1,5-dimethyl-6-oxopyr-idin-3-yl) -5-propylpyrimidin-2yl] ethanesulfonamide;

^ [5-butyl-4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide;

5- (2-ethyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one;

1-methyl-5- (5-methylsulfonyl-2-propylphenyl) pyridin-2-one;

- [2- (2-cyclopropylethyl) -5-methyl sulfonylphenyl] -1-methylpyridin-2-one;

5- (2-butyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one;

- [3 - [(4-methoxyphenyl) methoxy] -5-methyl sulfonylphenyl] -1,3-d-immethylpyridin-2one;

1,3-dimethyl-5- (3-methylsulfonyl-5-phenylmethoxyphenyl) pyridin-2-one;

5- [3- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

1,3-dimethyl-5- [3-methylsulfonyl-5- (2-phenylethoxy) phenyl] pyridin-2-one;

5- [3- (2-cyclopropylethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

1,3-dimethyl-5- [3-methylsulfonyl-5- (2,2,2-trifluoroethoxy) phenyl] pyridin-2-one;

1,3-d imethyl-5 - [3 - [(3-methyloxetane-3-yl) methoxy] -5-methyl sulfonylphenyl] pyridin2-one;

1,3-d imethyl-5 - [3-methylsulfonyl-5 - (pyridin-2-ylmethoxy) phenyl] pyridin-2-one;

5- [3 - [(2,6-dimethylphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2one;

5- [3 - [(2-chlorophenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

5- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5-methylsulfonylphenyl] -1,3dimethylpyridin-2-one;

- [[3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -5 methylsulfonylphenoxy] methyl] benzonitrile;

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- [3 - [(2,4-difluorophenyl) methoxy] -5-methyl sulfonylphenyl] -1,3-dimethylpyridin-2one;

1,3-dimethyl-5- [3-methylsulfonyl-5- (1-phenylethoxy) phenyl] pyridin-2-one;

5- [3 - [(2,3-dichlorophenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2one;

, 3-d imethyl-5 - [3-methylsulfonyl-5 - (pyridin-3-ylmethoxy) phenyl] pyridin-2-one;

- [[3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -5 methylsulfonylphenoxy] methyl] benzonitrile;

- (3-but-2-inoxy-5-methyl sulfonylphenyl) -1,3-dimethylpyridin-2-one;

1,3-dimethyl-5- [3-methylsulfonyl-5- (1-phenylethoxy) phenyl] pyridin-2-one;

Y- [3- (2,4-difluorophenoxy) -5- (1,5-dimethyl-6-oxopyridin-3yl) phenyl] ethanesulfonamide;

- [3 - [(4-methoxyphenyl) methoxy] -5-methyl sulfonylphenyl] -2-methylisoquinolin-1 one;

2-methyl-4- (3-methylsulfonyl-5-phenylmethoxyphenyl) isoquinolin-1-one;

4- [3- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one;

N - [4- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimide in-2yl] ethanesulfonamide;

N - [2- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyr-idin-3-yl) pyrimide in-4yl] ethanesulfonamide;

1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1-methylpyridin-2-one;

3-chloro-1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-chloro-1-methylpyridin-2-one;

3-methoxy-1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-methoxy-1-methylpyridin-2-one; N- [4- (1-methyl-6-oxopyrid-3-yl) -5-propylpyrimidin-2-yl] ethanesul phonamide a; Y- [5-butyl-4- (1-methyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide;

N - [4- (5-chloro-1-methyl-6-oxopyr-idin-3-yl) -5-propyl pyrimide in-2yl] ethanesulfonamide;

N - [5-butyl-4- (5-chloro-1-methyl-6-oxopyr-idin-3-yl) pyrimide in-2yl] ethanesulfonamide;

N - [4- (5-methoxy-1-methyl-6-oxopyr-idin-3-yl) -5-propylpyrimidin-2yl] ethanesulfonamide;

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N- [5-butyl-4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide;

N- [5-butyl-4- (1,5-dimethyl-6-oxopyrid in-3-yl) pyrimid in-2yl] methanesulfonamide a;

5- (2-but-2-inoxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one;

5- (2-but-2-inoxy-5-ethylsulfonylphenyl) -3-methoxy-1-methylpyridin-2-one;

- (5-ethylsulfonyl-2-pent-2-inoxyphenyl) -3-methoxy-1-methylpyridin-2-one;

5- [2- (3-cyclopropylprop-2-inoxy) -5-ethylsulfonylphenyl] -3-methoxy-1methylpyridin-2-one;

- [2- (2,4-d Ifluorophenoxy) -5-ethylsulfonylphenyl] -1 -methyl-3 (trifluoromethyl) pyridin-2-one;

- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -1,3-dimethylpyridin-2one;

X- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -5-phenylmethoxyphenyl] ethanesulfonamide;

- [2- (2,4-difluoroanilino) -5-ethylsulfonylphenyl] -1,3-d-immethylpyridin-2-one;

- [2 - [(4,4-difluorocyclohexyl) amino] -5-ethylsulfonylphenyl] -1,3-d-immethylpyrid in2-one;

- [2- (2,4-difluoroanilino) -5-methyl sulfonylphenyl] -1,3-dimethylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-methoxy-1-methylpyridin-2one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -3-methoxy-1 methylpyridin-2-one;

- [2- (4-hydroxycyclohexyl) oxy-5-methyl sulfonylphenyl] -1,3-d-immethylpyridin-2one;

X- [4- (2,4-Difluorophenoxy) -3- (1-methyl-5-methylsulfanyl-6-oxopyridin-3yl) phenyl] ethanesulfonamide;

- [2- (4-aminocyclohexyl) oxy-5-methyl sulfonylphenyl] -1,3-dimethylpyridin-2one;

1,3-dimethyl-5- [5-methylsulfonyl-2- (3,3,3-trifluoropropoxy) phenyl] pyridin-2-one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -1 - (2-hydroxyethyl) -3 methylpyridin-2-one;

5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1- (2-hydroxyethyl) -3methylpyridin-2-one;

- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1 -methyl-3 (methylamino) pyridin-2-one;

- 9 038715

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1 -methyl-3 (methylamino) pyridin-2-one;

N- [4- (2,4-difluorophenoxy) -3 - [1-methyl-5 - (methylamino) -b-oxopyr-idin-3 yl] phenyl] ethanesulfonamide;

- [5 - (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1,3-d-immethylpyr-idin-2 one;

N- [4- (2,4-difluorophenoxy) -3 - [1 -methyl-5 - (methylamino) b-oxopyridin-3 yl] phenyl] methanesulfonamide a;

- [2 - [(4,4-difluorocyclohexyl) amino] -5-methyl sulfonylphenyl] -1,3dimethylpyridin-2-one;

- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -3-methoxy-1-methylpyridin2-one;

- [2- (4,4-difluorocyclohexyl) oxy-5-methyl sulfonylphenyl] -1,3-d-immethylpyr-idin-2one;

- [2- (cyclopentylamino) -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

- [2- (cyclopentylamino) -5-methyl sulfonylphenyl] -1,3-d-immethylpyridin-2-one;

3-chloro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridin-2-one;

- (2-cyclopentyloxy-5-methyl sulfonylphenyl) -1,3-d-immethylpyr-idin-2-one;

1,3-d imethyl-5 - [5-methyl sulfonyl-2- (oxan-4-yloxy) phenyl] pyridin-2-one;

3-fluoro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridin-2-one;

5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -1,4-dimethylpyridin-2one;

5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1,4-dimethylpyridin-2-one;

1,3-dimethyl-5- [5-methylsulfonyl-2- (oxolan-3-ylamino) phenyl] pyridin-2-one;

1,3-dimethyl-5- [5-methylsulfonyl-2- (oxolan-3-yloxy) phenyl] pyridin-2-one;

1,3-dimethyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] pyridin-2one;

- [2- (cyclopropylmethylamino) -5-methyl sulfonylphenyl] -1-ethyl-3-methylpyridin-2one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -1-ethyl-3-methylpyridin2-one;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (4hydroxycyclohexyl) oxyphenyl] ethanesulfonamide;

- 10 038715

Ν- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (4hydroxycyclohexyl) oxyphenyl] methanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (4hydroxycyclohexyl) oxyphenyl] methanesulfonamide;

1,3-d imethyl-5 - [5-methyl sulfonyl-2- (oxane-4-ylamino) phenyl] pyrid-in-2-one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -3-fluoro-1-methylpyridin · 2-one;

- [2- (cyclopropylmethylamino) -5-methyl sulfonylphenyl] -3 - (dimethylamino) -1 methylpyridin-2-one;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxane-4yloxy) phenyl] methanesulfonamide a;

- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -3 - (dimethylamino) -1 methylpyridin-2-one;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxane-4yloxy) phenyl] ethanesulfonamide;

N- [4- (2,4-difluorophenoxy) -3 - (5-methoxy-1-methyl-6-oxopyrid-3 yl) phenyl] methanesulfonamide a;

N- [4- (2,4-difluorophenoxy) -3 - (5-methoxy-1-methyl-6-oxopyrid-3 yl) phenyl] ethanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxolan-3 yloxy) phenyl] methanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxolan-3 yloxy) phenyl] ethanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxane-3 yloxy) phenyl] methanesulfonamide;

N- [4- (4,4-difluorocyclohexyl) oxy-3 - (1,5-dimethyl-6-oxopyrid in-3 yl) phenyl] methanesulfonamide a;

N- [3 - (1,5-dimethyl-6-oxopyr-idin-3-yl) -4- (oxane-3 yloxy) phenyl] ethanesulfonamide;

N- [4- (4,4-difluorocyclohexyl) oxy-3 - (1,5-dimethyl-6-oxopyrid in-3 yl) phenyl] ethanesulfonamide;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

N- [4- (2,4-difluorophenoxy) -3 - (5-hydroxy-1-methyl-6-oxopyr-idin-3 yl) phenyl] ethanesulfonamide;

- 11 038715

4- (cyclopropylmethylamino) -3 - (1,5-dimethyl-6-oxopyr-idin-3 yl) benzenesulfonamide;

4- (cyclopropylmethylamino) -3 - (1-methyl-6-oxopyr-idin-3-yl) benzenesulfonamide;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -1,4-dimethylpyr-idin-2 one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -1,3-d-immethylpyr-idin-2one;

- (2-ethoxy-5-ethyl sulfonylphenyl) -1 - ( ² Hs) methyl-4-methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5 -etilsulfonilfenil] -1 - ⁽² Hg) methyl-4-metilpiridin2-one;

5- (2-ethoxy-5-ethylsulfonylphenyl) -1,4-dimethylpyridin-2-one;

- [2- (cyclobutylmethoxy) -5-methyl sulfonylphenyl] -1,3-d-immethylpyridin-2-one;

- [2- (cyclobutylmethoxy) -5-methyl sulfonylphenyl] -1-methylpyrid in-2-one;

- (5-ethylsulfonyl-2-methoxyphenyl) -3-hydroxy-1-methylpyrid in-2-one;

- [2- (cyclopropylmethylamino) -5-methyl sulfonylphenyl] -1,3-d-immethylpyridin-2one;

X- [4- (2,4-difluorophenoxy) -3- [5- (dimethylamino) -1-methyl-6-oxopyridin-3yl] phenyl] methanesulfonamide a;

N- [4- (2,4-difluorophenoxy) -3 - [5- (dimethylamino) -1-methyl-6-oxopyr-idin-3yl] phenyl] ethanesulfonamide;

- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1,3-d-immethylpyr-idin-2-one;

- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1,4-dimethylpyridin-2-one;

N- [3- (5-hydroxy-1-methyl-6-oxopyr-idin-3-yl) phenyl] methanesulfonamide;

- [2- (cyclopropylmethylamino) -5-methyl sulfonylphenyl] -1-methylpyridin-2-one;

3- (dimethylamino) -5- (2-ethoxy-5-ethylsulfonylphenyl) -1-methylpyridin-2-one;

- [2- (2,4-difluorophenoxy) -5 - (methyl sulfonylmethyl) phenyl] -1-methylpyridin-2-one;

X- [3- (1-methyl-6-oxo-5-phenylmethoxypyridin-3-yl) phenyl] methanesulfonamide;

X- [4- (2,4-Difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3yl) phenyl] ethanesulfonamide;

- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3 - (dimethylamino) -1 methylpyridin-2-one;

- [4-fluoro-2-methoxy-5 - (methyl sulfonylmethyl) phenyl] -1-methylpyridin-2-one;

5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one;

- [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -1,4-dimethylpyridin-2-one;

- 12 038715

X- [6- [3- (methanesulfonamido) phenyl] -4-methyl-3-oxopyrazin-2-yl] acetamide;

Ν- [3 - (1,4-dimethyl-6-oxopyridazin-3-yl) phenyl] ethanesulfonamide;

N- [3 - (1,5-dimethyl-6-oxopyrid azin-3-yl) phenyl] ethanesulfonamide;

X- [5- [3- (methanesulfonamido) phenyl] -1-methyl-2-oxopyridin-3-yl] propanamide;

X- [5- [3- (methanesulfonamido) phenyl] -1-methyl-2-oxopyridin-3-yl] acetamide;

-cyclobutyl-5 - [2- (cyclopropylmethoxy) -5-methyl sulfonylphenyl] -3 methylpyridin-2-one;

X- [3- (1-cyclobutyl-5-methyl-6-oxopyridin-3-yl) -4- (2,4 difluorophenoxy) phenyl] methanesulfonamide;

1-benzyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin-2one;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-methyl-1-propan-2-ylpyr-idin-2 one;

N- [5- (2,4-difluorophenoxy) -4- (5-methyl-6-oxo-1-propan-2-ylpyridin-3yl) pyrimidin-2-yl] ethanesulfonamide;

- [5 - (2,4-d ifluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3-methyl-1-propan-2ylpyridin-2-one;

T4- [5-butyl-4- (5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl) pyrimidin-2yl] ethanesulfonamide;

X- [5-butyl-4- (1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl) pyrimidin-2yl] ethanesulfonamide;

- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1-methyl-3-propan-2-ylpyr-idin-2 one;

X- [5- (2,4-difluorophenoxy) -4- (1-methyl-6-oxo-5-propan-2-ylpyridin-3yl) pyrimidin-2-yl] ethanesulfonamide; or

- [5 - (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1-methyl-3-propan-2ylpyridin-2-one.

One embodiment relates to a pharmaceutical composition comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In one embodiment, the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma.

One embodiment of the invention relates to a method for regulating gene transcription in a cell, comprising exposing a compound of formula (II) to a bromodomain-containing protein.

One embodiment of the invention relates to a method for regulating gene transcription in a cell, comprising exposing a compound of formula (II) to a bromodomain-containing protein.

One embodiment of the invention relates to a method of inhibiting the bromodomain-mediated recognition of the acetyllysine region of a protein, comprising exposing the bromodomain to a compound of formula (II).

One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to said patient a compound of formula (II) or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma.

Inclusion by reference

All publications, patents and patent applications mentioned in this description are incorporated by reference to the same extent as if each individual publication, patent or patent application were specifically and individually indicated as incorporated by reference.

Detailed description of the invention

As used herein and in the appended claims, the singular includes the plural, unless the context clearly indicates otherwise. Thus, for example, reference to the term agent includes many such agents, and reference to the term cell includes reference to one or more cells (or multiple cells) and their equivalents known to those skilled in the art, and so on. Where ranges are used throughout this application to describe physical properties such as molecular weight or chemical properties such as chemical formulas, all combinations and sub-combinations of the ranges and

- 13 038715 specific corresponding embodiments of the invention. The term about, when referring to a number or numerical range, means that the said number or numerical range is approximate within the experimental variability (or within the statistical error of the experiment), and thus the number or numerical range can range from 1 to 15 % of a specified number or range of numeric values. The term containing (and related terms such as contains or contains, or having or including) is not intended to be excluded in some other embodiments, for example, an embodiment of any chemical compound, composition, technique or method or the like described herein document may include or essentially consist of the described features.

Definitions.

Used in the present description and the appended claims, the following terms have the meanings indicated below, unless otherwise indicated.

Amino refers to the -NH2 radical.

Cyano refers to the -CN radical.

Nitro refers to the -NO2 radical.

Oxa refers to the -O- radical.

Oxo refers to the = O radical.

Thioxo refers to the = S radical.

Imino refers to the = N-H radical.

Oximo refers to the = N-OH radical.

Hydrazino refers to the = N-NH2 radical.

Alkyl refers to a straight or branched chain radical of only carbon and hydrogen atoms, not containing unsaturated bonds and having from one to fifteen carbon atoms (eg, C ₁ -C ₁₅ -alkyl). In some embodiments, alkyl contains from one to thirteen carbon atoms (eg, C ₁ -C _{1 3} -alkyl). In some embodiments, alkyl has one to eight carbon atoms (eg, C ₁ -C ₈ alkyl). In other embodiments, alkyl has one to five carbon atoms (eg, C ₁ -C ₅ alkyl). In other embodiments, alkyl has one to four carbon atoms (eg, C ₁ -C ₄ alkyl). In other embodiments, alkyl has one to three carbon atoms (eg, C ₁ -C ₃ alkyl). In other embodiments, alkyl contains one to two carbon atoms (eg, C1-C2 alkyl). In other embodiments, alkyl contains one carbon atom (eg, C ₁ alkyl). In other embodiments, alkyl contains from five to fifteen carbon atoms (eg, C ₅ C ₁₅ alkyl). In other embodiments, alkyl has five to eight carbon atoms (eg, C ₅ -C ₈ alkyl). In other embodiments, alkyl has two to five carbon atoms (eg, C ₂ -C ₅ alkyl). In other embodiments, alkyl contains three to five carbon atoms (eg, C ₃ -C ₅ alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl) , 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). Alkyl is attached to the rest of the molecule by a single bond. Unless specifically indicated otherwise in the description, the alkyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC (O) -R ^a , -N (R ^a ) 2, -C (O) R ^a , -C (O) OR ^a , -C (O) N (R ^a ) 2, -N (R ^a ) C (O) OR ^a , -OC (O) -N (R ^a ) 2, -N (R ^a ) C (O) R ^a , -N (R ^a ) S (O) tR ^a (where t is 1 or 2), - S (O) tOR ^a (where t is 1 or 2), -S (O) tR ^a (where t is 1 or 2) and -S (O) tN (R ^a ) ₂ (where t is 1 or 2) where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, methoxy, hydroxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl ylom), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) methoxy or trifluoromethyl).

Alkoxy refers to a radical attached through an oxygen atom of the formula —O-alkyl, where alkyl is an alkyl chain as defined above.

Alkenyl refers to a straight or branched chain radical group of only carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from one to twelve carbon atoms. In some embodiments, alkenyl contains two to eight carbon atoms. In other embodiments, alkenyl contains two to four carbon atoms. Alkenyl is attached to the rest of the molecule with a single bond, for example, ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1,4 -dienyl and the like Unless specifically indicated otherwise in the description, an alkenyl group is optionally substituted with one or

- 14 038715 more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC (O) -R ^a , -N (R ^a ) 2, - C (O) R ^a , -C (O) OR ^a , -C (O) N (R ^a ) 2, -N (R ^a ) C (O) OR ^a , -OC (O) -N (R ^a ) 2, -N (R ^a ) C (O) R ^a , -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -S (O) tOR ^a (where t is 1 or 2), -S (O) tR ^a (where t is 1 or 2) and -S (O) tN (R ^a ) 2 (where t is 1 or 2), where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or tri fluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

Alkynyl refers to a straight or branched chain radical group of only carbon and hydrogen atoms containing at least one carbon-carbon triple bond having from one to twelve carbon atoms. In some embodiments, alkynyl contains two to eight carbon atoms. In other embodiments, alkynyl contains two to four carbon atoms. Alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless specifically indicated otherwise in the description, an alkynyl group is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC (O) -R ^a , -N (R ^a ) 2, -C (O) R ^a , -C (O) OR ^a , -C (O) N (R ^a ) 2, -N (R ^a ) C (O) OR ^a , -OC (O) -N (R ^a ) 2, -N (R ^a ) C (O) R ^a , -N (R ^a ) S (O) tR ^a (where t is 1 or 2), - S (O) tOR ^a (where t is 1 or 2), -S (O) tR ^a (where t is 1 or 2) and -S (O) tN (R ^a ) 2 (where t is 1 or 2) where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, methoxy, hydroxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluorome thyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl methoxy or trifluoromethyl).

The term alkylene or alkylene chain refers to a straight or branched bivalent hydrocarbon chain connecting the rest of the molecule to a radical group consisting only of carbon and hydrogen atoms, free of unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, n-butylene and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and the radical group can pass through one carbon atom in the alkylene chain or through any two carbon atoms in the chain. In some embodiments, alkylene contains one to eight carbon atoms (eg, Ci-C ₈ alkylene). In other embodiments, alkylene contains one to five carbon atoms (eg, C ₁ -C ₅ alkylene). In other embodiments, alkylene contains one to four carbon atoms (eg, C ₁ -C 4 alkylene). In other embodiments, alkylene contains one to three carbon atoms (eg, C ₁ -C 3 alkylene). In other embodiments, alkylene contains one to two carbon atoms (eg, C ₁ -C ₂ alkylene). In other embodiments, alkylene contains one carbon atom (eg, C ₁ alkylene). In other embodiments, alkylene contains five to eight carbon atoms (eg, C ₅ -C 8 alkylene). In other embodiments, alkylene contains two to five carbon atoms (eg, C ₂ -C ₅ alkylene). In other embodiments, alkylene contains three to five carbon atoms (eg, C ₃ -C ₅ alkylene). Unless specifically indicated otherwise in the description, the alkylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC (O) -R ^a , -N (R ^a ) 2, -C (O) R ^a , -C (O) OR ^a , -C (O) N (R ^a ) 2, -N (R ^a ) C (O) OR ^a , -OC (O) -N (R ^a ) 2, -N (R ^a ) C (O) R ^a , -N (R ^a ) S (O) tR ^a (where t is 1 or 2), - S (O) tOR ^a (where t is 1 or 2), -S (O) tR ^a (where t is 1 or 2) and -S (O) tN (R ^a ) 2 (where t is 1 or 2) where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, methoxy, hydroxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl sc), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), hetero-15 038715 ryl (optionally substituted with halogen (optionally substituted with hetero-, hydroxy, methoxy, or trifluoromethyl) halogen, hydroxy, methoxy or trifluoromethyl).

The term alkynylene or alkynylene chain refers to a straight or branched bivalent hydrocarbon chain connecting the remainder of the molecule to a radical group consisting of only carbon and hydrogen atoms containing at least one carbon-carbon triple bond and having from one to twelve carbon atoms. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In some embodiments, alkynylene contains two to eight carbon atoms (eg, C ₂ -C ₈ alkynylene). In other embodiments, alkynylene contains two to five carbon atoms (eg, C ₂ -C 5 alkynylene). In other embodiments, alkynylene contains two to four carbon atoms (eg, C ₂ -C 4 alkynylene). In other embodiments, alkynylene contains two to three carbon atoms (eg, C ₂ -C 3 alkynylene). In other embodiments, alkynylene contains two carbon atoms (eg, C ₂ alkynylene). In other embodiments, alkynylene contains five to eight carbon atoms (eg, C ₅ -C ₈ alkynylene). In other embodiments, alkynylene contains two to five carbon atoms (eg, C ₂ -C ₅ alkynylene). In other embodiments, alkynylene contains three to five carbon atoms (eg, C ₃ -C ₅ alkynylene). Unless specifically indicated otherwise in the description, the alkynylene chain is optionally substituted with one or more of the following substituents: halogen, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC (O) -R ^a , -N (R ^a ) 2, -C (O) R ^a , -C (O) OR ^a , -C (O) N (R ^a ) 2, -N (R ^a ) C (O) OR ^a , -OC (O) -N (R ^a ) 2, -N (R ^a ) C (O) R ^a , -N (R ^a ) S (O) tR ^a (where t is 1 or 2), - S (O) _t OR ^a (where t is 1 or 2), -S (O) tR ^a (where t is 1 or 2) and -S (O) tN (R ^a ) ₂ (where t is 1 or 2), where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy methoxy or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluo pmethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroaryl (optionally substituted with halogen, optionally substituted with halogen, hydroxy, hydroxy, or trifluoromethyl methoxy or trifluoromethyl).

The term aryl refers to a radical formed from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and five to eight carbon atoms, where at least one of the rings in the ring system is completely unsaturated, i. E. it contains a cyclic delocalized (4n + 2) π-electron system in accordance with the Hückel theory. The ring system from which the aryl groups are derived includes, but is not limited to, groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically indicated otherwise in the description, the term aryl or the prefix ar- (such as in aralkyl) is intended to include aryl radicals independently substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a, -R ^b -OC (O) -R ^a , -R ^b -OC (O) -OR ^a , -R ^b -OC (O) N (R ^a ) 2, -R ^b -N (R ^a ) 2, -R ^b -C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c -C (O) N (R ^a ) 2, -R ^b -N (R ^a ) C (O) OR ^a , -R ^b N (R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tOR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) 2 (where t is 1 or 2), where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl, optionally hydroxy), aryl or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxymethyloxy, or trifluoromethyl) , methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R ^{b is} independently direct a bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

The term aralkyl refers to a radical of the formula —R ^c —aryl, where R ^c is an alkylene chain as defined above, for example methylene, ethylene and the like. Alkylene chain of aralkyl radical

- 16 038715 is optionally substituted as described above for the alkylene chain. The aryl moiety of the aralkyl radical is optionally substituted as described above for the aryl group.

The term aralkenyl refers to a radical of the formula —Rd-aryl, where R ^d is an alkenylene chain as defined above. The aryl moiety of the aralkenyl radical is optionally substituted as described above for the aryl group. The alkenylene chain of the aralkenyl radical is optionally substituted as defined above for the alkenylene group.

The term aralkynyl refers to a radical of the formula —R ^e -aryl, where R ^e is an alkynylene chain as defined above. The aryl moiety of the aralkynyl radical is optionally substituted as described above for the aryl group. The alkynylene chain of the aralkynyl radical is optionally substituted as defined above for the alkynylene chain.

The term aralkoxy refers to a radical attached through an oxygen atom of the formula —OR ^c —aryl, where R ^c is an alkylene chain as defined above, for example methylene, ethylene and the like. The alkylene chain of the aralkyl radical is optionally substituted as described above for the alkylene chain. The aryl moiety of the aralkyl radical is optionally substituted as described above for the aryl group.

The term carbocyclyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical of only carbon and hydrogen atoms, which includes fused or bridged ring systems of three to fifteen carbon atoms. In some embodiments, the carbocyclyl contains three to ten carbon atoms. In other embodiments, the carbocyclyl contains five to seven carbon atoms. Carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl can be saturated (i.e., containing only C-C single bonds) or unsaturated (i.e., containing one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as cycloalkyl. Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyl is also referred to as cycloalkenyl. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo [2.2.1] heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo [2.2.1] heptanyl, and the like. Unless otherwise specifically indicated in the description, the term carbocyclyl is intended to include carbocyclyl radicals that are optionally substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} -OC (O ) -R ^a , -R ^b -OC (O) -OR ^a , -R ^b -OC (O) -N (R ^a ) 2, -R ^b -N (R ^a ) 2, -R ^b -C ( O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c C (O) N (R ^a ) 2, -R ^b -N (R ^a ) C (O) OR ^a , -R ^b -N (R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b S (O) tR ^a (where t is 1 or and 2), -R ^b -S (O) tOR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) 2 (where t is 1 or 2), where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclylalkyloxy (optionally substituted with halogen), heterocyclylalkyloxy (optionally substituted with halogen) heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R ^b independently represents co a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

The term carbocyclylalkyl refers to a radical of the formula —R ^c —carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

Carbocyclylalkoxy refers to a radical attached through an oxygen atom of the formula —O — R ^c —carbocyclyl, wherein R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

The term carbocyclylalkynyl refers to a radical of the formula —R ^c —carbocyclyl, where R ^c is an alkynylene chain as defined above. The carbocyclyl moiety of the carbocyclylalkynyl radical is optionally substituted as defined above for the carbocyclyl group. In some embodiments, the carbocyclyl group is cycloalkyl

- 17 038715 group. The alkynylene moiety of the carbocyclylalkynyl radical chain is optionally substituted as defined above for the alkynylene chain.

As used herein, a carboxylic acid bioisoster refers to a functional group or moiety that exhibits similar physical, biological and / or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

etc.

Halo or halogen refers to the substituents bromine, chlorine, fluorine or iodine.

Fluoroalkyl refers to an alkyl radical as defined above which is substituted with one or more fluorine radicals as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl portion of the fluoroalkyl radical may optionally be substituted as defined above for the alkyl group.

Heterocyclyl refers to a stable 3 to 18 membered non-aromatic ring radical that contains two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the description, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Heteroatoms in a heterocyclyl radical can optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. Heterocyclyl can be attached to the rest of the molecule through an atom of the ring (s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl [1,3] dithianil, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, 2 octahydroliperinyl-2 , piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxothiomorpholinoxothiomorphol. Unless specifically indicated otherwise in the description, the term heterocyclyl is intended to include heterocyclyl radicals as defined above, which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted ^{heteroarylalkyl, -R b -OR a, -R b} - OC (O) -R ^a , -R ^b -OC (O) -OR ^a , -R ^b OC (O) -N (R ^a ) 2, -R ^b -N (R ^a ) 2, -R ^b - C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c -C (O) N (R ^a ) 2 , -R ^b N (R ^a ) C (O) OR ^a , -R ^b -N (R ^a ) C (O) R ^a , -R ^b -N (R ^a ) S (O) tR ^a (where t has the values 1 or 2), -R ^b -S (O) tR ^a (where t has s values 1 or 2), -R ^b -S (O) _t OR ^a (where t is 1 or 2) and -R ^b -S (O) tN (R ^a ) 2 (where t is 1 or 2) where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or , aryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heterocyclyl (optionally substituted with haloxyloxy) trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl) or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R ^b independently n is a direct bond, or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

N-heterocyclyl or N-attached heterocyclyl refers to a heterocyclyl radical as defined above containing at least one nitrogen atom and in which the point of attachment of the heterocyclyl radical to the remainder of the molecule passes through the nitrogen atom in the heterocyclyl radical. The N-heterocyclyl radical is optionally substituted as defined above for heterocyclyl radicals. Examples of such N-heterocyclyl radicals include, but

- 18 038715 are not limited to them, 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl and imidazolidinyl.

C-heterocyclyl or C-attached heterocyclyl refers to a heterocyclyl radical as defined above containing at least one heteroatom and in which the point of attachment of the heterocyclyl radical to the remainder of the molecule passes through the carbon atom in the heterocyclyl radical. The C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

Heterocyclylalkyl refers to a radical of the formula —R ^c —heterocyclyl, where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical on the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for the heterocyclyl group.

Heterocyclylalkoxy refers to a radical attached through an oxygen atom of the formula O — R ^{c is} heterocyclyl, wherein R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical on the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heterocyclyl moiety of the heterocyclylalkoxy radical is optionally substituted as defined above for the heterocyclyl group.

Heteroaryl refers to a radical formed from a 3- to 18-membered aromatic ring radical that contains from two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one of the rings in the ring system is completely unsaturated, i. E. it contains a cyclic delocalized (4n + 2) π-electron system in accordance with the Hückel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom (s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryl is attached to the rest of the molecule through a ring atom (s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo [d] thiazolyl, benzothiadiazolyl, benzo [b] [1,4] dioxepinyl, benzo [b] [1,4] oxazinyl, 1,4benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolil, benzodioxinil, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno [3,2d] pyrimidinyl, benzotriazo 1,2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidinyl, 5,6-dihydrobenzo [I] quinazolinyl, 5,6-dihydrobenzo [I] cinnolinyl, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo [3,2- c] pyridinyl, 5,6,7,8,9,10hexahydrocycloocta [d] pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta [d] pyridazinyl, 5,6,7,8,9,10hexahydrocycloocta [ d] pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindoles l, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6 7,8,9,10,10a-octahydrobenzo [b] quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinil, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo [3,4d] pyrimidinyl, pyridinyl pyrido [3,2-d] pyrimidinyl, pyrido [3,4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinyl 6,7,8-tetrahydrobenzo [4,5] thieno [2,3-d] pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidinyl, 5,6,7,8-tetrahydropyrido [4,5с] pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno [2,3-d] pyrimidinyl, thieno [3,2-d] pyrimidinyl, thieno [2, 3-c] pyridinyl and thiophenyl (i.e. thienyl). Unless specifically indicated otherwise in the description, the term heteroaryl is intended to include heteroaryl radicals as defined above, which are optionally substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano , nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a, -R ^b -OC (O) -R ^a , -R ^b -OC (O) -OR ^a , -R ^b -OC (O) -N (R ^a ) 2, -R ^b -N (R ^a ) 2 , -R ^b -C (O) R ^a , -R ^b -C (O) OR ^a , -R ^b -C (O) N (R ^a ) 2, -R ^b -OR ^c -C (O) N (R ^a ) 2, -R ^b -N (R ^a ) C (O) OR ^a , -R ^b -N (R ^a ) C (O) R ^a , -R ^b N (R ^a ) S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tR ^a (where t is 1 or 2), -R ^b -S (O) tOR ^a (where t

- 19 038715 is 1 or 2) and -R ^b -S (O) tN (R ^a ) ₂ (where t is 1 or 2), where each R ^{a is} independently hydrogen, alkyl (optionally substituted with halogen, hydroxy , methoxy or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, trifluoro, methyloxy substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), heteroarylogeno (optionally substituted with hydroxy) (optionally substituted with halogen, hydroxy, methoxy or trifluoromethyl), each R ^{b is} independently a direct bond , or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted, unless otherwise indicated.

N-heteroaryl refers to a heteroaryl radical as defined above containing at least one nitrogen atom and where the point of attachment of the heteroaryl radical to the remainder of the molecule passes through the nitrogen atom in the heteroaryl radical. The N-heteroaryl radical is optionally substituted as defined above for heteroaryl radicals.

C-heteroaryl refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the remainder of the molecule passes through the carbon atom in the heteroaryl radical. The C-heteroaryl radical is optionally substituted as defined above for heteroaryl radicals.

Heteroarylalkyl refers to a radical of the formula —R ^c —heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical via a nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkyl radical is optionally substituted as defined above for the heteroaryl group.

Heteroarylalkoxy refers to a radical attached through an oxygen atom of the formula —OR ^c —heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical via a nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for the alkylene chain. The heteroaryl moiety of the heteroarylalkoxy radical is optionally substituted as defined above for the heteroaryl group.

The compounds described herein can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R) - or (S) -. Unless otherwise indicated, all stereoisomeric forms of the compounds described herein are intended to be contemplated herein. When compounds described herein contain alkene double bonds, and unless otherwise indicated, the specification is intended to include both E and Z geometric isomers (eg, cis or trans). Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term geometric isomer refers to the E or Z geometric isomers (eg, cis or trans) alkene double bond. The term positional isomer refers to structural isomers around the central ring, such as ortho, meta, and para isomers around the benzene ring.

The term tautomer refers to a molecule in which a proton shift from one atom of the molecule to another atom of the same molecule is possible. The compounds provided herein may, in some embodiments, exist as tautomers. In cases where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of tautomers depends on several factors, including physical condition, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

- 20 038715

The term optional or optional means that the event or condition described hereinafter may or may not occur, and that the description includes cases where the event or condition occurs and cases in which it does not. For example, optionally substituted aryl means that the aryl radical may or may not be substituted, and that the disclosure includes both substituted aryl radicals and aryl radicals having no substituent.

The term pharmaceutically acceptable salt includes both acid addition and base addition salts. A pharmaceutically acceptable salt of any of the substituted heterocyclic derivatives of the compounds described herein is intended to encompass any and all forms of pharmaceutically acceptable salts. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

The term pharmaceutically acceptable acid addition salts refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed by inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid and the like. Also included are salts which are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyl alkanoic acids, alkanedionic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., and include, for example , acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid acid, p-toluenesulfonic acid, salicylic acid and the like. Salts exemplified thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprates, oxides, isobuty malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, etc. Also contemplated are salts of amino acids such as arginates, gluconates and galacturonates (see, for example, Berge S. M. et al., Pharmaceutical Salts, Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds can be prepared by reacting the free base forms with a sufficient amount of the desired acid to form the salt according to methods and procedures familiar to one of ordinary skill in the art.

The term pharmaceutically acceptable base addition salt refers to those salts that retain the biological effectiveness and properties of the free acids that are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the 33 free acid. Pharmaceutically acceptable base addition salts can be formed by metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N, N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine diamine, ethylucamine theobromine, pu-21 038715 rines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. See Berge et al., Supra.

Used in the present description, the terms treat or treat, or temporarily alleviate or reduce the intensity of the symptoms of a disease are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results, including, but not limited to, therapeutic effect and / or prophylactic effect. The term therapeutic effect refers to the elimination or weakening of the symptoms of the underlying disease being treated. In addition, the therapeutic effect is achieved by eliminating or ameliorating one or more physiological symptoms associated with the underlying disorder, whereby an improvement is observed in the patient, although the patient may still be suffering from the underlying disorder. For prophylactic treatment, the compositions can be administered to a patient at risk of developing a particular disease, or to a patient complaining of one or more physiological symptoms of a disease, even if the disease may not have been diagnosed.

The term prodrug is intended to mean a compound that can be converted under physiological conditions or by solvolysis to the biologically active compound described herein. Thus, the term prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable. The prodrug may be inactive when administered to a subject, but is converted in vivo to the active compound, for example, by hydrolysis. A prodrug compound often provides advantages in solubility, tissue compatibility, or sustained release in a mammal (see, eg, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 Elsevier, Amsterdam).

For a discussion of prodrugs, see Higuchi, T., et al., Pro-drugs as Novel Delivery Systems, A.C.S. Symposium Series, vol. 14, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

The term prodrug is also intended to include any covalently linked carriers that release the active compound in vivo when such a prodrug is administered to a mammal. Prodrugs of an active compound, as described herein, can be prepared by modifying functional groups present on the active compound such that the modifications are cleaved either by routine manipulation or in vivo to the parent active compound. Prodrugs include compounds in which a hydroxyl, amino, or mercapto group is bonded to any group that, when a prodrug of an active compound is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol or amine functional groups in active compounds and the like.

Unless otherwise indicated, the structures depicted herein are intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures shown, with the exception of replacing hydrogen with deuterium or tritium, or replacing carbon with ¹³ C or ¹⁴ C enriched carbon, are within the scope of the present invention.

The compounds of the present invention optionally contain unusual proportions of atomic isotopes of one or more of the atoms forming such compounds. For example, compounds can be labeled with isotopes such as, for example, deuterium ( ² H), tritium ( ³ H), iodine-125 ( ¹²⁵ I), or carbon-14 ( ¹⁴ C). All isotopic substitutions are considered ² H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ O, ¹⁷ O, ¹⁴ F, ¹⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ Cl, ³⁷ Cl, ⁷⁹ Br, ⁸¹ Br, ¹²⁵ I. All isotopic variants of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.

In certain embodiments, the compounds described herein, some or all of the atoms are replaced 1H atoms ² H. Methods for synthesis of deuterium-substituted derivatives of heterocyclic compounds are known in the art and include, but only as a non-limiting example, the following synthesis methods.

Deuterated starting materials are readily available and are subject to the synthetic methods described herein to prepare deuterium-containing substituted heterocyclic derivatives for the synthesis. A large number of deuterium-containing reagents and components are commercially available from chemical suppliers such as Aldrich Chemical Co.

Deuterium transfer reagents suitable for use in nucleophilic substitution reactions, such as methyl iodide-d ₃ (CD ₃ I), are readily available and can be used to transfer a deuterium-substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD3I is illustrated, by way of example only, in the reaction schemes below.

- 22 038715

Deuterium transfer reagents such as lithium aluminum deuteride (LiAlD4) are used to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD4 is illustrated, by way of example only, in the reaction schemes below.

Gaseous deuterium and palladium catalyst are used to reduce unsaturated carbon-carbon bonds and to effect reductive substitution of carbon-halogen bonds in aryls, as illustrated, by way of example only, in the reaction schemes below.

In one embodiment, the compound described herein contains one deuterium atom. In another embodiment, the compound described herein contains two deuterium atoms. In another embodiment, the compound described herein contains three deuterium atoms. In another embodiment, the compound described herein contains four deuterium atoms. In another embodiment, the compound described herein contains five deuterium atoms. In another embodiment, the compound described herein contains six deuterium atoms. In another embodiment, the compound described herein contains more than six deuterium atoms. In another embodiment, the compound described herein is completely substituted with deuterium atoms and does not contain irreplaceable 1H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic component is used as a starting material.

Substituted heterocyclic compounds.

This document describes substituted heterocyclic compounds that are inhibitors of bromodomain. These compounds and compositions containing these compounds can be used for the treatment of cancer and neoplasms. The compounds described herein may therefore be useful in the treatment of midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, bladder cancer, lung cancer and / or melanoma, and the like.

One embodiment relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof

where R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

- 23 038715

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, -OH, -CN, -OR ⁶¹ , -NHR ⁶¹ , -N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

R ¹ ^ < ^X4 -v ₃ T LO

A L

R ^a represents ^{X2 R}

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, -CH2-, -CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₃ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, alkyl, —CN, or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (I) wherein R ² is CH 3. Another embodiment relates to a compound of formula (I) wherein R ² is CD3. Another embodiment relates to a compound of formula (I) wherein X5 is N. Another embodiment relates to a compound of formula (I) where X6 is N. Another embodiment relates to a compound of formula (I) wherein X7 is N Another embodiment relates to a compound of formula (I) wherein X8 is N. Another embodiment relates to a compound of formula (I) wherein none of X5, X6, X7 or X8 is N. Another embodiment relates to a compound of formula (I) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (I) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (I) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (I) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (I) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (I) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (I) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (I) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (I) wherein Y is a bond. Another embodiment relates to a compound of formula (I) wherein Y is —CH2—. Another embodiment relates to a compound of formula (I) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (I) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (I) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (I) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (I) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (I) wherein Z is —N (R ²² ) CO ₂ R ²¹ . Another embodiment relates to a compound of Form-24 038715 mule (I), wherein Z is —N (R ²² ) CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (I) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (I) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (I) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (I) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (I) wherein W is —O—. Another embodiment relates to a compound of formula (I) wherein W is —NH—. Another embodiment relates to a compound of formula (I) wherein X is alkyl. Another embodiment relates to a compound of formula (I) wherein X is aryl. Another embodiment relates to a compound of formula (I) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (I) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (I) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (I) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (I) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (I) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound of formula (Ia), or a pharmaceutically acceptable salt thereof r ^a

° Formula (1a) where R ^{2 is} selected from CH3, CH ₂ CH ₃ , CH2CF3, CH ₂ F, CHF ₂ , CF3, CH ₂ D, CHD2 or CD3;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, -OH, -CN, -OR ⁶¹ , -NHR ⁶¹ , -N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

T AO AL

R ^a represents ^{X2 R} '

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond or —CH ₂ -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, alkyl, —CN, or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aral

- 25,038715 keels, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.

Another embodiment relates to a compound of formula (Ia) wherein R ² is CH3. Another embodiment relates to a compound of formula (Ia) wherein R ² is CD3. Another embodiment relates to a compound of formula (Ia) where X5 is N. Another embodiment relates to a compound of formula (Ia) where X6 is N. Another embodiment relates to a compound of formula (Ia) where X7 is N Another embodiment relates to a compound of formula (Ia) wherein X8 is N. Another embodiment relates to a compound of formula (Ia) wherein none of X5, X6, X7, or X8 is N. Another embodiment relates to a compound of formula (Ia) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (Ia) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (Ia) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (Ia) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (Ia) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (Ia) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (Ia) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (Ia) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (Ia) wherein Y is a bond. Another embodiment relates to a compound of formula (Ia) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (Ia) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (Ia) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (Ia) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (Ia) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (Ia) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (Ia) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (Ia) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (Ia) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (Ia) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (Ia) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (Ia) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (Ia) wherein W is —O—. Another embodiment relates to a compound of formula (Ia) wherein W is —NH—. Another embodiment relates to a compound of formula (Ia) wherein X is alkyl. Another embodiment relates to a compound of formula (Ia) wherein X is aryl. Another embodiment relates to a compound of formula (Ia) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (Ia) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (Ia) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (Ia) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (Ia) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (Ia) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib) r ^a

° Formula (Ib) where R ^{2 is} selected from CH ₃ ;

X5 is CH;

X6 is CR ⁶ ;

X7 is CR ⁷ ;

X8 is CH;

R ⁶ is hydrogen or halogen;

R ⁷ is hydrogen or halogen;

R ^a represents ^{X2 R} ;

X2 is CH;

R ¹³ represents -YZ;

- 26 038715

Y is selected from a bond or -CH2-;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ ,

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₃ R ²¹ ;

X3 is CR ¹⁴ where R ¹⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ alkoxy;

X4 is CR ¹⁵ where R ¹⁵ is hydrogen or halogen;

R ¹⁶ is —WX — where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ⁶ is halogen and R ⁷ is hydrogen.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ⁶ is hydrogen and R ⁷ is halogen.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ⁶ is hydrogen and R ⁷ is hydrogen.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is —CH2—. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is —CH2— and Z is —SO2R ²¹ or —N (R ²² ) SO ₂ R ²¹ . Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ²² is hydrogen or methyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond and Z is —N (R ²² ) SO2R ²¹ or —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond and Z is —SO2R ²¹ . Another embodiment relates to a compound or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond Z represents -SO2R ^21, and R ²¹ is heterocyclyl or heterocyclylalkyl. Another embodiment relates to a compound or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond, Z represents -SO2R ²¹ and R ²¹ is alkyl, cycloalkyl or cycloalkylalkyl. Another embodiment relates to a compound or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond, Z represents -SO2R ^21, R ²¹ is alkyl and said alkyl is a C ₁ -C ₄ alkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond and Z is —SO ₂ N (R ²² ) 2. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ²² is hydrogen or methyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond, Z is —SO2N (R ²² ) _2, and at least one R ²² is alkyl, cycloalkyl, or aralkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ²¹ is heterocyclyl or heterocyclylalkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ²² is hydrogen or methyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein at least one R ²² is alkyl, cycloalkyl, or aralkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein said alkyl is C ₁ -C ₄ alkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having

27 038715 the structure of formula (Ib) wherein said C1-C4 alkyl is C1-alkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein R ¹⁴ is hydrogen and R ¹⁵ is hydrogen.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —NH—. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —S—. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is a bond. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —O—.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein X is alkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —NH— and X is alkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —O— and X is alkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is a bond and X is alkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein X is cycloalkylalkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —NH— and X is cycloalkylalkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is a bond and X is cycloalkylalkyl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein X is aryl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —NH— and X is aryl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is —O— and X is aryl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein W is a bond and X is aryl.

Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond, Z is —SO2R ²¹ , W is —O— and X is aryl or cycloalkylalkyl. Another embodiment relates to a compound, or a pharmaceutically acceptable salt thereof, having the structure of formula (Ib), wherein Y is a bond, Z is —SO2R ²¹ , W is —O— and X is cycloalkylalkyl.

One embodiment relates to a compound of formula (II), or a pharmaceutically acceptable salt thereof

where R ² is alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, aralkyl, or heteroarylalkyl;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, -OH, -CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, -S-alkyl, cycloalkylalkoxy, heterocyclyl, aralkoxy, heteroaryloxy, or N-aryloxy (alkynyloxy H) COalkyl;

- 28 038715

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₃ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl, alkoxy, aryloxy, aralkyloxy, cycloalkylalkyloxy, heterocyclyloxy, heteroarylalkyloxy, or alkynyloxy;

R ¹⁶ is hydrogen, halogen, —N (H) COX, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkynyl , cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen.

One embodiment relates to a compound of formula (IIa) or a pharmaceutically acceptable salt thereof r ^a

R ⁶ ] <R ² ° Formula (Pa) where R ² is CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH2F, CHF2, CF ₃ , CH2D, CHD2 or CD ₃ ;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy;

^R1 ^ ^X4 ^

R ^a represents ^{X2 R} i

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond or -CH2-;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen.

- 29 038715

Another embodiment relates to a compound of formula (IIa) where X2 is N. Another embodiment relates to a compound of formula (IIa) where X3 is N. Another embodiment relates to a compound of formula (IIa) where X4 is N Another embodiment relates to a compound of formula (IIa) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (IIa) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (IIa) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (IIa) wherein X6 is CH. Another embodiment relates to a compound of formula (IIa) wherein X6 is

N. Another embodiment relates to a compound of formula (IIa) wherein X5 is CR ⁵ . Another embodiment relates to a compound of formula (IIa) where X5 is N. Another embodiment relates to a compound of formula (IIa) where R ⁵ is hydrogen, halogen or alkyl. Another embodiment relates to a compound of formula (IIa) wherein R ⁶ is hydrogen, halogen, or alkyl.

Another embodiment relates to a compound of formula (IIa) wherein Y is a bond. Another embodiment relates to a compound of formula (IIa) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (IIa) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (IIa) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (IIa) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IIa) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IIa) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (IIa) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (IIa) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (IIa) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (IIa) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (IIa) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (IIa) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (IIa) wherein W is —O—. Another embodiment relates to a compound of formula (IIa) wherein W is —NH—. Another embodiment relates to a compound of formula (IIa) wherein X is alkyl. Another embodiment relates to a compound of formula (IIa) wherein X is aryl. Another embodiment relates to a compound of formula (IIa) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IIa) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (IIa) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (IIa) wherein W is O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IIa) wherein R ⁶ is CD ₃ .

One embodiment relates to a compound of formula (IIb) or a pharmaceutically acceptable salt thereof r ^a

° Formula (Pb) where R ² is CH ₃ ;

X6 is CH;

X5 is CR ⁵ ;

R ⁵ is hydrogen;

R ⁶ is halogen or alkyl;

^R1 ^ ^X4 ^

R ^a represents ^{X2 R;}

X2 is N;

R ¹³ represents -YZ;

Y is selected from a bond or -CH ₂ -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO ₂ N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N;

X4 is CR ¹⁵ where R ¹⁵ is hydrogen, halogen, —CN, alkyl, or alkoxy;

- 30 038715

R ¹⁶ is —WX — where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (IIb) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (IIb) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (IIb) wherein R ⁶ is C1-C3 alkyl. Another embodiment relates to a compound of formula (IIb) wherein R ⁶ is C1-alkyl.

Another embodiment relates to a compound of formula (IIb) wherein Y is a bond. Another embodiment relates to a compound of formula (IIb) wherein Y is —CH2—. Another embodiment relates to a compound of formula (IIb) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (IIb) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (IIb) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IIb) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IIb) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (IIb) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (IIb) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (IIb) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (IIb) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (IIb), wherein R ²¹ represents a C1-C ₂ alkyl.

Another embodiment relates to a compound of formula (IIb) wherein W is —O—. Another embodiment relates to a compound of formula (IIb) wherein W is —NH—. Another embodiment relates to a compound of formula (IIb) wherein W is a bond. Another embodiment relates to a compound of formula (IIb) wherein X is alkyl. Another embodiment relates to a compound of formula (IIb) wherein X is aryl. Another embodiment relates to a compound of formula (IIb) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IIb) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (IIb) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (IIb) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IIb) wherein W is a bond and X is alkyl. Another embodiment relates to a compound of formula (IIb) wherein W is a bond and X is aryl. Another embodiment relates to a compound of formula (IIb) wherein W is a bond and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IIb) wherein R ⁶ is CD3.

One embodiment relates to a compound of formula (III) or a pharmaceutically acceptable salt thereof r ^a

° Formula (III) where R ² is CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF3, CH ₂ D, CHD2 or CD3;

X1 is CH or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom;

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO ₂ R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N ( R ²² ) CO ₂ R ²¹ ,

- 31 038715

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO ₂ N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (III) where X2 is N. Another embodiment relates to a compound of formula (III) where X3 is N. Another embodiment relates to a compound of formula (III) where X4 is N Another embodiment relates to a compound of formula (III) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (III) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (III) having the structure of formula (IIIa):

r ^a

° Formula (IIIa) where Ring B is a 6-membered ring having one nitrogen atom; R ^{23 is} selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, —COR ²⁴ , —CO2R ²⁴ , —CONH (R ²⁴ ), —CON (R ²⁴ ) 2, or SO2R ²⁴ ; and each R ^{24 is} independently selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (III) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (III) wherein X1 is CH. Another embodiment relates to a compound of formula (III) wherein X1 is N.

Another embodiment relates to a compound of formula (III) wherein Y is a bond. Another embodiment relates to a compound of formula (III) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (III) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (III) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (III) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (III) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (III) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (III) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (III) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (III) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (III) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (III) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (III) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (III) wherein W is —O—. Another embodiment relates to a compound of formula (III) wherein W is —NH—. Another embodiment relates to a compound of formula (III) wherein X is alkyl. Another embodiment relates to a compound of formula (III) wherein X is alkynyl. Another embodiment relates to a compound of formula (III) wherein X is aryl. Another embodiment relates to a compound of formula (III) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (III) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (III) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (III) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (III) wherein W is

- 32 038715 is —O— and X is aryl. Another embodiment relates to a compound of formula (III) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (III) wherein W is —O— and X is cycloalkylalkynyl.

One embodiment relates to a compound of formula (IV), or a pharmaceutically acceptable salt thereof

where Q is N and T is C or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring having one or more nitrogen atoms;

R ^{2 is} selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD _2, or CD ₃ ;

X1 is CH or N;

R ¹ Vx4

I Λό gA "

R ^a represents i

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond or —CH ₂ -;

Z is selected from -SO ₂ R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N ( R ²² ) CO ₂ R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (IV) where X2 is N. Another embodiment relates to a compound of formula (IV) where X3 is N. Another embodiment relates to a compound of formula (IV) where X4 is N Another embodiment relates to a compound of formula (IV) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (IV) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (IV), wherein the compound of formula (IV) is selected from the group:

Another embodiment relates to a compound of formula (IV), wherein the compound of formula (IV) has the structure:

- 33 038715

Another embodiment relates to a compound of formula (IV) wherein Q is N and T is C. Another embodiment relates to a compound of formula (IV) where Q is C and T is N. Another embodiment relates to a compound formula (IV), where R ² is CH ₃ . Another embodiment relates to a compound of formula (IV) wherein X1 is CH. Another embodiment relates to a compound of formula (IV) wherein X1 is N.

Another embodiment relates to a compound of formula (IV) wherein Y is a bond. Another embodiment relates to a compound of formula (IV) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (IV) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (IV) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (IV) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IV) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IV) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (IV) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (IV) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (IV) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (IV) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (IV) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (IV) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (IV) wherein W is —O—. Another embodiment relates to a compound of formula (IV) wherein W is —NH—. Another embodiment relates to a compound of formula (IV) wherein X is alkyl. Another embodiment relates to a compound of formula (IV) wherein X is aryl. Another embodiment relates to a compound of formula (IV) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IV) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (IV) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (IV) wherein W is —O— and X is cycloalkylalkyl.

Another embodiment relates to a compound of formula (V) or a pharmaceutically acceptable salt thereof r ^a

° Formula (V) where R ^{2 is} selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

^p1 ^ ^X4 'xs I LO

A X

R ^a represents ^{X2 R} '

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

- 34 038715

Y is selected from a bond or -CH2-;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ ,

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₃ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ where R ¹⁵ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (V) where X2 is N. Another embodiment relates to a compound of formula (V) where X3 is N. Another embodiment relates to a compound of formula (V) where X4 is N Another embodiment relates to a compound of formula (V) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (V) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (V) wherein R ² is CH3. Another embodiment relates to a compound of formula (V) wherein R ² is CD ₃ . Another embodiment relates to a compound of formula (V) where X5 is N. Another embodiment relates to a compound of formula (V) where X6 is N. Another embodiment relates to a compound of formula (V) where X7 is N Another embodiment relates to a compound of formula (V) wherein X8 is N. Another embodiment relates to a compound of formula (V) wherein none of X5, X6, X7, or X8 is N. Another embodiment relates to a compound of formula (V) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (V) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (V) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (V) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (V) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (V) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (V) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (V) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (V) wherein Y is a bond. Another embodiment relates to a compound of formula (V) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (V) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (V) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (V) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (V) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (V) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (V) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (V) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (V) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (V) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (V) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (V) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (V) wherein W is —O—. Another embodiment relates to a compound of formula (V) wherein W is —NH—. Another embodiment relates to a compound of formula (V) wherein X is alkyl. Another embodiment relates to a compound of formula (V) wherein X is aryl. Another embodiment relates to a compound of formula (V) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (V) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (V) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (V) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (V) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (V) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

- 35 038715

One embodiment relates to a compound of formula (VIa) or a pharmaceutically acceptable salt thereof r ^a

R ⁶

R

R ²

Formula (Via) where R ² is CH3 or CD3;

R ⁵ is hydrogen or CH3;

R ⁶ is hydrogen, CH3, Cl, F, Br, NH ₂ , N (CH ₃ ) ₂ , NH (alkyl), or CD3;

R ^a represents

R ¹³ represents -YZ;

Y is selected from a bond or -CH ₂ -;

Z is —SO2R ²¹ ;

R ¹⁴ is hydrogen, F or Cl;

R ¹⁶ is —WX, where W is —O— or —NH— and X is selected from CH3, CH2CH3, CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH ₂ - (cyclopropyl), C ₆ H ₅ , 4-Fluoro (C ₆ H ₄ ), 2,4-difluoro (C ₆ H ₃ ), 2-fluoro (C ₆ H4), 4-tetrahydropyranyl, 3-tetrahydropyranyl, oxolane -3-yl, 4,4-difluorocyclohexyl and 4-hydroxycyclohexyl; and each R ²¹ is CH ₃ or CH ₂ CH ₃ .

Another embodiment relates to a compound of formula (VIa) wherein Y is a bond. Another embodiment relates to a compound of formula (VIa) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (VIa) wherein W is —O—. Another embodiment relates to a compound of formula (VIa) wherein W is —NH—. Another embodiment relates to a compound of formula (VIa) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VIa) wherein R ² is CD3.

One embodiment relates to a compound of formula (VIb), or a pharmaceutically acceptable salt thereof

where R ² represents CH3 or CD3;

R ⁵ represents hydrogen or CH ₃ ;

R ⁶ is hydrogen, CH3, Cl, F, Br, NH ₂ , N (CH ₃ ) ₂ , NH (alkyl), or CD3;

R ^a represents

R ¹³ is —NHSO2R ²¹ ;

R ¹⁴ is hydrogen, F or Cl;

R ¹⁶ is —WX, where W is —O— or —NH— and X is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH ₂ - (cyclopropyl), C ₆ H ₅ , 4-fluoro (C ₆ H4), 2,4-difluoro (C ₆ H ₃ ), 2-fluoro (C ₆ H4), 4-tetrahydropyranyl, 3- tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl, and 4-hydroxycyclohexyl; and each R ²¹ is CH ₃ or CH ₂ CH ₃ .

Another embodiment relates to a compound of formula (VIb) wherein W is —O—. Another embodiment relates to a compound of formula (VIb) wherein W is —NH—. Another embodiment relates to a compound of formula (VIb) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VIb) wherein R ² is CD3.

One embodiment relates to a compound of formula (VIc), or a pharmaceutically acceptable salt thereof

- 36 038715

where R ² represents CH3 or CD3;

R ⁵ represents hydrogen or CH ₃ ;

R ⁶ is hydrogen, CH3, Cl, F, Br, NH ₂ , N (CH ₃ ) ₂ , NH (alkyl), or CD3;

R ^a represents

R ¹³ represents -YZ;

Y is selected from a bond or -CH ₂ -;

Z is —SO2R ²¹ ;

R ¹⁶ is —WX, where W is —O— or —NH— and X is selected from CH3, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , CH ₂ - (cyclopropyl), C ₆ H ₅ , 4-fluoro (C ₆ H ₄ ), 2,4-difluoro (C ₆ H ₃ ), 2-Fluoro (C ₆ H ₄ ), 4-tetrahydropyranyl, 3 -tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl and 4-hydroxycyclohexyl; and each R ²¹ is CH ₃ or CH ₂ CH ₃ .

Another embodiment relates to a compound of formula (VIc) wherein Y is a bond. Another embodiment relates to a compound of formula (VIc) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (VIc) wherein W is —O—. Another embodiment relates to a compound of formula (VIc) wherein W is —NH—. Another embodiment relates to a compound of formula (VIc) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VIc) wherein R ² is CD3.

One embodiment relates to a compound of formula (VId), or a pharmaceutically acceptable salt thereof

where R ² represents CH3 or CD3;

R ⁵ represents hydrogen or CH3;

R ⁶ is hydrogen, CH3, Cl, F, Br, NH ₂ , N (CH ₃ ) ₂ , NH (alkyl), or CD ₃ ;

R ^a represents

R ¹³ is —NHSO2R ²¹ ;

R ¹⁶ is —WX, where W is —O— or —NH— and X is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH ₂ - (cyclopropyl), C ₆ H ₅ , 4-fluoro (C ₆ H4), 2,4-difluoro (C ₆ H ₃ ), 2-Fluoro (C ₆ H ₄ ), 4-tetrahydropyranyl, 3 -tetrahydropyranyl, oxolan-3-yl, 4,4-difluorocyclohexyl and 4-hydroxycyclohexyl; and each R ²¹ is CH ₃ or CH ₂ CH ₃ .

Another embodiment relates to a compound of formula (VId) wherein W is —O—. Another embodiment relates to a compound of formula (VId) wherein W is —NH—. Another embodiment relates to a compound of formula (VId) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VId) wherein R ² is CD3.

One embodiment relates to a compound of formula (VIe) or a pharmaceutically acceptable salt thereof r ^a

R ⁶

R ²

Formula (Vie) where R ² is hydrogen, CH ₃ or CHF2;

R ⁶ is CH ₃ , CD3, cyclopropyl, NH (CH ₃ ), NH (CH ₂ CH ₃ ), F or Cl;

- 37 038715

R ^a represents

R ¹³ represents -YZ;

Y is selected from -NH- or -CH2-;

Z is selected from —SO2R ²¹ ;

R ¹⁴ represents hydrogen, CH ₃ or F;

X9 is N or CH;

R ¹⁶ is -WX, where W is -O- or -NH- and X is selected from CH ₃ , CH ₂ CH ₃ , CH2CH2CH3, CH2- (cyclopropyl), CH2CH2CFH2, 2,4-difluoro (C6H3), 2 , 3-difluoro (C6H3), 2-chloro-4fluoro (C ₆ H ₃ ), 2-fluoro (C ₆ H ₄ ) and 2-chloro (C ₆ H ₄ ); and each R ^{21 is} independently selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH _{3 , CH 2 CH 2 CHF 2} , CH 2 - (cyclopropyl) and cyclopropyl.

Another embodiment relates to a compound of formula (VIe) wherein Y is —NH—. Another embodiment relates to a compound of formula (VIe) wherein Y is —CH2—. Another embodiment relates to a compound of formula (VIe) wherein W is —O—. Another embodiment relates to a compound of formula (VIe) wherein W is —NH—. Another embodiment relates to a compound of formula (VIe) where X9 is N. Another embodiment relates to a compound of formula (VIe) where X9 is CH. Another embodiment relates to a compound of formula (VIe) wherein R ² is hydrogen. Another embodiment relates to a compound of formula (VIe) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VIe) wherein R ² is CHF 2.

One embodiment relates to a compound of formula (VII) or a pharmaceutically acceptable salt thereof r ^a

R ⁶ R ² ° formula (VII) wherein R ² represents CH _3, CH ₂ CH _3, CH2CF3, CH2F, CHF2, CF _3, CH2D, CHD2 or CD _3;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, -OH, -CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy and cycloalkylalkyl-S-;

^r1 V% ⁴ y3

I AO A Λ

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and

38,038715 each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (VII) where X2 is N. Another embodiment relates to a compound of formula (VII) where X3 is N. Another embodiment relates to a compound of formula (VII) where X4 is N Another embodiment relates to a compound of formula (VII) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (VII) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (VII) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VII) wherein X6 is CH. Another embodiment relates to a compound of formula (VII) wherein X6 is N. Another embodiment relates to a compound of formula (VII) wherein X5 is CR ⁵ . Another embodiment relates to a compound of formula (VII), wherein X5 is N. Another embodiment relates to a compound of formula (VII), wherein R ⁵ represents hydrogen, halogen or alkyl. Another embodiment relates to a compound of formula (VII) wherein R ⁶ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VII) wherein R ⁶ is heterocyclyl. Another embodiment relates to a compound of formula (VII) wherein R ⁶ is cycloalkylalkynyl. Another embodiment relates to a compound of formula (VII) wherein R ⁶ is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment relates to a compound of formula (VII) wherein Y is a bond. Another embodiment relates to a compound of formula (VII) wherein Y is —CH2—. Another embodiment relates to a compound of formula (VII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (VII) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (VII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (VII) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (VII) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (VII) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (VII) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (VII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (VII) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (VII) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VII) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (VII) wherein W is —O—. Another embodiment relates to a compound of formula (VII) wherein W is —NH—. Another embodiment relates to a compound of formula (VII) wherein X is alkyl. Another embodiment relates to a compound of formula (VII) wherein X is alkynyl. Another embodiment relates to a compound of formula (VII) wherein X is aryl. Another embodiment relates to a compound of formula (VII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (VII) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (VII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (VII) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (VII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (VII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (VII) wherein W is —O— and X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (VII) wherein R ⁶ is CD ₃ .

One embodiment relates to a compound of formula (VIIa) or a pharmaceutically acceptable salt thereof r ^a

⁰ Formula (Vila) where R ² is CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

- 39 038715

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, -OH, -CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy and cycloalkylalkyl-S-;

^R V ^X4 'X3 A 3k

R ^a represents ^{X2 R;}

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, -CH2- or -CH (C ₁ -C ₄ -alkyl) -;

Z is selected from —N (R ²² ) SO2R ²¹ , —N (R ²² ) CO2R ²¹ , —N (R ²² ) COR ^21, or —N (R ²² ) SO ₃ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or, optionally, when R ²¹ and R ²² are alkyl, R ²¹ and R ²² join to form a ring; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (VIIa) where X2 is N. Another embodiment relates to a compound of formula (VIIa) where X3 is N. Another embodiment relates to a compound of formula (VIIa) where X4 is N Another embodiment relates to a compound of formula (VIIa) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (VIIa) wherein X2 is CR ¹² , X3 is CR ¹⁴ , and X4 is CR ¹⁵ ...

Another embodiment relates to a compound of formula (VIIa) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (VIIa) wherein X6 is CH. Another embodiment relates to a compound of formula (VIIa) wherein X6 is N. Another embodiment relates to a compound of formula (VIIa) wherein X5 is CR ⁵ . Another embodiment relates to a compound of formula (VIIa), where X5 is N. Another embodiment relates to a compound of formula (VIIa), where R ⁵ is hydrogen, halogen or alkyl. Another embodiment relates to a compound of formula (VIIa) wherein R ⁶ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VIIa) wherein R ⁶ is heterocyclyl. Another embodiment relates to a compound of formula (VIIa) wherein R ⁶ is cycloalkylalkynyl. Another embodiment relates to a compound of formula (VIIa) wherein R ⁶ is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment relates to a compound of formula (VIIa) wherein Y is a bond. Another embodiment relates to a compound of formula (VIIa) wherein Y is —CH2—. Another embodiment relates to a compound of formula (VIIa) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (VIIa) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (VIIa) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (VIIa) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (VIIa) wherein R ²² is alkyl. Another embodiment relates to a compound of formula (VIIa), wherein R ²¹ and R ²² are both alkyl and join to form a ring. Another embodiment relates to a compound of formula (VIIa) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VIIa) wherein X4 is C — R ¹⁵ . Another embodiment relates to a compound of formula (VIIa) wherein W is —O—. Another embodiment relates to a compound of formula (VIIa) wherein W is —NH—. Another embodiment

40 038715 refers to a compound of formula (Viia) where X is alkyl. Another embodiment relates to a compound of formula (Vila) wherein X is alkynyl. Another embodiment relates to a compound of formula (VIIa) wherein X is aryl. Another embodiment relates to a compound of formula (Vila) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (Viia) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (Vila) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (Viia) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (Viia) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (Viia) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (Viia) wherein W is —O— and X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (Vila) wherein R ⁶ is CD ₃ .

One embodiment relates to a compound of formula (Viii) or a pharmaceutically acceptable salt thereof r ^a

° Formula (VIII) where R ^{2 is} selected from CH3, CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X5 is CR ⁵ or N; X6 is CR ⁶ or N; X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

I LO

A l

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (Viii) wherein R ² is CH3. Another embodiment relates to a compound of formula (Viii) wherein R ² is CD3. Another embodiment relates to a compound of formula (Viii) wherein X5 is

- 41 038715

N. Another embodiment relates to a compound of formula (VIII) wherein X6 is

N. Another embodiment relates to a compound of formula (VIII) wherein X7 is

N. Another embodiment relates to a compound of formula (VIII) wherein X8 is

N. Another embodiment relates to a compound of formula (VIII) wherein none of X5, X6, X7 or X8 is N. Another embodiment relates to a compound of formula (VIII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIII) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIII) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (VIII) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (VIII) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (VIII) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (VIII) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (VIII) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (VIII) wherein Y is a bond. Another embodiment relates to a compound of formula (VIII) wherein Y is —CH2—. Another embodiment relates to a compound of formula (VIII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (VIII) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (VIII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (VIII) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (VIII) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (VIII) wherein Z is —N (R ²² ) CO ₂ R ²¹ . Another embodiment relates to a compound of formula (VIII) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (VIII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (VIII) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (VIII) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VIII) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (VIII) wherein W is —O—. Another embodiment relates to a compound of formula (VIII) wherein W is —NH—. Another embodiment relates to a compound of formula (VIII) wherein X is alkyl. Another embodiment relates to a compound of formula (VIII) wherein X is aryl. Another embodiment relates to a compound of formula (VIII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (VIII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (VIII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (VIII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (VIII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIII) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound of formula (VIIIa) or a pharmaceutically acceptable salt thereof r ^a

° Formula (Villa) where R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD ₃ ;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

^R % ^X4 'xs A2 ^K R13 R ^a represents'

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, -CH ₂ - or -CH (C ₁ -C ₄ -alkyl) -;

Z is selected from —N (R ²² ) SO2R ²¹ , —N (R ²² ) CO2R ²¹ , —N (R ²² ) COR ^21, or —N (R ²² ) SO ₃ R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or, optionally, when R ²¹ and R ²² are alkyl, R ²¹ and R ²² join to form a ring; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (VIIIa) wherein R ² is CH3. Another embodiment relates to a compound of formula (VIIIa) wherein R ² is CD3. Another embodiment relates to a compound of formula (VIIIa) where X5 is N. Another embodiment relates to a compound of formula (VIIIa) where X6 is N. Another embodiment relates to a compound of formula (VIIIa) where X7 is N Another embodiment relates to a compound of formula (VIIIa) wherein X8 is N. Another embodiment relates to a compound of formula (VIIIa) where none of X5, X6, X7 or X8 is N. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (VIIIa) wherein Y is a bond. Another embodiment relates to a compound of formula (VIIIa) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (VIIIa) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (VIIIa) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (VIIIa) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (VIIIa) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (VIIIa) wherein R ²² is alkyl. Another embodiment relates to a compound of formula (VIIIa), wherein both R ²¹ and R ²² are alkyl and join to form a ring. Another embodiment relates to a compound of formula (VIIIa) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (VIIIa) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (VIIIa) wherein W is —O—. Another embodiment relates to a compound of formula (VIIIa) wherein W is —NH—. Another embodiment relates to a compound of formula (VIIIa) wherein X is alkyl. Another embodiment relates to a compound of formula (VIIIa) wherein X is aryl. Another embodiment relates to a compound of formula (VIIIa) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (VIIIa) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (VIIIa), wherein

- 43 038715

W is —O— and X is aryl. Another embodiment relates to a compound of formula (VIIIa) wherein W is —O— and X is cycloalkylalkyl.

Another embodiment relates to a compound of formula (VIIIa) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (VIIIa) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound of formula (IX) or a pharmaceutically acceptable salt thereof r ^a

Formula (IX) wherein Q is N and T is C or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring having one or more nitrogen atoms;

R ^{2 is} selected from CH ₃ , CH ₂ CH ₃ , CH2CF3, CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD2, or CD3;

X1 is CH or N;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ -, or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (IX) where X2 is N. Another embodiment relates to a compound of formula (IX) where X3 is N. Another embodiment relates to a compound of formula (IX) where X4 is N Another embodiment relates to a compound of formula (IX) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (IX) where X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

formula (IX), where the compound of the formula to the compound

Another embodiment relates to (IX) selected from the group:

Another embodiment relates to a compound of formula (IX) where Q is N and T is C. Another embodiment relates to a compound of formula (IX) where Q is C and T is N. Another embodiment is to a compound of formula (IX) wherein R ² is CH3. Another embodiment relates to a compound 44 038715 of formula (IX) wherein X1 is CH. Another embodiment relates to a compound of formula (IX) wherein X1 is N.

Another embodiment relates to a compound of formula (IX) wherein Y is a bond. Another embodiment relates to a compound of formula (IX) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (IX) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (IX) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (IX) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IX) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (IX) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (IX) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (IX) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (IX) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (IX) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (IX) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (IX) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (IX) wherein W is —O—. Another embodiment relates to a compound of formula (IX), wherein W is represents represents —NH—. Another embodiment relates to a compound of formula (IX) wherein X is alkyl. Another embodiment relates to a compound of formula (IX) wherein X is aryl. Another embodiment relates to a compound of formula (IX) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (IX) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (IX) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (IX) wherein W is —O— and X is cycloalkylalkyl.

One embodiment relates to a compound of formula (XII), or a pharmaceutically acceptable salt thereof

where R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD3;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO ₂ R ²¹ ,

- 45 038715

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO ₃ R ²¹ ;

X3 is S;

X4 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XII) wherein R ² is CH 3. Another embodiment relates to a compound of formula (XII) wherein R ² is CD3. Another embodiment relates to a compound of formula (XII) where X5 is N. Another embodiment relates to a compound of formula (XII) where X6 is N. Another embodiment relates to a compound of formula (XII) where X7 is N Another embodiment relates to a compound of formula (XII) where X8 is N. Another embodiment relates to a compound of formula (XII) where none of X5, X6, X7, or X8 is N. Another embodiment relates to a compound of formula (XII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XII) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XII) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (XII) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (XII) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (XII) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (XII) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (XII) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (XII) wherein Y is a bond. Another embodiment relates to a compound of formula (XII) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XII) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XII) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XII) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XII) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (XII) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (XII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XII) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (XII) wherein W is —O—. Another embodiment relates to a compound of formula (XII) wherein W is —NH—. Another embodiment relates to a compound of formula (XII) wherein X is alkyl. Another embodiment relates to a compound of formula (XII) wherein X is aryl. Another embodiment relates to a compound of formula (XII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XII) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

Another embodiment relates

RA

a compound of formula (XII), where is

Another embodiment relates to R ¹³

R ^le AJx2 and X2 represents N.

Another embodiment relates to a compound of formula (XII), where

R ^a is a compound of formula (XII), where r ^a is

- 46 038715 i ¹³

R ¹⁶ A ^ X2 'and X2 is CR ¹² .

Another embodiment relates to a compound of formula (XII), wherein R ^A is

Another embodiment relates to a compound of formula (XII), wherein R ^A is

- Γ ^ x3> and X4 represents N.

Another embodiment relates to a compound of formula (XII), wherein R ^A is

R ¹³

R ¹⁶ ^^ X3> and X4 is CR ¹⁴ .

One embodiment relates to a compound of formula (XIII) or a pharmaceutically acceptable salt thereof r ^a

° Formula (XIII) where R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD3;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) 2, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

R ^a is ^r12 '

R ¹² is hydrogen or C ₁ -C ₄ alkyl;

R ¹³ represents -YZ;

Y is selected from —CH2— or —CH (C ₁ -C ₄ alkyl) -;

Z is selected from —SO2R ²¹ , —SO2N (R ²² ) 2, or —CON (R ²² h;

R ¹⁵ is hydrogen, halogen or C ₁ -C ₄ -alkyl;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

- 47 038715

Another embodiment relates to a compound of formula (XIII) wherein R ² is

CH ₃ . Another embodiment relates to a compound of formula (XIII) wherein R ² is

CD ₃ . Another embodiment relates to a compound of formula (XIII) wherein X5 is

N. Another embodiment relates to a compound of formula (XIII) wherein X6 is

N. Another embodiment relates to a compound of formula (XIII) wherein X7 is

N. Another embodiment relates to a compound of formula (XIII) wherein X8 is

N. Another embodiment relates to a compound of formula (XIII) wherein none of X5, X6, X7 or X8 is N. Another embodiment relates to a compound of formula (XIII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XIII) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XIII) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (XIII) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (XIII) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (XIII) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (XIII) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (XIII) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (XIII) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XIII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XIII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XIII) wherein Z is —CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (XIII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XIII) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (XIII) wherein W is —O—. Another embodiment relates to a compound of formula (XIII) wherein W is —NH—. Another embodiment relates to a compound of formula (XIII) wherein X is alkyl. Another embodiment relates to a compound of formula (XIII) wherein X is aryl. Another embodiment relates to a compound of formula (XIII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XIII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XIII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XIII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XIII) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XIII) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound of formula (XIV), or a pharmaceutically acceptable salt thereof

where R ² represents CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, -OH, -CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy and cycloalkylalkyl-S-;

R ¹⁵

R ¹ Uy °

R ^a is ^r2 ;

R ¹² is hydrogen or C ₁ -C ₄ alkyl;

R ¹³ represents -YZ;

Y is selected from —CH ₂ - or —CH (C ₁ -C ₄ -αalkyl) -;

- 48 038715

Z is selected from —SO2R ²¹ , —SO2N (R ²² ) 2, or —CON (R ²² ) 2;

R ¹⁵ is hydrogen, halogen or C ₁ -C ₄ -alkyl;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XIV) wherein R ² is CH3. Another embodiment relates to a compound of formula (XIV) wherein X6 is CH. Another embodiment relates to a compound of formula (XIV) where X6 is N. Another embodiment relates to a compound of formula (XIV) where X5 is CR ⁵ . Another embodiment relates to a compound of formula (XIV), where X5 is N. Another embodiment relates to a compound of formula (XIV), where R ⁵ is hydrogen, halogen or alkyl. Another embodiment relates to a compound of formula (XIV) wherein R ⁶ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (XIV) wherein R ⁶ is heterocyclyl. Another embodiment relates to a compound of formula (XIV) wherein R ⁶ is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XIV) wherein R ⁶ is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment relates to a compound of formula (XIV) wherein Y is —CH2—. Another embodiment relates to a compound of formula (XIV) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XIV) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XIV) wherein Z is —CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (XIV) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XIV) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (XIV) wherein W is —O—. Another embodiment relates to a compound of formula (XIV) wherein W is —NH—. Another embodiment relates to a compound of formula (XIV) wherein X is alkyl. Another embodiment relates to a compound of formula (XIV) wherein X is alkynyl. Another embodiment relates to a compound of formula (XIV) wherein X is aryl. Another embodiment relates to a compound of formula (XIV) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XIV) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XIV) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XIV) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (XIV) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XIV) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XIV) wherein W is —O— and X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XIV) wherein R ⁶ is CD3.

One embodiment relates to a compound of formula (XV) or a pharmaceutically acceptable salt thereof ° Formula (XV) wherein Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X1 is CH or N;

^R1 ^ ^X4 ^

R ^a represents;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

- 49 038715

Y is selected from a bond, -CH2- or -CH _(C1-C4 alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ ,

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XV) where X2 is N. Another embodiment relates to a compound of formula (XV) where X3 is N. Another embodiment relates to a compound of formula (XV) where X4 is N Another embodiment relates to a compound of formula (XV) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (XV) where X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ .

Another embodiment relates to a compound of formula (XV), wherein the compound of formula (XV) has a formula selected from:

where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkylα, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2 ; and R ³¹ represents a C1-C ₄ -alkil.

Another embodiment relates to a compound of formula (XV), wherein the compound of formula (XV) has a formula selected from:

0,0, O and O where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkylα, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2; and R ³¹ represents a C1-C ₄ -alkil.

Another embodiment relates to a compound of formula (XV), wherein the compound of formula (XV) has a formula selected from:

where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkylα, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2 ; and R ³¹ represents a C1-C ₄ -alkil.

Another embodiment relates to a compound of formula (XV) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (XV) wherein X1 is CH. Another embodiment relates to a compound of formula (XV) wherein X1 is N.

Another embodiment relates to a compound of formula (XV) wherein Y is a bond. Another embodiment relates to a compound of formula (XV) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XV) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XV) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XV) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XV) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XV) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XV) wherein Z is —N (R ²² ) CO ₂ R ²¹ . Another embodiment relates to a compound of formula (XV) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment

50 038715 refers to a compound of formula (XV) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XV) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XV) wherein X3 is CR ¹⁴ . Another embodiment relates to a compound of formula (XV) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (XV) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (XV) wherein W is —O—. Another embodiment relates to a compound of formula (XV) wherein W is —NH—. Another embodiment relates to a compound of formula (XV) wherein X is alkyl. Another embodiment relates to a compound of formula (XV) wherein X is alkynyl. Another embodiment relates to a compound of formula (XV) wherein X is aryl. Another embodiment relates to a compound of formula (XV) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XV) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XV) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XV) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XV) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (XV) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XV) wherein W is —O— and X is cycloalkylalkynyl.

Another embodiment relates to a compound of formula (XVI) or a pharmaceutically acceptable salt thereof r ^a

° Formula (XVI) where R ^{2 is} selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl;

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy; or, optionally, when X4 is C — R ¹⁵ , R ¹⁴ and R ¹⁵ join to form a ring;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen or -WX, where W is a bond, -O-, -S-, or

- 51 038715

—NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; or, optionally, when X4 is C-R ¹⁵ , R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XVI) wherein X2 is

N. Another embodiment relates to a compound of formula (XVI) wherein X3 is

N. Another embodiment relates to a compound of formula (XVI) wherein X4 is

N. Another embodiment relates to a compound of formula (XVI) wherein X2 and X3 are N. Another embodiment relates to a compound of formula (XVI) wherein X2 is CR ¹² , X3 is CR ¹⁴ and X4 is CR ¹⁵ ...

Another embodiment relates to a compound of formula (XVI) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (XVI) wherein R ² is CD3. Another embodiment relates to a compound of formula (XVI) wherein X5 is N. Another embodiment relates to a compound of formula (XVI) wherein X6 is

N. Another embodiment relates to a compound of formula (XVI) wherein X7 is

N. Another embodiment relates to a compound of formula (XVI) wherein X8 is

N. Another embodiment relates to a compound of formula (XVI) wherein none of X5, X6, X7 or X8 is N. Another embodiment relates to a compound of formula (XVI) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XVI) wherein R ⁵ , R ⁶ , R ⁷ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XVI) wherein R ⁷ is halogen. Another embodiment relates to a compound of formula (XVI) wherein R ⁶ is halogen. Another embodiment relates to a compound of formula (XVI) wherein R ⁶ is heteroaryl. Another embodiment relates to a compound of formula (XVI) wherein R ⁶ is aryl. Another embodiment relates to a compound of formula (XVI) wherein R ⁶ is alkyl. Another embodiment relates to a compound of formula (XVI) wherein R ⁶ is aryl.

Another embodiment relates to a compound of formula (XVI) wherein Y is a bond. Another embodiment relates to a compound of formula (XVI) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XVI) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XVI) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XVI) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XVI) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XVI) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XVI) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (XVI) wherein Z is —N (R ²² ) CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (XVI) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XVI) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (XVI) wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (XVI) wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (XVI) wherein W is —O—. Another embodiment relates to a compound of formula (XVI) wherein W is —NH—. Another embodiment relates to a compound of formula (XVI) wherein X is alkyl. Another embodiment relates to a compound of formula (XVI) wherein X is aryl. Another embodiment relates to a compound of formula (XVI) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XVI) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XVI) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XVI) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XVI) wherein R ⁵ and R ⁸ are hydrogen. Another embodiment relates to a compound of formula (XVI) wherein R ⁵ and R ⁸ are hydrogen and R ⁶ is heteroaryl.

One embodiment relates to a compound of formula (XVII), or a pharmaceutically acceptable salt thereof

- 52 038715

r ^a

R ⁶

R ²

Formula (XVII) wherein R ² is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X6 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, -OH, -CN, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, amino, alkylamino, dialkylamino, heterocyclyl, cycloalkylalkylamino, alkoxy, cycloalkyloxy, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy, alkyl-S-, cycloalkylalkoxy and cycloalkylalkyl-S-;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO ₂ N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is S;

X4 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates fight fight fight fight fight

a compound of formula (XVII), where

R ^a represents with Another embodiment relates to

v. 'and X2 is N.

Another embodiment relates to X3 ^

'and X2 is CR ¹² . Another embodiment relates to R ¹³ X4 ^ /

R ¹⁶ ^ VX3

Another embodiment relates to .R ¹³ 'and X4 is N. Another embodiment relates to a compound of formula (XVII), where a compound of formula (XVII), where a compound of formula (XVII), where a compound of formula (XVII), where a compound of formula (XVII) ), where

R ^a

R ^a r ^a

R ^a r ^a represents represents represents represents sucker - 53 038715 fight

and X4 is CR ¹⁴ .

Another embodiment relates to a compound of formula (XVII) wherein R ² is CH3. Another embodiment relates to a compound of formula (XVII) wherein X6 is CH. Another embodiment relates to a compound of formula (XVII) wherein X6 is N. Another embodiment relates to a compound of formula (XVII) wherein X5 is C — R ⁵ . Another embodiment relates to a compound of formula (XVII) where X5 is N. Another embodiment relates to a compound of formula (XVII) where R ⁵ is hydrogen, halogen or alkyl. Another embodiment relates to a compound of formula (XVII) wherein R ⁶ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (XVII) wherein R ⁶ is heterocyclyl. Another embodiment relates to a compound of formula (XVII) wherein R ⁶ is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XVII) wherein R ⁶ is alkoxy, cycloalkyloxy, or cycloalkylalkoxy.

Another embodiment relates to a compound of formula (XVII) wherein Y is a bond. Another embodiment relates to a compound of formula (XVII) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XVII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XVII) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XVII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XVII) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XVII) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XVII) wherein Z is —N (R ²² ) CO ₂ R ²¹ . Another embodiment relates to a compound of formula (XVII) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (XVII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XVII) wherein R ²¹ is alkyl. Another embodiment relates to a compound of formula (XVII) wherein W is —O—. Another embodiment relates to a compound of formula (XVII) wherein W is —NH—. Another embodiment relates to a compound of formula (XVII) wherein X is alkyl. Another embodiment relates to a compound of formula (XVII) wherein X is alkynyl. Another embodiment relates to a compound of formula (XVII) wherein X is aryl. Another embodiment relates to a compound of formula (XVII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XVII) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XVII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XVII) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (XVII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XVII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XVII) wherein W is —O— and X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XVII) wherein R ⁶ is CD3.

One embodiment relates to a compound of formula (XVIII) or a pharmaceutically acceptable salt thereof r ^a

G

R ²

Formula (XVIII) wherein R ² is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X1 is CH or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

- 54 038715

Y is selected from a bond, -CH2- or -CH _(C1-C4 alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) ₂ , -N (R ²² ) CO2R ²¹ ,

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO ₂ N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is S;

X4 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen or -WX, where W is a bond, -O-, -S-, or

—NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

One embodiment relates to a compound of formula (XIX), or a pharmaceutically acceptable salt thereof

where Q is N and T is C or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring having one or more nitrogen atoms;

R ^{2 is} selected from CH3, CH ₂ CH3, CH ₂ CF3, CH ₂ F, CHF ₂ , CF3, CH ₂ D, CHD _2, or CD3;

X1 is CH or N;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) ₂ , -OSO ₂ N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is S;

X4 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen or -WX, where W is a bond, -O-, -S-, or

—NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XIX) where X2 is N. Another embodiment relates to a compound of formula (XIX) where X4 is N. Another embodiment relates to a compound of formula (XIX) where X2 is CR ¹² . Another embodiment relates to a compound of formula (XIX) wherein X4 is C — R ¹⁴ .

Another embodiment relates to a compound of formula (XIX), wherein the compound of formula (XIX) is selected from the group:

- 55 038715

Another embodiment relates to a compound of formula (XIX) where Q is N and T is C. Another embodiment relates to a compound of formula (XIX) where Q is C and T is N. Another embodiment relates to a compound formula (XIX), where R ² is CH ₃ . Another embodiment relates to a compound of formula (XIX) wherein X1 is CH. Another embodiment relates to a compound of formula (XIX), wherein X1 is N.

Another embodiment relates to a compound of formula (XIX) wherein Y is a bond. Another embodiment relates to a compound of formula (XIX) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XIX) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XIX) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XIX) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XIX) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XIX) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XIX) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (XIX) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (XIX) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XIX) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XIX) wherein W is —O—. Another embodiment relates to a compound of formula (XIX) wherein W is —NH—. Another embodiment relates to a compound of formula (XIX) wherein X is alkyl. Another embodiment relates to a compound of formula (XIX) wherein X is aryl. Another embodiment relates to a compound of formula (XIX) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XIX) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XIX) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XIX) wherein W is —O— and X is cycloalkylalkyl.

One embodiment relates to a compound of formula (XX), or a pharmaceutically acceptable salt thereof

where ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R ^{2 is} selected from CH3, CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD _2, or CD ₃ ;

X1 is CH or N;

R ^a represents

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -;

Z is selected from -SO ₂ R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N ( R ²² ) CO2 R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is S;

X4 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XX) wherein X2 is N. Another embodiment relates to a compound of formula (XX) wherein X4 is N.

- 56 038715

Another embodiment relates to a compound of formula (XX) wherein X2 is CR ¹² . Another embodiment relates to a compound of formula (XX) wherein X4 is

CR ¹⁴ .

Another embodiment relates to a compound of formula (XX), wherein the compound of formula (XX) has a formula selected from:

where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkyl, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2 ; and R ³¹ represents a C1-C ₄ -alkyl.

Another embodiment relates to a compound of formula (XX), wherein the compound of formula (XX) has a formula selected from:

⁰ , ⁰ - O _and and O where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkyl, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2; and R ³¹ represents a C1-C ₄ -alkyl.

Another embodiment relates to a compound of formula (XX), wherein the compound of formula (XX) has a formula selected from:

where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkyl, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2 ; and R ³¹ represents a C1-C ₄ -alkyl.

Another embodiment relates to a compound of formula (XX) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (XX) wherein X1 is CH. Another embodiment relates to a compound of formula (XX) wherein X1 is N.

Another embodiment relates to a compound of formula (XX) wherein Y is a bond. Another embodiment relates to a compound of formula (XX) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XX) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XX) wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XX) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XX) wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XX) wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XX) wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (XX) wherein Z is —N (R ²² ) CON (R ²² ) 2. Another embodiment relates to a compound of formula (XX) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XV) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XX) wherein W is —O—. Another embodiment relates to a compound of formula (XX) wherein W is —NH—. Another embodiment relates to a compound of formula (XX) wherein X is alkyl. Another embodiment relates to a compound of formula (XX) wherein X is alkynyl. Another embodiment relates to a compound of formula (XX) wherein X is aryl. Another embodiment relates to a compound of formula (XX) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XX) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XX) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XX) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XX) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (XX) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XX) wherein W is —O— and X is cycloalkylalkynyl.

- 57 038715

One embodiment relates to a compound of formula (XXI), or a pharmaceutically acceptable salt thereof

where R ² represents CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD ₂ or CD ₃ ;

X1 is CH or N;

ring B is an optionally substituted 5- or 6-membered heterocyclic ring containing at least one oxygen or nitrogen atom;

R ¹⁵

O

R ¹³

R ^a is ^r12 ;

R ¹² is hydrogen or C ₁ -C ₄ alkyl;

R ¹³ represents -YZ;

Y is selected from —CH ₂ - or —CH (C ₁ -C ₄ alkyl) -;

Z. selected from -SO2R ²¹ , -SO2N (R ²² ) 2 or -CON (R ²² b;

R ¹⁵ is hydrogen, halogen or C ₁ -C ₄ -alkyl;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl. One embodiment relates to a compound of formula (XXII), or a pharmaceutically acceptable salt thereof

where Q is N and T is C or Q is C and T is N;

Ring B is an optionally substituted 5-membered aromatic nitrogen-containing heteroaryl ring having one or more nitrogen atoms;

R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X1 is CH or N;

R ¹⁵

O

R ¹³

R ^a is ^r12 ;

R ¹² is hydrogen or C ₁ -C ₄ alkyl;

R ¹³ represents -YZ;

Y is selected from —CH ₂ - or —CH (C ₁ -C ₄ alkyl) -;

Z is selected from —SO2R ²¹ , —SO2N (R ²² ) 2, or —CON (R ²² ) 2;

R ¹⁵ is hydrogen, halogen or C ₁ -C ₄ -alkyl;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XXII), wherein the compound of formula (XXII) is selected from the group:

- 58 038715

Another embodiment relates to a compound of formula (XXII) where Q is N and T is C. Another embodiment relates to a compound of formula (XXII) where Q is C and T is N. Another embodiment is to a compound of formula (XXII) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (XXII) wherein X1 is CH. Another embodiment relates to a compound of formula (XXII) wherein X1 is N.

Another embodiment relates to a compound of formula (XXII) wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XXII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XXII) wherein Z22 is —SO ₂ N (R) ₂ . Another embodiment relates to a compound of formula (XXII) wherein Z is —CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (XXII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XXII) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XXII) wherein W is —O—. Another embodiment relates to a compound of formula (XXII) wherein W is —NH—. Another embodiment relates to a compound of formula (XXII) wherein X is alkyl. Another embodiment relates to a compound of formula (XXII) wherein X is aryl. Another embodiment relates to a compound of formula (XXII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XXII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XXII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XXII) wherein W is —O— and X is cycloalkylalkyl.

One embodiment relates to a compound of formula (XXIII), or a pharmaceutically acceptable salt thereof

where ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2, or CD3;

X1 is CH or N;

R ^a represents

R ¹² is hydrogen or C ₁ -C ₄ alkyl;

R ¹³ represents -YZ;

Y is selected from —CH ₂ - or —CH (C ₁ -C ₄ alkyl) -;

Z is selected from —SO ₂ R ²¹ , —SO2N (R ²² ) 2, or —CON (R ²² ) ₂ ;

R ¹⁵ is hydrogen, halogen or C ₁ -C ₄ -alkyl;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkynyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl; or, optionally, R ¹⁶ and R ¹⁵ join to form a ring;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

- 59 038715

Another embodiment relates to a compound of formula (XXIII), wherein the compound of formula (XXIII) has a formula selected from:

_R 30 ra XX ΐ

Ά-, -uf ,, -Uf „-w„

O, ^R O, O and and ^r3 ° O where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkyl, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2 , -CONHR ³¹ , -CON (R ³¹ ) 2; and R ³¹ represents a C1-C ₄ -alkyl.

Another embodiment relates to a compound of formula (XXIII), wherein the compound of formula (XXIII) has a formula selected from:

R ^A r ^a r ^a r ^a _r u ⁿ yS ^r3 ° xxx ^r3 XtS ^r3 XxS <UDG R ^{2 N} IR ^{2 s} 1 r ^{2 N} ϊ ^R2

Ο, O, O and and O where each R ^{30 is} independently selected from hydrogen, halogen, —CN, C ₁ -C ₄ -alkyl, —OH, —OR ³¹ , —NHR ³¹ , —N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2; and R ³¹ is A ^ -alkyl.

Another embodiment relates to a compound of formula (XXIII), wherein the compound of formula (XXIII) has a formula selected from:

R30 R ^a R ^a _R 30 R ^a R ^a pX ⁰ , ⁰ . О and ^R О _; where each R ^{30 is} independently selected from hydrogen, halogen, -CN, C1-C4-alkyl, -OH, -OR ³¹ , -NHR ³¹ , -N (R ³¹ ) 2, -CONHR ³¹ , -CON (R ³¹ ) 2 ; and R ³¹ represents a C1-C ₄ -alkyl.

Another embodiment relates to a compound of formula (XXIII) wherein R ² is CH ₃ . Another embodiment relates to a compound of formula (XXIII) wherein X1 is CH. Another embodiment relates to a compound of formula (XXIII) wherein X1 is N.

Another embodiment relates to a compound of formula (XXIII) wherein Y is —CH2—. Another embodiment relates to a compound of formula (XXIII) wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XXIII) wherein Z is —SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XXIII) wherein Z is —CON (R ²² ) ₂ . Another embodiment relates to a compound of formula (XXIII) wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIII) wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XXIII) wherein W is —O—. Another embodiment relates to a compound of formula (XXIII) wherein W is —NH—. Another embodiment relates to a compound of formula (XXIII) wherein X is alkyl. Another embodiment relates to a compound of formula (XXIII) wherein X is alkynyl. Another embodiment relates to a compound of formula (XXIII) wherein X is aryl. Another embodiment relates to a compound of formula (XXIII) wherein X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIII) wherein X is cycloalkylalkynyl. Another embodiment relates to a compound of formula (XXIII) wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XXIII) wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XXIII) wherein W is —O— and X is alkynyl. Another embodiment relates to a compound of formula (XXIII) wherein W is —O— and X is cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIII) wherein W is —O and X is cycloalkylalkynyl.

One embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof

R ¹⁴ R ¹ VCr

R ¹⁶

R ^B

Formula (XXIV) where R ¹³ represents -YZ;

Y is selected from a bond or -CH2-;

- 60 038715

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ ,

-N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2, -N (R ²² ) SO3R ²¹ or -N (R ²² ) 2;

R ¹⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

R ¹⁵ is halogen or UV, where U is a bond, —O— or —CH ₂ -; and V is —CN, alkyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ¹⁶ is hydrogen;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ^B is where R ² is CH ₃ ;

X5 is CH;

X6 is CR ⁶ ;

X7 is CR ⁷ ;

X8 is CH;

R ⁶ is hydrogen or halogen;

R ⁷ is hydrogen or halogen; or

R ^B is where R ² is CH3;

X6 is CH;

X5 is CR ⁵ ;

R ⁵ is hydrogen or halogen;

R ⁶ is hydrogen, alkyl, alkoxy, or halogen; or

R ^B is where Ring B is an optionally substituted 5-membered heteroaryl ring containing at least one oxygen or sulfur atom;

R ² represents CH ₃ ; and

X1 is CH.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is —CH ₂ -. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is —SO ₂ R ²¹ , —N (R ²² ) SO2R ^21, or —N (R ²² ) 2.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is —SO2R ²¹ or —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is —N (R ²² ) SO2R ²¹ . Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Z is —SO2R ²¹ .

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ²¹ is heterocyclyl or heterocyclylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ²¹ is alkyl and said alkyl is C ₁ -C ₄ alkyl.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ²² is alkyl, cycloalkyl, or aralkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ²² is hydrogen or methyl.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is hydrogen.

- 61 038715

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is a bond. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is —O—.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein U is —CH2—.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is alkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is aryl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is aralkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is heterocyclylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is heteroaryl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is heteroarylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein V is alkynyl.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is —N (R ²² ) SO2R ²¹ , U is —O— and V is aryl, aralkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond, Z is —SO2R ²¹ , U is —O— and V is aryl, aralkyl, or cycloalkylalkyl.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ^B is ⁰

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is halogen and R ⁷ is hydrogen. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen and R ⁷ is halogen. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is hydrogen and R ⁷ is hydrogen.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ^B is ^o

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is hydrogen and R ⁶ is alkyl. Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is methyl.

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein R ^B is ^o

Another embodiment relates to a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 5-membered heteroaryl ring containing one oxygen atom.

One embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof

Formula (XXV)

- 62 038715 where ring B represents an optionally substituted 5-, 6- or 7-membered non-aromatic carbocyclic ring;

R ^{2 is} selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ F, CHF ₂ , CF ₃ , CH ₂ D, CHD _2, or CD ₃ ;

X3 is CH or N;

R ^a represents ^{X2 R} ;

X2 is N or CR ¹² , where R ¹² is hydrogen, halogen, alkyl or alkoxy;

R ¹³ represents -YZ;

Y is selected from a bond or —CH ₂ -;

Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ;

X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, alkyl, cycloalkyl, or alkoxy;

X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, alkyl or alkoxy;

R ¹⁶ is hydrogen, halogen, or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

each R ^{21 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; and each R ^{22 is} independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 5-membered non-aromatic carbocyclic ring. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 6 membered non-aromatic carbocyclic ring. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 7-membered non-aromatic carbocyclic ring.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R ² is CH ₃ .

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X3 is CH. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X3 is N.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Y is a bond. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Y is —CH2—.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —SO2R ²¹ . Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —N (R ²² ) SO2R ²¹ .

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —SO ₂ N (R ²² ) 2. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —N (R ²² ) SO2N (R ²² ) 2. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —CON (R ²² ) 2. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —N (R ²² ) CO2R ²¹ . Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein Z is —N (R ²² ) CON (R ²² ) 2.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R ²¹ is alkyl, cycloalkyl, or cycloalkylalkyl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R ²¹ is alkyl.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is hydrogen, halogen, or alkyl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X4 is CR ¹⁵ . Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is —O—. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is —NH—.

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Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is alkyl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is aryl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein X is cycloalkylalkyl.

Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is —O— and X is alkyl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is —O— and X is aryl. Another embodiment relates to a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, wherein W is —O— and X is cycloalkylalkyl.

In some embodiments, the substituted heterocyclic compound described herein has the structure shown in table. one.

Table 1

An example of chemical synthesis Structure Name 2 one O t PA O 4- (3-methoxyphenyl) -2methylisoquinolin-1-one 3 O 4- (2-fluorophenyl) -2- methylisoquinolin-1-one 4 o k ° <M) / 4- (2-methoxyphenyl) -2- methylisoquinolin-1-one 5 .. OU O 4- (3 -aminophenyl) -2- methylisoquinolin-1-one 6 Υ _ο ΗΝ. ° Ό Of. O N-cyclopropyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide 7 OQ. O 2-methyl-4- (3-pyrrolidine-1 ylsulfonylphenyl) isoquinoline- 1st

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eight % ' / NH 0 X - [[3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methyl] methanesulfone Ministry of Foreign Affairs 9 0-0 = ° ο. And - ζ ρ X- [3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 10 / = \ Ο ° = G ^ D ζ Ν-ethyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide AND ° Ό CO. II 0 4- (3-ethylsulfonylphenyl) -2methylisoquinolin-1-one 12 ^Χ Ν ^ 0 = S = 0 τ ρΛ II 0 4- [3- (dimethylsulfamoylamino) phen yl] -2-methyl-1-oxoisoquinoline thirteen 0 = S-0 Ό Οφ 0 X- [3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide

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14 / = 4 θ ζ - / \ ^ = / / 2-methyl-4- (3-morpholine-4ylsulfonylphenyl) isoquinoline- 1st 15 ϊ? Ζ ^ΝΗ rV 'c $. X-benzyl-2-methoxy-5- (2-methyl- 1-oxoisoquinoline-4yl) benzenesulfonamide sixteen ΐ?, - ^ΝΗ Ϋ '° CQ. 0 2-methoxy-5 - (2-methyl-1 OXOISOCHINOLIN-4yl) benzenesulfonamide 17 0. —S = o τ Οζλ 0 X- [2-methyl-5- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide eighteen / = \ o 0 / = ^ ^ = ^{7 ο =} 0 · "° / X-benzyl-2-methoxy-5- (2-methyl1-oxoisoquinoline-4yl) benzamide nineteen ΗΝ.Λ. Τ ¢ 0. π 0 4- (3,4-d and hydro-2H-1,4benzoxazin-6-yl) -2methylisoquinolin-1-one

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twenty ° yx_ / CH? ° \ 7 2-methyl-4- (2-oxo-1,3- dihydroindol-6-yl) isoquinoline- 1st 21 O // ° f 3 - (2-methyl-1-oxoisoquinoline-4yl) benzenesulfonamide 22 OH HN./O CP 0 N- (2-hydroxyethyl) -3- (2-methyl- 1-oxoisoquinoline-4yl) benzenesulfonamide 23 r \ / 0 ^ 0 ° - O 4- (5-amino-2-fluorophenyl) -2methylisoquinolin-1-one 24 F _F V ΟζΧ о 4- (5-amino-2,4-difluorophenyl) -2methylisoquinolin-1-one 25 F ^ X> ^ NH ₂ rr СцХ 0 4- (3-amino-5-fluorophenyl) -2methylisoquinolin-1-one 26 О J ^{o =} C / O · / 4- (3-amino-4-fluorophenyl) -2methylisoquinolin-1-one

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27 ° Ό Su, 0 M-benzyl-3- (2-methyl-1- OXOISOCHINOLIN-4yl) benzenesulfonamide 28 o = s = o ΊΟ sL 0 X- [3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] propane-1 sulfonamide 29 ^ 0 = 5 = 0 τ 0 M- [3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] butane-1 -sulfonamide thirty Ο ζ-ω ο I U Ν- [2-methoxy-5- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 31 Λ ° Ό 0Q, 0 tert-butyl Ν-μ6τηπ-Ν- [3- (2- methyl 1-oxoisoquinoline-4yl) phenyl] carbamate 32 one τ Su, 2-methyl-4- [3- (methyl amino) phenyl] isoquinoline -1-he

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33 0 o = s— / sXk τ OCX and 0 Ν-μ6τηπ-Ν- [3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 34 0 o = s— Οςχ 0 N- [4-fluoro-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 35 O ^{o =} OAU o X- [2,4-difluoro-5- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 36 0 o = s— at oU 0 X- [3-fluoro-5- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 37 0 F - Sko Τ ΟξΧ 0 N- [2-fluoro-5 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 38 0 —s = o 1Ύ Cl ^z y ^ αΑ 0 X- [4-chloro-3- (2-methyl-1- OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide

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39 o O ₌ S - XX CQ. O N- [4-methyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 40 0 o = s— _c rr ^F aA II 0 M- [3- (2-methyl-1- oxoisoquinolin-4-yl) - 5 (trifluoromethyl) phenyl] methanesul fonamide 41 0 OzSL- 'XI ⁿ \ IL X iXX 0 M- [4-fluoro-3- [2-methyl-6- (1methylpyrazol-4-yl) -1 oxoisoquinoline-4yl] phenyl] methanesulfonamide 42 0 o = s - VV ¹ n <π 1 uy. N- [3- [2-methyl-6- (1 methylpyrazol-4-yl) -1 oxoisoquinoline-4yl] phenyl] methanesulfonamide 43 F - S = O 'XT ⁿ ' AaA o M- [2,4-difluoro-5- [2-methyl-6- (1methylpyrazol-4-yl) -1 oxoisoquinoline-4yl] phenyl] methanesulfonamide 44 '° Ό 'Ji I iXX 0 4- (3-ethylsulfonylphenyl) -2methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one

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o = s = o N- [4-chloro-3 - [2-methyl-6- (1 - 45 Ν-η methylpyrazol-4-yl) -1 - OXOISOCHINOLIN-4- yl] phenyl] ethansul f onamide 4- [2- (cyclopropylmethoxy) -5 - 46 '' to 1 ^Ν ~ π Υό ^ υ? ^ν ύΑ ^ν 0 methylsulfonylphenyl] -2methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one 0 o = s— Γ 0 Ν- [3 - (6-fluoro-2-methyl-1 - 47 OXOISOCHINOLIN-4- 4χχ 0 yl) phenyl] methanesulfonamide ^Η2 %? ^ ° Ό 3 - (6-fluoro-2-methyl-1 - 48 0 OXOISOCHINOLIN-4- yl) benzenesulfonamide 49 ΗΝ. ⁰ ° Ό 0 N-ethyl-3 - (6-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide ^ x ^ NHSC ^ Et ίΐ Ί Cl ^ f Ν- [4-chloro-3 - (6-fluoro-2-methyl-1 - 50 FyUx OXOISOCHINOLIN-4- γ Me yl) phenyl] ethanesulfonamide 0

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51 0 o ₌ s - т ιίΧΑι ΤΙ 0 Ν- [3 - (2-methyl-1-oxo-2,7 naphthyridine-4- yl) phenyl] methanesulfonamide o = s = o ^Η γ ^ Ν- [3 - (2-methyl-1-oxo-2,7 - 52 ίί ^ Αι 0 naphthyridine-4- yl) phenyl] ethanesulfonamide ΗΝ. > o ⁰ Г 11 N-ethyl-3 - (2-methyl-1-oxo-2,7 - 53 naphthyridine-4- guts 0 yl) benzenesulfonamide ... r-0 Ϊ 'Ζ ^ΝΗ X-benzyl-2-methoxy-5- (2-methyl- 54 1-oxo-2,7-naphthyride in-4- ίί ^ ΓΊ 0 yl) benzenesulfonamide η ₂ % ° ° Ό 3 - (2-methyl-1-oxo-2,7- 55 yA ^Ν Χί ^ χχΝ _ν 0 naphthyridine-4- yl) benzenesulfonamide & 2-methoxy-5- (2-methyl-1-oxo 56 0 2,7-naphthyr idin-4yl) benzenesulfonamide

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57 M ^s ο = ς / 'o M- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-2,7-naphthyr idin-4yl) phenyl] ethanesulfonamide 58 ο = έ— Ό Μ 0 N- [3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 59 HN _S 0 • ”o, JCQ 0 N-ethyl-3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide 60 ? o <, nh ^ y ° XXd X-benzyl-5- (7-fluoro-2-methyl-1oxoisoquinolin-4-yl) -2methoxybenzenesulfonamide 61 ^H 2 ^N. _s ? ° O o 3 - (7-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) benzenesulfonamide 62 0 = 1 = 0 t ΓΥ ^ 0 N- [3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide

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63 _ / € H> ° H / Ο _ ^ ° \ = ^ LL 4- (3-ethylsulfonylphenyl) -7 fluoro-2-methylisoquinolin-1-one 64 Q oZY / y _o / \ Y 5- (7-fluoro-2-methyl-1 oxoisoquinolin-4-yl) -2methoxybenzenesulfonamide 65 Ν — N X 0 2-methyl-4- (1-methylpyrazol-4yl) isoquinolin-1-one 66 Cp O 4- (furan-2-yl) -2- methylisoquinolin-1-one 67 OP pA 0 2-methyl-4- (1,3-oxazol-2yl) isoquinolin-1-one 68 / = N NH pA 0 2-methyl-4- (1 H-pyrazol-5 yl) isoquinolin-1-one 69 nCA ^ nA 0 2-methyl-4- (1-methylimide azol-2 yl) isoquinolin-1-one

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70 All aA 0 2-methyl-4-pyridin-2ylisoquinolin-1-one 71 (^ 11 N ^ N Wv'k about 2-methyl-4-pyrimidin-2ylisoquinolin-1-one 72 o = s = o _N V 0 M- [3- [2-methyl-6- (6- methylpyridin-3 -yl) -1 - OXOISOCHINOLIN-4- yl] phenyl] ethansul f onamide 73 / _o 041 / ° / -az and \ s ^T o ^T \ = J o N- [3 - (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] ethanesulfonamide 74 1 ° oJs— A Wv ^N4 0 N- [3 - (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] methansul phonamide 75 0Ύ0 t AA ⁿ \ o N- [3- (2,6-dimethyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide

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76 / _o νΗ? ° ax? O Ν- [3 - (6-ethyl-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide 77 О €> ° О ώ - z vy о ¹ \ = / Ν- [3 - (6-ethyl-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 78 o o = s - ^HN s ^ x \ m AQ, o Ν- [3- (2,6-dimethyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide 79 A ° '° X1 -Su dA kXX 0 4- (5-ethylsulfonyl-2methoxyphenyl) -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline- 1st 80 aa / = 4 o / W 'y ^ = / ⁷ o 4- (5-ethylsulfonyl-2-hydroxyphenyl) -2-methyl-6- (1methylpyrazol-4-yl) isoquinoline- 1st 81 k ° ν 'XA ⁿ \ II f ΐΓΥ ⁴ ! 0 4- (2-ethoxy-5- ethylsulfonylphenyl) -2-methyl6- (1-methylpyrazole-4- yl) isoquinolin-1-one 82 G o o / la _A ° O 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -2-methyl- 6- (1-methylpyrazole-4- yl) isoquinolin-1-one

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83 v Xl. ^ ^N kll T 0 4- (5-ethylsulfonyl-2propoxyphenyl) -2-methyl-6- (1methylpyrazol-4-yl) isoquinoline- 1st 84 1 ° ' ⁰ TI.% Uc _c ^ OH 0 4- [5-ethylsulfonyl-2- (2-hydroxyethoxy) phenyl] -2-methyl- 6- (1-methylpyrazole-4- yl) isoquinolin-1-one 85 s A ' ¹ ''' ” ⁿ kJL 1 0 4- [2- (2-aminoethoxy) -5 ethylsulfonylphenyl] -2-methyl- 6- (1-methylpyrazole-4- yl) isoquinolin-1-one 86 _F O = S = O> ... Xi n <II 1 o Ν- [2-fluoro-4-methoxy-5 - [2-methyl6- (1-methylpyrazol-4-yl) -1 oxoisoquinolin-4yl] phenyl] ethansul fonamide 87 o = s = o _ ΤΙ) O Ν- [3 - (2-methyl-1-oxo-6pyridin-2-yl-isoquinolin-4yl) phenyl] ethanesulfonamide 88 _F - ^ = 0 'Τ' 4- [4-fluoro-2-methoxy-5- (methyl sulfonyl methyl) phenyl] 2-methyl-6- (1-methylpyrazole-4- yl) isoquinolin-1-one 89 / ⁼ \ ° W Τ ^ω; ° ° = w) ^/ 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methylisoquinolin-1-one

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90 ⁰ \ 7 0 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6-fluoro2-methylisoquinolin-1-one 91 'XI fv 0 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -7-fluoro2-methylisoquinolin-1-one 92 Od '0 4- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -2methylisoquinolin-1-one 93 Ί o = s = o Μγ ^Ν 4 0 M- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxoisoquinoline-4yl) phenyl] ethanesulfonamide 94 O —S = o? O N- [3 - (1-methyl-6-oxopyrid in-3 yl) phenyl] methanesulfonamide 95 O o = s - y VO N- [3 - (1,4-dimethyl-6oxopyridin-3yl) phenyl] methanesulfonamide

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96 ^Z 'i'i? ⁷⁰ O N- [3 - (1,5-dimethyl-6oxopyridin-3yl) phenyl] methanesulfonamide 97 1 ° o4s— T χχ 0 M- [3- (1,4,5-trimethyl-6oxopyrid in-3 yl) phenyl] methanesulfonamide 98 o ~ o °° o 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 methylpyridin-2-one 99 o = s = o 0 X- [4- (2,4-difluorophenoxy) -3- (1methyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide one hundred 0 - s = o F ^ x ^. / ^NH хцх uch 0 X- [4- (2,4-difluorophenoxy) -3- (1methyl-6-oxopyrid in-3 yl) phenyl] methanesulfonamide 101 0 o = s'— G 0 X- [4- (2,4-difluorophenoxy) -3 (1,4-dimethyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide

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102 0 —s = o Ό. jQf " 2 0 M- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyr-idin-3 yl) phenyl] methanesulfonamide 103 oJs— W χχ ^F 0 X- [4- (2,4-difluorophenoxy) -3 (1,4,5-trimethyl-6-oxopyridin3-yl) phenyl] methanesulfonamide 104 o> ° ? O 3-amino-1-methyl-5- (3 - methylsulfonylphenyl) pyrazin2-one 105 U ° 0 3-amino-5- (3ethylsulfonylphenyl) -1 methylpyrazin-2-one 106 Ζ-ω _; Ο I II o N- [5 - (6-amino-4-methyl-5 oxopyrazin-2-yl) -2methoxyphenyl] methanesulfonami d 107 z ° <H> 'o 3-amino-1-methyl-5- (3 methylsulfonylphenyl) pyridine- 2nd

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108 ΣΕ ^{o =} O ^ Q / \ o o ^ \ 3-amino-5- (3ethylsulfonylphenyl) -1 methylpyrid in-2-one 109 X I iL z z - ω o PP / Ν- [5 - (5-amino-1-methyl-6oxopyrid in-3-yl) -2methoxyphenyl] methanesulfonami d 110 0 o = s - ^x o hit γ ^{4 1} 0 X- [2-methoxy-5- [1-methyl-5 (methylamino) -b-oxopyridin-3 yl] phenyl] methansul phonamide 111 0 o = s - ^x o T Λ HN ^ ^X y ⁰ X- [5- [5- (ethylamino) -1-methyl-6oxopyrid in-3-yl] -2methoxyphenyl] methanesulfonami d 112 \ II i? zz - ω o ^{o =} Q ^h ^ ^h ° / N- [5- [5- (cyclopropylmethylamino) -1 methyl-6-oxopyrid in-3-yl] -2methoxyphenyl] methanesulfones d

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from o o = s - ^x o ¹ O M- [5- [5- (dimethylamino) -1methyl-6-oxopyridin-3 -yl] -2methoxyphenyl] methanesulfones D 114 O - ° '- - ω: o ^{o =} \ V ~ O ~ ° / K- [5- [5- (diethylamino) -1-methyl6-oxopyrid in-3 -yl] -2methoxyphenyl] methanesulfones e 115 \ _ ^m > —L - Ζ O K> - O-O = ° 0 □ _ K- [3- (5-amino-1-methyl-6oxopyridin-3-yl) -4- (2,4difluorophenoxy) phenyl] ethanesul fonamide 116 ^ Js '° Il ίΓ' ° 0 3-amino-5- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 methylpyridin-2-one 117 > o ° <X> ⁷ l? ° ° 'and 4-ethoxy-3 - (1-methyl-6oxopyridin-3yl) benzenesulfonamide 118 F ⁵ g 0 4- (2,4-d ifluorophenoxy) -3 - (1 methyl-6-oxopyrid in-3 yl) benzenesulfonamide

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119 -π О ^{o =} GAO 'А 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3-fluoro- 1-methylpyridin-2-one 120 ω ^χ ° ^ - £ ^ = o o ^w y 5- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -3 -fluoro1-methylpyridin-2-one 121 "\ O O ^ \ __ / 0 ^ 0 ° A LL 5- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one 122 Г o = s = o ^F 'Q, Γχ? X- [4- (2,4-difluorophenoxy) -3- (5fluoro-1-methyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide 123 o = s = o A 0 X- [3- (2-methyl-1-oxo-2,6naphthyridin-4yl) phenyl] ethanesulfonamide 124 / O ~ CA O rf ° ^ = ⁷ N-ethyl-3 - (2-methyl-1-oxo-2,6naphthyridine-4yl) benzenesulfonamide

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125 0 O _: S— T nAnX Ά ^ [3- (2-methyl-1-oxo-2,6- naphthyridine-4- yl) phenyl] methanesulfonamide 126 ° Ό ^Ν χ 0 4- (3-ethylsulfonylphenyl) -2methyl-2,6-naphthyridin-1-one 127 οΧο F ZoZ 0 M- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-2,6-naphthyr idin-4yl) phenyl] ethanesulfonamide 128 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methyl-6- (4-methylpyrazol-1 yl) isoquinolin-1-one 129 % ο ° C ° <Χ> _ο / \ 11 ζ-ω — ν ¹ ό '^ X- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxoimidazo [1,5а] pyrazin-5 yl) phenyl] ethanesulfonamide 130 W ν ^ Α Ο 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -7methylimidazo [1,5-a] pyrazine-8- he

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131 A \ ^ Υχ ^Ν χ, 0 7-methyl-5- (3- methylsulfonylphenyl) imidazo [ 1,5-a] pyrazin-8-one 132 O O = S— γ and about X- [2-methoxy-5- (7-methyl-8oxoimidazo [1,5-a] pyrazine-5yl) phenyl] methanesulfonamide 133 θυ O'·· Χί ^ ΧχχΝχ. 0 5 - (3-ethylsulfonylphenyl) -7 methylimidazo [1,5-a] pyrazine-8- he 134 Η W 'Λ 0 X- [3- (5-chloro-1-methyl-6oxopyridin-3-yl) -4- (2,4difluorophenoxy) phenyl] ethanesul fonamide 135 sf. 0 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -2methylisoquinolin-1-one 136 A 'θ-θ = ο ί 6- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2,4d imethylpyridazin-3-one

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137 _ XA 0 6- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2.5 d-immethylpyridazin-3-one 138 o = s = o XuY uS ^F F 0 X- [4- (2,4-difluorophenoxy) -3- [1 methyl-6-oxo-5 (trifluoromethyl) pyridin-3 yl] phenyl] ethanesul lf onamide 139 0 = 1 = 0 'G 0 X- [4- (2,4-difluorophenoxy) -3- (4fluoro-1-methyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide 140 r 0 = 3 = 0 Ll 1J N- [3- (5-cyclopropyl-1-methyl-6oxopyridin-3-yl) -4- (2,4difluorophenoxy) phenyl] ethanesul fonamide 141 H ό "h IX ^2h N- {4- (2,4-difluorophenoxy) -3 - [1 ( ² Hs) methyl-6-oxopyridin-3 yl] phenyl} ethanesul phonamide 142 r \ - υ ° = O-0 ° X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-5,6,7,8-tetrahydro2,6-naphthyr idin-4yl) phenyl] ethanesulfonamide 143 0 o = s— of. 0 4- [5 - (cyclopropylmethoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -2-methylisoquinoline-1 - he

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144 ό ”° 5 - [5 - (cyclopropylmethoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -1,3-d-immethylpyrid in-2one 145 0 o = s— 4- [5 - (cyclopropylmethoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -2-methyl-6- (1 - methylpyrazol-4-yl) isoquinolin1-one 146 at -o about > —Ω · ο O 5- [5- (2,4-difluorophenoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -3-methoxy-1 - methylpyridin-2-one 147 О ^: С0— \ 5- [5- (2,4-difluorophenoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -1,3-d-immethylpyrid in-2- he 148 o = s— V sU 0 4- [5- (2,4-difluorophenoxy) -2 (methylsulfonylmethyl) pyrimid in-4-yl] -2-methylisoquinoline-1 - he 149 OH 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4yl] -1,3-d-immethylpyridin-2-one 150 △ -o about ° = \ h Y ^ h (L 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4yl] -3-methoxy-1-methylpyridin2-one

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151 %? N. .. 'OuCr 4- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4yl] -2-methylisoquinolin-1-one 152 О o = s— nk V-v αχ 0 X- [5- (cyclopropylmethoxy) -4 (2-methyl-1-oxoisoquinoline-4yl) pyrimidin-2yl] methanesulfonamide 153 O/ Before "O" M- [5- (cyclopropylmethoxy) -4 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] methanesulfonamide 154 0 o ^ sΗΝγΝ 0 X- [5- (cyclopropylmethoxy) -4 [2-methyl-6- (1-methylpyrazol-4yl) -1-OXOISOCHINOLIN-4yl] pyrimidin-2yl] methanesulfonamide 155 O = S = O HN. _N. Οζλ O X- [5- (cyclopropylmethoxy) -4 (2-methyl-1-oxoisoquinoline-4yl) pyrimidin-2yl] ethanesulfonamide 156 ^ot> ° XX sD 0 4- [5 - (cyclopropylmethoxy) -2 (1,1-dioxo-1,2-thiazolidin-2yl) pyrimidin-4-yl] -2methylisoquinolin-1-one

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157 0 = 1 = 0 ^Η Υϊ ΧΑγ-Νχ 0 X- [5- (cyclopropylmethoxy) -4 (6-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) pyrimidine-2yl] ethanesulfonamide 158 0 OzS ^ ΗΝ. ^, Ν. XI__ ⁰ \ 7 0 X- [5- (cyclopropylmethoxy) -4 (7-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) pyrimidine-2yl] methanesulfonamide 159 0 o = s - HN. _N. ⁰ \ 7 0 X- [5- (cyclopropylmethoxy) -4 (6-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) pyrimidine-2yl] methanesulfonamide 160 o = s = o HN. Xl ^ 1 ⁰ \ 7 ΓΡ ¹ 0 M- [5- (cyclopropylmethoxy) -4 (7-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) pyrimidine-2yl] ethanesulfonamide 161 0 ods- ^N ck 0 M- [5- (cyclopropylmethoxy) -4 (2-methyl-1-oxoisoquinolin-4yl) pyrimidin-2-yl] methylmethanesulfonamide 162 .N. V · '" X ' O X- [5- (cyclopropylmethoxy) -4 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-2-yl] -Methylmethanesulfonamide

- 89 038715

163 0 o = s— HN. _N. O (L 0 X- [5- (cyclopropylmethoxy) -4 (2-methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] methanesulfonamide 164 o = s = o HN. _N. Y 11 N \ IL ⁰ \ 7 0 X- [5- (cyclopropylmethoxy) -4 (2-methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide 165 o = s - HN. .N. _F пй o ^z aA ^f 0 M- [5- (2,4-difluorophenoxy) -4- (2methyl-1-oxoisoquinolin-4yl) pyrimidine-2yl] methanesulfonamide 166 p \ ° ° PP, ζ-ω ο I II o X- [5- (2,4-difluorophenoxy) -4 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] methanesulfonamide 167 0 -o about ζ-ω ο I II ο X- [5- (2,4-difluorophenoxy) -4- (5methoxy-1-methyl-6- oxopyrid in-3-yl) pyrimidin-2yl] methanesulfonamide 168 Α -ο ο ΑΑ ϊ-.ν- \ ο ' X- [5- (2,4-difluorophenoxy) -4- (5methoxy-1-methyl-6- oxopyrid in-3-yl) pyrimidin-2yl] ethanesulfonamide

- 90 038715

169 \ ° * ω - z hfnA o'A K- [5- (2,4-difluorophenoxy) -4 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] ethanesulfonamide 170 X o = s = o ΗΝ ,, Ν _v UJU CA ^F 0 K- [5- (2,4-difluorophenoxy) -4- (2methyl-1-oxoisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide 171 αχ ^F 0 4- [5- (2,4-difluorophenoxy) -2- (1,1-dioxo-1,2-thiazolidin-2yl) pyrimidin-4-yl] -2- methylisoquinolin-1-one 172 0 = S ^L HN ^ N. UA cv ^F 0 K- [5- (2,4-difluorophenoxy) -4- (2methyl- 1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidin-2yl] methanesulfonamide 173 oXo HN .___, N. W a> ’ K- [5- (2,4-difluorophenoxy) -4- (2methyl- 1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide 174 к '° ° XV _v ХХд 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -6-fluoro-2methylisoquinolin-1-one

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175 % ?. Hr ¹ O 2-methyl-4- [5-methylsulfonyl-2- (oxolan-3- yloxy) phenyl] isoquinolin-1-one 176 'Wo soo. 0 2-methyl-4- [5-methylsulfonyl-2 (oxane-4- yloxy) phenyl] isoquinolin-1-one 177 (o 0-0 = ° ° χ / l o \ - / 4- (2-ethoxy-5 - methylsulfonylphenyl) -2- methylisoquinolin-1-one 178 'Χλ ^ Su. O 2-methyl-4- (5-methylsulfonyl-2propoxyphenyl) isoquinoline-1- he 179 H? x ^ Su. 0 2-methyl-4- [5-methylsulfonyl-2 (oxane-3- yloxy) phenyl] isoquinolin-1-one 180 ° \ / ° BUT,, G Ί ίΎ of. O 4- [2- (trans-4- hydroxycyclohexyl) oxy-5methylsulfonylphenyl] -2- methylisoquinolin-1-one 181 ° \ / ° ^but '-. ^ \ / Y ⁵ Y 0 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenyl] -2-methylisoquinoline-1-one

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182 0 4- [2- (trans-4- aminocyclohexyl) oxy-5methylsulfonylphenyl] -2- methylisoquinolin-1-one 183 ν ° ζ Τ 4- [2- (cis-4- aminocyclohexyl) oxy-5methylsulfonylphenyl] -2- methylisoquinolin-1-one 184 0 4- (2-but-2-inoxy-5 methylsulfonylphenyl) -2methylisoquinolin-1-one 185 If ^{/ S} s ^ X ° γχ ΝίΧ / Ν ^ Η 0 4- (2-but-2-inoxy-5 ethylsulfonylphenyl) -2methylisoquinolin-1-one 186 h R HO ,, / Xz ^S \ L λ 1J ΝΧ'ο'ψ ' ^F yiA 0 6-fluoro-4- [2- (trans-4- hydroxycyclohexyl) oxy-5methylsulfonylphenyl] -2methylisoquinolin-1-one 187 B / I ZX / ^S \ '0 7-fluoro-4- [2- (trans-4- hydroxycyclohexyl) oxy-5methylsulfonylphenyl] -2methylisoquinolin-1-one 188 I О nR ° 4ZAO / \ t ° c ° 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenium l] -6-fluoro-2-methylisoquinoline-1 - he

- 93 038715

189 ° \ / ° 0 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenium l] -7-fluoro-2-methylisoquinoline-1 - he 190 % ?. L 11 G ° 1 n ΑΑ 0 2-methyl-4- [5-methylsulfonyl-2 (oxolan-3- yl amino) phenyl] isoquinol in-1 - he 191 ^ χ 'XI ο 1 η Sf. 0 2-methyl-4- [5-methylsulfonyl-2 (oxane-4- yl amino) phenyl] isoquinol in-1 - he 192 d AW ° ΑΑ0 / Ο \ 4- [2 - [(trans-4hydroxycyclohexyl) amino] -5 methylsulfonylphenyl] -2methylisoquinolin-1-one 193 £ _/ q-Ca jw ο 4- [2- (cyclopropylmethylamino) 5-ethylsulfonylphenyl] -2methylisoquinolin-1-one 194 'Χ1 ^ _ ^Ν Χ ~ 7 _l 1 n V αα 0 4- [2- (cyclopropylmethylamino) 5-methylsulfonylphenyl] -2methylisoquinolin-1-one 195 “Π / Α ο W W d ° Ο-ρ 'ϊ 4- [2- (cyclopropylmethylamino) - 5-ethylsulfonylphenyl] -7-fluoro- 2-methylisoquinolin-1-one

- 94 038715

196 "S? 1 and V 0 4- [2- (cyclopropylmethylamino) 5-methylsulfonylphenyl] -7fluoro-2-methylisoquinoline-1-one 197 W Xr ° o 7 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methyl-6- (trifluoromethyl) isoquinolin-1-one 198 0 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6- methoxy-2-methylisoquinoline-1 - he 199 0 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] 2-methylisoquinolin-1-one 200 γ AY '° nA \; Αν / Ν ₄ 0 4- [5 - (cyclopropylmethoxy) -2methylsulfonylpyridin-4-yl] 2-methylisoquinolin-1-one 201 %? 0 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] 7-fluoro-2-methylisoquinolin-1-one 202 'XX. ^Ρ Όγ 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] 6-fluoro-2-methylisoquinolin-1-one

- 95 038715

203 O 'ω ^x o ^ \ / mNZ ° O LL 4- [5- (cyclopropylmethoxy) -2methylsulfonylpyridin-4-yl] 7-fluoro-2-methylisoquinolin-1-one 204 O ° C ° = \ /) - K 1 \ JT \ ^ o / ^w o `` X ^ 4- (2-ethoxy-5- ethylsulfonylthiophene-3-yl) -2methylisoquinolin-1-one 205 r-, O.% ⁿ t EYS Χί ^ Χ ^ ^Ν 4 ΤΙ O 4- [2- (cyclopropylmethylamino) 5-ethylsulfonylthiophen-3-yl] -2methylisoquinolin-1-one 206 / \ o / WA ° ^O C / o 4- [3 - (cyclopropylmethoxy) -betylsulfonylpyridin-2-yl] -2methylisoquinolin-1-one 207 T £ F ° γ / γ irlch 0 4- [5- (cyclopropylmethoxy) -2ethylsulfonylpyridin-4-yl] -2methylisoquinolin-1-one 208 but L 7 ° 7 ^s x '° X1 - ^N -n ^N \ II I ΑΧ 0 4- [5- (2- hydroxyethylsulfonyl) -2- methoxyphenyl] -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline- 1st

- 96 038715

209 _F o = fo> Τώτ Ν-Π v? 0 X- [4- (cyclopropylmethoxy) -2φτορ-5 - [2-methyl-6- (1 methylpyrazol-4-yl) -1 OXOISOCHINOLIN-4yl] phenyl] ethansul fonamide 210 z V / \ y β _z ^w b ο = θ-θ ° \ 4- (5-ethylsulfonyl-2methoxyphenyl) -2-methyl-6- (1Hpyrazol-4-yl) isoquinolin-1-one 211 < _/ C ^ Cf ° D 'o .o 4- (2-ethoxy-5 methylsulfonylphenyl) -2methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one 212 'Ύ1 ^ν \ Π τ' [ΐγΊ 2-methyl-6- (1-methyl pyrazole-4yl) -4- (5-methylsulfonyl-2propoxyphenyl) isoquinoline-1- he 213 0 = S = 0 Η Ν к Г Η V ^N Μ. 0 M- [2- [2-methyl-6- (1 - methylpyrazol-4-yl) -1 - oxoisoquinolin-4-yl] pyridin4-yl] ethanesulfonamide 214 0 0 = S ^L NH ₂ Τι ΧΎ '00, 0 [4- (cyclopropylmethoxy) -3 - (2methyl-1-oxoisoquinoline-4yl) phenyl] sulfamate

- 97 038715

215 dX 0 [4- (cyclopropylmethoxy) -3 - (1,5dimethyl-6-oxopyridine-Zyl) phenyl] sulfamate 216 'XX Oy 4- (2-ethoxy-5 methylsulfonylphenyl) -2methyl-5,6,7,8- tetrahydroisoquinolin-1-one 217 'Χλ ^ Oy 0 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methyl-5,6,7,8- tetrahydroisoquinolin-1-one 218 7 Lk ο office. O M- [4- (cyclopropylmethoxy) -2fluoro-5- (2-methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) phenyl] methansul phonamide 219 at. OU 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2-methyl5,6,7,8-tetrahydroisoquinoline-1- he 220 'Hll_ ^Ν X “7 1 n V Su o T4- [2- (2-methyl-1oxoisoquinolin-4-yl) -4methylsulfonylphenyl] cyclopopanecarboxamide 221 'γχ s I n m UU \ O T4- [2- (2-methyl-1oxoisoquinolin-4-yl) -4methylsulfonylphenyl] propane Ministry of Foreign Affairs

- 98 038715

222 C ^ C? ⁰ o ο ^{/ Χ} \ = / M- [2- (2-methyl-1- oxoisoquinolin-4-yl) -4methylsulfonylphenyl] acetamide 223 ^N X “7 1 HV Off. 4- [2- (cyclopropylmethylamino) 5-methylsul phonylphenyl] -2methyl-5,6,7,8- tetrahydroisoquinolin-1-one 224 A, e z o ° OQ 'A 8- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6methyl-2- (1-methylpyrazole-4yl) pyrid o [4,3-d] pyrimidine-5 - he 225 ° ^w \ - '0-0 = ° ο z A AT z 1 8- (5-ethylsulfonyl-2propoxyphenyl) -6-methyl-2- (1methylpyrazol-4-yl) pyrido [4.30] pyrimidin-5-one 226 Al / ΛΑ 0 8- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -6-methyl2- (1-methylpyrazole-4- yl) pyrid o [4,3 -d] pyrimidine-5 - he 227 Ar / AW L z I 8- (2-ethoxy-5- ethylsulfonylphenyl) -6-methyl2- (1-methylpyrazole-4- yl) pyrid o [4,3 -d] pyrimidine-5 - he

- 99 038715

228 Λ σ ζ ο θο-ο / \ ^ ο ο 6-methyl-2- (1-methylpyrazol-4yl) -8- (5-methylsulfonyl-2propoxyphenyl) pyrid o [4,3 <1] pyrimidin-5-one 229 Α ο ° <w / ii 'o X- [4- (2,4-difluorophenoxy) -3 (1,5-dimethyl-6-oxopyridin-3 yl) phenyl] -Xmethyl methanesulfonamide 230 —S = o ^F A 0 X- [4- (2,4-difluorophenoxy) -3 (1,5-dimethyl-6-oxopyr-idin-3 yl) phenyl] -X- (oxetane-3yl) methanesulfonamide 231 ° = cNe O 8- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6methylpyrido [4,3-c1] pyrimidine- 5th 232 “V O '\ __ / ΟΌ ° ^ ° O 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6methylpyrido [4,3-c1] pyrimidin5-one 233 ° ohe 'x ° O 8- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -6methylpyrido [4,3-c1] pyrimidine- 5th 234 “V o \ / 0-0 = ° LL 8- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -6methylpyrido [4,3-c1] pyrimidin5-one

- 100 038715

235 0 5 - [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -7methyl- [1,2,4] triazolo [4,3а] pyrazin-8-one 236 ω - ζ '' Y0 y- ' X- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxo [1,2,4] triazolo [4,3-a] pyrazine-5yl) phenyl] ethanesulfonamide 237 ig Ύ- 0 7 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -5methyl- [1,3] oxazolo [4,5c] pyridin-4-one 238 ζ ^ ο ο ^{o =} CAO ^f '' ο 7 - [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2.5 dimethyl- [1,3] oxazolo [4.5 s] pyridin-4-one 239 ο —S = o tv "Λ O 5-methyl-7- [5- (methylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] - [1,3] oxazolo [4,5 -s] pyridine-4- he 240 o = s = o ^Ρ ΊΠ ГУ & 0 X- [4- (2,4-difluorophenoxy) -3- (5methyl-4-oxo [1,3] oxazolo [4.5 s] pyridine-7yl) phenyl] ethanesulfonamide

- 101 038715

241 O o O ° \ M) / - \ 1? ζ-ω - ν ¹ A T4- [4- (2,4-difluorophenoxy) -3 (2,5-dimethyl-4-oxo [1,3] oxazolo [4,5-c] pyridin-7 yl) phenyl] ethanesulfonamide 242 A AX ° l 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 (cyclopropylmethyl) -3 methylpyridin-2-one 243 5 . O A) N ° C 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3 methyl-1 - (2- methylpropyl) pyridin-2-one 244 ? - Oh R ~ A 0 ^ 0 ° O ' V 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 - (2methoxyethyl) -3-methylpyridin2-one 245 A O ' 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3 methyl-1 - (oxetan-3 ylmethyl) pyridin-2-one 246 A A θ-θ = „o ' V 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3 methyl-1- (1,3-oxazol-4ylmethyl) pyridin-2-one

- 102 038715

247 o = s = o HD K- [3- [1- (cyclopropylmethyl) -5methyl-6-oxopyridin-3 -yl] -4 (2,4difluorophenoxy) phenyl] ethanesul fonamide 248 |> - 'ζ-ω o ^t o K. [4- [1- (p ^{ik op} L p ^of saws ^{ti m} e l) -5metil oxopyrido-6-yn-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] methanesulfonamide 249 ° V \ / - \ / ° K. [4- [1- (p ^Lathe oirop ^{ilm til} e) -5metil oxopyrido-6-yn-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] ethanesulfonamide 250 l ° - s = o 1 - (cyclopropylmethyl) -5 - [4- (2,4difluorophenoxy) -1- (methylsulfonylmethyl) -boxopyrid in-3 -yl] -3 - methylpyridin-2-one 251 0-0 ° o ' 1-cyclopropyl-5- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -3methylpyridin-2-one 252 o ^o oo ° V. 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -6- methylfuro [2,3-c] pyridin-7-one

- 103 038715

253 y ° \ / - \ / ° LL X- [4- (2,4-difluorophenoxy) -3- (6methyl-7-oxofuro [2,3c] pyridin-4yl) phenyl] ethanesulfonamide 254 V ^ A ^s! ° W 'O 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one 255 o = s = o V w O N- [4- (cyclopropylmethoxy) -3 (6-methyl-7-oxofuro [2,3c] pyridin-4yl) phenyl] ethanesulfonamide 256 oh oh oh O X- [6- (2,4-difluorophenoxy) -5- (6methyl-7-oxofuro [2,3с] pyridin-4-yl) pyridin-3 yl] ethanesulfonamide 257 o = s = o A- O N- [6- (cyclopropylmethoxy) -5 (6-methyl-7-oxofuro [2,3с] pyridin-4-yl) pyridin-3 yl] ethanesulfonamide 258 —S = o xy y 6-methyl-4- [5- (methylsulfonylmethyl) -2 (2,2,2- trifluoroethoxy) phenyl] furo [2,3c] pyridin-7-one

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259 V a? OQn, 0 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] 6-methylfuro [2,3-c] pyridin-7-one 260 2 ° O o T ^u o F 2-chloro-4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one 261 0 = S-0 HN. _χχ II I ° Ά V-V Π Ί c-W 0 N- [6- (cyclopropyl methoxy) -5 (2-fluoro-6-methyl-7-oxofuro [2,3 c] pyridin-4-yl) pyridin-3 yl] ethanesulfonamide 262 o -3 = 0 F ^ x ^ s. W ο> \ ^Ν 4 o ^ [5- (2,4-difluorophenoxy) -4- (6methyl-7-oxofuro [2,3с] pyridin-4-yl) pyrimidin-2yl] methanesulfonamide 263 \.? - ω - ζ ⁶ αα ° А u_ M- [5- (2,4-difluorophenoxy) -4- (6methyl-7-oxofuro [2,3c] pyridin-4-yl) pyrimidin-2yl] ethanesulfonamide 264 οΧο Ш ’"? 0 ^ [5- (cyclopropylmethoxy) -4 (6-methyl-7-oxofuro [2,3c] pyridin-4-yl) pyrimidin-2yl] ethanesulfonamide

- 105 038715

265 τ ° <W ° 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -6-methyl7-oxothieno [2,3-c] pyridine-2carboxamide 266 I ω ο ° <> / - \ and ζ-ω — к ^χ 6'4 4- [2- (cyclopropylmethoxy) -5 (ethylsulfonylamino) phenyl] -6methyl-7-oxothieno [2,3с] pyridine-2-carboxamide 267 ν η ₂ ν 0 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6methyl-7-oxothieno [2,3c] pyridine-2-carboxamide 268 o = s ₌ o ΗΝ. Η ₂ Ν O ^ sX ^ ^N _x 0 4- [2- (cyclopropylmethoxy) -5 (ethylsulfonylamino) pyridin3 -yl] -6-methyl-7-oxothieno [2,3 c] pyridine-2-carboxamide 269 o = s = o wx 4¾ 0 X- [4- (2,4-difluorophenoxy) -3 (2,6-dimethyl-7-oxofuro [2,3 c] pyridin-4yl) phenyl] ethanesulfonamide 270 “Λ o about A / ΟΌ ° __o 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2.6dimethylfuro [2,3-c] pyridine-7- he

- 106 038715

271 rdh 0 T4- [4- (2,4-difluorophenoxy) -3- (5fluoro-1-methyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide 272 A О = (Y- \ = / / ω GP 3-chloro-5- [2- (cyclopropylmethoxy) -5 ethyl sulfonyl phenyl] -1 methylpyridin-2-one 273 MeO ₂ SN ^F \ ^^ ^F ΥΥ ^ 1 0 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4yl] -1-methyl-3-propan-2 ylpyridin-2-one 274 ... Α ^Γ Λ 0 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one 275 Sh OJ To / QA WITH ' 3-chloro-5- [2- (cyclopropylmethylamino) -5ethyl sulfonyl phenyl] -1 - methylpyridin-2-one 276 'OD ^F JA ^Nz n ₂ o 5- [2- (2,4-difluorophenoxy) -5 (methanesu lfonyl methyl) phenyl] 3 - ( ² H ₃ ) methyl-1-methyl-1,2-dihydropyridin-2-one 277 ^ x-NHSO ₂ Me ² H ₂ 0 X- [4- (2,4-difluorophenoxy) -3- [5 ( ² H ₃ ) methyl-1-methyl-6-oxo-1,6 dihydropyr-idin-3 yl] phenyl] methanesulfonamide

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278 ^^ NHSOsEt ² H ₂ 0 X- [4- (2,4-difluorophenoxy) -3- [5 ( ² Η ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyr-idin-3 yl] phenyl] ethane-1 -sulfonamide 279 <, -A \ ° ° y ^, Z-CO o T II o Ν- [3- (5-cyclopropyl-1-methyl-6oxopyridin-3-yl) -4- (2,4 difluorophenoxy) phenyl] methansul phonamide 280 Co 6 \ _ / Q-O ° O 3-cyclopropyl-5- [2 (cyclopropylmethoxy) -5 ethyl sulfonyl phenyl] -1 methylpyridin-2-one 281 about about A ° <w 'o ^t o X- [4- (2,4-difluorophenoxy) -3- (1methyl-6-oxo-5-pyrrolidin-1 ylpyridin-3- yl) phenyl] methanesulfonamide 282 '5 ^ ίΙ ίΓ' ° οΨ 5 - [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 -methyl- 3-pyrrolidin-1 -ylpyridin-2-one 283 \ __? ι τ -Γ \ / ° ^ ~ ο ° a A jA X- [4- (2,4-difluorophenoxy) -3- (5ethynyl-1-methyl-6-oxopyridin3-yl) phenyl] ethanesulfonamide 284 l ° <W Ώ 5 - [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-ethynyl- 1-methylpyridin-2-one

- 108 038715

285 0 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3 ethynyl-1-methylpyridin-2-one 286 —S = o χγ ^ΝΗ 0 M- [4- (2,4-difluorophenoxy) -3- (5ethynyl-1-methyl-6-oxopyridin3-yl) phenyl] methanesulfonamide 287 ίο Ο \ __ / 0 ^ 0 ° / ° ° L > 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -3 (difluoro methoxy) -1 - methylpyridin-2-one 288 st 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -1 -methyl3- (2,2,2- trifluoroethoxy) pyridin-2-one 289 ... -0 ) -O o ^ ~ \ O / \ II O ' PM- [3- [5- (difluoromethoxy) -1methyl-6-oxopyrid in-3 -yl] -4 (2,4difluorophenoxy) phenyl] ethanesul fonamide 290 Г o = s = o yhg А ° ^N ' M- [4- (2,4-difluorophenoxy) -3- [1 methyl-6-oxo-5- (2,2,2trifluoroethoxy) pyridin-3 yl] phenyl] ethanesul fonamide

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291 \ —Ω - * IX 3- (difluoromethoxy) -5- [2- (2,4- difluorophenoxy) -5 (ethylsulfonylmethyl) phenyl] -1 - methylpyrid in-2-one 292 o = s = o ХмУ ^F Λ ° 5- [2- (2,4-difluorophenoxy) -5 (ethylsulfonylmethyl) phenyl] -1 methyl-3- (2,2,2- trifluoroethoxy) pyridin-2-one 293 N-N 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 methyl-3 - (1-methylpyrazol-4yl) oxypyridin-2-one 294 Y ⁴ X 'l ° NN Y 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 methyl-3 - (1-propan-2-ylpyrazol4-yl) oxypyridin-2-one 295 at 'Λ 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1 methyl-3-phenoxypyridin-2-one 296 θ X / Οω-Ζ у - f ¹ Ocyо 'IX 14- [4- (1-butyl-5-methyl-6oxopyridin-3-yl) -5- (2,4difluorophenoxy) pyrimidin-2yl] methanesulfonamide

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297 \ o yy - 'o' ^ - [4- (1-butyl-5-methyl-6oxopyridin-3-yl) -5- (2,4 difluorophenoxy) pyrimidin-2yl] ethanesulfonamide 298 ° I Ο Φ-Ζ / - <\ ¹ Hitu LL Ν- [4- [1 - (cycle shoe methyl) - 5 methyl-6-oxopyrid in-3-yl] -5 (2,4-difluorophenoxy) pyrimidin2-yl] methanesulfonamide 299 V * '- ω - z / —c \ O ' at LL Ν- [4- [1 - (cycle shoe methyl) - 5 methyl-6-oxopyrid in-3 -yl] -5 (2,4-difluorophenoxy) pyrimidin2-yl] ethanesulfonamide 300 o = s = o HN .N. XT ¢ 3 and 0 M- [5-ethyl-4- (2-methyl-1- OXOISOCHINOLIN-4yl) pyrimidium-2yl] ethanesulfonamide 301 0 = (3-4 / ⁿ оУ 2-methyl-4- (2-methylsulfonyl-5-propylpyrimidin-4yl) isoquinolin-1-one 302 ° x / SulHo \ = / Ν 5- (5-ethyl-2- methylsulfonylpyrimidin-4yl) -1,3-d-imethylpyridin-2-one

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303 O before 1,3-dimethyl-5- (2methylsulfonyl-5 propylpyrimidin-4yl) pyridin-2-one 304 ^ DT ° t 4- (5-butyl-2- methylsulfonylpyrimidin-4yl) -2-methylisoquinolin-1-one 305 \ = <'—Ν 5- (5-butyl-2- methylsulfonylpyrimidin-4yl) -1,3-d-imethylpyridin-2-one 306 o = s = o HN .N. Xbx rd 0 N- [4- (2-methyl-1 oxoisoquinolin-4-yl) -5propylpyrimidin-2yl] ethanesulfonamide 307 aA. χ'η ~ \ o ' N- [4- (1,5-dimethyl-6oxopyrid in-3-yl) -5 ethylpyrimidin-2yl] ethanesulfonamide 308 O ' N- [4- (1,5-dimethyl-6oxopyrid in-3 -yl) -5 propylpyrimidin-2yl] ethanesulfonamide

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309 o = s = o XY CQ. 0 X- [5-butyl-4- (2-methyl-1- OXOISOCHINOLIN-4yl) pyrimidin-2yl] ethanesulfonamide 310 H / ° Δ π 0 N- [5-butyl-4- (1,5-dimethyl-6oxopyrid in-3-yl) pyrimidin-2yl] ethanesulfonamide 311 0. ° ΧΧ ^ αχ 0 4- [5 - (cyclopropylmethoxy) -2methylsulfonylpyrimidin-4yl] -2-methylisoquinolin-1-one 312 o 'ω ^χ Ο' \ __ / O-fV ° 5- (2-ethyl-5methylsulfonylphenyl) -1 methylpyrid in-2-one 313 iV * d 0 1-methyl-5 - (5-methylsulfonyl-2propylphenyl) pyridin-2-one 314 'V od 0 2-methyl-4- (5-methylsulfonyl-2propylphenyl) isoquinolin-1-one

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315 ^ Js ° (1 ίΓ '° O 5 - [2- (2-cyclopropylethyl) -5 methylsulfonylphenyl] -1 methylpyridin-2-one 316 / ⁼ \> ° w ° = o ^ o ^{/ Z} ( 4- (2-ethyl-5- methylsulfonylphenyl) -2- methylisoquinolin-1-one 317 .......5 0 5- (2-butyl-5methylsulfonylphenyl) -1 methylpyridin-2-one 318 'X1 ^ off. 4- (2-butyl-5- methylsulfonylphenyl) -2- methylisoquinolin-1-one 319 o y "° <> p 4- [2- (2-cyclopropylethyl) -5 methylsulfonylphenyl] -2methylisoquinolin-1-one 320 ο = ίο V7 .NH Υ ΤΥ ^χ ο'η ^ рА 0 N- [6- (cyclopropylmethoxy) -5 (2-methyl-1-oxoisoquinoline-4yl) pyridin-3yl] ethanesulfonamide

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321 O [Y θ 4- [2- (cyclopropylmethoxy) -5 methylsulfonylpyridin-3-yl] 2-methylisoquinolin-1-one 322 ν nAA Y JOT ⁰ fp XX / 'H 0 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylpyr idin-3-yl] -2methylisoquinolin-1-one 323 O- ° AA0 ° '6 5 - [3 - [(4-methoxyphenyl) methoxy] 5-methylsulfonylphenyl] -1,3dimethylpyridin-2-one 324 0c at A 1,3 - dimethyl - 5 - (3 - methyl sulfonyl-5 - phenylmethoxyphenyl) pyridine-2- he 325 A 0 5 - [3 - (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 326 ... ’CA Ά 0 1,3 - dimethyl- 5 - [3 - methyl sulfonyl-5 - (2- phenylethoxy) phenyl] pyridine-2- he

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327 / ... • utu 5 - [3 - (2-cyclopropylethoxy) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 328 o 'X 1,3-dimethyl-5- [3methylsulfonyl-5- (2,2,2trifluoroethoxy) phenyl] pyridine- 2nd 329 .. at 0 1,3 - dimethyl- 5 - [3 - [(3 methyloxetane-3-yl) methoxy] -5methylsulfonylphenyl] pyridine- 2nd 330 A. I 0 1,3 - dimethyl- 5 - [3 - methyl sulfonyl-5 - (pyridin-2- ylmethoxy) phenyl] pyridin-2-one 331 yyy. 5- [3 - [(2.6- dimethylphenyl) methoxy] -5 methylsulfonylphenyl] -1,3 dimethylpyridin-2-one 332 Χω o ' 5- [3 - [(2-chlorophenyl) methoxy] -5methylsulfonylphenyl] -1,3dimethylpyridin-2-one

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333 H ₄ o -'U / SUCHA ⁰ dX u_ 5- [3 - [[2- (difluoromethoxy) phenyl] methoxy] - 5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 334 \ O— / ⁷ yv 2- [[3 - (1,5-d imethyl-6oxopyrid in-3-yl) -5 methylsulfonylphenoxy] methyl] benzonitrile 335 _: P ° <W ⁷ L, '° o 5- [3 - [(2,4- d ifluorophenyl) methoxy] -5 methylsulfonylphenyl] -1,3 dimethylpyridin-2-one 336 Ογ 1,3 - dimethyl- 5 - [3 - methyl sulfonyl-5 - (1 - phenylethoxy) phenyl] pyridine-2- he 337 Cl ... X5 A 0 5- [3 - [(2,3- dichlorophenyl) methoxy] -5methylsulfonylphenyl] -1,3dimethylpyridin-2-one

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338 O \ O - ⁷ ° = Q-0 'A 1,3-dimethyl-5- [3- methylsulfonyl-5 - (pyridine-3 - ylmethoxy) phenyl] pyridin-2-one 339 A V 'DD 3 - [[3 - (1,5-d imethyl-6oxopyrid in-3-yl) -5 methylsulfonylphenoxy] methyl] benzonitrile 340 \ o— ⁷ 5 - (3-but-2-inoxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one 341 A γ DD o 1,3 - dimethyl- 5- [3- methyl sulfonyl-5 - (1 - phenylethoxy) phenyl] pyridine-2- he 342 X. CL ⁰ II pG U O '0 X- [3- (2,4-difluorophenoxy) -5 (1,5-dimethyl-6-oxopyr-idin-3 yl) phenyl] ethanesulfonamide

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343 η Op 0 4- [3 - [(4-methoxyphenyl) methoxy] 5-methylsulfonylphenyl] -2methylisoquinolin-1-one 344 G . ) --- x l— o o \ = / 2-methyl-4- (3-methylsulfonyl-5-phenyl methoxyphenyl) isoquinol and N-1-0N 345 'Hu Soo. 0 4- [3 - (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methylisoquinolin-1-one 346 \ γΑ ^O y-H ^% s K- [4- (2,4-difluorophenoxy) -6 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] ethanesulfonamide 347 Co ° X I ^ο Ύφ x '° \ j- ^ K- [2- (2,4-difluorophenoxy) -6 (1,5-dimethyl-6-oxopyridin-3 yl) pyrimidin-4yl] ethanesulfonamide

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348 Ά-θ Ο A ° = ο ^ _ο ω. 4- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5-methylsulfonylphenyl] -6- methylfuro [2,3-c] pyridin-7-one 349 Οχ ° \ ^ x5 ^s: ° TAP 0 6-methyl-4- (3-methylsulfonyl-5 phenylmethoxyphenyl) furo [2,3 c] pyridin-7-one 350 0 4- [3 - (cyclopropylmethoxy) -5 methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one 351 0/0 As' ^^ / = 4 ΙΨ / -) = ο '—Ν 1-methyl-5 - (2-methylsulfonyl-5 propylpyrimidine-4- yl) pyridin-2-one 352 V - S Ν '/ - \ / = ° 5- (5-butyl-2- methylsulfonylpyrimidin-4yl) -1-methylpyridin-2-one 353 ο / ° = \ Ζ> - ζ. , ^ζ / ω Ο 2 φ 3-chloro-1-methyl-5 - (2methylsulfonyl-5 propylpyrimidin-4yl) pyridin-2-one

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354 φ Ξ 04 Ο D / ζ y — F 40 / θ 5- (5-butyl-2- methylsulfonylpyrimidin-4yl) -3-chloro-1 -methylpyridin-2-one 355 0 ^ 0 Js' / UCX Δ GU 3-methoxy-1-methyl-5 - (2methylsulfonyl-5 propylpyrimidin-4yl) pyridin-2-one 356 Ο. / > ω ° = K-Qo / ° " 5- (5-butyl-2- methylsulfonylpyrimidine-4- yl) -3 -methoxy-1 -methylpyridin- 2nd 357 o = s = o Have 0 N- [4- (1-methyl-6-oxopyrid in-3 yl) -5-propyl pyrimid in-2yl] ethanesulfonamide 358 ° = ρΖ 0 / s M- [5-butyl-4- (1-methyl-6oxopyrid-3-yl) pyrimidin-2yl] ethanesulfonamide 359 N NHSO ₂ Et s, d 0 N- [4- (5-chloro-1-methyl-6oxopyrid-3-yl) -5 propylpyrimidin-2yl] ethanesulfonamide 360 N NHS0 ₂ Et 0 N- [5-butyl-4- (5-chloro-1-methyl-6oxopyrid in-3-yl) pyrimidin-2yl] ethanesulfonamide

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361 o = (n - G O ' N- [4- (5-m6tokch- 1 -methyl-6oxopyrid in-3 -yl) -5 propylpyrimidin-2yl] ethanesulfonamide 362 H, Ν. .N. / ° if V ^{> S} X / ⁰ Δ 0 II ^{4 1} 0 N- [5-butyl-4- (5-methoxy-1 methyl-6-oxopyrid in-3 yl) pyrimidin-2yl] ethanesulfonamide 363 H .N. .hL / ° ^{> o} χχ N- [5-butyl-4- (1,5-dimethyl-6oxopyrid in-3-yl) pyrimidin-2yl] methanesulfonamide 364 o 0-0 = ° 4 / A 4- [2- (cyclopropylmethoxy) -5 propan-2-ylsulfonylphenyl] -2methylisoquinolin-1-one 365 3 A H 0 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-methyl4H-pyrido [4,3-b] [1,4] oxazine 3,5-dione 366 to ° X H O 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-methyl3,4-dihydro-2H-pyrid o [4.3 b] [1,4] oxazin-5-one 367 ° T Ο ω-ζ 'Xr A' M- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxoimidazo [1,5а] pyrazine-5yl) phenyl] methanesulfonamide

- 122 038715

368 w n ^ A O 5 - [2- (cyclopropylmethoxy) -5 ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazine-8- he 369 o = s = o w 0 5- [2- (2,4-difluorophenoxy) -5 (ethylsulfonylmethyl) phenyl] -7methylimidazo [1,5-a] pyrazine-8- he 370 n ^ A 7-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2- trifluoroethoxy) phenyl] imidazo [1, 5-a] pyrazin-8-one 371 v ° w ll. 5 - [5 - (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -7methylimidazo [1,5-a] pyrazine-8- he 372 0 —S = o W 0 5- [2- (2,4-difluorophenoxy) -5 (methyl sulfonyl methyl) phenyl] 7-methylimidazo [1,5-a] pyrazin8-one 373 W zA 5- [2- (4.4- difluorocyclohexyl) oxy-5ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazine-8- he

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374 α _ο Υ 0 5 - (2-cyclopentyloxy-5 ethylsulfonylphenyl) -7methylimidazo [1,5-a] pyrazine-8- he 375 χ 0 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazine-8- he 376 γ Ll_ 5- [2- (2,4-difluorophenoxy) -5ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazine-8- he 377 θ "\ / 0-0 ° 7 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -5methylfuro [3,2-c] pyridin-4-one 378 λ ο Ο '\ / 0 ^ 0 ° __ο ο 7 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -5 - methylfuro [3,2-c] pyridin-4-one 379 to ο Μ ω-ζ Ο --1 / - and (UA A " T4- [4- (2,4-difluorophenoxy) -3- (5methyl-4-oxofuro [3,2с] pyridin-7yl) phenyl] ethanesulfonamide 380 ?. X ° ΐ ' ^ζ \ __ / Οχ Α " X- [4- (2,4-difluorophenoxy) -3- (5- methyl-4-oxofuro [3,2- c] pyridine-7- yl) phenyl] methanesulfonamide

- 124 038715

381 Υί ^υ —s = o 4- (cyclopropylmethoxy) -5 - (1 methyl-6-oxopyrid in-3-yl) -1 (methylsulfonylmethyl) pyridine -2-he 382 at 0 -s = o ό 5 - [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyridin-3-yl] -1,3dimethylpyridin-2-one 383 Ύ U 0 -s-o 0 4- [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyrid in-3-yl] -7-fluoro-2methylisoquinolin-1-one 384 o \ Lu ° ^o CAO ° O 4- [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyridin-3-yl] -2methylisoquinolin-1-one 385 'U ° -θ = ° 5- [4- (2,4-difluorophenoxy) -1 (methylsulfonylmethyl) -boxopyridin-3-yl] -1,3dimethylpyridin-2-one 386 Λ η 4- (2,4-difluorophenoxy) -5- (1methyl-6-oxopyridin-3 -yl) -1 (methylsulfonylmethyl) pyridine -2-he

- 125 038715

387 O II. / —SoYu oXY-Hu / M X X LL 4- [4- (2,4-difluorophenoxy) -1 (methylsulfonylmethyl) -boxopyrid in-3-yl] -2methylisoquinolin-1-one 388 ^{o =} 0 \ 3 ° o 5 - (2-but-2-inoxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one 389 ίο with O '\ __ / oAA ⁰ about ok 5 - (2-but-2-inoxy-5 ethylsulfonylphenyl) -3 methoxy-1-methylpyridin-2-one 390 -o about ⁷ Yp Ώ 5 - (5-ethylsulfonyl-2-pent-2inoxyphenyl) -3-methoxy-1 methylpyridin-2-one 391 L ⁷ °? 5 - [2- (3-cyclopropylprop-2inoxy) -5- ethylsulfonylphenyl] -3methoxy-1-methylpyridin-2-one 392 XY ° F ^and x g of 5- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -1 -methyl3 - (trifluoromethyl) pyridin-2-one 393 A? / Οχ / Χ, Χ * τχχ 4- [2- (cyclopropylmethoxy) -5 propan-2-ylsulfonylphenyl] -6methoxy-2-methylisoquinoline-1 - he

- 126 038715

394 ° JL _ fT 'γχ ° ^ [ jy 0 5 - [2- (cyclopropylmethoxy) -5 propan-2-ylsulfonylphenyl] 1,3-dimethylpyridin-2-one 395 0. A 0 Ν- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -5 phenylmethoxyphenyl] ethanesulfonamide 396 y / \ ^ o ° \ _ 5 - [2- (2,4-difluoroanilino) -5 ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 397 To ΙΖ ° <eChe 5- [2 - [(4.4- d ifluorocyclohexyl) amino] -5 ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 398 AU A O 5 - [2- (2,4-difluoroanilino) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 399 s \ _ ^{ί Ί 0} o Αλί o 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -3methoxy-1-methylpyridin-2-one 400 A -o about '40 O 5- [2- (2,4-difluorophenoxy) -5 (methyl sulfonyl methyl) phenyl] - 3-methoxy-1-methylpyridin-2-one

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401 O & 0 5- [2- (trans-4- hydroxycyclohexyl) oxy-5methylsulfonylphenyl] -1,3dimethylpyridin-2-one 402 -3 - (l o Am _o / \ II O ' ^ [4- (2,4-difluorophenoxy) -3- (1methyl-5-methylsulfanyl-6oxopyridine-3- yl) phenyl] ethanesulfonamide 403 about R W A 0 5- [2- (cis-4- aminocyclohexyl) oxy-5methylsulfonylphenyl] -1,3dimethylpyridin-2-one 404 O. ₀ P about 5- [2- (trans-4- aminocyclohexyl) oxy-5methylsulfonylphenyl] -1,3dimethylpyridin-2-one 405 7 \ ° ^{o =} CA ^ A ⁷ ° o 1,3 - dimethyl- 5 - [5 - methyl sulfonyl-2- (3,3,3trifluoropropoxy) phenyl] pyr or n-2-he 406 1 ° —S = o and young 5- [2- (2,4-difluorophenoxy) -5- (methyl sulfonyl methyl) phenyl] - 1 - (2-hydroxyethyl) -3 - methylpyridin-2-one 407 d ° 1 ^x he 5 - [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -1 (2-hydroxyethyl) -3 methylpyridin-2-one

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408 A nmDC ¹ 0 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1 methyl-3 - (methylamino) pyridine- 2nd 409 ίο -ω Ο ζ- 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -1 -methyl- 3 - (methylamino) pyridin-2-one 410 -Ζ ο / - \ ° ΑΑ ο ' T4- [4- (2,4-difluorophenoxy) -3- [1 methyl-5- (methylamino) -6oxopyridine-3- yl] phenyl] ethansul f onamide 411 xkl ^ d 0 5 - [5 - (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] 1,3-dimethylpyridin-2-one 412 0 - ^r s = ow ⁿ A M- [4- (2,4-difluorophenoxy) -3- [1 methyl-5- (methylamino) -6oxopyridine-3- yl] phenyl] methanesulfonamide 413 ° <W 'kA o 5- [2 - [(4.4- d ifluorocyclohexyl) amino] -5 methylsulfonylphenyl] -1,3 dimethylpyridin-2-one 414 Co o \ _ / Ш5о A 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -3 methoxy-1-methylpyridin-2-one

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415 σ about ° -OCHE / vo O 5- [2- (4.4- difluorocyclohexyl) oxy-5methylsulfonylphenyl] -1,3dimethylpyridin-2-one 416 ⁰ J o # L 0 5 - [2- (cyclopentylamino) -5 ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 417 aL 'O 0 5 - [2- (cyclopentylamino) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 418 0 o = e- _C1 Chl 0 3-chloro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2- trifluoroethoxy) phenyl] pyridine- 2nd 419 l dx 0 5 - (2-cyclopentyloxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one 420 P GU '° Αχ ^ Ν ^ 0 1,3-dimethyl-5- [5- methylsulfonyl-2- (oxane-4- yloxy) phenyl] pyridin-2-one 421 / А ° f GUL _ρ Α = -γ 0 3-fluoro-1-methyl-5 - [5 (methylsulfonylmethyl) -2 (2,2,2- trifluoroethoxy) phenyl] pyridine-

- 130 038715

2nd 422 b 0 5 - [2- (cyclopropylmethylamino) 5-methylsulfonylphenyl] -1,4dimethylpyridin-2-one 423 „JO 0 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1,4 dimethylpyridin-2-one 424 S ^% 0 HN ¢ - 0 N- [4- (1-methyl-6-oxopyrid in-3 yl) -5-phenylthiophen-2yl] ethanesulfonamide 425 Y AX 0 1,3 - dimethyl- 5 - [5 - methyl sulfonyl-2- (oxolan-3 ylamino) phenyl] pyridin-2-one 426 0 1,3-dimethyl-5- [5methylsulfonyl-2- (oxolan-3 yloxy) phenyl] pyridin-2-one 427 _F jQT ^ ⁰ <0 1,3-dimethyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2- trifluoroethoxy) phenyl] pyridine- 2nd

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428 ίΙ ίΓ '° ν n ι A o। 5 - [2- (cyclopropylmethylamino) - 5-methylsulfonylphenyl] -1 ethyl-3-methylpyridin-2-one 429 1 ° -18 = 0 V D O . 5- [2- (2,4-difluorophenoxy) -5 (methyl sulfonyl methyl) phenyl] 1-ethyl-3-methylpyrid in-2-one 430 oDo ^ΗΝ Χ ^ \ /^.OH 0 N- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (trans-4hydroxycyclohexyl) oxyphenyl] ethanesulfonamide 431 oXo V O '. ° ⁿ t 0 N- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (cis-4hydroxycyclohexyl) oxyphenyl] ethanesulfonamide 432 ^ο: λ ΗΝ Y — S \ yO c, and 0 N- [4- (1-methyl-6-oxopyrid in-3 yl) -5 - (2-methylphenyl) thiophen-2yl] ethanesulfonamide 433 o o = s— / -χ ^ ΟΗ : O N- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (trans-4hydroxycyclohexyl) oxyphenyl] methanesulfonamide

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434 1 o = s = o ^ LON Have 0 Ν- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (cis-4hydroxycyclohexyl) oxyphenyl] methanesulfonamide 435 0-), ^s : o HN ✓ s ί TO 0 N- [5 - (2-ethylphenyl) -4- (1-methyl6-oxopyrid in-3-yl) thiophene-2yl] ethanesulfonamide 436 _ P O 1,3 - dimethyl- 5 - [5 methylsulfonyl-2- (oxane-4ylamino) phenyl] pyridin-2-one 437 -η O ° = O-O / \ 1 £ ^{: O} 5- [2- (2,4-difluorophenoxy) -5 (methyl sulfonyl methyl) phenyl] 3-fluoro-1-methylpyridin-2-one 438 , 5 - z I z 'Lp ° '0 5 - [2- (cyclopropylmethylamino) - 5-methylsulfonylphenyl] -3 - (dimethylamino) -1 - methylpyridin-2-one 439 ¹ ^ -Q = "ύ" N- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (oxane-4yloxy) phenyl] methanesulfones d

- 133 038715

440 0 l fl ίΓ '° V and I y ¹ 0 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -3 - (dimethylamino) -1 - methylpyridin-2-one 441 P \ ° ° = py _o Ν- [3 - (1,5-dimethyl-6oxopyrid in-3-yl) -4- (oxane-4yloxy) phenyl] ethanesulfonamide 442 0 —s = o yyr O ¹ 0 M- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6oxopyridine-3- yl) phenyl] methanesulfonamide 443 г o = s = o already Ό- ¹ О M- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6oxopyridin-3yl) phenyl] ethanesulfonamide 444 0 -S ₌ O zhy A O Ν- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (oxolane- 3- yloxy) phenyl] methanesulfones d 445 \ _ ^{11 x} > - ω-ζ k \ / 0> - \ 7 - o '$ Ν- [3 - (1,5-dimethyl-6oxopyrid in-3 -yl) -4- (oxolane- 3- yloxy) phenyl] ethanesulfonamide

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446 Ρ O '. N- [3 - (1,5-dimethyl-6oxopyrid in-3-yl) -4- (oxane-3 yloxy) phenyl] methanesulfones d 447 0 —S = o w A 0 N- [4- (4.4- d ifluorocyclohexyl) oxy-3 - (1,5- dimethyl-6-oxopyrid yn-3 yl) phenyl] methanesulfonamide 448 Ρ. o θοΑ _o f \ II ζ-ω - v ¹ 6 '^ N- [3 - (1,5-dimethyl-6oxopyrid in-3-yl) -4- (oxane-3 yloxy) phenyl] ethanesulfonamide 449 V? ¹ ω - z о ^x .0 LL N- [4- (4.4- d ifluorocyclohexyl) oxy-3 - (1,5- dimethyl-6-oxopyrid yn-3 yl) phenyl] ethanesulfonamide 450 Co О ^W \ / Ο-Αχ о 'c 5 - [2- (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 451 o = s = o Ή XX V 0 0 [4- (2,4-difluorophenoxy) -3- (5hydroxy-1-methyl-6- oxopyridine-3- yl) phenyl] ethanesulfonamide

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452 X 0 4- (cyclopropylmethylamino) -3 (1,5-dimethyl-6-oxopyridin-3 yl) benzenesulfonamide 453 5_ ° 1 4- (cyclopropylmethylamino) -3 (1-methyl-6-oxopyrid in-3 yl) benzenesulfonamide 454 0 o = s— G 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] 1,4-dimethylpyridin-2-one 455 0 —S = o With 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] 1,3-dimethylpyridin-2-one 456 y ^b xx 5- (2-ethoxy-5 ethylsulfonylphenyl) -1 ( ² H ₃ ) methyl-4-methylpyridin-2-one 457 _ ,R AP. X Xd 0 D 5 - [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 ( ² H ₃ ) methyl-4-methylpyridin-2-one

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458 A 0 5- (2-ethoxy-5 ethylsulfonylphenyl) -1,4dimethylpyridin-2-one 459 [Γ ηρ> 0 A 0 5 - [2- (cyclobutylmethoxy) - 5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 460 A 0 5 - [2- (cyclobutylmethoxy) - 5 methylsulfonylphenyl] -1 methylpyridin-2-one 461 T ά 0 5 - (5-ethylsulfonyl-2methoxyphenyl) -3-hydroxy-1 methylpyrid in-2-one 462 A DH O 5 - [2- (cyclopropylmethylamino) 5-methylsulfonylphenyl] -1,3dimethylpyridin-2-one 463 About pA γφ ' M- [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyridine-3yl] phenyl] methanesulfonamide

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464 ... A -z o όΧ _o sy o ⁴ ^ [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyridine-3- yl] phenyl] ethansul f onamide 465 A 0 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 466 A 0 5 - [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -1,4dimethylpyridin-2-one 467 O II t ° T \ _ / θ-0 = ° about t Ν- [3 - (5-hydroxy-1 -methyl-6oxopyridine-3 - yl) phenyl] methanesulfonamide 468 < O 5 - [2- (cyclopropylmethylamino) - 5-methylsulfonylphenyl] -1 methylpyridin-2-one 469 ° o A ¹ 0 3 - (dimethylamino) -5 - (2-ethoxy-5 ethylsulfonylphenyl) -1 methylpyridin-2-one

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470 O O 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] - 1-methylpyridin-2-one 471 V / \ ι_ Ζ-ζΌ Ο Τ Η N- [3 - (1-methyl-6-oxo-5 phenylmethoxypyridin-3 yl) phenyl] methanesulfonamide 472 o = s = o νΑ U- 0 M- [4- (2,4-difluorophenoxy) -3 (1,5-dimethyl-6-oxopyr-idin-3 yl) phenyl] ethanesulfonamide 473 Co o \ ___ / 0 ^ 0 ° X 5 - [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1 methylpyridin-2-one 474 , 5 - Z О ⁷ >"'° о 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3 (dimethylamino) -1 methylpyridin-2-one 475 0 0 = 8 - P With 0 5 - [4-fluoro-2-methoxy-5 (methylsulfonylmethyl) phenyl] - 1-methylpyridin-2-one

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476 A O 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one 477 0 5 - [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -1,4dimethylpyridin-2-one 478 I ⁹ o = ^[ s - A A HIv pT ^X to 0 N- [6- [3- (methanesulfonamido) phenyl] -4methyl-3-oxopyrazine-2- sludge] acetamide 479 o = s = o A 0 N- [3 - (1,4-dimethyl-6oxopyrid azin-3 yl) phenyl] ethanesulfonamide 480 / '- \ H O ' N- [3 - (1,5-dimethyl-6oxopyrid azin-3 yl) phenyl] ethanesulfonamide 481 0 - ^r s = o A k 0 1 ⁰ N- [5- [3- (methanesu lf onamide o) phenyl] -1 methyl-2-oxopyrid in-3 - sludge] propanamide

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482 - ^f s = o A „ _; DD N- [5- [3- (methanesulfonamide o) phenyl] -1 methyl-2-oxopyridine-Zyl] acetamide 483 \ ° ° ⁼ G ^M Q ci y 1 -cyclobutyl-5 - [2 (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3methylpyridin-2-one 484 0 —s = o Ό A A N- [3 - (1-cyclobutyl-5-methyl-6oxopyridin-3-yl) -4- (2,4 difluorophenoxy) phenyl] methansul phonamide 485 \ ° A \ = / ° b 1-benzyl-5- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -3methylpyridin-2-one 486 'TTV 0 1,3-dimethyl-5- (2-methyl-5- methyl sulfonyl-2,3-dihydro-1 benzofuran-7-yl) pyridin-2-one 487 X o _o 0AX \ = / 4- [5 - (etylcylphonylmethyl) -2 (2,2,2-triftopetoxy) phenyl] -2methylisoxinolin- 1 -one

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488 0 ο = έ— Uduch 2-methyl-4- [5- (methylsulfonylmethyl) -2 (2,2,2- trifluoroethoxy) phenyl] isoquinol in-1-on 489 _h o e ° CAO ⁷ l ° “o 1,3 - dimethyl- 5 - (7- methyl sulfonyl-2,3-d and hydro- 1,4-benzodioxin-5-yl) pyridine- 2nd 490 0 o = s - yh Cy. 0 K- [2-ethyl-8- (2-methyl-1 oxoisoquinolin-4-yl) -3,4 dihydro-2H-chromene-6yl] methanesulfonamide 491 o = s = o XX [Γφχι 0 K- [2-ethyl-8- (2-methyl-1 oxoisoquinolin-4-yl) -3,4 dihydro-2H-chromene-6yl] ethanesulfonamide 492 ^ο ΟΟ / \ n ζ-ω - ν ¹ "o K- [8- (1,5-dimethyl-6oxopyrid in-3 -yl) -2-ethyl-3,4-dihydro-2H-chromene-6yl] ethanesulfonamide 493 yXO Su. 0 4- (2-cyclopropyl-5- methyl sulfonyl-2,3-dihydro-1 benzofuran-7 -yl) -2- methylisoquinolin-1-one 494 / = \ .. Р W _л о = 0-0 ^{/ Ζ} V 4- (2-ethyl-5-methylsulfonyl-2,3d and hydro-1-benzofuran-7-yl) -2methylisoquinolin-1-one

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495 Η ο ^Λ ° D [L / - y / 0 dx 0 N- [7- (1,5-dimethyl-6oxopyrid in-3-yl) -2-propyl 2,3-dihydro-1-benzofuran-5 yl] ethanesulfonamide 496 Η ο ^ ο к Η) - <Ц 0 N- [2-cycle opropyl-7- (1,5 dimethyl-6-oxopyrid in-3-yl) 2,3-dihydro-1-benzofuran-5 yl] ethanesulfonamide 497 Of? chkh, Su, 0 4- [3 - (methoxymethyl) -7methyl sulfonyl-2,3-d and hydro1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one 498 doo 'd' 5 - [3 - (methoxymethyl) -7methyl sulfonyl-2,3-d and hydro- 1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one 499 ^Οί Γ ~ χ ° χ dxl, Cy, 0 4- [3 - (methoxymethyl) -7methyl sulfonyl-2,3-d and hydro1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one 500 DH 0 5 - [3 - (methoxymethyl) -7methyl sulfonyl-2,3-d and hydro- 1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one 501 W Wed, oh 4- [2- (methoxymethyl) -7- methyl sulfonyl-2,3-d and hydro1,4-benzodioxin-5-yl] -2- methylisoquinolin-1-one

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502 / O . OO ^{o =} 0 ~ Q 'l? O 5 - [2- (methoxymethyl) -7 methyl sulfonyl-2,3-d and hydro- 1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one 503 ° \ ___ / ° / O O \ = / 4- [2- (methoxymethyl) -7 methyl sulfonyl-2,3-d and hydro1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one 504 oh oh CD O 4- [2- (cyclopropylmethoxy) -5 methylsulfonylphenyl] -2methyl-6,7-dihydro-5Hcyclopenta [c] pyridin-1-one 505 oo LL 0 4- [2- (cyclopropylmethoxy) -5 ethylsulfonylphenyl] -2-methyl6,7-dihydro-5Hcyclopenta [c] pyridin-1-one 506 ° ΦΑνΧ 'о. Άη O' \ X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-6,7-dihydro-5Hcyclopenta [c] pyridin-4yl) phenyl] methanesulfonamide 507 n ^F W ^ w ^F / LA / A iTsu A <Xd o X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-6,7-dihydro-5Hcyclopenta [c] pyridin-4yl) phenyl] ethanesulfonamide

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508 MeO ₂ S ^ N n η Αν О 1 5- (5-butyl-2- methylsulfonylpyrimidin-4yl) -3 -methyl-1-propan-2ylpyridin-2-one 509 EtO ₂ SHN N st νγ О ¹ ^ [5- (2,4-difluorophenoxy) -4- (5methyl-6-oxo-1-propane-2ylpyr-idin-3-yl) pyrimidin-2yl] ethanesulfonamide 510 o No. \ ω) = \ / ^ζ = < 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4yl] -3-methyl-1-propan-2 ylpyridin-2-one 511 EtO ₂ SHN Ν n η Αν 0 1 Ν- [5-butyl-4- (5-methyl-6-oxo-1 propan-2-ylpyrid in-3 yl) pyrimidin-2yl] ethanesulfonamide 512 EtO ₂ SHN Ν ιι η VV 1 0 Ν- [5-butyl-4- (1-methyl-6-oxo-5 propan-2-ylpyrid in-3 yl) pyrimidin-2yl] ethanesulfonamide 513 MeO ₂ S Ν Η Ί Αχ 1 0 5- (5-butyl-2- methylsulfonylpyrimidin-4yl) -1-methyl-3-propan-2ylpyridin-2-one 514 m δ Μ. ω / I - (ζ Σ / = \ / ^ζ Υ ° WU ^ [5- (2,4-difluorophenoxy) -4- (1methyl-6-oxo-5-propane-2- ilpyr idin-3-yl) pyrimidin-2yl] ethanesulfonamide

In some embodiments, the substituted heterocyclic compound described herein has the structure shown in table. 2.

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table 2

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- 149 038715

- 150 038715

- 151 038715

- 152 038715

- 153 038715

- 154 038715

- 155 038715

- 156 038715

- 157 038715

- 158 038715

- 159 038715

- 160 038715

- 161 038715

- 162 038715

- 163 038715

- 164 038715

- 165 038715

o _h p V ZHU gL O ^ NY n 0 _π o _s p V ui 0 00 N p N o IZ O / 0 = 00sA / ^ R op -H \ / X -p woo / M / F ° > About ZI Have Pts / R and X 10n ^ NT ^N 0 ° A / ° A \ tu_ M> = 0 ^o Y O ZI ⁷ <O ° W / M> 0 ° __O \ __ ZI / O A Y IZ o / o = 01-o / M i / ^ ° / o vz o / o = ^ 1 - Xa / M ^ n / ^ω ° ° X / ° Kr ^z v My0 ° y 0 ζι / (A o / Jy ⁷ MaO ° YO ZX \ o /

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- 167 038715

About __ρτ. \ / ° V / mA> ° y3f uo o -A 0 V < ^N qo ps ^z ^ x / SO ₂ Me Λ J LA- г _χ Ν 0 , N / y 0 Y _N , N S0 ₂ Me ^L ° I T su ^s ° ^2El / N 0 and γΥΑ 0 zy ^ _p _x NHSO ₂ Me Y _N ' ^N ^ / NHSO ₂ Et k y / ^N A 0 0 0 o Vz “W ^ NHSO ₂ Me V _N ' ^N ^ ^NHS ° 2 ^Et A Lgl / ^ν Ά 0 0 Ύ ° 0 ΎΊ i N NHSO ₂ Et N ^{N <} ^ ^{N HS} ° 2 ^Et 1 II and 1 F A ιΓΛ / ^N - n ^ ° 0 Pch 0

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L ° aJ ΑγΧΧ 0 V 14 ^^ ⁸ ° ²¹ ^ UA Al 0 ί / DDDN5O ₂ Me η n A Ν. D F ^^ F D AfA ζ ^Ν ΑΑ 0 ί YNZogMe A _f ν ^Ν AfA ζ ^Ν ΑΑ 0 ίΐ ^ DD ^ bDNZO ₂ E1 ^ Τ Τι ίΓ II F Ay Α 0 ί || SO ₂ Me 2. Αχ ν. D F ^^ F D -Α 0

V ν '^ νπ ³⁰² ^ Α ^γ r Ύ η 0 V Ν'-χΑΠ ³⁰² '^ ι ° γ , dO 0 ί Ν HSO ₂ Me η η] F ^^ F D -Α 0 ί x ^ / Cx ^ x ^ My3CrMe χΑρΧ ^ Ν F ^ -Α 0 ίί .0. Αι ^ Α ^ sc ^ Me II F And at Α 0 Ιί Π ^ θΥΑ ^ ⁸⁰²¹ ^ ® ρ4 ^ A _f ιΑα / ^ν Α ^0? 0

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, o Ί ax pT ^ EogMe Q 0 p SO ₂ Me A ^ o ^z F O R ^ l about NHSO ₂ Me F _x 9 1 A NHSO ₂ Et F D> F O 0 0 Ai .SO ₂ Me f | ^ SO ₂ Et II J II N A Q / ^N \ < O 0 0 R Q O NHSO ₂ Me F _x 9 1 A NHSO ₂ Et F ^ -N F ν '/ ^N > Y A 0 0 A , SO ₂ Me A , SO ₂ Me II J Vy ^ οΑχ A 3 at Q 0 O Q / ° _x SO ₂ Me R 9 i A p ^ SOzMe F ν ' O 0 O

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Preparation of substituted heterocyclic compounds.

The compounds used in the reactions described herein were prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. Commercially available chemicals were obtained from standard commercial sources including Acros Organics (Pittsburgh, PA), Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and

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Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge, NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD) and Wako Chemicals USA, Inc. (Richmond, VA).

Methods known to any person skilled in the art are determined using various reference books and databases. Suitable reference books and scholarships detailing the synthesis of the reagents used to prepare the compounds described herein, or referring to articles that describe the preparation, include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; S. R. Sandier et al., Organic Functional Group Preparations, 2nd Ed., Academic Press, New York, 1983; H. O. House, Modern Synthetic Reactions, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, Heterocyclic Chemistry, 2nd Ed., John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., Wiley-Interscience, New York, 1992. Additional pertinent reference books and papers detailing the synthesis of reagents used to prepare the compounds described herein, or references are made to articles that describe the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-601802; Otera, J. (editor) Modern Carbonyl Chemistry (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. Patai's 1992 Guide to the Chemistry of Functional Groups (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. Organic Chemistry 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., Intermediate Organic Chemistry 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; Organic Reactions (1942-2000) John Wiley & Sons, in 55 volumes; and Chemistry of Functional Groups by John Wiley & Sons, in 73 volumes.

Specific and similar reagents can also be identified using indices of known chemicals developed by the American Chemical Society's Register of Chemical Compounds, which are available in most public and university libraries, and online databases (the American Chemical Society, Washington, DC, available at contact for more details). Chemicals that are known but not commercially available in catalogs can be obtained from chemical synthesis companies, as many standard chemical suppliers (such as those listed above) offer custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of substituted heterocyclic compounds described herein is P. H. Stahl & C. G. Wermuth Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002.

General methods for synthesizing substituted heterocyclic derivatives are presented, but not limited to, in the following references: WO 2009/158396; WO 2005/63768; WO 2006/112666; Briet et al., Tetrahedron (2002), 58 (29), 5761-5766; WO 2008/77550; WO 2008/77551; WO 2008/77556; WO 2007/12421; WO 2007/12422; US 2007/99911; WO 2008/77550; Havera et al., J. Med. Chem. (1999) 42,3860-3873; WO 2004/29051; and US 2009/0054434. Additional examples of the synthesis of substituted heterocyclic derivatives are provided in the following references: WO 2012/171337; WO 2011/044157; WO 2009/097567; WO 2005/030791; EP 203216; Becknell et al., Bioorganic & Medicinal Chemistry Letters (2011), 21 (23), 70767080; Svechkarev et al., Visnik Kharkivs'kogo Natsional'nogo Universitetu im. V. N. Karazina (2007) 770,201207; Coskun et al., Synthetic Communications (2005), 35 (18), 2435-2443; Alvarez et al. Science of Synthesis (2005) 15, 839-906; Kihara et al., Heterocycles (2000), 53 (2), 359-372; Couture et al., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1999), (7), 789-794; Kihara et al., Heterocycles (1998), 48 (12), 2473-2476; Couture et al., Tetrahedron (1996), 52 (12), 4433-48; Couturre et al., Tetrahedron Letters (1996), 37 (21), 3697-3700; Natsugari et al., Journal of Medicinal Chemistry (1995), 38 (16), 310620; Moehrle et al., Archiv der Pharmazie (Weinheim, Germany) (1988), 321 (10), 759-64; Gore et al., Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1988), (3), 4813; Narasimhan et al., Journal of the Chemical Society, Chemical Communications (1987), (3), 191-2; Henry et al., Journal of Organic Chemistry (1975), 40 (12), 1760-6; Berti, Gazzetta Chimica Italiana (1960) 90,559-72; Berti et al., Annali di Chimica (Rome, Italy) (1959), 49, 2110-23; Berti et al., Annali di Chimica (Rome, Italy) (1959), 49, 1253-68; WO 2012/000595; Couture et al., Tetrahedron (1996), 52 (12), 4433-48; WO 2010/069504; WO 2010/069504; WO 2006/030032; WO 2005/095384; US 2005/0222159; WO 2013/064984; Mishra et al.,

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European Journal of Organic Chemistry (2013), 2013 (4), 693-700; Vachhani et al., Tetrahedron (2013), 69 (1), 359-365; Xie et al., European Journal of Medicinal Chemistry (2010), 45 (1), 210-218; Mukaiyama et al., Bioorganic & Medicinal Chemistry (2007), 15 (2), 868-885; JP 2005/089352; Wang et al., Molecules (2004), 9 (7), 574-582; WO 2000/023487; US 2006/0287341; CN 103183675; Hares et al., Egyptian Journal of Pharmaceutical Sciences (1991), 32 (1-2), 303-14; DE 2356005; DE 2133898; DE 2133998; US 3816422; DE 2011970; and Staehle et al., Justus Liebigs Annalen der Chemie (1973), (8), 1275-81. In some embodiments, the substituted heterocyclic compounds described herein are prepared using the general synthetic routes outlined in Schemes 1-6 below. These diagrams are provided as an example for a person skilled in the art and are not limiting. Additional methods for synthesizing substituted heterocyclic compounds described herein are readily available to those skilled in the art.

Scheme 1

The method for preparing compounds of formula (I) is shown in Scheme 1. 6-Bromo-2-methylisoquinoline-1 (2H) one (1-1) is subjected to a palladium-catalyzed cross-coupling reaction to obtain isoquinolinone 1-2. Bromination under acidic conditions gives compound 1-3. The isoquinolinone 1-4 is then obtained by a palladium-catalyzed cross-coupling reaction with boronic acid or an ester. Alternatively, palladium catalyzed cross coupling of compound 1-3 with 4,4,5,5-tetramethyl2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane under conditions described by Miyaura (Ishiyama et al., J. Org. Chem. 1995, 60, 7508-7510) gives the boronic ester 1-5. The isoquinolinone 1-6 is then obtained by a palladium-catalyzed cross-coupling reaction of compound 1-5 with a suitable halide.

Scheme 2

The method for preparing compounds of formula (I) is shown in Scheme 2. 6-Bromo-2-methylisoquinoline-1 (2H) one (2-1) is subjected to a palladium-catalyzed cross-coupling reaction with 4,4,5,5-tetramethyl-2 ( tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane to obtain the boronic ester 2-2. Next, a palladium-catalyzed cross-coupling reaction of compound 2-2 with a suitable halide affords compound 2-3. Bromination under acidic conditions gives compound 2-4. Next, using a palladium-catalyzed cross-coupling reaction with boronic acid or an ester, isoquinolinone 2-5 is obtained.

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Scheme 3

The method for preparing compounds of formula (II) is shown in Scheme 3. The 5-bromopyridin-2-ol derivative (3-1) is alkylated with methyl iodide under basic conditions to obtain the corresponding 5-bromo-1-methylpyridin-2 (1H) -one derivative (3-2). Next, using a palladium catalyzed cross-coupling reaction of compound 3-2 with a suitable halide, compound 3-3 is obtained.

Br R

BocHN

O

(Vos) ₂ O

4-2

Scheme 4

Br p! ^to Suzuki ki

h ₂ n about

4-1

R '

RX, NaH

RCHO, NaBH ₃ CN

H ₂ N О

I 4-3

Br

R.

R ^a

HCI

4-7

Bg

R ^! Suzuki Ki

% ^H O

4-5

R ¹

% ^H O

4-6

The method for preparing compounds of formula (II) is shown in Scheme 4. 3-amino-5-bromo-1methylpyridin-2 (1H) -one derivative 4-1 is used as a starting material for several synthetic routes. In one method, compound 4-1 is directly subjected to a palladium-catalyzed cross-coupling reaction to provide pyridone 4-3. The amino group of compound 4-3 is reductively aminated with an aldehyde and a reducing agent such as sodium cyanoborohydride to give the substituted amino compound 4-7. A second method involving selectively alkylating the amino group of compound 4-1 begins with protecting the amino group as BOC carbamate. Alkylation of carbamate under basic conditions followed by removal of carbamate with BOC under acidic conditions gives compound 4-5 as a secondary amine. Treatment of 4-5 with the appropriate halide under palladium catalyzed cross-coupling conditions affords compound 4-6.

Scheme 5

The method for preparing compounds of formula (IV) is shown in Scheme 5. 5-Bromo-1-methylpyrazin-2 (1H) one (5-1) is subjected to an imidazole annulation reaction by treatment with tosylmethyl isocyanide (TosMIC) under basic conditions (Hoogenboom et al., Organic Syntheses, Coll. Vol. 6, p. 987 (1988)) to give 5-bromo-7-methylimidazo [1,5-a] pyrazin-8 (7H) -one (5-2). Palladium catalyzed cross-coupling of 5-2 with a suitable halide affords 5-3.

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Scheme 6

The method for preparing compounds of formula (III) is shown in Scheme 6. 2,6-Naphthyridin-1-ol (6-1) is alkylated with methyl iodide under basic conditions to obtain 2-methyl-2,6-naphthyridin1 (2H) -one ( 6-2). Chlorination of 6-2 with N-chlorosuccinimide gives the chlorine compound 6-3. Treatment of 6-3 under palladium catalyzed cross-coupling conditions with the appropriate halide affords compound 6-4. Selective reduction of the 2,6-naphthyridinone derivative gives 5,6,7,8tetrahydro-2,6-naphthyridin-1 (2H) -one 6-5.

In each of the above methods or reaction schemes, various substituents may be selected from among the various substituents described herein in other examples.

Pharmaceutical compositions.

In some embodiments, a substituted heterocyclic compound as described herein is administered as a pure chemical. In other embodiments, the substituted heterocyclic compound described herein is combined with a pharmaceutically acceptable or acceptable carrier (also referred to herein as a pharmaceutically acceptable (or acceptable) adjuvant, a physiologically acceptable (or acceptable) adjuvant, or a physiologically acceptable (or acceptable) carrier) selected based on the selected route of administration and standard pharmaceutical practice, as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

Thus, provided herein is a pharmaceutical composition comprising at least one substituted heterocyclic compound or stereoisomer, pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. Carrier (s) (or excipient (s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and is harmless to the recipient (ie, subject) of the composition.

One embodiment relates to a pharmaceutical composition comprising a compound of formulas (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formulas (II), (IIa) or (IIb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (IV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (V), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formulas (VIa), (VIb), (VIc), (VId) or (VIe) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (VII) or (VIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (VIII) or (VIIIa), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (IX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XIV), or a pharmaceutically acceptable salt thereof, and pharmaceutically

- 177 038715 Essential excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XVI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XVII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XIX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XX), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XXI), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XXII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XXIII), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment provides a pharmaceutical composition comprising a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. One embodiment relates to a pharmaceutical composition comprising a compound of formula (XXV), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, a substituted heterocyclic compound as described herein is substantially pure as it contains less than about 5%, or less than about 1%, or less than about 0.1% other organic small molecules such as contaminating intermediates or by-products that are formed, for example, in one or more stages of the synthesis.

Suitable oral dosage forms include, for example, tablets, pills, sachets or capsules of hard or soft gelatin, methylcellulose, or other suitable material that dissolves easily in the gastrointestinal tract. Suitable non-toxic solid carriers are used which include, for example, pharmaceutically pure mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like (see, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

The dose of a composition containing at least one substituted heterocyclic compound described herein may differ depending on the condition of the patient (e.g., human), namely the stage of the disease, general health, age, and other factors that a specialist in the field of medicine will use to determine the dose.

The pharmaceutical compositions can be administered in a form consistent with the disease to be treated (or prevented) as determined by those of skill in the art. The appropriate dose and the appropriate duration and frequency of administration will be determined by factors such as the condition of the patient, the type and severity of the patient's illness, the particular form of the active ingredient, and the route of administration. In general, an appropriate dose and treatment regimen will determine the composition (s) in an amount sufficient to provide a therapeutic and / or prophylactic effect (e.g., improved clinical outcome, such as more frequent complete or partial remissions, or longer life without recurrence and / or overall survival, or a decrease in the severity of symptoms). Optimal doses can generally be determined using experimental models and / or clinical trials.

The optimal dose may depend on the patient's body weight, weight, or circulating blood volume.

Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times or more per day.

Inhibition of bromodomains.

Chromatin is a complex of DNA and protein from which chromosomes are formed. Histones are the main protein component of chromatin, acting as spool around which DNA molecules are wound. Changes in chromatin structure depend on covalent modifications of histone proteins and non-histone binding proteins. Several classes of enzymes are known that modify histones at various sites.

Epigenetics is the study of heritable changes in gene expression caused by mechanisms other than those caused by DNA sequence. Molecular mechanisms that play an important role in epigenetic regulation include DNA methylation and chromatin / histone modifications.

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The genomes of eukaryotic organisms are highly organized structures within the cell nucleus. To compact the 3 billion nucleotides of the human genome in the cell nucleus, a tremendous compaction is needed.

Histones are the main protein components of chromatin. There are six classes of histones (H1, H2A, H2B, H3, H4, and H5), which are subdivided into two classes: core histones (H2A, H2B, H3 and H4) and linker histones (H1 and H5). The basic unit of chromatin is a nucleosome, which includes about 147 DNA base pairs twisted around a core histone octamer, consisting of two copies of each of the core histones H2A, H2B, H3, and H4.

The basic nucleosome units are then further organized and condensed by grouping and folding the nucleosomes in such a way as to form an extremely condensed chromatin structure. A range of different condensation states is possible, so that the degree of density of the chromatin structure changes during the cell cycle, being most compact during the process of cell division.

Chromatin structure plays a decisive role in the regulation of gene transcription, which cannot efficiently occur due to highly condensed chromatin. Chromatin structure is regulated through a series of post-translational modifications of histone proteins, in particular histones H3 and H4, and most often in histone tails that extend beyond the structure of the nucleosomal core. These modifications include acetylation, methylation, phosphorylation, ribosylation, sumoylation, ubiquitination, citrullination, deimination, and biotinylation. The core of histones H2A and H3 can also be modified. Histone modifications are an integral part of various biological processes such as gene regulation, DNA repair, and chromosome condensation.

Acetylation of histones and bromodomains.

Acetylation of histones is usually associated with the activation of gene transcription, since this modification is known to weaken the interaction between DNA and the histone octamer due to changes in electrostatics. In addition to this physical change, specific proteins are known to bind to acetylated lysine residues within histones in order to read the epigenetic code. Bromodomains are small (~ 110 amino acids) special domains in proteins that are known to usually bind to acetylated lysine residues, but not exclusively, in the region of histones. As you know, there are about 50 proteins that contain bromodomains and which have a number of functions in the cell.

The family of bromodomain-containing proteins BET includes 4 proteins (BRD2, BRD3, BRD4, and BRD-t), which contain tandem bromodomains capable of binding to two acetylated lysine residues in close proximity, increasing the specificity of the interaction.

Bromodomain-containing proteins that recognize acetylated lysines on histones (such as BET proteins and non-BET proteins) have been implicated in proliferative disease. BRD4 deficient mice die shortly after implantation and are compromised in their ability to maintain their internal cell mass, and heterozygotes show defects in pre- and postnatal growth associated with reduced proliferation rates. BRD4 regulates genes expressed during M / G1, including genes associated with growth, and remains associated with chromatin throughout the cell cycle (Dey, et al. (2009) Mol. Biol. Cell 20: 4899-4909). BRD4 also physically associates with a mediator and P-TEFb (CDK9 / cyclin T1) to facilitate transcription elongation (Yang, et al. (2005) Oncogene 24: 1653-1662; Yang, et al. (2005) Mol. Cell 19: 535-545). CDK9 is a predictive target in chronic lymphocytic leukemia (CLL) and is associated with c-Myc-dependent transcription (Phelps, et al. Blood 113: 2637-2645; Rahl, et al. (2010) Cell 141: 432-445).

BRD4 is translocated to the NUT protein in patients with fatal midline carcinoma, an aggressive form of human squamous cell carcinoma (French, et al. (2001) Am. J. Pathol. 159: 1987-1992; French, et al. (2003) Cancer Res. 63 : 304-307). In vitro assay with RNAi supports a causal role for BRD4 in this repetitive t (15; 19) chromosomal translocation. In addition, inhibition of BRD4 has been shown to increase the blockage / differentiation of BRD4-NUT cell lines in vitro and in vivo (Filippakopoulos, et al. Selective Inhibition of BET Bromodomains, Nature (published online September 24, 2010)).

Bromodomain proteins (such as BET proteins) are also implicated in inflammatory diseases. BET proteins (e.g. BRD2, BRD3, BRD4, and BRDT) regulate histone acetylation-dependent assembly of chromatin complexes that regulate the expression of inflammatory genes (Hargreaves, et al. (2009) Cell 138: 129-145; LeRoy, et al. (2008 ) Mol. Cell 30: 51-60; Jang, et al. (2005) Mol. Cell 19: 523-534; Yang, et al. (2005) Mol. Cell 19: 535-545). Major inflammatory genes (secondary immune response genes) are suppressed by inhibition of bromodomains of the BET subfamily, and non-responsive genes (primary response genes) are stabilized for transcription. Inhibition of bromodomain BET protects against LPS-induced endotoxic shock and bacterial-induced sepsis in vivo (Nicodeme, et al. Suppression of Inflammation by a Synthetic Histone Mimic, Nature (published online November 10, 2010)).

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Bromodomain proteins (such as BET proteins) have also been found to play a role in the development of viral infections. For example, bromodomain-containing protein 4 is involved in the primary phase of human papillomavirus (HPV) infection, in which the viral genome is contained in the extrachromosomal episome in the basal epithelium. In some HPV strains, BRD4 binding to the HPV E2 protein results in the binding of the viral genome to chromosomes. E2 is critical for both E6 / E7 repression and the activation of HPV viral genes. BRD4 disruption or BRD4-E2 interaction blocks E2-dependent gene activation. BRD4 also functions by linking other classes of viral genomes to host chromatin (eg, herpes virus, Epstein-Barr virus).

Bromodomain-containing proteins have also been found to bind to acetylated lysine residues in proteins other than histones. For example, the bromodomain of the CREB binding protein, a transcriptional coactivator (CBP), allows the recognition of p53 with acetylated Lys382. Following DNA damage, interaction occurs between the bromodomain and acetyl-p53, promoting p53-induced transcriptional activation of the CDK inhibitor p21 and arrest of the cell cycle.

Another novel bromodomain-containing protein is BAZ2B, the biological function of which is believed to be similar to ACF1, the Drosophila BAZ2B ortholog. ACF complexes play a role in establishing a regular distance between nucleosomes during chromatin assembly and influencing different remodeling outcomes at target loci.

One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formulas (I), (Ia) or (Ib). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formulas (II), (IIa) or (IIb). One embodiment of the invention relates to a method for regulating gene transcription in a cell, wherein a bromodomain-containing protein is exposed to a compound of formula (III) or (IIIa). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (IV). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (V). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formulas (VIa), (VIb), (VIc), (VId) or (VIe). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (VII) or (VIIa). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (VIII) or (VIIIa). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (IX). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XII). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XIII).

One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XIV). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XV). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XVI). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XVII). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XVIII). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XIX). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XX). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XXI). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XXII). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XXIII). One embodiment of the invention relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XXIV). One option

180 038715 relates to a method for regulating gene transcription in a cell, in which a bromodomain-containing protein is exposed to a compound of formula (XXV).

One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (I), (Ia) or (Ib). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formulas (II), (IIa) or (IIb). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (III) or (IIIa). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (IV). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (V). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formulas (VIa), (VIb), (VIc), (VId) or (VIe). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (VII) or (VIIa). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (VIII) or (VIIIa). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (IX). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyl-lysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XIII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XIV). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XV). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XVI). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XVII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XVIII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XIX). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XX). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XXI). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XXII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XXIII). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XXIV). One embodiment of the invention relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the bromodomain is exposed to a compound of formula (XXV).

One embodiment relates to a method for regulating gene transcription in a cell, comprising subjecting a bromodomain-containing protein to a compound of formula (X) or a pharmaceutically acceptable salt thereof

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where R ^{2 is} selected from CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD3;

X5 is CR ⁵ or N;

X6 is CR ⁶ or N;

X7 is CR ⁷ or N;

X8 is CR ⁸ or N; where no more than two of X5, X6, X7 or X8 can be N;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁷ is hydrogen, halogen, -OH, -CN, -OR ⁶¹ , -NHR ⁶¹ , -N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁸ is hydrogen, halogen or alkyl; and

R ^A represents an aryl group or a heteroaryl group.

Another embodiment relates to a method for regulating transcription of a gene in a cell, wherein the compound of formula (X) has a structure in which R ^A is a substituted phenyl group.

Another embodiment relates to a method of inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, comprising subjecting the bromodomain to a compound of formula (X).

Another embodiment relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the compound of formula (X) has a structure in which R ^A is a substituted phenyl group.

One embodiment relates to a method for regulating gene transcription in a cell, comprising subjecting a bromodomain protein to the action of a compound of formula (XI) or a pharmaceutically acceptable salt thereof

where R ² is CH3, CH2CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD3;

X3 is CH or N;

X5 is CR ⁵ or N; with the proviso that if X3 is N then X5 is CR ⁵ and if X5 is N then X3 is CH;

R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, where each R ^{61 is} independently selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;

R ⁶ is hydrogen, halogen, —OH, —CN, alkyl, cycloalkyl, cycloalkylalkyl, amino, alkylamino, dialkylamino, cycloalkylalkylamino, alkoxy, or cycloalkylalkoxy; and R ^A represents an aryl group or a heteroaryl group.

Another embodiment relates to a method for regulating transcription of a gene in a cell, wherein the compound of formula (XI) has a structure in which R ^A is a substituted phenyl group.

Another embodiment relates to a method of inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, comprising subjecting the bromodomain to a compound of formula (XI). Another embodiment relates to a method for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein, wherein the compound of formula (XI) has a structure in which R ^A is a substituted phenyl group.

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Processing methods.

The compounds and compositions described herein are generally useful for inhibiting the activity of one or more proteins involved in epigenetic regulation. Thus, one embodiment relates to a method for modulating epigenetic regulation mediated by one or more proteins containing acetyllysine recognition motifs, also known as bromodomains (e.g., BET proteins such as BRD2, BRD3, BRD4 and / or BRDT, and non-BET proteins such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1 and / or BRPF1), by introducing a substituted heterocyclic compound as described herein.

In some embodiments, substituted heterocyclic compounds as described herein are capable of inhibiting the activity of a bromodomain protein such as BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ , TAF1 and / or BRPF1) or a mutant thereof, in a biological sample, in a manner suitable for a variety of purposes known to the person skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological samples, and biological research.

In some embodiments, a method is provided for inhibiting the activity of a bromodomain protein such as BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1 and / or BRPF1) or a mutant thereof, in a patient, comprising the step of administering to said patient a substituted heterocyclic compound as described herein, or a composition containing said compound.

In some embodiments, a method is provided for inhibiting the activity of a bromodomain protein such as BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1 and / or BRPF1) or a mutant thereof, in a biological sample, comprising the step of contacting said biological sample with a substituted heterocyclic compound, as described herein. In some embodiments, the bromodomain protein is a BET protein. In some embodiments, the BET protein is BRD4.

In some embodiments, a method is provided for inhibiting the activity of a bromodomain protein such as BET protein (BRD2, BRD3, BRD4 and / or BRDT), non-BET proteins (such as CBP, ATAD2A, GCN5L, BAZ2B, FALZ, TAF1 and / or BRPF1) or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a substituted heterocyclic compound as described herein. In some embodiments, the bromodomain protein is a BET protein. In some embodiments, the BET protein is BRD4.

Diseases and conditions treatable according to the methods of the present invention include cancer, neoplastic disease, and other proliferative processes. Thus, one aspect is a method of treating a patient having cancer, neoplastic disease, and other proliferative disorder, said method comprising administering a substituted heterocyclic compound as described herein to the patient. In one embodiment, the human patient is treated with a substituted heterocyclic compound as described herein and a pharmaceutically acceptable excipient, wherein said compound is present in a measurable amount to inhibit the activity of a bromodomain protein (such as BRD2, BRD3, BRD4 and / or BRDT) in the patient ...

The present invention also relates to a method for treating a subject, such as a human, suffering from cancer, neoplastic disease, and other proliferative process. The method includes administering to a subject in need of such treatment a therapeutically effective amount of one or more substituted heterocyclic compounds as described herein, which acts by inhibiting the bromodomain and, in general, by modulating gene expression to induce various cellular effects, in particular, induction or repression of gene expression, arrest of cell proliferation, induction of cell differentiation and / or induction of apoptosis.

The present invention also relates to a therapeutic method for modulating protein methylation, gene expression, cell proliferation, cell differentiation and / or apoptosis in vivo in the conditions, diseases, disorders or diseases described herein, in particular cancer, inflammatory disease and / or viral disease, comprising administering to a subject in need of such therapy a pharmacologically active and therapeutically effective amount of one or more substituted heterocyclic compounds as described herein.

The present invention also relates to a method of regulating the activity of an endogenous or heterologous promoter by contacting a cell with a substituted heterocyclic compound as described herein.

The present invention also provides a method for treating or ameliorating symptoms of cancer, neoplastic disease, or other proliferative process by administering an effective amount of a substituted heterocyclic compound as described herein to a mammal, in particular a human, in need of such treatment. In some aspects of the present invention, the disease to be treated with the methods of the present invention is cancer.

In some embodiments, the cancer is midline NUT carcinoma, prostate cancer, breast cancer, bladder cancer, lung cancer, or melanoma. In another embodiment, the cancer is Burkitt's lymphoma.

One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (I), (Ia) or (Ib), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (II), (IIa) or (IIb), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (III) or (IIIa), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (IV), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (V), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (VIa), (VIb), (VIc), (VId) or (VIe), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (VII) or (VIIa), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (VIII) or (VIIIa), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (IX), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XII), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XIII), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XIV), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XVI), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XVII), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XIX), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XX), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XXI), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XXII), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XXIII), or a pharmaceutically acceptable salt thereof. One embodiment relates to a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XXIV), or a pharmaceutically acceptable salt thereof. One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of formula (XXV), or a pharmaceutically acceptable salt thereof.

Other embodiments and applications will be apparent to those skilled in the art in light of the present disclosure. The following examples are given only to illustrate various embodiments and should not be construed as limiting in any way the present invention.

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Examples of

I. Chemical synthesis.

Unless otherwise indicated, reagents and solvents were obtained from commercial suppliers. Anhydrous solvents and oven-dried laboratory glassware sensitive to moisture and / or oxygen were used to transform the synthesis. The connection output has not been optimized. Response times are approximate and have not been optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise indicated. Spectra are reported in parts per million (δ) and binding constants (J) are reported in hertz. For 1H NMR spectra, the solvent peak was used as a reference peak.

The chemical structure of Example 1 is 2-methyl-4-phenylisoquinolin-1-one, which was purchased from commercial suppliers.

Example 2: 4- (3-methoxyphenyl) -2-methylisoquinolin-1-one

A mixture of 4-bromo-2-methylisoquinolin-1 (2H) -one (100 mg, 0.42 mmol) and (3-methoxyphenyl) boronic acid (70 mg, 0.46 mmol), PPh ₃ (66 mg, 0.25 mmol), Na ₂ CO ₃ (133 mg, 1.26 mmol) and Pd (dppf) Cl ₂ (62 mg, 0.084 mmol) in dioxane (2.5 ml) and water (0.5 ml) were heated overnight at 90 ° С. Extraction with ethyl acetate followed by preparative TLC (PE: EA = 1: 1) afforded the title compound (18 mg, 0.07 mmol) as a white solid in 17% yield.

1H NMR (DMSO, 400 MHz): δ 8.30 (d, 1H, J = 7.68), 7.68 (t, 1H, J = 7.56), 7.50-7.55 (m, 3H), 7.40 (t, 1H, J = 7.44 ), 6.97-7.00 (m, 3H), 3.78 (s, 3H), 3.54 (s, 3H). MS (m / z, relative intensity): 266 (M ⁺ , 1).

Examples 3-14 in table. 3 was prepared from 4-bromo-2-methylisoquinolin-1 (2H) -one and the corresponding boronic acid / ester in a manner similar to Example 2.

Table 3

Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 3 γ F 4- (2-fluorophenyl) - 2- methylisoquinoline- 1st (DMSO-T ₆ ) 3.57 (s, 3 Η) 7.20 (d, 7 = 7.42 Hz, 1 Η) 7.31 7.41 (m, 2 Η) 7.42-7.61 (m, 4 Η) 7.64 - 7.73 (m, 1 Η ) 8.32 (d, 7 = 7.81 Hz, 1 Η) 254 4 γ ОМе 4- (2- methoxyphenyl) -2- methylisoquinoline- 1st (DMSO-Тb) 3.54 (s, 3 Η) 3.67 (s, 3 Η) 7.00 -7.11 (m, 2 Η) 7.15 (d, 7 = 8.20 Hz, 1 Η) 7.25 (d, 7 = 6.83 Hz, 1 Η) 7.40 (s, 1 Η) 7.48 (dt, 7 = 15.91, 7.86 Hz, 2 Η) 7.61 (d, 7 = 7.42 Hz, 1 Η) 8.28 (d, 7 = 8.20 Hz, 1 Η) 266 5 CM f 4- (3-aminophenyl) - 2- methylisoquinoline- 1st (DMSO-Te) 3.55 (s, 3 Η) 5.19 (br.s., 2 Η) 6.55 (d, 7 = 7.33 Hz, 1 Η) 6.60 - 6.64 (m, 2 Η) 7.12 (1.7 = 7.83 Hz, 1 Η) 7.43 (s, 1 Η) 7.51 - 7.62 (m, 2 Η) 7.66-7.72 (m, 1 Η) 8.31 (d, 7 = 7.83 Hz, 1 Η) 251

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6 TA ^h about about ^v N-cyclopropyl-3 (2-methyl-1 oxoisoquinolin4yl) benzenesulfone amide (DMSO-70 0.36-0.41 (m, 2 Η) 0.47 - 0.52 (m, 2 Η) 2.16 (br. S., 1 H) 3.57 (s, 3 H) 7.44 (d, 7 = 8.20 Hz, 1 H ) 7.54 7.61 (m, 2 H) 7.68 - 7.77 (m, 3 H) 7.83 - 7.88 (m, 2 H) 7.96 (br. S., 1 H) 8.34 (d, 7 = 7.81 Hz, 1 H) 355 7 xp -7% o o 2-methyl-4- (3pyrrolidine-1ylsulfonylphenyl) isoquinoline-1-one (DMSO-Te) 1.67 (t, 7 = 6.64 Hz, 4 H) 3.18 (t, 7 = 6.44 Hz, 4 H) 3.57 (s, 3 H) 7.42 (d, 7 = 8.20 Hz, 1 H) 7.56 ( t, 7 = 7.61 Hz, 1 H) 7.61 (s, 1 H) 7.68 - 7.80 (m, 4 H) 7.85 (d, 7 = 6.83 Hz, 1 H) 8.33 (d, 7 = 8.20 Hz, 1 H) ... 369 eight jA ^h 0 0 T4 - [[3- (2-methyl-1- oxoisoquinoline- 4- yl) phenyl] methyl] methanesulfonamide (DMSO-Te) 2.87 (s, 3 H) 3.56 (s, 3 H) 4.22 (d, 7 = 6.05 Hz, 2 H) 7.31 - 7.44 (m, 3 H) 7.45 7.62 (m, 5 H) 7.64 - 7.72 (m, 1 H) 8.32 (d, 7 = 7.61 Hz, 1 H) 343 9 О w vVA _n ^ x H N- [3- (2-methyl-1- oxoisoquinoline- 4- yl) phenyl] methanes lfonamide (DMSO-Te) 3.03 (s, 3 H) 3.55 (s, 3H) 7.16 (d, 7 = 7.61 Hz, 1 H) 7.23 - 7.28 (m, 2 H) 7.45 (t, 7 = 8.30 Hz, 1 H ) 7.48 7.57 (m, 3 H) 7.67 - 7.72 (m, 1 H) 8.31 (d, 7 = 7.03 Hz, 1 H) 9.88 (br. S., 1 H) 329 10 Al ^h V% A zN ^ / 'A о о M-ethyl-3- (2- methyl-1- oxoisoquinoline- 4- yl) benzenesulfone amide (DMSO-Ts) 0.92 - 1.02 (m, 3 H) 2.76 - 2.86 (m, 2 H) 3.56 (s, 3 H) 7.43 (d, 7 = 8.20 Hz, 1 H) 7.53 - 7.60 (m, 2 H ) 7.64 (t, 7 = 5.66 Hz, 1 H) 7.68 7.75 (m, 3 H) 7.80 - 7.88 (m, 2 H) 8.29 - 8.36 (m, 1 H) 343

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and u H, S ₄ Me O O 4- (3ethylsulfonylphenyl) -2- methylisoquinolin1-one (CHLOROFORM-7) 1.33 (t, 7 = 7.42 Hz, 3 H) 3.18 (q, 7 = 7.42 Hz, 2 H) 3.65 -3.69 (br, 3H) 7.10 (s, 1 H) 7.43 (d, 7 = 8.01 Hz, 1 N) 7.51 7.57 (m, 1H) 7.60 -7.76 (t, 3 N) 7.93 - 7.98 (t, 2 N) 8.53 (dd, 7 = 8.01, 0.98 Hz, 1 N) 328 12 У |] АчхХ 'А Ν Ν ^н λ Me 4- [3- (dimethylsulfamo ylamino) phenyl] - 2-methyl-1- oxoisoquinoline (DMSO-Tb) 2.71 (s, 6 N) 3.55 (s, ZN) 7.10 (d, 7 = 7.03 Hz, 1 N) 7.22 - 7.25 (t, 2 N) 7.41 (t, 7 = 7.71 Hz, 1 N ) 7.48 (s, 1 N) 7.50 - 7.56 (t, 2 N) 7.67 7.72 (t, 1H) 8.31 (d, 7 = 7.81 Hz, 1 N) 10.02 (br. S., 1 N) 358 thirteen ... Uch IL V l Η N- [3- (2-methyl-1oxoisoquinoline- 4- yl) phenyl] ethanesu l fonamide (DMSO-7 ₆ ) 1.20 (t, 7 = 7.13 Hz, 3 N) 3.13 (q, 7 = 7.29 Hz, 2H) 3.55 (s, 3H) 7.14 (d, 7 = 7.03 Hz, 1 N) 7.25 (br . s., 2 Η) 7.38 - 7.59 (t, 4 Η) 7.69 (t, 7 = 7.61 Hz, 1 Η) 8.31 (d, 7 = 8.01 Hz, 1) 9.92 (s, 1 Η) 343 14 ΧνΟ oh oh 2-methyl-4- (3morpholine-4ylsulfonylphenyl) isoquinoline-1-one (DMSO4) 3.02 -3.09 (m, 4 Η) 3.68 (s, 3 Η) 3.73 -3.80 (m, 4 Η) 7.09 (s, 1 Η) 7.43 (d, 7 = 7.81 Hz, 1 Η) 7.53 7.58 ( t, 1 Η) 7.61 -7.73 (t, 3 Η) 7.78 -7.84 (t, 2H) 8.55 (d, 7 = 7.03 Hz, 1 Η) 385

Example 15 N-benzyl-2-methoxy-5- (2-methyl-1-oxoisoquinolin-4-yl) benzenesulfonamide

For about 3 min, N _{2 was} bubbled through a mixture of 4-bromo-2-methylisoquinolin-1 (2H) -one (56 mg, 0.24 mmol), [3- (benzylsulfamoyl) -4-methoxyphenyl] boronic acid (83 mg, 0.26 mmol), aqueous 2 M Na ₂ CO ₃ (0.375 ml) and Pd (dppf) Cl ₂ (9 mg, 0.001 mmol) in dioxane (1.5 ml), which was then exposed to microwaves at 120 ° С for 1 h and then filtered through a pad of anhydrous Na ₂ SO ₄ using ethyl acetate for transfer and rinsing. Chromatography on silica gel eluting with 0-60% EA in hexane over 6 min and continuing isocratic elution with 60% EA afforded the title compound (60 mg, 0.14 mmol) as a white solid in 58% yield.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.57 (s, 3H), 3.89 (s, 3H), 4.11 (d, J = 6.32 Hz, 2H), 7.16-7.23 (m, 6H), 7.34 (d , J = 8.08 Hz, 1H), 7.47 (s, 1H), 7.53-7.59 (m, 2H), 7.65 (d, J = 2.27 Hz, 1H), 7.72-7.77 (m, 1H), 7.94 (t, J = 6.32 Hz, 1H), 8.34 (d, J = 7.33 Hz, 1H). LCMS (M + H) + 435.

Examples 16-17 in table. 4 was prepared from 4-bromo-2-methylisoquinolin-1 (2H) -one and the corresponding boronic acid / ester in a manner similar to Example 15.

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Table 4

Example No. R ¹ Name '11 NMR (ppm (δ), 400 MHz) MS (M + H) sixteen CM T 0) o ω 7 2-methoxy-5 - (2methyl-1- oxoisoquinoline -4- yl) benzenesulf onamide (DMSO-A) 3.57 (s, 3 Η) 3.97 (s, 3H) 7.18 (s, 2H) 7.35 (d, 7 = 8.59 Hz, 1 H) 7.44 (d, 7 = 8.08 Hz, 1 H) 7.50 ( s, 1 H) 7.57 (t, 7 = 7.45 Hz, 1 H) 7.65 (dd, 7 = 8.46, 2.15 Hz, 1 H) 7.71 (t, 7 = 7.58 Hz, 1 H) 7.76 (d, 7 = 2.27 Hz, 1 H) 8.34 (d, 7 = 8.34 Hz, 1 H) 345 17 Ha N NHSO ₂ Me Ν- [2-Μετ4π-5 (2-methyl-1 oxoisoquinoline -4- yl) phenyl] methane sulfonamide (DMSO-A) 2.38 (s, 3 H) 3.02 (s, 3H) 3.57 (s, 3H) 7.24 (dd, 7 = 7.83, 1.77 Hz, 1 H) 7.34 (d, 7 = 1.52 Hz, 1 H) 7.38 (d, 7 = 7.83 Hz, 1 H) 7.50 (s, 1 H) 7.53 - 7.58 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.30 - 8.36 (m, 1 H) 9.18 (s, 1H) 343

Example 18 N-benzyl-2-methoxy-5- (2-methyl-1-oxoisoquinolin-4-yl) benzamide

Stage 1: N-benzyl-5-bromo-2-methoxybenzamide

To an ice bath cooled mixture of 5-bromo-2-methoxybenzoic acid (439 mg, 1.9 mmol) in 1: 1 CH ₂ Cl _2: DMF (4 mL) was added benzylamine (0.228 mL, 2.1 mmol), EDCI (438 mg, 2.3 mmol), HOBt (311 mg, 2.3 mmol) and NEtiPr ₂ (0.496 ml, 2.85 mmol). The mixture was then stirred at room temperature until the reaction was complete. Extraction with ethyl acetate, washing with saturated aqueous NaHCO ₃ , H ₂ O, saturated aqueous KHSO ₄ and brine, after isolation gave the title compound (550 mg) which was carried further without purification. LCMS (M + H) ⁺ 320, 322.

Stage 2: N-benzyl-2-methoxy-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

N _{2 was} bubbled through a mixture of the title compound N-benzyl-5-bromo-2-methoxybenzamide (174 mg, 0.54 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl-1,3, 2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (166 mg, 0.65 mmol), potassium acetate (159 mg, 1.62 mmol) and Pd (dppf) Cl ₂ (20 mg, 0.03 mmol) in anhydrous DMF (4.2 ml). After heating at 90 ° C for about 2 h under N2 by chromatography on silica gel, eluting with 0-40% EA in hexane over 7 min and continuing isocratically with 40% EA, the title compound (138 mg, 0.38 mmol) was obtained in as a white solid with a yield of 70%. LCMS (M + H) ⁺ 368.

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Stage 3: N-benzyl-2-methoxy-5- (2-methyl-1-oxoisoquinolin-4-yl) benzamide

For about 3 minutes, N _{2 was} bubbled through a mixture of N-benzyl-2-methoxy-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (51 mg, 0.14 mmol), 4-bromo-2-methylisoquinoline- 1 (2H) -one (30 mg, 0.13 mmol), aqueous 1M K ₃ PO ₄ (0.3 ml), and Pd (dppf) Cl ₂ (10 mg, 0.013 mmol) in dioxane (1.15 ml), which was then exposed to microwaves at 100 ° C for 1 hour. Treatment as described for Example 15 and purification by chromatography on silica gel eluting with 5-50% EA in hexane over 4 minutes and continuing isocratically with 50% EA gave the title compound ( 37 mg, 0.14 mmol) as a tan solid in 71% yield.

1H NMR (400 MHz, DMSO-d6) δ 3.57 (s, 3H), 3.97 (s, 3H), 4.52 (d, J = 6.06 Hz, 2H), 7.21-7.37 (m, 6H), 7.47-7.51 ( m, 2H), 7.56 (td, J = 5.37, 2.15 Hz, 2H), 7.68-7.73 (m, 1H), 7.79 (d, J = 2.27 Hz, 1H), 8.33 (d, J = 7.83 Hz, 1H ), 8.79 (t, J = 6.06 Hz, 1H). LCMS (M + H) + 399.

Examples 19-31 in table. 5 was prepared from 4-bromo-2-methylisoquinoline-1 (2H) -one and the corresponding boronic acid / ester in a manner similar to that described in example 18, step 3. For examples 20-26, the reaction temperature was increased to 120 ° C. Aniline hydrochlorides were prepared by treating aniline with anhydrous HCl in methanol as a final step.

Table 5

Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) nineteen o zi X 4- (3,4-dihydro- 2H-1,4- benzoxazine-6- silt) -2- methylisoquinols n-1-he (DMSO-Te) 3.50 - 3.59 (m, 3 Η) 4.14 - 4.19 (m, 2 Η) 5.87 (br.s., 1 H) 6.51 (dd, 7 = 8.08.2.02 Hz, 1 H) 6.61 (d , 7 = 2.02 Hz, 1 H) 6.74 (d, 7 = 8.08 Hz, lH) 7.38 (s, 1 H) 7.50 - 7.55 (m, 1 H) 7.58 (d, 7 = 7.83 Hz, 1 H) 7.66 7.72 (m, 1 H) 8.30 (d, 7 = 8.08 Hz, 1 H) 293 twenty Η 2-methyl-4- (2oxo-1,3dihydroindol-6yl) isoquinolin1-one (DMSO-Te) 3.55 (s, 2 H) 3.56 (s, 3 H) 6.85 (s, 1 H) 7.00 (dd, 7 = 7.58, 1.52 Hz, 1 H) 7.32 (d, 7 = 7.58 Hz, 1 H) 7.49 (s, 1 H) 7.53 - 7.58 (m, 2 H) 7.67 - 7.72 (m, 1 H) 8.31-8.35 (m, 1 H) 10.47 (s, 1 H) 291

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21 Χλ SO ₂ NH ₂ 3- (2-methyl-1OXOISOCHINOLINE- 4- yl) benzenesulfo namid (DMS0-7,) 3.59 (s, 3 N) 7.43 (s, 2 N) 7.48 (d, 7 = 8.08 Hz, 1 N) 7.56 - 7.61 (t, 2 N) 7.67 - 7.75 (t, 3 N) 7.87 - 7.92 (t, 2 N) 8.36 (d, 7 = 8.08 Hz, 1 N) 315 22 4 _ο ωχ 4 Ν- (2hydroxyethyl) -3 (2-methyl-1oxoisoquinolin4yl) benzenesulfonamide (DMS0-7,) 2.85 (q, 7 = 6.06 Hz, 2 N) 3.39 (q, 7 = 6.06 Hz, 2H) 3.59 (s, 3 N) 4.70 (t, 7 = 5.56 Hz, 1 N) 7.47 ( d, 7 = 8.08 Hz, 1 H) 7.56-7.59 (t, 1 H) 7.61 (s, 1 H) 7.66 7.77 (w, 4 H) 7.83 -7.88 (t, 2 H) 8.36 (d, 7 = 8.08 Hz, 1H) 359 23 Ύχ \ Ρ ^^ ΝΗ ₂ HCI 4- (5-amino-2fluorophenyl) -2- methylisoquinols n-1-he hydrochloride (DMSO-Te) 3.57 (s, 3 N partially closed) 7.08 7.22 (t, 2 N) 7.24 (d, 7 = 9.60 Hz, 1 N) 7.32 (1, 7 = 9.09 Hz, 1 N) 7.54-7.60 ( t, 2 H) 7.67 - 7.73 (t, 1 H) 8.32 (d, 7 = 7.83 Hz, 1 H) 269 24 ΑΑ 4 ^^ ΝΗ ₂ ηοι 4- (5-amino-2,4difluorophenyl) -2- methylisoquinols H-1-OH hydrochloride (DMSO-Te) 3.55 (s, 3 H) 6.83 (dd, 7 = 9.73, 7.96 Hz, 1 H) 7.19-7.28 (w, 2 H) 7.51 - 7.58 (t, 2 H) 7.67 - 7.72 (t, 1 N) 8.30 (d, 7 = 8.08 Hz, 1 N) 287 25 Λ, „ 4- (3-amino-5fluorophenyl) -2- methylisoquinols n-1-he hydrochloride (DMSO-7 ₆ ) 3.55 (s, 3 Η) 6.47 - 6.56 (m, 2 Η) 6.59 (s, 1 Η) 7.51 (s, 1 Η) 7.52 7.62 (m, 2 Η) 7.69-7.75 (m, 1 Η) 8.32 (d, 7 = 8.08 Hz, 1H) 269

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26 χχ ^Γ 4 ^^ NH ₂ HCI 4- (3-amino-4fluorophenyl) -2- methylisoquinols n-1-he hydrochloride (DMSO-Te) 3.55 (s, 3 Η) 6.64 (d, 7 = 2.53 Hz, 1 Η) 6.89 (dd, 7 = 8.59, 2.02 Hz, 1 Η) 7.13 (dd, 7 = 11.49, 8.21 Hz, 1 Η) 7.45 (s, 1 Η) 7.52 7.58 (m, 2 Η) 7.67-7.74 (m, 1 Η) 8.32 (d, 7 = 7.07 Hz, 1 Η) 269 27 fT ⁿ 0 \\ o o M-benzyl-3- (2methyl-1- oxoisoquinoline 4- yl) benzenesulfonamide (DMSO-Тb) 3.59 (s, 3 Η) 4.08 (d, 7 = 6.06 Hz, 2 Η) 7.17 - 7.29 (m, 5 Η) 7.40 (d, 7 = 7.83 Hz, 1 Η) 7.54 (s, 1 Η) 7.58 (t, 7 = 7.58 Hz, 1 Η) 7.68 - 7.76 (m, 3 Η) 7.80 (s, 1 Η) 7.85 (td, 7 = 4.48, 1.89 Hz, 1 Η) 8.26 (t, 7 = 6.32 Hz, 1 Η) 8.35 (d, 7 = 8.08 Hz, 1 Η) 405 28 H _Ν N M- [3- (2-methyl-1- oxoisoquinoline- 4yl) phenyl] propa n-1- sulfonamide (DMSO-Тb) 0.96 (t, 7 = 7.45 Hz, ZN) 1.72 (sxt, 7 = 7.48 Hz, 2 Η) 3.10-3.15 (m, 2 Η) 3.57 (s, 3 Η) 7.16 (d, 7 = 7.58 Hz, 1 Η) 7.26-7.30 (m, 2 Η) 7.43 - 7.59 (m, 4 Η) 7.68 - 7.73 (m, 1 Η) 8.34 (d, 7 = 7.83 Hz, 1 Η) 9.91 (s, 1H ) 357 29 ь ^ΙΖ. About ωί H- [3- (2-methyl-1oxoisoquinoline- 4yl) phenyl] butane 1-sulfonamide (DMSO-Te) 0.84 (t, 7 = 7.33 Hz, 3H) 1.37 (sxt, 7 = 7.38 Hz, 2H) 1.67 (dt, 7 = 15.35, 7.61 Hz, 2H) 3.10-3.18 (m, 2 H) 3.57 (s, 3H) 7.16 (d, 7 = 7.58 Hz, 1 H) 7.24 7.33 (m, 2 H) 7.41 -7.60 (m, 4 H) 7.64 - 7.74 (m, 1 371

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H) 8.34 (d, 7 = 8.08 Hz, 1 H) 9.91 (s, 1 N) thirty Nx / ^OMe XX NHSO ₂ Me N- [2-mctokch-5 (2-methyl-1 oxoisoquinoline- 4- yl) phenyl] methane ulfonamide (DMSO-Tb) 3.00 (s, 3 N) 3.57 (s, 3 N) 3.90 (s, ZN) 7.18-7.23 (m, 1 N) 7.24 7.30 (t, 1 N) 7.33 (d, 7 = 2.27 Hz , 1 H) 7.47 (s, 1 H) 7.55 (dd, 7 = 7.58, 5.05 Hz, 2 H) 7.65 - 7.73 (m, 1 H) 8.31 - 8.37 (t, 1 H) 9.04 (s, 1 H) 359 31 χι% N (Me) CO ₂ tert-butyl Nmethyl-M- [3- (2methyl-1oxoisoquinoline- 4yl) phenyl] carbam at (DMSO-7 ₆ ) 1.41 (s, 9 Η) 3.24 (s, 3 Η) 3.57 (s, 3 Η) 7.25 (d, 7 = 7.33 Hz, 1 Η) 7.32 - 7.38 (t, 2 Η) 7.44 7.60 (t, 4 Η) 7.67-7.73 (t, 1 Η) 8.34 (d, 7 = 7.83 Hz, 1H) 365

Example 32: 2-methyl-4- [3- (methylamino) phenyl] isoquinolin-1-one hydrochloride

To the title compound of Example 31 (48 mg, 0.13 mmol) was added 4M HCl in dioxane (3 mL). After stirring for about 1 hour, the volatiles were removed in vacuo. Hexane was added and evaporated (x2). The resulting white solid was dried in vacuo to give the title compound (39 mg, 0.13 mmol) in quantitative yield.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.85 (s, 3H), 3.57 (s, 3H), 7.10 (br. S., 3H), 7.44 (br. S., 1H), 7.517. 60 (m, 3H), 7.68-7.74 (m, 1H), 8.34 (d, J = 7.58 Hz, 1H). LCMS (M + H) + 265.

Example 33: N-methyl-N- [3- (2-methyl-1-oxoisoquinolin-4-yl) phenyl] methanesulfonamide

N (Me) SO ₂ Me

O

To the title compound of Example 32 (35 mg, 0.12 mmol) in anhydrous CH ₂ Cl ₂ (0.3 ml), pyridine (0.1 ml) and NEtiPr ₂ (0.021 ml, 0.12 mmol) was added methanesulfonyl chloride (0.011 ml, 0.14 mmol). After 0.5-1 h, ice was added to the mixture, followed by the addition of water and ethyl acetate. _{Extraction, washing with H 2} O, 1: 1 with aqueous saturated KHSO ₄ : H 2 O and brine, and purification on silica gel eluting with 35-80% EA in hexane over 6 min and continuing isocratically with 80% EA gave the title compound (22 mg, 0.06 mmol) as a cream-colored solid in 54% yield.

1H NMR (400 MHz, DMSO-d6) δ ppm 3.00 (s, 3H), 3.30 (s, 3H), 3.58 (s, 3H), 7.40 (d, J = 7.58 Hz, 1H), 7.45-7.61 (m , 6H), 7.71 (td, J = 7.58, 1.26 Hz, 1H), 8.34 (dd, J = 8.21, 1.14 Hz, 1H). LCMS (M + H) ⁺ 343.

Examples 34-40 in table. 6 was obtained in one stage by sulfonylation of aniline of examples 2326 from table. 5 using methanesulfonyl chloride, in a manner similar to that described in Example 33 (1 step from said Example No.), or in two steps from 4-bromo-2-methylisoquinolin-1 (2H) -one and the corresponding aniline boronic acid / ester in a manner, analogous to that described in example 23, followed by sulfonylation of aniline with methanesulfonyl chloride in a manner analogous to that described in example 33 (2 steps).

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Table 6

O

Example No. R ¹ Name Stage number (from Example No.) '11 NMR (ppm (δ), 400 MHz) MS (M + H) 34 ph about. ° zi th Ν- [4-φτορ-3 (2-methyl-1oxoisoquino lin-4yl) phenyl] methansu lf she MFA one stage (from Example 23) Ή NMR (400 MHz, DMSO-t / ₆ ) δ ppm 3.04 (s, 3 Η) 3.57 (s, 3 Η) 7.227.27 (m, 2 Η) 7.30 - 7.40 (m, 2 Η) 7.53 -7.59 ( m, 1 Η) 7.61 (s, 1 Η) 7.66 7.74 (m, 1 Η) 8.32 (d, 7 = 8.08 Hz, 1 Η) 9.83 (s, 1 Η) 347 35 f O.? ; ω U- ° 'ZI ή Ν- [2,4- difluoro-5- (2methyl-1- oxoisoquino lin-4yl) phenyl] methanesulfone Ministry of Foreign Affairs one stage (from Example 24) Ή NMR (400 MHz, DMSO-Te) δ ppm 3.08 (s, 3 H) 3.57 (s, 3 H) 7.24 (d, 7 = 8.08 Hz, 1 H) 7.45 (t, 7 = 8.21 Hz, 1 H) 7.53 7.60 (m, 2 H) 7.62 (s, 1 H) 7.70 (t, 7 = 7.58 Hz, 1 H) 8.32 (d, 7 = 7.83 Hz, 1 H) 9.70 (s, 1 H) 365 36 % N Me Η Ν- [3-φτορ-5 (2-methyl-1oxoisoquino lin-4yl) phenyl] methanesulfone MID one stage (from Example 25) ¹ NMR (400 MHz, DMSO-A) δ ppm 3.12 (s, 3 H) 3.57 (s, 3 H) 7.01 7.13 (m, 3 H) 7.54 - 7.63 (m, 3 H) 7.70 - 7.77 (m, 1 H) 8.33 (d, 7 = 8.08 Hz, 1 H) 10.16 (s, 1 H) 347

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37 ъ ωί s' ° φ Ν- [2-phτορ-5 (2-methyl-1oxoisoquino lin-4yl) phenyl] methanesulfone MID one stage (from Example 26) Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 3.09 (s, 3 Η) 3.57 (s, 3 Η) 7.287.36 (m, 1 Η) 7.39 - 7.48 (m, 2 Η) 7.49 - 7.60 (m , 3 Η) 7.67 - 7.74 (m, 1 Η) 8.34 (d, 7 = 8.08 Hz, 1 Η) 9.75 (s, 1 Η) 347 38 Clxzx XI nhso ₂ m Ν- [4-χπορ-3 (2-methyl-1oxoisoquino lin-4yl) phenyl] methanesulfone MID 2 stages Ή NMR (400 MHz, DMSO-J ₆ ) δ ppm 3.08 (s, 3 Η) 3.56 (s, 3 Η) 7.07 (d, 7 = 7.83 Hz, 1 Η) 7.23 (d, 7 = 2.78 Hz, 1 Η ) 7.33 (dd, 7 = 8.72.2.65 Hz, 1 Η) 7.51 - 7.62 (m, 3 Η) 7.64 - 7.70 (m, 1 Η) 8.28 - 8.36 (m, 1 Η) 10.04 (s, 1 Η) 363, 365 39 XI% NHSO ₂ Me M- [4-methyl3- (2-methyl- one- oxoisoquino lin-4yl) phenyl] methanesulfone Ministry of Foreign Affairs 2 stages Ή NMR (400 MHz, DMSO-Tb) δ ppm 2.01 (s, 3 Η) 3.00 (s, 3H) 3.56 (s, 3 H) 7.02 (d, 7 = 8.08 Hz, 1 H) 7.06 (d, 7 = 2.53 Hz, 1 H) 7.22 (dd, 7 = 8.21, 2.40 Hz, 1 H) 7.33 (d, 7 = 8.34 Hz, 1 H) 7.45 (s, 1 H) 7.51 - 7.56 (m, 1 H) 7.63 - 7.68 (m, 1 H) 8.32 (d, 7 = 8.08 Hz, 1 H) 9.71 (s, 1 H) 343 40 CF ₃ χι% NHSO ₂ Me Ν- [3- (2- methyl-1 - oxoisoquino lin-4-yl) -5 (trifluorometh yl) phenyl] methanesulfone Ministry of Foreign Affairs 2 stages ¹ NMR (400 MHz, DMSO-TB) δ ppm 3.14 (s, 3 H) 3.58 (s, 3 H) 7.49 7.52 (m, 2 H) 7.54-7.61 (m, 3 H) 7.64 (s, 1 H) 7.70 - 7.76 (m, 1 H) 8.35 (d, 7 = 8.08 Hz, 1 H) 10.29 (s, 1H) 397

Example 41: N- [4-fluoro-3- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinolin-4-yl] phenyl] methanesulfonamide.

Stage 1: 2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (3.8 g, 16 mmol), 1-methyl-4- (tetramethyl-1,3,2 dioxaborolan-2-yl) -1H-pyrazole (6.69 g, 32 mmol) , CsF (7.29 g, 48 mmol), Pd (PPh _{3) 2} Cl ₂ (0.4 g, 1 mmol) in dioxane / H ₂ O (60/10 mL) was stirred at 90 ° C for 12 h under N2 atmosphere. The mixture was concentrated and the residue was purified by silica gel chromatography (PE: EA = 2: 1) to give the title compound (3.1 g, 81%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.40 (d, J = 12 Hz, 1H), 7.87 (s, 1H), 7.74 (s, 1H), 7.59-7.56 (dt, J1 = 4 Hz, J2 = 8 Hz, 2H), 7.07 (d, J = 4 Hz, 1H), 6.48 (d, J = 8 Hz, 1H), 3.98 (s, 3H), 3.61 (s, 3H). LCMS: 240.0 (M + H) +.

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Stage 2: 4-bromo-2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

Bromine (1.8 g, 11.25 mmol) in HOAc (6 ml) was added to the title compound 2-methyl6- (1-methylpyrazol-4-yl) isoquinolin-1-one (3 g, 12.5 mmol) in HOAc (24 ml ) at 0 ° C. The mixture was stirred at 30 ° C for 15 min, rapidly cooled with H ₂ O (100 mL) and the resulting yellow solid was collected by filtration to give the title compound (2.04 g, 56%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 28.8 Hz, 2H), 7.82 (d, J = 15.6 Hz, 2H), 7.65 (d, J = 8 Hz, 2H), 7.38 (s, 1H), 4.00 (s, 3H), 3.61 (s, 3H). LCMS: 318.0 (M + H) +.

Stage 3: 4- (5-amino-2-fluorophenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

4-Bromo-2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one (35 mg, 0.11 mmol), 4-fluoro-3- (4,4,5,5 tetramethyl-1,3 , 2-dioxaborolan-2-yl) aniline (29 mg, 0.12 mmol), Pd (dppf) Cl ₂ (8 mg, 0.01 mmol), and aqueous 1 M K ₃ PO ₄ (0.3 ml) in dioxane (1.2 ml) Microwave at 120 ° C for 1.25 h. The experiment was carried out in a manner similar to that described for Example 18, step 3. Chromatography on silica gel eluting with 100% EA followed by 10% methanol in EA gave the title compound (25 mg, 0.07 mmol) as a cream-colored solid with a yield of 64%. LCMS (M + H) ⁺ 349.

Stage 4: N- [4-fluoro-3- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinolin-4-yl] phenyl] methanesulfonamide

4- (5-Amino-2-fluorophenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one (25 mg, 0.07 mmol) in pyridine (0.1 ml) and anhydrous CH ₂ Cl ₂ (0.3 ml) was treated with methanesulfonyl chloride (0.007 ml, 0.09 mmol) in a manner similar to that described in example 33. After similar processing, chromatography on silica gel, eluting with 50-100% EA in hexane for 4 min and continuing isocratically with 100% EA, obtained the title compound (24 mg, 0.06 mmol) as a white solid in 78% yield.

1H NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.22-7.45 (m, 4H), 7.59 (s, 1H), 7.76 ( dd, J = 8.34, 1.52 Hz, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.29 (d, J = 8.34 Hz, 1H), 9.82 (s, 1H). LCMS (M + H) ⁺ 427.

Examples 42-45 in table. 7 was prepared from the title compound of Example 41 step 2 in one step using the corresponding phenylboronic acid / ester in a similar manner to Example 18 step 3 (1 step) or in two steps from aniline boronic acid / ester followed by sulfonylation of aniline with either methanesulfonyl chloride or ethanesulfonyl chloride in a manner analogous to that described in example 41, steps 3 and 4 (2 steps).

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Table 7

Example No. R ¹ Name No. stages (from Example No.) '11 NMR (ppm (δ), 400 MHz) MS (M + H) 42 AA C> O, k 11% X N 'Me N X- [3- [2-methyl6- (1methylpyrazol4-yl) -1- OXOISOCHINOLI n-4yl] phenyl] meta-nsulfonamide one stage (DMSO-TB) 3.07 (s, 3 Η) 3.56 (s, 3 Η) 3.85 (s, 3 Η) 7.23 (d, 7 = 7.83 Hz, 1 Η) 7.28 (d, 7 = 8.08 Hz, 1 Η) 7.34 (s, 1 Η) 7.41 7.54 (m, 2 Η) 7.66 (s, 1 Η) 7.72 - 7.80 (m, 1 Η) 7.86 (s, lH) 8.16 (s, 1 H) 8.30 (d, 7 = 8.34 Hz, 1 H) 9.87 (s, 1 H) 409 43 ^F YY ^F VA _NHS o _2Me K- [2,4-difluoro5- [2-methyl-6 (1- methylpyrazol4-yl) -1- oxoisoquinoli n-4- yl] phenyl] methanesulfonamide 2 stages (DMSO-Тb) 3.10 (s, 3 H) 3.55 (s, 3 H) 3.85 (s, 3 H) 7.33 (s, 1 H) 7.44 7.63 (m, 3 H) 7.77 (dd, 7 = 8.59, 1.52 Hz, 1 H) 7.89 (s, lH) 8.19 (s, 1 H) 8.28 (d, 7 = 8.34 Hz, 1 H) 9.71 (s, 1 H) 445 44 jCl 4- (3ethylsulfonyl phenyl) -2methyl-6- (1methylpyrazole- 4yl) isoquinolin1-one one stage (DMSO-Тb) 1.17 (t, 7 = 7.33 Hz, 3H) 3.40 (q, 7 = 7.41 Hz, 2 H) 3.58 (s, 3 H) 3.85 (s, 3 H) 7.56 (s, 1 H) 7.63 (s, 1 H) 7.75 - 8.00 (m, 6 H) 8.16 (s, lH) 8.32 (d, 7 = 8.34 Hz, 1 H) 409 45 ^CI ^ A XI A ^^ NHSOzEt N- [4-xnop-3- [2methyl-6- (1methylpyrazol4-yl) -1oxoisoquinoli n-4yl] phenyl] ethanes ulfonamide 2 stages (DMSO-TB) 1.14-1.28 (m, 3H) 3.11 -3.28 (m, 2 H) 3.55 (s, 3 H) 3.84 (s, 3H) 7.13 (s, 1H) 7.26 (d, 7 = 2.53 Hz, 1 H) 7.36 (dd, 7 = 8.72, 2.65 Hz, 1 H) 7.54 (s, 1 H) 7.61 (d, 7 = 8.84 Hz, 1 H) 7.72 - 7.77 (m, 1 H) 7.81 (s, lH ) 8.12 (s, 1 H) 8.28 (d, 7 = 8.34 Hz, 1 H) 10.08 (s, 1 H) 457, 459

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Example 46 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one.

Stage 1: 2-bromo-1- (cyclopropylmethoxy) -4-methanesulfonylbenzene

A mixture of 2-bromo-4-methanesulfonylphenol (7.2 g, 29 mmol), (chloromethyl) cyclopropane (4.3 g, 32 mmol) and K ₂ CO ₃ (8 g, 58 mmol) in acetone (80 ml) was stirred at 80 ° С over 5 h. The mixture was rapidly cooled with water (40 ml). Extraction with ethyl acetate and purification by preparative HPLC gave the title compound (2.5 g, 28.6%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.12 (d, J = 2.3 Hz, 1H), 7.84 (dd, J1 = 2.3 Hz, J2 = 8.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H) , 3.99 (d, J = 6.7 Hz, 2H), 3.05 (s, 3H), 1.23-1.43 (m, 1H), 0.70 (d, J = 7.9 Hz, 2H), 0.44 (d, J = 5.4 Hz, 2H).

Stage 2: 2-methyl-6- (1-methylpyrazol-4-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) isoquinoline-1-one

O

A mixture of the title compound of Example 41, step 2 (1.4 g, 4.41 mmol), 4,4,5,5 tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2- dioxaborolane (2.24 g, 8.83 mmol), KOAc (1.08 g, 11.08 mmol), Pd (dppf) Cl ₂ (100 mg, 0.137 mmol) in dioxane (50 ml) were stirred at 90 ° С for 12 h under N ₂ ... Purification by silica gel column chromatography (PE: EA = 3: 1) afforded the title compound (200 mg, 12%) as a yellow solid.

Ή NMR (CDCl ₃ , 400 MHz) δ 8.55 (d, J = 1.5 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.71 (d, J = 16.8 Hz, 2H), 4.00 (s, 3H), 3.63 (s, 3H), 1.40 (s, 12H).

Step 3: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one

O

A mixture of 2-bromo-1- (cyclopropylmethoxy) -4-methanesulfonylbenzene (20.8 mg, 0.068 mmol), 2-methyl6- (1-methylpyrazol-4-yl) -4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) isoquinolin-1-one (30 mg, 0.08 mmol), NaHCO ₃ (14.28 mg, 0.17 mmol), and Pd (dppf) Cl ₂ (10 mg, 0.014 mmol) in dioxane ( 2.0 mL) and H ₂ O (0.5 ml) was exposed to microwaves in N2 atmosphere at 100 ° C for 30 min. Purification by preparative HPLC afforded the title compound (11 mg, 28%) as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1H), 7.98-8.04 (m, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H) , 7.63 (s, 1H), 7.58-7.62 (m, 1H), 7.19-7.21 (m, 1H), 7.11-7.15 (m, 1H), 7.09 (s, 1H), 3.93 (s, 3H), 3.83 -3.91 (m, 2H), 3.66 (s, 3H), 3.12 (s, 3H), 0.94-1.04 (m, 1H), 0.30-0.40 (m, 2H), 0.00-0.12 (m, 2H). LCMS: 464.1 (M + H) +.

Example 47 N- [3- (6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl] methanesulfonamide.

Stage 1: 6-fluoro-2-methylisoquinolin-1-one

Sodium hydride (60% in mineral oil) (211 mg, 5.27 mmol) was added to 6-fluoro-1,2-dihydroisoquinolin-1-one (716 mg, 4.39 mmol) in anhydrous DMF (6 ml) cooled in an ice bath. The mixture was stirred for about 30 min at room temperature and methyl iodide (0.328 mL, 5.27 mmol) was added dropwise. After 1 h, the reaction was estimated to be about 60% complete and additional methyl iodide (0.2 mL, 3.2 mmol) was added. After about 1 hour, ice, water and ethyl acetate were added to the mixture. After extraction with ethyl acetate, the title compound (836 mg) was obtained as a cream solid and was used without purification.

Stage 2: 4-bromo-6-fluoro-2-methylisoquinolin-1-one

Bromine (232 mg, 1.45 mmol, 0.097 ml) in acetic acid (1.0 ml) was quickly added dropwise to 6 197 038715 fluoro-2-methylisoquinolin-1-one (283 mg, 1.61 mmol) in acetic acid (7.0 ml) in an atmosphere of N ₂ and cooled in an ice bath. The ice bath was removed and the thick slurry was stirred for 10 min at room temperature. Ice, water and ethyl acetate were added. Extraction with ethyl acetate, washing with aqueous 0.5N. NaOH, H ₂ O, saturated aqueous KHSO 4 and brine gave the title compound as a cream solid (313 mg) which was used without purification.

Stage 3: N- [3- (6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl] metαnsulfonamide

For about 3 min, N _{2 was} bubbled through a mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (41 mg, 0.16 mmol), (3-methanesulfonamidophenyl) boronic acid (38 mg, 0.18 mmol), aqueous 1 M K ₃ PO ₄ (0.3 ml) and Pd (dppf) Cl ₂ (12 mg, 0.016 mmol) in dioxane (1.2 ml), which was then exposed to microwaves for 1 h at 120 ° С. The experiment was performed in a similar manner to that described for Example 18, Step 3. Purification using chromatography on silica gel eluting with 40-80% EA in hexane over 5 min and continuing isocratically with 80% EA gave the title compound (28 mg, 0.08 mmol ) as a cream-colored solid with 38% overall yield in steps 13.

1H NMR (400 MHz, DMSO-d ₆ ) δ 3.06 (s, 3H), 3.56 (s, 3H), 7.15-7.22 (m, 2H), 7.25-7.31 (m, 2H), 7.41 (td, J = 8.65, 2.65 Hz, 1H), 7.45-7.52 (m, 1H), 7.61 (s, 1H), 8.40 (dd, J = 9.09, 6.06 Hz, 1H), 9.88 (s, 1H). LCMS (M + H) + 347.

Examples 48-50 in table. 8 was prepared from the title compound of Example 47, step 2 in one step using the corresponding phenylboronic acid / ester in a similar manner to Example 47, step 3 (1 step), or in two steps from the corresponding aniline boronic acid / complex ether in a manner analogous to that described in example 47, step 3, followed by sulfonylation of aniline or methanesulfonyl chloride, or ethanesulfonyl chloride in a manner similar to that described in example 41, step 4 (2 steps).

Table 8

Example No. R ¹ Name No. stages (from Example No.) Ή NMR (ppm (δ), 400 MHz) MS (Μ + Η) 48 A SO ₂ NH ₂ 3- (6-fluoro-2methyl-1- oxoisoquino lin-4yl) benzenes lfonamide one (DMSO-Тb) 3.58 (s, 3 Η) 7.11 (dd, 7 = 10.61, 2.53 Hz, 1 Η) 7.41 7.49 (m, 3 Η) 7.65 7.76 (m, 3 Η) 7.87 7.93 (m, 2 Η) 8.42 (dd, 7 = 8.84, 6.06 Hz, 1 Η) 333 49 AH ⁿ O O Ν-3τηπ-3- (6fluoro-2methyl-1oxoisoquino lin-4yl) benzenes lfonamide one (DMSO-Te) 1.00 (t, 7 = 7.33 Hz, 3) 2.81 2.89 (m, 2 Η) 3.58 (s, 3 Η) 7.09 (dd, 7 = 10.36, 2.53 Hz, 1 Η) 7.44 (td, 7 = 8.65, 2.40 Hz, 1 Η) 7.65 (t, 7 = 5.68 Hz, 1 Η) 7.69 (s, 1 Η) 7.72 - 7.79 (m, 2 Η) 7.82-7.90 (m, 2 Η) 8.42 (dd , 7 = 9.09, 6.06 Hz, 1 Η) 361

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50 t 1 4 ^^ NHSO ₂ E Ν- [4-χπορ-3 (6-fluoro-2methyl-1oxoisoquino lin-4yl) phenyl] et ansulfone MID 2 (DMSO-Te) 1.22 (t, 7 = 7.33 Hz, 3 N) 3.16 3.24 (m, 2H) 3.56 (s, 3 N) 6.72 (dd, 7 = 10.23, 2.40 Hz, 1 N) 7.24 (d, 7 = 2.53 Hz, 1 N) 7.34 (dd, 7 = 8.59, 2.78 Hz, 1 N) 7.40 (td, 7 = 8.72, 2.53 Hz, 1 N) 7.60 (d, 7 = 8.84 Hz, 1 N) 7.65 (s , 1 N) 8.38 (dd, 7 = 8.84, 5.81Hz, 1 N) 9.86 10.28 (w, 1 N) 395, 397

Example 51 N- [3- (2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl] methanesulfonamide.

Stage 1: 2-methyl-2,7-naphthyridin-1-one

IiTVA νΆχ about

Sodium hydride (2.9 g, 72.5 mmol, 60% in oil) was added in portions to 2Н-2,7-naphthyridin-1-one (3.5 g, 24.0 mmol) in dry DMF (50 ml) at 0 ° С. After stirring at 0 ° C for 30 min, MeI (17.0 g, 118.7 mmol) was added and the mixture was stirred for an additional 30 min. Saturated aqueous NH ₄ Cl (250 ml) and ethyl acetate (100 ml) were added. Extraction with ethyl acetate and purification by silica gel chromatography (DCM: MeOH = 100: 1 to 10: 1) gave the title compound (0.5 g, 13.1%) as a yellow solid.

1H NMR (CDCi ₃ , 400 MHz) δ 9.54 (1H, s), 8.64-8.62 (1H, d, J = 5.6 Hz), 7.27-7.26 (1H, d, J = 5.2 Hz), 7.227.20 (1H , d, J = 5.6 Hz), 6.37-6.35 (1H, d, J = 7.2 Hz), 3.54 (3H, s).

Stage 2: 4-bromo-2-methyl-2,7-naphthyridin-1-one

Br dA o

Bromine (1.1 g, 6.87 mmol) in acetic acid (10 ml) was added dropwise to 2-methyl-2,7naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60 ml) at 10-15 ° С ... After stirring at 15 ° C for 1 hour, the mixture was concentrated in vacuo. Purification by silica gel chromatography (DCM: MeOH = 50: 1 to 10: 1) afforded the title compound (0.45 g, 27.4%) as a yellow solid.

1H NMR (CDCi ₃ , 400 MHz) δ 9.61 (1H, s), 8.86-8.85 (1H, d, J = 5.6 Hz), 7.62-7.60 (1H, d, J = 5.6 Hz), 7.56 (1H, s ), 3.63 (3H, s).

Stage 3: N- [3- (2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl] methanesulfonamide _ ^. NHSO ₂ Me

ΓΥί mDxD o

A mixture of 4-bromo-2-methyl-2,7-naphthyridin-1-one (50 mg, 0.21 mmol), [3 (methanesulfonamido) phenyl] boronic acid (68 mg, 0.31 mmol), Pd (dppf) Ci ₂ ( 15.3 mg, 0.021 mmol) and aqueous K ₃ PO ₄ (1M, 0.3 ml, 0.3 mmol) in dioxane (3 ml) were exposed to microwaves at 90 ° С for 40 min. Purification by silica gel chromatography (PE: EA = 100: 1 to 1: 1) followed by preparative HPLC gave the title compound (48.1 mg, 69.8%) as a white solid.

1H NMR (400 MHz, metαnol-d ₄ ) δ 9.56 (s, 1H), 8.68 (d, J = 6.4 Hz, 1H), 7.96 (s, 1H), 7.81 (d, J = 6.4 Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.37 (d, J = 2.0 Hz, 1H), 7.34 (d, J = 1.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 3.71 ( s, 3H), 3.03 (s, 3H). LCMS: 330.0 (M + H) ⁺ .

Examples 52-56 in table. 9 was prepared from the title compound of Example 51, Step 2 in one step using the corresponding phenylboronic acid / ester in a similar manner to Example 51, Step 3.

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Table 9

Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 52 ίΑι ° o Η N- [3- (2- methyl-1- oxo-2,7 naphthyridine- 4- yl) phenyl] ethansulfone Ministry of Foreign Affairs Ή NMR (400 MHz, CDCh) δ 9.71 (s, 1 Η), 8.72 (d, J = 6.0 Hz, 1 Η), 7.48 (t, J = 7.6 Hz, 1 Η), 7.37 (d, J = 6.0 Hz, 1 Η), 7.29-7.26 (m, 3), 7.20 (d, J = 7.6 Hz, 1 Η), 6.74 (s, 1 Η), 3.69 (s, 3 Η), 3.21 (q, J = 7.6 Hz, 2), 1.43 (t, J = 7.6 Hz, 3 Η) 344 53 n Y'bz oh oh N-ethyl-3- (2- methyl-1- oxo-2,7 naphthyridine- 4- sludge) benzenes lfonamide Ή NMR (400 MHz, CDCh) δ 9.72 (s, 1 Η), 8.73 (d, J = 5.6 Hz, 1 Η), 7.95 (d, J = 7.2 Hz, 1 Η), 7.92 (s, 1 Η) , 7.67-7.62 (m, 2 Η), 7.33 (s, 1 Η), 7.30 (d, J = 5.6 Hz, 1 Η), 4.48 (s, 1 Η), 3.70 (s, 3 Η), 3.13- 3.12 (m, 2 Η), 1.18 (1, J = 7.2 Hz, 3 Η) 344 54 1 T ⁿ 'Y O O M-benzyl-2methoxy-5 (2-methyl-1oxo-2,7naphthyridin4yl) benzenesulfonamide Ή NMR (400 MHz, CDCh) δ 9.72 (s, 1 Η), 8.74 (d, J = 5.6 Hz, 1 Η), 7.93 (s, 1 Η), 7.54 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1 Η), 7.27-7.26 (s, 6 Η), 7.19 (d, J = 3.2 Hz, 1 Η) 7.06 (d, J = 8.4 Hz, 1 Η), 5.26 (s, 1 Η), 4.20 (d, J = 5.2 Hz, 2 Η), 3.96 (s, ZN), 3.70 (s, 3 Η) 436 55 A so ₂ nh ₂ 3- (2-methyl1-oxo-2,7naphthyridine- 4- sludge) benzenes lfonamide Ή NMR (400 MHz, DMSO-d6) δ 9.46 (d, J = 9.2 Hz, 1 Η), 8.73 (d, J = 5.6 Hz, 1 Η), 7.89-7.88 (m, 3 Η), 7.73-7.69 (m, 2 Η), 7.39-7.38 (d, J = 5.2 Hz, 1 Η), 3.60 (s, ZN) 316

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56 CN t (D Ξ o about ω A 2-methoxy-5 (2-methyl-1oxo-2,7 naphthyridine- 4il) benzenes lfonamide NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1 Η), 8.72 (d, J = 5.6 Hz, 1 Η), 7.80 (s, 1Η), 7.77 (d, J = 2.4 Hz, 1 H ), 7.65-7.63 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1 H), 7.34 (d, J = 8.4 Hz, 1H), 7.33 (d, J = 5.2 Hz, 1 H), 3.97 ( s, 3 H), 3.59 (s, 3 H) 346

Example 57 N- [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl] ethanesulfonamide.

Stage 1: 4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

A mixture of 3-bromo-4- (2,4-difluorophenoxy) aniline (300 mg, 1 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5 tetramethyl-1,3,2- dioxaborolan-2-yl) -1,3,2-dioxaborolane (518 mg, 2 mmol), KOAc (300 mg, 3 mmol) and Pd (dppf) Cl ₂ (73.2 mg, 0.1 mmol) in dioxane (6 ml) exposed to microwaves at 100 ° C for 2 h. Purification by silica gel chromatography (PE: EA = 10: 1 to 5: 1) afforded the title compound (200 mg, 56%). LCMS: 348.0 (M + H) +.

Step 2: 4- [5-amino-2- (2,4-difluorophenoxy) phenyl] -2-methyl-2,7-naphthyridin-1-one

For 5 min, N2 was bubbled through a mixture of 4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (64.8 mg, 0.187 mmol), the title compound of Example 51, Step 2 (30.0 mg, 0.124 mmol), K ₂ CO ₃ (51.6 mg, 0.374 mmol) and Pd (dppf) Cl ₂ (18.3 mg, 0.025 mmol) in dioxane (2.0 mL) and water (0.2 ml) which was then exposed to microwaves at 100 ° C for 1 h. Purification by preparative TLC (DCM: MeOH = 20: 1, Rf = 0.5) gave the title compound (25.0 mg, 53%) in the form of a yellow resin. LCMS: 380.0 (M + H) +.

Stage 3: N- [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxo-2,7-naphthyridin-4-yl) phenyl] ethanesulfonamide

Ethanesulfonyl chloride (25.4 mg, 0.198 mmol) was added to 4- [5-amino-2- (2,4-difluorophenoxy) phenyl] -2-methyl-2,7-naphthyridin-1-one (25.0 mg, 0.066 mmol) and TEA (20.0 mg, 0.198 mmol) in DCM (5 ml) at 0 ° C. The mixture was stirred at room temperature for 18 h and then purified by preparative HPLC to give the title compound (8.5 mg, 27.4%) as a yellow gum.

¹ H NMR (metαnol-d4, 400 MHz) δ 9.54 (s, 1H), 8.68 (d, J = 4.4 Hz, 1H), 8.00 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.38-7.33 (m, 2H), 7.09-6.99 (m, 2H), 6.96-6.94 (d, J = 8.4 Hz, 1H), 6.91-6.85 (m, 1H), 3.70 (s, 3H), 3.15 ( q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). LCMS: 472.1 (M + H) ⁺ .

Example 58: N- [3- (7-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl] methanesulfonamide.

Stage 1: 7-fluoro-2-methylisoquinolin-1-one

In an N2 atmosphere, sodium hydride (710 mg, 29.4 mmol) was added to 7-fluoro-2H-isoquinolin-1-one (4 g, 24.55 mmol) in dry DMF (40 ml) at 0 ° С. After stirring at 0 ° C for 20 min, CH ₃ I (5.2 g, 36.7 mmol) was added. The mixture was stirred at 26 ° C for 2 h. Saturated aqueous NH ₄ Cl (20 ml) was added and after extraction with ethyl acetate, purification by silica gel chromatography (PE: EA = 10: 1) gave the title compound (2.2 g, 50%) as an off-white solid

- 201 038715 substance.

Ή NMR (CDC13, 400 MHz) δ 8.06 (dd, Ji = 9.6 Hz, J2 = 2.8 Hz, 1H), 7.50 (dd, J1 = 8.8 Hz, J2 = 5.2 Hz, 1H), 7.38-7.36 (m, 1H ), 7.03 (d, J = 7.6 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H), 3.61 (s, 3H). LCMS: 178.1 [M + H] + Step 2: 4-bromo-7-fluoro-2H-isoquinolin-1-one

Bg

O

Bromine (3.8 g, 24 mmol) in acetic acid (6 ml) was slowly added to a mixture of 7-fluoro-2methylisoquinolin-1-one (4 g, 22.4 mmol) in acetic acid (8 ml) at 0 ° С. After stirring at 26 ° C for 2 hours, the mixture was poured into water (100 ml) and the solid was collected by filtration. Purification by silica gel chromatography (PE: EA = 20: 1) afforded the title compound (1.4 g, 44%) as an off-white solid.

¹ H NMR (CDCh, 400 MHz) δ 8.11 (d, J = 9.2 Hz, 1H), 7.84 (dd, J ₁ = 9.6 Hz, J ₂ = 4.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.34 (s, 1H), 3.62 (3H, s). LCMS: 255.9 [M + H] ⁺ .

Step 3: N- [3- (7-fluoro-2-methyl-1-oxoisoquinolin-4-yl) phenyl] methanesulfonamide

4-Bromo-7-fluoro-2H-isoquinolin-1-one was treated with [3- (methanesulfonamido) phenyl] boronic acid in a manner analogous to Example 51, step 3. Isolation and purification also gave the title compound (18 mg, 26.5%) as a white solid.

¹ H NMR (400 MHz, CDCl3) δ 8.17 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H), 7.52 (dd, J1 = 8.0 Hz, J2 = 4.0 Hz, 1H), 7.50-7.45 (m, 1H), 7.38-7.32 (m, 1H), 7.31-7.27 (m, 2H), 7.26-7.21 (m, 1H), 7.03 (s, 1H), 6.72 (brs, 1H), 3.67 (s, 3H) , 3.09 (s, 3H). LCMS: 347.0 (M + H) +.

Examples 59-64 in table. 10 was prepared from the title compound of Example 58, Step 2 using the appropriate phenylboronic acid / ester in a similar manner to Example 18, Step 3.

Table 10

Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 59 Xjl 4 ^ 4 ^ _S o ₂ NHEt N-ethyl-3 - (7-fluoro2-methyl-1- oxoisoquinoline- 4- yl) benzenesulfone amide (CDCh) 8.17 (dd, Ji = 9.6 Hz, J ₂ = 2.4 Hz, 1 Η), 7.937.92 (m, 2 Η), 7.64-7.63 (s, 2 Η), 7.46-7.45 (m, 1 Η ), 7.36-7.35 (m, 1 Η), 7.06 (s, 1 Η), 4.58 (brs, 1 Η), 3.143.07 (m, 2 Η), 1.16 (t, J = 7.2 Hz, 3 Η) 361 60 r χ X ^^ SOsNHBn N-benzyl-5- (7fluoro-2-methyl-1oxoisoquinolin4-yl) -2methoxybenzenesul phonamide (CDCh) 8.20 (dd, Ji = 9.3 Hz, J ₂ = 2.8 Hz, 1 Η), 7.96 (d, J = 2.4 Hz, 1H), 7.54 (dd, b = 8.5 Hz, J ₂ = 2.3 Hz, 1 H), 7.47-7.44 (m, 1 H), 7.41-7.36 (m, 1 H), 7.30-7.25 (m, 3 H), 7.227.20 (m, 2 H), 7.06 (d, J = 8.5 Hz, 1 H), 7.04 (s, 1 H), 5.34 (t, J = 6.0 Hz, 1 H), 4.21 (d, J = 6.3 Hz, 2 H), 3.97 (s, 3H), 3.70 (s , 3H) 453

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61 Οχ 4 ^^ SO ₂ NH ₂ 3- (7-fluoro-2- methyl-1- oxoisoquinoline- 4- yl) benzenesulfone amide (CDCh) 7.13 (dd, Ji = 9.6 Hz, J ₂ = 2.8 Hz, 1 Η), 7.037.01 (m, 2 Η), 6.84-6.82 (m, 2 Η), 6.76-6.74 (m, 1 Η ), 6.69 (s, 1 Η), 6.676.66 (m, 1 Η), 6.58-6.56 (m, 2 Η), 2.71 (s, ZN) 333 62 οχ Ν- [3- (7-φτορ-2methyl-1- oxoisoquinoline- 4yl) phenyl] ethansul phonamide (CDCh) 8.17 (dd, Ji = 9.2 Hz, J ₂ = 2.8 Hz, 1 H), 7.53 (dd, G = 8.8 Hz, J ₂ = 3.6 Hz, 1 H), 7.44 (t, J = 8.4 Hz, 1 H), 7.28-7.27 (m, 3 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.03 (s, 1 H), 6.79 (s, 1 H), 3.67 (s, 3H), 3.20 (q, J = 7.2 Hz, 2 H), 1.43 (t, J = 7.2 Hz, 3 H) 361 63 V ^^ SO ₂ Et 4- (3- ethylsulfonylphenyl) -7-fluoro-2- methylisoquinoline- 1st (CDCh) 1.15 (t, 7 = 7.45 Hz, 3H) 3.38 (q, 7 = 7.41 Hz, 2 H) 3.60 (s, 3 H) 7.52 - 7.57 (m, 1 H) 7.61 - 7.67 (m, 2 H ) 7.78 - 7.87 (m, 2 H) 7.91 - 8.03 (m, 3 H) 346 64 T Z / О о ω У 5- (7-fluoro-2- methyl-1- oxoisoquinoline- 4-yl) -2- methoxybenzenesul phonamide (DMSO-d6) 7.98 (d, J = 7.2 Hz, 1 H), 7.74 (s, 1 H), 7.65-7.61 (m, 2H), 7.517.48 (m, 2H), 7.35 (d, J = 8.4 Hz, 1H), 7.18 (s, 2 H), 3.97 (s, 3 H), 3.57 (s, 3 H) 363

Example 65: 2-methyl-4- (1-methylpyrazol-4-yl) isoquinolin-1-one

For 3 min, N _{2 was} bubbled through a mixture of 4-bromo-2-methylisoquinolin-1 (2H) -one (54 mg, 0.23 mmol), (1-methylpyrazol-4-yl) boronic acid (31 mg, 0.25 mmol), aqueous 2 M Na ₂ CO ₃ (0.375 ml) and Pd (dppf) Cl ₂ (8 mg, 0.01 mmol) in 1,4-dioxane (1.5 ml), which was then exposed to microwaves at 120 ° С for 1 h. Carrying out the experiment in a manner similar to that described in example 18, step 3, and chromatographically sequentially on silica gel twice, eluting with 15-80% EA in hexane for 6 minutes and continuing isocratically with 80% EA, followed by a second chromatography with 15-100% EA in hexane over 6 min and proceeding isocratically with 100% EA provided the title compound (28 mg, 0.12 mmol) as a cream solid in 51% yield.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.54 (s, 3H), 3.92 (s, 3H), 7.50 (s, 1H), 7.55 (ddd, J = 8.02, 5.87, 2.27 Hz, 1H), 7.60-7.64 (m, 1H), 7.70-7.80 (m, 2H), 7.95 (s, 1H), 8.31 (d, J = 7.83 Hz, 1H). LCMS (M + H) + 240.

Examples 66-71 in table. 11 was prepared from 4-bromo-2-methylisoquinolin-1 (2H) -one in a similar manner to Example 65 using commercially available boronic acids / esters or from commercially available tin compounds using standard Stille coupling type reaction conditions.

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Table 11

P) Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 66 A 4- (furan-2-yl) -2- methylisoquinoline- 1st (CHLOROFORM-7) 3.61 3.70 (w, 3 H) 6.50 - 6.57 (w, 2 H) 7.37 (s, 1H) 7.50 -7.58 (m, 2 H) 7.69 (ddd, 7 = 8.30, 7.03, 1.46 Hz, 1 N) 7.93 (d, 7 = 8.20 Hz, 1 N) 8.51 (dd, 7 = 8.01, 0.98 Hz, 1 N) 226 67 f 2-methyl-4- (1,3- oxazole-2yl) isoquinoline-1 - he (CHLOROFORM-7) 3.72 (s, 3 H) 7.30 (s, 1 Η) 7.56-7.61 (m, 1 Η) 7.74 (s, 1 Η) 7.79 (ddd, 7 = 8.40, 7.03, 1.37 Hz, 1 Η ) 7.99 (s, 1 Η) 8.52 (dd, 7 = 8.01, 0.98 Hz, 1 Η) 8.93 (d, 7 = 8.40 Hz, 1 Η) 227 68 Have Oh n 2-methyl-4- (1Hpyrazole-5yl) isoquinoline-1 - he (CHLOROFORM-7) 3.61 3.71 (m, 3 Η) 6.66 (br. S., 1 H) 7.34 (s, 1 H) 7.57 (t, 7 = 7.42 Hz, 1 H) 7.68 (t, 7 = 7.52 Hz , 1 H) 7.76 (d, 7 = 8.01 Hz, 1 H) 7.83 (br. S., 1 H) 8.52 (d, 7 = 7.81 Hz, 1 H) 226 69 A Me 2-methyl-4- (1methylimidazole-2yl) isoquinoline-1 - he (METHANOL-7 ₄ ) 3.55 (s, 3 H) 3.65 (s, 3H) 7.10 (br. S., 1H) 7.17 (br. S., 1 H) 7.28 (s, 1 H) 7.54 - 7.62 (m , 2 H) 7.71 (t, 7 = 7.61 Hz, 1 H) 8.41 (d, 7 = 8.20 Hz, 1 H) 240 70 b 2-methyl-4-pyridin2-ylisoquinoline-1 - he (MET ANOL-J ₄ ) 3.69 (s, 3 H) 7.48 (d, 7 = 5.86 Hz, 1 H) 7.58 (br. S., 2H) 7.65 (d, 7 = 7.81 Hz, 1 H) 7.71 (t , 7 = 7.22 Hz, 1 H) 7.76 - 7.80 (m, 1 H) 7.98 (t, 7 = 7.03 Hz, 1 H) 8.42 (d, 7 = 7.81 Hz, 1 H) 8.68 (d, 7 = 3.32 Hz , 1 H) 237 71 A 2-methyl-4- pyrimidine-2- orisoquinolin-1-one (MET ANOL-J ₄ ) 3.73 (s, 3 H) 7.41 (t, 7 = 4.88 Hz, 1 H) 7.59 (t, 7 = 7.71 Hz, 1 H) 7.76 (t, 7 = 7.71 Hz, 1 H) 8.27 (s, 1 H) 8.42 (d, 7 = 8.20 Hz, 1 H) 8.82 (d, 7 = 8.40 Hz, 1 H) 8.90 (d, 7 = 4.88 Hz, 2 H) 238

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Example 72 N- [3- [2-methyl-6- (6-methylpyridin-3-yl) -1-oxoisoquinolin-4-yl] phenyl] ethanesulfonamide.

Stage 1: 2-methyl-6- (6-methylpyridin-3-yl) isoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (160 mg, 0.67 mmol), (6-methylpyridin-3-yl) boronic acid (166 mg, 0.32 mmol), Pd (dppf) Cl ₂ (60 mg, 0.08 mmol) and saturated aqueous NaHCO ₃ (0.6 ml) in dioxane (6.5 ml) were exposed to microwaves at 110 ° С for 1.5 h. Purification using chromatography on silica gel (PE: EA = 3: 1 to 2: 3) gave the title compound (160 mg, 95.2%) as a yellow solid. LCMS: 251.2 (M + H) +.

Stage 2: 4-bromo-2-methyl-6- (6-methylpyridin-3-yl) isoquinolin-1-one

Bromine (97 mg, 0.61 mmol) in acetic acid (0.61 ml) was added dropwise to 2-methyl-6- (6methylpyridin-3-yl) isoquinolin-1-one (160 mg, 0.64 mmol) in acetic acid (6 ml ) at 0 ° C. After stirring at room temperature for 17 minutes, water (22 ml) was added and the pH was adjusted to 7-8 with 1M NaOH. Extraction with ethyl acetate and purification by silica gel chromatography (PE: EA = 2: 1 to 3: 2) afforded the title compound (135 mg, 64.3%) as a yellow solid. LCMS: 329.0 (M + H) ⁺ .

Stage 3: N- [3- [2-methyl-6- (6-methylpyridin-3-yl) -1-oxoisoquinolun-4-yl] phenyl] ethanesulfonamide

A mixture of 4-bromo-2-methyl-6- (6-methylpyridin-3-yl) isoquinolin-1-one (135 mg, 0.41 mmol), [3 (ethylsulfonylamino) phenyl] boronic acid (141 mg, 0.62 mmol), Pd (dppf) Cl ₂ (35 mg, 0.05 mmol) and aqueous 1 M K ₃ PO ₄ (1.03 ml) in dioxane (6 ml) were exposed to microwaves at 100 ° C for 1 h. Purification by chromatography on silica gel ( PE: EA = 3: 1 to 1: 2) followed by preparative HPLC gave the title compound (25 mg, 14.1%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.74 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 3.59 (s, 3H), 3.59 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H). LCMS: 434.1 (M + H) ⁺ .

Examples 73-74 in table. 12 was prepared from 6-bromo-2-methylisoquinolin-1-one and phenylboronic acid in three steps in a manner similar to that described in Example 72, steps 1-3. In Example 74, [3 (methanesulfonamido) phenyl] boronic acid was replaced by [3- (ethylsulfonylamino) phenyl] boronic acid in step 3.

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Table 12

Example No. R ¹ Name ^х Н NMR (ppm (δ), 400 MHz) MS (M + H) 73 Ethyl In [3- (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] ethanesulfone Ministry of Foreign Affairs (DMSO-dd) 9.94 (brs, 1 Η), 8.41 (d, J = 8.4 Hz, 1 Η), 7.85 (d, J = 8.4 Hz, 1H), 7.74 (s, 1H), 7.67 (d, J = 7.6 Hz, 2 H), 7.57 (s, 1 H), 7.507.45 (m, 3 H), 7.42 (d, J = 7.6 Hz, 1 H), 7.38 (s, 1H), 7.30 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 7.6 Hz, 1 H), 3.59 (s, 3 H), 3.14 (q, J = 7.2 Hz, 2 H), 1.19 (t, J = 7.2 Hz, 3H) 419 74 Methyl M- [3- (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] methanesulfonamide (CHLOROFORM-ίΖ) 8.60 (d, J = 8.4 Hz, 1 H), 7.78 (dd, Ji = 8.4 Hz, J ₂ = 1.6 Hz, 1H), 7.72 (d, J = 1.2 Hz, 1 H), 7.60 -7.58 (m, 2 H), 7.49-7.36 (m, 5 H), 7.31 (d, J = 7.6 Hz, 1 H), 7.26-7.23 (m, 1 H), 7.10 (s, 1 H), 6.47 (s, 1H), 3.70 (s, 3H), 3.08 (s, 3H) 405

Example 75 K- [3- (2,6-dimethyl-1-oxoisoquinolin-4-yl) phenyl] ethanesulfonamide.

Stage 1: 2,6-dimethylisoquinolin-1-one

A mixture of 6-bromo-2-methylisoquinolin-1-one (200.0 mg, 0.84 mmol), methylboronic acid (251.0 mg, 4.2 mmol), Pd (PPh ₃ ) ₄ (93.0 mg, 0.08 mmol), K ₂ CO ₃ (232.0 mg, 1.68 mmol) and H2O (2 drops) in dioxane (10.0 mL) were exposed to microwaves at 120 ° C for 1 h. Purification by silica gel chromatography (PE: EA = 5: 1) gave the title compound ( 120.0 mg, 82.8%) as a light yellow solid. LCMS: 174.3 (M + H) +.

Stage 2: 4-bromo-2,6-dimethylisoquinolin-1-one

2,6-Dimethylisoquinolin-1-one (120.0 mg, 0.60 mmol) in acetic acid (4 ml) was treated with Br ₂ (96 mg, 0.6 mmol) in acetic acid (0.6 ml) at 0 ° С in a manner similar to that described in example 72, step 2. Isolation in a similar manner afforded the title compound (145.0 mg, 82.9%) as a white-yellow solid.

¹ H NMR (CDClj, 400 MHz) δ 8.33 (d, J = 8.0 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.35 (s, 1H), 3.60 ( s, 3H), 2.54 (s, 3H). LCMS: 252.1 (M + H) ⁺ .

Stage 3: K- [3- (2,6-dimethyl-1-oxoisoquinolin-4-yl) phenyl] ethanesulfonamide

4-Bromo-2,6-dimethylisoquinolin-1-one (75.0 mg, 0.30 mmol), [3- (ethylsulfonylamino) phenyl] boronic acid (82.0 mg, 0.36 mmol), Pd (dppf) Cl ₂ (22 mg, 0.03 mmol) and aqueous 1 M K ₃ PO ₄ (0.75 ml) in dioxane (4 ml) were reacted in a manner similar to Example 72, step 3. Isolation, also in a similar manner, gave the title compound (60.0 mg, 48.1% )

- 206 038715 in the form of a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.42 (d, J = 8.4 Hz, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.297.27 ( m, 2H), 7.24 (d, J = 8.0 Hz, 1H), 7.03 (s, 1H), 6.68 (s, 1H), 3.65 (s, 3H), 3.21 (q, J = 7.2 Hz, 2H), 2.42 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). LCMS: 357.0 (M + H) +.

Examples 76-78 in table. 13 was obtained in three steps in a similar manner as in example 75, steps 1-3. In Examples 76 and 77, ethylboronic acid was replaced by methylboronic acid in Step 1. In Examples 77 and 78, [3- (methanesulfonamido) phenyl] boronic acid was replaced by [3 (ethylsulfonylamino) phenyl] boronic acid in Step 3.

Table 13

O

Example No. R ¹ R ² Name '11 NMR (ppm (δ), 400 MHz) MS (M + H) 76 Ethyl Ethyl K- [3- (6-ethyl-2methyl-1oxoisoquinoline- 4yl) phenyl] ethanes lfonamide (CDCh) 8.41 (d, J = 8.4 Hz, 1 Η), 7.42 (t, J = 8.4 Hz, 1 Η), 7.38 (d, J = 8.4 Hz, 1H), 7.297.25 (m, 2 H) , 7.19 (d, J = 7.6 Hz, 1 H), 7.00 (s, 1 H), 6.90 (s, 1 H), 3.61 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H) , 2.67 (q, J = 7.6 Hz, 2 H), 1.39 (t, J = 7.6 Hz, 3H), 1.19 (1, J = 7.6 Hz, 3 H) 371 77 Ethyl Methyl K- [3- (6-ethyl-2methyl-1oxoisoquinoline- 4yl) phenyl] methanes ulfonamide (CDCh) 8.45 (d, J = 8.4 Hz, 1 H), 7.48 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1H), 7.327.26 (m, 5 H) , 7.04 (s, 1 H), 6.66 (s, 1 H), 3.65 (s, 3 H), 3.10 (s, 3H), 2.70 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3 H) 357 78 Methyl Methyl N- [3- (2.6- dimethyl-1- oxoisoquinoline- 4- yl) phenyl] methanes ulfonamide (DMSO-de) 9.88 (brs, 1 H), 8.23 (d, J = 8.0 Hz, 1H), 7.497.45 (m, 2 H), 7.39 (d, J = 8.4 Hz, 1 H), 7.33 ( s, 1 H), 7.287.24 (m, 2 H), 7.19 (d, J = 8.0 Hz, 1 H), 3.55 (s, 3 H), 3.06 (s, 3 H), 2.39 (s, 3 H) 343

Example 79: 4- (5-ethylsulfonyl-2-methoxyphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinoline-1one.

Stage 1: 2-bromo-4-ethylsulfanyl-1-fluorobenzene

EtI (3.12 g, 20 mmol) was added to a mixture of 3-bromo-4-fluorobenzenethiol (2.07 g, 10 mmol) and K ₂ CO ₃ (4.14 g, 30 mmol) in acetone (20 ml). The mixture was stirred at room temperature for 12 h, filtered and the volatiles were removed in vacuo to give the title compound (2.34 g) as a light yellow oil which was used without purification.

1H NMR (CDCl ₃ , 400 MHz): d 7.54 (dd, J1 = 6.4 Hz, J2 = 2.4 Hz, 1H), 7.26-7.25 (m, 1H), 7.05 (t, J = 8.4 Hz, 1H), 2.91 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.6 Hz, 3H).

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Stage 2: 2-bromo-4-ethylsulfonyl-1-fluorobenzene

Br

To 2-bromo-4-ethylsulfanyl-1-fluorobenzene (2.2 g, 9.36 mmol) in DCM (20 mL) was added t-CPBA (6.47 g, 37.4 mmol). The mixture was stirred at room temperature for 12 h. Aqueous saturated Na ₂ S ₂ O ₃ (100 ml) _{was added and extraction with CH 2} Cl ₂ gave the title compound (1.5 g, 50%) as a yellow solid which was used without cleaning.

1H NMR (CDCl ₃ , 400 MHz) δ 8.15 (dd, J1 = 6.4 Hz, J2 = 2.4 Hz, 1H), 7.88-7.85 (m, 1H), 7.32 (t, J = 8.4 Hz, 1H), 3.14 ( q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.6 Hz, 3H).

Stage 3: 2-bromo-4-ethylsulfonyl-1-methoxybenzene O O

Br

A mixture of 2-bromo-4-ethylsulfonyl-1-fluorobenzene (0.6 g, 2.25 mmol) and sodium methoxide (1.2 g, 22.2 mmol) in THF (20 ml) was stirred at room temperature for 18 h. Water (30 ml) was added , and extraction with ethyl acetate followed by chromatography on silica gel (PE: EA = 10: 1 to 1: 1) gave the title compound (0.5 g, 79.4%) as a yellow solid.

¹ H NMR (CDCl3, 400 MHz) δ 8.08 (d, J = 2.4 Hz, 1H), 7.87-7.84 (dd, J, = 8.6 Hz, J2 = 2.4 Hz, 1H), 7.04 (d, J = 8.8 Hz , 1H), 3.99 (s, 3H), 3.11 (q, J = 7.4 Hz, 2H), 1.30 (t, J = 7.4 Hz, 3H).

Stage 4: 4- (5-ethylsulfonyl-2-methoxyphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

For 5 min, N2 was bubbled through a mixture of 2-bromo-4-ethylsulfonyl-1-methoxybenzene (300 mg, 1.07 mmol) of the title compound of Example 46, step 2 (300 mg, 0.82 mmol), K ₃ PO ₄ (435.6 mg, 2.05 mmol) and Pd (dppf) Cl ₂ (120.2 mg, 0.16 mmol) in dioxane (8 ml) and water (0.8 ml), which was then exposed to microwaves at 110 ° С for 30 min. Purification by silica gel chromatography (DCM: MeOH = 100: 0 to 20: 1) afforded the title compound (200 mg, 55.7%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, J = 8.4 Hz, 1H), 8.03 (dd, 11 = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H) , 7.72 (s, 1H), 7.64 (s, 1H), 7.63-7.61 (m, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 1.2 Hz, 1H), 7.09 ( s, 1H), 3.97 (s, 3H), 3.85 (s, 3H), 3.68 (s, 3H), 3.18 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). LCMS: 438.1 (M + H) ⁺ .

Example 80: 4- (5-ethylsulfonyl-2-hydroxyphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinoline-1one

At -78 ° C, a 4M solution of BBr ₃ (2.3 ml, 9.2 mmol) in CH ₂ Cl _{2 was} added to the title compound of Example 79 (200.0 mg, 0.458 mmol) in dry CH ₂ Cl ₂ (8 ml). The mixture was heated under reflux for 18 h. Extraction with CH ₂ Cl ₂ and purification by silica gel chromatography (DCM: MeOH = 100: 1 to 20: 1) gave the title compound (70 mg, 36.1%) as a brown solid matter.

1H NMR (CDClj, 400 MHz) δ 8.39 (d, J = 8.4 Hz, 1H), 7.99 (s, 1H), 7.87 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.80 (s, 1H), 7.79 (s, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 1.2 Hz, 1H), 7.18 (d, J = 8.8 Hz, 1H), 3.91 (s, 3H), 3.67 (s, 3H), 3.25 (q, J = 7.6 Hz, 2H), 1.27 (t, J = 7.6 Hz, 3H). LCMS: 424.0 (M + H) +.

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Example 81: 4- (2-ethoxy-5-ethylsulfonylphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

A mixture of the title compound of Example 80 (25.0 mg, 0.059 mmol), ethyl iodide (27.7 mg, 0.177 mmol) and K ₂ CO ₃ (24.5 mg, 0.177 mmol) in acetone (2 ml) was stirred at room temperature for 18 h. Extraction with CH ₂ Cl ₂ , purification by preparative TLC (PE: EA = 2: 1) gave the title compound (15.8 mg, 60%) as a white solid.

¹ H NMR (CDCls, 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1H), 7.97 (dd, J1 = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H ), 7.68 (s, 1H), 7.62 (s, 1H), 7.61 (dd, J, = 8.4 Hz, J ₂ = 1.6 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.15 (d , J = 8.4 Hz, 1H), 7.08 (s, 1H), 4.3 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 3H), 3.17 (q, J = 7.6 Hz , 2H), 1.35 (t, J = 7.6 Hz, 3H), 1.18 (t, J = 7.2 Hz, 3H). LCMS: 452.1 (M + H) +.

Examples 82-84 in table. 14, the title compound of Example 80 was O-alkylated with the appropriate alkyl halide in a similar manner to Example 81. Example 85 in Table II. 14 was obtained in two stages by O-alkylation of tert-butyl N- (2-bromoethyl) carbamate in the same way as in example 81, followed by deprotection of the Boc group in a manner similar to that described in example 32.

Table 14

Example No. R ¹ Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 82 4- [2- (cyclopropylmethoc si) -5- ethylsulfonylphen yl] -2-methyl-6- (1 methylpyrazole-4yl) isoquinoline-1 - he (CDC1 ₃ ) 8.51 (d, J = 8.4 Hz, 1 Η), 7.97 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 ( s, 1 H), 7.64 (s, 1 H), 7.62 (dd, D = 8.4Hz, J ₂ = 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1H), 3.96 (s, 3 H), 3.913.86 (m, 2H), 3.67 (s, 3H), 3.17 (q, J = 7.6 Hz, 2 H ), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H). 478 83 4- (5- ethylsulfonyl-2propoxyphenyl) -2methyl-6- (1methylpyrazole-4yl) isoquinoline-1 - he (CDC1 ₃ ) 8.51 (d, J = 8.4 Hz, 1 H), 7.97 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1 H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s, 1 H), 7.64 (s, 1 H), 7.62 (dd, D = 8.4Hz, J ₂ = 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1 H), 7.11 (s, 1H), 3.96 (s, 3 H), 3.913.86 (m, 2H), 3.67 (s, 3H), 3.17 (q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H). 466

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84 4- [5- ethylsulfonyl-2- (2- hydroxyethoxy) phenyl] -2-methyl-6- (1 methylpyrazole-4yl) isoquinoline-1 - he (CDCh) 8.51 (d, J = 8.4 Hz, 1 Η), 7.97 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 7.88 (d, J = 2.8 Hz, 1 H), 7.70 (s , 1 H), 7.64 (s, 1 H), 7.62 (dd, G = 8.4Hz, J ₂ = 1.6 Hz, 1H), 7.21 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 3.96 (s, 3H), 3.913.86 (m, 2H), 3.67 (s, 3 H), 3.17 (q, J = 7.6 Hz, 2 H), 1.34 (t, J = 7.6 Hz, 3 H), 0.99-0.96 (m, 1 H), 0.38-0.35 (m, 2 H), 0.10-0.02 (m, 2 H). 468 85 nh ₂ 4- [2- (2aminoethoxy) -5ethylsulfonylphen yl] -2-methyl-6- (1methylpyrazole-4yl) isoquinoline-1 - he (Metanol-d4) 8.38 (d, J = 8.4 Hz, 1 H), 8.06 (dd, Ji = 8.4 Hz, J ₂ = 2.4 Hz, 1 H), 8.05 (s, 1 H), 7.89 (d, J = 2.4 Hz, 1 H), 7.83 (s, 1 H), 7.76 (dd, Ji = 8.4 Hz, J ₂ = 1.2 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1 H), 7.44 (s , 1 H), 7.27 (d, J = 1.2 Hz, 1 H), 4.46-4.32 (m, 2 H), 3.92 (s, 3H), 3.67 (s, 3H), 3.27 (q, J = 7.2 Hz , 2 H), 3.25-3.17 (m, 1 H), 3.04-2.96 (m, 1 H), 1.28 (t, J = 7.2 Hz, 3H)

Example 86 N- [2-fluoro-4-methoxy-5- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinoline-4yl] phenyl] ethanesulfonamide.

Stage 1: 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene and 1-bromo-2-fluoro-4-methoxy-5-nitrobenzene

At 0 ° С sodium methoxide (344 mg, 6.3 mmol) in dry MeOH (7 ml) was added dropwise to 1-bromo2,4-difluoro-5-nitrobenzene (1 g, 4.2 mmol) in dry MeOH (18 ml). The mixture was stirred at room temperature for 10 hours and then heated under reflux for 8 hours. After extraction, purification by silica gel chromatography (PE: EA = 1: 0 to 10: 1) gave a mixture of the two title compounds ( 765 mg, 72.9%) in a ratio of about 2: 1 as a yellow solid. LCMS: 249.9 (M + H) +.

Stage 2: 5-bromo-2-fluoro-4-methoxyaniline

Zinc dust (0.95 g, 14.5 mmol) was added to a mixture of the two title compounds from step 1 (725 mg, 2.9 mmol) in a 2: 1 mixture of MeOH: saturated aqueous NH ₄ Cl (10 ml) at 0 ° C. After stirring at room temperature for 30 min, extraction with ethyl acetate and purification by silica gel chromatography (PE: EA = 1: 0 to 10: 1), the title compound (260 mg, 41%) was obtained as a yellow solid, purified from the corresponding regioisomers.

'and NMR (400 MHz, DMSO-d6) δ 7.00 (d, J = 9.6 Hz, 1H), 6.94 (d, J = 13.2 Hz, 1H), 4.88 (s, 2H), 3.72 (s, 3H). LCMS: 219.9 (M + H) ⁺ .

Stage 3: N- (5-bromo-2-fluoro-4-methoxyphenyl) ethanesulfonamide

At 0 ° С, ethanesulfonyl chloride (1.4 g, 10.9 mmol) was added dropwise to a solution of 5-bromo-2-fluoro-4methoxyaniline (3.5 g, 24.0 mmol) in pyridine (1.3 g, 16.4 mmol) and dry CH ₂ Cl ₂ (20 ml). After re-210 038715 stirring at room temperature for 10 h, extraction with CH2C12 and purification by silica gel chromatography (PE: EA = 10: 0 to 3: 1), the title compound (2.5 g, 73.5%) was obtained as yellow solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 11.6 Hz, 1H), 6.27 (s, 1H), 3.89 (s, 3H), 3.10 (q, J = 7.6 Hz, 2H), 1.40 (t, J = 7.6 Hz, 3H). LCMS: 334.0 (M + Na) +.

Step 4: N- [2-fluoro-4-methoxy-5- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinoline-4yl] phenyl] ethanesulfonamide

F

J ^ NHSO ₂ Et \ 1J, ¹ ½ MeO ^ Y

n. II I

Yay oh

A mixture of N- (5-bromo-2-fluoro-4-methoxyphenyl) ethanesulfonamide (63 mg, 0.20 mmol), the title compound of Example 46, step 2 (75 mg, 0.21 mmol), Pd (dppf) Cl ₂ (19 mg, 0.03 mmol) and aqueous K ₃ PO ₄ (1M, 0.5 ml, 0.5 mmol) in dioxane (3 ml) were exposed to microwaves at 100 ° С for 1 h. Purification by chromatography on silica gel (PE: EA = 1 : 1 to 1: 4) followed by preparative HPLC gave the title compound (25 mg, 26.3%) as a white solid.

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.48 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 6.85 (d, J = 12.0 Hz, 1H), 6.37 (s, 1H), 3.94 (s, 3H) , 3.75 (s, 3H), 3.65 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.46 (t, J = 7.2 Hz, 3H). LCMS: 471.1 (M + H) +.

Example 87: N- [3- (2-methyl-1-oxo-6-pyridin-2-yl-isoquinolin-4-yl) phenyl] ethanesulfonamide.

Stage 1: 2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one

DH-o

Ay 'hAzh

O

For 5 min, N _{2 was} bubbled through a mixture of 6-bromo-2-methylisoquinolin-1-one (0.5 g, 2.1 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane -2-yl) -1,3,2-dioxaborolane (0.8 g, 3.1 mmol), Pd (dppf) Cl ₂ (153.6 mg, 0.21 mmol) and KOAc (0.51 g, 5.2 mmol) in dioxane (5 ml), which was then exposed to microwaves at 110 ° C for 40 minutes. Purification by silica gel chromatography (PE: EA = 20: 1 to 5: 1) afforded the title compound (0.45 g, 75.0%) as a yellow gum.

Stage 2: 2-methyl-6-pyridin-2-ylisoquinolin-1-one

A mixture of 2-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (420 mg, 1.47 mmol), 2-bromopyridine (698 mg, 4.42 mmol), Pd (dppf) Cl ₂ (107 mg, 0.15 mmol), and saturated aqueous NaHCO ₃ (3.5 ml) in DMSO (25 ml) were exposed to microwaves at 150 ° С for 45 min. Extraction with ethyl acetate, purification by silica gel chromatography (PE: EA = 3: 1 to 3: 2) afforded the title compound (160 mg, 46.0%) as a white solid.

¹ H NMR (CDCl3, 400 MHz) δ 8.76 (d, J = 4.8 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 1.2 Hz, 1H), 8.07 (dd, J1 = 8.4 Hz, J ₂ = 1.6 Hz, 1H), 7.85-7.82 (m, 2H), 7.34-7.30 (m, 1H), 7.11 (d, J = 7.2 Hz, 1H), 6.6 (d, J = 7.2 Hz, 1H), 3.64 (s, 3H). LCMS: 237.2 (M + H) +.

Stage 3: 4-bromo-2-methyl-6-pyridin-2-yl-isoquinolin-1-one

At 0 ° С, bromine (78 mg, 0.49 mmol) in acetic acid (0.3 ml) was added dropwise to 2-methyl-6pyridin-2-ylisoquinolin-1-one (115 mg, 0.49 mmol) in acetic acid (20 ml) ... The mixture was stirred at room temperature for 20 minutes. Extraction with CH ₂ Cl ₂ and purification by silica gel chromatography (PE: EA = 5: 1 ~ 1: 1) gave the title compound (73.0 mg, 47.7%) as a yellow solid.

¹ H NMR (CDCl3, 400 MHz) δ 8.79 (d, J = 4.4 Hz, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.85 (t, J = 7.2 Hz, 1H), 7.42 (s, 1H), 7.36-7.34 (m, 1H), 3.64 (s, 3H). LCMS: 314.9 (M + H) +.

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Stage 4: N- [3- (2-methyl-1-oxo-6-pyridin-2-yl-isoquinolin-4-yl) phenyl] ethanesulfonamide ^^^ NHSO ₂ Et

J

N aA o

For 5 min, N _{2 was} bubbled through a mixture of 4-bromo-2-methyl-6-pyridin-2-yl-isoquinolin-1-one (48.1 mg, 0.153 mmol), [3- (ethylsulfonylamino) phenyl] boronic acid (35.0 mg, 0.153 mmol), Pd (dppf) Cl ₂ (22.3 mg, 0.03 mmol), and aqueous 1 M K3PO4 (0.38 ml, 0.38 mmol, 1 M) in dioxane (5 ml), which was then exposed to microwaves at 80 ° С for 20 minutes. Purification by silica gel chromatography (PE: EA = 3: 1 to 1: 2) followed by preparative HPLC gave the title compound (2.5 mg, 3.9%) as a white solid.

1H NMR (methanol-d4, 400 MHz) δ 8.69 (d, J = 8.4 Hz, 1H), 8.59 (d, J = 8.4 Hz, 1H), 8.23 (d, J = 1.2 Hz, 1H), 8.15-8.22 (m, 1H), 8.10 (dd, J1 = 8.4 Hz, J ₂ = 1.6 Hz, 2H), 7.65-7.62 (m, 1H), 7.50-7.45 (m, 3H), 7.38-7.30 (m, 2H) , 3.71 (s, 3H), 3.16 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H). LCMS: 420.1 (M + H) +.

Example 88: 4- [4-fluoro-2-methoxy-5- (methylsulfonylmethyl) phenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one.

Stage 1: 4- [4-fluoro-2-methoxy-5- (methylsulfonylmethyl) phenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinoline-1-one

F

A, CO ₂ Me

Bg

At 0-10 ° C. Br ₂ (24 g, 150 mmol) in acetic acid (100 ml) was added dropwise to a solution of methyl 2-fluoro-4-hydroxybenzoate (25.5 g, 150 mmol) in acetic acid (600 mL). The mixture was stirred at room temperature overnight. Extraction with ethyl acetate and purification by silica gel chromatography (100% DCM) afforded the title compound (32.0 g, 86.5%) as a white solid.

1H NMR (methanol-d ₄ , 400 MHz) δ 8.03 (d, J = 7.2 Hz, 1H), 6.68 (d, J = 12.0 Hz, 1H), 3.86 (s, 3H). LCMS: 249.1 (M + H) ⁺ .

Stage 2: 5-methyl 5-bromo-2-fluoro-4-methoxybenzoate

F

J ^, CO ₂ Me

Bg

Methyl iodide (10.6 g, 74.9 mmol) was added dropwise to 4- [4-fluoro-2-methoxy-5 (methylsulfonylmethyl) phenyl] -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one (6.0 g, 24.1 mmol) and K ₂ CO ₃ (9.98 g, 72.3 mmol) in MeCN (120 ml). The mixture was heated at 80 ° C overnight. Extraction with ethyl acetate and purification by silica gel chromatography (PE: EA = 60: 1 to 40: 1) afforded the title compound (5.1 g, 80.4%) as a white solid which was used without purification.

1H NMR (CDCl3, 400 MHz) δ 8.15 (d, J = 7.6 Hz, 1H), 6.66 (d, J = 12.0 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H). LCMS: 263.0 (M + H) ⁺ .

Stage 3: (5-bromo-2-fluoro-4-methoxyphenyl) methanol

F

PAon

Bg

DIBAL-H (45.6 ml, 1M in toluene) was added dropwise to a solution of 5-methyl 5-bromo-2-fluoro-4methoxybenzoate (5.0 g, 19.0 mmol) in anhydrous CH ₂ Cl ₂ (300 ml) at -78 ° С ... The mixture was stirred at 78 ° C for 3 h and then rapidly cooled with MeOH and water. The mixture was filtered and the filter cake was washed with CH ₂ Cl ₂ . The filtrate was washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (4.18 g, 94.4%) as a white solid which was used without purification.

1H NMR (DMSO-06, 400 MHz) δ 7.59 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 12.4 Hz, 1H), 5.25 (t, J = 5.6 Hz, 1H), 4.45 (d , J = 5.6 Hz, 2H), 3.84 (s, 3H).

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Stage 4: 1-bromo-5- (bromomethyl) -4-fluoro-2-methoxybenzene

PBr ₃ (4.7 g, 17.4 mmol) was added dropwise to a solution of (5-bromo-2-fluoro-4-methoxyphenyl) methanol (4.1 g, 17.4 mmol) in anhydrous CH ₂ Cl ₂ (40 ml) at 0 ° С. The mixture was stirred at room temperature for 3 hours and poured into ice water. The pH was adjusted to 8 with saturated aqueous NaHCO ₃ . Extraction with CH ₂ Cl ₂ gave the title compound (4.9 g, 94.8%) as a white solid which was used without purification.

¹ H NMR (DMSO-d6, 400 MHz) δ 7.56 (d, J = 8.0 Hz, 1H), 6.65 (d, J = 11.6 Hz, 1H), 4.46 (s, 2H), 3.89 (s, 3H).

Stage 5: 1-bromo-4-fluoro-2-methoxy-5- (methylsulfanylmethyl) benzene

Thiomethoxide (1.19 g, 17.0 mmol) was added to a solution of 1-bromo-5- (bromomethyl) -4-fluoro-2methoxybenzene (4.9 g, 16.4 mmol) in anhydrous DMF (25 ml) at 0 ° С. The mixture was stirred at room temperature for 5 hours and then poured into water (40 ml). Extraction with ethyl acetate provided the title compound (4.3 g, 99.0%) as a colorless oil which was used without purification.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.50 (d, J = 8.0 Hz, 1H), 6.64 (d, J = 11.2 Hz, 1H), 3.88 (s, 3H), 3.63 (s, 2H), 2.04 (s, 3H).

Stage 6: 1-bromo-4-fluoro-2-methoxy-5- (methylsulfonylmethyl) benzene F

Br

Oxone (20.9 g, 34.1 mmol) in H ₂ O (100 ml) was added dropwise to a solution of 1-bromo-4-fluoro-2methoxy-5- (methylsulfanylmethyl) benzene (4.3 g, 16.2 mmol) in MeOH (100 ml) at 0 ° C. The mixture was then stirred at room temperature for 3 hours and then poured into water. Extraction with ethyl acetate, washing with saturated aqueous Na ₂ SO ₃ (40 ml) and brine gave a solid which was triturated with 1:10 / EA: MTBE to give the title compound (4.40 g, 93.0%) as a white solid.

1H NMR (CDClj, 400 MHz) δ 7.66 (d, J = 8.0 Hz, 1H), 6.72 (d, J = 11.2 Hz, 1H), 4.22 (s, 2H), 3.92 (s, 3H), 2.83 (s , 3H). LCMS: 318.9 (M + Na) +.

Step 7: 4- [4-fluoro-2-methoxy-5- (methylsulfonylmethyl) phenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinoline-1-one

F

T | ^ A ^ 5O ₂ Me n \\ X o

1-Bromo-4-fluoro-2-methoxy-5- (methylsulfonylmethyl) benzene (34.0 mg, 0.114 mmol), the title compound of Example 46, step 2 (50.0 mg, 0.137 mmol), Pd (dppf) Cl ₂ ( 20.0 mg, 0.027 mmol) and 1 M aqueous K ₃ PO ₄ (0.47 ml, 0.47 mmol) in dioxane (3.0 ml) were exposed to microwaves at 100 ° С for 40 min. Preparative HPLC obtained the title compound (10.0 mg, 18%) as a light yellow solid.

1H NMR (CDCl3, 400 MHz) δ 8.47 (d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 7.73 (s, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.42 (d , J = 8.4 Hz, 1H), 7.27 (s, 1H), 7.05 (s, 1H), 6.85 (d, J = 12.0 Hz, 1H), 4.32 (d, J = 6.4 Hz, 2H), 3.93 (s , 3H), 3.77 (s, 3H), 3.64 (s, 3H), 2.93 (s, 3H). LCMS: 456.1 (M + H) ⁺ .

Example 89 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one. Stage 1: 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one

Suspension of 4-bromo-2-methylisoquinolin-1-one (100 mg, 0.42 mmol), bis (pinacolato) diborone (214

- 213 038715 mg, 0.84 mmol), Pd (dppf) Cl ₂ (31 mg, 0.04 mmol) and potassium acetate (104 mg, 1.05 mmol) in dioxane (2 ml) in a nitrogen atmosphere was heated to 90 ° С for 135 min ... The suspension was then cooled to room temperature and diluted with ethyl acetate (8 ml). The mixture was washed with aqueous saturated NaHCO ₃ solution (8 ml) and brine (8 ml). The organic phase was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by normal phase column chromatography (10-90% EtOAc / hexanes) to afford the title compound (44 mg, 37%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.43 (d, J = 7.9 Hz, 1H), 8.40 (dd, J = 8.2 Hz, 0.9 Hz, 1H), 7.68 (s, 1H), 7.65 (ddd, J = 8.2, 8.2, 1.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 3.63 (s, 3H), 1.38 (s, 12H). LCMS (M + H) + 286.

Step 2: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 18, Step 3, replacing 2-bromo-1- (cyclopropylmethoxy) -4-methylsulfonylbenzene with 4-bromo-2methylisoquinoline-1 (2H) -one and 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one on N-benzyl-2-methoxy-5- (tetramethyl-1,3,2-dioxaborolane- 2-yl) benzamide.

1H NMR (DMSO-d ₆ , 400 MHz) δ 0.09 (m, 2H), 0.29 (m, 1H), 0.35 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.57 (s , 3H), 3.95 (m, 2H), 7.16 (d, J = 7.9 Hz, 1H), 7.37 (d, J = 8.8 Hz, 1H), 7.53 (m, 2H), 7.65 (t, J = 7.6 Hz , 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 8.8, 2.4 Hz, 1H), 8.30 (d, J = 8.1 Hz, 1H). LCMS (M + H) + 384.

Alternatively, 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2methylisoquinolin-1-one can be prepared as described below.

Stage 1: 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one

A mixture of 4-bromo-2-methylisoquinolin-1-one (8.0 g, 33.6 mmol), bis (pinacolato) diborone (17.1 g, 67.2 mmol), KOAc (6.6 g, 67.2 mmol), Pd ₂ (dba) ₃ (3.1 g, 3.36 mmol) and X-Phos (1.6 g, 3.36 mmol) in anhydrous dioxane (200 ml) were stirred at 60 ° С for 12 h.The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE: EA = 15: 1) to give the title compound (6.0 g, 62%) as a solid.

Step 2: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one.

A mixture of the title compound from Step 1 (5.0 g, 17.5 mmol), 2-bromo-1 (cyclopropylmethoxy) -4-methylsulfonylbenzene (6.4 g, 21 mmol), K3PO4 (9.3 g, 43.9 mmol) and Pd (dppf) Cl2 (1.4 g, 1.75 mmol) in dioxane / water (100 ml / 10 ml) was stirred at 60 ° C for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (EA: DCM = 1: 4). The appropriate fractions were combined and concentrated under reduced pressure. The resulting solid was recrystallized from DCM / MTBE (1: 1, 50 ml) to afford the title compound (4.0 g, 60%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (dd, J1 = 8.0 Hz, J ₂ = 0.8 Hz, 1H), 7.98 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.53 (m, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.10 (m, 2H), 3.88 (m, 2H), 3.66 (s, 3H), 3.09 (s , 3H), 1.02-0.98 (m, 1H), 0.44-0.38 (m, 2H), 0.11-0.09 (m, 2H). LCMS: 384.1 (M + H) +.

Example 90: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-fluoro-2-methylisoquinolin-1-one.

Step 1: 2- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a similar manner to Example 89, Step 1, substituting 4-bromo-2methylisoquinolin-1-one for 2-bromo-1- (cyclopropylmethoxy) -4-methylsulfonylbenzene.

1H NMR (CDCl3, 400 MHz) δ 0.46 (m, 2H), 0.60 (m, 2H), 1.24 (m, 1H), 1.35 (s, 12H), 3.02 (s, 3H), 3.97

- 214 038715 (d, J = 6.0, 2H), 6.91 (d, J = 8.7 Hz, 1H), 7.92 (dd, J = 8.7, 2.5 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H) ... LCMS (M + H) ⁺

353.

Step 2: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 18, Step 3, replacing the title compound of Example 47, Step 2 with 4-bromo-2-methylisoquinolin 1 (2H) -one and 2- [2- (cyclopropylmethoxy) - 5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane on N-benzyl-2-methoxy-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide.

1H NMR (DMSO-d ₆ , 400 MHz) δ 0.12 (m, 2H), 0.32 (m, 1H), 0.39 (m, 1H), 0.99 (m, 1H), 3.22 (s, 3H), 3.56 (s , 3H), 3.97 (m, 2H), 6.82 (dd, J = 10.5, 2.4 Hz, 1H), 7.39 (m, 2H), 7.61 (s, 1H), 7.82 (d, J = 2.3 Hz, 1H) , 7.98 (dd, J = 8.74, 2.4 Hz, 1H), 8.36 (dd, J = 8.9, 6.1 Hz, 1H). LCMS (M + H) + 402.

Example 91: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 18, Step 3, replacing the title compound of Example 58, Step 2 with 4-bromo-2-methylisoquinoline 1 (2H) -one and 2- [2- (cyclopropylmethoxy) - 5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane on N-benzyl-2-methoxy-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide.

1H NMR (DMSO-d ₆ , 400 MHz) δ 0.10 (m, 2H), 0.30 (m, 1H), 0.39 (m, 1H), 0.94 (m, 1H), 3.22 (s, 3H), 3.58 (s , 3H), 3.95 (m, 2H), 7.24 (dd, J = 9, 5.3 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.56 (m, 1H) , 7.81 (d, J = 2.4 Hz, 1H), 7.96 (m, 2H). LCMS (M + H) ⁺ 402.

Example 92: 4- [2- (2,4-difluorophenoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 18, Step 3, replacing 1- (2-bromo-4-methylsulfonylphenoxy) -2,4-difluorobenzene with 4-bromo-2methylisoquinoline-1 (2H) -one and 2- methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one on K-benzyl-2-methoxy-5- (tetramethyl-1,3, 2-dioxaborolan-2-yl) benzamide.

1H NMR (DMSO-d6, 400 MHz) δ 3.27 (s, 3H), 3.58 (s, 3H), 7.03 (d, J = 9.2 Hz, 1H), 7.13 (m, 1H), 7.35 (m, 2H) , 7.48 (m, 1H), 7.54 (t, J = 7.5, 1H), 7.67 (s, 1H), 7.69 (m, 1H), 7.97 (m, 1H), 7.98 (s, 1H), 8.30 (d , J = 8.1, 1H). LCMS (M + H) ⁺ 442.

Example 93: N- [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxoisoquinolin-4-yl) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 18, Step 3, substituting 4-bromo-2methylisoquinolin-1 (2H) -one for N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide and 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one on N-benzyl-2-methoxy-5- (tetramethyl-1, 3,2-dioxaborolan-2-yl) benzamide.

1H NMR (DMSO-d ₆ , 400 MHz) δ 1.23 (t, J = 7.3 Hz, 3H), 3.13 (q, J = 7.8 Hz, 2H), 3.53 (s, 3H), 6.95 (m, 2H), 7.09 (m, 1H), 7.28 (m, 3H), 7.51 (m, 2H), 7.65 (t, J = 6.9 Hz, 1H), 8.26 (d, J = 0.8 Hz, 1H), 9.83 (s, 1H ). LCMS (M + H) ⁺ 471.

- 215 038715

Example 94: N- [3- (1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

A mixture of 5-bromo-1-methylpyridin-2-one (100 mg, 0.532 mmol), [3- (methanesulfonamido) phenyl] boronic acid (171.1 mg, 0.798 mmol), KOAc (130.0 mg, 1.326 mmol) and Pd (dppf ) Cl ₂ (38.9 mg, 0.05 mmol) in dioxane / H ₂ O (2 ml / 0.5 ml) was stirred at 90 ° С for 20 min. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA = 1: 1) to give the title compound (30.0 mg, 20%) as a brown solid.

1H NMR (CDCl3, 400 MHz) δ 7.65-7.60 (dd, J1 = 7.6 Hz, J2 = 2.4 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.41 (t, J = 8.0 Hz, 1H ), 7.33 (s, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.86 (brs, 1H), 6.67 (d, J = 9.2 Hz, 1H ), 3.65 (s, 3H), 3.05 (s, 3H). LCMS (M + H) ⁺ 279.

Example 95: N- [3- (1,4-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide.

Stage 1: 5-bromo-1,4-dimethylpyridin-2-one

NaH (288.0 mg, 12.0 mmol) was added to a solution of 5-bromo-4-methylpyridin-2-ol (1.12 g, 6.0 mmol) in anhydrous THF (20 ml), and the reaction mixture was stirred at 0 ° С for 30 min. Then methyl iodide (1.7 g, 12.0 mmol) was added and stirred at room temperature for 3 h. Saturated NH ₄ Cl (100 ml) was added and the resulting mixture was extracted with ethyl acetate (100 ml × 3). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1 to 2: 1) to give the title compound (1.0 g, 83.3%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.44 (s, 1H), 6.94 (s, 1H), 3.51 (s, 3H), 2.24 (s, 3H). LCMS (M + H) + 202.

Stage 2: N- [3- (1,4-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

5-Bromo-1,4-dimethylpyridin-2-one was treated with [3- (methanesulfonamido) phenyl] boronic acid in a similar manner to Example 94 to give the title compound as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.43 (t, J = 8.0 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.69 (s, 1H), 3.67 (s, 3H), 3.07 (s, 3H), 2.16 (s, 3H). LCMS (M + H) ⁺ 293.

Example 96 N- [3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

Stage 1: 5-bromo-1,3-dimethylpyridin-2-one

The title compound from Step 1 was prepared in a similar manner to Example 95, Step 1, substituting 5-bromo-3-methylpyridin-2-ol for 5-bromo-4-methylpyridin-2-ol to give 5-bromo-1 , 3-dimethylpyridin-2-one.

¹ H NMR (CDCl3, 400 MHz): 7.30 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 1.6 Hz, 1H), 3.53 (s, 3H), 2.16 (s, 3H). LCMS (M + H) ⁺ 202.

Stage 2: N- [3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

5-Bromo-1,3-dimethylpyridin-2-one was treated with [3- (methanesulfonamido) phenyl] boronic acid 216 038715 in a similar manner to Example 94 to give the title compound as a white solid.

¹ H NMR (DMSO-d ₆ , 400 MHz): 9.74 (s, 1H), 7.91 (d, J = 2.4 Hz, 1H), 7.62 (s, 1H), 7.37 (t, J = 7.6 Hz, 1H) ,

7.32 (s, 1H), 7.29 (d, J = 7.6 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 3.52 (s, 3H), 3.02 (s, 3H), 2.08 (s, 3H ). LCMS (M + H) + 293.

Example 97: N- [3- (1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide.

Stage 1: 5-bromo-3,4-dimethyl-1H-pyridin-2-one

To a mixture of 5-bromo-3,4-dimethylpyridine-2-amine (0.6 g, 3.0 mmol), H ₂ SO ₄ (98%, 1.62 mL) and H2O (18 ml) was added NaNO ₂ (243.6 mg of solution, 4.2 mmol of ) in H2O (1.6 ml) dropwise at 0 ° С. The mixture was then stirred at 31 ° C for 30 min and filtered. The resulting solid was washed with water to give the title compound (375.0 mg, 62%) as a white solid.

1H NMR (CDCl * ,, 400 MHz) δ 7.48 (s, 1H), 2.32 (s, 3H), 2.19 (s, 3H). LCMS (M + H) + 202.

Stage 2: 5-bromo-1,3,4-trimethylpyridin-2-one

NaH (96.0 mg, 2.4 mmol) was added to a solution of 5-bromo-3,4-dimethyl-1H-pyridin-2-one (402.0 mg, 2.0 mmol) in anhydrous THF (20 ml). The resulting mixture was stirred at 0 ° C for 30 minutes. Methyl iodide (568.0 mg, 4.0 mmol) was added and the reaction was stirred at 32 ° C for 3 h. Then saturated aqueous NH ₄ Cl (100 ml) was added and the mixture was extracted with ethyl acetate (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1 to 2: 1) to give the title compound (350.0 mg, 80%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.38 (s, 1H), 3.52 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H). LCMS (M + H) + 216.

Stage 3: N- [3- (1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

5-Bromo-1,3,4-trimethylpyridin-2-one was treated with [3- (methanesulfonamido) phenyl] boronic acid in a similar manner to Example 94 to give the title compound as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.42 (s, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.24 (s, 1H), 7.16 (s, 1H), 7.08 (s, 1H), 7.05 (d, J = 7.6 Hz, 1H), 3.59 (s, 3H), 3.06 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H). LCMS (M + H) + 307.

Example 98 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one.

Stage 1: 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one

A solution of 5-bromo-1-methylpyridin-2-one (200.0 mg, 1.06 mmol), bis (pinacolato) diborone (410.0 mg, 1.61 mmol), potassium acetate (270 mg, 2.67 mmol) and Pd (dppf) Cl ₂ ( 80 mg, 0.11 mmol) in dioxane (5 ml) was heated at 100 ° С for 2 h under the influence of microwaves. The mixture was filtered, washed with water and extracted with ethyl acetate (20 ml x 3). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated to give the crude title compound (59.0 mg, 23.6%). LCMS (M + H) + 236.

- 217 038715

Step 2: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one

1-Methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one was treated with 2-bromo-1 (cyclopropylmethoxy) -4-methylsulfonylbenzene in a manner analogous to described in Example 94 to provide the title compound.

¹ H NMR (CDCl ₃ , 400 MHz): δ 7.86 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.68-765 (m, 2H ), 7.03 (d, J = 8.4 Hz, 1H), 6.66 (d, J = 8.8 Hz, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.64 (s, 3H), 3.07 (s, 3H ), 1.28-1.25 (m, 1H), 0.69-0.65 (m, 2H), 0.34-0.38 (m, 2H). LCMS (M + H) ⁺ 334.

Example 99 K- [4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide.

Step 1: 5- [5-amino-2- (2,4-difluorophenoxy) phenyl] -1-methylpyridin-2-one

A mixture of the title compound, step 1 in example 57 (100 mg, 0.289 mmol), 5-bromo-1methylpyridin-2-one (45.27 mg, 0.240 mmol), K ₃ PO ₄ (127.6 mg, 0.60 mmol) and Pd ( dppf) Cl ₂ (20 mg, 0.027 mmol) in dioxane / H ₂ O (4 / 0.5 ml) was stirred at 100 ° С for 40 min under the action of microwaves. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA = 1: 2) to give the title compound (60 mg, 76%). LCMS (M + H) + 328.

Stage 2: X- [4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide

To a solution of 5- [5-amino-2- (2,4-difluorophenoxy) phenyl] -1-methylpyridin-2-one (30 mg, 0.09 mmol) in DCM (4 ml) was added TEA (27.3 mg, 0.27 mmol) and EtSO ₂ Cl (35.39 mg, 0.27 mmol). The mixture was stirred at 30 ° C for 12 hours. Water (4 ml) was added and the mixture was extracted with DCM (4 ml x 3). The organic layer was concentrated and the residue was purified by preparative HPLC to give the title compound (10 mg, 26%) as a light yellow gum.

1H NMR (CDCl ₃ , 400 MHz) δ 7.68-7.66 (m, 2H), 7.28 (d, J = 2.4 Hz, 1H), 7.13-7.10 (m, 1H), 7.09 (s, 1H), 7.00-6.92 (m, 2H), 6.84-6.86 (m, 1H), 6.78 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 3.65 (s, 3H), 3.14 (q, J = 7.2 Hz, 2H), 1.41 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ 421.

Example 100: X- [4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 99 substituting ethanesulfonyl chloride for methanesulfonyl chloride in Step 2 to give the title compound as a light yellow gum.

1H NMR (CDCl ₃ , 400 MHz) δ 7.64-7.62 (m, 2H), 7.29 (d, J = 4.8 Hz, 1H), 7.13-7.12 (m, 1H), 6.69-6.95 (m, 2H), 6.79 (m, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.62 (d, J = 9.4 Hz, 1H), 3.61 (s, 3H), 3.04 (s, 3H). LCMS (M + H) ⁺ 407.

Example 101 K- [4- (2,4-difluorophenoxy) -3- (1,4-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 100 substituting 5-bromo-1-methylpyridin-2-one for 5-bromo-1,4dimethylpyridin-2-one in Step 1 to give the title

- 218 038715 connections.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.21-7.16 (m, 4H), 6.95-6.93 (m, 2H), 6.86-6.80 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.53 (s, 1H), 3.57 (s, 3H), 3.04 (s, 3H), 2.10 (s, 3H). LCMS (M + H) ⁺ 421.

Example 102: N- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 100 substituting 5-bromo-1-methylpyridin-2-one for 5-bromo-1,3dimethylpyridin-2-one to give the title compound.

¹ H NMR (CDClj, 400 MHz) δ 7.53 (s, 2H), 7.40 (s., 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.17 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 6.99-6.90 (m, 2H), 6.87-6.80 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.19 (s, 3H). LCMS (M + H) ⁺ 421.

Example 103 N- [4- (2,4-difluorophenoxy) -3- (1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 100 substituting 5-bromo-1-methylpyridin-2-one for 5-bromo-1,3,4trimethylpyridin-2-one to give the title compound.

¹ H NMR (methanol-d ₄ , 400 MHz) δ 7.65 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.39 (s, 1H), 7.05 -7.01 (m, 2H), 6.94-6.91 (m, 2H), 3.55 (s, 3H), 3.31 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H). LCMS (M + H) ⁺ 453.

Example 104 3-amino-1-methyl-5- (3-methylsulfonylphenyl) pyrazin-2-one

Stage 1: 3-amino-5-bromo-1-methylpyrazin-2-one

A solution of 3,5-dibromo-1-methylpyrazin-2-one (500.0 mg, 2.46 mmol), NH ₃ H ₂ O (5.0 ml) in dioxane (30.0 ml) was heated at 105 ° С for 20 h. The mixture was concentrated, diluted with EtOAc (50 mL) and filtered to give the title compound (300.0 mg, 79.0%) which was used without purification. LCMS (M + H) + 204.

Stage 2: 3-amino-1-methyl-5- (3-methylsulfonylphenyl) pyrazin-2-one

Solution of 3-amino-5-bromo-1-methylpyrazin-2-one (81.0 mg, 0.4 mmol), (3methylsulfonylphenyl) boronic acid (120.0 mg, 0.6 mmol), Cs ₂ CO ₃ (391.0 mg, 1.2 mmol), Pd (PPh ₃ ) ₄ (20.0 mg, 0.017 mmol) in dioxane (20.0 ml) and water (2.0 ml) was stirred at 95 ° С for 12 h under N ₂ . The mixture was concentrated and purified by silica gel chromatography (PE: EA = 3: 2) to give the title compound (20.0 mg, 18%).

¹ H NMR (DMSO-d6 400 MHz): δ 8.35 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.80 (d, J = 8.0 Hz, 1H), 7.73 (s, 1H), 7.66 (t, J = 8.0 Hz, 1H), 6.93 (brs, 2H), 3.50 (s, 3H), 3.24 (s, 3H). LCMS (M + H) ⁺ 280.

Example 105: 3-amino-5- (3-ethylsulfonylphenyl) -1-methylpyrazin-2-one

The compound was prepared in a manner similar to that described in Example 104, step 2, substituting (3-methylsulfonylphenyl) boronic acid for (3-ethylsulfonylphenyl) boronic acid to give

- 219 038715 of the specified connection header.

¹ H NMR (DMSO-d6 400 MHz): δ 8.30 (t, J = 1.6 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.71 ( s, 1H), 7.65 (t, J = 8.0 Hz, 1H), 6.90 (brs, 2H), 3.48 (s, 3H), 3.29 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ 294.

Example 106: N- [5- (6-amino-4-methyl-5-oxopyrazin-2-yl) -2-methoxyphenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 104, Step 2, substituting (3-methylsulfonylphenyl) boronic acid for [3 (methanesulfonamido) -4-methoxyphenyl] boronic acid to provide the title compound.

¹ H NMR (DMSO-d6 400 MHz): δ 8.91 (s, 1H), 7.68 (d, J = 2.4 Hz, 1H), 7.61 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.38 ( s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 6.88-6.64 (m, 2H), 3.84 (s, 3H), 3.46 (s, 3H), 2.95 (s, 3H). LCMS (M + H) ⁺ 325.

Example 107: 3-amino-1-methyl-5 - (3-methylsulfonylphenyl) pyridin-2-one

The compound was prepared in a similar manner to Example 104, Step 2, replacing 3-amino-5-bromo-1-methylpyridin-2-one with 3-amino-5-bromo-1-methylpyrazin-2-one to provide the title compound ...

¹ H NMR (metαnol-d4, 400 MHz) δ 8.06 (t, J = 2.0 Hz, 1H), 7.89-7.85 (m, 2H), 7.67 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 3.67 (s, 3H), 3.17 (s, 3H). LCMS (M + H) ⁺ 279.

Example 108 3-amino-5- (3-ethylsulfonylphenyl) -1-methylpyridin-2-one

The compound was prepared in a similar manner to Example 105 substituting 3-amino-5-bromo-1-methylpyrazin-2-one for 3-amino-5-bromo1-methylpyridin-2-one to give the title compound.

¹ H NMR (methanol ^, 400 MHz) δ 8.01 (t, J = 2.0 Hz, 1H), 7.88-7.83 (m, 2H), 7.68 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 3.67 (s, 3H), 3.26 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). LCMS (m + H) ⁺ 293.

Example 109: N- [5- (5-amino-1-methyl-6-oxopyridin-3-yl) -2-methoxyphenyl] methanesulfonamide

The compound was prepared in a similar manner to Example 106 substituting 3-amino-5-bromo-1-methylpyrazin-2-one for 3-amino-5-bromo1-methylpyridin-2-one to give the title compound.

¹ H NMR (methanol-d ^ 400 MHz) δ 7.53 (d, J = 2.4 Hz, 1H), 7.34 (dd, J ₁ = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.18 (d, J = 2.4 Hz , 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 3.92 (s, 3H), 3.64 (s, 3H), 2.94 (s, 3H). LCMS (M + H) + 324.

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Example 110 N- [2-methoxy-5- [1-methyl-5- (methylamino) -6-oxopyridin-3yl] phenyl] methanesulfonamide.

Stage 1: tert-butyl N- (5-bromo-1-methyl-2-oxonyridin-3-yl) carbamate o

\ JL .NHBoc

V

Br

To a solution of 3-amino-5-bromo-1-methylpyridin-2-one (404.0 mg, 2.0 mmol) in DCM (30 ml) was added (Boc) ₂ О (654.0 mg, 3.0 mmol), Et ₃ N (606.0 mg , 6.0 mmol) dropwise and DMAP (123.0 mg, 1.0 mmol). The reaction mixture was stirred for 12 h at 30 ° C, quickly cooled with saturated aqueous NH ₄ Cl (50 ml), extracted with EA (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. Chromatography over silica gel (PE: EA = 2: 1) afforded the crude title compound (400.0 mg) as a green solid which was carried over to the next step. LCMS (M-55) ⁺ 247.

Stage 2: tert-butyl N- (5-bromo-1-methyl-2-oxopyridin-3-yl) -N-methylcarbamate

To a solution of tert-butyl N- (5-bromo-1-methyl-2-oxopyridin-3-yl) carbamate (150.0 mg, crude) in DMF (10 ml) was added NaH (60.0 mg, 1.5 mol, 60% in oil ) in portions at 0 ° C. The solution was stirred for 30 min, then CH ₃ I (231.0 mg, 1.5 mmol) was added dropwise at 0 ° С. The reaction mixture was stirred for 2 h at 30 ° C. The reaction was quickly quenched with saturated aqueous NH ₄ Cl (15 ml), extracted with EA (20 ml), washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (120.0 mg, crude) as a green solid which was used immediately in the next step without purification.

Stage 3: 5-bromo-1-methyl-3- (methylamino) pyridin-2-one

HCl / dioxane (1 ml, 4 M ) dropwise with stirring at 30 ° C. The reaction mixture was stirred at 30 ° C for 30 min. The mixture was filtered and the filter cake was collected. The filtrate was adjusted to pH 9 with saturated aqueous NaHCO ₃ , extracted with ethyl acetate (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a green solid which was combined with the filter cake to give the title compound (43.2 mg).

¹ H NMR (CDCl ₃ 400 MHz): δ 6.74 (d, J = 2.4 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 5.15 (s, 1H), 3.53 (s, 3H), 2.83 (s, 3H). LCMS (M + H) ⁺ 217.

Stage 4: N- [2-methoxy-5- [1-methyl-5- (methylamino) -6-oxopyridin-3-yl] phenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 106 substituting 3-amino-5-bromo-1-methylpyrazin-2-one for the title compound from Step 3.

1H NMR (methanol-d ₄ , 400 MHz): δ 7.55 (d, J = 2.0 Hz, 1H), 7.38 (dd, J1 = 8.8, J2 = 2.4 Hz, 1H), 7.13-7.08 (m, 2H), 6.52 (d, J = 2.0 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 2.94 (s, 3H), 2.88 (s, 3H). LCMS (M + H) ⁺ 338.

Example 111 N- [5- [5- (ethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfone amide

Stage 1: tert-butyl N- (5-bromo-1-methyl-2-oxopyridin-3-yl) -N-ethyl carbamate

To a solution of the title compound from Example 110 Step 1 (150.0 mg, crude) in

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DMF (10 mL) was added NaH (60.0 mg, 1.5 mmol, 60% in oil) in portions at 0 ° С and stirred for 30 min, then iodoethane (234.0 mg, 1.5 mmol) was added dropwise at 0 ° С. The reaction mixture was stirred for 2 h at 30 ° C. The mixture was then rapidly cooled with saturated aqueous NH ₄ Cl (15 ml), extracted with ethyl acetate (20 ml), washed with brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (120.0 mg, crude) in the form of a light green solid, which was carried further without purification.

Stage 2: 5-bromo-3- (ethylamino) -1-methylpyridin-2-one

HCl / dioxane (1 ml, 4 M ) dropwise with stirring at 30 ° C. The reaction mixture was stirred for 30 min at 30 ° C. The mixture was then filtered and the filter cake was collected. The filtrate was adjusted to pH 9 with saturated aqueous NaHCO ₃ , extracted with EA (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give a light green solid which was combined with the filter cake to give the title compound (46.0 mg). which was transferred further without purification.

¹ H NMR (CDCl3 400 MHz): δ 6.72 (d, J = 2.4 Hz, 1H), 6.20 (d, J = 1.6 Hz, 1H), 3.51 (s, 3H), 3.09 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). LCMS (M + H) + 231.

Step 3: N- [5- [5- (ethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 106 substituting 3-amino-5-bromo-1-methylpyrazin-2-one for the title compound from Step 2.

1H NMR (CDCl ₃ 400 MHz): δ 7.63 (d, J = 2.0 Hz, 1H), 6.16 (dd, J1 = 8.4 Hz, J1 = 2.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H) , 6.82-6.80 (m, 1H), 6.39 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.64 (s, 3H), 3.19 (q, J = 7.2 Hz, 2H), 2.98 ( s, 3H), 1.32 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ 352.

Example 112 N- [5- [5- (cyclopropylmethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide

To a solution of the compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 ml) and AcOH (0.3 ml) was added cyclopropanecarbaldehyde (14.0 mg, 0.2 mmol) dropwise with stirring at 30 ° C. _{NaBH 3} CN (24.5 mg, 0.4 mol) was added in portions at 30 ° С. The reaction mixture was stirred for 2 h at 30 ° C. The reaction mixture was then rapidly cooled with saturated aqueous NH4Cl (5 ml), extracted with EtOAc (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC to afford the title compound (10.0 mg, 13.2%) as a light green solid.

1H NMR (methanol-d4, 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 8.4, 2.4 Hz, 1H), 7.16-7.07 (m, 2H), 6.61 (d , J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.66 (s, 3H), 3.05 (s, 2H), 2.95 (s, 3H), 1.21-1.14 (m, 1H), 0.64-0.56 ( m, 2H), 0.35-0.28 (m, 2H). LCMS (M + H) ⁺ 378.

Example 113: N- [5- [5- (dimethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide

To a solution of the compound from Example 109 (64.6 mg, 0.2 mmol) in MeOH (3 ml) and AcOH (0.3 ml), add

- 222 038715 HCHO (30.0 mg, 1.0 mmol) was carried out dropwise with stirring at 30 ° С. _{NaBH 3} CN (61 mg, 1.0 mol) was added in portions at 30 ° С. The reaction mixture was stirred for 2 h at 30 ° C. The reaction mixture was then rapidly cooled with saturated aqueous NH4Cl (5 ml), extracted with EtOAc (20 ml), dried over Na ₂ SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 2: 3) to give the title compound (30 mg, 43%) as a light green solid.

'and NMR (metαnol-d4, 400 MHz): δ 7.54 (d, J = 2.4 Hz, 1H), 7.47 (d, J 2.4 Hz, 1H), 7.37 (dd, J' = 2.4, ^ = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 3.93 (s, 3H), 3.63 (s, 3H), 2.94 (s, 3H), 2.86 ( s, 6H). LCMS (M + H) + 352.

Example 114: N- [5- [5- (diethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 113 substituting formaldehyde for acetaldehyde.

'and NMR (methanol-d4, 400 MHz): δ 7.55 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.37 (dd, J' = 8.4 Hz, J ₂ = 2.4 Hz, 1H), 7.17-7.11 (m, 1H), 7.06 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 3.65 (s, 3H), 3.34 (m, 4H), 2.97 ( s, 3H), 1.11 (t, J = 7.2 Hz, 6H). LCMS (M + H) + 380.

Example 115 N- [3- (5-amino-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide.

Step 1: 3-amino-5- [5-amino-2- (2,4-difluorophenoxy) phenyl] -1-methylpyridin-2-one

O

The title compound from Step 1 was prepared in a similar manner to Example 107 substituting (3methylsulfonylphenyl) boronic acid for the title compound of Example 57, Step 1. LCMS (M + H) + 344.

Stage 2: N- [3- (5-amino-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

O

The title compound was prepared in a similar manner to Example 99 Step 2.

'and NMR (DMSO-d6, 400 MHz) δ 9.78 (s, 1H), 7.45-7.39 (m, 1H), 7.23-7.22 (m, 2H), 7.14 (dd, J, = 7.2 Hz, J2 = 1.6 Hz, 1H), 7.10-7.02 (m, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.79 (d, J = 2.0 Hz, 1H), 3.49 (s, 3H), 3.09 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.6 Hz, 3H). LCMS (M + H) ⁺ 436.

Example 116 3-amino-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 107 substituting (3-methylsulfonylphenyl) boronic acid for the title compound of Example 90, Step 1.

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1H NMR (CDCl ₃ , 400 MHz) δ 7.84-7.81 (m, 2H), 7.11 (d, J = 2.0 Hz, 1H), 7.02 (d, J = 2.4 Hz, 1H), 6.84 (d,

J = 2.4 Hz, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.65 (s, 3H), 3.06 (s, 3H), 1.31-1.27 (m, 1H), 0.68 (q, J = 5.6 Hz, 2H), 0.37 (q, J = 5.2 Hz, 2H). LCMS (M + H) ⁺ 349.

Example 117: 4-ethoxy-3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide

A mixture of the title compound of Example 98 Step 1 (40 mg, 0.17 mmol), Pd (dppf) Cl ₂ (10 mg, 8%) and 3-bromo-4-ethoxybenzene-1-sulfonamide (48 mg, 0.17 mmol) suspended in 1,4-dioxane (880 μl) and saturated bicarbonate solution (aq.) (220 μl). The mixture was heated to 95 ° C using microwave (standard) for 60 min. The crude reaction mixture was filtered through a short plug of celite, the plug was washed with additional 1,4-dioxane (1 ml), and the combined filtrate was purified by preparative HPLC. Fractions were combined and lyophilized to give the title compound (14 mg, 27%) as a white solid.

1H NMR (DMSO, 400 MHz): δ 1.33 (t, J = 6.9, 3H), 3.49 (s, 3H), 4.15 (q, J = 6.9, 2H), 6.45 (d, J = 9.4 Hz, 1H) , 7.20-7.23 (m, 3H), 7.64 (dd, J = 2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H). LCMS (M + H) + = 309.

Example 118 4- (2,4-Difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide

Stage 1: 3-bromo-4-fluorobenzenesulfonamide

A solution of 3-bromo-4-fluorobenzenesulfonyl chloride (1 g, 3.3 mmol, 90% purity) was stirred at 0 ° С in THF (15 ml) and DCM (5 ml), treated with aqueous ammonium hydroxide (28%) by adding dropwise for 15 minutes. After stirring at 0 ° C for 210 min, the mixture was acidified (pH 1) by adding 1N. HCl (aq). After the mixture was concentrated in vacuo to near dryness, it was treated with water (50 ml), sonicated for 3 min and filtered. After the filter cake was washed sequentially with water (50 ml) and hexanes (100 ml), it was dried in vacuo to give the title compound (503 mg, 60%) as a white solid, which was carried further without purification. LCMS (M-H) ^- = 253.

Stage 2: 3-bromo-4- (2,4-difluorophenoxy) benzenesulfonamide

A solution of 3-bromo-4-fluorobenzenesulfonamide (400 mg, 1.6 mmol) and 2,4-difluorophenol (228 mg, 1.76 mmol) in DMSO (16 ml) was treated with cesium carbonate (1 g, 3.2 mmol). The resulting mixture was heated to 120 ° C for 20 min using microwave (standard). The mixture was treated with water (100 ml) and was extracted with EtOAc (3x50 ml). The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give a tan solid. The solid was purified by silica gel chromatography (12 g ISCO, 30% EtOAc in hexanes, 30 ml / min) to give the title compound (340 mg, 58%) as a tan solid. LCMS (M-H) ^- = 362.

Step 3: 4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide

3-Bromo-4- (2,4-difluorophenoxy) benzenesulfonamide (1 eq., 62 mg), the title compound of Example 98, step 1 (40 mg, 0.17 mmol), Pd (dppf) Cl ₂ (10 mg, 8%) in 1,4-dioxane (880 μl) and a saturated solution of bicarbonate (aq.) (220 μl) were reacted at 105 ° C for 30 min in a manner similar to that described in example 117. Treatment and preparative HPLC, also similar thus, the title compound (12 mg, 18%) was obtained as a white solid.

¹ H NMR (DMSO, 400 MHz): δ 3.51 (s, 3H), 6.49 (d, J = 9.4, 1H), 4.15 (q, J = 6.9, 2H), 6.45 (d, J = 9.4 Hz, 1H ), 7.20-7.23 (m, 3H), 7.64 (dd, J = 2.6, 9.4 Hz, 1H), 7.72-7.74 (m, 2H), 7.89 (d, J = 2.6 Hz, 1H). LCMS (M + H) ⁺ = 393.

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Example 119 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one.

Stage 1: 5-bromo-3-fluoro-1-methylpyridin-2-one

A mixture of 5-bromo-3-fluoropyridin-2-ol (1 g, 5.2 mmol), iodomethane (356 mg, 5.7 mmol) and K ₂ CO ₃ (1.4 g, 10.4 mmol) in DMF (10 ml) was stirred at room temperature over 12 h. The mixture was treated with water (70 ml) and was extracted with EtOAc (3x50 ml).

The combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1 g, 93%) as a white solid, which was carried further without purification. LCMS (M + H) + = 207.

Stage 2: 3-fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one

A mixture of 5-bromo-3-fluoro-1-methylpyridin-2-one (1 g, 4.9 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl1,3,2-dioxaborolan-2-yl) - 1,3,2-dioxaborolane (2.5 g, 9.8 mmol), KOAc (1.2 g, 12.3 mmol), and Pd (dppf) Cl ₂ (286 mg, 8%) were suspended in 1,4-dioxane (15 ml). After purging the reaction vial with nitrogen for 5 min, the mixture in a closed vial was stirred at 80 ° C for 1 h. The mixture was treated with water (70 ml) and extracted with EtOAc (3x40 ml). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a dark residue. The residue was purified by silica gel chromatography (12 g ISCO, gradient 05-75% EtOAc in hexanes) to afford the title compound (682 mg, 55%) as a reddish brown solid.

Step 3: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one

3-Fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (40 mg, 0.16 mmol), 2-bromo- 1- (cyclopropylmethoxy) -4-methanesulfonylbenzene (49 mg, 0.16 mmol), Pd (dppf) Cl2 (12 mg, 10%) in 1,4-dioxane (880 μl) and saturated bicarbonate solution (aq.) (220 μl ) was reacted, worked up and purified in a manner similar to Example 117. The title compound (22 mg, 46%) was obtained as a tan solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 0.31-0.42 (m, 2H), 0.53-0.63 (m, 2H), 1.17-1.34 (m, 1H), 3.20 (s, 3H), 3.58 (s, 3H), 3.95-4.06 (m, 2H), 7.24-7.33 (m, 1H), 7.72-7.79 (m, 1H), 7.80-7.87 (m, 1H), 7.84 (s, 1H), 7.887.93 ( m, 1H). LCMS (M + H) + = 351.

Example 120 5- [2- (2,4-difluorophenoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one

The title compound of Example 119 Step 2 (40 mg, 0.16 mmol), 1- (2-bromo-4methylsulfonylphenoxy) -2,4-difluorobenzene (58 mg, 0.16 mmol), Pd (dppf) Cl ₂ (12 mg, 10%) in 1,4-dioxane (880 μl) and saturated bicarbonate solution (aq) (220 μl) were reacted, worked up and purified in a manner similar to Example 117. The title compound (26 mg, 46%) was obtained as a tan solid.

1H NMR (400 MHz, DMSO-d6) δ 3.25 (s, 3H), 3.60 (s, 3H), 6.91-6.99 (m, 1H), 7.16-7.30 (m, 1H), 7.497.62 (m, 2H ), 7.76-7.86 (m, 2H), 8.00 (m, 2H). LCMS (M + H) + = 410.

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Example 121: 5- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one

The title compound of the example

119, stage 2 (40 mg, 0.16 mmol), 1- (2-bromo-4 ethylsulfonylphenoxy) -2,4-difluorobenzene (60 mg, 0.16 mmol), Pd (dppf) Cl ₂ (12 mg, 10%) in 1,4-dioxane (880 μl) and saturated bicarbonate solution (aq) (220 μl) were reacted, treated and purified in a manner similar to Example 117. The title compound (18 mg, 27%) was obtained as a tan -brown solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 1.13 (t, J = 7.33 Hz, 3H), 3.34 (q, J = 7.33 Hz, 2H), 3.59 (s, 3H), 6.92-6.98 (m, 1H), 7.19-7.27 (m, 1H), 7.50-7.61 (m, 2H), 7.76-7.84 (m, 2H), 7.92-7.96 (m, 1H), 7.97-8.01 (m, 1H). LCMS (M + H) + = 424.

Example 122 N- [4- (2,4-Difluorophenoxy) -3- (5-fluoro-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide.

Stage 1: N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 3-bromo4- (2,4-difluorophenoxy) aniline (328 mg, 1.1 mmol) and pyridine (178 μL, 2.2 mmol) in dichloromethane (2 ml) at 0 ° C in a nitrogen atmosphere. After the mixture was left to warm to room temperature and stirred overnight, it was treated with 1N. HCl (10 ml) and extracted with dichloromethane (3x10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (430 mg, 99%) as a tan solid which was carried further without purification. LCMS (M-H) ^- = 391.

Stage 2: A [4- (2,4-difluorophenoxy) -3- (5-fluoro-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide

A 'o

N- [3-Bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide (77 mg, 0.2 mmol), the title compound of Example 119, step 2 (50 mg, 0.2 mmol), Pd (dppf) Cl2 ( 14 mg, 10%) in 1,4-dioxane (1 ml) and saturated bicarbonate solution (aq) (333 μl) were reacted, treated and purified in a similar manner to Example 117. The title compound (31 mg, 27%) was obtained as a tan solid.

¹ H NMR (400 MHz, DMSO-d6) δ 1.22 (t, J = 7.3, 3H), 3.11 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 6.86 (d, J = 8.6 Hz , 1H), 7.02-7.12 (m, 1H), 7.13-7.23 (m, 2H), 7.26 (d, J = 2.8 Hz, 1H), 7.35-7.52 (m, 1H), 7.60 (m, 1H), 7.79 (s, 1H), 9.48-9.96 (m, 1H). LCMS (M + H) ⁺ = 439.

Example 123: N- [3- (2-methyl-1-oxo-2,6-naphthyridin-4-yl) phenyl] ethanesulfonamide.

Stage 1: 4-chloro-2-methyl-2,6-naphthyridin-1-one

N-chlorosuccinimide (0.8 g, 6.2 mmol) was added in portions to a solution of 2-methyl-2,6-naphthyridine-1one (1.0 g, 6.2 mmol) in acetonitrile (25 ml), which was then heated at 65 ° С for 18 h Extraction with ethyl acetate and purification by silica gel chromatography (PE: EA = 5: 1-1: 1) afforded the title compound from Step 1 (0.6 g, 56%) as a yellow solid.

¹ H NMR (CDCl3, 400 MHz) δ 9.29 (s, 1H), 8.81 (d, J = 3.6 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H), 7.31 (s, 1H), 3.63 ( s, 3H). LCMS: 195.0 (M + H) +.

- 226 038715

Stage 2: N- [3- (2-methyl-1-oxo-2,6-naphthyridin-4-yl) phenyl] ethanesulfonamide ^^^ NHSO ₂ Et ί J

O

A mixture of 4-chloro-2-methyl-2,6-naphthyridin-1-one (50.0 mg, 0.26 mmol), [3- (ethylsulfonylamino) phenyl] boronic acid (88.0 mg, 0.38 mmol), Pd (dppf) Cl ₂ (15.3 mg, 0.026 mmol) and K ₃ PO ₄ (190 mg, 0.9 mmol) in dioxane (3 ml) and water (0.5 ml) were exposed to microwaves at 120 ° С for 2 h. Purification by chromatography on silica gel ( PE: EA = 10: 1 to 1: 1) followed by preparative HPLC gave the title compound (5.9 mg, 6.8%) as a yellow solid.

1H NMR (methanol-d4, 400 MHz) δ 8.99 (brs, 1H), 8.71 (d, J = 6.0 Hz, 1H), 8.39 (d, J = 5.6 Hz, 1H), 7.62 (s, 1H), 7.51 (t, J = 8.0 Hz, 1H), 7.41-7.40 (m, 1H), 7.36 (dd, Ji = 8.0 Hz, ^ = 1.2 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 3.72 (s, 3H), 3.17 (q, J = 7.6 Hz, 2H), 1.35 (t, J = 7.6 Hz, 3H). LCMS: 344.1 (M + H) +.

Examples 124-126 in table. 15 was prepared from the title compound of Example 123, Step 1, using the appropriate phenylboronic acid / ester, in a similar manner to Example 123, Step 2. Example 127 in the table. 15 was prepared in two steps from the title compound of Example 123, Step 1, and the title compound of Example 57, Step 1, by coupling an aniline boronic acid ester in a manner similar to Example 123, Step 1, except that the temperature increased from 120 to 150 ° C and NMP was used instead of dioxane (step 1), followed by sulfonylation of aniline in a manner similar to that described in example 57, step 3 (step 2).

Table 15

R ¹

O

Example No. R ¹ Name '11 NMR (ppm (δ), 400 MHz) MS (M + H) 124 oh oh N-ethyl-3 - (2-methyl-1 oxo-2,6-naphthyr idin4yl) benzenesulfonamid (Methanol-04) 8.86 (d, J = 0.8 Hz, 1 H), 8.70 (d, J = 5.6 Hz, 1 H), 8.28 (dd, Ji = 5.6 Hz, 4 ₂ = 0.8 Hz, 1 H), 7.98 -7.95 (m, 2 H), 7.787.75 (m, 2 H), 7.60 (s, 1 H), 3.71 (s, 3H), 2.98 (q, J = 7.2 Hz, 2 H), 1.10 (t , J = 7.2 Hz, 3 H) 344 125 jQ V Η Ν- [3- (2-methyl-1-oxo2,6-naphthyridine-4yl) phenyl] methanesu l fonamide (CD ₃ OD) 8.98 (s, 1 H), 8.70 (d, J = 5.2 Hz, 1H), 8.34 (d, J = 5.2 Hz, 1H), 7.60 (s, 1 H), 7.52 (t, J = 8.0 Hz, 1 N), 7.40 (s, 1 N), 7.36 (d, J = 8.0 Hz, 1 N), 7.31 (d, 3 = 8.0 Hz, 1N), 3.71 (s, ZN), 3.04 ( s, ЗН) 330

- 227 038715

126 οχ Oh oh 4- (3- ethylsulfonylphenyl) -2-methyl-2,6 naphthyridin-1-one (CD ₃ OD) 9.02 (s, 1 N), 8.78 (d, 1 = 5.2 Hz, 1 N), 8.57 (d, J = 5.2 Hz, 1 N), 8.09 (s, 1 N), 8.06 (d , J = 7.6 Hz, 1 N), 7.93 (d, J = 7.6 Hz, 1 N), 7.85 (t, J = 7.6 Hz, 1 N), 7.80 (s, 1 N), 3.74 (s, ZN) , 3.33 (q, J = 7.6 Hz, 2 H), 1.29 (t, J = 7.6 Hz, 3 H) 329 127 f XX oA o 1 N- [4- (2,4- d ifluorophenoxy) -3 - (2methyl-1-oxo-2,6- naphthyridine-4yl) phenyl] ethanesulfo namid (CD3OD) 9.02 (s, 1 N), 8.78 (d, 1 = 5.2Hz, 1 N), 8.57 (d, J = 5.2 Hz, 1 N), 8.09 (s, 1 N), 8.06 (d, J = 7.6 Hz, 1 N), 7.93 (d, J = 7.6 Hz, 1H), 7.85 (t, J = 7.6 Hz, 1 N), 7.80 (s, 1 N), 3.74 (s, 3N), 3.33 ( q, J = 7.6 Hz, 2 N), 1.29 (t, J = 7.6 Hz, 3 N) 472

Example 128 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6- (4-methylpyrazol-1yl) isoquinolin-1-one.

Stage 1: 2-methyl-6- (4-methylpyrazol-1-yl) isoquinolin-1-one

6-Bromo-2-methylisoquinolin-1-one (300.0 mg, 1.27 mmol), 4-methyl-1H-pyrazole (210.0 mg, 2.54 mmol), CuI (30.0 mg, 0.127 mmol) and K ₂ CO ₃ (360.0 mg , 2.54 mmol) in NMP (3.0 ml) was exposed to microwaves at 195 ° C for 5 h. Extraction with ethyl acetate followed by chromatography on silica gel (PE: EA = 5: 1) gave the title compound from Step 1 (160.0 mg, 52%) as a light yellow solid.

1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 8.8 Hz, 1H), 7.84 (s, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.74 (dd, J1 = 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.59 (s, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.52 (d, J = 7.6 Hz, 1H), 3.62 (s, 3H), 2.19 (s, 3H). LCMS: 240.0 (M + H) +.

Stage 2: 4-bromo-2-methyl-6- (4-methylpyrazol-1-yl) isoquinolin-1-one

Bromine (94 mg, 0.59 mmol) in acetic acid (2 ml) was added dropwise to a solution of 2-methyl-6- (4methylpyrazol-1-yl) isoquinolin-1-one (140.0 mg, 0.583 mmol) in acetic acid (4 ml) at 0 ° C. The mixture was then stirred at room temperature for 17 minutes and rapidly cooled with water (10 ml). The pH was adjusted to about 7-8 with aqueous 1 M NaOH. Extraction with ethyl acetate followed by purification using silica gel chromatography (PE: EA = 1: 1) afforded the title compound from Step 2 (120.0 mg, 56%) as a light yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, J = 8.8 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.89 (s, 1H), 7.87 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.63 (s, 1H), 7.42 (s, 1H), 3.62 (s, 3H), 2.20 (s, 3H). LCMS: 319.8 (M + H) ⁺ .

Stage 3: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6- (4-methylpyrazol-1 yl) isoquinolin-1-one

4-Bromo-2-methyl-6- (4-methylpyrazol-1-yl) isoquinolin-1-one (40.0 mg, 0.126 mmol), title compound of Example 90 Step 1 (53.2 mg, 0.152 mmol), Pd (dppf) Cl ₂ (200.0 mg, 0.05 mmol), and aqueous 1 M K ₃ PO ₄ (0.38 ml, 0.38 mmol) in dioxane (3 ml) were heated in microwaves at 100 ° С for 1 h.

Purification by preparative HPLC afforded the title compound (15.0 mg, 25%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.57 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.73 (s, 1H), 7.54 (s, 1H), 7.50 (s, 1H), 7.14 (s, 1H), 7.12 (s, J = 9.2 Hz, 1H), 3.96-3.83 (m, 2H ), 3.68 (s, 3H), 3.13 (s, 3H), 2.15 (s, 3H), 1.01-0.94 (m, 1H), 0.38-0.28 (m, 2H), 0.08-0.02 (m, 2H). LCMS: 464.1 (M + H) +.

Example 129 N- [4- (2,4-difluorophenoxy) -3- (7-methyl-8-oxoimidazo [1,5-a] pyrazin-5-yl) phenyl] etαnsulfonamide.

Step 1: 5-bromo-7-methylimidazo [1,5-a] pyrazin-8-one

Bg

O

A NaH suspension (235.0 mg, 5.9 mmol ) in THF (2 ml) at 0 ° C under N ₂ . After stirring at 0 ° C for 30 min, the mixture was stirred at 30 ° C for an additional 1.5 h. The reaction mixture was rapidly cooled with H ₂ O (20 ml) at 0 ° C, and was extracted with EtOAc (30 ml x 2). The organic phases were combined, washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by column chromatography (PE: EA = 1/1) to give the title compound (300.0 mg, 50%) as a light yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.06 (d, J = 4.4 Hz, 1H), 6.61 (s, 1H), 3.48 (s, 3H). LCMS (M + H) ⁺ 228.

Step 2: 5- [5-amino-2- (2,4-difluorophenoxy) phenyl] -7-methylimidazo [1,5-a] pyrazin-8-one

A solution of 5-bromo-7-methylimidazo [1,5-a] pyrazin-8-one (114.0 mg, 0.5 mmol), the title compound of Example 57, step 1 (208.0 mg, 0.6 mmol), Pd (dppf) ₂ Cl ₂ (37.0 mg, 0.05 mmol), NaHCO ₃ (126.0 mg, 1.5 mmol) in dioxane (10 ml) and Н ₂ О (1 ml) were stirred under the action of microwaves at 110 ° С in an N2 atmosphere for 3 h. Solvent evaporated to give the crude material which was purified by column chromatography (PE: EA = 3/1) to give the title compound (110 mg, 60%) as a yellow solid.

1H NMR (CDCl3 400 MHz) δ 7.94 (s, 1H), 7.82 (s, 1H), 6.93-6.82 (m, 2H), 6.79-6.74 (m, 4H), 6.41 (s, 1H), 3.50 (s , 3H). LCMS (M + H) ⁺ 369.

Stage 3: N- [4- (2,4-difluorophenoxy) -3- (7-methyl-8-oxoimidαzo [1,5-a] pyrazine-5yl) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 99, Step 2, substituting the title compound from Step 2 for the title compound of Example 99, Step 1.

1H NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.50 (d, J = 2.4 Hz, 1H), 7.30 (dd, J1 = 8.8 Hz, J2 = 2.4, 1H) , 7.20-7.16 (m, 1H), 6.99-6.87 (m, 2H), 6.83 (s, 1H), 6.55 (d, J = 8.8 Hz, 1H), 3.59 (s, 3H), 3.13 (q, J = 7.2 Hz, 2H), 1.39 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ 461.

Example 130 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -7-methylimidazo [1,5-a] pyrazin8-one

The title compound was prepared in a similar manner to Example 129.

- 229 038715 step 2, substituting 4- (2,4-difluorophenoxy) -3- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline to give the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.08 (dd, J1 = 8.8 Hz, J ₂ = 2.4, 1H), 8.03 (s, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.58 (s , 1H), 7.16 (d, J = 8.8 Hz, 1H), 6.50 (s, 1H), 3.97 (d, J = 7.2 Hz, 2H), 3.54 (s, 3H), 3.11 (s, 3H), 1.15 -1.02 (m, 1H), 0.59-0.49 (m, 2H), 0.26-0.17 (m, 2H). LCMS (M + H) ⁺ 374.

Example 131 7-methyl-5- (3-methylsulfonylphenyl) imidazo [1,5-a] pyrazin-8-one

A solution of the compound from Example 129, step 1 (80 mg, 0.35 mmol), (3methylsulfonylphenyl) boronic acid (77 mg, 0.6 mmol), Na ₂ CO ₃ (106 mg, 1 mmol), Pd (PPh ₃ ) ₂ Cl ₂ ( 30.0 mg) in dioxane (3 ml) and water (0.5 ml) was stirred at 120 ° С for 18 h under N ₂ . After cooling to room temperature, the mixture was filtered, concentrated and purified by preparative HPLC to give the title compound (20.0 mg, 20%).

1H NMR (methanol-d ₄ , 400 MHz): δ 8.70-8.65 (m, 1H), 8.30-8.20 (m, 2H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.88 (t, J = 8.0 Hz, 1H), 7.22 (s, 1H), 3.56 (s, 3H), 3.24 (s, 3H). LCMS (M + H) ⁺ 304.

Example 132 N- [2-methoxy-5- (7-methyl-8-oxoimidazo [1,5-a] pyrazin-5-yl) phenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 131 substituting (3-methylsulfonylphenyl) boronic acid for [3- (methanesulfonamido) -4-methoxyphenyl] boronic acid to give the title compound.

1H NMR (methanol-d ₄ , 400 MHz): δ 8.81 (s, 1H), 8.29 (s, 1H), 7.70 (s, 1H), 7.50 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H), 4.01 (s, 3H), 3.56 (s, 3H), 3.08 (s, 3H). LCMS (M + H) ⁺ 349.

Example 133 5- (3-Ethylsulfonylphenyl) -7-methylimidazo [1,5-a] pyrazin-8-one

The title compound was prepared in a similar manner to Example 131 substituting (3-methylsulfonylphenyl) boronic acid for (3-ethylsulfonylphenyl) boronic acid to give the title compound.

1H NMR (methanol-d ₄ , 400 MHz): δ 8.83 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.89 (t, J = 8.0 Hz, 1H), 7.24 (s, 1H), 3.56 (s, 3H), 3.31 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H). LCMS (M + H) ⁺ 318.

Example 134: N- [3- (5-chloro-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 122, substituting for 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3-fluoro-1 methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one. LCMS (M + H) + 455.

- 230 038715

Example 135: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 89 substituting 2-bromo-1- (cyclopropylmethoxy) -4methylsulfonylbenzene for 2-bromo-1- (cyclopropylmethoxy) -4-ethylsulfonylbenzene. LCMS (M + H) + 398.

Example 136 6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,4-dimethylpyridazin-3-one

The title compound was prepared in a similar manner to Example 90, substituting 4-bromo-6-fluoro-2-methylisoquinolin-1-one for 6-chloro-2,4-dimethylpyridazin-3-one. LCMS (M + H) ⁺ 349.

Example 137: 6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,5-dimethylpyridazin-3-one

The title compound was prepared in a similar manner to Example 90, substituting 4-bromo-6-fluoro-2-methylisoquinolin-1-one for 6-chloro-2,5-dimethylpyridazin-3-one. LCMS (M + H) ⁺ 349.

Example

138:

N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (trifluoromethyl) pyridin-3yl] phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 122 replacing 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (trifluoromethyl) pyridine -2-one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one. LCMS (M + H) ⁺ 489.

Example

139:

X- [4- (2,4-difluorophenoxy) -3- (4-fluoro-1-methyl-6-oxopyridin-3yl) phenyl] ethanesulfonamide

Stage 1: 2-chloro-5- [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoropyridine

A mixture of 2-chloro-4-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (170 mg, 0.66 mmol), 2-bromo-1- ( 2,4-difluorophenoxy) -4-nitrobenzene (326 mg, 0.98 mmol), Pd ₂ (dba) ₃ (30 mg, 5%) and tricyclohexylphosphine (280 mg, 10%) were suspended in 1,4-dioxane (4 ml ) and aqueous 1 M K ₃ PO ₄ (2 ml). The mixture was heated to 70 ° C using microwave (standard) for 45 min. The crude reaction mixture was filtered through a short plug of celite and the plug of celite was washed with EtOAc (~ 50 ml). The filtrate was washed with water (2x30 ml), brine, dried over sodium sulfate,

- 231 038715 filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (12 g ISCO, gradient 05-75% EtOAc in hexanes) to give the free base of the title compound, 2-chloro-5- [2- (2,4-difluorophenoxy) -5 -nitrophenyl] -4fluoropyridine, as a yellow solid (144 mg, 57%). LCMS (M + H) + = 381.

Step 2: 5- [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoro-1-methylpyridin-2-one

A mixture of 2-chloro-5- [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoropyridine (140 mg, 0.37 mmol), KOH (62 mg, 1.11 mmol), Pd ₂ (dba) ₃ ( 17 mg, 5%) and XPhos (18 mg, 10%) were suspended in 1,4-dioxane (1.9 ml) and water (316 μl). After purging the reaction vial with nitrogen for 5 min, the mixture in a closed vial was stirred at 100 ° C for 1 h. After the mixture was cooled to room temperature, it was treated with 1N HCl. HCl (aq) (1 ml) and EtOAc (5 ml). The biphasic mixture was filtered through a short celite plug and the celite plug was rinsed with EtOAc (~ 50 ml). The filtrate was washed with water (2x30 ml), brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an orange solid, 5- [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoropyridine-2- ol (LCMS (M + H) + = 363). After diluting the solid with DMF (2.4 ml), it was treated with K ₂ CO ₃ (112 mg) and MeI (23 μl). After stirring at room temperature for 5 h, the mixture was treated with water (10 ml) and extracted with EtOAc (3x10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 05-95% EtOAc in hexanes) to give the title compound, 5 [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoro -1-methylpyridin-2-one, as tan solid (95 mg). LCMS (M + H) + = 377.

Step 3: 5- [5-amino-2- (2,4-difluorophenoxy) phenyl] -4-fluoro-1-methylpyridin-2-one

A mixture of 5- [2- (2,4-difluorophenoxy) -5-nitrophenyl] -4-fluoro-1-methylpyridin-2-one (90 mg, 0.24 mmol), ammonium chloride (26 mg, 0.48 mmol), iron powder (67 mg, 1.2 mmol) suspended in THF (500 μl), water (180 μl) and ethanol (500 μl), heated to 100 ° C using microwave radiation (standard) for 3 h. The crude reaction mixture was filtered through a short the celite plug and the celite plug were rinsed with heated (50 ° C) MeOH (~ 10 ml). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (20 ml) and washed with saturated bicarbonate solution (aq.), Dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound, 5- [5-amino-2- (2,4 difluorophenoxy) phenyl] -4-fluoro-1-methylpyridin-2-one (75 mg, 90%). LCMS (M + H) + = 347. This substance was transferred further without further purification.

Stage 4: sulfonamide

N- [4- (2,4-difmorphenoxy) -3- (4-fluor-1-methyl-6-oxoniridin-3-yl) phenyl] ethane-

Ethylsulfonyl chloride (177 mg, 1.4 mmol) was added dropwise to a stirred solution of 5- [5amino-2- (2,4-difluorophenoxy) phenyl] -4-fluoro-1-methylpyridin-2-one (72 mg, 0.21 mmol) and pyridine (50 μl, 0.63 mmol) in dichloromethane (500 μl) at 0 ° С under nitrogen atmosphere. The mixture was left to warm to room temperature and stirred for 2 h, after which it was treated with 1N. HCl (3 ml) and extracted with dichloromethane (3x10 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (4 g ISCO, gradient 0-10% MeOH in dichloromethane) to give the title compound, N- [4 (2,4-difluorophenoxy) -3- (4-fluoro-1 -methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide (66 mg, 72%), as a white solid.

¹ H NMR (400 MHz, DMSO-d6) δ 1.18-1.26 (m, 3H), 3.07-3.16 (m, 2H), 3.45 (s, 3H), 6.22-6.33 (m, 1H),

- 232 038715

6.82-6.93 (m, 1H), 7.01-7.16 (m, 2H), 7.18-7.28 (m, 2H), 7.38-7.49 (m, 1H), 7.95-8.05 (m, 1H), 9.77-9.87 (s ,

1H). LCMS (M + H) + = 439.

Example 140 N- [3- (5-cyclopropyl-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 122, substituting for 3-cyclopropyl-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one. LCMS (M + H) + 461.

Example 141: No. {4- (2,4-difluorophenoxy) -3- [1- ( ² H ₃ ) methyl-6-oxopyridin-3-yl] phenyl} ethanesulfonamide

The title compound was prepared in a manner analogous to that described in Example 122, substituting 1- ⁽² H ₃₎ methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine 2-one on 3-fluoro-1-methyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one. LCMS (M + H) + 424.

Example 142: No. [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-4yl) phenyl] ethanesulfonamide

The title compound of Example 127 (240 mg, 0.5 mmol) was hydrogenated (50 psi) at room temperature in anhydrous EtOH (30 ml) for 18 h using PtO ₂ (0.1 g). Purification by preparative HPLC provided the title compound (40 mg, 16.7%) as a white solid.

¹ H NMR (methanol-J4, 400 MHz) δ 7.36 (s., 1H), 7.23 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.14 (d, J = 2.8 Hz, 1H), 7.06 -6.96 (m, 2H), 6.91-6.86 (m, 2H), 3.83-3.49 (m, 2H), 3.53 (s, 3H), 3.16-2.89 (m, 2H), 3.08 (q, J = 7.2 Hz , 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 7.2 Hz, 3H). LCMS (M + H) + 476.

Example 143 4- [5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -2methylisoquinolin-1-one.

Step 1: 5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-ol one

To the title compound of Example 152, Step 1 (5.00 g, 31.6 mmol) in THF (50 mL) at 0 ° C was added NaH (1.26 g, 31.6 mmol, 60% in mineral oil). Ethyl formate (2.57 g, 34.76 mmol) was added at 0 ° С, and the mixture was heated at 70 ° С for 2 h. The mixture was then cooled to room temperature, and a premixed solution of 2 (methylsulfonyl) ethanimidamide (6.44 g, 47.4 mmol) and EtONa (4.3 g, 63.2 mmol) in ethanol (50 ml). The mixture was heated at 90 ° C for 12 h, cooled to room temperature, and the solvent was removed in vacuo. Water (50 ml) was added to the residue and the pH was adjusted to 5 with 1M HCl. The resulting precipitate was collected and washed with water (100 ml), ethanol (50 ml) and methanol (30 ml) to give the title compound (1.9 g, yield: 23.4%) as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 11.49 (s, 1H), 6.83 (s, 1H), 6.49 (s, 2H), 3.63 (d, J = 6.8 Hz, 2H), 3.04 (s, 3H ), 1.14-1.10 (m, 1H), 0.52-0.49 (m, 2H), 0.27-0.24 (m, 2H). LCMS: 259.0 (M + 1) ⁺ .

Stage 2: 4-chloro-5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidine w CI

To the title compound from Step 1 (1.9 g, 7.36 mmol) in MeCN (30 mL) was added

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Me4NCl (1.6 g, 14.72 mmol) and POC13 (6.8 g, 44.16 mmol). The mixture was heated at 80 ° C for 6 h. After concentration in vacuo, the residue was extracted with EA. Trituration with methanol (20 ml) afforded the title compound (1 g, yield: 49.3%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.60 (s, 1H), 5.50 (s, 2H), 3.85 (d, J = 6.8 Hz, 2H), 3.09 (s, 3H), 1.31-1.28 (m, 1H ), 0.70-0.65 (m, 2H), 0.39-0.36 (m, 2H). LCMS: 277.1 (M + 1) +.

Step 3: 4- [5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -2methylisoquinolin-1-one

The title compound from Step 2 (100 mg, 0.36 mmol), the title compound of Example 89, Step 1 (124 mg, 0.43 mmol), Pd (dppf) Cl ₂ (27 mg, 0.03 mmol) and K3PO4 (154 mg , 0.72 mmol) in dioxane (5 ml) and water (5 drops) were purged with N ₂ and heated to 70 ° С for 18 h. After concentration in vacuo, the residue was purified using chromatography on silica gel followed by preparative HPLC to obtain the the title compound (61.7 mg, 42.7%) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.29 (d, J = 7.2 Hz, 1H), 7.69-7.65 (m, 3H), 7.53 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 3.76 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 3.26 (s, 3H), 0.94-0.88 (m, 1H), 0.35-0.31 (m, 2H) , 0.100.08 (m, 2H). LCMS: 400.1 (M + 1) +.

Example 144: 5- [5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3dimethylpyridin-2-one w

Λ ¹ 'about

The title compound of Example 143, step 2, was reacted with 1,3dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in a similar manner to described in Example 143, Step 3, to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.60 (s, 1H), 3.86 (d, J = 6.8 Hz, 2H), 3.67 (s , 3H), 3.11 (s, 3H), 2.24 (s, 3H), 1.29-1.27 (m, 1H), 0.72-0.67 (m, 2H), 0.39-0.35 (m, 2H). LCMS: 364.1 (M + 1) +.

Example 145: 4- [5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -2-methyl-6- (1methylpyrazol-4-yl) isoquinolin-1-one

The title compound of Example 143, Step 2, was reacted with the title compound of Example 46, Step 2 in a similar manner to Example 143, Step 3 to provide the title compound.

1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J = 8.4 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.5 (d, J = 8.4 Hz, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 3.87 (s, 3H), 3.85-3.80 (m, 4H), 3.57 (s, 3H), 3.28 (s, 3H), 0.88-0.87 (m, 1H), 0.30-0.25 (m, 2H), 0.07-0.04 (m, 2H). LCMS: 480.2 (M + 1) +.

Example 146 5- [5- (2,4-Difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -3-methoxy-1methylpyridin-2-one.

Step 1: 5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-ol

Ethyl formate (1.8 g, 24.3 mmol) and 2- (2,4-difluorophenoxy) acetic acid ethyl ester (4.3 g , 19.9 mmol) in anhydrous THF (10 ml). The suspension was stirred at room temperature for 0.5 h and then heated under reflux for 3 h, cooled and concentrated in vacuo. The residue was dissolved in EtOH (50 ml) and 2- (methylsulfonyl) ethanimidamide (3.0 g, 22.1 mmol) was added and the mixture was heated under reflux for 18 h. After concentration in vacuo, water (50 ml) was added and the pH was adjusted to values 5 with acetic acid. After extracting with EA, the residue was dissolved in EA (20 ml) and PE (150 ml) was added. The resulting precipitate (3.0 g, crude) was collected as a gray solid to give the title compound. LCMS: 317.1 (M + 1) +.

Stage 2: 4-chloro-5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidine

CI

To the title compound from Step 1 (3.0 g) and N (CH ₃ ) ₄ C1 (1.6 g, 14.2 mmol) in anhydrous MeCN (30 mL) was added POCl ₃ (8.7 g, 56.9 mmol) dropwise. The mixture was stirred at room temperature for 0.5 h and then at 70 ° C for 6 h. After concentration in vacuo, add water and extract with EA to give the title compound (3.0 g) as a light yellow solid. LCMS: 335.1 (M + 1) ⁺ .

Step 3: 5- [5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -3-methoxy-1methylpyridin-2-one

O

The title compound of Example 287, step 1, was treated with 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in the same manner as in example 119, step 2, to obtain 3-methoxy-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin2-one, which was then reacted with with the title compound from Step 2 in a similar manner to Example 143 Step 3 to provide the title compound.

¹ H NMR (DMSO-d6, 400 MHz) δ 8.37 (s, 1H), 8.36 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.60-7.54 (m, 1H ), 7.51-7.45 (m, 1H), 7.22-7.18 (m, 1H), 4.78 (s, 2H), 3.77 (s, 3H), 3.56 (s, 3H), 3.20 (s, 3H). LCMS: 438.1 (M + 1) ⁺ .

Example 147: 5- [5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3 dimethylpyridin-2-one

The title compound of Example 146, step 2, was reacted with 1,3dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in a similar manner to described in Example 143, Step 3, to provide the title compound.

'and NMR (DMSO-d6, 400 MHz) δ 8.58 (d, J = 2.0 Hz, 1H), 8.35 (s, 1H), 8.13 (s, 1H), 7.60-7.54 (m, 1H), 7.52-7.46 (m, 1H), 7.22-7.17 (m, 1H), 4.76 (s, 2H), 3.56 (s, 3H), 3.18 (s, 3H), 2.08 (s, 3H). LCMS: 422.1 (M + 1) ⁺ .

Example 148: 4- [5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -2methylisoquinolin-1-one

The title compound of Example 146, Step 2, was reacted with the title compound of Example 89, Step 1 in a similar manner to Example 143, Step 3 to provide the title compound.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.62 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.91 (s, 1H), 7.69-7.68 (m, 2H), 7.58-7.54 (m, 1H), 7.45-7.34 (m, 2H), 7.07-7.03 (m, 1H), 4.83 (s, 2H), 3.58 (s, 3H), 3.17 (s, 3H). LCMS: 458.1 (M + 1) ⁺ .

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Example 149 5- [5- (2,4-Difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1,3-dimethylpyridin-2one.

Step 1: 5- (2,4-difluorophenoxy) -2-methylsulfanylpyrimidin-4-ol

To a solution of ethyl ester of 2- (2,4-difluorophenoxy) acetic acid (8.0 g, 37.01 mmol) and ethyl formate (4.11 g, 55.51 mmol) in dry THF (200 mL), NaH (1.55 g, 38.75 mmol) was slowly added at 0 ° C. The mixture was then heated under reflux for 2 h.Sodium ethoxide (3.02 g, 44.41 mmol) and S-methylthiopseudourea hemisulfate (6.17 g, 44.41 mmol) in EtOH (100 ml) were stirred at 20 ° С for 2 h. , and then the resulting mixture was added to the above THF solution. The combined mixture was heated under reflux for 12 h. After concentration in vacuo, water (20 ml) and HCl (10 ml, aq, 1N) were added. The suspended solids were collected, washed with water (50 ml x 3) and EtOH (50 ml x 3) and dried to give the title compound (6.0 g, 60.0% yield) as a light yellow solid.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.84 (s, 1H), 7.42-7.34 (m, 1H), 7.04-7.01 (m, 1H), 6.95 (t, J = 9.6 Hz, 1H), 2.47 (s, 3H). LCMS: 271.1 (M + 1) ⁺ .

Stage 2: 4-chloro-5- (2,4-difluorophenoxy) -2-methylsulfanylpyrimidine

The title compound from Step 1 (5.30 g, 19.63 mmol), POCl ₃ (18.06 g, 117.78 mmol), (Me) 4NCl (3.23 g, 29.47 mmol) in dry CH3CN (60 mL) was refluxed for 12 am The mixture was poured into ice water (50 ml) and was extracted with EA. Concentration in vacuo gave the crude title compound (4.0 g) which was carried over to the next step. LCMS: 288.99 (M + 1) +.

Stage 3: 4-chloro-5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidine

To a solution of the title compound from Step 2 (4.60 g, 15.93 mmol) in CH ₂ Cl ₂ (200 mL) was slowly added mCPBA (13.75 g, 79.68 mmol) at 0 ° C. The mixture was stirred at 20 ° C for 12 h and then saturated aqueous Na2SO3 (200 ml) was added. Extraction with EA and chromatography on silica gel afforded the title compound (2.0 g, 39.1% yield) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.18 (s, 1H), 7.31-7.27 (m, 1H), 7.10-7.01 (m, 2H), 3.36 (s, 3H). LCMS: 320.8 (M + 1) ⁺ .

Step 4: 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1,3-dimethylpyridin-2-one

A mixture of the title compound from Step 3 (100 mg, 0.31 mmol), 1,3-dimethyl-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (93 mg, 0.37 mmol), Pd (dppf) Cl ₂ (23 mg, 0.31 mmol) and K ₃ PO ₄ (199 mg, 0.94 mmol) in dioxane / water (3 ml / 0.5 ml) were purged with N ₂ and heated at 70 ° C for 12 h. Concentration in vacuo and silica gel chromatography (PE: EA = 3: 1 ~ 0: 1) followed by preparative HPLC gave the title compound (45 mg, 35.4%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.57 (s, 1H), 8.25 (s, 1H), 8.15 (s, 1H), 7.25-7.24 (m, 1H), 7.12-7.07 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 3.68 (s, 3H), 3.38 (s, 3H), 2.25 (s, 3H). LCMS: 407.9 (M + 1) ⁺ .

Example 150 Methylpyridin-2-one

5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3-methoxy-1-

The title compound of Example 149, step 3, was reacted with 3-methoxy

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1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (see Example 146, step 3) in a manner similar to that described in example 149 , step 4, to provide the title compound.

¹ H NMR (CDCl3, 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.08 (m, 1H), 7.08-7.04 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M + 1) +.

Example 151: 4- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -2-methylisoquinolin-1 one

The title compound of Example 149, Step 3, was reacted with the title compound of Example 89, Step 1 in a similar manner to Example 149, Step 4 to provide the title compound.

¹ H NMR (CDCl3, 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1H), 8.32 (s, 1H), 7.68 (s, 3H), 7.59-7.56 (m, 1H), 7.147.08 (m , 1H), 7.05-7.00 (m, 1H), 6.96-6.92 (m, 1H), 3.72 (s, 3H), 3.39 (s, 3H). LCMS: 443.9 (M + 1) +.

Example 152 N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] methanesulfonamide.

Stage 1: ethyl 2- (cyclopropylmethoxy) acetate

Diazoacetic acid ethyl ester (80.00 g, 0.70 mol) was added dropwise to cyclopropanemethanol (60.66 g, 0.84 mol) and [Rh (Ac ₂ O) ₂ ] ₂ (3.1 g, 7.02 mmol) in anhydrous CH ₂ Cl ₂ (800 ml ) at 0 ° C. The mixture was stirred at 0 ° C for 30 min and at room temperature for 4 h. Extraction with CH ₂ Cl ₂ and silica gel chromatography (PE: EA = 100: 1 ~ 50: 1) gave the title compound (100 g, yield 90.4%) as a colorless oil.

¹ H NMR (CDCl ₃ , 400 MHz) δ 4.23-4.19 (m, 2H), 4.09 (s, 2H), 3.38-3.36 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H), 1.10- 1.07 (m, 1H), 0.57-0.52 (m, 2H), 0.24-0.20 (m, 2H).

Stage 2: 5- (cyclopropylmethoxy) -2-methylsulfanylpyrimidin-4-ol

OH

To a stirred suspension of NaH (35.20 g, 0.88 mol, 60% in mineral oil) in anhydrous THF (1000 ml) were added ethyl formate (88.80 g, 0.90 mol) and the title compound from Step 1 (126.0 g, 0.80 mol) in anhydrous THF (100 ml). The mixture was stirred at room temperature for 0.5 h and heated under reflux for 3 h. temperature for 1 hour, after which this mixture was added to the previously obtained mixture. This combined mixture was heated under reflux for 15 hours, cooled, and the pH was adjusted to 5 with acetic acid. Concentration in vacuo, silica gel chromatography (DCM: MeOH = 50/1 ~ 10/1) gave the title compound (30.00 g, 17.7% yield) as a yellow solid.

¹ H NMR (CDCl3, 400 MHz) δ 12.08 (s, 1H), 7.49 (s, 1H), 3.83-3.80 (m, 2H), 2.55 (s, 3H), 1.37-1.28 (m, 1H), 0.65 -0.62 (m, 2H), 0.37-0.34 (m, 2H).

Stage 3: 4-chloro-5- (cyclopropylmethoxy) -2-methylsulfanylpyrimidine

To the title compound from Step 2 (29.00 g, 136.79 mmol) and N (CH ₃ ) ₄ Cl (22.47 g, 205.19 mmol) in anhydrous MeCN (300 mL) was added POCl ₃ (123.93 g, 820.74 mmol). The mixture was stirred at room temperature for 30 min and at 70 ° C for 1 h. After concentration in vacuo, extraction with EA and chromatography on silica gel (PE: EA = 50: 1 ~ 5: 1) gave the title compound (20 g , 63.6% yield) as a white solid.

¹ H NMR (CDCl3, 400 MHz) δ 8.16 (s, 1H), 3.95 (d, J = 6.8Hz, 2H), 2.56 (s, 3H), 1.33-1.28 (m, 1H), 0.720.70 (m , 2H), 0.41-0.37 (m, 2H). LCMS: 230.9 (M + 1) +.

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Step 4: 4-chloro-5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidine

To the title compound from Step 3 (19.0 g, 82.60 mmol) in dry CH ₂ Cl ₂ (200 mL) at 0 ° C was added m-CPBA (42.62 g, 247.80 mmol) over 15 min. The mixture was stirred at 0 ° C for 30 min and at room temperature overnight. Added saturated aqueous Na ₂ SO ₃ (100 ml) and was extracted with CH ₂ Cl ₂ . Trituration with MTBE (300 ml) afforded the title compound (17 g, 78.3% yield) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.37 (s, 1H), 4.13 (d, J = 6.8 Hz, 2H), 3.33 (s, 3H), 1.39-1.35 (m, 1H), 0.790.74 (m , 2H), 0.49-0.45 (m, 2H). LCMS: 263.0 (M + 1) +.

Step 5: 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -2-methylisoquinolin-1-one

The title compound from Step 4 (5.00 g, 19.08 mmol), the title compound of Example 89, Step 1 (5.98 g, 20.99 mmol), K ₃ PO ₄ (12.13 g, 57.24 mmol) and Pd (dppf) Cl ₂ (1.40 g, 1.91 mmol) in dioxane / H ₂ O (50 ml / 5 ml) was purged with N2 and heated at 80 ° С for 8 h. Chromatography on silica gel (PE: EA = 10/1 ~ 1/1) gave the title compound (5.01 g, yield: 68%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.53 (s, 2H), 7.67-7.63 (m, 2H), 7.57-7.52 (m, 2H), 4.06 (d, J = 6.8 Hz, 2H), 3.71 (s , 3H), 3.37 (s, 3H), 1.17 (m, 1H), 0.61 (m, 2H), 0.30 (m, 2H). LCMS: 386.1 (M + 1) +.

Stage

6:

No. [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2 yl] methanesulfonamide

Sodium hydride (0.93 g, 23.37 mmol, 60% in mineral oil) was added to MeSO ₂ NH ₂ (2.22 g, 23.37 mmol) in dry DMF (30 ml) at 0 ° C for 15 min. The mixture was stirred at 0 ° C for 1 h and the title compound from step 5 (3.00 g, 7.79 mmol) was added. The mixture was heated at 60 ° C. for 6 hours. After cooling, ice water was added and the pH was adjusted to 5 with acetic acid. The suspended solids were collected and washed with MTBE (50 ml) to give the title compound (3 g, yield: 96.7%) as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 9.80 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.42 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.70 (m , 2H), 7.56 (t, J = 7.6 Hz, 1H), 3.87 (d, J = 7.2 Hz, 2H), 3.70 (s, 3H), 3.39 (s, 3H), 1.12 (m, 1H), 0.58 (m, 2H), 0.24 (m, 2H). LCMS: 401.1 (M + 1) +.

Example 153: N- [5- (cyclonronylmethoxy) -4- (1,5-dimethyl-6-oxonyridin-3-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 152, step 4, was reacted with 1,3dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in a similar manner to described in Example 152, Step 5, and the resulting product was treated with MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to give the title compound.

1H NMR (DMSO-d ₆ , 400 MHz) δ 10.97 (s, 1H), 8.67 (s, 1H), 8.42 (s, 1H), 8.14 (s, 1H), 4.03 (d, J = 6.4 Hz, 2H ), 3.54 (s, 3H), 3.35 (s, 3H), 2.08 (s, 3H), 1.33-1.31 (m, 1H), 0.63-0.61 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 365.0 (M + 1) +.

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Example 154: N- [5- (cyclopropylmethoxy) -4- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinolin-4yl] pyrimidin-2-yl] methanesulfonamide

The title compound of Example 152, Step 4, was reacted with the title compound of Example 46, Step 2, in a similar manner to Example 152, Step 5, and the resulting product was treated with MeSO ₂ NH ₂ in a similar manner to Example. 152, step 6, to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 11.15 (s, 1H), 8.56 (s, 1H), 8.27 (s, 1H), 8.25 (d, J = 7.6 Hz, 1H), 7.98 (s, 1H), 7.79 (s, 1H), 7.77 (d, J = 9.6 Hz, 1H), 7.70 (s, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.85 (s, 3H), 3.57 (s, 3H) , 3.32 (s, 3H), 1.00-0.99 (m, 1H), 0.37-0.32 (m, 2H), 0.14-0.12 (m, 2H). LCMS: 481.0 (M + 1) +.

Example 155: N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 152, Step 5, was treated with EtSO ₂ NH _{2 in} place of MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz) δ 9.00 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.38 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.69 ( m, 2H), 7.57 (t, J = 7.6 Hz, 1H), 3.86 (d, J = 6.8 Hz, 2H), 3.70 (s, 3H), 3.63 (q, J = 7.2 Hz, 2H), 1.43 ( t, J = 7.2 Hz, 3H), 1.13 (m, 1H), 0.57 (m, 2H), 0.25 (m, 2H). LCMS: 415.0 (M + 1) +.

Example 156 4- [5- (cyclopropylmethoxy) -2- (1,1-dioxo-1,2-thiazolidin-2-yl) pyrimidin-4-yl] -2methylisoquinolin-1-one

The title compound of Example 152, Step 5, was treated with 1,1-dioxidoisothiazolidine in place of MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to afford the title compound.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.56 (s, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 3.93-3.91 (m, 4H), 3.59 (s, 3H), 2.38-2.31 (m, 2H), 1.06 -1.01 (m, 1H), 0.44-0.39 (m, 2H), 0.20-0.16 (m, 2H). LCMS: 427.1 (M + H) +.

Example 157: N- [5- (cyclopropylmethoxy) -4- (6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 47, step 2, was treated with 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in a similar manner to that described in example 89, step 1, and the resulting 6-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one was coupled with the specified in title compound of Example 152, Step 4, in a manner similar to Example 152, Step 5, and the resulting 4- [5 (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -6-fluoro-2-methylisoquinoline-1- it was treated with EtSO ₂ NH _{2 in} place of MeSO ₂ NH ₂ in a similar manner to Example 152, step 6 to give the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.04 (brs, 1H), 8.54 (s, 1H), 8.36 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 8.01 (s, 1H) , 7.65 (dd, J1 = 11.2 Hz, J2 = 2.4 Hz, 1H), 7.45-7.38 (m, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 3.48 (q,

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J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H), 1.16-1.04 (m, 1H), 0.50-0.42 (m, 2H), 0.27-0.20 (m, 2H). LCMS: 433.0 (M + 1) +.

Example 158 N- [5- (cyclopropylmethoxy) -4- (7-fluoro-2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 58, step 2, was treated with 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in a similar manner to that described in example 89, step 1, and the resulting 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one was coupled with the specified in title compound of Example 152, Step 4, in a manner similar to Example 152, Step 5, and the resulting 4- [5 (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -7-fluoro-2-methylisoquinoline-1- this was treated with MeSO ₂ NH ₂ in a similar manner to Example 152 step 6 to give the title compound.

1H NMR (DMSO-d ₆ , 400 MHz) δ 11.15 (s, 1H), 8.55 (s, 1H), 8.36 (dd, J1 = 9.2 Hz, J2 = 6.0 Hz, 1H), 8.00 (s, 1H), 7.60 (dd, J1 = 11.2 Hz, J2 = 2.4 Hz, 1H), 7.44-7.37 (m, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.58 (s, 3H), 3.32 (s, 3H ), 1.15-1.03 (m, 1H), 0.49-0.42 (m, 2H), 0.26-0.20 (m, 2H). LCMS: 419.0 (M + 1) ⁺ .

Example 159 N- [5- (cyclopropylmethoxy) -4- (6-fluoro-2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 47, step 2, was treated with 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in a similar manner to that described in example 89, step 1, and the resulting 6-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one was coupled with the specified in title compound of Example 152, Step 4, in a manner similar to Example 152, Step 5, and the resulting 4- [5 (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -6-fluoro-2-methylisoquinoline-1- this was treated with MeSO2NH2 in a similar manner to Example 152 step 6 to give the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.14 (brs, 1H), 8.56 (s, 1H), 7.96 (dd, ^ = 9.2 Hz, J2 = 3.2 Hz, 1H), 7.88 (s, 1H) , 7.85 (dd, Ji = 9.2 Hz, J2 = 3.6 Hz, 1H), 7.62-7.55 (m, 1H), 3.94 (d, J = 6.8 Hz, 2H), 3.60 (s, 3H), 3.32 (s, 3H), 1.11-0.99 (m, 1H), 0.47-0.40 (m, 2H), 0.23-0.16 (m, 2H). LCMS: 419.0 (M + 1) ⁺ .

Example 160 N- [5- (cyclopropylmethoxy) -4- (7-fluoro-2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 58, step 2, was treated with 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in a similar manner to that described in example 89, step 1, and the resulting 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one was coupled with the specified in title compound of Example 152, Step 4, in a manner similar to Example 152, Step 5, and the resulting 4- [5 (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -7-fluoro-2-methylisoquinoline-1- it was treated with EtSO ₂ NH _{2 in} place of MeSO ₂ NH ₂ in a similar manner to Example 152, step 6 to give the title compound.

1H NMR (CDCl ₃ 400 MHz) δ 8.53 (dd, J1 = 8.8 Hz, J ₂ = 6.0 Hz, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J = 8.8 Hz, 1H), 7.27-7.23 (m, 1H), 3.88 (d, J = 6.8 Hz, 2H), 3.69 (s, 3H), 3.60 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.16-1.13 (m, 1H), 0.62-0.56 (m, 2H), 0.27-0.26 (m, 2H). LCMS: 433.2 (M + 1) ⁺ .

- 240 038715

Example 161 N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2-yl] -Nethylmethanesulfonamide

Ethyl iodide (95 mg, 0.6 mmol) and K ₂ CO ₃ (55 mg, 0.4 mmol) were added to a solution of the title compound of Example 152 (80 mg, 0.2 mmol) in MeCN (5 ml). After boiling under reflux for 1 h, the mixture was cooled, concentrated in vacuo and extracted with CH ₂ Cl ₂ . Purification by HPLC gave the title compound (13.42 mg, yield: 15.2%) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.63 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 4.02 (q, J = 6.8 Hz, 2H), 3.97 (d, J = 7.2 Hz, 1H), 3.60 ( s, 3H), 3.43 (s, 3H), 1.25 (t, J = 6.8 Hz, 1H), 1.10-1.07 (m, 1H), 0.46-0.42 (m, 2H), 0.24-0.20 (m, 2H) ... LCMS: 429.1 (M + H) +.

Example 162: N- [5- (cyclopropylmethoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] -Nethylmethanesulfonamide o

The title compound of Example 153 was treated with ethyl iodide in a similar manner to Example 161 to provide the title compound.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.36-0.42 (m, 2H), 0.60-0.66 (m, 2H), 1.25 (t, J = 6.82 Hz, 3H), 1.291.40 (m, 1H) , 2.09 (s, 3H), 3.48 (s, 3H), 3.56 (s, 3H), 3.88-4.20 (m, 4H), 8.13 (s, 1H), 8.49 (s, 1H), 8.69 (s, 1H ). LCMS: 393 (M + H) ⁺ .

Example 163 N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4yl) pyrimidin-2-yl] methanesulfonamide.

Stage 1: 2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

F about

The title compound was prepared by N-methylation of 5,6,7,8tetrahydroisoquinolin-1 (2H) -one in a manner similar to Example 47, step 1.

¹ H NMR (CDClj, 400 MHz): δ 7.02 (d, J = 7.2 Hz, 1H), 5.90 (d, J = 7.2 Hz, 1H), 3.49 (s, 3H), 2.54-2.45 (m, 4H) , 1.74-1.69 (m, 4H).

Stage 2: 4-bromo-2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

Br '4 O

The title compound was prepared by bromination of the title compound from Step 1 in a manner similar to Example 47 Step 2. LCMS: 241.9 (M + H) ⁺ .

Stage 3: 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -5,6,7,8-tetrahydroisoquinoline-1-

The title compound from Step 2 (3.3 g, 13.7 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (6.96 g, 27.4 mmol), Pd ₂ (dba) ₃ (400 mg, 0.43 mmol), Xphos (400 mg, 0.84 mmol), and anhydrous KOAc (1.02 g, 41.1 mmol) in anhydrous dioxane (50 mL) were heated at 50 ° С under N ₂ for 12 hours. Silica gel chromatography (PE: EA = 5: 1) afforded the title compound (1.5 g, yield: 38%) as a yellow solid.

- 241 038715 ¹ H NMR (CDCl3, 400 MHz): δ 7.62 (s, 1H), 5.28 (s, 3H), 2.82-2.76 (m, 2H), 2.55-2.33 (m, 2H), 1.72-1.70 ( m, 4H), 1.31 (s, 12H). LCMS: 290.0 (M + H) ⁺ .

Step 4: 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -2-methyl-5,6,7,8tetrahydroisoquinolin-1-one

The title compound from Step 3 (200 mg, 0.69 mmol), the title compound of Example 152, Step 4 (218 mg, 0.83 mmol), K ₃ PO ₄ (440 mg, 2.07 mmol) and Pd (dppf) Cl ₂ (51 mg, 0.7 mmol) in 6: 1 dioxane / water (7 ml) was purged with nitrogen and heated at 70 ° C for 8 h. Chromatography on silica gel (PE: EA = 1: 1) gave the title compound ( 180 mg, yield: 67%) as a light yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz): δ 8.42 (s, 1H), 7.48 (s, 1H), 4.04 (d, J = 7.2 Hz, 2H), 3.60 (s, 3H), 3.35 (s, 3H ), 2.65-2.62 (m, 2H), 2.54-2.50 (m, 2H), 1.80-1.78 (m, 2H), 1.77-1.67 (m, 2H), 1.28-1.25 (m, 1H), 0.73-0.71 (m, 2H), 0.41-0.38 (m, 2H).

Step 5: N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4yl) pyrimidin-2-yl] methanesulfonamide

The title compound from Step 4 was treated with MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

¹ H NMR (CDC% 400 MHz): δ 8.18 (s, 1H), 7.38 (s, 1H), 3.74 (d, J = 6.4 Hz, 2H), 3.51 (s, 3H), 3.28 (s, 3H) , 2.60-2.53 (m, 2H), 2.50-2.46 (m, 2H), 1.74-1.71 (m, 2H), 1.64-1.59 (m, 2H), 1.13-1.10 (m, 1H), 0.60-0.58 ( m, 2H), 0.25-0.24 (m, 2H). LCMS: 405.1 (M + H) ⁺ .

Example 164 N- [5- (cyclopropylmethoxy) -4- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4yl) pyrimidin-2-yl] ethanesulfonamide

The title compound of Example 163 Step 4 was treated with EtSO2NH2 instead of MeSO2NH2 in a similar manner to Example 152, Step 6 to provide the title compound.

¹ H NMR (DMSO-d6, 400 MHz): δ 8.32 (s, 1H), 7.64 (s, 1H), 3.83 (d, J = 6.8 Hz, 2H), 3.44 (s, 3H), 3.30-3.20 ( m, 2H), 2.47-2.41 (m, 4H), 1.67-1.57 (m, 4H), 1.19-1.13 (m, 4H), 0.51-0.49 (m, 2H), 0.24-0.22 (m, 2H). LCMS: 419.1 (M + H) +.

Example

165: N- [5- (2,4-difluorophenoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 151 was treated with MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 11.50 (s, 1H), 8.59 (s, 1H), 8.25 (s, J = 8.0 Hz, 1H), 7.87 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.54 (t, J = 7.2 Hz, 1H), 7.34-7.28 (m, 1H), 7.20-7.13 (m, 1H), 6.90 (t, J = 8.8 Hz, 1H), 3.54 (s, 3H), 3.35 (s, 3H). LCMS: 459.0 (M + 1) ⁺ .

- 242 038715

Example 166 N- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 149, Step 4, was treated with MeSO2NH2 in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.36 (s, 1H), 8.10-8.12 (m, 2H), 6.98-7.05 (m, 2H), 6.87-6.92 (m, 1H), 3.64 (s, 3H), 3.45 (s, 3H), 2.22 (s, 3H). LCMS: 423.0 (M + 1) +.

Example 167: N- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide

The title compound of Example 150 was treated with MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (DMSO-d6, 400 MHz) δ 11.37 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H), 7.58 (s, 1H), 7.54-7.50 (m, 1H), 7.28- 7.23 (m, 1H), 7.10-7.06 (m, 1H), 3.74 (s, 3H), 3.52 (s, 3H), 3.39 (s, 3H). LCMS: 439.0 (M + 1) ⁺ .

Example 168: N- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 150 was treated with EtSO ₂ NH _{2 in} place of MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12 -7.07 (m, 1H), 7.04-7.01 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M + 1) ⁺ .

Example 169 N- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 149 Step 4 was treated with EtSO ₂ NH _{2 in} place of MeSO 2 NH 2 in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (DMSO-d6, 400 MHz) δ 9.07 (s, 1H), 8.42 (s, 1H), 8.15 (s, 1H), 8.11 (s, 1H), 7.03-6.97 (m, 1H), 6.91- 6.87 (m, 1H), 3.66-3.61 (m, 5H), 2.22 (s, 3H), 1.44 (t, J = 7.6 Hz, 3H). LCMS: 437.0 (M + 1) ⁺ .

Example

170: N- [5- (2,4-difluorophenoxy) -4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound of Example 151 was treated with EtSO ₂ NH ₂ instead of MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 9.15 (s, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.34 (s, 1H), 8.02 (d, J = 8.0 Hz, 1H),

- 243 038715

7.71-7.67 (m, 2H), 7.54 (t, J = 7.6 Hz, 1H), 6.92-6.86 (m, 2H), 6.79-6.75 (m, 1H), 3.67 (s, 3H), 3.58 (q, J = 7.6 Hz,

2H), 1.39 (t, J = 7.6 Hz, 3H). LCMS: 473.0 (M + 1) ⁺ .

Example 171 4- [5- (2,4-difluorophenoxy) -2- (1,1-dioxo-1,2-thiazolidin-2-yl) pyrimidin-4-yl] -2methylisoquinolin-1-one

The title compound of Example 151 was treated with 1,1-dioxidoisothiazolidine in place of MeSO ₂ NH ₂ in a similar manner to Example 152, Step 6 to afford the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.63 (s, 1H), 8.24 (d, J = 8.0 Hz, 1H), 7.86 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H) , 7.65 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.31-7.26 (m, 1H), 7.13-7.07 (m, 1H), 6.89-6.87 (m, 1H ), 3.97 (t, J = 6.4 Hz, 2H), 3.57 (t, J = 7.2 Hz, 2H), 3.54 (s, 3H), 2.40-2.33 (m, 2H). LCMS: 485.2 (M + H) ⁺ .

Example 172 N- [5- (2,4-difluorophenoxy) -4- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin-4yl) pyrimidin-2-yl] methanesulfonamide

The title compound of Example 149 Step 3 was reacted with the title compound of Example 163 Step 3 in a similar manner to Example 163 Step 4 and the resulting product was treated with MeSO2NH2 in a manner similar to Example 163 Step 5 to provide the title compound.

1H NMR (DMSO-d6, 400 MHz): δ 8.16 (s, 1H), 7.46 (s, 1H), 7.25-7.20 (m, 1H), 6.90-6.84 (m, 2H), 3.34 (s, 3H) , 2.80 (s, 3H), 2.41-2.29 (m, 4H), 1.60-1.48 (m, 4H). LCMS: 463.1 (M + H) ⁺ .

Example 173: N- [5- (2,4-difluorophenoxy) -4- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinoline-4yl) pyrimidin-2-yl] ethanesulfonamide

The title compound of Example 149, Step 3, was reacted with the title compound of Example 163, Step 3, in a similar manner to Example 163, Step 4, and the resulting 4- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -2-methyl5,6,7,8-tetrahydroisoquinolin-1-one was treated with EtSO ₂ NH ₂ instead of MeSO ₂ NH ₂ in a manner similar to Example 163, step 5, to give connection header.

1H NMR (DMSO-d6, 400 MHz): δ 8.38 (s, 1H), 7.61 (s, 1H), 7.35-7.31 (m, 1H), 7.04-6.95 (m, 2H), 3.41 (s, 3H) , 3.30-3.20 (m, 2H), 2.42-2.40 (m, 2H), 2.32-2.30 (m, 2H), 1.61-1.51 (m, 4H), 1.18 (t, J = 7.2 Hz, 3H). LCMS: 477.1 (M + H) +.

Example 174: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-fluoro-2-methylisoquinolin-1-one

A mixture of 4-bromo-6-fluoro-2-methylisoquinolin-1-one (500.00 mg, 1.95 mmol), 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (1.07 g, 2.92 mmol), K ₃ PO ₄ (1.24 g, 5.85 mmol) and Pd (dppf) Cl ₂ (0.1 g, cat.) In dioxane / Н ₂ О (30 ml / 4 ml ) was stirred at 70 ° С for 12 h in an Ar atmosphere. The mixture was concentrated and the residue was purified by column chromatography (PE: EA = 1: 1) to give a pink solid. This pink solid was further purified by column chromatography (DCM: EA = 4: 1) to afford the title compound (0.13 g, 16%) as a light yellow solid.

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1H NMR (CDCl ₃ , 400 MHz) δ 8.54 (brs, 1H), 7.96 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H),

7.22-7.20 (m, 1H), 7.15-7.13 (m, 1H), 7.1 (d, J = 8.8 Hz, 1H), 6.78 (dd, J1 = 10.4 Hz, J2 = 2.4 Hz, 1H), 3.90 (t , J = 7.6

Hz, 2H), 3.68 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H), 1.06-1.02 (m, 1H), 0.50-0.43 (m , 2H), 0.150.14 (m, 2H). LCMS (M + H) ⁺ = 416.0 (M + 1) ⁺ .

Example 175 2-methyl-4- [5-methylsulfonyl-2- (oxolan-3-yloxy) phenyl] isoquinolin-1-one.

Stage 1: 4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

A mixture of compound 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (4.1 g, 14.5 mmol), 2-bromo-4- methylsulfonyl-1-fluorobenzene (3.5 g, 13.8 mmol), obtained in a similar way as in example 79, steps 1-2, CsF (6.3 g, 41.3 mmol) and Pd (dppf) Cl ₂ (1.0 g, 1.38 mmol) in DME (70 ml) and MeOH (35 ml) were stirred at 70 ° C for 12 h under N ₂ . The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA = 2: 1 ~ 0: 1) to give the title compound (3.4 g, 74.4%) as a red solid. LCMS (M + H) ⁺ = 331.9 (M + 1) ⁺ .

Stage 2: 2-methyl-4- [5-methylsulfonyl-2- (oxolan-3-yloxy) phenyl] isoquinolin-1-one

NaH (66.0 mg, 1.65 mmol, 60% in mineral oil) was added to a solution of oxolan-3-ol (175.0 mg, 1.99 mmol) in anhydrous DMF (3 ml) at 0 ° С and then stirred at 0 ° С for 0.5 including 4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one (110.0 mg, 0.33 mmol). The mixture was stirred at 0 ° C for 0.5 h and then at room temperature for 3 h. The mixture was then rapidly cooled with aqueous saturated NH ₄ Cl (20 ml) and extracted with EA (20 ml x3). The combined organic layers were washed with brine (40 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give the title compound (62.0 mg, 39.7%) as a light yellow solid matter.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, J = 7.6 Hz, 1H), 8.00 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H) , 7.58-7.51 (m, 2H), 7.11-7.03 (m, 3H), 5.01-4.98 (m, 1H), 3.97 (dd, J1 = 10.4 Hz, J2 = 4.8 Hz, 1H), 3.763.70 (m , 2H), 3.67 (s, 3H), 3.61-3.42 (m, 1H), 3.11 (s, 3H), 2.18-1.88 (m, 2H). LCMS (M + H) ⁺ = 400.0 (M + 1) ⁺ .

Example 176 2-methyl-4- [5-methylsulfonyl-2- (oxan-4-yloxy) phenyl] isoquinolin-1-one

The title compound was prepared in a similar manner to Example 175 substituting oxolan-3-ol for oxan-4-ol in step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1H), 8.00 (dd, J ₁ = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.89 (d, J = 2.4 Hz, 1H), 7.63-7.50 (m, 2H), 7.19 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.09 (s, 1H), 4.65-4.61 (m, 1H ), 3.71 (s, 3H), 3.53-3.45 (m, 4H), 3.11 (s, 3H), 1.92-1.88 (m, 2H), 1.62-1.54 (m, 2H). LCMS (M + H) + = 414.1 (M + 1) ⁺ .

Example 177: 4- (2-ethoxy-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 175.

- 245 038715 by substituting oxolan-3-ol for ethanol in step 2.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1H), 8.01 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H ), 7.57 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.2 Hz, 2H), 7.08 (s, 1H), 4.12-4.09 (m , 2H), 3.68 (s, 3H), 3.10 (s, 3H), 1.18 (t, J = 7.2 Hz, 1H). LCMS (M + H) + = 358.0 (M + 1) +.

Example 178: 2-methyl-4- (5-methylsulfonyl-2-propoxyphenyl) isoquinoline-1-one

The title compound was prepared in a similar manner to Example 175 substituting oxolan-3-ol for propan-1-ol in step 2.

1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J = 8.0 Hz, 1H), 8.00 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.07 ( s, 1H), 4.00-3.94 (m, 2H), 3.67 (s, 3H), 3.10 (s, 3H), 1.60-1.52 (m, 2H), 0.68 (t, J = 7.2 Hz, 1H). LCMS (M + H) + = 372.0 (M + 1) +.

Example 179 2-methyl-4- [5-methylsulfonyl-2- (oxan-3-yloxy) phenyl] isoquinolin-1-one

The title compound was prepared in a similar manner to Example 175 substituting oxolan-3-ol for oxan-3-ol in step 2.

1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J = 8.0 Hz, 1H), 7.98 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.56 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12-7.06 (m, 2H), 4.43-4.41 (m , 1H), 3.79-3.78 (m, 1H), 3.67 (s, 3H), 3.66-3.63 (m, 1H), 3.39-3.34 (m, 2H), 3.10 (s, 3H), 2.02-1.93 (m , 2H), 1.59-1.48 (m, 2H). LCMS (M + H) + = 414.1 (M + 1) +.

Example

180:

4- [2- (trans-4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -2 methylisoquinoline-1-one.

Step 1: 4- [2- [4- [tert-butyl (dimethyl) silyl] oxycyclohexyl] oxy-5-methylsulfonylphenyl] -2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 175 by substituting oxolan-3-ol for trans-4- [tert-butyl (dimethyl) silyl] oxycyclohexan-3-ol in Step 2. LCMS (M + H ) + = 542.2 (M + 1) +.

Stage 2: 4- [2- (trans-4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -2-methylisoquinoline-1one

To a solution of the title compound from Step 1 (180.0 mg, 0.33 mmol) in dry MeOH (5 ml) and DCM (3 ml) was added HCl / MeOH (0.3 ml, 1.2 mmol, 4 M) dropwise at 0 ° C and then stirred at room temperature for 20 minutes. TLC has shown that the starting materials have been used up completely. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound (130.0 mg, 97.8%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.50 (d, J = 7.6 Hz, 1H), 7.98 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H) , 7.55 (t, J = 6.8 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 4.42-4.35 (m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.10 (s, 3H), 2.01-1.89 (m, 2H), 1.71-1.65 (m, 2H),

- 246 038715

1.36-1.34 (m, 4H). LCMS (M + H) + = 428.1 (M + 1) ⁺ .

Example 181 4- [5-ethylsulfonyl-2- (trans-4-hydroxycyclohexyl) oxyphenyl] -2-methylisoquinolin1-one.

Step 1: 4- [2- [4- [tert-butyl (dimethyl) silyl] oxycyclohexyl] oxy-5-ethylsulfonylphenyl] -2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 175 by substituting 2-bromo-4-methylsulfonyl-1-fluorobenzene for 2-bromo-4-ethylsulfonyl-1-fluorobenzene in Step 1. LCMS (M + H) ⁺ = 345.9 (M + 1) ⁺ .

Stage 2: 4- [5-ethylsulfonyl-2- (trans-4-hydroxycyclohexyl) oxyphenyl] -2-methylisoquinoline-1one

NaH (139.0 mg, 3.47 mmol, 60% in mineral oil) was added to a solution of trans-1,4-cyclohexanediol (504.0 mg, 4.34 mmol) in anhydrous DMF (4 ml) at 0 ° С and then stirred at 0 ° С for for 1 h. Added the compound from step 1 (100.0 mg, 0.29 mmol). The mixture was stirred at 0 ° C for 0.5 h and then at room temperature for 18 h. The mixture was then rapidly cooled with MeOH (4 ml) and filtered. The filtrate was purified by preparative HPLC to give the title compound (37.0 mg, 30.0%) as an off-white solid.

1H NMR (CDCl ₃ , 40 MHz) δ 8.51 (d, J = 7.6 Hz, 1H), 7.94 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H) , 7.56 (t, J = 6.8 Hz, 1H), 7.51 (t, J = 6.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 8.8 Hz, 1H), 7.05 (s, 1H), 4.43-4.18 (m, 1H), 3.67 (s, 3H), 3.65-3.62 (m, 1H), 3.16 (q, J = 7.6 Hz, 2H), 2.00-1.90 (m, 2H ), 1.71-1.65 (m, 2H), 1.42-1.30 (m, 7H). LCMS (M + H) ⁺ = 442.0 (M + 1) ⁺ .

Example 182: 4- [2- (trans-4-aminocyclohexyl) oxy-5-methylsulfonylphenyl] -2-methylisoquinoline-1one

A mixture of 4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one (200 mg, 0.60 mmol), trans-4aminocyclohexan-1-ol (278 mg, 2.42 mmol) and Cs ₂ CO ₃ (591 mg , 1.81 mmol) in DMSO (4 ml) was stirred at 120 ° С for 12 h. Water (20 ml) was added and the mixture was extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by preparative HPLC to afford the title compound (103.15 mg, 36.9%) as its hydrochloric acid salt.

1H NMR (DMSO-d6, 400 MHz) δ 8.28 (d, J = 8.0 Hz, 1H), 8.10 (s, 3H), 7.95 (dd, 31 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.80 (d , J = 2.4 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.51-7.49 (m, 3H), 7.14 (d, J = 8.0 Hz, 1H), 4.50-4.44 (m, 1H) , 3.56 (s, 3H), 3.22 (s, 3H), 2.95-2.85 (m, 1H), 2.00-1.94 (m, 2H), 1.84 (d, J = 11.2 Hz, 2H), 1.47-1.41 (m , 2H), 1.20-1.12 (m, 2H). LCMS (M + H) ⁺ = 427.1 (M + H) ⁺ .

Example 183: 4- [2- (cis-4-aminocyclohexyl) oxy-5-methylsulfonylphenyl] -2-methylisoquinoline-1one

NaH (127

- 247 038715 mg, 3.17 mmol, 60% in mineral oil) in one serving at 0 ° C. The mixture was stirred at 0 ° С for 30 min, 4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one (150.00 mg, 0.45 mmol) was added in one portion, and the mixture was stirred at 0 ° С for 2 h. The reaction was diluted with water (20 ml) and extracted with EA (3x20 ml). The combined organic layers were washed with saturated brine (2x20 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound as its hydrochloric acid salt (91.01 mg, 47.1%).

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.29 (d, J = 8.0 Hz, 1H), 8.00 (s, 3H), 7.95 (dd, J1 = 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.56 (s, 1H), 7.51 (t, J = 7.2 Hz, 1H), 7.40 (d, J = 8.8 Hz , 1H), 7.40 (d, J = 8.0 Hz, 1H), 4.70 (s, 1H), 3.59 (s, 3H), 3.22 (s, 3H), 2.96-2.94 (m, 1H), 1.85-1.82 ( m, 1H), 1.64-1.46 (m, 5H), 1.32-1.26 (m, 1H), 1.04-0.98 (m, 1H). LCMS (M + H) + = 427.0 (M + H) +.

Example 184: 4- (2-But-2-inoxy-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 175 substituting oxolan-3-ol for but-2-yn-1-ol in step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.87 (s, 1H), 7.59-7.50 (m, 2H), 7.32 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.08 (s, 1H), 4.68 (s, 2H), 3.67 (s, 3H), 3.11 (s, 1H), 1.85 (s, 1H). LCMS (M + H) + = 382.1 (M + H) ⁺ .

Example 185: 4- (2-But-2-inoxy-5-ethylsulfonylphenyl) -2-methylisoquinolin-1-one

O

The title compound was prepared in a similar manner to Example 181 by substituting trans-1,4-cyclohexanediol for but-2-yn-1-ol in Step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, J = 7.6 Hz, 1H), 8.00 (dd, J1 = 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.83 (s, 1H), 7.61 (d , J = 7.6 Hz, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 8.8 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.12 (s, 1H ), 4.68 (s, 2H), 3.72 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.85 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H). LCMS (M + H) + = 396.0 (M + H) ⁺ .

Example 186 6-fluoro-4- [2- (trans-4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -2methylisoquinolin-1-one

Stage 1: 6-fluoro-4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 174 by substituting 2- [2 ( cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane. LCMS (m + H) ⁺ = 349.9 (M + H) +.

Stage 2: 4- [2- [4- [tert-butyl (dimethyl) silyl] oxycyclohexyl] oxy-5-methylsulfonylphenyl] -6fluoro-2-methylisoquinoline-1-one

O

The title compound was prepared in a similar manner to Example 180 Step 1 by substituting 4- (2-248 038715 fluoro -5-methylsulfonylphenyl) -2-methylisoquinolin-1-one. The crude material was used immediately in the next step without further purification. LCMS (M + H) + = 560.3 (M + H) ⁺ .

Stage 3: 6-fluoro-4- [2- (trans-4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -2methylisoquinolin-1-one

From tert-butyl (dimethyl) silyl ether deprotected in a manner similar to that described in example 180, step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 8.53-8.49 (m, 1H), 7.99 (dd, 11 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.21- 7.18 (m, 1H), 7.12 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 6.78 (dd, J1 = 10.0 Hz, J2 = 2.4 Hz, 1H), 4.46-4.44 (m, 1H ), 3.66-3.65 (m, 4H), 3.10 (s, 3H), 2.02-1.99 (m, 2H), 1.73-1.71 (m, 2H), 1.43-1.37 (m, 4H). LCMS (M + H) ⁺ = 446.0 (M + H) +.

Example 187 7-fluoro-4- [2- (trans-4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 186 by substituting 4-bromo-6-fluoro-2-methylisoquinolin-1-one for 4-bromo-7-fluoro-2-methylisoquinolin-1-one in Step 1.

Ή NMR (CDCl3, 400 MHz) δ 8.16-8.14 (m, 1H), 7.99 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.28-7.27 (m, 1H), 7.18-7.12 (m, 2H), 7.01 (s, 1H), 4.43-4.42 (m, 1H), 3.67-3.66 (m, 4H), 3.10 (s, 3H), 1.98-1.97 (m, 2H), 1.72-1.71 (m, 2H), 1.39-1.32 (m, 4H). LCMS (M + H) ⁺ = 446.0 (M + H) ⁺ .

Example 188: 4- [5-ethylsulfonyl-2- (trans-4-hydroxycyclohexyl) oxyphenyl] -6-fluoro-2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 186 by substituting 2- (2- fluoro-5-methylsulfonylphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 1.

1H NMR (CDCl ₃ , 400 MHz) δ 8.53-8.50 (m, 1H), 7.97-7.94 (m, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.22-7.18 (m, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 6.79-6.76 (m, 1H), 4.46-4.44 (m, 1H), 3.70-3.64 (m, 4H), 3.16 (q, J = 7.6 Hz, 2H), 2.00-1.88 (m, 3H), 1.72-1.71 (m, 2H), 1.40-1.30 (m, 7H). LCMS (M + H) ⁺ = 460.1 (M + H) ⁺ .

Example 189 4- [5-ethylsulfonyl-2- (trans-4-hydroxycyclohexyl) oxyphenyl] -7-fluoro-2methylisoquinolin-1-one.

Stage 1: 4- (5-ethylsulfonyl-2-fluorophenyl) -7-fluoro-2-methylisoquinolin-1-one

A mixture of 4-bromo-7-fluoro-2-methylisoquinolin-1-one (100 mg, 0.39 mmol), 2- (5-ethylsulfonyl-2fluorophenyl) -4,4,5,5-tetramethyl-1,3,2- dioxaborolane (148 mg, 0.47 mmol), Pd (dppf) Cl ₂ (29 mg, 0.04 mmol) and K ₃ PO ₄ (207 mg, 0.98 mmol) in dioxane (6 ml) and Н ₂ О (1 ml) were heated to 70 ° C for 18 h in an atmosphere of N ₂ . The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA = 1: 1) to give compound 12 (70 mg, yield: 49%) as a yellow solid, 249 038715. LCMS (M + H) + = 364.1 (M + H) +.

Stage 2: 4- [2- [4- [tert-butyl (dimethyl) silyl] oxycyclohexyl] oxy-5-ethylsulfonylphenyl] -7 fluoro-2-methylisoquinoline-1-one

TBSO,

To a solution of trans-4- [tert-butyl (dimethyl) silyl] oxycyclohexan-1-ol (87 mg, 0.38 mmol) in dry DMF (2 ml) was added NaH (15 mg, 0.38 mmol, 60% in mineral oil) in portions under N2 at 0 ° C and the mixture was stirred at 20 ° C for 1 h. Then the title compound from Step 1 (70 mg, 0.19 mmol) was added and the mixture was stirred at 20 ° C for 4 h. The mixture quickly cooled with H2O (5 ml) and extracted with EtOAc (3x5 ml). The combined organic layers were dried over Na ₂ SO ₄ and concentrated to give the title compound as a yellow gum (65 mg) which was used immediately in the next step without further purification. LCMS (M + H) + = 574.3 (M + H) ⁺ .

Stage 3: 4- [5-ethylsulfonyl-2- (trans-4-hydroxycyclohexyl) oxyphenyl] -7-fluoro-2methylisoquinolin-1-one

Tert-butyl (dimethyl) silyl ether was deprotected in a manner similar to Example 180, step 2.

1H NMR (CDCl3, 400 MHz) δ 8.16 (dd, Ji = 9.2 Hz, J2 = 2.4 Hz, 1H), 5 7.96 (dd, Ji = 8.4 Hz, b = 2.4 Hz, 1H), 7.82 (d, J = 2.4 Hz, 1H), 7.32-7.29 (m, 1H), 7.18-7.11 (m, 2H), 7.01 (s, 1H), 4.42-4.42 (m, 1H), 3.67 (s, 3H), 3.18 (q , J = 7.6 Hz, 2H), 1.97-1.88 (m, 3H), 1.72-1.71 (m, 2H), 1.40-1.32 (m, 7H). LCMS (M + H) + = 460.1 (M + H) ⁺ .

Example 190 2-methyl-4- [5-methylsulfonyl-2- (oxolan-3-ylamino) phenyl] isoquinolin-1-one

Stage 1: N- (2-bromo-4-methylsulfonylphenyl) oxolan-3-amine

A mixture of 2-bromo-1-fluoro-4-methylsulfonylbenzene (0.8 g, 3.16 mmol), oxolan-3-amine (1.38 g, 15.8 mmol) and K ₂ CO ₃ (0.87 g, 6.32 mmol) in DMSO (15 ml) stirred at 100 ° C for 5 hours. The mixture was cooled to room temperature and water (50 ml) was added. The mixture was extracted with EtOAc (50 ml x 3) and the combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4, filtered and concentrated. The residue was purified by column chromatography (PE: EA = 50: 1 ~ 3: 1) to give the title compound (0.7 g, yield: 69.16%).

1H NMR (CDCl3, 400 MHz) δ 8.00 (d, J = 1.2 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.8 Hz, 1H), 5.03 (d, J = 6.4 Hz, 1H), 4.23-4.13 (m, 1H), 4.07-3.98 (m, 2H), 3.96-3.87 (m, 1H), 3.83-3.76 (m, 1H), 3.03 (s, 3H), 2.43-2.32 (m, 1H), 1.98-1.88 (m, 1H). LCMS (M + H) + = 320.0, 322.0.

Stage 2: 2-methyl-4- [5-methylsulfonyl-2- (oxolan-3-ylamino) phenyl] isoquinolin-1-one

A mixture of 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (100 mg, 0.35 mmol), compounds from step 1 (102 mg , 0.32 mmol), K ₃ PO ₄ (186 mg, 0.88 mmol) and Pd (dppf) Cl ₂ (29 mg, 0.04 mmol) in dioxane (5 ml) and H2O (1 ml) were purged with nitrogen 3 times and then stirred at 70 ° C for 18 h in an atmosphere of N ₂ . The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (56.02 mg, yield: 40.1%) as a light yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, J = 8.0 Hz, 1H), 7.89 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.69 (s, 1H), 7.64-7.52 ( m, 2H), 7.13 (s, 1H), 7.13-7.08 (m, 1H), 6.78 (dd, Ji = 8.8 Hz, J2 = 5.6 Hz, 1H), 4.17 (s, 2H), 3.94-3.86 (m , 1H), 3.79-3.72 (m, 1H), 3.72-3.64 (m, 1H), 3.67 (s, 3H), 3.58-3.49 (m, 1H), 3.07 (s, 3H), 2.32-2.18 (m , 1H),

- 250 038715

1.76-1.63 (m, 1H). LCMS (M + H) + = 399.1 (M + H) ⁺ .

Example 191 2-methyl-4- [5-methylsulfonyl-2- (oxane-4-ylamino) phenyl] isoquinolin-1-one.

Stage 1: N- (2-bromo-4-methylsulfonylphenyl) oxane-4-amine

The title compound was prepared in a similar manner to Example 190 Step 1 by substituting oxolan-3-amine for oxan-3-amine.

1H NMR (CDCl ₃ , 400 MHz) δ 7.98 (d, J = 1.8 Hz, 1H), 7.70 (dd, J1 = 8.8 Hz, J ₂ = 1.8 Hz, 1H), 6.70 (d, J = 8.8 Hz, 1H ), 4.85 (d, J = 7.2 Hz, 1H), 4.08-3.99 (m, 2H), 3.69-3.60 (m, 1H), 3.60-3.52 (m, 2H), 3.03 (s, 3H), 2.102. 02 (m, 2H), 1.68-1.55 (m, 2H). LCMS (M + H) + = 334.0 (M + H) ⁺ , 336.0.

Stage 2: 2-methyl-4- [5-methylsulfonyl-2- (oxane-4-ylamino) phenyl] isoquinolin-1-one

The title compound was prepared in a similar manner to Example 190 Step 2 by replacing N- (2-bromo-4-methylsulfonylphenyl) oxan-4-amine with N- (2-6pom-4methylsulfonylphenyl) oxolan-3-amine.

1H NMR (CDCl3, 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1H), 7.85 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.63-7.52 (m, 2H), 7.16-7.11 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 4.00 (d, J = 7.6 Hz, 1H), 3.93-3.82 (m, 2H) , 3.64 (s, 3H), 3.63-3.54 (m, 1H), 3.51-3.42 (m, 2H), 3.06 (s, 3H), 1.95-1.87 (m, 2H), 1.37-1.24 (m, 1H) ... LCMS (M + H) + = 413.0 (M + H) ⁺ .

Example 192: 4- [2 - [(trans-4-hydroxycyclohexyl) amino] -5-methylsulfonylphenyl] -2methylisoquinolin-1-one

A mixture of 4- (2-fluoro-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one (150 mg, 0.45 mmol) and trans4-aminocyclohexan-1-ol (417 mg, 3.62 mmol) in NMP (0.2 ml) was heated in for 20 min at 200 300 ° C. The cooled brownish residue was purified by preparative HPLC to afford the title compound (55.64 mg, 28.8%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.54 (d, J = 8.0 Hz, 1H), 7.86 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H) , 7.60-7.55 (m, 2H), 7.15-7.13 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 3.91-3.85 (m, 1H), 3.67 (s, 3H), 3.633.55 (m, 1H), 3.37-3.34 (m, 1H), 3.06 (s, 3H), 2.04-1.92 (m, 5H), 1.44-1.35 (m, 2H), 1.11-1.02 (m, 2H). LCMS (M + H) + = 427.1 (M + H) ⁺ .

Example 193: 4- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 190 Step 2 by substituting N- (2-6pom-4methylsulfonylphenyl) oxolan-3-amine for 2-bromo-N- (cyclopropylmethyl) -4-ethylsulfonylaniline.

1H NMR (CDCl ₃ , 400 MHz) δ 8.51 (d, J = 7.6 Hz, 1H), 7.80 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.61-7.51 (m, 3H), 7.15 ( d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.32 (t, J = 4.8 Hz, 1H), 3.62 (s, 3H), 3.09 ( q, J = 7.2 Hz, 2H), 3.01 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H), 0.95-0.89 (m, 1H), 0.46-0.38 (m, 2H), 0.12-0.05 (m, 2H). LCMS (M + H) + = 397.1 (M + H) ⁺ .

- 251 038715

Example 194: 4- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 190 Step 2 by substituting N- (2-6pom-4methylsulfonylphenyl) oxolan-3-amine for 2-bromo-N- (cyclopropylmethyl) -4-methylsulfonylaniline.

1H NMR (CDCl3, 400 MHz) δ 8.54 (d, J = 7.6 Hz, 1H), 7.80 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.60-7.55 (m, 2H), 7.17 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 4.24-4.23 (m, 1H), 3.66 (s, 3H), 3.06 (s, 3H), 3.03-2.99 (m, 2H), 0.93-0.91 (m, 1H), 0.45-0.37 (m, 2H), 0.12-0.054 (m, 2H). LCMS (M + H) + = 383.1.

Example 195: 4- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -7-fluoro-2-methylisoquinolin-1 one.

Stage 1: 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one

A mixture of compound 4-bromo-7-fluoro-2-methylisoquinolin-1-one (1.2 g, 4.69 mmol), bis (pinacolato) diborone (2.38 g, 9.37 mmol), AcOK (1.38 g, 14.07 mmol), Pd ₂ ( dba) ₃ (429 mg, 0.47 mmol) and X-phos (224 mg, 0.47 mmol) in dioxane (20 ml) were stirred at 70 ° С for 18 h under N2. The mixture was concentrated and the residue was purified by column chromatography to give the title compound (0.8 g, yield: 56.3%).

1H NMR (CDCl3, 400 MHz) δ 8.42 (dd, J1 = 9.2 Hz, J2 = 4.2 Hz, 1H), 8.06 (dd, ^ = 9.2 Hz, J2 = 2.8 Hz, 1H), 7.65 (s, 1H), 7.42-7.35 (m, 1H), 3.64 (s, 3H), 1.38 (s, 12H). LCMS (M + H) ⁺ = 304.1.

Step 2: 4- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -7-fluoro-2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 193 by substituting 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline- 1-one on 2methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline-1-one.

1H NMR (CDCl3, 400 MHz) δ 8.17 (d, J = 8.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 7.38-7.29 (m, 1H), 7.21 -7.13 (m, 1H), 7.11 (s, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.67 (s, 3H), 3.11 (q, J = 7.2 Hz, 2H), 3.01 (d, J = 6.8 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H), 0.99-0.85 (m, 1H), 0.51-0.36 (m, 2H), 0.17-0.02 (m, 2H). LCMS (M + H) ⁺ = 415.1.

Example 196: 4- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -7-fluoro-2-methylisoquinolin1-one

The title compound was prepared in a similar manner to Example 195 by substituting 2-6pom-N (cyclopropylmethyl) -4-ethylsulfonylaniline for 2-bromo-N- (cyclopropylmethyl) -4-methylsulfonylaniline in Step 2.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.19 (dd, J1 = 9.2 Hz, J2 = 2.8 Hz, 1H), 7.86 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.66 (d, J = 2.4 Hz, 1H), 7.37-7.30 (m, 1H), 7.18 (dd, Ji = 8.8 Hz, J2 = 4.8 Hz, 1H), 7.11 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H ), 4.14 (s, 1H), 3.68 (s, 3H), 3.06 (s, 3H), 3.01 (d, J = 6.8 Hz, 2H), 0.98-0.84 (m, 1H), 0.51-0.37 (m, 2H), 0.160.02 (m, 2H). LCMS (M + H) ⁺ = 401.1.

- 252 038715

Example 197: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6- (trifluoromethoxy) isoquinolin-1-one

A mixture of 4-bromo-2-methyl-6- (trifluoromethyl) isoquinolin-1-one (40 mg, 0.13 mmol), 2- [2 (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (46 mg, 0.13 mmol), K ₃ PO ₄ (68 mg, 0.33 mmol) and Pd (dppf) Cl ₂ (10 mg, 0.01 mmol) in dioxane (0.9 ml) and H2O (0.09 ml) was degassed with N2 for 10 min and then stirred at 60 ° C for 1.6 h. The reaction mixture was diluted with EtOAc (5 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography to give the title compound (27 mg, 46%).

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.51 (d, J1 = 8.4 Hz, 1H), 8.0 (dd, J1 = 8.7 Hz, J2 = 2.5 Hz, 1H), 7.87 (s, 1H), 7.85 ( m, 1H), 7.72 (s, 1H), 7.39 (m, 2H), 4.02 (m, 1H), 3.86 (m, 1H), 3.61 (s, 3H), 3.23 (s, 3H), 0.90 (m , 1H), 0.31 (m, 2H), 0.09 (m, 2H). LCMS (M + H) + = 452.2.

Example 198: 4- (2- (cyclopropylmethoxy) -5- (methylsulfonyl) phenyl) -6-methoxy-2methylisoquinoline-1 (2H) -one

O

The title compound of Example 90, step 2 (30 mg, 0.075 mmol) in N, N dimethylacetamide was treated with an excess of 25% sodium methoxide in methanol and heated at 85 ° C until the reaction was complete. Chromatography on silica gel (40-80% EA in hexane over 8 min, then isocratic mode) afforded the title compound 23 mg, 0.056 mmol, 74%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.06-0.20 (m., 2H), 0.27-0.43 (m, 2H), 0.83-1.05 (m, 1H), 3.22 (s, 3H), 3.53 ( s, 3H), 3.73 (s, 3H), 3.83-4.16 (m, 2H), 6.47 (s, 1H), 7.04-7.20 (m, 1H), 7.36 (d, J = 8.59 Hz, 1H), 7.50 (s, 1H), 7.81 (s, 1H), 7.96 (d, J = 6.82 Hz, 1H), 8.23 (d, J = 8.59 Hz, 1H). LCMS: 414 (M + H) ⁺ .

Example 199 4- [3- (cyclopropylmethoxy) -6-methylsulfonylpyridin-2-yl] -2-methylisoquinolin-1 one.

Stage 1: 6-methylsulfonylpyridin-3-ol

A mixture of 6-chloropyridin-3-ol (2.00 g, 15.44 mmol), MeSO ₂ Na (2.36 g, 23.16 mmol), CuI (882.16 mg, 4.63 mmol), L-proline (533.28 mg, 4.63 mmol) and K ₂ CO ₃ (640.19 mg, 4.63 mmol) in DMSO (20 ml) was loaded into a microwave tube. The sealed tube was heated at 140 ° C for 3 h under the influence of microwaves. After cooling to room temperature, water (100 ml) was added. The mixture was extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford the title compound (1.2 g, 44.8%) as a yellow solid.

1H NMR (methanol-d ₄ , 400 MHz) δ 8.24 (d, J = 2.4 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.37 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 3.15 (s, 3H).

Stage 2: 2-iodo-6-methylsulfonylpyridin-3-ol and 4-iodo-6-methylsulfonylpyridin-3-ol

A mixture of the title compound from Step 1 (3.0 g, 17.34 mmol), I ₂ (6.6 g, 26.01 mmol), NaHCO ₃ (2.2 g, 26.20 mmol) and KI (0.72 g, 4.34 mmol) in THF (30 mL) and H ₂ O (30 ml) was stirred at

60 ° C for 18 h. Water (100 ml) was added and the mixture was extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg) and 2-iodo-6-methylsulfonylpyridin-3-ol (700.0 mg).

2-Iodo-6-methylsulfonylpyridin-3-ol:

1H NMR (CDCl ₃ , 400 MHz) δ 12.08 (brs, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.19 (s, 3H).

4-Iodo-6-methylsulfonylpyridin-3-ol:

1H NMR (CDCl3, 400 MHz) δ 12.0 (brs, 1H), 8.24 (s, 1H), 8.17 (s, 1H), 3.20 (s, 3H).

Step 3: 3- (cyclopropylmethoxy) -2-iodo-6-methylsulfonylpyridine

A mixture of 2-iodo-6-methylsulfonylpyridin-3-ol (500.0 mg, 1.67 mmol), bromomethylcyclopropane (248.4 mg, 1.84 mmol) and K ₂ CO ₃ (461.3 mg, 33.4 mmol) in ACN (15 mL) was stirred at 80 ° C for 4 h. Water (30 ml) was added and the mixture was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (500.0 mg, 84.8%).

1H NMR (CDCl3, 400 MHz) δ 7.96 (d, J = 8.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 4.09 (d, J = 6.8 Hz, 2H), 3.22 (s, 3H ), 1.36-1.22 (m, 1H), 0.69-0.57 (m, 2H), 0.43-0.37 (m, 2H). LCMS: 354.0 (M + 1) +.

Stage 4:

Mixture of 3- (cyclopropylmethoxy) -2-iodo-6-methylsulfonylpyridine (140.0 mg, 0.40 mmol), 2-methyl4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline -1-one (136.5 mg, 0.48 mmol), K ₃ PO ₄ (252.7 mg, 1.19 mmol) and Pd (dppf) Cl ₂ (29.2 mg, 0.04 mmol) in dioxane (5 ml) and H2O (1 ml) were stirred at 70 ° C for 18 h in an atmosphere of N ₂ . The mixture was filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (81.0 mg, 53.1%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.33 (dd, J1 = 8.4 Hz, J ₂ = 1.2 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H ), 7.74 (s, 1H), 7.67 (t, J = 8.4 Hz, 1H), 7.55 (t, J = 8.4 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.60 (s, 3H), 3.25 (s, 3H), 1.10-0.98 (m, 1H), 0.45-0.37 (m, 2H), 0.23-0.17 (m, 2H). LCMS: 385.1 (M + 1) ⁺ .

Example 200: 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyridin-4-yl] -2-methylisoquinolin-1 one.

Step 1: 5- (cyclopropylmethoxy) -4-iodo-2-methylsulfonylpyridine

The title compound was prepared in a similar manner to Example 199 Step 3 by substituting 2-iodo-6-methylsulfonylpyridin-3-ol for 4-iodo-6-methylsulfonylpyridin-3-ol.

1H NMR (CDCh, 400 MHz) δ 8.35 (s, 1H), 8.32 (s, 1H), 4.20 (d, J = 7.2 Hz, 2H), 3.23 (s, 3H), 1.36-1.25 (m, 1H) , 0.67-0.58 (m, 2H), 0.44-0.37 (m, 2H). LCMS: 354.0 (M + 1) ⁺ .

Step 2: 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyridin-4-yl] -2-methylisoquinolin-1-one

O

The title compound was prepared in a similar manner to Example 199 Step 4 by substituting 3 (cyclopropylmethoxy) -2-iodo-6-methylsulfonylpyridine for 5- (cyclopropylmethoxy) -4-iodo-2-methylsulfonylpyridine.

1H NMR (CDCl ₃ , 400 MHz) δ 8.66 (s, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.70-7.66 (m, 2H), 7.577.54 (t , J = 7.2 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.12 (d, J = 6.8 Hz, 2H), 3.57 (s, 3H), 3.28 (s, 3H), 1.05-0.92 (m, 1H), 0.43-0.27 (m, 2H), 0.18-0.10 (m, 2H). LCMS: 385.1 (M + 1) ⁺ .

- 254 038715

Example 201: methylisoquinolin-1-one

4- [3- (cyclopropylmethoxy) -6-methylsulfonylpyridin-2-yl] -7-fluoro-2-

The title compound was prepared in a similar manner to Example 199 Step 4 by substituting 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) isoquinolin-1one to 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one.

1H NMR (DMSO-d6, 400 MHz) δ 8.07 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 (s , 1H), 7.65-7.45 (m, 2H), 4.01 (d, J = 6.4 Hz, 2H), 3.61 (s, 3H), 3.25 (s, 3H), 1.11-0.98 (m, 1H), 0.48- 0.35 (m, 2H), 0.27-0.15 (m, 2H). LCMS: 403.1 (M + 1) +.

Example 202: 4- [3- (cyclopropylmethoxy) -6-methylsulfonylpyridin-2-yl] -6-fluoro-2methylisoquinolin-1-one

YyS about

The title compound was prepared in a similar manner to Example 199, Step 4, by substituting 6-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) isoquinolin-1one to 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one.

1H NMR (DMSO-d6, 400 MHz) δ 8.37 (dd, J1 = 8.8 Hz, J2 = 6.4 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.82 (d , J = 8.8 Hz, 1H), 7.45-7.36 (td, J1 = 10.8 Hz, J2 = 2.4 Hz, 1H), 7.18 (dd, J1 = 10.8 Hz, J2 = 2.4 Hz, 1H), 4.03 (d, J = 7.2 Hz, 2H), 3.59 (s, 3H), 3.25 (s, 3H), 1.15-1.03 (m, 1H), 0.48-0.39 (m, 2H), 0.28-0.20 (m, 2H). LCMS: 403.1 (M + 1) ⁺ .

Example 203 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyridin-4-yl] -7-fluoro-2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 200, Step 2, by substituting 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) isoquinolin-1one to 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.08 (d, J = 8.4 Hz, 1H), 7.97 (dd, Ji = 9.2 Hz, h = 2.8 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.75 (s, 1H), 7.62-7.55 (td, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.50 (dd, J1 = 9.2 Hz, J2 = 5.2 Hz, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 3.25 (s, 3H), 1.11-0.99 (m, 1H), 0.46-0.39 (m, 2H), 0.24-0.18 (m, 2H). LCMS: 403.2 (M + 1) ⁺ .

Example 204: 4- (2-ethoxy-5-ethylsulfonylthiophen-3-yl) -2-methylisoquinolin-1-one

Mixture of 3-bromo-2-ethoxy-5-ethylsulfonylthiophene (18.0 mg, 0.06 mmol), 2-methyl-4- (4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinoline-1 -one (24 mg, 0.08 mmol), K3PO4 (42 mg, 0.20 mmol) and Pd (dppf) Cl ₂ (6 mg, 0.008 mmol) in dioxane (0.5 ml) and Н ₂ О (0.05 ml) were stirred at 60 ° C for 1.5 h. The reaction mixture was then poured with water (6 ml) and was extracted with EtOAc (2x5 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by normal phase silica gel column chromatography to give the title compound (10.5 mg, 46%).

- 255 038715

1H NMR (DMSO-d6, 400 MHz) δ 8.29 (d, J = 7.9 Hz, 1H), 7.71 (dd, J = 7.6, 7.6 Hz, 1H), 7.57 (m, 3H), 7.35 (d, J = 7.9 Hz, 1H), 4.25 (m, 2H), 3.54 (s, 3H), 3.38 (m, 2H), 1.24 (m, 6H). LCMS: 378.05 (M + 1) +.

Example 205: 4- [2- (cyclopropylmethylamino) -5-ethylsulfonylthiophen-3-yl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 204 by substituting 3-bromo-2-ethoxy-5ethylsulfonylthiophene for 3-bromo-N- (cyclopropylmethyl) -5-ethylsulfonylthiophen-2-amine.

1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1H), 7.70 (m, 1H), 7.53 (dd, J = 7.6, 7.6 Hz, 1H), 7.5 (s, 1H) , 7.32 (s, 1H), 7.26 (d, J = 8.0 Hz, 1H), 6.91 (m, 1H), 3.53 (s, 3H), 3.25 (m, 2H), 2.95 (m, 2H), 1.20 ( dd, J = 7.3, 7.3 Hz, 3H), 1.05 (m, 1H), 0.43 (m, 2H), 0.18 (m, 2H). LCMS: 403.1 (M + 1) ⁺ .

Example 206 4- [3- (cyclopropylmethoxy) -6-ethylsulfonylpyridin-2-yl] -2-methylisoquinolin-1-one.

Stage 1: 5-bromo-2-ethylsulfanylpyridine

NaSEt (13.3 g, 158.3 mmol) was added in one portion to a solution of 2,5-dibromopyridine (25 g, 105.5 mmol) in anhydrous DMSO (50 ml) at room temperature. The mixture was stirred for 18 hours. The mixture was then diluted with water (500 ml) and extracted with ethyl acetate (200 ml x 3). The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE: EA = 20: 1 ~ 10: 1) to give the title compound as a light yellow oil (21 g, yield: 91.3%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.49 (dd, J1 = 2.0 Hz, J2 = 0.4 Hz, 1H), 7.59 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.08 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H), 3.16 (q, J = 7.2 Hz, 2H), 1.38 (t, 3H). LCMS: 217.8 (M + 1) ⁺ ; 219.8.

Stage 2: 5-bromo-2-ethylsulfonylpyridine / X AD

To a solution of the title compound from Step 1 (21 g, 96.3 mmol) in DCM (200 mL) was slowly added m-CPBA (58.2 g, 289 mmol, 85% purity) at 0 ° C and then stirred at 20 ° C for for 3 h. The reaction mixture was rapidly cooled with saturated aqueous Na ₂ SO ₃ (200 ml) and then extracted with DCM (200 ml x 2).

The combined organic layers were washed with saturated aqueous NaHCO ₃ (200 ml), water (200 ml) and brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give 22 g of the crude (~ 90% purity) specified in the title compound as a white solid, which was used in the next step without further purification.

1H NMR (CDCl3, 400 MHz) δ 8.82 (d, J = 2.0 Hz, 1H), 8.13 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 8.01 (d, J = 8.0 Hz), 3.43 ( q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H). LCMS: 249.8 (M + 1) ⁺ ; 251.8.

Stage 3: 2-ethylsulfonyl-5-methoxypyridine

To a solution of the title compound from Step 2 (21 g, 84 mmol) in MeOH (150 mL) was added MeONa (11.3 g, 210 mmol). The mixture was heated under reflux for 5 hours. The mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was triturated with isopropyl ether and filtered. The filtrate was concentrated under reduced pressure to give the title compound (4.5 g, 23% yield over two steps) as a yellow oil.

1H NMR (CDCh, 400 MHz) δ 8.42 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.37 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 3.97 (s, 1H), 3.38 (q, J = 7.2 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

Stage 4: 6-ethylsulfonylpyridin-3-ol

The title compound from Step 3 (4.5 g, 22.4 mmol) and pyridinium hydrochloride (26 g, 224 mmol) were heated to 160 ° C for 4 h. The mixture was cooled to room temperature, diluted

- 256 038715 water (100 ml) and was extracted with EtOAc (100 ml x3). The combined organic layers were washed with brine (200 ml), dried over Na ₂ SO ₄ and concentrated. The residue was purified by column chromatography to give the title compound (3 g, 72%) as a yellow solid.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.87 (s, 1H), 8.86 (s, 1H), 8.45 (d, J = 8.4 Hz, 1H), 7.93 (dd, J ₁ = 8.8 Hz, J2 = 2.4 Hz, 1H), 3.82 (q, J = 7.2 Hz, 2H), 1.72 (t, J = 7.2 Hz, 3H). LCMS: 187.9 (M + 1) +.

Step 5: 6-ethylsulfonyl-2-iodopyridin-3-ol and 6-ethylsulfonyl-4-iodopyridin-3-ol

To a solution of the title compound from Step 4 (3 g, 16 mmol) in a mixture of THF (20 mL) and H2O (20 mL) were added KI (662 mg, 4 mmol) and iodine (6.1 g, 24 mmol). The reaction was stirred at room temperature for 1 hour and then heated to 60 ° C for another 17 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to remove THF. The mixture was diluted with water (100 ml) and was extracted with DCM (10 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC to give 6-ethylsulfonyl-2-iodopyridin-3-ol and 6-ethylsulfonyl-4-iodopyridin-3-ol as white solids.

6-Ethylsulfonyl-2-iodopyridin-3-ol:

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.85 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 3.30 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). LCMS: 313.8 (M + 1) +;

6-ethylsulfonyl-4-iodopyridin-3-ol:

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.23 (s, 1H), 8.18 (s, 1H), 3.31 (q, J = 7.2 Hz, 2H, overlapping with the solvent peak), 1.10 (t, J = 7.2 Hz, 3H). LCMS: 313.8 (M + 1) +.

Step 6: 3- (cyclopropylmethoxy) -6-ethylsulfonyl-2-iodopyridine

The title compound was prepared in a similar manner to Example 199 Step 3 by substituting 2-iodo-6-methylsulfonylpyridin-3-ol for 6-ethylsulfonyl-2-iodopyridin-3-ol.

¹ H NMR (CDCl3, 400 MHz) δ 7.98 (d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.02 (d, J = 6.8 Hz, 2H), 3.40 (q, J = 7.2 Hz, 2H), 1.38-1.26 (m, 4H), 0.77-0.73 (m, 2H), 0.49-0.46 (m, 2H). LCMS: 367.8 (M + 1) +.

Step 7: 4- [3- (cyclopropylmethoxy) -6-ethylsulfonylpyridin-2-yl] -2-methylisoquinolin-1-one

To a solution of the title compound from Step 6 (45 mg, 0.12 mmol) and 2-methyl-4- (4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one ( 50 mg, 0.16 mmol) in dioxane (2.5 ml) and H2O (0.5 ml), Pd (dppf) Cl ₂ (9 mg, 0.013 mmol) and K3PO4 (86 mg, 0.4 mmol) were added in one portion at room temperature in an N2 atmosphere. The mixture was stirred for 12 h at 90 ° C under N2. Water (15 ml) was added and the mixture was extracted with DCM (30 ml x 3). The combined organic phases were dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (16 mg, yield: 32%) as a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 8.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.53-7.49 (m, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.38 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 3.92 (d, J = 7.2 Hz, 2H), 3.68 (s, 3H), 3.41 (q, J = 6.8 Hz, 2H), 1.33 (t, 3H), 1.08-1.02 (m, 1H), 0.54-0.48 (m, 2H), 0.22-0.21 (m, 2H). LCMS: 399.1 (M + 1) +.

Example 207 4- [5- (cyclopropylmethoxy) -2-ethylsulfonylpyridin-4-yl] -2-methylisoquinolin-1-one.

Step 1: 5- (cyclopropylmethoxy) -2-ethylsulfonyl-4-iodopyridine

The title compound was prepared in a similar manner to Example 199.

- 257 038715 step 3, by replacing 6-ethylsulfonyl-4-iodopyridin-3-ol with 2-iodo-6-methylsulfonylpyridin-3-ol.

1H NMR (CDCl3, 400 MHz) δ 8.48 (s, 1H), 8.11 (s, 1H), 4.12 (d, J = 6.8 Hz, 2H), 3.37 (q, J = 7.6 Hz, 2H), 1.39-1.27 (m, 4H), 0.76-0.73 (m, 2H), 0.48-0.46 (m, 2H). LCMS: 367.8 (M + 1) +.

Step 2: 4- [5- (cyclopropylmethoxy) -2-ethylsulfonylpyridin-4-yl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 206, Step 7, by substituting 3- (cyclopropylmethoxy) -6ethylsulfonyl-2-iodopyridine for 6-ethylsulfonyl-4-iodopyridin-3-ol.

1H NMR (CDCl3, 400 MHz) δ 8.54-8.52 (m, 1H), 8.45 (s, 1H), 8.05 (s, 1H), 7.63-7.58 (m, 1H), 7.56-7.52 (m, 1H), 7.16 (d, J = 8.8 Hz, 1H), 4.01 (d, J = 7.2 Hz, 2H), 3.68 (s, 3H), 3.44 (q, J = 7.2 Hz, 2H), 1.36 (t, 3H), 1.091.05 (m, 1H), 0.50-0.48 (m, 2H), 0.19-0.18 (m, 2H). LCMS: 399.1 (M + 1) +.

Example 208 4- [5- (2-Hydroxyethylsulfonyl) -2-methoxyphenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one.

Stage 1: 2- (4-methoxyphenyl) sulfanyl ethyl acetate

4-Methoxybenzene-1-thiol (15.7 g, 0.11 mol), 2-bromoethyl acetate (18.8 g, 0.11 mol), and K2CO3 (46.6 g, 0.34 mol) in acetone (200 ml) were stirred at room temperature for 12 h, then the mixture was filtered. After extraction with CH ₂ Cl ₂ and chromatography on silica gel (PE: EA = 1: 0-10: 1), the title compound (21.1 g, 83.3%) was obtained as a colorless oil.

¹ H NMR (CDCl3, 400 MHz) δ 7.40 (dd, J1 = 6.8 Hz, J2 = 2.0 Hz, 2H), 6.86 (dd, J1 = 6.8 Hz, J2 = 2.0 Hz, 2H), 4.18 (t, J = 7.2 Hz, 2H), 3.80 (s, 3H), 3.02 (t, J = 7.2 Hz, 2H), 2.03 (s, 3H). LCMS: 139.0 (M-87) ⁺ .

Stage 2: 2- (4-methoxyphenyl) sulfonylethyl acetate

m-CPBA (80.3 g, 467 mmol) was added to the title compound, step 1 (21.1 g, 93.4 mmol) in CH ₂ Cl ₂ (500 ml). After stirring at room temperature for 12 h, the mixture was subjected to extraction with CH ₂ Cl ₂ and silica gel chromatography (PE: EA = 1: 0 ~ 1: 1) to give the title compound (20.0 g, 83.3%) as a colorless oils.

¹ H NMR (CDCl3, 400 MHz) δ 7.85 (dd, J1 = 6.8 Hz, J2 = 2.0 Hz, 2H), 7.04 (dd, J1 = 6.8 Hz, J2 = 2.0 Hz, 2H), 4.39 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.43 (t, J = 6.0 Hz, 2H), 1.89 (s, 3H). LCMS: 280.9 (M + Na) +.

Stage 3: 2- (3-bromo-4-methoxyphenyl) sulfonylethanol

Br2 (25 g, 155.0 mmol) was added dropwise over 30 min to the title compound from step 2 (8.0 g, 31.0 mmol) in acetic acid (100 ml) at 0 ° C. The mixture was heated at 50 ° C for 12 h. Aqueous Na ₂ SO ₃ (200 ml) was added and the pH was adjusted to 8 with saturated aqueous NaHCO ₃ . The mixture was subjected to extraction with EA and silica gel chromatography (PE: EA = 1: 0 ~ 1: 1) to give the title compound (2.7 g, 27.3%) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J = 2.4 Hz, 1H), 7.87 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H) , 4.05-4.00 (m, 5H), 3.34-3.67 (m, 3H). LCMS: 316.9, 318.9 (M + Na) +.

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Stage 4: 2- [2- (3-bromo-4-methoxyphenyl) sulfonylethoxy] oxane O / —OTHP

.0

To the title compound from Step 3 (1.0 g, 3.4 mmol) in CH2C12 (10 mL) was added 3,4 dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridinium p-toluenesulfonate (64.6 mg, 0.34 mmol) ... After stirring at room temperature for 12 hours, the mixture was subjected to extraction with CH ₂ Cl ₂ and silica gel chromatography (PE: EA = 1: 0 ~ 5: 1) to give the title compound (1.1 g, 85.6%) as a yellow oil. ...

Ή NMR (CDCl ₃ , 400 MHz) δ 8.11 (d, J = 2.4 Hz, 1H), 7.86 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.00 (d, J = 8.8 Hz, 1H) , 4.51 (dd, Ji = 4.0 Hz, J2 = 2.4 Hz, 1H), 4.09-4.03 (m, 1H), 3.98 (s, 3H), 3.84-3.79 (m, 1H), 3.79-3.74 (m, 1H ), 3.50-3.46 (m, 1H), 3.45-3.42 (m, 2H), 1.58-1.37 (m, 6H). LCMS: 401.0, 403.0 (M + Na) +.

Step 5: 2- [2-methoxy-5- [2- (oxan-2-yloxy) ethylsulfonyl] phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane _n / —OTHP

The title compound from Step 4 (700 mg, 1.8 mmol), 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane ( 938 mg, 3.6 mmol), Pd (dppf) Cl ₂ (263 mg, 0.36 mmol), and AcOK (1.05 g, 10.8 mmol) in 1,4-dioxane (7 ml) were stirred at 70 ° С for 12 h. After by column chromatography on silica gel (PE: EA = 1: 0 ~ 1: 1), the title compound (300 mg, 39.2%) was obtained as a yellow oil.

1H NMR (CDCl3, 400 MHz) δ 8.20 (d, J = 2.4 Hz, 1H), 7.94 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.52 (t, J = 4.0 Hz, 1H), 4.08-4.01 (m, 2H), 3.91 (s, 3H), 3.82-3.74 (m, 2H), 3.43 (t, J = 2.4 Hz, 2H), 1.581 .42 (m, 6H), 1.35 (s, 12H). LCMS: 343.0 (M + H-THP) +.

Step 6: 4- [2-methoxy-5- [2- (oxan-2-yloxy) ethylsulfonyl] phenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinoline-1-one

The title compound from Step 5 (325 mg, 0.76 mmol), the title compound of Example 41, Step 2 (201 mg, 0.64 mmol), Pd (dppf) Cl ₂ (66 mg, 0.08 mmol) and AcOK (125 mg , 1.28 mmol) in 1,4-dioxane (6 ml) was heated at 70 ° C for 12 h. Column chromatography on silica gel (PE: EA = 5: 1 ~ 0: 1) gave the title compound (80 mg, 23.6%) as a gray solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1H), 8.03 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H) , 7.58-7.69 (m, 2H), 7.14-7.18 (m, 2H), 7.06 (s, 1H), 4.50 (t, J = 4.4 Hz, 2H), 4.06-4.15 (m, 1H), 3.93 (s , 3H), 3.84-3.90 (m, 1H), 3.84 (s, 3H), 3.71-3.80 (m, 2H), 3.65 (s, 3H), 3.49 (t, J = 5.6 Hz, 2H), 3.41- 3.47 (m, 1H), 1.25-1.67 (m, 6H). LCMS: 538.2 (M + H) ⁺ ; 454.1 (M + H-THP) +.

Step 7: 4- [5- (2-hydroxyethylsulfonyl) -2-methoxyphenyl] -2-methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one

The title compound from Step 6 (80 mg, 0.15 mmol) and pyridinium p-toluenesulfonate (59 mg, 0.31 mmol) in DCM (2 ml) were stirred at room temperature for 5 h. After purification by preparative TLC (DCM: MeOH = 10: 1) The title compound (16.47 mg, 24.4%) was obtained as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 8.4 Hz, 1H), 8.05 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.88 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.59-7.62 (m, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H), 7.07 (s, 1H), 4.03-4.11 (m, 2H), 3.94 (s, 3H), 3.86 (s, 3H), 3.66 (s, 3H), 4.16 (t, J = 5.2 Hz, 2H), 2.72 (t, J = 6.4 Hz, 1H) ... LC-MS:

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454.1 (M + H) ⁺ .

Example 209:

N- [4- (cyclopropylmethoxy) -2-fluoro-5- [2-methyl-6- (1-methylpyrazol-4-yl) -1oxoisoquinolin-4-yl] phenyl] ethanesulfonamide

The title compound was prepared in 4 steps in a similar manner to Example 86, except that the cyclopropylmethanol alkoxide was replaced with sodium methoxide in step 1.

1H NMR (DMSO-d6, 400 MHz) δ 9.46 (s, 1H), 8.26 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 7.84 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.27-7.25 (m, 1H), 7.16 (d, J = 12.4 Hz, 1H), 3.97-3.96 (m, 2H), 3.85 (s, 3H), 3.54 (s, 3H), 3.13-3.07 (m, 2H), 1.30-1.26 (m, 2H), 0.91-0.90 (m, 1H), 0.27-0.22 (m, 2H), 0.04-0.09 (m, 2H ). LCMS: 511.1 (M + 1) ⁺ .

Example 210 4- (5-ethylsulfonyl-2-methoxyphenyl) -2-methyl-6- (1H-pyrazol-4-yl) isoquinolin-1-one

The title compound was prepared in a similar manner to Example 79 using 4 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1 H-pyrazole instead of 1-methyl-4- (tetramethyl-1,3,2 -dioxaborolan2-yl) -1 H-pyrazole.

1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J = 8.4 Hz, 1H), 8.02 (s, 2H), 7.97-8.00 (m, 1H), 7.75-7.79 (m, 2H), 7.50 ( s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 1.2 Hz, 1H), 3.82 (s, 3H), 3.54 (s, 3H), 3.31 (q, J = 7.2 , 2H), 1.13 (t, J = 7.2 Hz, 3H). LCMS: 424.0 (M + 1) +.

Example 211 4- (2-ethoxy-5-methylsulfonylphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin-1-one

2- (2-Ethoxy-5-methanesulfonylphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared in an analogous manner as in Example 90, step 1 and linked to the title compound of Example 41. , step 2, in a similar manner to Example 90, step 2 to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz) δ 8.48 (d, J = 8.4 Hz, 1H), 8.06-8.02 (m, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.61 (d, J = 1.6 Hz, 1H), 7.18 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 4.12 (q, J = 7.2 Hz, 2H), 3.94 (s, 3H), 3.66 (s, 3H), 3.12 (s, 3H), 1.17 (t, J = 7.2 Hz, 3H). LCMS: 438.1 (M + 1) ⁺ .

Example 212 2-methyl-6- (1-methylpyrazol-4-yl) -4- (5-methylsulfonyl-2-propoxyphenyl) isoquinolin1-one

2- (5-Methanesulfonyl-2-propoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was prepared in an analogous manner as in Example 90, step 1 and linked to the title compound of Example 41. , step 2, in a similar manner to Example 90, step 2 to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz) δ 8.49 (d, J = 8.4 Hz, 1H), 8.02 (s, J = 6.8 Hz, 1H), 7.90 (d, J = 2.4 Hz, 1H), 7.68 (s, 1H), 7.61 (s, 1H), 7.60 (d, J = 6.8 Hz, 1H), 7.18 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.08 (s, 1H), 4.00 ( m, 2H), 3.93 (s, 3H), 3.66 (s, 3H), 3.12 (s, 3H), 1.56 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H). LCMS: 452.0 (M + 1) ⁺ .

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Example 213: No. [2- [2-methyl-6- (1-methylpyrazol-4-yl) -1-oxoisoquinolin-4-yl] pyridin-4yl] ethanesulfonamide n

h and ν Ί I o

The title compound was prepared by sulfonylation of 2-chloropyridin-4-amine with ethanesulfonyl chloride and the resulting product was coupled with the title compound of Example 46, step 2.

1H NMR (CDCl3, 400 MHz) δ 10.65 (brs, 1H), 8.56 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 8.22 (s, 1H), 8.01-7.73 (m, 4H) , 7.37 (s, 1H), 7.18 (s, 1H), 3.87 (s, 3H), 3.59 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). LCMS: 424.0 (M + 1) +.

Example 214 [4- (cyclopropylmethoxy) -3 - (2-methyl-1-oxoisoquinolin-4-yl) phenyl] sulfamate.

Stage 1: [3-bromo-4- (cyclopropylmethoxy) phenyl] sulfamate

Br

3-Bromo-4- (cyclopropylmethoxy) phenol (970 mg, 4.0 mmol) and sulfamoyl chloride (1.95 g, 16.0 mmol) in DMA (15 ml) were stirred at room temperature for 5 h. the title compound (1.0 g, yield: 78.0%), which was used without purification.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.28 (d, J = 2.8 Hz, 1H), 7.24 (dd, J1 = 8.8 Hz, J ₂ = 2.8 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 5.07 (s, 2H), 3.89 (d, J = 6.8 Hz, 2H), 1.35-1.25 (m, 1H), 0.70-0.63 (m, 2H), 0.43-0.36 (m, 2H). LCMS: 322.0 (M + 1) ⁺ .

Stage 2: [4- (cyclopropylmethoxy) -3- (2-methyl-1-oxoisoquinolin-4-yl) phenyl] sulfamate

The title compound from Step 1 (300 mg, 0.935 mmol), the title compound of Example 89, Step 1 (293 mg, 1.028 mmol), K ₃ PO ₄ (595 mg, 2.805 mmol) and Pd (dppf) Cl ₂ (15 mg) in dioxane (5 ml) and H ₂ O (1 ml) was heated at 70 ° C for 18 h under N ₂ , after which it was found that the sulfamoyl group had been cleaved to phenol. Purification by HPLC gave phenol (59 mg, 0.184 mmol) which was treated again with sulfamoyl chloride (100 mg, 0.87 mmol) in DMA (3 ml) in a manner similar to Step 1. Preparative HPLC gave the title compound (64.21 mg, yield: 87.02%) as a gray solid.

1H NMR (CDCl3, 400 MHz) δ 8.48 (d, J = 8.0 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.35 (dd, J1 = 9.2 Hz, J ₂ = 2.4 Hz, 1H), 7.30-7.27 (m, 1H), 7.26-7.22 (m, 1H), 7.04 (s, 1H), 6.98 (d, J = 9.2 Hz, 1H), 5.14 (s, 2H), 3.82-3.73 (m, 2H), 3.62 (s, 3H), 1.03-1.90 (m, 1H), 0.45-0.32 (m, 2H), 0.13-0.03 (m, 2H). LCMS: 401.0 (M + 1) ⁺ .

Example 215 [4- (cyclopropylmethoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] sulfamate

The title compound was prepared in a similar manner to Example 214, step 2, except that 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) -2 (1H) -pyridinone was replaced with the title compound of Example 89, Step 1.

1H NMR (CDCl3, 400 MHz) δ 7.54 (d, J = 2.0 Hz, 1H), 7.50 (s, 1H), 7.23-7.18 (m, 2H), 6.92-6.87 (m, 1H), 5.20 (s, 2H), 3.84 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 2.20 (s, 3H), 1.25-1.17 (m, 1H), 0.66-0.59 (m, 1H), 0.36-0.29 (m, 1H). LCMS: 365.1 (M + 1) ⁺ .

Example 216: 4- (2-ethoxy-5-methylsulfonylphenyl) -2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

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2-Bromo-1-ethoxy-4-methanesulfonylbenzene was obtained in a manner similar to that described in example

46, step 1, except that iodoethane was replaced with (chloromethyl) cyclopropane. The title compound of Example 163, Step 3, and 2-bromo-1-ethoxy-4-methanesulfonylbenzene were reacted in a similar manner as in Example 89, Step 2 to provide the title compound.

1H NMR (CDCl3, 400 MHz): δ 7.92 (dd, J1 = 8.8 Hz, b = 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H) , 6.69 (d, J = 8.8 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 3.59 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.33- 2.18 (m, 2H), 1.65-1.61 (m, 4H), 1.45-1.02 (t, J = 7.2 Hz, 3H). LCMS: 362.0 (M + H) +.

Example 217: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-5,6,7,8tetrahydroisoquinolin-1-one

O

The title compound of Example 163, Step 3, and 2-bromo-1- (cyclopropylmethoxy) -4methylsulfonylbenzene, were reacted in a similar manner as in Example 89, Step 2 to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz): δ 7.92 (dd, J1 = 8.4 Hz, J ₂ = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.06 (s, 1H), 7.02 ( d, J = 8.4 Hz, 1H), 3.92-3.87 (m, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.70-2.60 (m, 2H), 2.40-2.30 (m, 2H) , 1.771.64 (m, 4H), 1.21-1.17 (m, 1H), 0.63-0.61 (m, 2H), 0.29-0.27 (m, 2H). LCMS: 388.1 (M + H) ⁺ .

Example 218 N- [4- (cyclopropylmethoxy) -2-fluoro-5- (2-methyl-1-oxo-5,6,7,8-tetrahydroisoquinolin4-yl) phenyl] methanesulfonamide

N- [5-bromo-4- (cyclopropylmethoxy) -2-fluorophenyl] methanesulfonamide was prepared in 3 steps in a manner similar to that described in Example 86, except that the cyclopropylmethanol alkoxide was replaced with sodium methoxide in step 1 and the methanesulfonyl chloride was replaced with ethanesulfonyl chloride by Step 3: The title compound of Example 163, Step 3, and N- [5-6pom-4 (cyclopropylmethoxy) -2-fluorophenyl] methanesulfonamide, were reacted in a similar manner as Example 89, Step 2 to provide the title compound ...

1H NMR (CDCl3, 400 MHz): δ 7.29 (d, J = 9.2 Hz, 1H), 6.96 (s, 1H), 6.70 (d, J = 12.0 Hz, 1H), 6.21 (s, 1H), 3.76- 3.75 (m, 2H), 3.56 (s, 3H), 3.02 (s, 3H), 2.70-2.60 (m, 2H), 2.36-2.17 (m, 2H), 1.80-1.70 (m, 2H), 1.691. 64 (m, 2H), 1.20-1.10 (m, 1H), 0.60-0.50 (m, 2H), 0.27-0.25 (m, 2H). LCMS: 421.1 (M + H) ⁺ .

Example 219: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -2-methyl-5,6,7,8-tetrahydroisoquinolin-1-one

2-Bromo-1- (cyclopropylmethoxy) -4- (ethanesulfonyl) benzene was prepared in a manner similar to Example 79, step 3, except that the cyclopropylmethanol alkoxide was replaced with sodium methoxide. The title compound of Example 163, Step 3, and 2-bromo-1 (cyclopropylmethoxy) -4- (ethanesulfonyl) benzene, were reacted in a similar manner as in Example 89, Step 2 to provide the title compound.

1H NMR (DMSO-d6, 400 MHz): δ 7.83 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.56 (d, J = 2.4 Hz, 1H), 7.43 (s, 1H), 7.65 ( d, J = 8.8 Hz, 1H), 4.02-3.90 (m, 2H), 3.43 (s, 3H), 3.29-3.23 (m, 2H), 2.49-2.44 (m, 4H), 1.61-1.50 (m, 4H), 1.15-1.08 (m, 5H), 0.53-0.51 (m, 2H), 0.29-0.27 (m, 2H). LCMS: 402.0 (M + H) ⁺ .

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Example 220 Propane Carboxamide

N- [2- (2-methyl-1-oxoisoquinolin-4-yl) -4-methylsulfonylphenyl] cyclo-

2-Bromo-4-methanesulfonylaniline was coupled to the title compound of Example 89, step 1, in a manner similar to Example 89, step 2. The resulting product was reacted with cyclopropanecarbonyl chloride using diisopropylethylamine in THF to provide the title compound ...

1H NMR (CDCl ₃ , 400 MHz) δ 9.38 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.53-7.64 (m, 3H), 6.94 (d, J = 8.0 Hz, 1H), 3.59 (s, 3H), 3.25 (m, 3H), 1.64 (brs, 1H ), 0.520.75 (m, 4H). LCMS: 397.0 (M + 1) +.

Example 221 N- [2- (2-methyl-1-oxoisoquinolin-4-yl) -4-methylsulfonylphenyl] propanamide

The title compound was prepared in a similar manner to Example 220, except that the propanoyl chloride was replaced by cyclopropanecarbonyl chloride.

1H NMR (CDCl ₃ , 400 MHz) δ 8.70 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 6.4 Hz, 1H), 8.04 (dd, J = 2.0, 8.8 Hz, 1H), 7.88 ( d, J = 2.0 Hz, 1H), 7.55-7.65 (m, 2H), 7.19 (s, 1H), 7.01-7.20 (m, 2H), 3.67 (s, 3H), 3.11 (s, 3H), 2.00 -2.21 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). LCMS: 385.0 (M + 1) ⁺ .

Example 222 N- [2- (2-methyl-1-oxoisoquinolin-4-yl) -4-methylsulfonylphenyl] acetamide

The title compound was prepared in a similar manner to Example 220, except that the acetyl chloride was replaced by cyclopropanecarbonyl chloride.

1H NMR (CDCl ₃ , 400 MHz) δ 8.67 (d, J = 8.8 Hz, 1H), 8.51 (d, J = 7.6 Hz, 1H), 8.03 (dd, J = 2.0, 6.8 Hz, 1H), 7.86 ( d, J = 2.0 Hz, 1H), 7.62-7.67 (m, 1H), 7.57-7.62 (m, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 7.07-7.10 (m, 1H) , 3.54 (s, 3H), 3.10 (s, 3H), 1.96 (s, 3H). LCMS: 371.0 (M + 1) ⁺ .

Example

223:

4- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -2-methyl-5,6,7,8tetrahydroisoquinolin-1-one

The sulfonyl compound of Example 194 was coupled as described in Example 163 to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz): δ 7.89 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.51 (d, J = 2.4 Hz, 1H), 7.10 (s, 1H), 6.69 (d , J = 8.8 Hz, 1H), 3.62 (s, 3H), 3.04-3.02 (m, 5H), 2.67-2.62 (m, 2H), 2.26-2.24 (m, 2H), 1.78-1.76 (m, 2H ), 1.75-1.74 (m, 2H), 1.05-1.02 (m, 1H), 0.58-0.54 (m, 2H), 0.23-0.21 (m, 2H). LCMS: 387.0 (M + H) ⁺ .

Example 224 8- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methyl-2- (1-methylpyrazol-4yl) pyrido [4,3-b] pyrimidin-5-one.

Stage 1: ethyl 4-methyl-2- (1-methylpyrazol-4-yl) pyrimidine-5-carboxylate

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Ethyl 2-chloro-4-methylpyrimidine-5-carboxylate (1.0 g, 5.0 mmol), 1-methyl-4- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.24 g, 6.0 mmol) , K ₃ PO ₄ (3.18 mg, 15.0 mmol) and Pd (dppf) Cl ₂ (100 mg) in dioxane (15 ml) and H ₂ O (3 ml) were heated at 120 ° С for 18 h in an atmosphere of N ₂ ... Chromatography on silica gel (PE: EA = 3: 1 to 1: 1) afforded the title compound (72 mg, yield: 32.0%).

¹ H NMR (CDClj, 400 MHz) δ 9.08 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 4.40 (q, J = 7.2 Hz, 2H), 3.98 (s, 3H), 2.82 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). LCMS: 247.1 (M + 1) +.

Stage 2: ethyl 4 - [(E) -2- (dimethylamino) ethenyl] -2- (1-methylpyrazol-4-yl) pyrimidine-5-carboxylate and ethyl 2- (1-methylpyrazol-4-yl) -4 - [(E) -2-pyrrolidin-1-ylethenyl] pyrimidine-5-carboxylate

The title compound from Step 1 (800 mg, 3.22 mmol), DMF-DMA (15.0 ml) and pyrrolidine (3.0 ml) were heated at 120 ° C for 5 h. Extraction of EA gave a mixture of the title compounds (500 mg, ~ 70:30 by LC-MS) which were used without purification. LCMS: 328.1 (M + 1) ⁺ .

Stage 3: 6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3-d] pyrimidin-5-one

A mixture of the title compounds from Step 2 (500 mg) was treated with ethanolic methylamine (15 mL, 30% CH ₃ NH ₂ in EtOH) and heated at 80 ° C for 5 h. After concentration, the resulting solids were triturated with hexane (10 ml) and collected to give the title compound (220 mg, 55.0%).

¹ H NMR (CDClj, 400 MHz) δ 9.57 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.00 (s, 3H), 3.61 (s, 3H). LCMS: 242.0 (M + 1) ⁺ .

Stage 4: 8-bromo-6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3-d] pyrimidin-5-one

The title compound of Step 3 (220 mg, 0.912 mmol) and Br ₂ (146 mg, 0.912 mmol) in HOAc (15 mL) was stirred at room temperature for 2 hours.

Water (150 ml) was added and the resulting solid was collected and triturated with DCM: PE = 10: 1 (10 ml) to give the title compound (200 mg, yield: 69.0%).

'H NMR (CDCl ₃ , 400 MHz) δ 9.54 (s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.77 (s, 1H), 4.01 (s, 3H), 3.62 (s, 3H).

Step 5: 8- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methyl-2- (1-methylpyrazol-4yl) pyrido [4,3-d] pyrimidin-5-one

The title compound from Step 4 (200 mg, 0.627 mmol), the title compound of Example 90, Step 1 (266 mg, 0.752 mmol), K ₃ PO ₄ (400 mg, 1.881 mmol) and Pd (dppf) Cl ₂ (10 mg) in dioxane (4 ml) and H2O (1 ml) was heated at 70 ° С for 18 h under N2 atmosphere. Preparative HPLC afforded the title compound (104.5 mg, 35.8%) as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.24-8.18 (m, 2H), 8.07 (s, 1H), 7.96 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.77 (s, 1H), 7.10 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.91 (d, J = 7.2 Hz, 2H), 3.68 (s, 3H), 3.12 (s, 3H) , 1.131.01 (m, 1H), 0.54-0.44 (m, 2H), 0.21-0.14 (m, 1H). LCMS: 466.1 (M + 1) ⁺ .

Example 225 8- (5-ethylsulfonyl-2-propoxyphenyl) -6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3d] pyrimidin-5-one.

Stage 1: 2-bromo-4-ethylsulfonyl-1-propoxybenzene

- 264 038715

NaH (112 mg, 2.80 mmol, 60% in mineral oil) was added to a solution of p-propanol (224 mg, 3.74 mmol) in THF (10 ml) at 0 ° С. After stirring at 0 ° C for 30 min, 2-bromo4- (ethanesulfonyl) -1-fluorobenzene (500 mg, 1.87 mmol) was added and the mixture was stirred at room temperature for 4 h. By addition of saturated NH ₄ Cl (10 ml) followed by extraction with EA gave the title compound (300 mg, yield: 52.3%) which was used immediately.

Stage 2: 2- (5-ethylsulfonyl-2-propoxyphenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound from Step 1 (300 mg, 0.98 mmol), 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane ( 622 mg, 2.45 mmol), KOAc (288 mg, 2.94 mmol), Pd ₂ (dba) ₃ (92 mg, 0.10 mmol), and X-Phos (62 mg, 0.13 mmol) in dioxane (5 mL) were purged with Ar and heated at 70 ° C for 12 hours. Extraction with CH ₂ Cl ₂ and chromatography on silica gel (PE: EA = 20: 1 ~ 5: 1) gave the title compound (200 mg, yield: 57.7%) as a gray solid. ...

1H NMR (CDCl ₃ , 400 MHz) δ 8.13 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.02 (t, J = 5.6 Hz, 2H), 3.13 (q, J = 7.2 Hz, 2H), 1.89 (q, J = 6.8 Hz, 2H), 1.36-1.25 (m, 15H), 1.12 (t, J = 6.8 Hz, 3H). LCMS: 272.9 (M + 1) +.

Stage 3: 8- (5-ethylsulfonyl-2-propoxyphenyl) -6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3d] pyrimidin-5-one

The title compound from Step 2 (60 mg, 0.17 mmol), the title compound of Example 224, Step 4 (64 mg, 0.20 mmol), K3PO4 (108 mg, 0.51 mmol) and Pd (dppf) Cl ₂ (15 mg , 0.02 mmol) in dioxane (8 mL) was purged with N2 and heated at 70 ° C for 18 h. Extraction with CH ₂ Cl ₂ and preparative HPLC gave the title compound (66.11 mg, yield: 83.3%) as a gray solid. ...

1H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.19 (s, 1H), 8.12 (d, J = 2.4 Hz, 1H), 8.06 (s, 1H), 7.96 (dd, J1 = 8.8 Hz , J2 = 2.4 Hz, 1H), 7.70 (s, 1H), 7.15 (d, J = 8.4 Hz, 1H), 4.03-3.95 (m, 5H), 3.67 (s, 3H), 3.20 (q, J = 7.2 Hz, 2H), 1.67-1.60 (m, 2H), 1.36 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 7.2 Hz, 3H). LCMS: 468.2 (M + 1) ⁺ .

Example 226: 8- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-2- (1-methylpyrazol-4yl) pyrido [4,3-d] pyrimidin-5-one

The title compound was prepared in three steps in a similar manner to Example 225, except that cyclopropylmethanol was replaced by n-propanol in step 1.

1H NMR (CDCl ₃ , 400 MHz) δ 9.64 (s, 1H), 8.22 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.07 (s, 1H), 7.92 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.77 (s, 1H), 7.10 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.90 (d, J = 6.8 Hz, 2H), 3.68 ( s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.08-1.06 (m, 1H), 0.52-0.47 (m, 2H), 0.21-0.17 (m, 2H). LCMS: 480.2 (M + H) +.

- 265 038715

Example 227: d] pyrimidin-5-one

8- (2-ethoxy-5-ethylsulfonylphenyl) -6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3-

The title compound was prepared in three steps in a similar manner to Example 225, except that ethanol was replaced by n-propanol in step 1.

¹ H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.19 (s, 1H), 8.10 (s, 1H), 8.06 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 4.13 (q, J = 6.8 Hz, 2H), 3.95 (s, 3H), 3.67 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 6.8 Hz, 3H). LCMS: 454.1 (M + H) +.

Example 228: 8- (2-ethoxy-5-ethylsulfonylphenyl) -6-methyl-2- (1-methylpyrazol-4-yl) pyrido [4,3d] pyrimidin-5-one

^f X N-AV

O

2-Bromo-4-methylsulfonyl-1-propoxybenzene was prepared in a manner similar to Example 46, step 1, except that 1-chloropropane was replaced by (chloromethyl) cyclopropane and the resulting product was used to prepare 4.4, 5,5-tetramethyl-2- (5-methylsulfonyl-2-propoxyphenyl) -1,3,2-dioxaborolane in a similar manner to Example 225, step 2 which was then used to prepare the title compound in a similar manner to Example 225 , stage 3.

¹ H NMR (CDCl3, 400 MHz) δ 9.64 (s, 1H), 8.19 (s, 1H), 8.16 (d, J = 2.4 Hz, 1H), 8.07 (s, 1H), 7.99 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.70 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 4.01 (t, J = 6.4 Hz, 2H), 3.96 (s, 3H), 3.68 ( s, 3H), 3.12 (s, 3H), 1.67-1.61 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H). LCMS: 454.1 (M + H) ⁺ .

Example 229: No. [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] -Nmethylmethanesulfonamide

The title compound of Example 102 (56 mg, 0.13 mmol) in DMF (0.2 ml) was treated with NaH (60% dispersion in oil, 6 mg, 0.16 mmol). After about 15 min, methyl iodide (0.012 mL, 0.2 mmol) was added. After completion of the reaction by silica gel chromatography, the title compound (55 mg, 0.13 mmol) was obtained as a cream solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.96-2.17 (s, 3H), 2.98 (s, 3H), 3.25 (s, 3H), 3.49 (s, 3H), 6.82 (d, J = 8.84 Hz, 1H), 7.21-7.40 (m, 3H), 7.40-7.54 (m, 2H), 7.59 (s, 1H), 7.82 (d, J = 2.53 Hz, 1H). LCMS (M + H) ⁺ 435.

Example 230 N- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] -N- (oxetane-3yl) methanesulfonamide

The title compound of Example 102 (46 mg, 0.11 mmol), Cs ₂ CO ₃ (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 ml) was exposed to microwaves at 130 ° C for 2 h. Additional oxetan-3-yl 4methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs ₂ CO ₃ (126 mg, 0.39 mmol) were added and microwave exposure was resumed at 130 ° C for another 2 h. The mixture was purified by chromatography on silica gel (EA) with

266 038715 afforded the title compound (20 mg, 0.04 mmol) as a cream solid in 38% yield.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H), 2.98 (s, 3H), 3.50 (s, 3H), 4.41 (t, J = 6.82 Hz, 2H), 4.58 (t, J = 6.95 Hz, 2H), 5.30 (quin, J = 7.01 Hz, 1H), 6.83 (d, J = 8.84 Hz, 1H), 7.06-7.20 (m, 1H), 7.22-7.35 (m, 2H),

7.39 (d, J = 2.53 Hz, 1H), 7.43-7.57 (m, 1H), 7.60 (s, 1H), 7.83 (d, J = 2.27 Hz, 1H). LCMS (M + H) + 477.

Example 231: d] pyrimidin-5-one.

8- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylpyrido [4,3 Stage 1: 6H-nupugo [4,3-d] nupuMuguH-5-oH

In an atmosphere of N _2, ethyl 3-oxobutanoate (40.12 g, 0.31 mol) and 1,3,5-triazine (25.00 g, 0.31 mol) in dry EtOH (90 ml) were heated at 80 ° С for 2 h, EtONa ( 8.39 g, 0.12 mol) and continued heating at 80 ° C for 18 h. The mixture was concentrated and water (300 ml) was added. Acidification with concentrated HCl (50 ml) gave a precipitate which was collected and washed with cold acetone (20 ml) and dried in vacuo to give the title compound (1.20 g, yield: 2.6%) as a brown solid.

1H NMR (DMSO-d6, 400 MHz) δ 11.92 (brs, 1H), 9.41 (s, 1H), 9.32 (s, 1H), 7.72 (dd, Ji = 7.6 Hz, J2 = 6.4 Hz, 1H), 6.57 (d, J = 7.6 Hz, 1H).

Stage 2: 8-bromo-6H-pyrido [4,3-d] pyrimidin-5-one

To the title compound from Step 1 (200 mg, 1.36 mmol) in DMF (20 mL) was added NBS (242 mg, 1.36 mmol) at 0 ° C. The resulting mixture was stirred at 15 ° C for 2 h and then concentrated and treated with acetone (20 ml). The resulting solid was collected to give the title compound (220 mg, yield: 71.6%) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 12.25 (brs, 1H), 9.46 (s, 1H), 9.42 (s, H), 8.12 (d, J = 6.0 Hz, 1H).

Step 3: 8-bromo-6-methylpyrido [4,3-d] pyrimidin-5-one

Sodium hydride (21 mg, 0.53 mmol, 60% in mineral oil) was added to the title compound from step 2 (100 mg, 0.44 mmol) in DMF (10 ml) at 0 ° C. After stirring for 0.5 h, MeI (126 mg, 0.88 mmol) was added and stirring continued at 0 ° C for 2 h. Subsequent extraction with EA gave the title compound (80 mg, yield: 75.3%) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 9.47 (s, 1H), 9.46 (s, 1H), 8.53 (s, 1H), 3.54 (s, 3H). LCMS: 240.0, 242.0 (M + H) ⁺ .

Step 4: 8- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidine-5one

The title compound from Step 3 (100 mg, 0.42 mmol), the title compound of Example 90, Step 1 (147 mg, 0.42 mmol), Pd (dppf) Cl ₂ (62 mg, 0.08 mmol), K ₃ PO ₄ (221 mg, 1.04 mmol) in dioxane (4 ml) and H2O (0.5 ml) was purged with N2 and heated at 100 ° С for 18 h. Subsequent extraction with CH ₂ Cl ₂ , chromatography on silica gel (PE: EA = 2: 1 ~ 0: 1) and preparative HPLC gave the title compound (54.57 mg, yield: 34.2%) as a yellow solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 9.54 (s, 1H), 9.30 (s, 1H), 8.18 (s, 1H), 7.93 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 3.91 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 3.20 (s, 3H), 0.94-0.92 (m, 1H), 0.35-0.30 (m, 2H), 0.10-0.06 (m, 2H). LCMS: 386.0 (M + H) ⁺ .

- 267 038715

Example 232 8- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidin5-one

2- [2- (Cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane from Example 226 was reacted with the title compound from Example 231, step 3 in a similar manner to Example 231, step 4 to provide the title compound.

Ή NMR (DMSO-d6, 400 MHz) δ 9.54 (s, 1H), 9.30 (s, 1H), 8.17 (s, 1H), 7.88 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 3.92 (d, J = 6.8 Hz, 2H), 3.61 (s, 3H), 3.27 (q, J = 7.2 Hz , 2H), 1.14 (t, J = 7.2 Hz, 3H), 0.94-0.93 (m, 1H), 0.34-0.32 (m, 2H), 0.10-0.08 (m, 2H). LCMS: 400.0 (M + H) ⁺ .

Example 233 8- [2- (2,4-Difluorophenoxy) -5-methylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidin5-one.

Step 1: 8- (2-fluoro-5-methylsulfonylphenyl) -6-methylpyrido [4,3-d] pyrimidin-5-one

2-Bromo-1-fluoro-4-methylsulfonylbenzene was replaced with the title compound of Example 225, step 1, and converted to 2- (2-fluoro-5-methylsulfonylphenyl) -4,4,5,5-tetramethyl-1, 3,2dioxaborolane in a similar manner to Example 225, step 2 and then reacted with the title compound of Example 231, step 3 in a similar manner to Example 231, step 4. LCMS: 333.9 (M + H) ⁺ .

Stage 2: 8- [2- (2,4-difluorophenoxy) -5-methylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidine-5one

The title compound from Step 2 (60 mg, crude), 2,4-difluorophenol (35 mg, 0.27 mmol) and Cs ₂ CO ₃ (176 mg, 0.54 mmol) in DMSO (2 ml) were heated at 100 ° C for Extraction with EA and preparative HPLC afforded the title compound (10.04 mg, yield: 13.6% over two steps) as a yellow solid.

Ή NMR (CDCl3, 400 MHz) δ 9.73 (s, 1H), 9.34 (s, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.92 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H ), 7.72 (s, 1H), 7.19-7.17 (m, 1H), 6.97-6.89 (m, 3H), 3.72 (s, 3H), 3.12 (s, 3H). LCMS: 444.1 (M + H) ⁺ .

Example 234 8- [2- (2,4-Difluorophenoxy) -5-ethylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidin-5 one.

Stage 1: 1- (2-bromo-4-ethylsulfonylphenoxy) -2,4-difluorobenzene

2-Bromo-1-fluoro-4-ethylsulfonylbenzene (130 mg, 0.49 mmol), 2,4-difluorophenol (78 mg, 0.60 mmol) and Cs ₂ CO ₃ (478 mg, 1.47 mmol) in DMSO (5 ml) were heated at 100 ° C. for 12 hours. Extraction with EA gave the title compound (150 mg, yield: 80.5%) as a gray solid.

Ή NMR (CDCl ₃ , 400 MHz) δ 8.18 (d, J = 2.0 Hz, 1H), 7.75 (dd, J1 = 8.4 Hz, J ₂ = 1.6 Hz, 1H), 7.22-7.16 (m, 1H), 7.06 -6.95 (m, 2H), 6.80 (d, J = 8.8 Hz, 1H), 3.16 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H). LCMS: 395.8 (M + NH4) +.

Stage 2: dioxaborolane

2- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-268 038715

The title compound from Step 1 was replaced with the title compound of Example 225, Step 1, and reacted in a similar manner to Example 225, Step 2.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.11 (d, J = 2.8 Hz, 1H), δ 7.95 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.55-7.50 (m, 1H) , 7.29-7.23 (m, 1H), 7.16-7.12 (m, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.32 (q, J = 7.2 Hz, 2H), 1.26 (s, 12H), 1.12 (t, J = 7.2 Hz, 3H). LCMS: 342.8 (M + H) (free boronic acid) ⁺ .

Step 3: 8- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -6-methylpyrido [4,3-d] pyrimidin-5-one

The title compound from Step 2 was replaced with the title compound of Example 225, Step 2, and the title compound of Example 231, Step 3 was replaced with the title compound of Example 224, Step 4, and reacted in a similar manner to that described in Example 225, step 3.

¹ H NMR (CDCl ₃ , 400 MHz) δ 9.60 (s, 1H), 9.27 (s, 1H), 8.12 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.94 (dd, J1 = 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.32-7.25 (m, 1H), 7.15-7.09 (m, 1H), 7.03-6.97 (m, 2H), 3.70 (s, 3H), 3.27 (q, J = 7.6 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H). LCMS: 458.0 (M + H) +.

Example 235 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -7-methyl- [1,2,4] triazolo [4.3a] pyrazin-8-one.

Stage 1: 5-bromo-7H- [1,2,4] triazolo [4,3-a] pyrazin-8-one

Bg

O

HCl (1 N ., 5.00 ml). The mixture was heated at 110 ° C for 4 h and concentrated to give the title compound (400 mg, yield: 85%) as a yellow solid, which was used without purification.

1H NMR (DMSO-d ₆ , 400 MHz): δ 11.78 (s, 1H), 9.25 (s, 1H), 7.25 (d, J = 6.0 Hz, 1H). LCMS: 214.9 (M + H) ⁺ .

Step 2: 5-bromo-7-methyl- [1,2,4] triazolo [4,3-a] pyrazin-8-one

To a solution of the title compound from Step 1 (400 mg, 1.86 mmol) in DMF (4 mL) was added NaH (149 mg, 3.72 mmol, 60% in mineral oil) in portions at 0 ° C. under N ₂ . The mixture was stirred at 20 ° C for 1 h and methyl iodide (792 mg, 5.58 mmol) was added. After stirring at 20 ° C. for 5 hours, water was added. Extraction with methylene chloride: 2-propanol (10: 1) gave the title compound (200 mg, yield: 47%) as a light yellow solid which was used without purification.

¹ H NMR (DMSO-d6, 400 MHz): δ 9.26 (s, 1H), 7.60 (s, 1H), 3.42 (s, 3H). LCMS: 228.9 (M + H) ⁺ .

Step 3: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -7-methyl- [1,2,4] triazolo [4,3а] pyrazin-8-one

The title compound from Step 2 (40 mg, 0.175 mmol), the title compound from Example 90, Step 1 (62 mg, 0.175 mmol), K ₃ PO ₄ (93 mg, 0.438 mmol) and Pd ( dppf) Cl ₂ (13 mg, 0.018 mmol) in dioxane (2 ml) and H2O (1 ml) were purged with N2 and exposed to microwaves at 70 ° C for 2 h.Chromatography on silica gel (PE: EA = 1: 4) followed by preparative HPLC gave the title compound (31.89 mg, yield: 48.6%) as an off-white solid.

1H NMR (DMSO-d6, 400 MHz): δ 8.91 (s, 1H), 8.06 (dd, Ji = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.43- 7.04 (m, 2H), 4.04 (d, J = 6.8 Hz, 2H), 3.52 (s, 3H), 3.23 (s, 3H), 0.99-0.96 (m, 1H), 0.41-0.36 (m, 2H) , 0.230.20 (m, 2H). LCMS: 375.0 (M + H) ⁺ .

Example 236 N- [4- (2,4-difluorophenoxy) -3- (7-methyl-8-oxo [1,2,4] triazolo [4,3-a] pyrazine-5yl) phenyl] ethanesulfonamide

The title compound of Example 235, step 2 (40 mg, 0.175 mmol), N- [4- (2,4 difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl) phenyl] ethanesulfonamide (77 mg, 0.175 mmol), K ₃ PO ₄ (93 mg, 0.438 mmol) and Pd (dppf) Cl ₂ (13 mg, 0.018 mmol) in dioxane (2 ml) and H2O (1 ml ) purged with N2 and exposed to microwaves at 70 ° C for 2 h. Preparative HPLC obtained the title compound (38.75 mg, yield: 49.3%) as an off-white solid.

1H NMR (CDCl ₃ , 400 MHz): δ 8.60 (s, 1H), 7.64 (d, J = 2.8 Hz, 1H), 7.45 (dd, Ji = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.10-7.05 (m, 1H), 6.99-6.88 (m, 3H), 6.74 (d, J = 8.8 Hz, 1H), 3.67 (s, 3H), 3.18 (q, J = 7.2 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H). LCMS: 462.0 (M + H) ⁺ .

Example 237 7- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -5-methyl- [1,3] oxazolo [4,5c] pyridin-4-one.

Stage 1: 3-nitro-4-hydroxy-1-methylpyridin-2-one

NaH (176 mg, 4.4 mmol, 60% in mineral oil) was added to 4-hydroxy-3-nitro-1H-pyridin-2-one (300 mg, 1.9 mmol) in DMF (5 ml) at 0 ° С in an atmosphere N ₂ . After stirring at 0 ° C for 30 min, CH ₃ I (272 mg, 1.9 mmol) in DMF (5 mL) was added dropwise and the mixture was stirred for 2 h at 25 ° C. Saturated aqueous NH ₄ Cl was added, the pH was adjusted to ˜3 with 1N. HCl and extraction with EA gave a residue, which was triturated with MeOH (0.5 ml): EA (10 ml): PE (5 ml). After filtration, the fine powder was evaporated to give the title compound (300 mg, 91%) as a yellow solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.75 (d, J = 7.2 Hz, 1H), 6.17 (d, J = 7.2 Hz, 1H), 3.54 (s, 3H). LCMS: 171.0 (M + 1) +.

Stage 2: 1-methyl-3-nitro-4-phenylmethoxypyridin-2-one

To the title compound from Step 1 (300 mg, 1.7 mmol) in CH3CN (15 mL) was added K ₂ CO ₃ (726 mg, 5.2 mmol) at 25 ° C. under N2. After stirring for 30 min, benzyl bromide (450 mg, 2.6 mmol) was added and the mixture was heated at 50 ° C for 20 h. After extraction with CH ₂ Cl _{2, the} residue was triturated with PE: EA (3: 1) to give the title compounds (250 mg, 54%) as a yellow solid.

1H NMR (CDCl3, 400 MHz) δ 7.43-7.29 (m, 6H), 6.12 (d, J = 7.2 Hz, 1H), 5.27 (s, 2H), 3.57 (s, 3H). LCMS: 261.0 (M + 1) ⁺ .

Stage 3: 3-amino-4-hydroxy-1-methylpyridin-2-one hydrochloride

To the title compound from Step 2 (2.00 g, 7.69 mmol, 1.00 eq.) In MeOH (50 ml) / EtOH (50 ml) / DMF (10 ml) was added Pd-C (10%, 0.2 g) under atmosphere N2. The suspension was purged three times with H2 and hydrogenated with balloon hydrogen for 5 h. The catalyst was removed by filtration, and anhydrous HCl in methanol (10 mL, 1.25 M) was added. Concentration gave a residue, which was treated a second time with HCl in methanol. Evaporation of the volatiles and trituration with DCM (30 ml) / hexane (30 ml) gave the title compound (1.29 g, 7.30 mmol, yield: 95%) as

- 270 038715 pink HCl salt after drying.

NMR (DMSO-d ₆ , 400 MHz) δ 9.45-8.02 (br, 3H), 7.64 (d, J = 7.6 Hz, 1H), 3.27 (d, J = 7.6 Hz, 1H), 3.43 (s, 3H ). LCMS: 163.0 (M + Na) ⁺ .

Step 4: 5-methyl- [1,3] oxazolo [4,5-c] pyridin-4-one

The title compound from Step 3 (500 mg, 2.8 mmol) in triethylorthoformate (10 ml) was heated to reflux for 5 h. The mixture was concentrated in vacuo at 55 ° C and purified by chromatography on silica gel (PE: EA = 1: 1) to give the title compound (130 mg, yield: 30%) as a yellow solid.

¹ H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 3.69 (s, 3H).

Step 5: 7-bromo-5-methyl- [1,3] oxazolo [4,5-c] pyridin-4-one

To the title compound from Step 4 (100 mg, 0.7 mmol) in CH3CN (5 mL) was added NBS (154 mg, 0.8 mmol) at 20 ° C. After 2 h, the mixture was concentrated in vacuo at 45 ° C. Purification by silica gel chromatography (PE: EA = 5: 1 ~ 2: 1) afforded the title compound (70 mg, yield: 45%) as a yellow solid.

NMR (CDCl * ,, 400 MHz) δ 8.04 (s, 1H), 7.52 (s, 1H), 3.69 (s, 3H).

Step 6: 7- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -5-methyl- [1,3] oxazolo [4,5c] pyridin-4-one

The title compound from Step 5 (60 mg, 0.3 mmol) in dioxane (2 ml) and H ₂ O (0.4 ml) was stirred at 15 ° C under N2 for 30 min. Added Pd (dppf) Cl ₂ (19 mg, 0.026 mmol), the title compound of Example 90, step 1 (120 mg, 0.3 mmol) and K ₃ PO ₄ (166 mg, 0.8 mmol) at 15 ° C under N2 ... The reaction mixture was heated at 60 ° C for 12 h. Purification by silica gel chromatography (EA) and preparative HPLC provided the title compound (20.63 mg, 20%) as a yellow solid.

NMR (CDCl ₃ , 400 MHz) δ 8.03 (d, J = 2.0 Hz, 1H), 8.02 (s, 1H), 7.96 (dd, ^ = 8.4 Hz, J2 = 2.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.76 (s, 3H), 3.1 (s, 3H), 1.18 (m, 1H), 0.60 (m, 2H), 0.30 ( m, 2H). LCMS: 375.1 (M + H) ⁺ .

Example 238 7- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,5-dimethyl- [1,3] oxazolo [4,5c] pyridin-4-one

The title compound was prepared from the title compound of Example 237, Step 3, in a manner similar to Example 237, Steps 4-6, except that triethyl orthoacetate was replaced with triethyl orthoformate.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.25 (q, J = 4.72 Hz, 2H), 0.48 (q, J = 5.89 Hz, 2H), 1.11 (m, 1H), 2.54 (s, 3H) , 3.21 (s, 3H), 3.60 (s, 3H), 4.00 (d, J = 6.82 Hz, 2H), 7.34 (d, J = 8.59 Hz, 1H), 7.88-7.98 (m, 3H). LCMS: 389 (M + H) ⁺ .

Example 239 5-methyl-7- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] - [1,3] oxazolo [4,5-c] pyridin-4-one

The title compound of Example 237, Step 5, and the title compound at 271 038715, Measure 370, Step 1 were reacted in a similar manner to Example 237, Step 6 to provide the title compound.

¹ H NMR (CDCl3, 400 MHz) δ 8.00 (s, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 4.42 (q, J = 8.0 Hz, 2H), 4.28 (s, 2H), 3.74 (s, 3H), 2.87 (s, 3H). LCMS: 417.0 (M + H) ⁺ .

Example 240: N- [4- (2,4-difluorophenoxy) -3- (5-methyl-4-oxo [1,3] oxazolo [4,5-c] pyridine-7yl) phenyl] ethanesulfonamide

N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethanesulfonamide was prepared from the title compound of Example 122, step 1, and 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane in a manner similar to that described in Example 208, step 5, and reacted with the title compound of Example 237, step 5, in a manner similar to that described in Example 237, step 6.

1H NMR (CDCl ₃ , 400 MHz) δ 8.01 (s, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J = 2.4 Hz, 1H), 7.22 ( dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 6.84 (m, 2H), 3.74 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.2 Hz, 3H). LCMS: 462.1 (M + H) +.

Example 241 N- [4- (2,4-difluorophenoxy) -3- (2,5-dimethyl-4-oxo [1,3] oxazolo [4,5-c] pyridin-7yl) phenyl] ethanesulfonamide

7-Bromo-2,5-dimethyl- [1,3] oxazolo [4,5-c] pyridin-4-one, obtained in example 238, and N- [4- (2,4difluorophenoxy) -3- (4 , 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethanesulfonamide prepared in Example 240 was reacted in a similar manner to Example 237 Step 6 to provide the title compound.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (t, J = 6.95 Hz, 3H), 2.45 (s, 3H), 3.13 (d, J = 7.83 Hz, 2H), 3.58 (s, 3H), 6.95 (d, J = 8.59 Hz, 1H), 7.03-7.30 (m, 3H), 7.30-7.48 (m, 2H), 7.91 (s, 1H), 9.86 (s, 1H). LCMS: 476 (M + H) ⁺ .

Example 242 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1- (cyclopropylmethyl) -3methylpyridin-2-one.

Step 1: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1H-pyridin-2-one

5-Bromo-3-methyl-1H-pyridin-2-one (950 mg, 5.05 mmol), the title compound of Example 90, step 1 (2.93 g, 5.95 mmol), Pd (dppf) Cl ₂ (365 mg, 0.5 mmol) and K ₃ PO ₄ (2.14 g, 10.1 mmol) in dioxane (30 ml) and water (5 ml) were purged with N2 and heated at 70 ° С for 12 h.Chromatography on silica gel (PE: DCM: EA = 3: 0: 1 to 0: 1: 3) gave the crude title compound (990 mg) as a yellow solid which was used immediately in the next step.

1H NMR (CDCl ₃ , 400 MHz) δ 12.57 (brs, 1H), 7.84 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.03 (d, J = 8.8 Hz, 1H), 3.96 (d, J = 7.2 Hz, 1H), 3.07 (s, 3H), 2.24 (s, 3H), 1.40-1.25 (m, 1H), 0.67-0.65 (m, 2H), 0.370 .36 (m, 2H). LCMS: 334.1 (M + 1) ⁺ .

Step 2: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1- (cyclopropylmethyl) -3methylpyridin-2-one

The title compound from Step 1 (80 mg), K2CO3 (77 mg, 0.56 mmol), bromomethylcyclo-272 038715 propane (62 mg, 0.46 mmol) in DMF (2 mL) was heated at 70 ° C for 4 h. Extraction EA and preparative HPLC gave the title compound (17 mg) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.85-7.83 (m, 2H), 7.67 (d, J = 2.0 Hz, 1H), 7.53 (s, 1H), 7.03 (d, J = 9.2 Hz,

1H), 3.95 (d, J = 6.8 Hz, 1H), 3.89 (d, J = 7.2 Hz, 1H), 3.07 (s, 3H), 2.23 (s, 3H), 1.34-1.26 (m, 2H), 0.68-0.65 (m,

2H), 0.65-0.61 (m, 2H), 0.44-0.43 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 388.2 (M + 1) +.

Example

243:

methylpropyl) pyridin-2-one

5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (2-

The title compound from Example 242, Step 1, was reacted in a similar manner to Example 242, Step 2, except that 1-bromo-2-methylpropane was replaced with bromomethylcyclopropane to provide the title compound.

¹ H NMR (CDCl3, 400 MHz) δ 7.85-7.82 (m, 2H), 7.56 (s, 1H), 7.53 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.94 (d, J = 7.2 Hz, 1H), 3.83 (d, J = 7.2 Hz, 1H), 3.07 (s, 3H), 2.30-2.26 (m, 1H), 2.23 (s, 3H), 1.28-1.27 (m, 1H) , 1.00 (s, 3H), 0.98 (s, 3H), 0.69-0.65 (m, 2H), 0.38-0.35 (m, 2H). LCMS: 390.2 (M + 1) ⁺ .

Example 244 methylpyridin-2-one

5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1- (2-methoxyethyl) -3-

The title compound from Example 242, Step 1, was reacted in a similar manner to Example 242, Step 2, except that 1-bromo-2-methoxyethane was replaced with bromomethylcyclopropane to provide the title compound.

1H NMR (CDCl ₃ , 400 MHz) δ 7.86-7.83 (m, 2H), 7.65 (d, J = 1.6 Hz, 1H), 7.59 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 4.22 (t, J = 4.8 Hz, 1H), 3.96 (d, J = 6.8 Hz, 1H), 3.74 (t, J = 4.8 Hz, 1H), 3.34 (s, 3H), 3.07 (s, 3H), 2.23 (s, 3H), 1.30-1.27 (m, 1H), 0.70-0.66 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 392.2 (M + 1) ⁺ .

Example 245: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (oxetane-3ylmethyl) pyridin-2-one ° h / °

Oh

Sodium hydride (42 mg, 1.04 mmol, 60% in mineral oil) was added to the title compound from example 242 step 1 (80 mg) in anhydrous DMF (4 ml) After stirring for 1 h, oxetane-3- yl methyl methanesulfonate (173 mg, 1.04 mmol) and stirring continued for 18 h. Extraction of EA from 1M HCl and purification by preparative HPLC afforded the title compound (24.0 mg) as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 7.85 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.51 (s, 1H), 7.03 (d, J = 8.8 Hz , 1Н), 4.83 (t, J = 7.2 Hz, 1Н), 4.57 (t, J = 6.4 Hz, 1Н), 4.30 (d, J = 7.2 Hz, 1Н), 3.95 (d, J = 6.8 Hz, 1Н ), 3.62-3.56 (m, 1H), 3.07 (s, 3H), 2.21 (s, 3H), 1.32-1.27 (m, 1H), 0.72-0.68 (m, 2H), 0.40-0.36 (m, 2H ). LCMS: 404.1 (M + 1) ⁺ .

Example 246 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (1,3-oxazol-4ylmethyl) pyridin-2-one

The title compound from Example 242, Step 1, was reacted in a similar manner to Example 245 except that 1,3-oxazole-4-273 038715 ylmethyl methanesulfonate was replaced with oxetan-3-ylmethylmethanesulfonate to provide the title compound ...

1H NMR (CDCl3, 400 MHz) δ 7.82 (s, 5H), 7.52 (s, 1H), 7.01 (d, J = 9.2 Hz, 1H), 5.11 (s, 2H), 3.94 (d, J = 6.8 Hz , 1H), 3.06 (s, 3H), 2.21 (s, 3H), 1.27-1.24 (m, 1H), 0.68-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 415.1 (M + 1) ⁺ .

Example 247 N- [3- [1- (cyclopropylmethyl) -5-methyl-6-oxonyridin-3-yl] -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

5-Bromo-3-methyl-1H-pyridin-2-one was N-alkylated with bromomethylcyclopropane to give 5-bromo-1- (cyclopropylmethyl) -3-methylpyridin-2-one. 5-Bromo-1- (cyclopropylmethyl) -3-methylpyridin-2one (100 mg, 0.41 mmol), [2- (2,4-difluorophenoxy) -5- (ethylsulfonylamino) phenyl] boronic acid (217 mg, 0.5 mol) , K ₃ PO ₄ (263 mg, 1.24 mmol) and Pd (dppf) Cl ₂ (30 mg, 41.3 mmol) in dioxane (8 ml) / water (1 ml) were purged with N2 and heated at 70-80 ° С for 12 h. Preparative HPLC afforded the title compound (56.0 mg, 28.6% yield) as a dull red semi-solid.

1H NMR (CDCl3, 400 MHz): δ 7.74 (s, 1H), 7.61 (s, 1H), 7.28 (d, J = 2.0 Hz, 1H), 7.10-7.15 (m, 1H), 6.927.00 (m , 2H), 6.82-6.89 (m, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.71 (br. S., 1H), 3.93 (d, J = 7.2 Hz, 3H), 3.12-3.21 (m, 2H), 2.24 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H), 1.22-1.33 (m, 1H), 0.57-0.67 (m, 2H), 0.36-0.43 (m, 2H ). LCMS: 475.1 (M + 1) ⁺ .

Example 248 N- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] methanesulfonamide.

Stage 1: 5-bromo-1- (cyclopropylmethyl) -3-methylpyridin-2-one

Potassium carbonate (1.32 g, 9.57 mmol) was added to 5-bromo-3-methyl-2-hydroxypyridine (600 mg, 3.19 mmol) and bromomethylcyclopropane (861 mg, 6.38 mmol) in DMF (6 ml). After heating at 70 ° C for 3 hours, extraction with EA and chromatography on silica gel (PE: EA = 30: 1 ~ 10: 1) gave the title compound (510 mg, yield: 66.0%) as a white solid.

1H NMR (CDCl3, 400 MHz) δ 7.39 (d, J = 2.0 Hz, 1H), 7.26 (d, J = 2.0 Hz, 1H), 3.77 (d, J = 6.8 Hz, 2H), 2.15 (s, 3H ), 0.65-0.60 (m, 2H), 0.40-0.37 (m, 2H). LCMS: 242.1; 244.1 (M + H) ⁺ .

Stage 2: 1- (cyclopropylmethyl) -3-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin2-one

The title compound from Step 1 (480 mg, 1.98 mmol), 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane ( 1.01 g, 3.96 mmol), KOAc (582 mg, 5.94 mmol), and Pd (dppf) Cl ₂ (146 mg, 0.20 mmol) in dioxane (9 ml) were purged with N2 and heated to 70 ° С for 8 h. After chromatography on silica gel (PE: EA = 30: 1 ~ 10: 1) gave the title compound (415 mg, ~ 70% purity by ¹ H NMR, yield: 55.1%) as a light yellow oil.

1H NMR (CDCl3, 400 MHz) δ 7.69 (s, 1H), 7.49 (s, 1H), 3.82 (d, J = 6.8 Hz, 2H), 2.14 (s, 3H), 1.32 (s, 12H), 1.27 -1.1.16 (m, 1H), 0.61-0.56 (m, 2H), 0.42-0.39 (m, 2H). LCMS: 290.3 (M + H) +.

Step 3: 1- (cyclopropylmethyl) -5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3methylpyridin-2-one

The title compound of Example 149 Step 3 (200 mg, 0.62 mmol), the title compound 274 038715 e from Step 2 (250 mg, 0.69 mmol, 70% purity), Pd (dppf) Cl ₂ (88 mg, 0.12 mmol) and K ₃ PO ₄ (3

M, 0.6 ml) in dioxane (6 ml) was purged with N2 and heated to 70 ° C for 4 h. Chromatography on silica gel (PE: EA = 3: 1 ~ 1: 1) gave the title compound (220 mg, yield: 78.8%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.45 (d, J = 2.0 Hz, 1H), 8.25 (s, 1H), 8.16 (s, 1H), 7.24-7.22 (m, 1H), 7.127.10 (m , 1H), 7.10-7.03 (m, 1H), 3.92 (d, J = 7.2 Hz, 2H), 3.38 (s, 3H), 2.26 (s, 3H), 1.27-1.21 (m, 1H), 0.65- 0.60 (m, 2H), 0.42-0.38 (m, 2H). LCMS: 448.1 (M + H) ⁺ .

Step 4: N- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] methanesulfonamide

Methanesulfonamide (68 mg, 0.71 mmol), NaH (28 mg, 0.7 mmol, 60% in mineral oil) and the title compound from step 3 (80 mg, 0.18 mmol) in DMF (2 ml) were reacted in a similar manner to that described in example 152 step 6 to afford the title compound (45.00 mg, yield: 54.4%) as an off-white solid.

1H NMR (CDCl3, 400 MHz) d 8.81 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 8.12 (s, 1H), 7.05-6.98 (m, 2H) , 6.91-6.89 (m, 1H), 3.87 (d, J = 7.2 Hz, 2H), 3.45 (s, 3H), 2.23 (s, 3H), 1.25-1.22 (m, 1H), 0.64-0.59 (m , 2H), 0.40-0.37 (m, 2H). LCMS: 463.1 (M + H) +.

Example 249: N- [4- [1 - (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] ethanesulfonamide

The title compound of Example 248 Step 3 was treated with EtSO ₂ NH _{2 in} place of MeSO 2 NH 2 in a similar manner to Example 248, Step 4 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 9.09 (s, 1H), 8.60 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.04-6.96 (m, 2H), 6.91-6.89 ( m, 1H), 3.87 (d, J = 7.2 Hz, 2H), 3.64 (q, J = 7.2 Hz, 2H), 2.22 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H), 1.25- 1.23 (m, 1H), 0.62-0.60 (m, 2H), 0.38-0.37 (m, 2H). LCMS: 477.2 (M + H) +.

Example 250: 1- (cyclopropylmethyl) -5- [6- (2,4-difluorophenoxy) -3- (methylsulfonylmethyl) -4oxocyclohexa-1, 5-diene-1 -yl] -3 -methylpyridin-2-one

The title compound from Example 248, Step 2, was reacted with the title compound from Example 381, Step 4 in a similar manner to Example 248, Step 3 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 7.47 (s, 1H), 7.41 (s, 1H), 7.37 (s, 1H), 7.18-7.16 (m, 1H), 7.04-7.02 (m, 1H), 7.01- 6.98 (m, 1H), 5.69 (s, 1H), 5.17 (s, 2H), 3.86 (d, J = 7.2 Hz, 2H), 2.99 (s, 3H), 2.20 (s, 3H), 1.28-1.27 (m, 1H), 0.65-0.60 (m, 2H), 0.42-0.39 (m, 2H). LCMS: 477.1 (M + H) +.

Example 251 1-Cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-methylpyridin2-one

Stage 1: 5-bromo-1-cyclopropyl-3-methylpyridin-2-one

At room temperature, NBS (63 mg, 0.35 mmol) was added to 1-cyclopropyl-3-methylpyridin2-one (Racine, et al. Chemical Communications 2013, 49, 67, 7412-7414) (53 mg, 0.36 mmol) in CH ₃ CN (0.7 ml). After 1 hour, extraction of EA from saturated aqueous NaHCO ₃ provided the title compound as yellow solids in quantitative yield.

Step 2: 1 -cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-methylpyridine-2-

The title compound from Step 1 was reacted with 2- [2 (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane in a manner similar to Example 224, Step 5 Chromatography on silica gel (40-75% EA in hexane) afforded the title compound (31 mg, 0.08 mmol, 42%) as a tan foam that turned glass on standing.

1H NMR (400 MHz, CDCl ₃ ) δ ppm 0.36-0.42 (m, 2H), 0.60-0.75 (m, 2H), 0.81-1.02 (m, 1H, partially closed), 1.05-1.37 (m, 7H, partially closed), 2.22 (s, 3H), 3.12 (q, J = 7.41 Hz, 2H), 3.43 (br. s., 1H), 3.94 (d, J = 6.82 Hz, 2H), 7.01 (d, J = 9.35 Hz, 1H), 7.45-7.53 (m, 1H), 7.62 (br. S., 1H), 7.72-7.83 (m, 2H). LCMS: 388 (M + 1) +.

Example 252 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methylfuro [2,3-c] pyridin-7-one.

Stage 1: 4-bromo-6H-furo [2,3-c] pyridin-7-one

Br o

A mixture of 6Н-furo [2,3-c] pyridin-7-one (1.0 g, 7.4 mmol) in DMF (30 ml) was treated with NBS (1.32 g, 7.4 mmol) in three equal portions at 0 ° С. After stirring the resulting mixture at 15 ° C for 2 h, it was treated with water (100 ml) and was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 3: 1) to afford the title compound (600 mg, 38%) as a yellow solid.

1H NMR (DMSO-d6, 400 MHz) δ 11.92 (s, 1H), 8.23 (s, J = 2.0 Hz, 1H), 7.47 (s, 1H), 6.88 (m, 1H), 6.88 (s, 1H) ...

Stage 2: 4-bromo-6-methylfuro [2,3-c] pyridin-7-one Br o

To a solution of the title compound from Step 1 (500 mg, 2.3 mmol) stirred at 0 ° C in DMF (5 mL) was added NaH (68 mg, 2.81 mmol, 60% in mineral oil). After stirring at 0 ° С for 30 min, methyl iodide (400 mg, 2.8 mmol) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 4 h. The reaction mixture was treated with saturated NH4Cl (aq, 30 ml) and extracted with EtOAc (30 ml x2). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (PE / EtOAc = 10: 1) to give the title compound (500 mg, 94%).

1H NMR (CDCl3, 400 MHz) δ 7.78 (d, J = 2.0 Hz, 1H), 7.30 (s, 1H), 6.70 (d, J = 2.0 Hz, 1H), 3.66 (s, 3H). LCMS (M + H) + = 229.

Step 3: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methylfuro [2,3-c] pyridin-7-one

A mixture of the title compound from Step 2 (150 mg, 0.66 mmol), 2- [2 (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (336 mg, 1.0 mmol), NaHCO ₃ (167 mg, 1.99 mmol), Pd (dppf) Cl ₂ (35 mg, 0.048 mmol) in dioxane / H ₂ O (10 ml / 2.5 ml) were bubbled with argon for 5 min. The mixture in a sealed vial was stirred at 80 ° C for 18 h. The reaction mixture was concentrated, treated with DCM (30 ml), washed with water (30 ml) and brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under vacuum. The resulting 276,038,715 residue was purified by preparative HPLC to give the title compound (63 mg, 25%) as a yellow solid.

1I NMR (CDCl ₃ , 400 MHz) δ 7.90-7.86 (m, 2H), 7.75 (d, J = 1.6 Hz, 1H), 7.31 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.57 (d, J = 1.6 Hz, 1H), 3.95 (d, J = 6.8 Hz, 2H), 3.74 (s, 3H), 3.18-3.12 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 3H), 1.16-1.15 (m, 1H), 0.61-0.55 (m, 2H), 0.31-0.27 (m, 2H). LCMS (M + H) + = 388.

Example 253 N- [4- (2,4-difluorophenoxy) -3- (6-methyl-7-oxofuro [2,3-c] pyridin-4yl) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Step 3 of Example 252 by substituting N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) phenyl] ethanesulfonamide on 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

'and NMR (CDCl ,, 400 MHz) δ 7.74 (s, 1H), 7.38 (m, 2H), 7.15 (m, 1H), 6.93-9.92 (m, 2H), 6.82-6.76 (m, 3H), 6.44 (s, 1H), 3.72 (s, 3H), 3.19-3.16 (q, J = 7.2 Hz, 2H), 1.45 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ = 461.

Example 254: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3-c] pyridine-7one

A mixture of 2- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (115 mg, 0.33 mmol), 4-bromo-6-methyl-6H, 7H- furo [2,3-c] pyridin-7-one (75 mg, 0.33 mmol), K ₃ PO ₄ (175 mg, 0.83 mmol), Pd (dppf) Cl ₂ (24 mg, 10%) in dioxane / I ₂ O (2.2 ml / 200 μl) was bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 70 ° C for 90 minutes. The reaction mixture was filtered through a short celite plug; the celite plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a brown residue. The resulting residue was purified by preparative HPLC to give the title compound (60 mg, 49%) as a white solid. LCMS (M + H) ⁺ = 374.

Example 255: N- [4- (cyclopropylmethoxy) -3- (6-methyl-7-oxofuro [2,3-c] pyridin-4yl) phenyl] ethanesulfonamide.

Stage 1: 2-bromo-1- (cyclopropylmethoxy) -4-nitrobenzene

A 0.2 M solution of cyclopropylmethanol (441 μL, 5.5 mmol) in THF, stirred at 0 ° С in a nitrogen atmosphere, was treated with 2 equal portions of KOtBu (579 mg, 5.2 mmol). After 5 minutes, the ice bath was removed; the mixture was stirred for 30 min at room temperature before being immersed in an ice bath and cooled to 0 ° C. A solution of 2-bromo-1-fluoro-4-nitrobenzene (1 g, 4.5 mmol) in THF (3 ml) was added dropwise. After 20 minutes, the ice bath was removed and the mixture was stirred overnight. The reaction mixture was quickly cooled with water (50 ml) and was extracted with EtOAc (3x50 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using an EtOAc gradient (5 to 50%) in hexanes to give the title compound (1.07 g, 88%) as a yellow solid.

Stage 2: 3-bromo-4- (cyclopropylmethoxy) aniline

ZV ^NH2 V?

^v Br

A mixture of 2-bromo-1- (cyclopropylmethoxy) -4-nitrobenzene (1.07 g, 3.9 mmol), ammonium chloride (421 mg, 7.8 mmol) and iron powder (1.1 g, 20 mmol) suspended in THF (6.5 ml), water (2.5 ml) and ethanol (6.5 ml), heat to 95 ° C using microwave radiation (standard) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with MeOH (~ 10 ml). The resulting filtrate was concentrated in vacuo. Received in

- 277 038715 as a result, the residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (939 mg, 90%). This substance was transferred further without further purification. LCMS (M + H) + = 242.

Stage 3: N- [3-bromo-4- (cyclopropylmethoxy) phenyl] ethane-1-sulfonamide

Ethylsulfonyl chloride (233 μL, 2.4 mmol) was added to a stirred solution of 3-bromo-4 (cyclopropylmethoxy) aniline (520 mg, 2.2 mmol) and pyridine (520 μL, 6.5 mmol) in DCM (4 mL) at 0 ° С under nitrogen atmosphere ... After that, the mixture was left to warm to room temperature and stirred for 12 h, then treated with 1N. HCl (15 ml) and extracted with DCM (3x15 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using an EtOAc gradient (10 to 100%) in hexanes to give the title compound (711 mg, 98%) as a yellow solid. LCMS (M + H) ⁺ = 335.

Stage 4: sulfonamide

N- [4- (cyclopropylmethoxy) -3- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethane-1-

A mixture of N- [3-bromo-4- (cyclopropylmethoxy) phenyl] etαn-1-sulfonamideα (711 mg, 2.1 mmol), 4,4,5,5 tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane-2 -yl) -1,3,2-dioxaborolane (1.1 g, 4.3 mmol), KOAc (470 mg, 4.8 mmol), Pd ₂ (dba) ₃ (59 mg, 3%) and 1,3,5,7- tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (62 mg, 10%) was suspended in anhydrous dioxane (14 ml). The stirred mixture was sealed and purged with nitrogen for 6 minutes using an oil bubbler as the outlet. After the nitrogen inlet and outlet was removed and the mixture in a closed vial was stirred at 70 ° C for 3 hours. After cooling to about 35 ° C, the reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc (75 ml). The filtrate was treated with water and extracted with EtOAc; the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The residue was purified by silica gel column chromatography using an EtOAc gradient (5 to 100%) in hexanes to give the title compound (527 mg, 65%). LCMS (M + H) ⁺ = 382.

Step 5: N- [4- (cyclopropylmethoxy) -3 - (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) phenyl] ethanesulfonamide

A mixture of N- [4- (cyclopropylmethoxy) -3- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethane-1sulfonamide (138 mg, 0.38 mmol), 4-bromo-6-methyl-6H, 7Н-furo [2,3-c] pyridin-7-one (75 mg, 0.33 mmol), K3PO4 (175 mg, 0.83 mmol), Pd (dppf) Cl ₂ (24 mg, 10%) in dioxane (2.2 ml ) and H2O (200 μL) were bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 70 ° C for 4 hours. The reaction mixture was then filtered through a short plug of celite, the celite plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by preparative HPLC to give the title compound (21 mg, 16%) as a tan solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.15-0.28 (m, 2H), 0.35-0.52 (m, 2H), 0.95-1.13 (m, 1H), 1.14-1.26 (m, 3H), 2.98 -3.09 (m, 2H), 3.57-3.65 (m, 3H), 3.77-3.87 (m, 2H), 7.04-7.22 (m, 3H), 7.55-7.64 (m, 1H), 8.058.17 (m, 1H), 9.49-9.57 (m, 1H). LCMS (M + H) ⁺ = 403.

- 278 038715

Example 256: N- [6- (2,4-difluorophenoxy) -5- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyridin-3yl] tansulfonamide.

Stage 1: 3-bromo-2- (2,4-difluorophenoxy) -5-nitropyridine

A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and 2,4-difluorophenol (1 ml, 11 mmol) in NMP (20 ml) was treated with cesium carbonate (3.9 g, 12 mmol). The resulting mixture was heated to 60 ° C for 12 hours. The mixture was treated with water (100 ml) and was extracted with EtOAc (3 x 50 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. The solid was purified by silica gel column chromatography (gradient 5 to 30% EtOAc in hexanes) to give the free base of the title compound (2 g, 59%) as a yellow solid. LCMS (M + H) + = 332.

Stage 2: 5-bromo-6- (2,4-difluorophenoxy) pyridin-3-amine

A mixture of 3-bromo-2- (2,4-difluorophenoxy) -5-nitropyridine (1.9 g, 5.9 mmol), ammonium chloride (637 mg, 11.8 mmol) and iron powder (1.65 g, 30 mmol) suspended in THF ( 10 ml), water (3 ml) and ethanol (10 ml), heated to 90 ° C using microwave radiation (standard) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50 ° C) MeOH (~ 50 ml).

The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (824 mg, 46%). LCMS (M + H) + = 302.

Stage 3: 6- (2,4-difluorophenoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-amine

A mixture of 5-bromo-6- (2,4-difluorophenoxy) pyridin-3-amine (400 mg, 1.33 mmol), 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolane-2 -yl) -1,3,2-dioxaborolane (675 mg, 2.7 mmol), KOAc (325 mg, 3.3 mmol), Pd ₂ (dba) ₃ (36 mg, 3%) and 1,3,5,7- tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane (38 mg, 10%) was suspended in dioxane (9 ml). The stirred reaction mixture was capped and purged with nitrogen for 5 to 7 minutes using an oil bubbler as the outlet. After removing the nitrogen inlet and outlet, the mixture in a closed vial was stirred at 80 ° C for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc (50 ml). The filtrate was treated with water and extracted with EtOAc; the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The residue was purified by silica gel column chromatography using a gradient (20-70%) EtOAc in hexanes to give the title compound (163 mg, 35%). LCMS (M + H) + = 349.

Stage 4: N- [6- (2,4-difluorophenoxy) -5- (4,4,5,5-tetra-methyl-1,3,2-dioxαborolαn-2-yl) pyridin-3yl] ethanesulfonamide

Ethylsulfonyl chloride (50 μl, 52 mmol) was added to a stirred solution of 6- (2,4 difluorophenoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3-amine (163 mg, 0.5 mmol) and pyridine (113 μl) in DCM (2.4 ml) at 0 ° С under nitrogen atmosphere.

The mixture was then allowed to warm to room temperature and stirred for 12 h, then treated with water (15 ml) and extracted with DCM (3x15 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using an EtOAc gradient (0 to 100%) in DCM to give the title compound (181 mg, 88%) as a tan solid.

- 279 038715

LCMS (M + H) + = 441.

Stage 5: sludge] ethanesulfonamide

N- [6- (2,4-difluorophenoxy) -5- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyridine-3-

A mixture of N- [6- (2,4-difluorophenoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3yl] ethanesulfonamide (145 mg, 0.38 mmol ), 4-bromo-6-methyl-6H, 7H-furo [2,3-c] pyridin-7-one (75 mg, 0.33 mmol), K3PO4 (175 mg, 0.83 mmol), Pd (dppf) Cl ₂ (24 mg, 10%) in dioxane / H ₂ O (2.2 ml / 200 μl) was bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 70 ° C for 4 h. After the reaction mixture was filtered through a short plug of celite, the plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by preparative HPLC to give the title compound (50 mg, 33%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.18-1.28 (m, 3H), 3.10-3.21 (m, 2H), 3.59-3.65 (m, 3H), 6.85-6.95 (m, 1H), 7.07 -7.19 (m, 1H), 7.35-7.51 (m, 2H), 7.73-7.79 (m, 1H), 7.80-7.85 (m, 1H), 7.90-7.97 (m, 1H), 8.148.20 (m, 1H), 9.78-10.09 (m, 1H). LCMS (M + H) ⁺ = 461.

Example 257 N- [6- (cyclopropylmethoxy) -5- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyridin-3yl] ethanesulfonamide.

Stage 1: 3-bromo-2- (cyclopropylmethoxy) -5-nitropyridine

A solution of 3-bromo-2-chloro-5-nitropyridine (2.4 g, 10 mmol) and cyclopropylmethanol (970 μL, 12 mmol) in THF (50 mL) was treated with KOtBu (3.3 g, 15 mmol). After stirring at room temperature for 12 h, the mixture was treated with water (150 ml) and extracted with EtOAc (3x50 ml); the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give a yellow solid. The solid was purified by column chromatography on silica gel using an EtOAc gradient (5 to 30%) in hexanes to give the title compound (1.3 g, 48%) as a yellow solid. LCMS (M + H) ⁺ = 274.

Stage 2: 5-bromo-6- (cyclopropylmethoxy) pyridin-3-amine

A mixture of 3-bromo-2- (cyclopropylmethoxy) -5-nitropyridine (1 g, 3.7 mmol), ammonium chloride (600 mg, 11.1 mmol) and iron powder (1.05 g, 19 mmol) suspended in THF (6.2 ml), water (2.3 ml) and ethanol (6.2 ml), heat to 100 ° C using microwave radiation (standard) for 5 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was washed with warm (50 ° C) MeOH (50 ml). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (100 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound (539 mg, 60%). LCMS (M + H) ⁺ = 244.

Stage 3: N- [5-bromo-6- (cyclopropylmethoxy) πyridin-3-yl] ethanesulfonamide

Ethylsulfonyl chloride (170 μL, 1.8 mmol) was added to a stirred solution of 5-bromo-6 (cyclopropylmethoxy) pyridin-3-amine (440 mg, 1.8 mmol) and pyridine (725 μL) in DCM (4.5 mL) at 0 ° С under atmosphere nitrogen. After the mixture was left to warm to room temperature and stirred for 12 hours, it was treated with 1N. HCl (15 ml) and extracted with DCM (3x15 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using an EtOAc gradient (0 to 100%) in DCM to afford the title compound (181 mg, 88%) as a tan solid. LCMS (M + H) ⁺ = 336.

Stage 4: N- [6- (cyclopropylmethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxαborolan-2-yl) pyridin-3

- 280 038715 yl] ethanesulfonamide

A mixture of N- [5-bromo-6- (cyclopropylmethoxy) pyridin-3-yl] ethanesulfonamide (150 mg, 0.45 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane -2-yl) -1,3,2-dioxaborolane (285 mg, 1.13 mmol), KOAc (132 mg, 1.35 mmol) and Pd (dppf) ₂ (Cl) ₂ (33 mg, 10%) were suspended in anhydrous dioxane (5 ml). The stirred reaction mixture was capped and purged with nitrogen for 5 minutes using an oil bubbler as the outlet. After removing the nitrogen inlet and outlet, the mixture in a closed vial was stirred at 70 ° C for 3 hours. After cooling to room temperature, the reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc. The filtrate was treated with water and separated; after which the aqueous layer was washed with EtOAc (3x25 ml), the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an auburn residue. The residue was purified by silica gel column chromatography using a gradient of 5 to 70% EtOAc in hexanes to afford the title compound (112 mg, 65%). LCMS (M + H) + = 383.

Step 5: N- [6- (cyclopropylmethoxy) -5 - (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyridin-3 yl] ethanesulfonamide

A mixture of N- [6- (cyclopropylmethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3yl] ethanesulfonamide (145 mg, 0.38 mmol), 4- bromo-6-methyl-6H, 7H-furo [2,3-c] pyridin-7-one (25 mg, 0.11 mmol), K ₃ PO ₄ (58 mg, 0.28 mmol), Pd (dppf) Cl ₂ ( 8 mg, 10%) in dioxane / H ₂ O (1 ml / 100 μl) was bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 65 ° C for 12 hours. The reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc (15 ml).

The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by preparative HPLC to give the title compound (21 mg, 48%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.23-0.32 (m, 2H), 0.41-0.52 (m, 2H), 1.08-1.19 (m, 1H), 1.20-1.29 (m, 3H), 3.05- 3.16 (m, 2H), 3.58-3.63 (m, 3H), 3.64-3.66 (m, 1H), 4.08-4.17 (m, 2H), 6.72-6.82 (m, 1H), 7.587.65 (m, 1H ), 7.67-7.73 (m, 1H), 7.95-8.06 (m, 1H), 8.10-8.18 (m, 1H), 9.41-9.86 (m, 1H). LCMS (M + H) + = 404.

Example 258 6-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] furo [2,3c] pyridin-7-one.

Stage 1: 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo [2,3-c] pyridin-7-one

A solution of 4-bromo-6-methylfuro [2,3-c] pyridin-7-one (200 mg, 0.88 mmol), 4,4,5,5-tetramethyl-2 (tetramethyl-1,3,2-dioxaborolane- 2-yl) -1,3,2-dioxaborolane (447 mg, 1.76 mmol), KOAc (259 mg, 2.64 mmol), Pd ₂ (dba) ₃ (82 mg, 0.09 mmol), X-Phos (52 mg, 0.11 mmol) in dioxane (5 ml) was bubbled with nitrogen for 5 min and then stirred at 70 ° C for 12 h.The reaction mixture was concentrated, treated with DCM (30 ml), washed with water (30 ml) and brine (30 ml) , dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE: EA = 20: 1 ~ 5: 1) to give the title compound (130 mg, 54%) as a gray solid.

1H NMR (CDCl3, 400 MHz) δ 7.73 (s, 1H), 7.62 (s, 1H), 7.01 (s, 1H), 3.68 (s, 3H), 1.35 (s, 12H). LCMS (M + H) + = 276.

- 281 038715

Stage 2: 6-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] furo [2,3-c] pyridin7-one

A mixture of 2-bromo-4- (methylsulfonylmethyl) -1- (2,2,2-trifluoroethoxy) benzene (100 mg, 0.29 mmol), 6methyl-4- (4,4,5,5-tetramethyl-1,3, 2-dioxaborolan-2-yl) furo [2,3-c] pyridin-7-one (96 mg, 0.35 mmol), K3PO4 (184 mg, 0.87 mmol), Pd (dppf) Cl ₂ (22 mg, 10% ) in dioxane / H ₂ O (2 ml / 1 ml) was bubbled with nitrogen for 5 min. The sealed vial was heated to 70 ° C for 2 hours. The reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to give the title compound (40 mg, 33%) as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J = 2.0 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.41-7.38 (m, 1H), 7.37 (s, 1H), 7.02 (d, J = 8.4, 1H), 6.72 (d, J = 2.0 Hz, 2H), 4.37 (q, J = 8.0 Hz, 2H), 4.27 (s, 2H), 3.73 (s, 3H), 2.89 ( s, 3H). LCMS (M + H) + = 416.

Example 259: 4- [3- (cyclopropylmethoxy) -6-methylsulfonylpyridin-2-yl] -6-methylfuro [2,3c] pyridin-7-one

Mixture of 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo [2,3-c] pyridin-7-one (50 mg, 0.18 mmol) , 3- (cyclopropylmethoxy) -2-iodo-6-methylsulfonylpyridine (53 mg, 0.15 mmol), K3PO4 (114 mg, 0.54 mmol), Pd (dppf) Cl ₂ (13 mg, 0.018 mmol) in dioxane (5 ml) bubbled with nitrogen for 5 min and then stirred at 70 ° C for 12 h. The reaction mixture was concentrated, treated with DCM (30 ml), washed with water (30 ml) and brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative HPLC to give the title compound (35 mg, yield: 52%) as an off-white solid.

¹ H NMR (CDCl3, 400 MHz) δ 8.42 (s, 1H), 8.10 (s, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.51 (s, 1H), 6.66 (d, J = 1.6 Hz, 1H), 4.08 (d, J = 7.6 Hz, 2H), 3.77 (s, 3H), 3.26 (s, 3H), 1.26-1.19 (m, 1H), 0.68-0.63 (m, 2H), 0.37 -0.33 (m, 2H). LCMS (M + H) + = 375.

Example 260 2-chloro-4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one.

Stage 1: 2-chloro-7-methoxyfuro [2,3-c] pyridine

A 0.13 M solution of 7-methoxyfuro [2,3-c] pyridine (250 mg, 1.7 mmol) in THF was stirred at -78 ° C in a nitrogen atmosphere, treated with n-BuLi (1.6 M in hexanes, 450 μL, 5.2 mmol) drops for 30 seconds. The mixture was gradually heated to -15 ° C over 7 to 10 minutes. After 1 h at -15 ° C, the mixture was cooled to -65 ° C and worked up by adding dropwise a 0.26 M solution of hexachloroethane (473 mg, 2 mmol) in THF over 3 min. After stirring at -65 ° C for 15 min, the mixture was allowed to gradually warm to room temperature. After the mixture was left stirring overnight, it was quickly cooled with water (5 ml) and was extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine (10 ml), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel using an EtOAc gradient (5 to 30%) in hexanes to give the title compound (266 mg, 87%) as an amber oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.99-4.08 (m, 3H), 7.13 (s, 1H), 7.25 (d, J = 5.31 Hz, 1H), 7.95 (d, J = 5.31 Hz, 1H). LCMS (M + H) + = 184.

Stage 2: 2-chlorofuro [2,3-c] pyridin-7-ol

0.25 M solution of 2-chloro-7-methoxyfuro [2,3-c] pyridine (263 mg, 1.4 mmol) in DCM, stirred at -0 ° C under nitrogen atmosphere, was treated with BBr ₃ (1 M in DCM, 4.3 ml, 4.3 mmol) drop by drop over

- 282 038715 min. The mixture was allowed to gradually warm to room temperature. After the mixture was left stirring overnight, it was poured into ice water and extracted with DCM (3x15 ml). The combined organic layers were washed with water and brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using an EtOAc gradient (15 to 75%) in hexanes to afford the title compound (115 mg, 47%) as a light yellow solid. LCMS (M + H) + = 170.

Stage 3: 4-bromo-2-chlorofuro [2,3-c] pyridin-7-ol

A 0.15 M solution of 2-chlorfuro [2,3-c] pyridin-7-ol (113 mg, 0.7 mmol) in DMF, stirred in the dark at 0 ° С in a nitrogen atmosphere, was treated with NBS (120 mg, 0.7 mmol) with three equal portions. The ice bath was removed; the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with 10% aqueous sodium thiosulfate solution (5 ml) and extracted with EtOAc (3x30 ml). The combined organic layers were washed with water (15 ml), brine (20 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (hexanes / EtOAc = 4: 1) to give the title compound (145 mg, 87%) as a white solid. LCMS (M + H) + = 249.

Stage 4: 4-bromo-2-chloro-6-methylfuro [2,3-c] pyridin-7-one

0.2 M solution of 4-bromo-2-chlorofuro [2,3-c] pyridin-7-ol (143 mg, 0.6 mmol) and K ₂ CO ₃ (200 mg, 1.45 mmol) in DMF, stirred at 0 ° С in nitrogen atmosphere, treated with MeI (99 mg, 0.7 mmol). The ice bath was removed; the mixture was stirred at room temperature overnight. The reaction mixture was treated with water (15 ml) and was extracted with EtOAc (3x10 ml). The combined organic layers were washed with water (15 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using an EtOAc gradient (10 to 100%) in hexanes to afford the title compound (113 mg, 85%) as a white solid. LCMS (M + H) + = 263.

Step 5: 2-chloro-4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one

O

A mixture of 2- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (33 mg, 0.09 mmol), 4-bromo-2-chloro-6-methylfuro [ 2,3-c] pyridin-7-one (25 mg, 0.09 mmol), K ₃ PO ₄ (50 mg, 0.24 mmol), Pd (dppf) Cl ₂ (7 mg, 10%) in dioxane / Н ₂ О (700 μl / 70 μl) was bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 70 ° C for 90 minutes. The reaction mixture was filtered through a short celite plug; the celite plug was rinsed with EtOAc (10 ml). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by preparative HPLC to give the title compound (27 mg, 69%) as an off-white solid.

¹ H NMR (400 MHz, DMSO-d6) δ ppm 0.23-0.34 (m, 2H), 0.44-0.55 (m, 2H), 1.00-1.13 (m, 1H), 3.19-3.24 (m, 3H), 3.61 (s, 3H), 3.94-4.05 (m, 2H), 6.82-6.89 (m, 1H), 7.10-7.16 (m, 1H), 7.26-7.35 (m, 1H), 7.70-7.78 (m, 1H) , 7.87-7.94 (m, 1H). LCMS (M + H) + = 409.

Example 261 2-fluoro-4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one.

Stage 1: 2-fluoro-7-methoxyfuro [2,3-c] pyridine

° \

The title compound was prepared in a similar manner to Step 1 of Example 260.

- 283 038715 by replacing N-fluorobenzenesulfonamide with hexachloroethane.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 4.01 (s, 3H), 6.46 (m, 1H), 7.25 (d, J = 5.4 Hz, 1H), 7.96 (d, J = 5.4 Hz, 1H) ... LCMS (M + H) + = 168.

Stage 2: 2-fluorofuro [2,3-c] pyridin-7-ol

he

The title compound was prepared in a similar manner to Step 2 of Example 260 by substituting 2-chloro-7-methoxyfuro [2,3-c] pyridine for 2-fluoro-7-methoxyfuro [2,3-c] pyridine. LCMS (M + H) + = 154.

Stage 3: 4-bromo-2-fluorofuro [2,3-c] pyridin-7-ol

Bg

he

The title compound was prepared in a similar manner to Step 3 of Example 260 by substituting 2-chlorofuro [2,3-c] pyridin-7-ol for 2-fluorofuro [2,3-c] pyridin-7-ol. LCMS (M + H) + = 233.

Stage 4: 4-bromo-2-fluoro-6-methylfuro [2,3-c] pyridin-7-one

Bg

O

The title compound was prepared in a similar manner to Step 4 of Example 260 by replacing 4-bromo-2-fluorofuro [2,3-c] pyridin-7-ol with 4-bromo-2-chlorofuro [2,3-c ] pyridin-7-ol. LCMS (M + H) + = 247.

Step 5: 2-fluoro-4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one

O

A mixture of N- [6- (cyclopropylmethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-3yl] ethanesulfonamide (31 mg, 0.08 mmol), 4- bromo-2-fluoro-6-methylfuro [2,3-c] pyridin-7-one (20 mg, 0.08 mmol), K ₃ PO ₄ (36 mg, 0.17 mmol), Pd (dppf) Cl ₂ (6 mg , 8%) in dioxane / H ₂ O (830 μL / 100 μL) was bubbled with nitrogen for 10 min. The mixture in a sealed vial was stirred at 67 ° C for 90 minutes. The reaction mixture was filtered through a short celite plug; the celite plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by column chromatography on silica gel using a gradient of MeOH (0 to 2%) in DCM. Fractions were combined and concentrated in vacuo to give a white solid (10 mg). Solid, slight impurity [LCMS (M + H) + = 578]; therefore it was diluted with MeOH (1 ml) and 1N. NaOH (aq) (500 μl) and purified by preparative HPLC to give the title compound (6 mg, 17%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.28 (m, 2H), 0.43-0.58 (m, 2H), 0.56-0.58 (m, 1H), 1.24 (m, 3H), 3.09 (m, 2H ), 3.60 (s, 3H), 4.12 (m, 2H), 6.16-6.34 (m, 1H), 7.52-7.72 (m, 1H), 7.77 (s, 1H), 7.90-8.14 (m, 1H), 9.37-10.62 (bs, 1H). LCMS (M + H) + = 422.

Example 262 N- [5- (2,4-difluorophenoxy) -4- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyrimidin-2yl] methanesulfonamide.

Stage 1: 4- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -6-methylfuro [2,3c] pyridin-7-one

A mixture of 4-chloro-5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidine (155 mg, 0.48 mmol), 4-bromo-2fluoro-6-methylfuro [2,3-c] pyridin-7-one (120 mg , 0.44 mmol), NaHCO ₃ (92 mg, 1.1 mmol), Pd (dppf) Cl ₂ (32 mg, 10%) in dioxane / H ₂ O (4 ml / 200 μL) were bubbled with nitrogen for 7 min. The mixture is hermetically sealed for

- 284 038715 covered vial was stirred at 70 ° C for 8 h. LC-MS analysis showed complete consumption of the key reagent of the reaction. The reaction mixture was filtered through a short celite plug; the celite plug was rinsed with DCM. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in DCM to give the title compound (151 mg, 79%) as a yellow solid. LCMS (M + H) + = 434.

Stage 2: K- [5- (2,4-difluorophenoxy) -4- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyrimidin-2yl] methanesulfonamide

A solution of methanesulfonamide (61 mg, 0.65 mmol) in DMF (2 ml), stirred at 0 ° С in a nitrogen atmosphere, was treated with NaH (99 mg, 0.7 mmol). After the ice bath was removed, the mixture was stirred at room temperature for 15 minutes. The resulting suspension was treated with a solution of 4- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -6-methylfuro [2,3-c] pyridin-7-one (70 mg, 0.16 mmol) in DMF (1 ml). After cessation of nitrogen supply, the closed mixture was heated to 70 ° C for 3 h. After cooling to 0 ° C, the reaction mixture was vigorously stirred and treated with water (500 μl). After 5 min, the cooled mixture was treated with 1N. HCl (aq) (1 ml). The resulting suspension was filtered; the filter cake was washed with additional 1N. HCl (aq) (1 ml) and isopropyl ether (5 ml) to give the title compound (50 mg, 70%) as an off-white solid.

Ή NMR (400 MHz, DMSO-d6) δ ppm 3.34 (s, 3H), 3.60 (s, 3H), 7.06 (m, 1H), 7.28 (m, 1H), 7.49 (m, 1H), 7.80 (s , 1H), 8.23 (s, 1H), 8.43 (m, 2H), 11.50 (bs, 1H). LCMS (M + H) + = 449.

Example 263 K- [5- (2,4-difluorophenoxy) -4- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound (46 mg, 62%) was prepared in a similar manner to Step 2 of Example 262, substituting methanesulfonamide for ethanesulfonamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.20-1.27 (m, 3H), 3.43-3.57 (m, 2H), 3.57-3.67 (s, 3H), 7.00-7.13 (m, 1H), 7.20 -7.37 (m, 1H), 7.41-7.54 (m, 1H), 7.72-7.87 (m, 1H), 8.15-8.28 (m, 1H), 8.30-8.49 (m, 2H), 11.2511.48 (bs, 1H). LCMS (M + H) + = 463.

Example 264 K- [5- (cyclopropylmethoxy) -4- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyrimidin-2yl] ethanesulfonamide.

Step 1: 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -6-methylfuro [2,3c] pyridin-7-one

The title compound was prepared in a similar manner to Step 1 of Example 262 by substituting 4-chloro-5- (2,4difluorophenoxy) -2-methylsulfonylpyrimidine for 4-chloro-5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidine. LCMS (M + H) + = 376.

Stage 2: N- [5- (cyclopropylmethoxy) -4- (6-methyl-7-oxofuro [2,3-c] pyridin-4-yl) pyrimidin-2yl] ethanesulfonamide

The title compound was prepared in a similar manner to Step 2 of Example 262 by substituting methanesulfonamide for ethanesulfonamide and substituting 4- [5- (cyclopropylmethoxy) -2-285 038715 methylsulfonylpyrimidin-4-yl] -6-methylfuro [2,3 -c] pyridin-7-one on 4- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4-yl] -6-methylfuro [2,3-c] pyridin-7-one. LCMS (M + H) + = 405.

Example 265 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-7-oxothieno [2,3c] pyridine-2-carboxamide.

Stage 1: methyl 4-bromo-6-methyl-7-oxothieno [2,3-c] pyridine-2-carboxylate

K2CO3 (358 mg , 2.6 mmol). After stirring at 0 ° C for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 20 min, at 50 ° C for 2 h, and at room temperature for 10 h. The reaction mixture was treated with water (8 ml) and extracted with EtOAc (30 ml x 3). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M + H) ⁺ = 303.

Stage 2: 4-bromo-6-methyl-7-oxothieno [2,3-c] pyridine-2-carboxamide Br o

In a sealed tube, a solution of methyl 4-bromo-6-methyl-7-oxothieno [2,3-c] pyridine-2-carboxylate (250 mg, 65 mmol) in MeOH (6 ml), stirred at room temperature, was treated with 2N HCl. NH3 in methanol (8 ml). The sealed tube was heated to 45 ° C for 60 hours. After cooling to 0 ° C, the resulting suspension was filtered; the filter cake was washed with chilled (0 ° C) MeOH (3 ml) and isopropyl ether (3 ml) to give the title compound (215 mg, 95%) as a white solid. LCMS (M + H) ⁺ = 288.

Stage 3: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-7-oxothieno [2,3-c] pyridine2-carboxamide, ^, SO ₂ Et JJ nh ₂ o

A mixture of 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (77 mg, 0.22 mmol), 4-bromo-6-methyl-7-oxothieno [ 2,3-c] pyridine-2-carboxamide (50 mg, 0.18 mmol), K3PO4 (93 mg, 0.44 mmol), Pd (dppf) Cl ₂ (13 mg, 10%) in dioxane / H ₂ O (1.6 ml / 160 μl) was bubbled with nitrogen for 5 min. The mixture in a sealed vial was stirred at 65 ° C for 3 hours. The reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with EtOAc (15 ml). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a tan residue. The resulting residue was purified by preparative HPLC to give the title compound (20 mg, 26%) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.20 (m, 2H), 0.36 (m, 2H), 0.98 (m, 1H), 1.14 (m, 3H), 3.21-3.31 (m, 2H) , 3.61 (s, 3H), 3.98 (m, 2H), 7.38 (d, J = 8.6 Hz, 1H), 7.65-7.75 (m, 3H), 7.78 (d, J = 2.0 Hz, 1H), 7.91 ( dd, J = 8.6, 2.0 Hz, 1H), 8.24 (s, 1H). LCMS (M + H) ⁺ = 447.

Example 266 4- [2- (cyclopropylmethoxy) -5- (ethylsulfonylamino) phenyl] -6-methyl-7-oxothieno [2,3c] pyridine-2-carboxamide

The title compound was prepared in a similar manner to Step 3 of Example 265 by replacing N- [4- (cyclopropylmethoxy) -3- (tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethane-1sulfonamide with 2 - [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.09-0.19 (m, 2H), 0.27-0.39 (m, 2H), 0.86-1.02 (m, 1H), 1.18-1.27

- 286 038715 (m, 3H), 2.97-3.09 (m, 2H), 3.59 (s, 3H), 3.77-3.86 (m, 2H), 7.07-7.16 (m, 2H), 7.21-7.27 (m, 1H ), 7.53-7.58 (m, 1H), 7.61-7.67 (m, 1H), 7.67-7.72 (m, 1H), 8.19-8.30 (m, 1H), 9.46-9.60 (m, 1H). LCMS (M + H) + = 462.

Example 267 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methyl-7-oxothieno [2,3c] pyridine-2-carboxamide

The title compound was prepared in a similar manner to Step 3 of Example 265 by substituting 2- [ 2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.11-0.26 (m, 2H), 0.27-0.41 (m, 2H), 0.89-1.05 (m, 1H), 3.21 (s, 3H), 3.61 (s, 3H), 3.91-4.04 (m, 2H), 7.34-7.41 (m, 1H), 7.63-7.76 (m, 3H), 7.81-7.88 (m, 1H), 7.92-7.99 (m, 1H), 8.21- 8.29 (m, 1H). LCMS (M + H) + = 433.

Example 268: 4- [2- (cyclopropylmethoxy) -5 - (ethylsulfonylamino) pyridin-3-yl] -6-methyl-7 oxothieno [2,3-c] pyridine-2-carboxamide _NHSO ₂ Et nV ² Λ J / tukh nh ₂ o

The title compound was prepared in a similar manner to Step 3 of Example 265 by substituting N- [6- (cyclopropylmethoxy) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridine-3yl] ethanesulfonamide on 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.17-0.35 (m, 2H), 0.39-0.57 (m, 2H), 1.23 (m, 4H), 3.00-3.17 (m, 2H), 3.60 (s , 3H), 4.01-4.26 (m, 2H), 6.11-6.40 (m, 1H), 7.52-7.69 (m, 1H), 7.74-7.84 (m, 1H), 7.94-8.09 (m, 1H), 9.14 -10.31 (m, 1H). LCMS (M + H) + = 463.

Example 269 N- [4- (2,4-difluorophenoxy) -3- (2,6-dimethyl-7-oxofuro [2,3-c] pyridin-4yl) phenyl] ethanesulfonamide.

Stage 1: 7-methoxy-2-methylfuro [2,3-c] pyridine Me

ОМе

To a solution of 7-methoxyfuro [2,3-c] pyridine (2.9 g, 19.6 mmol) in THF (20 ml) stirred under argon, i-BuLi (7.8 ml, 19.6 mmol) was added at -78 ° C; the mixture was transferred to a -30 ° C ice bath and stirred for 2 h. The mixture was cooled to -78 ° C and MeI (4.2 g, 29.4 mmol) was added. After the reaction mixture was stirred at room temperature for 18 h, it was rapidly cooled with water (30 ml) and extracted with DCM (50 ml x 3). The combined organic layers were washed with brine (30 ml x 3), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (3.2 g, 100%) as a yellow solid. This substance was transferred further without further purification. LCMS (M + H) + = 164.

Stage 2: 4-bromo-7-methoxy-2-methylfuro [2,3-c] pyridine

A solution of 7-methoxy-2-methylfuro [2,3-c] pyridine (3.2 g, 19.6 mmol) in ACN (30 ml) was treated with NBS (3.5 g, 19.7 mmol). After the mixture was stirred at room temperature for 18 h, it was concentrated in vacuo and purified by silica gel chromatography (PE / EA = 30: 1 ~ 5: 1) to give the title compound (3.0 g, 64%) as a yellow solid. LCMS (M + H) + = 243.

Stage 3: 4-bromo-2-methyl-6H-furo [2,3-c] pyridin-7-one

BBr ₃ (15.5 g, 62.0 mmol) dropwise. The mixture was stirred at 0 ° C for 3 h. The mixture was concentrated in vacuo to give the title compound (2.50 g, 88%). The material was used immediately in the next step without any further purification. LCMS (M + H) + = 229.

Stage 4: 4-bromo-2,6-dimethylfuro [2,3-c] pyridin-7-one Br

O

The title compound was prepared in a similar manner to Step 2 of Example 252 by substituting 4-bromo-6H, 7H-furo for 4-bromo-2-methyl-6H-furo [2,3-c] pyridin-7-one [2,3-c] pyridin-7-one.

1H NMR (CDClj, 400 MHz) δ 7.26 (s, 1H), 6.32 (s, 1H), 3.64 (s, 3H), 2.49 (s, 3H). LCMS (M + H) + = 243.

Step 5: N- [4- (2,4-difluorophenoxy) -3- (2,6-dimethyl-7-oxofuro [2,3-c] pyridin-4yl) phenyl] ethanesulfonamide

A mixture of 4-bromo-2,6-dimethylfuro [2,3-c] pyridin-7-one (200 mg, 0.83 mol), X- [4- (2,4-difluorophenoxy) 3- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethanesulfonamide (364 mg, 0.99 mmol), Pd (dppf) Cl ₂ (66 mg, 0.09 mmol), K3PO4 (527 mg, 2.49 mmol) in dioxane / water (4 ml / 1 ml) was bubbled with argon for 5 min. The mixture was heated to 70 ° С for 18 h. After cooling to room temperature, the reaction mixture was poured into water (10 ml) and extracted with EtOAc (40 ml × 3). The combined organic layers were washed with brine (20 ml x 2), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (49 mg, 12%) as a yellow solid.

1H NMR (CDCl3, 400 MHz) δ 7.35-7.33 (m, 2H), 7.12 (m, 1H), 6.95-6.89 (m, 2H), 6.81 (m, 2H), 6.43 (s, 1H), 6.38 ( s, 1H), 3.71 (s, 3H), 3.16 (q, J = 7.2 Hz, 2H), 2.47 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). LCMS (M + H) + = 475.

Example 270: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -2,6-dimethylfuro [2,3-c] pyridin7-one

The title compound was prepared in a similar manner to Step 5 of Example 269 by substituting N- [ 4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) phenyl] ethanesulfonamide.

¹ H NMR (CDCl3, 400 MHz) δ 7.89 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.85 (d, J = 2.4 Hz, 1H), 7.34 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.24 (s, 1H), 3.94 (m, 2H), 3.78 (s, 3H), 3.14 (q, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.32 ( t, J = 7.2 Hz, 3H), 1.18-1.16 (m, 1H), 0.64-0.59 (m, 2H), 0.32-0.28 (m, 2H). LCMS (M + H) + = 402.

Example 271 N- [4- (2,4-difluorophenoxy) -3- (5-fluoro-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

O

The title compound was prepared in a similar manner to Example 122, replacing N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] methanesulfonamide with A [3-bromo-4- (2,4difluorophenoxy) phenyl] ethanesulfonamide ...

1H NMR (400 MHz, DMSO-d6) δ ppm 2.98-3.07 (m, 3H), 3.52-3.60 (m, 3H), 6.80-6.94 (m, 1H), 7.10 (s, 1H), 7.14-7.24 ( m, 2H), 7.24-7.28 (m, 1H), 7.38-7.51 (m, 1H), 7.57-7.66 (m, 1H), 7.76-7.86 (m, 1H), 9.67-9.76 (m, 1H). LCMS (M + H) + = 425.

- 288 038715

Example 272: 3-chloro-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 119, replacing 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3-fluoro-1methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and 2-bromo-1- (cyclopropylmethoxy) 4 -ethylsulfonylbenzene on 2-bromo-1- (cyclopropylmethoxy) -4-methanesulfonylbenzene. LCMS (M + H) + = 382.

Example 273: 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1-methyl-3-propan-2ylpyridin-2-one

The title compound was prepared in three steps. Using conditions similar to those described by Malhotra, et al. in Organic Letters 2013, vol. 15, no. 14, p. 3698-3701 (illustrative material, compounds 4c and 3a), 3,5-dibromo-1-methylpyridin-2-one was alkylated at 3 positions using isopropyl magnesium bromide to give 5-bromo-1-methyl-3-propane-2 -ylpyridin-2-one, which was then reacted with 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane using the conditions analogous to those described in example 248, stage 2, to obtain pinacolin ester of 1-methyl-3-propan-2-yl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridin-2-one. This pinacolin ester was then replaced with the pinacolin ester of Example 149, step 4, and reacted in a similar manner to provide the title compound. LCMS (M + H) + = 436.

Example 274: 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 119, substituting 2-bromo-1- (cyclopropylmethoxy) -4methanesulfonylbenzene for 2-bromo-1- (cyclopropylmethoxy) -4-ethylsulfonylbenzene. LCMS (M + H) + = 366.

Example 275: 3-chloro-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 119, replacing 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3-fluoro-1methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and N- (cyclopropylmethyl) -4ethylsulfonyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline on 2-bromo-1- (cyclopropylmethoxy) -4-methanesulfonylbenzene. LCMS (M + H) + = 3 81.

Example 276: 5- [2- (2,4-difluorophenoxy) -5- (methanesulfonylmethyl) phenyl] -3- ( ² H ₃ ) methyl-1-methyl-1,2-dihydropyridin-2-one

The title compound was prepared in a manner analogous to that described in Example 119, substituting 2 3- ⁽² H ₃₎ methyl 1-methyl-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2- dihydropyridin-2-one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and 2-bromo-1- ( 2,4-289 038715 difluorophenoxy) -4- (methylsulfonylmethyl) benzene on 2-bromo-1 - (cyclopropylmethoxy) -4methanesulfonylbenzene.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.93 (s, 3H), 3.49 (s, 3H), 4.42-4.52 (m, 2H), 6.81-6.89 (m, 1H),

7.04-7.16 (m, 1H), 7.20-7.29 (m, 1H), 7.30-7.35 (m, 1H), 7.43-7.51 (m, 2H), 7.53-7.57 (m, 1H), 7.75-7.82 (m ,

1H). LCMS (M + H) + = 423.

Example 277: N- [4- (2,4-difluorophenoxy) -3- [5- (H ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyridine-3yl] phenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 122, substituting Ν- [3-6ρομ-4- (2,4-difluorophenoxy) phenyl] for N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] methanesulfonamide. ethanesulfonamide and 3- ( ² H ₃ ) methyl-1-methyl-5- (tetramethyl-1,3,2-dioxaborolan-2yl) -1,2-dihydropyridin-2-one on 3-fluoro-1-methyl-5 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) pyridin-2-one.

1H NMR (400 MHz, DMSO-d6) δ ppm 2.98-3.05 (m, 3H), 3.44-3.50 (m, 3H), 6.84-6.92 (m, 1H), 7.01-7.18 (m, 3H), 7.21- 7.26 (m, 1H), 7.38-7.47 (m, 1H), 7.47-7.51 (m, 1H), 7.73-7.79 (m, 1H), 9.61-9.78 (bs, 1H). LCMS (M + H) + = 424.

Example 278: N- [4- (2,4-difluorophenoxy) -3- [5- (H ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyridin-3yl] phenyl] ethane-1-sulfonamide

The title compound was prepared in a manner analogous to that described in Example 122, replacing 3- ⁽² H ₃₎ methyl 1-methyl-5- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-dihydropyridin -2-one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.25 (m, 3H), 3.05-3.16 (m, 2H), 3.45-3.49 (m, 3H), 6.85-6.92 (m, 1H), 6.99- 7.20 (m, 4H), 7.23 (m, 1H), 7.38-7.46 (m, 1H), 7.46-7.50 (m, 1H), 7.71-7.79 (m, 1H), 9.60-9.85 (m, 1H). LCMS (M + H) + = 438.

Example 279 N- [3- (5-cyclopropyl-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 122, substituting for 3-cyclopropyl-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and N- [3-6pom-4- ( 2,4-difluorophenoxy) phenyl] methanesulfonamide on N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.46-0.54 (m, 2H), 0.77-0.88 (m, 2H), 1.93-2.07 (m, 1H), 2.98-3.05 (m, 3H), 3.44- 3.51 (m, 3H), 6.89-6.95 (m, 1H), 7.00-7.12 (m, 3H), 7.13-7.19 (m, 1H), 7.21-7.25 (m, 1H), 7.397.48 (m, 1H ). 7.71 (s, 1H). 9.56-9.82 (bs, 1H). LCMS (M + H) + = 447.

Example 280: 3-cyclopropyl-5 - [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin2-one

The title compound was prepared in a similar manner to Example 119, substituting for 3-cyclopropyl-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2 -one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and 2-bromo-1- (cyclopropylmethoxy) - 4-ethylsulfonylbenzene on 2-bromo-1- (cyclopropylmethoxy) -4-methanesulfonylbenzene.

- 290 038715

1H NMR (400 MHz, DMSO-d6) δ ppm 0.33-0.41 (m, 2H), 0.55-0.61 (m, 2H), 0.63-0.69 (m, 2H), 0.83-0.91 (m, 2H), 1.07- 1.14 (m, 3H), 1.19-1.25 (m, 1H), 2.01-2.12 (m, 1H), 3.23-3.30 (m, 2H), 3.52 (s, 3H), 3.92-4.00 (m, 2H), 7.22-7.29 (m, 2H), 7.70-7.80 (m, 3H). LCMS (M + H) + = 388.

Example 281 N- [4- (2,4-Difluorophenoxy) -3- (1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3yl) phenyl] methanesulfonamide

The title compound was prepared in a similar manner to Example 122, replacing 1-methyl-3-pyrrolidin-1-yl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridin-2-one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and N- [3-6pom -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide on N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide. LCMS (M + H) + = 476.

Example 282 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3-pyrrolidin-1 ylpyridin-2-one

The title compound was prepared in a similar manner to Example 119, replacing 1-methyl-3-pyrrolidin-1-yl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridin-2-one on 3fluoro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one and 2-bromo-1 ( cyclopropylmethoxy) -4-ethylsulfonylbenzene to 2-bromo-1- (cyclopropylmethoxy) -4methanesulfonylbenzene.

1H NMR (400 MHz, DMSO-d6) δ ppm 0.33-0.40 (m, 2H), 0.53-0.61 (m, 2H), 1.08-1.14 (m, 3H), 1.20-1.29 (m, 1H), 1.81- 1.90 (m, 4H), 3.23-3.30 (m, 2H), 3.35-3.35 (m, 1H), 3.35-3.40 (m, 3H), 3.48 (s, 3H), 3.94-4.03 (m, 2H), 6.60-6.66 (m, 1H), 7.21-7.28 (m, 1H), 7.31-7.38 (m, 1H), 7.68-7.79 (m, 2H). LCMS (M + H) + = 417.

Example 283 N- [4- (2,4-Difluorophenoxy) -3- (5-ethynyl-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide.

Stage 1: 5-bromo-3-iodo-1-methylpyridin-2-one

NaH (2.4 g, 60.02 mmol, 60% in mineral oil). After the mixture was stirred at 0 ° C for 1 h, iodomethane (11.4 g, 80.03 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 1 hour. The mixture was poured into ice water (200 ml); the resulting precipitate was filtered, collected and dried to give the title compound (12 g, 95%) as a light yellow solid. This material was used without any further purification.

1H NMR (CDCl ₃ , 400 MHz): δ 8.01 (d, J = 3.2 Hz, 1H), 7.46 (d, J = 3.2 Hz, 1H), 3.60 (s, 3H). LCMS (M + H) + = 315.

Stage 2: 5-bromo-1-methyl-3- (2-trimethylsilylethynyl) pyridin-2-one

A mixture of 5-bromo-3-iodo-1-methylpyridin-2-one (8.0 g, 25.48 mmol), ethynyltrimethylsilane (2.7 g, 27.52 mmol), CuI (485 mg, 2.55 mmol), Pd (PPh ₃ ) ₂ Cl ₂ (1.79 g, 2.55 mmol) and triethylamine (12.9 g, 127.4 mmol) in dry THF (100 ml) was heated to 60 ° С under nitrogen for 2 h. The mixture was concentrated, and the residue was purified by column chromatography on silica gel (PE : EA = 5: 1) to give the title compound (6 g, 82%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz): δ 7.61 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 3.54 (s, 3H), 0.25 (s, 9H). LCMS (M + H) + = 285.

- 291 038715

Stage 3: 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (2-trimethylsilylethynyl) pyridin-2-one

A mixture of 5-bromo-1-methyl-3- (2-trimethylsilylethynyl) pyridin-2-one (9.0 g, 31.67 mmol), 4,4,5,5 tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane- 2-yl) -1,3,2-dioxaborolane (20.1 g, 79.16 mmol), Pd ₂ (dba) ₃ (1.8 g, 3.17 mmol), X-Phos (1.5 g, 3.17 mmol) and KOAc (18.65 g, 189.99 mmol) in anhydrous dioxane (200 ml) was stirred at 70 ° C under argon for 12 h. After the mixture was concentrated in vacuo, the residue was purified using silica gel column chromatography (PE: EA = 4: 1) to give of the title compound (3.5 g, 33%) as an off-white solid.

1H NMR (CDCl ₃ , 400 MHz): δ 7.88 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 3.56 (s, 3H), 1.31 (s, 12H), 0.25 (s, 9H). LCMS (M + H) + = 332 and 250.

Stage 4: N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (2-trimethylsilylethynyl) nurudin-3yl] phenyl] ethanesulfonamide

A mixture of 1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3- (2-trimethylsilylethynyl) pyridin-2-one (200 mg, 0.6 mmol) , N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide (197 mg, 0.5 mmol), Pd (dppf) Cl ₂ (37 mg, 0.05 mmol) and K3PO4 (267 mg, 1.26 mmol) in dioxane (6 ml) and H2O (0.6 ml) was stirred at 70 ° C under argon for 12 h. After the mixture was concentrated, the residue was purified by column chromatography on silica gel (PE: EA = 2: 1) to give the title compound (100 mg, 38%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz): δ 7.82 (d, J = 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.167.12 (m, 1H), 6.99-6.91 (m, 2H), 6.87-6.83 (m, 1H), 6.78 (m, 1H), 6.65 (s, 1H), 3.61 (s, 3H), 3.14 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H), 024 (s, 9H). LCMS (M + H) ⁺ = 517.

Step 5: N- [4- (2,4-difluorophenoxy) -3- (5-etunyl-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide

O

To a mixture of N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (2-trimethylsilylethynyl) πyridin-3yl] phenyl] ethanesulfonamide (100 mg, 0.19 mmol) in EtOH ( 10 ml) was added K2CO3 (157 mg, 1.14 mmol). The reaction was stirred at 20 ° С for 12 h, poured into H2O (30 ml) and extracted with DCM (20 ml × 3). The organic phase was washed with brine (20 ml), dried over anhydrous MgSO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (48 mg, 56%) as an off-white solid.

1H NMR (CDCl ₃ , 400 MHz): δ 7.90 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.26 (d, J = 2.8 Hz, 1H), 7.147.11 (m, 1H), 7.01-6.94 (m, 2H), 6.89-6.86 (m, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.55 (s, 1H), 3.67 (s, 3H), 3.34 (s, 1H), 3.14 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ = 445.

Example 284 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-ethynyl-1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 283 substituting N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide for 2-bromo-1- (cyclopropylmethoxy) -4-ethylsulfonylbenzene in Step 4 ...

- 292 038715

1H NMR (CDCl ₃ , 400 MHz): δ 7.93 (d, J = 2.4 Hz, 1H), 7.84-7.81 (m, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.68 (d,

J = 2.8 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 7.2 Hz, 2H), 3.66 (s, 3H), 3.35 (s, 1H), 3.13 (q, J = 7.2 Hz, 2H),

1.32-1.27 (m, 4H), 0.71-0.67 (m, 2H), 0.40-0.37 (m, 2H). LCMS (M + H) + = 372.

Example 285: 5 - [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-ethynyl-1-methylpyridin-2-one

O

The title compound was prepared in a similar manner to Example 283 substituting N- [3-6pom-4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide for 2-bromo-1- (cyclopropylmethoxy) -4-methylsulfonylbenzene in Step 4.

1H NMR (CDCl ₃ , 400 MHz) δ 7.92 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J = 1.6 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 6.8 Hz, 3H), 3.65 (s, 3H), 3.34 (s, 1H), 3.07 (s, 3H), 1.28- 1.27 (m, 1H), 0.70-0.68 (m, 2H), 0.38-0.37 (m, 2H). LCMS (M + H) + = 358.

Example 286 N- [4- (2,4-difluorophenoxy) -3- (5-ethynyl-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide

O

The title compound was prepared in a similar manner to Example 283, replacing N- [3-bromo-4- (2,4-difluorophenoxy) phenyl] methanesulfonamide with N- [3-6pom-4- (2,4difluorophenoxy) phenyl] ethanesulfonamide in step 4.

1H NMR (CDCl ₃ , 400 MHz): δ 7.89 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 7.26-7.25 (m, 1H), 7.15-7.10 (m, 1H), 7.03-6.94 (m, 2H), 6.91-6.84 (m, 1H), 6.78 (d, J = 11.6 Hz, 1H), 6.45 (s, 1H), 3.66 (s, 3H), 3.35 (s , 1H), 3.04 (s, 3H). LCMS (M + H) ⁺ = 431.

Example 287 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3- (difluoromethoxy) -1methylpyridin-2-one.

Stage 1: 5-bromo-3-methoxy-1-methylpyridin-2-one

NaH (2.16 g, 53.95 mmol, 60% in mineral oil). After 30 min, iodomethane (9.33 g, 65.78 mmol) was added over 5 min. After the mixture was stirred at room temperature for 12 h, it was quickly cooled with water (20 ml) and extracted with EtOAc (100 ml x 3). The combined organic layers were washed with brine (100 ml x 3), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (5.5 g, 96%). The material was transferred to the next stage without additional purification. LCMS (M + H) + = 219.

Stage 2: 5-bromo-3-hydroxy-1-methylpyridin-2-one

Bg

-Ao

_{BBr 3} (12.87 g, 51.4 mmol) was added to a solution of 5-bromo-3-methoxy-1-methylpyridin-2-one (5.60 g, 25.7 mmol) stirred at 0 ° С in DCM (100 ml). The ice bath was removed and the mixture was stirred at room temperature for 5 h. After the mixture was cooled to 0 ° C, it was rapidly cooled with MeOH (5 ml), concentrated to near dryness and purified by silica gel column chromatography to give the title compound (3 g, 57%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.49 (s, 1H), 6.80 (s, 1H), 3.44 (s, 3H). LCMS (M + H) + = 205.

Step 3: 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-hydroxy-1-methylpyridin-2-one

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To a mixture of 5-bromo-3-hydroxy-1-methylpyridin-2-one (1.00 g, 4.9 mmol), 2- [2- (cyclopropylmethoxy) 5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1, 3,2-dioxaborolane (1.80 g, 4.9 mmol) in dioxane (30 mL) and H ₂ O (5 mL) was added K ₃ PO ₄ (3.12 g, 14.7 mmol), Pd (dppf) Cl ₂ (358 mg, 0.49 mmol). After purging the mixture with nitrogen, the mixture was stirred at 90 ° C under microwave irradiation for 1 hour. After filtration of the mixture, the filtrate was concentrated to dryness. The resulting residue was purified by preparative HPLC to provide the title compound (0.9 g, 51%) as a purple solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.81 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.16-7.15 (m, 2H), 3.95 ( d, J = 6.8 Hz, 2H), 3.70 (s, 3H), 3.12 (q, J = 7.6 Hz, 2H), 1.32-1.27 (m, 4H), 0.70-0.67 (m, 2H), 0.390.36 (m, 2H). LCMS (M + H) + = 364.

Step 4: 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3- (difluoromethoxy) -1-methylpyridin2-one

A mixture of 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), sodium chlorodifluoroacetate (252 mg, 1.65 mmol), K2CO3 (70 mg, 0.51 mmol) in dioxane (4 ml) was stirred at 100 ° C for 18 h. After filtration of the mixture, the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (16 mg, 28%) as a light pink solid.

1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.49 (d, J = 2.4

Hz, 1H), 7.04 (m, 1H), 3.95 (m, 2H), 3.69 (s, 3H), 3.13 (m, 3H), 1.33-1.26 (m, 4H), 0.72-0.67 (m, 2H) , 0.39-0.36 (m, 2H). LCMS (M + H) + = 414.

Example 288 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3- (2,2,2trifluoroethoxy) pyridin-2-one

Mixture of 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 mg, 0.14 mmol), Cs ₂ CO ₃ (134.48 mg, 0.42 mmol) in DMF (2 ml) was stirred at 20 ° С for 2 h. After filtration of the mixture, the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (29 mg, 47%) as an off-white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.84 (m, 1H), 7.77 (m, 1H), 7.41 (m, 2H), 7.04 (m, 1H), 4.58 (m, 2H), 3.95 (m, 2H ), 3.70 (s, 3H), 3.14 (m, 2H), 1.33-1.27 (m, 4H), 0.72-0.69 (m, 2H), 0.39-0.35 (m, 2H). LCMS (M + H) + = 446.

Example 289 N- [3- [5- (difluoromethoxy) -1 -methyl-6-oxopyridin-3-yl] -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide.

Stage 1: 5-bromo-3- (difluoromethoxy) -1-methylpyridin-2-one

Bg

Ao

The title compound was prepared in a similar manner to Step 4 in Example 287, replacing 5-bromo-3-hydroxy-1-methylpyridin-2-one with 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-hydroxy-1 -methylpyridin-2-one. LCMS (M + H) + = 255.

Stage 2: X- [3- [5- (difluoromethoxy) -1-methyl-6-oxopyridin-3-yl] -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

- 294 038715

A mixture of 5-bromo-3- (difluoromethoxy) -1-methylpyridin-2-one (50 mg, 0.20 mmol), N- [4- (2,4 difluorophenoxy) -3- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] ethanesulfonamide (88 mg, 0.18 mmol), Pd (dppf) Cl ₂ (11 mg) and K ₃ PO ₄ (85 mg, 0.40 mmol) in dioxane (5 ml ) and water (5 drops) were purged with nitrogen, capped and heated to 70 ° C for 8 h. After filtration of the mixture, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (13 mg, 13%) as white solid.

1H NMR (CDCl3, 400 MHz) δ 7.53 (m, 2H), 7.25 (m, 1H), 7.05 (m, 1H), 7.12 (m, 1H), 7.02-6.97 (m, 2H), 6.97-6.95 ( m, 1H), 6.77 (m, 1H), 6.48 (bs, 1H), 3.67 (s, 3H), 3.15 (q, J = 7.4 Hz, 2H), 1.42 (t, J = 7.4 Hz, 3H). LCMS (M + H) ⁺ = 487.

Example 290 N- [4- (2,4-Difluorophenoxy) -3- [1-methyl-6-oxo-5- (2,2,2-trifluoroethoxy) pyridin-3yl] phenyl] ethanesulfonamide.

Stage 1: 5-bromo-1-methyl-3- (2,2,2-trifluoroethoxy) pyridin-2-one

The title compound was prepared in a similar manner to Example 288, replacing 5-bromo-3-hydroxy-1-methylpyridin-2-one with 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-hydroxy-1- methylpyridin-2-one. LCMS (M + H) ⁺ = 287.

Step 2: N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (2,2,2-trifluoroethoxy) pyridin-3yl] phenyl] ethanesulfonamide

A mixture of 5-bromo-1-methyl-3- (2,2,2-trifluoroethoxy) pyridin-2-one (50 mg, 0.18 mmol), N- [4- (2,4 difluorophenoxy) -3- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] ethanesulfonamide (79 mg, 0.18 mmol), Pd (dppf) Cl2 (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 ml) and water (5 drops) were purged with nitrogen, capped and heated to 70 ° C for 8 h. After filtration of the mixture, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (11 mg, 11% ) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.39 (m, 1H), 7.32 (m, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.12 (dd, J1 = 2.8 Hz, J ₂ = 8.8 Hz , 1H), 6.99-6.93 (m, 2H), 6.88-6.83 (m, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.47 (bs, 1H), 4.56 (m, 2H), 3.65 ( s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). LCMS (M + H) ⁺ = 519.

Example 291: 3- (difluoromethoxy) -5- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -1methylpyridin-2-one

A mixture of 5-bromo-3- (difluoromethoxy) -1-methylpyridin-2-one (50 mg, 0.20 mmol),

2- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.18 mmol), Pd (dppf) Cl ₂ (11 mg) and K3PO4 (76 mg, 0.36 mmol) in dioxane (5 ml) and water (5 drops) were purged with nitrogen, closed and heated to 70 ° С for 8 h. After filtration of the mixture, the filtrate was concentrated under vacuum and purified from by preparative HPLC to give the title compound (21 mg, 22%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.62 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 7.40 (d, J = 2.0 Hz, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.09-6.96 (m, 3H), 6.93-6.88 (m, 1H), 6.78 (m, 1H), 4.21 (s, 2H), 3.70 (s, 3H), 2.97 (q , J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H). LCMS (M + H) + = 486.

- 295 038715

Example 292 5- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -1-methyl-3- (2,2,2trifluoroethoxy) pyridin-2-one

A mixture of 5-bromo-1-methyl-3- (2,2,2-trifluoroethoxy) pyridin-2-one (50 mg, 0.18 mmol), 2- [2- (2,4 difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl ] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (88 mg, 0.20 mmol), Pd (dppf) Cl ₂ (11 mg) and K3PO4 (85 mg, 0.40 mmol) in dioxane (5 ml) and water (5 drops) were purged with nitrogen, capped and heated to 70 ° C for 8 h. After filtration of the mixture, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (21 mg, 22%) in the form of a white solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.41 (m, 2H), 7.35 (m, 1H), 7.30 (m, 1H), 7.07-6.96 (m, 2H), 6.92-6.87 (m, 1H), 6.80 (m, 1H), 4.51 (m, 2H), 4.21 (s, 2H), 3.69 (s, 3H), 2.97 (m, 2H), 1.44 (m, 3H). LCMS (M + H) + = 518.

Example 293 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3 - (1-methylpyrazol-4yl) oxypyridin-2-one.

Stage 1: 5-bromo-1-methyl-3- (1-methylpyrazol-4-yl) oxypyridin-2-one

A 0.3 M solution of 5-bromo-3-chloro-1-methylpyridin-2-one (124 mg, 0.56 mmol) in DMF was treated with Cs ₂ CO ₃ (546 mg, 1.7 mmol). The mixture was sonicated for 30 seconds before heating to 140 ° C. with microwave (standard) for 150 minutes. The resulting suspension was diluted with water and extracted with EtOAc (15 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting solid was purified by column chromatography on silica gel using an EtOAc gradient (5 to 60%) in hexanes to afford the title compound (33 mg, 19%) as a tan solid. LCMS (M + H) ⁺ = 285.

Step 2: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3 - (1-methylpyrazol-4yl) oxypyridin-2-one

A mixture of 5-bromo-1-methyl-3- (1-methylpyrazol-4-yl) oxypyridin-2-one (30 mg, 0.11 mmol), 2- [2 (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4.4, 5,5-tetramethyl-1,3,2-dioxaborolane (44 mg, 0.16 mmol), Pd (dppf) Cl2 (8 mg) and K3PO4 (57 mg, 0.26 mmol) in dioxane (1.5 ml) and water (200 μl ) purged with nitrogen, capped and heated to 75 ° C for 12 h. After filtering the mixture through a thin pad of celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (35 mg, 78%) as an off-label white solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.12-0.36 (m, 2H), 0.46-0.61 (m, 2H), 0.99-1.17 (m, 1H), 3.14-3.23 (m, 3H), 3.55 -3.60 (m, 3H), 3.75-3.83 (m, 3H), 3.88-3.96 (m, 2H), 7.18-7.32 (m, 2H), 7.32-7.40 (m, 1H), 7.687.91 (m, 4H). LCMS (M + H) ⁺ = 430.

Example 294 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3- (1-propan-2ylpyrazol-4-yl) oxypyridin-2-one.

Stage 1: 1-propan-2-ylpyrazol-4-ol

0.4 M solution of 1-propan-2-yl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrazole (472 mg, 2 mmol) in THF, stirred at 0 ° C, treated with 2.5 M aqueous NaOH solution (1.6 mL, 4 mmol) and 30% H ₂ O ₂ (aq.) (453 uL, 4 mmol). The ice bath was removed and the mixture was left stirring at room temperature for 1 hour. After the pH was adjusted to a value of 3 by adding aqueous 2N. H ₂ SO ₄ , the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid was purified by column chromatography on silica gel using an EtOAc gradient (5 to 90%) in hexanes to give the title compound (240 mg, 95%) as a white solid. LCMS (M + H) ⁺ = 127.

Step 2: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-iodo-1-methylpyridin-2-one

A 0.2 M solution of the title compound (264 mg, 0.8 mmol) from Example 98 in DMF stirred at 0 ° C. was treated with three equal portions of N-iodosuccinimide (187 mg, 84 mmol). After 15 min, the ice bath was removed and the mixture was stirred at room temperature for 2 h. The reaction mixture was treated with 10% sodium thiosulfate (aq) (5 ml) and extracted with EtOAc (20 ml x 3). The combined organic layers were washed with water and brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give a crude solid. The resulting solid was purified by column chromatography on silica gel using an EtOAc gradient (0 to 100%) in DCM to give the title compound (333 mg, 91%) as a white solid. LCMS (M + H) + = 460.

Step 3: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3- (1-propan-2-ylpyrazol4-yl) oxypyridin-2-one

A mixture of 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-iodo-1-methylpyridin-2-one (91 mg, 0.2 mmol), 1-propan-2-ylpyrazol-4-ol (45 mg, 0.36 mmol), CuI (4 mg, 10%), 2,2,6,6-tetramethyl-3,5heptandione (8 μL, 0.04 mmol), and K3PO4 (85 mg, 0.4 mmol) in DMSO (1 mL) were purged with nitrogen in 10 min, capped and warmed to 110 ° C for 13 h. After filtering the mixture through a thin pad of Celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (36 mg, 40%) as a white solid substances.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.18-0.26 (m, 2H), 0.44-0.53 (m, 2H), 1.03-1.10 (m, 1H), 1.37-1.43 (m, 6H), 3.17 -3.21 (m, 3H), 3.54-3.61 (m, 3H), 3.87-3.93 (m, 2H), 4.33-4.46 (m, 1H), 7.20-7.25 (m, 1H), 7.257.28 (m, 1H), 7.33-7.36 (m, 1H), 7.70-7.74 (m, 1H), 7.76-7.85 (m, 4H). LCMS (M + H) ⁺ = 458.

Example 295: 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3-phenoxypyridine-2one

The title compound was prepared in a similar manner to Step 3 of Example 294 substituting 1-propan-2-ylpyrazol-4-ol for phenol.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.23-0.30 (m, 2H), 0.41-0.50 (m, 2H), 1.05-1.16 (m, 1H), 3.17-3.22 (m, 3H), 3.54 -3.61 (m, 3H), 3.88-3.97 (m, 2H), 6.95-7.01 (m, 2H), 7.04-7.11 (m, 1H), 7.21-7.27 (m, 1H), 7.307.37 (m, 2H), 7.49-7.54 (m, 1H), 7.77-7.83 (m, 1H), 7.83-7.92 (m, 2H). LCMS (m + H) ⁺ = 426.

Example 296 N- [4- (1-Butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidin-2yl] methanesulfonamide

The title compound was prepared in four steps in a similar manner to Example 248 except that 1-iodobutane was replaced by bromomethylcyclopropane in step 1.

1H NMR (CDCl ₃ , 400 MHz) δ 8.95 (s, 1H), 8.40 (s, 1H), 8.17 (s, 1H), 8.09 (s, 1H), 7.04-6.95 (m, 2H), 6.90-6.88 (m, 1H), 4.01 (t, J = 6.8 Hz, 2H), 3.45 (s, 3H), 2.22 (s, 3H), 1.75-1.72 (m, 2H), 1.39-1.33 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). LCMS: 465.1 (M + H) ⁺ .

Example 297: N- [4- (1-butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidine-2

- 297 038715 yl] ethanesulfonamide

The title compound was prepared in four steps in a similar manner to Example 248, except that 1-iodobutane was replaced with bromomethylcyclopropane in step 1 and EtSO ₂ NH _{2 was} replaced with MeSO 2 NH 2 in step 4.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.83 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.04-6.95 (m, 2H), 6.94- 6.88 (m, 1H), 4.00 (t, J = 7.2 Hz, 2H), 3.64 (q, J = 7.2 Hz, 2H), 2.21 (s, 3H), 1.75-1.72 (m, 2H), 1.45 (t , J = 7.2 Hz, 3H), 1.37-1.33 (m, 2H), 0.93 (t, J = 7.2 Hz, 3H). LCMS: 479.1 (M + H) ⁺ .

Example 298 N- [4- [1- (cyclobutylmethyl) -5-methyl-6-oxopuridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] methanesulfonamide

The title compound was prepared in four steps in a similar manner to Example 248 except that 1- (bromomethyl) cyclobutane was replaced by bromomethylcyclopropane in step 1.

1H NMR (CDCl ₃ , 400 MHz) δ 8.96 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.02-6.96 (m, 2H), 6.91-6.89 (m, 1H), 4.03 (d, J = 7.2 Hz, 2H), 3.44 (s, 3H), 2.82-2.74 (m, 1H), 2.21 (s, 3H), 2.04-2.03 (m, 2H), 1.891.85 (m, 2H), 1.79-1.74 (m, 2H). LCMS: 477.1 (M + H) ⁺ .

Example 299 N- [4- [1- (cyclobutylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2-yl] ethanesulfonamide

The title compound was prepared in four steps in a similar manner to Example 248 except that (bromomethyl) cyclobutane was replaced with bromomethylcyclopropane in step 1 and EtSO ₂ NH _{2 was} replaced with MeSO ₂ NH ₂ in step 4.

1H NMR (CDCl ₃ , 400 MHz) δ 8.38 (d, J = 2.4 Hz, 1H), 8.13 (s, 1H), 8.08 (s, 1H), 7.04-6.98 (m, 2H), 6.976.88 (m , 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.63 (q, J = 7.2 Hz, 2H), 2.80-2.76 (m, 1H), 2.20 (s, 3H), 2.04-2.03 (m, 2H), 1.89-1.76 (m, 4H), 1.44 (t, J = 7.2 Hz, 3H). LCMS: 491.1 (M + H) +.

Example 300: N- [5-ethyl-4- (2-methyl-1-oxo-isoquinolin-4-yl) pyrimidin-2-yl] ethanesulfonamide.

Stage 1:

4-Chloro-5-ethyl-2-methylsulfonylpyrimidine was prepared in a manner similar to that described in Example 152, steps 2-4, except that ethylbutanoate was replaced by ethyl 2 (cyclopropylmethoxy) acetate in step 2. The 4-chloro- 5-ethyl-2methylsulfonylpyrimidine and the title compound of Example 89, Step 1, were reacted in a similar manner to Example 152, Step 5. Silica gel chromatography (PE: EA = 1: 1 ~ 0: 1) afforded the title compound (120 mg, yield: 77%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.90 (s, 1H), 8.55 (d, J = 8 Hz, 1H), 7.64-7.55 (m, 2H), 7.28 (s, 1H), 7.07 (d, J = 8 Hz, 1H), 3.69 (s, 3H), 3.39 (s, 3H), 2.67 (q, J = 8 Hz, 2H), 1.17 (t, J = 8 Hz, 3H). LCMS: 344.0 (M + 1) ⁺ .

Stage 2: N- [5-ethyl-4- (2-methyl-1-oxoisoquinolin-4-yl) pyrimidin-2-yl] ethanesulfonamide

- 298 038715

The title compound from Step 1 was treated with EtSO2NH2 in a similar manner to Example 155 to provide the title compound.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.59 (s, 1H), 8.53 (d, J = 8 Hz, 1H), 7.63 (t, J = 8 Hz, 1H), 7.55 (t, J = 8 Hz , 1H), 7.23 (d, J = 12 Hz, 1H), 7.17 (s, 1H), 3.68 (s, 3H), 3.64 (t, J = 8 Hz, 2H), 2.52 (q, J = 8 Hz , 2H), 1.44 (t, J = 8 Hz, 3H), 1.09 (t, J = 8 Hz, 3H). LCMS: 373.0 (M + 1) +.

Examples 301, 303-305 in table. 16 was prepared in a similar multi-step manner as in Example 300, step 1, where ethyl pentanoate was converted to 4-chloro-2-methylsulfonyl-5-propyl pyrimidine and ethyl hexanoate was converted to 5-butyl 4-chloro-2-methylsulfonyl pyrimidine. Both 4-chloro-2-methylsulfonyl-5-propylpyrimidine and 5-butyl-4-chloro-2-methylsulfonylpyrimidine thus obtained were each linked to the title compound of Example 89, Step 1, or 1,3-dimethyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2 (1H) -pyridinone in a similar manner to Example 152 Step 5 to provide the title compounds. Example 302 was prepared from 4chloro-5-ethyl-2-methylsulfonylpyrimidine (described in example 300, step 1) and 1,3-dimethyl-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolane-2- yl) -2 (1H) -pyridinone, which also reacted in a manner similar to that described in example 152, step 5.

Example 302 in table. 16 was prepared from 4-chloro-5-ethyl-2-methylsulfonylpyrimidine (described in example 300, step 1) and 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) -2 (1H) -pyridinone, which were also reacted in a manner similar to that described in Example 152, step 5.

Table 16

Example No. Structure Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) 301 ΛΑ 7 О = (7 (, ⁿ / ω Т о 2-methyl-4- (2methyl sulfonyl -5- propyl pyrimide in-4- sludge) isoquinoline- 1st (CDCb, 400 MHz) δ 8.88 (s, 1 Η), 8.54 (d, J = 8 Hz, 1 Η), 7.65-7.55 (m, 2 Η), 7.06 (d, J = 8 Hz, 1 Η) , 3.69 (s, 3 Η), 3.39 (s, 3 Η), 2.61 (t, J = 8 Hz, 2 Η), 1.56-1.50 (m, 2 Η), 0.83 (t, J = 7.6 Hz, 3 Η). 358 302 N ^ SO ₂ Me UY Τ 'O 5- (5-ethyl-2 methyl sulfonyl pyrimidine-4- yl) -1,3- dimethylpyridin -2-one (CDCb, 400 MHz) δ 8.73 (s, 1 Η), 7.84 (s, 1 Η), 7.55 (s, 1 Η), 3.67 (s, 3 Η), 3.37 (s, 3 Η), 2.90 (q , J = 7.6 Hz, 2 Η), 2.23 (s, 3 Η), 1.33 (t, J = 7.6 Hz, ZN) 308

- 299 038715

303 (D about V / Z. / - \ / ° 1,3-dimethyl-5- (2- methyl sulfonyl -5- propyl pyrimide in-4- yl) pyridin-2-one 322 304 N SO ₂ Me off. O 4- (5-butyl-2 methyl sulfonyl pyrimidin-4yl) -2- methylisoquinoli N-1-OH 372 305 _N SO ₂ Me D 'o 5- (5-butyl-2 methyl sulfonyl pyrimidin-4yl) -1,3- dimethylpyridin -2-one (CDCh, 400 MHz) δ 8.70 (s, 1 Η), 7.84 (s, 1 Η), 7.55 (s, 1 Η), 3.67 (s, 3 Η), 3.37 (s, 3 Η), 2.84 (t , J = 8.0 Hz, 2 Η), 2.24 (s, ZN), 1.68 (m, 2 H, water peak overlap), 1.41 (t, 2 H), 0.96 (t, J = 7.2 Hz, 3 H). 336

Examples 306-310 in table. 17 was prepared in a similar manner to Example 300 Step 2 wherein Examples 301-305 were each treated with EtSO ₂ NH ₂ to provide the title compound.

Table 17

Example No. Structure Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) Derived from Example No. 306 N NHSO ₂ Et off. O H- [4- (2-methyl-1- OXOISOCHINOLIN-4yl) -5propylpyrimidin-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.58 (s, 1 Η), 8.54 (d, J = 8 Hz, 1 Η), 7.64 (t, J = 8 Hz, 1H), 7.56 (t, J = 8 Hz, 1 H), 7.24 (s, 1 H), 7.18 (s, 1 H), 3.69 (s, 3 H), 3.673.61 (m, 2 H), 2.47 (t, J = 8 Hz, 2H), 1.511 .47 (t, J = 8 Hz, 2 H), 1.45-1.41 (t, 1 = 8 Hz, ZN), 0.81 (t, J = 8 Hz, ZN). 387 301 307 N NHSO ₂ Et VO D 'o N- [4- (1,5-dimethyl-6oxopyrid-3-yl) 5-ethylpyrimidine-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.47 (s, 1 Η), 7.69 (s, 1 Η), 7.55 (s, 1 Η), 3.67 (m, 5 Η), 2.75 (q, J = 8 Hz, 2 Η ), 2.24 (s, 3 Η), 1.45 (t, J = 8 Hz, 3 Η), 1.26 (t, J = 8 Hz, ZN) 337 302

- 300 038715

308 N NHSO ₂ Et ^ YX A 'o N- [4- (1,5-dimethyl-6oxopyrid in-3-yl) 5-propylpyrimidin2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.42 (s, 1 Η), 7.67 (d, 3 = 2Hz, 1 Η), 7.53 (s, 1 Η), 3.69 (t, J = 8 Hz, 2 Η), 3.65 ( d, J = 8 Hz, 3 Η), 2.66 (q, J = 8 Hz, 2 Η), 2.23 (s, 3 Η), 1.62-1.60 (m, 2 Η), 1.45 (t, J = 8 Hz , 3 Η), 0.98 (t, J = 8 Hz, 3 Η) 351 303 309 N NHSO ₂ Et ^ yh Oy o LH [5-butyl-4- (2methyl-1- OXOISOCHINOLIN-4yl) pyrimidin-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.57 (s, 1 Η), 8.53 (d, J = 8 Hz, 1 Η), 7.657.61 (m, 1 Η), 7.587.53 (m, 1 Η), 7.24 ( d, J = 8T _U , 1H), 7.17 (s, 1 H), 3.68 (s, 3 H), 3.67-3.61 (m, 2H), 2.48 (t, J = 8 Hz, 2 H), 1.46- 1.39 (m, 5 H), 1.23-1.16 (m, 2 H), 0.76 (t, J = 7.2 Hz, ZN) 401 304 310 N NHSO ₂ Et ^ UD Ao LR [5-butyl-4- (1,5- dimethyl-6oxopyridine-3yl) pyrimidine-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.47 (s, 1 Η), 7.71 (s, 1 Η), 7.55 (s, 1 Η), 3.68-3.62 (m, 5 Η), 2.69 (t, J = 8 Hz, 2 Η), 2.23 (s, ZN), 1.551.46 (m, 2 Η), 1.401.37 (m, 5 Η), 0.94 (1, J = 7.2 Hz, 3 Η) 365 305

Example 311 4- [5- (cyclopropylmethoxy) -2-methylsulfonylpyrimidin-4-yl] -2-methylisoquinolin1-one

O

The title compound of Example 152, Step 5, was purified by preparative HPLC to give a cream powder.

1H NMR (CDCl ₃ , 400 MHz) δ 8.53 (s, 2H), 7.67-7.63 (m, 2H), 7.57-7.52 (m, 2H), 4.06 (d, J = 6.8 Hz, 1H), 3.71 (s , 3H), 3.37 (s, 3H), 1.17 (m, 1H), 0.61 (m, 2H), 0.30 (m, 2H). LCMS: 386.1 (M + 1) +.

Example 312 5- (2-ethyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one.

Stage 1: 1-ethyl-4-methylsulfonyl-2-nitrobenzene

Bromo-4-methylsulfonyl-2-nitrobenzene (2 g, 7.0 mmol), ethyl boronic acid (0.57 g, 7.7 mmol), K ₂ CO ₃ (3.0 g, 21 mmol), Pd (dppf) Cl ₂ (0.29 g, 0.35 mmol) in 1,4-dioxane / water (4: 1) (24 ml) was heated at 85 ° C under N2 overnight. Chromatography over silica gel (PE: EA = 6: 1) afforded the title compound (0.66 g, 40%) as a brown solid.

- 301 038715

Stage 2: 2-ethyl-5-methylsulfonylaniline

SO ₂ Me h ₂ n ^

The title compound from Step 1 (0.6 g, 2.6 mmol) and palladium-carbon (0.18 g) in CH3OH (20 ml) were hydrogenated at 1 atm hydrogen pressure. over 6 h. Silica gel chromatography (PE: EA = 6: 1) afforded the title compound (0.49 g, 94%) as a brown liquid.

Stage 3: 1-ethyl-2-iodo-4-methylsulfonylbenzene

SO ₂ Me d

To the title compound from Step 2 (155 mg, 0.8 mmol) in 5 M HCl (3 ml) and H2O (4 ml) cooled to 0 ° C was added NaNO ₂ (66 mg, 0.96 mmol). After stirring at 0 ° С for 30 min, KI (1.33 g, 8 mmol) in water (2 ml) was added, and the mixture was warmed to room temperature and stirred for 1 h. Chromatography on silica gel (PE: EA = 3: 1 ) gave the title compound (213 mg, 86%) as a brown solid.

Stage 4: 5- (2-ethyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one or ί to

The title compound from Step 3 (62 mg, 0.2 mmol), 1-methyl-5- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) pyridin-2-one (57 mg , 0.24 mmol), K2CO3 (82 mg, 0.6 mmol), Pd (dppf) Cl ₂ (6.2 mg) in 1,4-dioxane / water (4: 1) (5 ml) were heated at 85 ° С in an N2 atmosphere for throughout the night. Chromatography on silica gel (PE: EA = 1: 1) provided the title compound (56.6 mg, 97%) as a brown oil.

1H NMR (300 MHz, CDCI3): δ 1.66 (3H, t, J = 6.0 Hz), 2.63-2.71 (2H, m), 3.05 (3H, s), 3.60 (3H, s), 6.64 (1H, d , J = 9.0 Hz), 7.28-7.33 (2H, m), 7.48 (1H, d, J = 9.0 Hz), 7.70 (1H, s), 7.82-7.85 (1H, m). LCMS: 292 (M + 1) +.

Example 313: 1-methyl-5- (5-methylsulfonyl-2-propylphenyl) pyridin-2-one

The title compound was prepared in four steps in a similar manner to Example 312, steps 1-4, except that propylboronic acid was replaced by ethylboronic acid in step 1.

1H NMR (CDCI3, 400 MHz): δ 7.91 (d, J = 6.8 Hz, 1H), 7.77 (d, J = 15.2 Hz, 2H), 7.62-7.58 (m, 2H), 6.66 (d, J = 8.4 Hz, 1H), 3.67 (s, 3H), 3.16 (s, 3H), 2.74-2.78 (m, 2H), 1.63-1.58 (m, 2H), 0.93-0.90 (m, 3H). LCMS: 306 (M + 1) ⁺ .

Example 314: 2-methyl-4- (5-methylsulfonyl-2-propylphenyl) isoquinolin-1-one

The title compound was prepared in four steps in a similar manner to Example 312, Steps 1-4, except that the propylboronic acid was replaced by ethylboronic acid in Step 1 and the title compound of Example 89, Step 1 was replaced with 1- methyl 5- (4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in step 4.

¹ H NMR (CD3OD, 400 MHz): δ 8.67 (d, J = 8.0 Hz, 1H), 8.20 (dd, 31 = 1.6 Hz, J2 = 2.4 Hz, 1H), 7.84 (s, 1H), 7.71-7.67 (m, 2H), 7.63-7.59 (m, 1H), 7.42 (s, 1H), 7.08 (d, J = 8.8 Hz, 1H), 3.71 (s, 3H), 3.18 (m, 3H), 2.64- 2.57

- 302 038715 (m, 1H), 2.51-2.44 (m, 1H), 1.59-1.50 (m, 2H), 0.82-0.78 (m, 3H). LCMS: 356 (M + 1) +.

Example 315 5- [2- (2-cyclopropylethyl) -5-methylsulfonylphenyl] -1-methylpyridin-2-one.

Stage 1: 2- (2-cyclopropylethynyl) -5-methylsulfonylaniline

Bromo-4-methylsulfonyl-2-nitrobenzene (1.5 g, 5.36 mmol), ethynylcyclopropane (0.7 g, 10.72 mmol), K2CO3 (1.5 g, 10.72 mmol) in CH3CN (30 ml), Pd (ACN) ₂ Ci ₂ (55.5 mg, 0.21 mmol) and X-phos (128 mg, 0.27 mmol) under N ₂ were heated at 45 ° C for 3 h.Extraction with EA and preparative TLC (PE: EtOAc = 5: 1) gave the title compound ( 1.2 d).

Stage 2: 2- (2-cyclopropylethyl) -5-methylsulfonylaniline h ₉ n

SO ₂ Me

The title compound from Step 1 (1.2 g) was hydrogenated in MeOH (45 ml) in a manner similar to Example 312 Step 2. Preparative HPLC gave the title compound (422 mg, 41%).

1H NMR (CDC13, 400 MHz): δ 7.19-7.13 (m, 3H), 2.95 (s, 3H), 2.60-2.56 (m, 2H), 1.50-1.44 (m, 2H), 0.68-0.65 (m, 1H), 0.43-0.38 (m, 2H), 0.03-0.01 (m, 2H).

Stage 3: 1- (2-cyclopropylethyl) -2-iodo-4-methylsulfonylbenzene

The title compound of Step 2 (442 mg, 1.85 mmol) in 5 M HCl (10 mL) was treated with NaNO ₂ (167 mg, 2.41 mmol) followed by KI (3.07 g, 18.50 mmol) in H2O (8 mL) in a manner as described in example 312, step 3. Extraction of EA and chromatography on silica gel (PE: EA = 10: 1) gave the title compound (600 mg, 93%).

1H NMR (CDCi ₃ , 400 MHz): δ 8.27 (d, J = 1.6 Hz, 1H), 7.74 (dd, 11 = 1.6 Hz, J2 = 6.4 Hz, 1H), 7.32 (d, J = 7.6 Hz, 1H ), 2.98 (s, 3H), 2.86-2.82 (m, 2H), 1.47-1.41 (m, 2H), 0.69-0.64 (m, 1H), 1.42-0.37 (m, 2H), 0.04-0.01 (m , 2H).

Step 4: 5- [2- (2-cyclopropylethyl) -5-methylsulfonylphenyl] -1-methylpyridin-2-one

The title compound from Step 3 (120 mg, 0.34 mmol), 1-methyl-5- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) pyridin-2-one (89 mg , 0.37 mmol), Na ₂ CO ₃ (72 mg, 0.68 mmol), and Pd (dppf) Cl ₂ (15 mg) in DMF / H2O (6 ml / 1.5 ml) in an N2 atmosphere were heated at 100 ° С for 1 h Extraction with EA and preparative TLC (PE: EtOAc = 0: 1) afforded the title compound (62 mg, 55%).

1H NMR (CD3OD, 400 MHz): δ 7.92 (dd, J1 = 2.4 Hz, J ₂ = 5.6 Hz, 1H), 7.81 (d, J = 2 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H ), 7.65-7.61 (m, 2H), 6.69 (m, J = 9.2 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.89-2.86 (m, 2H), 1.51-1.45 ( m, 2H), 0.68-0.65 (m, 1H), 0.45-0.40 (m, 2H), 0.04-0.00 (m, 2H). LCMS: 332 (M + 1) +.

Example 316 4- (2-ethyl-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound of Example 312, Step 3, was reacted with the title compound of Example 89, Step 1 in a similar manner to Example 312, Step 4 to provide the title compound.

1H NMR (400 MHz, CDC13): δ 1.10 (3H, t, J = 8.0 Hz), 2.51-2.56 (2H, m), 3.10 (3H, s), 3.67 (3H, s), 6.977.02 ( 2H, m), 7.52-7.59 (3H, m), 7.80 (1H, s), 7.97 (1H, d, J = 8.0 Hz), 8.54 (1H, d, J = 8.0 Hz). LCMS: 342 (M + 1) +.

- 303 038715

Example 317 5- (2-Butyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one

The title compound was prepared in four steps in a similar manner to Example 312 Steps 1-4, except that butylboronic acid was replaced by ethylboronic acid in Step 1.

1H NMR (400 MHz, MeOH-d4): δ 0.89 (3H, t, J = 8.0 Hz), 1.28-1.35 (2H, m), 1.54-1.58 (2H, m), 2.73-2.77 (2H, m) , 3.16 (3H, s), 3.67 (3H, s), 6.67 (1H, d, J = 4.0 Hz), 7.58-7.62 (2H, m), 7.78 (2H, d, J = 12.0 Hz), 7.89- 7.92 (1H, m). LCMS: 320 (M + 1) ⁺ .

Example 318 4- (2-Butyl-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound was prepared in four steps in a similar manner to Example 312, Steps 1-4, except that butylboronic acid was substituted for ethylboronic acid in Step 1, and the title compound of Example 89, Step 1, was replaced with 1- methyl 5- (4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in step 4.

1H NMR (300 MHz, MeOH-d ₄ ): δ 0.73 (3H, t, J = 7.5 Hz), 1.14-1.21 (2H, m), 1.43-1.51 (2H, m), 2.45-2.64 (2H, m ), 3.17 (3H, s), 3.70 (3H, s), 7.07 (1H, d, J = 9.0 Hz), 7.41 (1H, s), 7.57-7.70 (3H, m), 7.82 (1H, d, J = 3.0 Hz), 7.98-8.01 (1H, m), 8.44-8.47 (1H, m). LCMS: 370 (M + 1) +.

Example 319: 4- [2- (2-cyclopropylethyl) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound of Example 315, Step 3, was reacted with the title compound of Example 89, Step 1 in a similar manner to Example 315, Step 4 to provide the title compound.

1H NMR (CD3OD, 400 MHz): δ 8.67 (d, J = 8.0 Hz, 1H), 8.21 (dd, J1 = 2.0 Hz, J ₂ = 6.0 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H ), 7.92-7.86 (m, 2H), 7.82-7.79 (m, 1H), 7.61 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 3.91 (s, 3H), 3.38 (s, 3H), 2.94-2.89 (m, 1H), 2.83-2.77 (m, 1H), 1.64-1.55 (m, 2H), 0.75-0.71 (m, 1H), 0.51-0.47 (m, 2H), 0.01- 0.00 (m, 2H). LCMS: 382 (M + 1) ⁺ .

Example

320:

sludge] ethanesulfonamide

N- [6- (cyclopropylmethoxy) -5- (2-methyl-1-oxoisoquinolin-4-yl) pyridine-3-

A mixture of N- [5-bromo-6- (cyclopropylmethoxy) pyridin-3-yl] etαnsulfonamide (60 mg, 0.21 mmol), 2methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) isoquinolin-1-one (77 mg, 0.23 mmol), Pd ₂ (dba) ₃ (7 mg), XPhos (7 mg) and K3PO4 (111 mg, 0.51 mmol) in dioxane (1.2 ml) and water (140 μL) was purged with nitrogen, capped and heated to 70 ° C for 2 h. After filtering the mixture through a thin pad of Celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (45 mg, 52%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.09-0.15 (m, 2H), 0.29-0.40 (m, 2H), 0.97-1.08 (m, 1H), 1.20-1.28 (m, 3H), 3.07 -3.16 (m, 2H), 3.56 (s, 3H), 4.02-4.18 (m, 2H), 7.17-7.22 (m, 1H), 7.52 (s, 3H), 7.62-7.69 (m, 1H), 8.06 -8.11 (m, 1H), 8.27-8.33 (m, 1H), 9.47-10.31 (m, 1H). LCMS (M + H) ⁺ = 414.

- 304 038715

Example 321 4- [2- (cyclopropylmethoxy) -5-methylsulfonylpyridin-3-yl] -2-methylisoquinolin-1 one.

Stage 1: 3-bromo-2-chloro-5-methylsulfonylpyridine

A 0.5 M solution of 5-bromo-6-chloropyridine-3-sulfonyl chloride (1.5 g, 5.2 mmol) in THF was added dropwise to a mixture of NaHCO ₃ (521 mg) and sodium sulfite (847 mg) and stirred at room temperature in water (15 ml). The reaction mixture was heated to 70 ° С for 2 h. After cooling to room temperature, the reaction mixture was treated with iodomethane (1.5 ml, 23 mmol) and then heated to

50 ° C for 12 h. The reaction mixture was extracted with EtOAc (20 ml x 3); the combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid was purified by silica gel column chromatography (20% EtOAc in hexanes) to afford the title compound (952 mg, 68%). LCMS (M + H) ⁺ = 271.

Stage 2: 3-bromo-2- (cyclopropylmethoxy) -5-methylsulfonylpyridine

A solution of cyclopropylmethanol (146 μL, 1.8 mmol), stirred in DMF (3 mL) at 0 ° С, was treated with NaH (75 mg, 1.9 mmol, 60% in mineral oil). After stirring at 0 ° С for 30 min, the reaction mixture was treated by adding dropwise a solution of 3-bromo-2-chloro-5methylsulfonylpyridine (400 mg, 1.5 mmol) in DMF (3 ml). After the ice bath was removed, the mixture was stirred at room temperature for 14 h. The reaction mixture was treated with water and extracted with EtOAc (30 ml x 2). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using an EtOAc gradient (5 to 85%) in hexanes to afford the title compound (298 mg, 65%). LCMS (M + H) ⁺ = 307.

Step 3: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylpyridin-3-yl] -2-methylisoquinolin-1-one

A mixture of 3-bromo-2- (cyclopropylmethoxy) -5-methylsulfonylpyridine (67 mg, 0.22 mmol), 2-methyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (60 mg, 0.21 mmol), Pd ₂ (dba) ₃ (6 mg), XPhos (7 mg), and K3PO4 (111 mg, 0.51 mmol) in dioxane (1.2 ml) and water (140 μl) ) purged with nitrogen, capped and heated to 70 ° C for 2 h. After filtering the mixture through a thin pad of celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (58 mg, 73%) as a white solid substances.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.12-0.26 (m, 2H), 0.28-0.47 (m, 2H), 1.02-1.15 (m, 1H), 3.30-3.32 (m, 3H), 3.54 -3.62 (m, 3H), 4.02-4.41 (m, 2H), 7.17-7.27 (m, 1H), 7.52-7.59 (m, 1H), 7.60-7.64 (m, 1H), 7.647.71 (m, 1H), 8.16-8.22 (m, 1H), 8.26-8.35 (m, 1H), 8.70-8.79 (m, 1H). LCMS (M + H) + = 385.

Example 322: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylpyridin-3-yl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 321 substituting iodomethane for iodoethane in Step 1.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.09-0.15 (m, 2H), 0.31-0.40 (m, 2H), 0.98-1.07 (m, 1H), 1.20-1.28 (m, 3H), 3.07 -3.17 (m, 2H), 3.54-3.58 (m, 3H), 3.99-4.16 (m, 2H), 7.16-7.23 (m, 1H), 7.50-7.59 (m, 3H), 7.637.70 (m, 1H), 8.06-8.11 (m, 1H), 8.27-8.32 (m, 1H), 9.40-10.08 (m, 1H). LCMS (M + H) ⁺ = 399.

- 305 038715

Example 323: 5- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one

A mixture of 1-bromo-3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylbenzene (450 mg, 1.2 mmol), 1,3 dimethyl-5- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) pyridin-2-one (300 mg, 1.2 mmol), Pd (dppf) Cl ₂ (88 mg) and K3PO4 (654 mg, 3 mmol) in dioxane (8 ml) and water (800 μl) purged with nitrogen for 7 min, capped and heated to 75 ° C for 1 h. After filtration of the mixture through a thin celite pad, the filtrate was concentrated in vacuo and purified by column chromatography on silica gel using an EtOAc gradient (5 to 100%) in DCM to afford the title compound (416 mg, 83%) as a tan solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.05-2.14 (s, 3H), 3.25-3.28 (s, 3H), 3.49-3.57 (s, 3H), 3.74-3.81 (s, 3H), 5.12 -5.22 (s, 2H), 6.93-7.03 (m, 2H), 7.34-7.47 (m, 3H), 7.52-7.59 (m, 1H), 7.64-7.72 (m, 1H), 7.82-7.90 (m, 1H), 8.14-8.22 (m, 1H). LCMS (M + H) ⁺ = 414.

Example 324 1,3-dimethyl-5- (3-methylsulfonyl-5-phenylmethoxyphenyl) pyridin-2-one

Stage 1: 5- (3-hydroxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one

A solution of 5- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one (410 mg, 1 mmol) in AcOH (10 ml) was heated to 100 ° C for 8 hours After cooling to room temperature, the reaction mixture was evaporated to dryness under vacuum. The resulting residue was diluted with water and extracted with EtOAc (50 ml x 3); the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid was suspended in ethyl ether, sonicated for 3 min and filtered. The filter cake was collected to give the title compound (290 mg, 68%) as a gray solid. LCMS (M + H) + = 294.

Stage 2: 1,3-dimethyl-5- (3-methylsulfonyl-5-phenylmethoxyphenyl) pyridin-2-one

Closed mixture of 5- (3-hydroxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one (25 mg, 0.085 mmol), benzyl bromide (20 mg, 0.12 mmol) and Na ₂ CO ₃ (18 mg, 0.17 mmol ) in DMF (600 μl) was heated to 80 ° C for 90 min. The mixture was filtered and the filter cake washed with ACN (500 μl), the filtrate was purified by preparative HPLC to give the title compound (8 mg, 25%) as a tan solid.

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 2.08-2.13 (m, 3H), 3.26-3.28 (m, 3H), 3.51-3.57 (m, 3H), 5.22-5.34 (m, 2H), 7.33 -7.47 (m, 4H), 7.48-7.53 (m, 2H), 7.54-7.60 (m, 1H), 7.67-7.71 (m, 1H), 7.83-7.88 (m, 1H), 8.178.22 (m, 1H). LCMS (M + H) ⁺ = 384.

Examples 325-340 in table. 18, the title compound from Step 1 of Example 324 was Oalkylated with the appropriate alkyl halide in the same manner as in Step 2 of Example 324. In Examples 332-340, Cs ₂ CO _{3 was} replaced by Na ₂ CO ₃ .

- 306 038715

Table 18

MeC ^ S ^^^^ OR-,

I r about

Example No. R ¹ Name MS (M + H) 325 5 - [3 - (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 348 326 G 1,3-dimethyl-5- [3-methylsulfonyl-5 (2-phenylethoxy) phenyl] pyridin-2-one 398 327 5 - [3 - (2-cyclopropylethoxy) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 362 328 , A ^F 1,3-dimethyl-5- [3-methylsulfonyl-5 (2,2,2- trifluoroethoxy) phenyl] pyridin-2-one 376 329 Oh? 1,3-dimethyl-5- [3 - [(3-methyloxetan-3 yl) methoxy] -5- methylsulfonylphenyl] pyridin-2-one 378 330 1,3-dimethyl-5- [3-methylsulfonyl-5 (pyridine-2- ylmethoxy) phenyl] pyridin-2-one 385 331 Asr 5 - [3 - [(2,6-dimethylphenyl) methoxy] -5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 412 332 th 5 - [3 - [(2-chlorophenyl) methoxy] -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 419 333 _ν aJO 5- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5methyl sulfonyl phenyl] -1,3- dimethylpyridin-2-one 450

- 307 038715

334 2 - [[3- (1,5-dimethyl-6-oxopyridine-3- yl) -5- methyl sulfonylphenoxy] methyl] benzonitrile 409 335 5 - [3 - [(2,4-d ifluorophenyl) methoxy] -5methyl sulfonylphenyl] -1,3dimethylpyridin-2-one 420 336 1,3-dimethyl-5- [3-methylsulfonyl-5- (1-phenylethoxy) phenyl] pyridin-2-one 398 337 Cl Cl .2 aXdA 5 - [3 - [(2,3-d ichlorophenyl) methoxy] -5methyl sulfonylphenyl] -1,3dimethylpyridin-2-one 453 338 0 1,3-dimethyl-5- [3-methylsulfonyl-5 (pyridin-3 - ylmethoxy) phenyl] pyridin-2-one 385 339 An 3 - [[3 - (1,5-dimethyl-6-oxopyr-idin-3 yl) -5- methyl sulfonylphenoxy] methyl] benzonitrile 409 340 5 - (3-but-2-inoxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one 346

Example 341: 1,3-dimethyl-5- [3-methylsulfonyl-5 - [(1R) -1-phenylethoxy] phenyl] pyridin-2-one

O

A solution of (1S) -1-phenylethan-1-ol (14 mg, 0.11 mmol) in THF (1 ml), stirred at room temperature under nitrogen atmosphere, was treated with triphenylphosphine (38 mg, 0.15 mmol) and 5- (3-hydroxy -5methylsulfonylphenyl) -1,3-dimethylpyridin-2-one (33 mg, 0.11 mmol). After 30 min, the reaction mixture was treated with DIAD (29 mg, 0.15 mmol). The nitrogen supply was stopped and the mixture was stirred (closed system) for 18 hours. After the reaction mixture was diluted with EtOAc (10 ml), it was washed with water, saturated sodium bicarbonate solution (aq.), Dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was diluted with ACN (1 ml) and purified by preparative HPLC to give the title compound (21 mg, 48%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 (d. J = 6.4, 3H), 2.08 (s, 3H), 3.20 (s, 3H), 3.52 (s, 3H), 5.705.80 (q. J = 6.4, 1H), 7.23-7.31 (m, 2H), 7.35-7.41 (m, 2H), 7.44-7.51 (m, 3H), 7.56-7.63 (m, 1H), 7.73-7.80 (m, 1H ), 8.08-8.15 (m, 1H). LCMS (M + H) + = 398.

Example 342 N- [3 - (2,4-difluorophenoxy) -5- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide.

Stage 1: 1- (3-bromo-5-nitrophenoxy) -2,4-difluorobenzene

F

Bg

A mixture of 2,4-difluorophenol (286 mg, 2.2 mmol) and 1-bromo-3-fluoro-5-nitrobenzene (440 mg, 2 mmol) in

- 308 038715

DMF (4.5 ml) was treated with K ₂ CO ₃ (304 mg, 2.2 mmol). The mixture was heated to 100 ° C using microwave (standard) for 5 h. The resulting suspension was diluted with water and was extracted with EtOAc (15 ml x 3). The combined organic layers were washed with 1N. NaOH (aq.) (15 ml), water (15 ml), brine, dried over MgSO ₄ and concentrated in vacuo. The crude solid was purified by column chromatography on silica gel using a gradient of EtOAc (5 to 25%) in hexanes to afford the title compound (200 mg, 30%) as a yellow solid. LCMS (M + H) + = 339.

Stage 2: 3-bromo-5- (2,4-difluorophenoxy) aniline

A mixture of 1- (3-bromo-5-nitrophenoxy) -2,4-difluorobenzene (54 mg, 0.16 mmol), ammonium chloride (18 mg, 0.32 mmol) and iron powder (45 mg, 0.80 mmol) suspended in THF ( 300 μl), water (100 μl) and ethanol (300 μl), heated to 100 ° C using microwave radiation (standard) for 3 h. The crude reaction mixture was filtered through a short plug of celite; the celite plug was rinsed with MeOH (~ 5 ml). The resulting filtrate was concentrated in vacuo. The resulting residue was diluted with EtOAc (50 ml) and washed with saturated bicarbonate solution (aq), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude solid was purified by column chromatography on silica gel using an EtOAc gradient (5 to 20%) in hexanes to afford the title compound (48 mg, 100%) as a yellow solid. LCMS (M + H) ⁺ = 301.

Step 3: N- [3-bromo-5- (2,4-difluorophenoxy) phenyl] ethanesulfonamide

Ethylsulfonyl chloride (15 μL, 0.16 mmol) was added dropwise to a stirred solution of 3 bromo-5- (2,4-difluorophenoxy) aniline (48 mg, 0.16 mmol) and pyridine (40 μL, 0.48 mmol) in DCM (320 μL) at 0 ° C in a nitrogen atmosphere. After the mixture was left to warm to room temperature and stirred for 12 hours, it was treated with 1N. HCl (1 ml) and extracted with DCM (3x5 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified by column chromatography on silica gel using an EtOAc gradient (5 to 60%) in hexanes to afford the title compound (60 mg, 95%) as a tan solid. LCMS (M + H) ⁺ = 393.

Step 4: N- [3- (2,4-difluorophenoxy) -5- (1,5-dumethyl-6-oxopuridin-3-yl) phenyl] ethanesulfonamide

A mixture of N- [3-bromo-5- (2,4-difluorophenoxy) phenyl] ethanesulfonamide (70 mg, 0.17 mmol), 1,3-dimethyl 5- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) pyridin-2-one (44 mg, 0.18 mmol), Pd (dppf) Cl ₂ (12 mg) and K ₃ PO ₄ (92 mg, 0.42 mmol) in dioxane (1 ml) and water (133 μl) was purged with nitrogen, capped and heated to 75 ° C for 1 h. After filtration of the mixture through a thin celite pad, the filtrate was concentrated in vacuo and purified by column chromatography on silica gel using a gradient of MeOH (0 to 10%) in DCM to give the title compound (69 mg, 94%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.22 (m, 3H), 2.07 (s, 3H), 3.08-3.20 (m, 2H), 3.50 (s, 3H), 6.65-6.70 (m, 1H), 6.92-6.96 (m, 1H), 7.05-7.10 (m, 1H), 7.12-7.19 (m, 1H), 7.28-7.37 (m, 1H), 7.47-7.55 (m, 1H), 7.56- 7.59 (m, 1H), 7.87-7.95 (m, 1H), 9.76-9.94 (m, 1H). LCMS (M + H) ⁺ = 435.

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Example 343: 4- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

A mixture of 1-bromo-3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylbenzene (103 mg, 0.28 mmol), 2methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) isoquinolin-1-one (79 mg, 0.28 mmol), Pd (dppf) Cl ₂ (20 mg) and K ₃ PO ₄ (153 mg, 0.7 mmol) in dioxane (1.9 ml) and water (100 μl ) was purged with nitrogen for 10 min, covered and heated to 75 ° C for 15 h. After filtration of the mixture through a thin layer of celite, the filtrate was concentrated in vacuo and purified by column chromatography on silica gel using an EtOAc gradient (5 to 100%) in DCM to give the title compound (100 mg, 80%) as a tan solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 3.30 (s, 3H), 3.58 (s, 3H), 3.77 (s, 3H), 5.14-5.28 (m, 2H), 6.88-7.04 (m, 2H ), 7.32-7.80 (m, 9H), 8.29-8.43 (m, 1H). LCMS (M + H) + = 450.

Example 344 2-methyl-4- (3-methylsulfonyl-5-phenylmethoxyphenyl) isoquinoline-1-one

Stage 1: 4- (3-hydroxy-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 324, substituting 5- [3 - [(4methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one in Step 1. LCMS (M + H) + = 330.

Stage 2: 2-methyl-4- (3-methylsulfonyl-5-phenylmethoxyphenyl) isoquinolin-1-one

Closed mixture of 4- (3-hydroxy-5-methylsulfonylphenyl) -2-methylisoquinolin-1-one (25 mg, 0.076 mmol), benzyl bromide (20 mg, 0.12 mmol) and Cs ₂ CO ₃ (50 mg, 0.15 mmol) in DMF (600 μl) was heated to 80 ° C for 3 h. The mixture was filtered and the filter cake washed with ACN (500 μl), the filtrate was purified by preparative HPLC to give the title compound (12 mg, 38%) as a reddish brown solid. LCMS (M + H) + = 420.

Example 345: 4- [3 - (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 344 substituting benzyl bromide for cyclopropylmethyl bromide in Step 2. LCMS (M + H) + = 384.

Example 346: N- [4- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide.

Stage 1: 5- (2,6-dichloropyrimidin-4-yl) -1,3-dimethylpyridin-2-one

A mixture of 2,4,6-trichloropyrimidine (275 mg, 1.5 mmol), 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (246 mg, 1 mmol), Pd (OAc) 2 (20 mg), triphenylphosphine (16 mg) and 2 M

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Na ₂ CO ₃ (1 ml, 2 mmol) in THF (6.7 ml) was purged with nitrogen for 5 min, covered and heated to 80 ° С for 3 h. After filtration of the mixture through a thin celite pad, the filtrate was concentrated in vacuo and purified with column chromatography on silica gel using a gradient (0 to

100%) EtOAc in DCM to give the title compound (150 mg, 55%) as a white solid. LCMS (M + H) ⁺ = 271.

Stage 2: 5- [2-chloro-6- (2,4-difluorophenoxy) pyrimidin-4-yl] -1,3-dimethylpyridin-2-one and 5- [6-chloro2- (2,4-difluorophenoxy) pyrimidin-4-yl] -1,3-dimethylpyridin-2-one

A mixture of 2,4-difluorophenol (25 mg, 0.19 mmol) and 5- (2,6-dichloropyrimidin-4-yl) -1,3-dimethylpyridin2-one (50 mg, 0.19 mmol) in DMF (0.5 ml) and THF (0.5 ml) was treated with K2CO3 (304 mg, 0.23 mmol). The mixture was stirred at room temperature for 3 hours. The resulting suspension was diluted with water and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with 1N. NaOH (aq.) (5 ml), water (15 ml), brine, dried over MgSO ₄ and concentrated in vacuo. The crude solid was purified by column chromatography on silica gel using an EtOAc gradient (0 to 50%) in DCM to give an unseparated mixture of the regioisomeric title compounds (66 mg, 96% overall) as a white solid. LCMS (M + H) + = 364 for two regioisomers.

Stage

3:

N- [4- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2 yl] ethanesulfonamide

A solution of ethanesulfonamide (80 mg, 0.73 mmol) in DMF (2 ml) was treated with NaH (27 mg, 0.68 mmol, 60% by weight). After 15 min, the mixture was treated with a solution in DMF (1 ml) of the title compounds obtained in step 2. The reaction mixture was stirred at 50 ° C for 14 h. The resulting suspension was diluted with water and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Preparative HPLC isolated both regioisomers as examples 346 and 347. The title compound (6 mg, 8%) was obtained as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.08 (t, J = 7.1 Hz, 3H), 2.07 (s, 3H), 3.11 (q, J = 7.1 Hz, 2H), 3.54 (s, 3H) , 6.81 (s, 1H), 7.17 (m, 1H), 7.47 (s, 2H), 7.79 (s, 1H), 8.37 (s, 1H), 11.37 (bs, 1H). LCMS (M + H) ⁺ = 437.

Example 347: N- [2- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-4yl] ethanesulfonamide

This regioisomer was also isolated by preparative HPLC Example 346 step 3. The title compound (2 mg, 3%) was obtained as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.06-1.13 (m, 3H), 2.08-2.12 (m, 3H), 3.11-3.23 (m, 2H), 3.54-3.57 (m, 3H), 7.14 -7.28 (m, 2H), 7.45-7.54 (m, 2H), 8.04-8.09 (m, 1H), 8.52-8.57 (m, 1H), 10.92-11.26 (m, 1H), both as white solids ... LCMS (M + H) ⁺ = 437.

Example 348 4- [3 - [[2- (Difluoromethoxy) phenyl] methoxy] -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one.

Step 1: 4- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -6-methylfuro [2,3-c] pyridine-7one

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A mixture of 1-bromo-3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylbenzene (470 mg, 1.27 mmol), 6methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl) furo [2,3-c] pyridin-7-one (316 mg, 1.15 mmol), Pd (dppf) Cl ₂ (84 mg) and K3PO4 (610 mg, 2.9 mmol) in dioxane (7 ml) and water (700 μl) was purged with nitrogen for 7 min, capped and heated to 70 ° C for 2 h and to room temperature over 48 h. After the mixture was diluted with EtOAc (5 ml) and water (5 ml), it was filtered through a thin layer of celite. After the filtrate was separated, the aqueous layer was washed with EtOAc (25 ml x 3). The combined organic layers were washed with water and brine, dried over MgSO ₄ and concentrated in vacuo. The crude solid was purified by column chromatography on silica gel using an EtOAc gradient (0 to 100%) in DCM to give the title compound (375 mg, 74%) as a white solid. LCMS (M + H) ⁺ = 440.

Stage 2: 4- (3-hydroxy-5-methylsulfonylphenyl) -6-methylfuro [2,3-c] pyridin-7-one

A solution of 4- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -6-methylfuro [2,3-c] pyridin-7one (370 mg, 0.84 mmol) in AcOH (6 ml) was heated to 100 ° C for 12 hours. After cooling to room temperature, the reaction mixture was evaporated to dryness in vacuo. The resulting residue was diluted with water and extracted with EtOAc (20 ml x 3); the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting solid was suspended in a 1: 1 mixture of EtOAc and hexanes, sonicated for 1 min and filtered. The filter cake was collected to give the title compound (210 mg, 78%) as a gray solid. LCMS (M + H) ⁺ = 320.

Step 3: 4- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5-methylsulfonylphenyl] -6-methylfuro [2,3c] pyridin-7-one

Closed mixture of 4- (3-hydroxy-5-methylsulfonylphenyl) -6-methylfuro [2,3-c] pyridin-7-one (25 mg, 0.08 mmol), 1- (bromomethyl) -2- (difluoromethoxy) benzene ( 28 mg, 0.12 mmol) and Cs ₂ CO ₃ (50 mg, 0.15 mmol) in DMF (900 μL) was heated to 80 ° С for 3 h. The mixture was filtered, and the filter cake was washed with ACN (500 μL), the filtrate was purified by preparative HPLC to give the title compound (22 mg, 58%) as a white solid. LCMS (M + H) ⁺ = 476.

Example 349: 6-methyl-4- (3-methylsulfonyl-5-phenylmethoxyphenyl) furo [2,3-c] pyridin-7-one

The title compound was prepared in a similar manner to Example 348 substituting 1- (bromomethyl) -2- (difluoromethoxy) benzene for benzyl bromide in Step 2. LCMS (M + H) + = 410.

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Example 350: 4- [3- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -6-methylfuro [2,3-c] pyridine-7-

The title compound was prepared in a similar manner to Example 348 substituting 1- (bromomethyl) -2- (difluoromethoxy) benzene for bromomethylcyclopropane in Step 3. LCMS (M + H) + = 374.

Examples 351-356 in table. 19 was obtained in a similar multi-step manner as in example 300, step 1, where either ethyl pentanoate was converted to 4-chloro-2-methylsulfonyl-5-propylpyrimidine, or ethylhexanoate was converted to 5-butyl-4-chloro-2-methylsulfonylpyrimidine, then each of which reacted with a) 3-methoxy-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl) pyridin-2-one (described in example 146, step 3) , b) the title compound of Example 98, step 1, or c) 3-chloro-1-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine -2-one (described in Example 134) in a manner similar to Example 152, step 5 to provide the title compound.

Table 19

An example of chemical synthesis Structure Name '11 NMR (ppm (δ), 400 MHz) MS (Μ + Η) 351 / ω O f 1-methyl-5- (2methyl sulfoni l-5- propyl pyrimide in-4- yl) pyridine-2- he (CDCh, 400 MHz) δ 8.72 (s, 1 Η), 8.00 (s, 1 Η), 7.67 (q, J = 6.8 Hz, 1 Η), 6.67 (d, J = 9.6 Hz, 1), 3.68 (s, 3 Η), 3.38 (s, 3 Η), 2.82 (t, J = 8.0 Hz, 2 Η), 1.73 (m, 2 Η), 1.00 (t, J = 7.2 Hz, 3 Η). 308 352 / ω O 2 about 5- (5-butyl-2methyl sul lf oni lpyrimidin-4yl) -1- methylpyridin2-one 322

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353 N SO ₂ Me cAO 3-chloro-1-methyl5- (2methyl sulfoni l-5- propylpyrimide in-4yl) pyridin-2one 342 354 about 7 ° AA ^z / ω 5- (5-butyl-2methyl sulfoni lpyrimidin-4yl) -3-chloro-1methylpyridin2-one 356 355 o ^x 7 / ω O 2 f 3-methoxy-1methyl-5- (2methyl sul lf they l-5- propylpyrimide in-4- yl) pyridine-2- he 338 356 N SO ₂ Me LC O 5- (5-butyl-2methyl sul lf oni lpyrimidin-4yl) -3-methoxy- one- methylpyridin2-one 352

Examples 357-362 in table. 20 was prepared in a similar manner to Example 300, Step 2, wherein Examples 351-356 were each treated with EtSO ₂ NH ₂ to provide the title compound. Example 363 in table. 20 was prepared in a similar manner to Example 152 Step 6 wherein Example 305 was treated with MeSO ₂ NH ₂ to provide the title compound.

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Table 20

An example of chemical synthesis Structure Name Ή NMR (ppm (δ), 400 MHz) MS (M + H) Derived from Example No. 357 N ^ NHSO ₂ Et Ϊ О N- [4- (1-methyl-6oxopyridin-3yl) -5propylpyrimidine -2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.45 (s, 1 Η), 7.84 (s, 1 Η), 7.68 (d, J = 9.6 Hz, 1 Η), 6.68 (d, J = 9.2 Hz, 1 Η), 3.68 (s, 3 Η), 3.64 (t, J = 7.6 Hz, 2), 2.67 (t, J = 8.0 Hz, 2 Η), 1.64 (q, J = 7.6 Hz, 2), 1.45 (t, J = 7.2 Hz, 3), 0.98 (t, J = 7.2 Hz, 3 Η) 337 351 358 N NHSO ₂ Et V 'О N- [5-6ymn-4- (lmethyl-6oxopyridin-3yl) pyrimidin-2yl] ethanesulfonamid (CDCh, 400 MHz) δ 8.44 (s, 1 Η), 7.84 (s, 1 Η), 7.69 (d, J = 9.6 Hz, 1 Η), 6.68 (d, J = 9.2 Hz, 1 Η), 3.68 (s, 3 Η), 3.64 (t, J = 7.6 Hz, 2 Η), 2.68 (t, J = 7.6 Hz, 2H), 1.57 (t, J = 8.0 Hz, 2 H), 1.46 (d, J = 7.6 Hz, 3 H), 1.41 (t, J = 8.4 Hz, 2 H), 0.93 (t, J = 7.2 Hz, 3 H) 351 352

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359 N NHSO ₂ E a 0 Ν- [4- (5-χπορ-1methyl-6oxopyridin-3 yl) -5propylpyrimidine -2yl] ethanesulfonamid (CDCh, 400 MHz) δ 8.47 (s, 1 Η), 7.87 (d, J = 2.8 Hz, 1 Η), 7.78 (d, J = 2.0 Hz, 1 Η), 3.72 (s, 3 Η), 3.65 (q, J = 7.2 Hz, 2 Η), 2.67 (t, J = 8.0 Hz, 2H), 1.65 (d, J = 8.0 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H), 1.00 (t, J = 7.2 Hz, 3 H) 371 353 360 CM ο ω ζ у - σ bо / θ X- [5-butyl-4- (5chloro-1-methyl-6oxopyrid in-3 yl) pyrimidin-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.48 (s, 1 H), 7.90 (d, J = 2.4 Hz, 1 H), 7.80 (d, J = 2.4 Hz, 1 H), 3.74 (s, 3 H), 3.66 (q, J = 7.2 Hz, 2 H), 2.70 (t, J = 8.0 Hz, 2H), 1.61 (m, 2H), 1.47 (t, J = 7.2 Hz, 3 H), 1.42 (q, J = 8.0 Hz, 2 H), 1.00 (t, J = 7.2 Hz, 3 H) 385 354 361 Sh CM ο ω / ζ ° Ν- [4- (5-methoxy-1 methyl-6oxopyridin-3yl) -5propylpyrimidine -2yl] ethanesulfonamid (CDCh, 400 MHz) δ 8.46 (s, 1 H), 7.40 (d, J = 1.6 Hz, 1 H), 7.05 (s, 1 H), 3.89 (s, 3 H), 3.68 (s, 3H) , 3.65 (t, J = 8.0 Hz, 2 H), 2.69 (t, J = 8.0 Hz, 2 H), 1.67 (m, 2 H), 1.44 (t, J = 7.2 Hz, 3 H), 1.00 ( t, J = 7.2 Hz, 3 H) 367 355

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362 N NHSO ₂ VJ dx 0 I- [5-butyl-4- (5methoxy-1-methyl6-oxopyridin-3 yl) pyrimidin-2yl] ethanesulfonamide (CDCh, 400 MHz) δ 8.43 (s, 1 Η), 7.39 (d, J = 2.0 Hz, 1 Η), 7.03 (d, J = 2 Hz, 1 Η), 3.89 (s, 3 Η), 3.68 (s, 3 Η), 3.64 (d, J = 8.0 Hz, 2 Η), 2.71 (t, J = 8.0 Hz, 2H), 1.67 (m, 2 H, covered by a water peak), 1.45 (t, J = 7.2 Hz, 3 Η), 1.39 (q, J = 7.2 Hz, 2), 0.94 (t, J = 7.2 Hz, 3 Η) 381 356 363 N NHSO ₂ M ld 0 Ν- [5-butyl-4- (1,5dimethyl-6oxopyridin-3yl) pyrimidin-2yl] methanesulfon MID (CDCh, 400 MHz) δ 8.47 (s, 1 Η), 7.70 (d, J = 2 Hz, 1 Η), 7.55 (s, 1 Η), 3.66 (s, 3), 3.46 (s, 3 Η ), 2.69 (t, J = 8.0 Hz, 2), 2.23 (s, ZN), 1.56 (q, J = 8.0 Hz, 2), 1.38 (q, J = 7.2 Hz, 2 Η), 0.94 ( t, J = 7.2 Hz, 3 Η) 351 305

Example 364 4- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -2-methylisoquinolin-1-one.

Stage 1: 5-bromo-7H- [1,2,4] triazolo [4,3-a] pyrazin-8-one

CHA

Br

The title compound was prepared in three steps from 3-bromo-4-fluorobenzenethiol in a manner similar to Example 79 Steps 1-3 except that 2-iodopropane was replaced by ethyl iodide in Step 1 and the cyclopropylmethanol alkoxide was replaced with sodium methoxide at stage 3.

¹ H NMR (CDCl3, 400 MHz) δ 8.05 (d, J = 2.4 Hz, 1H), 7.76 (dd, J1 = 2.4 Hz, J2 = 8.4, 1H), 6.97 (d, J = 8.4 Hz, 1H), 3.18 (m, 1H), 1.29 (d, J = 6.8 Hz, 6H), 0.86 (m, 1H), 0.71 (d, J = 6.8 Hz, 2H), 0.45 (d, J = 5.6 Hz, 2H). LCMS: (M + H +): 333.0; 335.0.

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Stage 2: 4- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -2-methylisoquinolin-1-one

The title compound from Step 1 was coupled to the title compound of Example 89, Step 1 in a similar manner as Example 89, Step 2 to provide the title compound as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 7.2 Hz, 1H), 7.91 (dd, J1 = 6.4 Hz, J ₂ = 8.4, 1H), 7.80 (d, J = 2.4 Hz, 1H) , 7.51-7.57 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 7.09 (t, J = 8.4 Hz, 1H), 3.89 (s, 2H), 3.67 (s, 3H), 3.18- 3.25 (m, 1H), 1.33 (d, J = 6.8 Hz, 6H), 0.99-1.02 (m, 1H), 0.414 (m, 2H), 0.11 (s, 2H). LCMS: (M + H +): 412.

Example 365 8- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-4H-pyrido [4,3b] [1,4] oxazine-3,5-dione.

Step 1: 6-methyl-4H-pyrido [4,3-b] [1,4] oxazine-3,5-dione

To a solution of the title compound of Example 237, step 3 (1.6 g, 9.01 mmol, 1.00 eq.) In CH ₂ Cl ₂ (150 ml) at 0 ° C under N _{2 was} added chloroacetyl chloride (0.75 ml, 9 mmol) dropwise ... Then pyridine (2.2 ml, 37 mmol) was added and the mixture was stirred for 5 h at room temperature. Saturated aqueous KHSO4 (100 ml) was added and the aqueous layer was extracted a total of three times with CH ₂ Cl ₂ . The combined organic layers were dried over Na ₂ SO ₄ , filtered and then acetone (200 ml) was added followed by the addition of cesium carbonate (14.6 g, 45 mmol) directly to the filtrate (250 ml). The mixture was then heated at 50 ° C for 2 hours. The volume was reduced and water was added. Extraction with 3: 1 CH ₂ Cl ₂ : isopropanol followed by trituration with 1: 2 with EA / PE gave the title compound (400 mg, yield: 24.67%) as a yellow solid.

¹ H NMR (CDClj, 400 MHz) δ 8.17-8.14 (br, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.07 (d, J = 7.2 Hz, 1H), 4.69 (s, 1H), 3.59 (s, 3H). LCMS: 181.0 (M + H) +.

Stage 2: 8-bromo-6-methyl-4H-pyrido [4,3-b] [1,4] oxazine-3,5-dione

At room temperature, NBS (89 mg, 0.5 mmol) was added to the title compound from Step 1 (90 mg, 0.5 mmol) in anhydrous CH3CN (1 mL). After stirring for about 2 h, additional NBS (75 mg, 0.4 mmol) was added and the reaction was complete after 20 min. Extraction with EA and chromatography on silica gel gave the title compound (51 mg, 0.39 mmol) in 39% yield.

Stage

3:

b] [1,4] oxazine-3,5-dione

8- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-4H-pyrido [4.3 The title compound with

step 2 reacted (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane with 2- [2 in a manner similar to that described in example 224, step 5. Chromatography on silica gel (40 -100% EA in hexane over 8 min) gave the title compound.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ ppm 0.27-0.33 (m, 2H), 0.51-0.57 (m, 2H), 1.11 (t, J = 7.33 Hz, 3H), 1.141.22 (m, 1H, partially closed), 3.22-3.28 (m, 2H), 3.51 (s, 3H), 3.96 (d, J = 7.07 Hz, 2H), 4.54 (s, 2H), 7.27 (d, J = 8.84 Hz, 1H), 7.52 (s, 1H), 7.67 (d, J = 2.02 Hz, 1H), 7.79-7.92 (m, 1H), 10.10 (s, 1H). LCMS: 419 (M + H) +.

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Example 366: 8- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -6-methyl-3,4,4а, 8а-tetrahydro-2Hpyrido [4,3-b] [1,4] oxazin-5-one

The title compound of Example 365 Step 3 in anhydrous THF was treated with excess 1 M LAH in THF at room temperature. After about 30 min, ice, water, methanol and 1 M HCl were added followed by the addition of saturated aqueous NaHCO ₃ and extraction with EA. Chromatography on silica gel (EA followed by 5% methanol in EA) afforded the title compound as a clear glass.

1H NMR (DMSO-d6, 400 MHz) δ ppm 0.32 (br.s., 2H), 0.54 (br.s., 2H), 1.03-1.30 (m, 4H), 3.45 (br. S., 3H) , 3.94 (br. S., 2H), 4.09 (br. S., 2H), 5.03 (br. S., 1H), 7.05 (br. S., 1H), 7.22 (br. S., 1H) , 7.62 (br. S., 1H), 7.78 (br. S., 1H).

1H NMR (DMSO-d6 / DCl, 400 MHz) δ ppm 0.29 (br. S., 2H), 0.55 (br. S, 2H), 1.10 (br. S., 4H), 3.25 (br. S., 2H), 3.45 (br. S., 2H), 3.51 (br. S., 3H), 3.93 (br. S., 2H), 4.43 (br. S., 2H), 7.27 (br. S., 1H), 7.69 (br s, 1H), 7.84 (br s, 2H). LCMS: 405 (M + H) +.

Example 367:

N- [4- (2,4-difluorophenoxy) -3- (7-methyl-8-oxoimidazo [1,5-a] pyrαzin-5 yl) phenyl] methanesulfonamide

To a solution of the title compound from Example 129, step 2 (140 mg, 0.38 mmol) in THF (20 mL) was added pyridine (152 mg, 1.90 mmol). Then, methanesulfonyl chloride (48 mg, 0.46 mmol) was added to the solution at 0 ° С. The solution was left to warm to room temperature and heated to boiling under reflux overnight. The reaction mixture was concentrated under reduced pressure to yield a crude material which was purified by preparative HPLC to afford the title compound (75.26 mg, 44%) as a yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.60 (s, 1H), 8.15 (s, 1H), 7.50 (d, J = 2.8 Hz, 1H), 7.30 (dd, J = 8.8, 2.4 Hz, 1H), 7.18 (td, J = 8.8, 5.3 Hz, 1H), 7.00-6.88 (m, 2H), 6.83 (s, 1H), 6.78 (d, J = 8.8 Hz, 1), 3.60 (s, 3H), 3.03 (s, 3H). LCMS: 447.0 (M + 1) ⁺ .

Example 368 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -7-methylimidazo [1,5-a] pyrazin-8 one

Into a microwave vial containing 5-bromo-7-methylimidazo [1,5-a] pyrazin-8-one (150 mg, 0.66 mmol), 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4.4 , 5,5-tetramethyl-1,3,2-dioxaborolane (290 mg, 0.80 mmol) and NaHCO ₃ (1 ml, 2 M) in dioxane (3 ml), Pd (dppf) Cl ₂ (80 mg, 0.10 mmol). The mixture was purged with N ₂ for 2 minutes and sealed. The reaction was irradiated with microwaves at 100 ° C for 2 h. Water (20 ml) was added and the mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with brine (20 ml), dried over Na ₂ SO _4, filtered and concentrated in vacuo. The residue was purified by column chromatography (PE: EA = 5: 1 to 1: 1) to give the title compound (55.3 mg, 22%) as a light yellow solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.03 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 2H), 7.94 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.15 (d, J = 8.8 Hz, 1H), 6.49 (s, 1H), 3.96 (d, J = 6.4 Hz, 2H), 3.54 (s, 3H), 3.16 (q, J = 7.6 Hz, 1H), 1.33 (t, J = 7.6 Hz, 1H), 1.08 (s, 1H), 0.54 (d, J = 7.2 Hz, 2H), 0.54 (d, J = 4.4 Hz, 2H). LCMS: 388.1 (M + 1) ⁺ .

Example 369 5- [2- (2,4-Difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -7-methylimidazo [1.5a] pyrazin-8-one.

Step 1: 2- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2 dioxaborolane

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A mixture of 2-bromo-1- (2,4-difluorophenoxy) -4- (ethylsulfonylmethyl) benzene (250 mg, 0.64 mmol), bis (pinacolato) diborone (255 mg, 0.96 mmol), KOAc (189 mg, 1.92 mmol) and Pd (dppf) Cl ₂ (44 mg, 0.06 mmol) in dioxane (5 ml) was stirred at 70 ° С for 18 h under N2 atmosphere. The mixture was concentrated and the residue was purified by column chromatography to give the title compound (150 mg, 53.4%) as a yellow solid. LCMS: 439.2 (M + 1) +.

Step 2: 5- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -7-methylimidazo [1,5-a] pyrazin8-one

A mixture of the title compound from Step 1 (150 mg, 0.34 mmol), the title compound from Example 129, Step 1 (87 mg, 0.38 mmol), K ₃ PO ₄ (217 mg, 1.02 mmol) and Pd (dppf) Cl ₂ (22 mg, 0.03 mmol) in dioxane (5 ml) and H2O (1 ml) were stirred at 70 ° С for 18 h in an N2 atmosphere. The resulting mixture was filtered and concentrated. The residue was purified by preparative HPLC to afford the title compound (70.0 mg, 45%) as a yellow solid.

1H NMR (DMSO-d6, 400 MHz) δ 8.83 (s, 1H), 8.33 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.57 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz , 1H), 7.53-7.41 (m, 2H), 7.37 (s, 1H), 7.20-7.12 (m, 1H), 6.93 (d, J = 8.8 Hz, 1H), 4.54 (s, 2H), 3.45 ( s, 3H), 3.09 (q, J = 7.6 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H). LCMS: 460.1 (M + 1) ⁺ .

Example 370 7-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] imidazo [1,5a] pyrazin-8-one.

Stage 1: 4,4,5,5-tetramethyl-2- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1,3,2 dioxaborolane o o

The title compound was prepared in a similar manner to Example 369, Step 1 by substituting 2-bromo-1 (2.4 -difluorophenoxy) -4- (ethylsulfonylmethyl) benzene. LCMS: 395.2 (M + 1) ⁺ .

Step 2: 7-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] imidazo [1,5а] pyrazin-8-one

The title compound was prepared in a similar manner to Example 369 Step 2 by substituting 4,4,5,5-tetramethyl-2- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] 1,3,2-dioxaborolane on 2- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl1,3,2-dioxaborolane.

1H NMR (DMSO-d6, 400 MHz) δ 8.64 (s, 1H), 8.32 (s, 1H), 7.64 (dd, Ji = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.56 (s, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.25 (s, 1H), 4.86 (q, J = 8.8 Hz, 2H), 4.53 (s, 2H), 3.44 (s, 3H), 2.94 (s, 3H) ... LCMS: 416.1 (M + 1) ⁺ .

Example 371 5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -7-methylimidazo [1,5a] pyrazin-8-one.

Step 1: 2- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -4,4,5,5-tetramethyl-1,3,2 dioxaborolane

- 320 038715

The title compound was prepared in a similar manner to Example 369, Step 1 by substituting 2-bromo-1 (2.4 -difluorophenoxy) -4- (ethylsulfonylmethyl) benzene. LCMS: 409.2 (M + 1) ⁺ .

Stage 2: 5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -7-methylimidazo [1,5а] pyrazin-8-one

The title compound was prepared in a similar manner to Example 369, Step 2, by substituting 2- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -4,4,5,5-tetramethyl1 , 3,2-dioxaborolane on 2- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl1,3,2-dioxaborolane.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.99 (s, 1H), 8.47 (s, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.52 (s, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 4.82 (q, J = 8.4 Hz, 2H), 4.48 (s, 2H), 3.42 (s, 3H), 3.04 (q, J = 7.2 Hz, 2H), 2.94 (t, J = 7.2 Hz, 3H). LCMS: 430.1 (M + 1) +.

Example a] pyrazin-8-one.

Dioxaborolane stage

372: 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -7-methylimidazo [1,5

1: 2- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl-1,3,2-

The title compound was prepared in a similar manner to Example 369, Step 1 by substituting 2-bromo-1 (2,4-difluorophenoxy ) -4- (ethylsulfonylmethyl) benzene. LCMS: 442.2 (M + 18) ⁺ .

Stage 2: 5- [2- (2,4-difluorophenoxy) -5 - (methylsulfonylmethyl) phenyl] -7-methylimidazo [1,5а] pyrazin-8-one

The title compound was prepared in a similar manner to Example 369 Step 2 by substituting 2- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl1,3 , 2-dioxaborolane on 2- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -4,4,5,5-tetramethyl1,3,2-dioxaborolane.

Ή NMR (DMSO-d6, 400 MHz) δ 8.59 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 2.0 Hz, 1H), 7.57 (dd, J1 = 8.8 Hz, J ₂ = 2.0 Hz, 1H), 7.52-7.39 (m, 2H), 7.30 (s, 1H), 7.18-7.11 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 4.55 (s, 2H), 3.44 (s, 3H), 2.96 (s, 3H). LCMS: 446.1 (M + 1) ⁺ .

Example 373 5- [2- (4,4-Difluorocyclohexyl) oxy-5-ethylsulfonylphenyl] -7-methylimidazo [1,5a] pyrazin-8-one.

Stage 1: 2- (5-ethylsulfonyl-2-fluorophenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Bromo-4-ethylsulfonyl-1-fluorobenzene (5.00 g, 18.72 mmol), AcOK (3.88 g, 56.16 mmol, 3 eq.), Pi-321 038715 nakolin ether (9.51 g, 37.44 mmol, 2 eq.), Pd ₂ (dba) ₃ (17.14 g, 18.72 mmol, 1 eq.) and XPhos (9.24 g, 18.72 mmol, 1 eq.) in dioxane (300 ml) were degassed and then heated to 60 ° C overnight under N2. The reaction mixture was poured into H2O (300 ml). The mixture was extracted with EA (3x250 ml). The combined organic phases were washed with saturated brine (300 ml), dried over anhydrous MgSO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give the title compound (1.87 g, 32%) as gray solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.34-8.31 (m, 1H), 8.01-7.98 (m, 1H), 7.22 (d, J = 8.8 Hz, 1H), 3.14 (q, J = 7.6 Hz, 2H ), 1.37 (s, 12H), 1.27 (t, J = 7.6 Hz, 3H).

Stage 2: 5- (5-ethylsulfonyl-2-fluorophenyl) -7-methylimidazo [1,5-a] pyrazin-8-one

5-Bromo-7-methylimidazo [1,5-a] pyrazin-8-one (600 mg, 2.63 mmol, 0.83 eq.), The title compound from Step 2 (1.00 g, 3.18 mmol, 1.00 eq.), K ₃ PO ₄ (2.03 g, 9.55 mmol, 3.00 eq.) And Pd (dppf) Cl ₂ (118 mg, 0.16 mmol, 0.05 eq.) In dioxane (20 ml) were degassed and then heated to 60 ° С overnight in an atmosphere of N ₂ . The reaction mixture was poured into water. The mixture was extracted with EA (3x25 ml). The organic phase was washed with brine (30 ml), dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo to give a residue, which was purified by silica gel chromatography to give the title compound (600 mg, yield: 56.24%).

1H NMR (CDCl ₃ , 400 MHz) δ 8.50 (s, 1H), 8.17 (s, 1H), 8.12-8.08 (m, 2H), 7.50 (t, J = 8.8 Hz, 1H), 6.90 (s, 1H ), 3.59 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 0.89-0.83 (m, 3H).

Step 3: 5- [2- (4,4-difluorocyclohexyl) oxy-5-ethylsulfonylphenyl] -7-methylimidazo [1,5a] pyrazin-8-one

To a solution of 4,4-difluorocyclohexan-1-ol (162 mg, 1.19 mmol) in THF (10 ml), NaH (48 mg, 1.19 mmol, 60% in mineral oil) was added in one portion at 25 ° С in an N2 atmosphere. The mixture was stirred at 25 ° C for 30 min, then the title compound from step 2 (200 mg, 0.6 mmol) was added and the mixture was stirred at 25 ° C for 18 h. The reaction mixture was poured into ice-water (v / v = 1/1) (150 ml) and stirred for 20 min. The aqueous phase was extracted with EA (40 ml x 3). The combined organic phase was washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (57.35 mg, 22%) as a white solid.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.04 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 4.90-4.84 (brs, 1H), 3.44 (s, 3H), 3.32 (q, J = 7.2 Hz, 2H ), 1.85-1.83 (m, 4H), 1.69-1.61 (m, 4H), 1.15 (t, J = 7.2 Hz, 3H). LCMS: 452.2 (M + H) +.

Example 374 5- (2-cyclopentyloxy-5-ethylsulfonylphenyl) -7-methylimidazo [1,5-a] pyrazin-8-one

The title compound was prepared in a similar manner to Example 373 by substituting 4,4-difluorocyclohexan-1-ol for cyclopentanol in Step 3.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.34 (s, 1H), 8.16 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.91 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.24 (s, 1H), 5.04-5.01 (brs, 1H), 3.43 (s, 3H), 3.31 (q, J = 6.8 Hz, 2H), 1.91-1.80 (m, 2H) , 1.621.30 (m, 6H), 1.14 (t, J = 6.8 Hz, 3H). LCMS: 402.2 (M + H) ⁺ .

- 322 038715

Example 375 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -7-methylimidazo [1,5a] pyrazin-8-one

The title compound was prepared in a similar manner to Example 373 by substituting 4,4-difluorocyclohexan-1-ol for cyclopropylmethanamine in Step 3.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.28-8.24 (m, 2H), 7.76 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H ), 6.47-6.41 (brs, 1H), 3.44 (s, 3H), 3.18 (q, J = 7.2 Hz, 2H), 3.06-3.01 (m, 2H), 1.12 (t, J = 6.8 Hz, 3H) , 1.06-0.98 (m, 1H), 0.42-0.37 (m, 2H), 0.16-0.11 (m, 2H). LCMS: 387.2 (M + H) ⁺ .

Example 376: 5- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -7-methylimidazo [1,5-a] pyrazin-8-one

The title compound was prepared in a similar manner to Example 373 by substituting 4,4-difluorocyclohexan-1-ol for 2,4-difluorophenol in Step 3.

¹ H NMR (CDCl ₃ , 400 MHz) δ 8.05 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.97 (dd, J1 = 8.8 Hz, J ₂ = 2.4 Hz, 1H), 7.16- 7.10 (m, 1H), 7.05-7.00 (m, 1H), 6.98-6.93 (m, 1H), 7.97 (dd, Ji = 8.8 Hz, J ₂ = 1.2 Hz, 1H), 3.55 (s, 3H), 3.18 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). LCMS: 446.1 (M + H) ⁺ .

Example 377 7- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -5-methylfuro [3,2-c] pyridine-4one.

Stage 1: 7-bromo-5-methylfuro [3,2-c] pyridin-4-one

HNa (56 mg, 1.4 mmol, 60% dispersion in mineral oil) in three portions. After stirring at room temperature for 45 min, MeI (87 μL, 1.4 mmol) was added dropwise over 5 min. The reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was then cooled to 0 ° C. followed by the addition of saturated aqueous NH4Cl (5 ml) dropwise. The resulting mixture was extracted with EtOAc (3x5 ml). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound. LCMS: 227.9 (M + H) ⁺ .

Stage 2: 5-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo [3,2-c] pyridin-4-one

The title compound was prepared in a similar manner to Example 255, Step 4, by replacing 7-bromo-5-methylfuro [3,2-c] pyridin-4-one with No. [4- (cyclopropylmethoxy) -3 (tetramethyl- 1,3,2-dioxaborolan-2-yl) phenyl] ethane-1-sulfonamide. LCMS: 276.1 (M + H) +.

Step 3: 7- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -5-methylfuro [3,2-c] pyridin-4-one

The title compound was prepared in a similar manner to Example 197.

- 323 038715 by replacing 5-methyl-7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) furo [3,2-c] pyridin-4-one with 2- [2 (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 2-bromo-1 (cyclopropylmethoxy) -4-methylsulfonylbenzene on 4-bromo-2-methyl- 6- (trifluoromethyl) isoquinolin-1-one.

1H NMR (CDCl ₃ , 400 MHz) δ 8.05 (s, 1H), 7.92 (dd, J1 = 8.6 Hz, J2 = 1.8 Hz, 1H), 7.50 (m, 2H), 7.07 (m, 2H), 3.95 ( d, J = 6.7 Hz, 2H), 3.70 (s, 3H), 3.1 (s, 3H), 1.15 (m, 1H), 0.57 (m, 2H), 0.28 (m, 2H). LCMS: 374.1 (M + H) +.

Example 378 7- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -5-methylfuro [3,2-c] pyridin-4-one

The title compound was prepared in a similar manner to Example 197 by substituting 2- [ 2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 7-bromo-5-methylfuro [3,2-c] pyridin-4-one on 4-bromo -2-methyl-6- (trifluoromethyl) isoquinolin-1-one.

¹ H NMR (DMSO-d6, 400 MHz) δ 7.88 (m, 4H), 7.33 (d, J = 9.4 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 4.02 (d, J = 6.8 Hz, 2H), 3.58 (s, 3H), 3.28 (m, 2H), 1.12 (t, J = 7.4 Hz, 3H), 1.08 (m, 1H), 0.45 (m, 2H), 0.24 (m, 2H ). LCMS: 388.1 (M + H) ⁺ .

Example 379:

yl) phenyl] ethanesulfonamide

N- [4- (2,4-difluorophenoxy) -3- (5-methyl-4-oxofuro [3,2-c] pyridine-7-

The title compound was prepared in a similar manner to Example 197 by substituting N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl ) phenyl] ethanesulfonamide on 2- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5tetramethyl-1,3,2-dioxaborolane and 7-bromo-5-methylfuro [3,2-c] pyridine -4-one on 4-bromo-2-methyl-6 (trifluoromethyl) isoquinolin-1-one.

1H NMR (DMSO-d ₆ , 400 MHz) δ 9.83 (s, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.78 (s, 1H), 7.37 (m, 2H), 7.24 (dd, J1 = 8.8 Hz, J2 = 2.7 Hz, 1H), 7.14 (m, 1H), 7.03 (m, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.93 (d, J = 8.8 Hz, 1H), 3.54 (s, 3H), 3.12 (q, J = 7.3 Hz, 2H), 1.12 (t, J = 7.3 Hz, 3H). LCMS: 461.2 (M + H) +.

Example 380: N- [4- (2,4-difluorophenoxy) -3- (5-methyl-4-oxofuro [3,2-c] pyridine-7yl) phenyl] methanesulfonamide

O

The title compound was prepared in a similar manner to Example 197 by substituting N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl ) phenyl] methanesulfonamide on 2- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -4,4,5,5tetramethyl-1,3,2-dioxaborolane and 7-bromo-5-methylfuro [3,2-c] pyridine -4-one on 4-bromo-2-methyl-6 (trifluoromethyl) isoquinolin-1-one.

1H NMR (DMSO-d6, 400 MHz) δ 9.77 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 (s, 1H), 7.38 (m, 2H), 7.25 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 7.12 (m, 1H), 7.04 (m, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.54 (s, 3H), 3.02 (s, 3H). LCMS: 447.1 (M + H) ⁺ .

Example 381 4- (cyclopropylmethoxy) -5- (1-methyl-6-oxopyridin-3-yl) -1- (methylsulfonylmethyl) pyridin-2-one

Step 1: 5-bromo-4- (cyclopropylmethoxy) -2-methoxypyridine

- 324 038715

To a solution of cyclopropylmethanol (446 mg, 6.18 mmol) in THF (10 ml) was added NaH (247 mg, 6.18 mmol, 60% in mineral oil) in one portion at 0 ° С. The reaction mixture was heated to 20 ° C over 30 min and stirred at 20 ° C for 10 min. Then 5-bromo-4-chloro-2methoxypyridine (550 mg, 2.47 mmol) was added in one portion and the mixture was stirred at 70 ° C for 4 h. The mixture was diluted with saturated aqueous ammonia solution (50 ml) and extracted with EtOAc (2x30 ml) ... The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the crude material, which was purified by silica gel column chromatography (PE: EA = 20: 1 to 10: 1) to give the title compound (450 mg, 70.6% ) in the form of a colorless oil.

1H NMR (CDCl3, 400 MHz) δ 8.11 (s, 1H), 6.18 (s, 1H), 3.90 (s, 3H), 3.89-3.88 (m, 2H), 1.39-1.27 (m, 1H), 0.70- 0.67 (m, 2H), 0.46-0.43 (m, 2H). LCMS (M + H) + = 258.0 (M + 1) ⁺ ; 260.0.

Stage 2: 5-bromo-4- (cyclopropylmethoxy) pyridin-2-ol

To a solution of the title compound from Step 1 (450 mg, 1.74 mmol) in DMF (5 mL) were added LiCl (370 mg, 8.72 mmol) and TsOH-H ₂ O (1.52 g, 8.72 mmol) at room temperature. The mixture was heated to 120 ° C and stirred for 1 h. The mixture was diluted with water (100 ml) and was extracted with EtOAc (3x100 ml). The combined organic phase was washed with saturated brine (2x200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title compound (380 mg, yield: 88.9%) as a yellow solid, which was used immediately on the next stage without additional purification.

1H NMR (CDCl3, 400 MHz) δ 7.49 (s, 1H), 5.91 (s, 1H), 3.87 (d, J = 6.8 Hz, 2H), 1.36-1.22 (m, 1H), 0.710.67 (m, 2H), 0.46-0.42 (m, 2H). LCMS: 244.0 (M + 1) ⁺ ; 246.0.

Stage 3: 5-bromo-4- (cyclopropylmethoxy) -1 - (methylsulfanylmethyl) pyridin-2-one o Aa ^V Br

To a solution of the title compound from step 2 (330 mg, 1.35 mmol) in DMF (5 ml) was added NaH (40 mg, 2 mmol, 60% in mineral oil) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. Then chloromethyl methyl sulfide (131 mg, 1.35 mmol) was added. The mixture was warmed to room temperature and stirred for 5 h. The mixture was rapidly cooled with saturated aqueous NH ₄ Cl (30 ml) and was extracted with EA (10 ml x 3). The combined organic layers were washed with saturated brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EA = 3: 1) to give the title compound (205 mg, 50%) as a yellow oil.

1H NMR (CDCl ₃ , 400 MHz) δ 7.60 (s, 1H), 5.86 (s, 1H), 4.96 (s, 1H), 3.84 (d, J = 6.8 Hz, 2H), 2.17 (s, 3H), 1.32-1.25 (m, 1H), 0.70-0.67 (m, 2H), 0.41-0.39 (m, 2H).

Step 4: 5-bromo-4- (cyclopropylmethoxy) -1- (methylsulfonylmethyl) pyridin-2-one

To a solution of the title compound from Step 3 (150 mg, 0.5 mmol) in DCM (5 ml) was added mCPBA (340 mg, 1.9 mmol). The mixture was stirred at 15 ° C for 2.5 h. Water (30 ml) was added and the resulting mixture was extracted with EtOAc (120 ml x3). The combined organic phases were washed with saturated brine (40 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 5: 1 to 2: 1) to give the title compound (120 mg, 72%) as a yellow solid.

1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.91 (s, 1H), 5.10 (s, 2H), 3.89 (d, J = 6.8 Hz, 2H), 2.98 (s, 3H), 0.90 -0.86 (m, 1H), 0.75-0.70 (m, 2H), 0.45-0.42 (m, 2H). LCMS: 335.9 (M + 1) ⁺ ; 337.

- 325 038715

Step 5: 4- (cyclopropylmethoxy) -5- (1-methyl-6-oxopyridin-3-yl) -1- (methylsulfonylmethyl) pyridin-2-one

The title compound from Step 4 (50 mg, 0.15 mmol), 1-methyl-5- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) pyridin-2-one (42 mg , 0.18 mmol), Pd (dppf) Cl ₂ (11 mg, 14.9 _{mmol) and K 3} PO ₄ (63 mg, 0.3 mmol) in dioxane (5 ml) and water (5 drops) were degassed and then heated to 70 ° С in a N2 atmosphere throughout the night. The reaction mixture was then concentrated under reduced pressure. The residue was purified by column chromatography (PE: DCM: EA = 3: 0: 1 to 0: 1: 4) followed by preparative HPLC to give the title compound (17.09 mg, 31.5%) as an off-white solid.

1H NMR (CDCl3, 400 MHz) δ 7.50 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 9.2 Hz, 1H), 5.96 (s, 1H), 5.16 (s, 2H), 3.86 (d, J = 6.8 Hz, 1H), 3.63 (s, 3H), 2.99 (s, 3H), 1.26-1.21 (m, 1H), 0.700 .66 (m, 2H), 0.36-0.32 (m, 2H). LCMS: 365.0 (M + 1) ⁺ .

Example 3 82: 5- [4- (cyclopropylmethoxy) -1 - (methylsulfonylmethyl) -6-oxopyridin-3-yl] -1,3dimethylpyridin-2-one

The title compound was prepared in a similar manner to Example 381 by substituting 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2- she on 1-methyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in step 5.

1H NMR (CDCl ₃ , 400 MHz) δ 7.35 (s, 1H), 7.32 (s, 2H), 5.97 (s, 1H), 5.16 (s, 2H), 3.87 (s, J = 7.2 Hz, 2H), 3.62 (s, 3H), 2.99 (s, 3H), 2.20 (s, 3H), 1.25-0.24 (m, 1H), 0.70-0.65 (m, 2H), 0.36-0.35 (m, 2H). LCMS: 379.0 (M + 1) +.

Example 383: 4- [4- (cyclopropylmethoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -7-fluoro-2methylisoquinolin-1-one

The title compound was prepared

in a manner similar to that described in example 381, by replacing 7-fluoro-2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one with 1methyl -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in step 5.

1H NMR (CDCl ₃ , 400 MHz) δ 8.13 (dd, J1 = 9.2 Hz, J2 = 2.4 Hz, 1H), 7.37 (s, 1H), 7.35-7.32 (m, 1H), 7.307.28 (m, 1H ), 7.03 (s, 1H), 5.99 (s, 3H), 5.13 (d, J = 13.6 Hz, 1H), 4.91 (d, J = 13.6 Hz, 1H), 3.78 (t, J = 6.4 Hz, 2H ), 3.65 (s, 3H), 3.04 (s, 3H), 1.03-0.97 (m, 1H), 0.48-0.42 (m, 2H), 0.11 (s, 2H). LCMS: 433.1 (M + 1) ⁺ .

Example 384: 4- [4- (cyclopropylmethoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 381 by replacing 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one with 1-methyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in step 5.

1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J = 8.0 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.38

- 326 038715 (s, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.07 (s, 1H), 5.99 (s, 1H), 5.45 (d, J = 14.4 Hz, 1H), 4.89 (d , J = 14.4 Hz, 1H), 3.79 (t, J = 8.0 Hz, 2H), 3.65 (s, 3H), 3.04 (s, 3H), 1.02-0.96 (m, 1H), 0.46-0.39 (m, 2H), 0.10 (s, 2H). LCMS: 415.1 (M + 1) +.

Example 385 5- [4- (2,4-Difluorophenoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -1,3dimethylpyridin-2-one.

Stage 1: 5-bromo-4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) pyridin-2-one

The title compound was prepared in a similar manner to Example 381 Steps 1-4 by substituting cyclopropylmethanol for 2,4-difluorophenol in Step 1.

¹ H NMR (CDCl3, 400 MHz) δ 7.71 (s, 1H), 7.21 (m, 1H), 7.01 (m, 2H), 5.66 (s, 1H), 5.1 (s, 2H), 2.96 (s, 3H ).

Step 2: 5- [4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -1,3dimethylpyridin-2-one

The title compound was prepared in a similar manner to Example 382 by substituting 5-bromo-4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) pyridin-2-one for the title compound from Step 1.

¹ H NMR (CDCl3, 400 MHz) δ 7.40 (s, 1H), 7.37 (s, 1H), 7.33 (s, 1H), 7.21-7.11 (m, 1H), 7.07-6.93 (m, 2H), 5.68 (s, 1H), 5.16 (s, 2H), 3.61 (s, 3H), 2.99 (s, 3H), 2.20 (s, 3H). LCMS: 437.0 (M + 1) ⁺ .

Example 386: 4- (2,4-difluorophenoxy) -5- (1-methyl-6-oxopyridin-3-yl) -1 - (methylsulfonylmethyl) pyridin-2-one

The title compound was prepared in a similar manner to Example 381 by substituting 5-bromo-4 (cyclopropylmethoxy) -1 for 5-bromo-4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) pyridin-2-one - (methylsulfonylmethyl) pyridin-2-one in step 5.

1H NMR (CDCl3, 400 MHz) δ 7.53 (dd, Ji = 2.4 Hz, G = 9.6 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.44 (s, 1H), 7.19-7.13 (m , 1H), 7.07-7.00 (m, 1H), 7.00-6.93 (m, 1H), 6.64 (d, J = 9.2 Hz, 1H), 5.68 (s, 1H), 5.17 (s, 2H), 3.61 ( s, 3H), 2.98 (s, 3H). LCMS: 423.0 (M + 1) ⁺ .

Example 387: 4- [4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -2methylisoquinolin-1-one

The title compound was prepared in a similar manner to Example 384 by substituting 5-bromo-4 (cyclopropylmethoxy) -1 for 5-bromo-4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) pyridin-2-one - (methylsulfonylmethyl) pyridin-2-one.

¹ H NMR (CDCl3, 400 MHz) δ 8.50 (d, J = 8.0 Hz, 1H), 7.72-7.67 (m, 1H), 7.57-7.52 (m, 1H), 7.49 (d, J = 9.2 Hz, 2H ), 7.20 (s, 1H), 7.08-7.02 (m, 1H), 7.01-6.94 (m, 1H), 6.93-6.86 (m, 1H), 5.74 (s, 1H), 5.46 (d, J = 14.4 Hz, 1H), 4.92 (d, J = 14.4 Hz, 1H), 3.68 (s, 3H), 3.05 (s, 3H). LCMS: 473.0 (M + 1) ⁺ .

- 327 038715

Example 388 5- (2-But-2-inoxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one.

Stage 1: 5- (2-fluoro-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one

O

A mixture of 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (2.50 g, 10.0 mmol), 2-bromo-1 -fluoro-4-methylsulfonylbenzene (2.54 g, 10.0 mmol), CsF (3.8 g, 25.0 mmol), Pd (dppf) Cl ₂ (0.73 g, 1.0 mmol) in DME (50 ml) and MeOH (25 ml) were stirred at 80 ° С for 18 h in an atmosphere of N2. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE: EA = 2: 1 ~ 0: 1) to give the title compound (1.8 g, 61%) as a red solid. LCMS: 295.9 (M + H) +.

Stage 2: 5- (2-but-2-inoxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one o

1J o

NaH (109 mg, 2.72 mmol, 60% in mineral oil) was added to a solution of but-2-yn-1-ol (191 mg, 2.72 mmol) in anhydrous DMF (3 ml) at 0 ° С. The mixture was stirred at this temperature for 1 h. The title compound from step 1 (200 mg, 0.68 mmol) was added and the reaction mixture was stirred at 0 ° C for 2 h. The mixture was then rapidly cooled with saturated NH ₄ Cl ( 20 ml) and extracted with EtOAc (20 ml x3). The combined organic layers were washed with brine (40 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (56.01 mg, 23.9%) as a light yellow solid substances.

1H NMR (CDCl3, 400 MHz) δ 7.88 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.46 (s, 2H), 7.24 (d, J = 8.8 Hz, 1H), 4.79 (d, J = 2.0 Hz, 2H), 3.62 (s, 3H), 3.08 (s, 3H), 2.22 (s, 3H), 1.87 (s, 3H). LCMS: 346.0 (M + H) +.

Example 389 5- (2-But-2-inoxy-5-ethylsulfonylphenyl) -3-methoxy-1-methylpyridin-2-one.

Step 1: 5- (5-ethylsulfonyl-2-fluorophenyl) -3-methoxy-1-methylpyridin-2-one

To a solution of 5-bromo-3-methoxy-1-methylpyridin-2-one (694 mg, 3.18 mmol), 2- (5-ethylsulfonyl-2fluorophenyl) -4,4,5,5-tetramethyl-1,3,2 -dioxaborolane (1 g, 3.18 mmol), Pd (dppf) Cl ₂ (233 mg, 318.00 mmol) in dioxane (26 ml) and H2O (2.6 ml) were added K ₃ PO ₄ (2.02 g, 9.54 mmol, 3.00 eq. ). The reaction was stirred at 70 ° C under N ₂ for 6 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE / EA = 3/1 to 1/2) to give the title compound (0.9 g , 87%) as a brown solid.

1H NMR (CDCl3, 400 MHz) δ 7.93 (dd, J1 = 7.2 Hz, J2 = 2.0 Hz, 1H), 7.88-7.84 (m, 1H), 7.35 (dd, J1 = 10.0 Hz, J2 = 8.8 Hz, 1H ), 7.23 (d, J = 1.6 Hz, 1H), 6.83 (s, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.16 (q, J = 7.6 Hz, 2H), 1.33 (t , J = 7.6 Hz, 3H). LCMS: 325.9 (M + H) +.

Step 2: 5- (2-but-2-inoxy-5-ethylsulfonylphenyl) -3-methoxy-1-methylpyridin-2-one

O

The title compound was prepared in a similar manner to Example 388 Step 2 by substituting 5- (2

- 328 038715 fluoro-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one.

1H NMR (CDCl ₃ , 400 MHz) δ 7.88 (d, J = 8.8 Hz, 1H), 7.80 (s, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.97 ( s, 1H), 4.78 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.87 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). LCMS: 376.0 (M + H) ⁺ .

Example 390 5- (5-ethylsulfonyl-2-pent-2-inoxyphenyl) -3-methoxy-1-methylpyridin-2-one

The title compound was prepared in a similar manner to Example 389 by substituting but-2-yn-1-ol for pent-2-yn-1-ol in Step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 7.86 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 1H) , 7.18 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 1.6 Hz, 1H), 4.80 (s, 2H), 3.87 (s, 3H), 3.67 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 2.24 (q, J = 7.6 Hz, 2H), 1.32 (t, J = 7.6 Hz, 3H), 1.14 (t, J = 7.6 Hz, 3H). LCMS: 390.2 (M + H) ⁺ .

Example 391 Methylpyridin-2-one

- [2- (3-cyclopropylprop-2 -inoxy) -5-ethylsulfonylphenyl] -3-methoxy-1 -

The title compound was prepared in a similar manner to Example 389 by substituting but-2-yn-1-ol for 3-cyclopropylprop-2-yn-1-ol in Step 2.

1H NMR (CDCl ₃ , 400 MHz) δ 7.87 (d, J = 8.8 Hz, 1H), 7.79 (s, 1H), 7.22-7.20 (m, 2H), 7.00 (s, 1H), 4.77 (s, 2H ), 3.88 (s, 3H), 3.70 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.31-1.29 (m, 1H), 0.84 -0.81 (m, 2H), 0.69-0.67 (m, 2H). LCMS: 402.0 (M + H) ⁺ .

392:

Example

N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (trifluoromethyl) pyridin-3 yl] phenyl] ethanesulfonamide.

Stage 1: 5-bromo-1-methyl-3- (trifluoromethyl) pyridin-2-one

To a solution of 5-bromo-3- (trifluoromethyl) pyridin-2-ol (6 g, 25 mmol), stirred at room temperature in THF (5 ml), was added NaH (1.5 g, 37 mmol, 60% in mineral oil) ... After stirring for 30 min, methyl iodide (7.1 g, 50 mmol) was added. After stirring at room temperature for 3 h, the reaction mixture was treated with water (100 ml) and was extracted with EtOAc (100 ml × 3). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (6 g, 97%) as a tan solid. The solid was used further without any further purification.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.79 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.0 Hz, 1H), 3.60 (s, 3H). LCMS (M + H) + = 256.

Stage 2: 1-methyl-5 - (3,3,4,4-tetramethylborolan-1-yl) -3 - (trifluoromethyl) pyridin-2-one

Suspension of compound 5-bromo-1-methyl-3- (trifluoromethyl) pyridin-2-one (3 g, 11.8 mmol), 4,4,5,5 tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane-2 -yl) -1,3,2-dioxaborolane (3.6 g, 14.1 mmol), KOAc (3 g, 30.6 mmol) and Pd (dppf) ₂ Cl ₂ (200 mg) in dioxane (50 ml) were stirred at 90 ° С for 4 h. After the reaction mixture was concentrated in vacuo, the resulting residue was purified by silica gel column chromatography (PE: EA = 3: 1 ~ 1: 1) to give the title compound (1.2 g, 34% ) as a red solid.

- 329 038715

Ή NMR (CDCl ₃ , 400 MHz) δ 8.02 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 2.0 Hz, 1H), 3.60 (s, 3H), 1.32 (s, 12H).

LCMS (M + H) + = 304.

Step 3: 5- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -1 -methyl-3- (trifluoromethyl) pyridin-2one

A mixture of 1-methyl-5- (3,3,4,4-tetramethylborolan-1-yl) -3- (trifluoromethyl) pyridin-2-one (100 mg, 0.33 mmol), 1- (2-bromo-4- ethylsulfonylphenoxy) -2,4-difluorobenzene (100 mg, 0.27 mmol), Pd (dppf) Cl ₂ (24 mg) and K3PO4 (107 mg, 0.80 mmol) in dioxane (4 ml) and water (1 ml) were purged with nitrogen, capped and heated to 90 ° C for 4 h. After filtering the mixture through a thin pad of celite, the filtrate was concentrated in vacuo and purified by preparative HPLC to give the title compound (43 mg, 34%) as a white solid.

1H NMR (CDCl3, 400 MHz) δ ppm 8.11 (s, 1H), 7.88 (s, 2H), 7.80 (m, 1H), 7.23-7.10 (m, 1H), 7.09-6.91 (m, 2H), 6.91 -6.78 (m, 1H), 6.25 (s, 1H), 3.70 (s, 3H), 3.15 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). LCMS (M + H) + = 474.

Example 393: 4- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -6-methoxy-2methylisoquinolin-1-one

Bromo-6-methoxy-2-methylisoquinolin-1-one (previously obtained in WO 2013/142390) was reacted with 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolane-2- yl) -1,3,2 dioxaborolane in a manner similar to that described in example 248, step 2, to obtain 6-methoxy2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) isoquinolin-1-one, which is then reacted with the title compound of Example 364, Step 1, in a manner similar to Example 364, Step 2 to provide the title compound.

1H NMR (CDCl3, 400 MHz) δ 8.45 (d, J = 8.4 Hz, 1H), 7.91 (dd, J1 = 2.0 Hz, J2 = 8.8, 1H), 7.06-7.27 (m, 3H), 6.53 (d, J = 2.8 Hz, 1H), 3.89 (m, 2H), 3.78 (s, 3H), 3.65 (s, 3H), 3.22 (m, 1H), 1.33 (d, J = 6.4 Hz, 6H), 1.03 ( q, J = 6.8 Hz, 1H), 0.45 (m, 2H), 0.14 (s, 2H). LCMS: 442.0 (M + H) +.

Example 394 5- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -1,3-dimethylpyridin-2-one

The title compound of Example 364, step 1, was reacted with 1,3dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one in a similar manner to described in Example 364, Step 2, to provide the title compound.

'll NMR (CDClj, 400 MHz) δ 7.75-7.79 (m, 2H), 7.59 (s, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.96 (d, J = 6.8 Hz, 2H), 3.67 (s, 3H), 3.15-3.25 (m, 1H), 2.24 (s, 3H), 1.31 (d, J = 7.2 Hz, 6H), 1.27 (d, J = 7.2 Hz, 1H), 0.66-0.70 (m, 2H), 0.38 (q, J = 5.2 Hz, 2H). LCMS: 376.0 (M + H) ⁺ .

Example 395 N- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -5-phenylmethoxyphenyl] ethanesulfonamide.

Stage 1: N- (3-bromo-5-phenylmethoxyphenyl) ethanesulfonamide

Ethylsulfonyl chloride (113 μL, 1.2 mmol) was added dropwise to a stirred solution of 3-bromo-5-phenylmethoxyaniline (284 mg, 1.0 mmol) and pyridine (247 μL, 3.1 mmol) in DCM (5 mL) at 0 ° С under nitrogen atmosphere. After the mixture was left to warm to room temperature and stirred for 14 h, it was treated with 1N. HCl (1 ml) and extracted with DCM (3x5 ml); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The crude solid was purified with

330 038715 by column chromatography on silica gel using an EtOAc gradient (5 to 95%) in hexanes to give the title compound (345 mg, 94%) as an amber oil which solidified on standing. LCMS (M + H) + = 371.

Stage 2: N- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -5-phenylmethoxyphenyl] ethanesulfonamide

O

A mixture of N- (3-bromo-5-phenylmethoxyphenyl) ethanesulfonamide (60 mg, 0.16 mmol), 1,3-dimethyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl ) pyridin-2-one (40 mg, 0.16 mmol), Pd (dppf) Cl ₂ (12 mg) and K3PO4 (88 mg, 0.40 mmol) in dioxane (1.5 mL) and water (150 μL) were purged with nitrogen, closed and heated to 75 ° C for 2 h. After filtering the mixture through a thin pad of Celite, the filtrate was concentrated in vacuo and purified by column chromatography on silica gel using a gradient of MeOH (0 to 10%) in DCM to afford the title compound ( 69 mg, 94%) as an off-white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.24 (m, 3H), 2.04-2.13 (m, 3H), 3.04-3.17 (m, 2H), 3.48-3.54 (m, 3H), 5.08- 5.17 (m, 2H), 6.74-6.80 (m, 1H), 6.90-6.98 (m, 2H), 7.33-7.49 (m, 5H), 7.59-7.63 (m, 1H), 7.907.95 (m, 1H ), 9.57-10.01 (bs, 1H). LCMS (M + H) + = 413.

Examples 396-482 in table. 21 was prepared using Suzuki reaction conditions to add an appropriately substituted aryl group to an appropriately substituted pyridinone. After the Suzuki reaction, chemical treatment was also carried out, if necessary, to obtain the title compound.

Table 21

An example of chemical synthesis Structure Name MS (M + H) 396 O 5- [2- (2,4-difluoroanilino) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one 419.1 397 RB 0. T | 5- [2 - [(4.4- difluorocyclohexyl) amino] -5 ethylsulfonylphenyl] -1,3dimethylpyridin-2-one 425.1 398 R R “P 5- [2- (2,4-difluoroanilino) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 405.1 399 ... .0 A 1 o 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-methoxy- 1-methylpyridin-2-one 378.1 400 O / p- 'o- O 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -3 methoxy-1-methylpyridin-2-one 436.0

- 331 038715

401 ο Ρ / V ^OH / 0 5- [2- (4-trans- hydroxycyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 392.1 402 o = s = o W A ' 1 about M- [4- (2,4-difluorophenoxy) -3 - (1 methyl-5-methylsulfanyl-6oxopyridin-3 yl) phenyl] ethanesulfonamide 467.10 403 about P A 0 5- [2- (4-cis- aminocyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 391.2 404 T z Q O / SHU ° 6 5- [2- (4-trans- aminocyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 391.1 405 0 ../ 'Ol a ^f V 0 1,3-dimethyl-5 - [5 - methyl sulfonyl-2- (3,3,3 trifluoropropoxy) phenyl] pyridi n-2-he 390.0 406 O v / —ώ-Ο ° w / - / o “ 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 - (2-hydroxyethyl) -3 - methylpyridin-2-one 450.2 407 Ί o = s = o A about L HE 5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1 - (2-hydroxyethyl) -3 - methylpyridin-2-one 434.1 408 A ¹ o 5- [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1 -methyl- 3 - (methylamino) pyridin-2-one 376.2

- 332 038715

409 Ζ O.) ^z \ 7 ° ° = (^ - '<? 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 -methyl-3 (methylamino) pyridin-2-one 377.2 410 A o = s = o W A ' X- [4- (2,4-difluorophenoxy) -3 - [1 methyl-5- (methylamino) -6oxopyridin-3yl] phenyl] ethanesulfonamide 450.1 411 0 = 1 = 0 A 0 5- [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -1,3dimethylpyridin-2-one 404.1 412 I I 9 -z ζ-ω-ο ' O "P X- [4- (2,4-difluorophenoxy) -3 - [1 methyl-5- (methylamino) -6oxopyridin-3 - yl] phenyl] methanesulfonamide 436.0 413 ⁷ IZ T | 5- [2 - [(4.4- difluorocyclohexyl) amino] -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 411.0 414 ... 0 ⁰ u ηΆΆ-7 1 η V <ЛД ¹ о 5- [2- (cyclopropylmethylamino) 5-ethylsulfonylphenyl] -3 methoxy-1-methylpyridin-2-one 377.1

- 333 038715

415 oh, d O 5- [2- (4.4- difluorocyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 412.1 416 d w A ' 0 5- [2- (cyclopentylamino) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one 375.2 417 d- ⁰ A 0 5- [2- (cyclopentylamino) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 361.1 418 0 o = s- cO ' 0 3-chloro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he 410.0 419 p Ap 'o ~ b 5 - (2-cyclopentyloxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one 362.1 420 p ° Wp 'o th 1,3-dimethyl-5- [5- methylsulfonyl-2- (oxane-4- yloxy) phenyl] pyridin-2-one 378.1

- 334 038715

421 0 O = SΑθν A- 0 3-fluoro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he 394.1 422 To..... O 5- [2- (cyclopropylmethylamino) 5-methylsulfonylphenyl] -1,4dimethylpyridin-2-one 347.0 423 ... O ϊ O 5- [2- (cyclopropylmethylamino) 5-ethylsulfonylphenyl] -1,4dimethylpyridin-2-one 361.1 424 ° aala oh N- [4- (l -methyl-6-oxopyridin-3 yl) -5-phenylthiophen-2yl] ethanesulfonamide 375.0 425 about ⁷ V 1,3-dimethyl-5- [5methylsulfonyl-2- (oxolan-3 ylamino) phenyl] pyridin-2-one 363.1 426 OU A0 1,3-dimethyl-5 - [5 - methyl sulfonyl-2- (oxolan-3 - yloxy) phenyl] pyridin-2-one 364.0

- 335 038715

427 , LL 6 o / ζΧΧΧ I / \ ο-ω ^ δ 1,3-dimethyl-5 - [5 - (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he 390.0 428 A 0 ¹ 5- [2- (cyclopropylmethylamino) - 5-methyl sulfonylphenyl] -! -ethyl- 3-methylpyridin-2-one 361.1 429 O / - ω = 0 ο τ “Π 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 ethyl-3-methylpyridin-2-one 434.0 430 Ί o = s = o Τ Ο Τ '0 X- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (4-trans- hydroxycyclohexyl) oxyphenyl] ethanesulfonamide 421.1 431 Ί o = s = o W Τ ' ο X- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (4-cis- hydroxycyclohexyl) oxyphenyl] ethanesulfonamide 421.1 432 οΆ ΝΗ τχφ ΤΧι τ 0 N- [4- (l -methyl-6-oxopyridin-3 yl) - 5 - (2-methylphenyl) thiophene-2yl] ethanesulfonamide 389.1

- 336 038715

433 o o = s - z ^ « ^OH . O M- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (4-transhydroxycyclohexyl) oxyphenyl] methanesulfonamide 407.1 434 one o = s = o ^ .. 0 ^ A- 0 X- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (4-cis- hydroxycyclohexyl) oxyphenyl] methanesulfonamide 407.1 435 < _s .o O'- ^S , x NH Vо X- [5- (2-ethylphenyl) -4- (1-methyl-6oxopyr-idin-3-yl) thiophene-2yl] ethanesulfonamide 403.1 436 o \ Xo o Ay — L / ⁷ IZ 0 1,3-dimethyl-5 - [5 methylsulfonyl-2- (oxane-4ylamino) phenyl] pyridin-2-one 377.1 437 0 o = s- 'TV?' l 0 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -3 fluoro-1-methylpyridin-2-one 424.1 438 / O. P --Z. ^/ ΧΣ 7 5- [2- (cyclopropylmethylamino) 5-methyl sulfonyl phenyl] -3 (dimethylamino) -1 methylpyridin-2-one 376.2

- 337 038715

439 0 o = s- 'VA A 0 X- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (oxane-4- yloxy) phenyl] methanesulfonamide 393.1 440 y ¹ 0 5- [2- (cyclopropylmethylamino) 5-ethylsulfonylphenyl] -3 (dimethylamino) -1 methylpyridin-2-one 390.2 441 at o = s = o A 0 X- [3- (1,5-dimethyl-6oxopyr-idin-3-yl) -4- (oxane-4yloxy) phenyl] ethanesulfonamide 407.1 442 A О /, у Ο-ω-ζ О - o ^T X- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6-oxopyridin3-yl) phenyl] methanesulfonamide 437.1 443 o = s = o Hmm? ' Λ ^{r 1} 0 H- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6-oxopyridin3-yl) phenyl] ethanesulfonamide 451.1 444 0 o = s— A ' 0 X- [3- (1,5-dimethyl-6oxopyr-idin-3-yl) -4- (oxolan-3 yloxy) phenyl] methanesulfonamide 379.0

- 338 038715

445 oXo Aw O X- [3- (1,5-dimethyl-6oxopyr idin-3-yl) -4- (oxolan-3 yloxy) phenyl] ethanesulfonamide 393.2 446 About os— ‘αο A 0 X- [3- (1,5-dimethyl-6- oxopyr idin-3-yl) -4- (oxane-3 - yloxy) phenyl] methanesulfonamide 393.1 447 0 o = sw Al 0 N- [4- (4.4- difluorocycle ohexyl) oxy-3 - (1,5dimethyl-6-oxopyrid in-3 - yl) phenyl] methanesulfonamide 427.1 448 Ί os = o UG A 0 X- [3- (1,5-dimethyl-6oxopyr-idin-3-yl) -4- (oxane-3 yloxy) phenyl] ethanesulfonamide 407.1 449 oXo 0 N- [4- (4.4- difluorocycle ohexyl) oxy-3 - (1,5dimethyl-6-oxopyrid in-3 - yl) phenyl] ethanesulfonamide 441.1 450 о _z 0-C> ° C 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one 362.1

- 339 038715

451 o = s = o w X ^F 0 X- [4- (2,4-difluorophenoxy) -3- (5hydroxy-1-methyl-6oxopyr-idin-3 yl) phenyl] ethanesulfonamide 437.0 452 h ₂ nO 0 4- (cyclopropylmethylamino) -3 (1,5-d-immethyl-6-oxopyrid in-3 yl) benzenesulfonamide 348.1 453 O 4- (cyclopropylmethylamino) -3 (1-methyl-6-oxopyridin-3 yl) benzenesulfonamide 334.1 454 o w “Π 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] 1,4-dimethylpyridin-2-one 420.0 455 0 o = s- 0 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] 1,3-dimethylpyridin-2-one 420.1 456 O. R ~ _ / _Ίό ° 0 \ —D / OO \ 5- (2-ethoxy-5-ethylsulfonylphenyl) -1 ( ² H ₃ ) methyl-4-methylpyridin-2-one 339.0 457 .0 VV Ύ 0 5- [2- (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -1 ( ² H ₃ ) methyl-4-methylpyridin-2-one 365.0

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458 ^ΰ Χ1 HD. O 5- (2-ethoxy-5ethylsulfonylphenyl) -1,4dimethylpyridin-2-one 336.1 459 O. 9 \ A ° Ύγ5 ⁷ o 5 - [2- (cyclobutylmethoxy) -5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 362.1 460 o.P ' ^ω χ' o 5 - [2- (cyclobutylmethoxy) -5 methylsulfonylphenyl] -1 methylpyridin-2-one 348.1 461 I ° A O / O ° F> p 'o \ 5 - (5-ethyl sulfonyl-2 methoxyphenyl) -3-hydroxy-1 methylpyridin-2-one 323.9 462 OW ° 5X? 0 5- [2- (cyclopropylmethylamino) 5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 347.1 463 o o = s “hell hell ' ¹ o X- [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyr idin-3 - yl] phenyl] methanesulfonamide 450.1

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464 / i 9 —z ζ-ω = ο PP ^k 'о A “Π M- [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyridin-3yl] phenyl] ethanesulfonamide 464.1 465 _ 0 A 0 5- [2- (cyclopropylmethylamino) 5-ethyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 361.1 466 _ 0 : O 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1,4dimethylpyridin-2-one 362.1 467 0 os- T iA 0 N- [3- (5-hydroxy-1-methyl-6oxopyr idin-3 - yl) phenyl] methanesulfonamide 295.0 468 ύ 0 5- [2- (cyclopropylmethylamino) 5-methyl sulfonyl phenyl] -1 methylpyridin-2-one 333.1 469 A ° <v A ' ¹ 0 3- (dimethylamino) -5- (2-ethoxy-5ethylsulfonylphenyl) -1 methylpyridin-2-one 365.1

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470 o ^ ώ = θ y 'o A AND 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 - methylpyridin-2-one 406.0 471 , oA Ο = ω-ζ O ^- \ O ¹ Y O N- [3- (1-methyl-6-oxo-5 phenylmethoxypyridine-3yl) phenyl] methanesulfonamide 385.0 472 I 9 /) - H 7 - (O ' O A “P X- [4- (2,4-difluorophenoxy) -3- (1,5dimethyl-6-oxopyrid in-3 yl) phenyl] ethanesulfonamide 435.1 473 G ΖΤ <° 5- [2- (cyclopropylmethylamino) - 5-ethyl sulfonyl phenyl] -1 methylpyridin-2-one 347.1 474 ° v А ¹ о 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3 (dimethylamino) -1 methylpyridin-2-one 377.1

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475 O ^O: K ⁷ / = \ o / 5- [4-fluoro-2-methoxy-5 (methylsulfonylmethyl) phenyl] -1 - methylpyridin-2-one 326.0 476 <4 ^ ⁰ 11 A 0 5- [2- (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one 348.1 477 OH 5 0 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -1,4dimethylpyridin-2-one 348.1 478 \ I I 9 λ — ζ ζ-ω-Ο чх / N- [6- [3- (methanesulfonamido) phenyl] -4methyl-3-oxopyrazine-2- sludge] acetamide 337.0 479 oio D h 0 Ch- [3- (1,4-dimethyl-6oxopyridazin-3 yl) phenyl] ethanesulfonamide 308.0 480 oho t A 0 Ch- [3- (1,5-dimethyl-6oxopyridazin-3 yl) phenyl] ethanesulfonamide 308.0 481 0 o = s- Τ ηνΑλ A ⁰ N- [5- [3- (methanesulfonamido) phenyl] -1 methyl-2-oxopyr idin-3 - sludge] propanamide 350.0 482 0 o-s— 1 nmDD A о N- [5- [3- (methanesulfonamido) phenyl] -1 methyl-2-oxopyr idin-3 - sludge] acetamide 336.0

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Example 483 1-Cyclobutyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin2-one

Stage 1: 1-cyclobutyl-3-methylpyridine-1-I chloride

Cyclobutylamine (2.3 g, 32 mmol) was added to 1- (2,4-dinitrophenyl) -3-methylpyridinium chloride (J. Org. Chem. 1997, 62, 729-33) (8.0 g, 31 mmol) in n-butanol (120 ml) at 20 ° C, and the dark red solution was heated under reflux overnight. Concentration in vacuo gave a residue which was treated with water (20 ml) and the precipitate was removed by filtration and this operation was repeated twice. The combined aqueous phase was basified with concentrated ammonia (2 ml) and washed twice with EtOAc. Evaporation of the water gave the title compound (3.2 g, 70%) as a brown oil. LCMS: 148 M ⁺ .

Stage 2: 1-cyclobutyl-3-methylpyridin-2-one

A stirred solution of the title compound from Step 2 (2.8 g, 18.9 mmol) in water (30 ml) was cooled to 5 ° C and K ₃ Fe (CN) ₆ in water (30 ml) was added dropwise over 1 hour. KOH (16.7 g, 298.6 mmol) in water (5 ml) and toluene (30 ml) was added and the mixture was heated at 40 ° С for 30 min. The organic layer was separated and the aqueous layer was extracted with DCM. The combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ , filtered and concentrated. Silica gel chromatography (DCM) afforded the title compound (1.9 g, 62%) as a yellow oil. LCMS: 164 (M + H) ⁺ .

Stage 3: 5-bromo-1-cyclobutyl-3-methylpyridin-2-one

The title compound from Step 3 (1.5 g, 9.2 mmol) in acetic acid (30 mL) was stirred at room temperature for 10 min. Then bromine (1.51 g, 9.5 mmol) was added slowly and after about 2 h the mixture was diluted with water and extracted with DCM. The organic solution was washed with water, brine and dried over Na ₂ SO ₄ , filtered, concentrated and purified by silica gel chromatography (DCM) to give the title compound (2.0 g, 82%) as a yellow oil. LCMS: 242, 244 (M + H) ⁺ .

Step 4: 1-cyclobutyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin-2 one

The title compound from Step 4 (27 mg, 0.11 mmol), the title compound of Example 90, Step 1 (46 mg, 0.13 mmol), K2CO3 (46 mg, 0.33 mmol) and Pd (dppf) ₂ Cl ₂ (8 mg, 0.011 mmol) in DMF (2 ml) was purged with N2 and exposed to microwaves at 100 ° C. After 2 h, the mixture was concentrated in vacuo and DCM was added, then washed with water, brine and dried over Na ₂ SO ₄ . Purification by preparative TLC provided the title compound (25 mg, 58%) as a white solid.

¹ H NMR (CDCl3, 400 MHz): δ 7.85-7.81 (m, 2H), 7.79 (d, J = 1.6 Hz, 1H), 7.47 (s, 1H), 7.02 (d, J = 8.4 Hz, 1H) , 5.27-5.23 (m, 1H), 3.94 (d, J = 8.0 Hz, 2H), 3.07 (s, 3H), 2.57-2.50 (m, 2H), 2.32-2.24 (m, 2H), 2.21 (s , 3H), 1.93-1.84 (m, 2H), 1.31-1.25 (m, 1H), 0.70-0.65 (m, 2H), 0.40-0.36 (m, 2H). LCMS: 388 (M + H) ⁺ .

Example 484: N- [3- (1-cyclobutyl-5-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide

The title compound of the example

483, step 3 (27 mg, 0.11 mmol), N- [4- (2.4-345 038715 difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) phenyl] methanesulfonamide (55 mg, 0.13 mmol), K ₂ CO ₃ (46 mg, 0.33 mmol) and Pd (dppf) ₂ Cl ₂ (8 mg, 0.011 mmol) in DMF (2 ml) were reacted and purified by the method similar to Example 483 Step 4 to give the title compound (16 mg, 32%) as a white solid.

¹ H NMR (CDCl3, 400 MHz): δ 7.65 (s, 1H), 7.42 (s, 1H), 7.26-7.27 (m, 1H), 7.13 (dd, J = 8.8, 2.8 Hz, 1H), 6.97- 6.89 (m, 2H), 6.83 (d, J = 9.2 Hz, 2H), 6.54 (s, 1H), 5.09-5.18 (m, 1H), 3.04 (s, 3H), 2.53-2.46 (m, 2H) , 2.232.18 (m, 2H), 2.16 (s, 3H), 1.87-1.81 (m, 2H). LCMS: 461 (M + H) +.

Example 485 1-Benzyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin-2-one

O

The title compound was prepared in a similar manner to Example 483 Steps 1-4 except that the benzylamine was replaced by cyclobutylamine in Step 1.

¹ H NMR (CDCl3, 400 MHz): δ 7.79 (s, 1H), 7.62 (d, J = 2.8 Hz, 1H), 7.49-7.51 (m, 1H), 7.34-7.38 (m, 4H), 7.29- 7.32 (m, 2H), 6.98 (d, J = 8.8 Hz, 1H), 5.20 (s, 2H), 3.89-3.94 (m, 2H), 3.04 (s, 3H), 2.22 (s, 3H), 1.13 -1.18 (m, 1H), 0.58-0.62 (m, 2H), 0.28-0.34 (m, 2H). LCMS: 424 (M + H) ⁺ .

Example 486 1,3-dimethyl-5- (2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) pyridin-2one.

Stage 1: 2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

A mixture of 5-bromo-2-methyl-2,3-dihydro-1-benzofuran (1.0 g, 4.72 mmol), CH ₃ SO ₂ Na (730 mg, 7.08 mmol), L-proline (110 mg, 0.94 mmol), K2CO3 (120 mg, 0.94 mmol) and CuI (89 mg, 0.47 mmol) in DMSO (10 ml) were irradiated with microwaves at 140 ° С for 2 h. The mixture was extracted with EtOAc (2x30 ml). The combined organic layers were washed with brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give the crude material, which was purified by silica gel column chromatography (PE / EA = 2/1) to give the title compound (500 mg, 50%).

1H NMR (CDCl3, 400 MHz) δ 7.71-7.70 (m, 2H), 6.86-6.82 (m, 1H), 5.08-5.03 (m, 1H), 3.41-3.35 (m, 1H), 3.02 (s, 3H ), 2.89-2.83 (m, 1H), 1.56 (d, J = 6.4 Hz, 3H).

Stage 2: 7-bromo-2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

To a mixture of the title compound from Step 1 (300 mg, 1.42 mmol) in DCM (10 mL) were added Fe (159 mg, 2.84 mmol) and Br ₂ (454 mg, 2.84 mmol) in one portion under N2. The mixture was stirred at room temperature for 6 hours. The reaction mixture was washed with saturated aqueous Na ₂ SO ₃ (200 ml) and extracted with DCM (30 ml x 2). The combined organic layers were washed with brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3/1) to give the title compound (300 mg, 73%) as a yellow solid.

1H NMR (CDCl3, 400 MHz) δ 7.90 (d, J = 1.6 Hz, 1H), 7.64 (d, J = 1.6 Hz, 1H), 5.20-5.14 (m, 1H), 3.53-3.47 (m, 1H) , 3.01-2.95 (m, 1H), 3.04 (s, 3H), 1.56 (d, J = 6.4 Hz, 3H). LCMS: 291.0 (M + 1) ⁺ ; 293.0.

Stage 3: 1,3-dimethyl-5- (2-methyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) pyridin-2-one

A solution of the title compound from step 2 (300 mg, 1.03 mmol), 1,3-dimethyl-5- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-one (309 mg, 1.24 mmol), Pd (dppf) Cl ₂ (76 mg, 0.103 mmol), Na ₂ CO ₃ (328 mg, 3.09 mmol) in dioxane (8 ml) and H2O (1 ml) were stirred at 80 ° С under N2 for 16 hours. The solvent was removed under reduced pressure to give a residue which

346 038715 was purified by silica gel column chromatography (PE / EA = 1/2) to give the title compound (60.0 mg, 18%) as a yellow solid.

¹ H NMR (DMSO-d6, 400 MHz) δ 8.02 (s, 1H), 7.76 (s, 1H), 7.74 (s, 1H), 7.66 (s, 1H), 5.15-5.13 (m, 1H), 3.51 (s, 3H), 3.49-3.42 (m, 1H), 3.19 (s, 3H), 2.94-2.88 (m, 1H), 2.07 (s, 3H), 1.44 (d, J = 5.2 Hz, 3H). LCMS: 334.1 (M + 1) +.

Example 487 4- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -2-methylisoquinolin-1-one.

Stage 1: methyl 3-bromo-4- (2,2,2-trifluoroethoxy) benzoate

To a solution of methyl 3-bromo-4-fluorobenzoate (100 mg, 0.43 mmol) in DMF, 2,2,2 trifluoroethanol (52 mg, 0.52 mmol), K ₂ CO ₃ (119 mg, 0.86 mmol) were added, and the mixture was stirred at 60 ° C for 2 h. The mixture was cooled and water (50 ml) was added. The aqueous layer was extracted with EtOAc (30 ml x 3). The combined organic layers were washed with water (30 ml x3), brine (30 ml), dried over anhydrous Na2SO4, filtered, concentrated and purified by silica gel chromatography (PE: EA = 20: 1) to give compound 3 (95 mg, 88 %) as a white solid.

Ή NMR (CDCl3, 400 MHz) δ 8.29 (d, J = 2.0 Hz, 1H), 8.00 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 4.48 (q, J = 8.0 Hz, 2H), 3.92 (s, 3H). LCMS: 313.0 (M + 1) ⁺ .

Stage 2: [3-bromo-4- (2,2,2-trifluoroethoxy) phenyl] methanol

To a solution of the title compound from Step 1 (2.00 g, 5.85 mmol) in THF (20.0 mL) was added LiAlH ₄ (0.18 g, 4.68 mmol) in several portions at -40 ° C. The mixture was kept at -40 ° C and stirred for 45 minutes. The reaction was quickly cooled with water (0.2 ml), 15% aqueous NaOH (0.2 ml) and additional water (0.6 ml). The mixture was stirred at room temperature for 15 minutes. Then it was dried over Na ₂ SO ₄ and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatography (PE: EA = 5: 1 ~ 3: 1) to give the title compound (1.62 g, 89%) as a white solid.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 7.55 (d, J = 2.0 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H), 4.83 (q, J = 8.8 Hz, 2H), 4.44 (s, 2H).

Stage 3: 2-bromo-4- (chloromethyl) -1- (2,2,2-trifluoroethoxy) benzene

A solution of the title compound from Step 2 (300 mg, 1.05 mmol) in DCM (10 ml) was cooled to 0 ° C and treated with triethylamine (91 mg, 1.15 mmol) and methanesulfonyl chloride (142 mg, 1.25 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The mixture was then diluted with DCM (10 ml) and washed with 1M hydrochloric acid (10 ml) and saturated NaHCO ₃ (10 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography to give the title compound (260 mg, 82%) as a white solid.

¹ H NMR (CDCl3, 400 MHz) δ 7.63 (d, J = 2.0 Hz, 1H), 7.32 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H) , 4.53 (s, 2H), 4.42 (q, J = 8.0 Hz, 2H).

Stage 4: 2-bromo-4- (ethylsulfanylmethyl) -1- (2,2,2-trifluoroethoxy) benzene

To a solution of the title compound from Step 3 (2.00 g, 6.59 mmol) in DCM (200 mL) were added TEA (1 g, 9.89 mmol), NaI (898 mg, 5.99 mmol) and EtSH (613 mg, 9.89 mmol). The mixture was stirred at 30 ° C for 4 h. The reaction was poured into water (10 ml) and extracted with EtOAc (10 ml x 3). The combined organic layers were washed with brine (30 ml), dried over anhydrous Na ₂ SO ₄ and filtered. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (PE: EA = 1: 0 ~ 3: 1) to give the title compound (2.1 g, 96.8%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.55 (d, J = 2.0 Hz, 1H), 7.24 (dd, J ₁ = 8.4 Hz, J2 = 2.0 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H ), 4.42 (q, J = 8.0 Hz, 2H), 3.66 (s, 2H), 2.47-2.41 (m, 2H), 1.26-1.22 (m, 3H).

Stage 5: 2-bromo-4- (ethylsulfonylmethyl) -1- (2,2,2-trifluoroethoxy) benzene

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To a solution of the title compound from Step 4 (2.10 g, 6.38 mmol) in DCM (210 mL) was added MCPBA (4.41 g, 25.53 mmol) in several portions. The mixture was stirred at 25 ° C for 12 hours. The reaction was poured into saturated aqueous Na ₂ SO ₃ (100 ml) and extracted with DCM (80 ml x 3). The combined organic layers were washed with saturated NaHCO ₃ (100 ml x 2) and brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE: EA = 1: 0 ~ 2: 1) to give the title compound (2.10 g, 91%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.64 (d, J = 2.0 Hz, 1H), 7.37 (dd, J ₁ = 8.4 Hz, J2 = 2.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H ), 4.43 (q, J = 8.0 Hz, 2H), 4.15 (s, 2H), 2.91 (q, J = 7.6 Hz, 2H), 1.39 (t, J = 7.6 Hz, 3H).

Step 6: 4- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -2-methylisoquinolin-1-one

The title compound from Step 5 (200 mg, 0.58 mmol), 2-methyl-4- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (197 mg , 0.69 mmol), Pd (PPh ₃ ) ₄ (67 mg, 58.0 _{mmol) and Na 2} CO ₃ (184 mg, 1.74 mmol) in dioxane (6 ml) and water (6 drops) were degassed and then heated to 70 ° С for 18 hours in an atmosphere of N ₂ . The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (PE: EA = 5: 1 ~ 1: 1), followed by purification by preparative HPLC to give the title compound (164.44 mg, 67%) as an off-label white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1H), 7.58-7.48 (m, 3H), 7.40 (d, J = 2.4 Hz, 1H), 7.22 (d, J = 8.0 , 1H), 7.07 (t, J = 8.0, 2H), 4.30 (q, J = 8.0 Hz, 2H), 4.23 (s, 2H), 3.67 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 1.43 (t, J = 7.6 Hz, 3H). LCMS: 440.0 (M + 1) +.

Example 488 2-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] isoquinolin-1-one.

Stage 1: 2-bromo-4- (methylsulfanylmethyl) -1- (2,2,2-trifluoroethoxy) benzene

The title compound was prepared in a similar manner to Example 487 Step 4 by substituting ethanethiol for methanethiol.

1H NMR (CDCl ₃ , 400 MHz) δ 7.56 (d, J = 2.0 Hz, 1H), 7.25 (dd, J ₁ = 8.4 Hz, J ₂ = 2.0 Hz, 1H), 6.93-6.90 (m, 1H), 4.44-4.35 (m, 2H), 3.63 (s, 2H), 2.02 (s, 3H).

Stage 2: 2-bromo-4- (methylsulfonylmethyl) -1- (2,2,2-trifluoroethoxy) benzene

The title compound was prepared in a similar manner to Example 487 Step 5 by substituting 2-bromo-4 (ethylsulfanylmethyl) - for 2-bromo-4- (methylsulfanylmethyl) -1- (2,2,2-trifluoroethoxy) benzene 1- (2,2,2-trifluoroethoxy) benzene.

1H NMR (CDCl ₃ , 400 MHz) δ 7.65 (d, J = 2.0 Hz, 1H), 7.38 (dd, J ₁ = 8.4 Hz, J2 = 2.4 Hz, 1H), 7.12-7.06 (m, 1H), 4.43 (q, J = 8.0 Hz, 2H), 4.19 (s, 2H), 2.82 (s, 3H).

Stage 3: 2-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] isoquinoline-1-one

The title compound was prepared in a similar manner to Example 487 Step 6 by replacing 2-bromo-4- (methylsulfonylmethyl) -1- (2,2,2-trifluoroethoxy) benzene with 2-bromo-4 (ethylsulfonylmethyl) - 1- (2,2,2-trifluoroethoxy) benzene.

1H NMR (CDCl ₃ , 400 MHz) δ 8.52 (d, J = 8.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.41 (d, J = 2.0 Hz, 1H), 7.22 (d, J = 8.0 , 1H), 7.08-7.06 (m, 2H), 4.33-4.27 (m, 4H), 3.67 (s, 3H), 2.87 (s, 3H). LCMS: 426.0 (M + 1) ⁺ .

Example 489 1,3-dimethyl-5 - (7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl) pyridin-2-one

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The title compound was prepared in a similar manner to Example 486 by substituting 5-bromo-2-methyl-2,3-dihydro-1-benzofuran for 6-bromo-2,3-dihydro-1,4-benzodioxin in step one.

1H NMR (CDCl3, 400 MHz) δ 7.51 (m, 2H), 7.44 (d, J = 2.4 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 4.38 (m, 4H), 3.68 (s , 3H), 3.08 (s, 3H), 2.24 (s, 3H). LCMS: 336.0 (M + 1) +.

Example 490: N- [2-ethyl-8- (2-methyl-1-oxoisoquinolin-4-yl) -3,4-dihydro-2H-chromene-6yl] methanesulfonamide.

Stage 1: 3,4-dihydro-2H-chromene-2-ylmethanol

AA

A mixture of 4-oxochromene-2-carboxylic acid (20.0 g, 105 mmol) and Pd / C (3.0 g, w / w = 10%) in AcOH (200 ml) was placed in a Parr apparatus for hydrogenation in an H2 atmosphere (50 psi) and stirred for 25 hours at room temperature. The mixture was then filtered and concentrated. The residue was suspended in water (300 ml), stirred for 10 min, filtered and dried to give 3,4-dihydro2H-chromene-2-carboxylic acid (13.5 g, 72%) as a white solid. To a solution of BH ₃ (57 ml, 114 mmol, 2.0 M in THF) was slowly added this carboxylic acid in THF (120 ml) at 0 ° C. The reaction mixture was then warmed to room temperature and stirred for 5 hours at this temperature. Added dropwise THF / H2O (30 ml, 1: 1) while maintaining the temperature between 0-5 ° C and stirring for 20 min. K2CO3 (26.0 g, 189 mmol) was added and the reaction was stirred vigorously for 30 min. The THF layer was separated and concentrated to give the title compound (11.0 g, 89%) as a brown oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.10-7.03 (m, 2H), 6.86-6.81 (m, 2H), 4.14-4.08 (m, 1H), 3.85-3.68 (m, 2H), 2.92-2.84 (m, 1H), 2.80-2.73 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.79 (m, 1H). LCMS: 165 (M + 1) ⁺ .

Stage 2: 3,4-dihydro-2H-chromen-2-ylmethyl trifluoromethanesulfonate aa

Trifluoromethanesulfonic anhydride (19.6 g, 69.5 mmol) in DCM (15 ml) was added to a solution of the title compound from step 1 (9.50 g, 57.9 mmol) in DCM (100 ml) and pyridine (11.0 g, 139 mmol) cooled to -5 ° C. The reaction was then stirred at 0 ° C for 1 h. Water (150 ml) was added and the reaction was extracted with DCM (150 ml). The organic layer was washed with 1M HCl (180 ml), water (100 ml) and aqueous NaHCO ₃ solution (100 ml). The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (13.5 g, 79%) as a pale brown oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.12-7.04 (m, 2H), 6.90-6.83 (m, 2H), 4.66-4.61 (m, 2H), 4.36-4.31 (m, 1H), 2.96-2.79 (m, 2H), 2.09-2.03 (m, 1H), 1.95-1.84 (m, 1H). LCMS: 314 (M + NH ₄ ) +.

Stage 3: 2-ethyl-3,4-dihydro-2H-chromene on

MeMgBr (45.6 ml, 137 mmol, 3 M in ether) was added to a mixture of the title compound from step 2 (13.5 g, 45.6 mmol) and CuBr-Me ₂ S (1.61 g, 7.74 mmol) in THF (150 ml) at -5 ° C. The reaction mixture was stirred at room temperature for 2 h. Then it was poured into a solution of NH ₄ Cl (55 g, 1.04 mol) in water (200 ml) and extracted with DCM (3x150 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.66 g, 90%) as a brown oil.

1H NMR (400 MHz, CDCl ₃ ): δ 7.09-7.02 (m, 2H), 6.82-6.78 (m, 2H), 3.93-3.87 (m, 1H), 2.84-2.72 (m, 2H), 2.02-1.96 (m, 1H), 1.81-1.61 (m, 3H), 1.04 (t, J = 7.2 Hz, 3H).

Stage 4: 2-ethyl-6-nitro-3,4-dihydro-2H-chromene and 2-ethyl-8-nitro-3,4-dihydro-2H-chromene

The title compound from step 3 (1.0 g, 6.17 mmol) was added to HNO3 (5 ml, 65-68%) at 0 ° C, warmed to room temperature and stirred for 1 h. Then it was poured into ice-water , was extracted with EtOAc (50 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (PE / EA, 100: 1 to

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50: 1) to give a mixture of the title compounds (600 mg), which was used in the next step.

Stage 5: N- (2-ethyl-3,4-dihydro-2H-chromen-6-yl) methanesulfonamide

A mixture of the title compounds from step 4 (600 mg) was suspended in MeOH (6 ml) and saturated NH ₄ Cl solution (2 ml). Fe (810 mg, 14.5 mmol) was added and the mixture was heated to 85 ° C for 2.5 h. The mixture was then filtered and extracted with EtOAc. The organic layer was dried and concentrated under reduced pressure to obtain a crude mixture of 2-ethyl-3,4-dihydro-2H-chromen-6-amine and 2-ethyl-3,4-dihydro-2H-chromen-8-amine. This mixture was dissolved in DCM (10 ml) and TEA (0.8 ml) and methanesulfonyl chloride (400 mg, 3.50 mmol) was added. The mixture was stirred at room temperature for 1 h, then extracted with DCM (45 ml x2), dried over Na ₂ SO ₄ , filtered, concentrated under reduced pressure and purified by column chromatography (PE / EA 50: 1 to 20: 1 to 10: 1) to afford the title compound (190 mg, 12% over three steps) as a yellow solid.

1H NMR (300 MHz, CDCl ₃ ): δ 6.99-6.80 (m, 2H), 6.78 (d, J = 8.7 Hz, 1H), 6.16 (s, 1H), 3.95-3.90 (m, 1H), 2.96 ( s, 3H), 2.83-2.76 (m, 2H), 2.04-1.97 (m, 1H), 1.81-1.64 (m, 3H), 1.05 (t, J = 7.2 Hz, 3H). LCMS: 273 (M + NH4) ⁺ .

Stage 6: N- (8-bromo-2-ethyl-3,4-dihydro-2H-chromen-6-yl) methanesulfonamide

To a solution of the title compound from Step 5 (170 mg, 0.667 mmol) in ACN (6 mL) was added NBS (156 mg, 0.867 mmol). The mixture was stirred for 7 hours at room temperature, then extracted with DCM, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 3: 1) to afford the title compound (105 mg, 47%) as a gray solid.

1H NMR (400 MHz, CDCl ₃ ): δ 7.23 (d, J = 2.4 Hz, 1H), 6.96 (d, J = 2.4 Hz, 1H), 6.24 (s, 1H), 4.01-3.99 (m, 1H) , 2.97 (s, 3H), 2.84-2.77 (m, 2H), 2.04-1.99 (m, 1H), 1.85-1.66 (m, 3H), 1.09 (t, J = 7.2 Hz, 3H).

Stage

7:

N- [2-ethyl-8- (2-methyl-1-oxoisoquinolin-4-yl) -3,4-dihydro-2H-chromene-6yl] methanesulfonamide

A mixture of the title compound from Step 6 (105 mg, 0.315 mmol), 2-methyl-4- (4,4,5,5 tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (108 mg, 0.379 mmol), K2CO3 (131 mg, 0.949 mmol), and Pd (dppf) Cl ₂ (23.1 mg, 0.032 mmol) in dioxane / Н ₂ О (10 ml / 3 ml) were heated to 85 ° С for 2 h The reaction mixture was then filtered and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA 50: 1 to 20: 1 to 10: 1) to give the title compound (25 mg, 19%).

1H NMR (400 MHz, CD3OD) δ 8.31 (d, J = 8.4 Hz, 1H), 7.59-7.55 (m, 1H), 7.47-7.43 (m, 1H), 7.31-7.23 (m, 2H), 7.05 ( s, 1H), 6.95 (d, J = 2.8 Hz, 1H), 3.77-3.71 (m, 1H), 3.60 (s, 3H), 2.95-2.75 (m, 5H), 1.95-1.92 (m, 1H) , 1.66-1.54 (m, 1H), 1.38-1.22 (m, 2H), 0.59-0.55 (m, 1.25H), 0.42-0.38 (m, 1.75H). LCMS: 413.0 (M + 1) +.

Example 491: sludge] ethanesulfonamide

N- [2-ethyl-8- (2-methyl-1-oxoisoquinolin-4-yl) -3,4-dihydro-2H-chromene-6-

The title compound was prepared in a similar manner to Example 490 by substituting methanesulfonyl chloride for ethanesulfonyl chloride in step 5.

1H NMR (400 MHz, CD3OD): δ 8.39 (d, J = 7.6 Hz, 1H), 7.67-7.63 (m, 1H), 7.56-7.52 (m, 1H), 7.37-7.30 (m, 2H), 7.12 (s, 1H), 7.03 (d, J = 2.8 Hz, 1H), 3.86-3.81 (m, 1H), 3.69 (s, 3H), 3.10 (q, J = 7.2 Hz, 2H), 3.02-2.81 ( m, 2H), 2.03-1.99 (m, 1H), 1.75-1.41 (m, 3H), 1.36 (t, J = 7.6 Hz, 3H), 0.67-0.62 (m, 1.25H), 0.51-0.48 (m ,

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1.75H). LCMS: 427.0 (M + 1) +.

Example 492 N- [8- (1,5-dimethyl-6-oxopyridin-3-yl) -2-ethyl-3,4-dihydro-2H-chromene-6yl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 491 by substituting 1,3-dimethyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2- it is on 2-methyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one.

1H NMR (400 MHz, CD3OD): δ 7.69 (s, 1H), 7.66 (s, 1H), 7.02 (m, 1H), 7.0 (s, 1H), 3.96-3.93 (m, 1H), 3.65 (s , 3H), 3.07 (q, J = 7.5 Hz, 2H), 2.93-2.82 (m, 2H), 2.18 (s, 3H), 2.08-2.04 (m, 1H), 1.72-1.66 (m, 3H), 1.34 (t, J = 7.6 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H). LCMS: 391.0 (M + 1) ⁺ .

Example 493: 4- (2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) -2methylisoquinolin-1-one.

Stage 1: 7-bromo-2-cyclopropyl-5-methylsulfonyl-1-benzofuran /^^^ SO ₂ Me о

Br

_{Ethynylcyclopropane (240 mg, 3.64 mmol) and Cu 2} O (260 mg, 1.82 mmol) were added to a solution of 2,6-dibromo-4-methylsulfonylphenol (1 g, 3.30 mmol) in pyridine (40 ml). The reaction mixture was degassed with N ₂ . The mixture was heated to 130 ° C for 3 h, then concentrated and purified by column chromatography (PE to PE / EA = 3/1) to give the title compound (510 mg, 53%) as a gray solid.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.99 (s, 1H), 7.93 (s, 1H), 6.52 (s, 1H), 3.07 (s, 3H), 2.13-2.11 (m, 1H), 1.13- 1.05 (m, 4H).

Stage 2: 7-bromo-2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran

To a solution of the title compound from Step 1 (250 mg, 0.79 mmol) in Et ₃ SiH (516 mg, 4.44 mmol) at 0 ° C was added TFA (5.43 g, 47.59 mmol) in one portion. The reaction mixture was warmed to room temperature and stirred for 48 hours. An aqueous NaOH solution (10 ml, 1N) was slowly added to the above solution. The mixture was extracted with EtOAc (10 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE to PE / EA = 2/1) to give the title compound (83 mg, 33%) as a white solid.

1H NMR (CDCl ₃ , 400 MHz) δ 7.90 (s, 1H), 7.64 (s, 1H), 4.47-4.43 (m, 1H), 3.51-3.47 (m, 1H), 3.23-3.17 (m, 1H) , 3.04 (s, 3H), 1.24-1.22 (m, 1H), 0.74-0.55 (m, 3H), 0.44-0.41 (m, 1H).

Stage 3: 4- (2-cyclopropyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) -2methylisoquinolin-1-one

To a solution of the title compound from Step 2 (80 mg, 252 μmol) in dioxane (10.00 ml) and H ₂ O (1.00 ml) was added Pd (dppf) Cl ₂ (9 mg, 12.61 μmol), K ₃ PO ₄ ( 134 mg, 631 μmol) and 2-methyl-4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (79 mg, 278 μmol) in one serving. The reaction mixture was degassed with N2 and heated to 90 ° C for 3 h. The mixture was then concentrated and purified by preparative HPLC to give the title compound (18.36 mg, 19% yield).

1H NMR (CDCl ₃ , 400 MHz) δ 8.53-8.51 (d, J = 8.0 Hz, 1H), 7.79 (s, 1H), 7.75 (s, 1H), 7.63-7.56 (m, 2H), 7.33-7.31 (d, J = 8.0 Hz, 1H), 7.15 (s, 1H), 4.43-4.37 (m, 1H), 3.68 (s, 3H), 3.50-3.46 (m, 1H), 3.32-3.16 (m, 1H ), 3.09 (s, 3H), 1.21-1.06 (m, 1H), 0.60-0.59 (m, 2H), 0.39-0.32 (m, 2H). LCMS: 396.0 (M + 1) ⁺ .

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Example 494: 4- (2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) -2-methylisoquinoline-1one.

Stage 1: 2-ethyl-7-iodo-5-methylsulfonyl-1-benzofuran

But-1-in (128 mg, 2.36 mmol) and Cu ₂ O (135 mg, 0.944 mmol). The mixture was stirred at 130 ° C for 3 hours under nitrogen atmosphere. The residue was cooled to 25 ° C, diluted with 1N. HCi (200 ml) and extracted with EtOAc (30 ml x2). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (PE: EA = 10: 1 to 5: 1) to give the title compound (400 mg, 48%) as a solid.

1H NMR (CDCi ₃ , 400 MHz) δ 8.14 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 1.6 Hz, 1H), 6.62 (s, 1H), 3.09 (s, 3H), 2.90 ( q, J = 7.6 Hz, 2H), 1.38 (t, J = 7.6 Hz, 3H). LCMS: 350.9 (M + H +).

Stage 2: 4- (2-ethyl-5-methylsulfonyl-1-benzofuran-7-yl) -2-methylisoquinolin-1-one

To a solution of 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (82 mg, 286 μmol) and the title compound from step 1 (100 mg, 286 μmol) in H2O (2 ml) and dioxane (20 ml), Pd (dppf) Cl ₂ (21 mg, 28.6 μmol, 0.10 eq.) And Na ₂ CO ₃ (61 mg, 572 μmol) were added ... The mixture was degassed with nitrogen and heated to 90 ° C for 4 h, then cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EA = 3: 1 to 1: 1) followed by preparative HPLC to give the title compound (35.57 mg, 33%) as a white solid.

1H NMR (CDCi ₃ , 400 MHz) δ 8.56 (d, J = 7.2 Hz, 1H), 8.19 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.607.57 ( m, 2H), 7.29-7.27 (m, 2H), 6.60 (s, 1H), 3.73 (s, 3H), 3.15 (s, 3H), 2.75 (q, J = 7.2 Hz, 2H), 1.28 (t , J = 7.2 Hz, 3H). LCMS: 382.0 (M + H +).

Stage 3: 4- (2-ethyl-5-methylsulfonyl-2,3-dihydro-1-benzofuran-7-yl) -2-methylisoquinolin-1-one

To a solution of the title compound from step 2 (130 mg, 340 μmol) in MeOH (3 ml) was added Pd / C (70 mg, 10% w / w) in one portion. The reaction mixture was stirred at 25 ° C under an atmosphere of H ₂ (15 psi) for 8 hours. The mixture was then filtered through celite. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to give the title compound (12.4 mg) as a gray solid.

1H NMR (CDC13, 300 MHz) δ 8.54-8.51 (d, J = 7.5 Hz, 1H), 7.79-7.75 (m, 2H), 7.75-7.54 (m, 2H), 7.327.29 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 4.90-4.85 (m, 1H), 3.69 (s, 3H), 3.49-3.41 (m, 1H), 3.06-3.00 (m, 1H), 1.851.70 ( m, 2H), 0.96-0.91 (t, J = 7.5 Hz, 3H). LCMS: 384.0 (M + 1).

Example 495 N- [7- (1,5-dimethyl-6-oxopyridin-3-yl) -2-propyl-2,3-dihydro-1-benzofuran-5yl] ethanesulfonamide.

Stage 1: 2-cyclopropyl-7-iodo-5-nitro-1-benzofuran

A solution of 2,6-diiodo-4-nitrophenol (10 g, 25.6 mmol), ethynylcyclopropane (1.9 g, 28.8 mmol) and Cu ₂ O (1.9 mg, 13.2 mmol) in 100 ml of dry pyridine was heated under reflux for 2 h. The reaction mixture was poured into 1 L of water and stirred for 10 minutes. The resulting mixture was filtered. The filter cake was purified by column chromatography on silica gel eluting with EtOAc / PE (0-20%) to give the title compound (6.6 g, 78% yield) as a yellow solid.

1H NMR (CDCi ₃ , 400 MHz): δ 8.47 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.4 Hz, 1H), 6.58 (s, 1H), 2.13-2.07 (m, 1H) , 1.14-1.04 (m, 4H).

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Stage 2: 2-cyclopropyl-7-iodo-1-benzofuran-5-amine

To a solution of the title compound from Step 1 (2.0 g, 6.0 mmol) and Fe (1.0 g, 18 mmol) in MeOH (80 ml) was added a saturated solution of NH ₄ Cl (10 ml). The reaction mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature and poured into 400 ml of DCM. The resulting mixture was filtered and the filtrate was washed with water (100 ml) and brine. The organic layer was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (1.5 g, 83% yield) as a red oil, which was used immediately in the next step.

1H NMR (CDCl ₃ , 400 MHz): δ 6.87 (d, J = 2.4 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H), 6.19 (s, 1H), 3.45 (br, 2H), 1.97 -1.90 (m, 1H), 0.95-0.85 (m, 4H). LCMS: 300 (M + 1) +.

Stage 3: N- (2-cyclopropyl-7-iodo-1-benzofuran-5-yl) ethanesulfonamide

To a solution of the title compound from Step 2 (1.0 g, 3.3 mmol) in 20 mL of dry DCM was added a solution of pyridine (793 mg, 10 mmol) in DCM (10 mL) followed by EtSO2Cl (473 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 1 hour. The mixture was diluted with DCM (20 ml) and washed with water (20 ml x 2) and brine. The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude title compound (1.3 g, 100% yield), which was used immediately in the next step.

1H NMR (CDCl ₃ , 400 MHz): δ 7.42 (d, J = 2.0 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 6.88 (br, 1H), 6.40 (s, 1H), 3.09 (q, J = 7.2 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H), 2.04-2.08 (m, 1H), 1.06-0.97 (m, 4H). LCMS: 409 (M + 18) ⁺ .

Stage 4: N- [2-cyclopropyl-7- (1,5-dimethyl-6-oxopyridin-3-yl) -1-benzofuran-5yl] ethanesulfonamide

To a solution of the title compound from Step 3 (500 mg, 1.3 mmol) and 1,3-dimethyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2 -one (380 mg, 1.5 mmol) in 10 ml of DMF, K ₂ CO ₃ (50 mg, 3.8 mmol), water (2 ml), and Pd (dppf) Cl ₂ (30 mg) were added in an atmosphere of N ₂ . The reaction mixture was heated to 100 ° C for 1 h. The resulting mixture was poured into 100 ml of water and was extracted with DCM (100 ml x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with EtOAc to give the title compound (230 mg, 47% yield) as a white solid.

1H NMR (CDCl ₃ , 400 MHz): δ 7.81 (d, J = 3.6 Hz, 1H), 7.67-7.66 (m, 1H), 7.26 (t, J = 1.2 Hz, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.54 (br, 1H), 6.36 (d, J = 0.8 Hz, 1H), 3.67 (s, 3H), 3.14-3.06 (m, 2H), 2.25 (s, 3H), 2.11- 2.00 (m, 1H), 1.38-1.43 (m, 3H), 1.09-0.92 (m, 4H). LCMS: 387 (M + 1) ⁺ .

Stage 5: N- [7- (1,5-dimethyl-6-oxopyridin-3-yl) -2-npropyl-2,3-dihydro-1-benzofuran-5yl] ethanesulfonamide

O

A mixture of the title compound from step 4 (70 mg, 0.18 mmol) and 10 mg Pd / C in 40 ml MeOH was stirred under H ₂ atmosphere at room temperature for 1 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure. ... The residue was purified by preparative HPLC to afford the title compound (10 mg, 14% yield) as a white solid.

1H NMR (CDCl ₃ , 300 MHz): δ 7.77 (d, J = 2.1 Hz, 1H), 7.56 (s, 1H), 7.04 (s, 1H), 7.01 (s, 1H), 6.26 (d, J = 2.7 Hz, 1H), 4.88-4.84 (m, 1H), 3.61 (s, 3H), 3.34-3.26 (m, 1H), 3.09 (q, J = 7.5 Hz, 2H), 2.90-2.84 (m, 1H ),

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2.21 (s, 3H), 1.87-1.82 (m, 1H), 1.72-1.63 (m, 1H), 1.56-1.43 (m, 2H), 1.38 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.5 Hz,

3H). LCMS: 391 (M + 1) +.

Example 496: N- [2-cyclopropyl-7- (1,5-dimethyl-6-oxopyridin-3-yl) -2,3-dihydro-1-benzofuran-5yl] ethanesulfonamide

To a mixture of the title compound from Example 495, step 4 (30 mg, 0.08 mmol) in Et ₃ SiH (1 ml) in a sealed tube, TFA (0.2 ml) was added at 0 ° C. The mixture was left to warm to room temperature and was stirred overnight. The resulting mixture was diluted with DCM (30 ml) and washed with 1N. NaOH, water and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was recrystallized from EtOAc to give the title compound (3 mg, 10% yield) as a white solid.

¹ H NMR (CDCl ₃ , 300 MHz): δ 7.77 (s, 1H), 7.57 (s, 1H), 7.04 (d, J = 3.0 Hz, 2H), 6.44 (s, 1H), 4.37-4.29 (m , 1H), 3.63 (s, 3H), 3.37-3.29 (m, 1H), 3.13-3.03 (m, 3H), 2.22 (s, 3H), 1.40 (t, J = 7.5 Hz, 3H), 1.26- 1.14 (m, 1H), 0.71-0.33 (m, 4H). LCMS: 389 (M + 1) ⁺ .

Example 497 4- [3 - (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one.

Stage 1: (6-bromo-2,3-dihydro-1,4-benzodioxin-2-yl) methanol and (6-bromo-2,3-dihydro-1,4-benzodioxin-3-yl) methanol

To a mixture of NaOH (1.6 g, 39.7 mmol) in THF (120 mL) and H ₂ O (40 mL) was added 4-bromobenzene-1,2-diol (5 g, 26.5 mmol). Oxiran-2-ylmethanol (7.35 g, 79.5 mmol) was added in portions at room temperature under N ₂ . The reaction was stirred at 100 ° C for 4 hours. The mixture was then cooled to room temperature and extracted with EtOAc (50 ml x 2). The organic layers were washed with brine (40 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5/1) to give a mixture of the title compounds (4.7 g, 73%). LCMS: 166 (M-80) ⁺ .

Stage 2: (6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-2-yl) methanol and (6-methylsulfonyl2,3-dihydro-1,4-benzodioxin-3-yl) methanol

The mixture from Step 1 (1 g, 4.08 mmol) was subjected to the experimental conditions described in Example 486 Step 1 to give a mixture of the title compounds (650 mg, 65%). LCMS: 245.1 (M + 1) ⁺ .

Stage 3: 2- (methoxymethyl) -6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin and 3- (methoxymethyl) 6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin

NaH (614 mg, 15.35 mmol) was added to a solution of the mixture from step 2 (2.5 g, 10.23 mmol) in THF (30 ml) at 0 ° С. The reaction was stirred at 0 ° C for 1 h. CH ₃ I (1.45 g, 10.23 mmol) was added to the reaction mixture while maintaining the internal temperature at about 0 ° C. The reaction mixture was stirred at room temperature for an additional 3 hours. The mixture was then rapidly cooled with ice and extracted with EtOAc (30 ml x 3). The combined organic phases were washed with saturated brine (20 ml x 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 3/1) to give a mixture of the title compounds (1.5 g, 57%) as an oil. The mixture was further separated into its four separate components using chiral SFC to give two enantiomers of 2 (methoxymethyl) -6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine (200 mg each) and two enantiomers of 3- (methoxymethyl) - 6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin (200 and 120 mg, respectively). Their absolute stereochemistry has not been determined.

2- (Methoxymethyl) -6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin:

1H NMR (CDCl ₃ , 400 MHz) δ 7.44 (d, J = 1.6 Hz, 1H), 7.41 (dd, J1 = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.03 (d, J = 8.0

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Hz, 1H), 4.42-4.31 (m, 2H), 4.10 (dd, Ji = 11.6 Hz, J2 = 7.6 Hz, 1H), 3.71-3.58 (m, 2H), 3.42 (s, 3H), 3.01 (s , 3H).

LCMS: 259 (M + 1) +.

3- (Methoxymethyl) -6-methylsulfonyl-2,3-dihydro-1,4-benzodioxin:

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.47 (d, J = 2.0 Hz, 1H), 7.41 (dd, J ₁ = 8.8 Hz, J2 = 2.0 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 4.40-4.30 (m, 2H), 4.18-4.10 (dd, J1 = 11.2 Hz, J2 = 7.2 Hz, 1H), 3.70-3.58 (m, 2H), 3.42 (s, 3H), 3.00 (s , 3H). LCMS: 259 (M + 1) ⁺ .

Stage 4: 5-bromo-3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a similar manner to Example 486 step 2 by substituting 2- methyl 5-methylsulfonyl-2,3 dihydro-1-benzofuran.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.70 (d, J = 2.0 Hz, 1H), 7.46 (d, J = 2.0 Hz, 1H), 4.53 (dd, J ₁ = 2.2 Hz, J ₂ = 11.4 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.21 (m, 1H), 3.73-3.63 (m, 2H), 3.45 (s, 3H), 3.03 (s, 3H).

Step 5: 4- [3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one

A mixture of the title compound from Step 4 (20 mg, 0.06 mmol), 2-methyl-4- (4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one (20 mg, 0.07 mmol), Na ₂ CO ₃ (19 mg, 0.18 mmol), Pd (dppf) Cl ₂ (7 mg, 0.01 mmol) in dioxane (2 ml) and Н ₂ О (0.2 ml) were stirred at 80 ° С for 12 hours in an atmosphere of N2. The reaction mixture was poured with H ₂ O (10 ml) and was extracted with EtOAc (3x10 ml). The combined organic phases were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography followed by preparative HPLC to give the title compound (12 mg, 24% ). The absolute stereochemistry has not been determined.

¹ H NMR (DMSO-d ₆ , 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1H), 7.68-7.63 (m, 1H), 7.55-7.52 (m, 3H), 7.42 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.43-4.35 (m, 2h), 4.21-4.12 (m, 1H), 3.56 (s, 3H), 3.44-3.41 (m, 2H), 3.23 (s, 3H), 3.09 (s, 3H). LCMS: 416.0 (M + H) ⁺ .

Example 498: 5- [3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a manner similar to Example 497 by substituting 1,3-dimethyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) pyridin-2-one on 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one in step 5.

¹ H NMR (CDCl ₃ , 400 MHz) δ 7.53 (s, 1H), 7.49 (s, 1H), 7.43 (m, 2H), 4.45-4.37 (m, 2H), 4.18-4.17 (m, 1H), 3.68-3.62 (m, 5H), 3.44 (s, 3H), 3.07 (s, 3H), 2.21 (s, 3H). LCMS: 380 (M + H) ⁺ .

Example 499 4- [3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a similar manner to Example 497 by replacing the compound,

- 355 038715 used in step 4, in its enantiomer.

1H NMR (DMSO-d ₆ , 400 MHz) δ 8.30 (d, J = 8.0 Hz, 1H), 7.68 (t, J = 8.0 Hz, 1H), 7.55-7.51 (m, 3H), 7.42 (s, 1H ), 7.28 (d, J = 8.0 Hz, 1H), 4.42-4.35 (m, 2H), 4.21-4.14 (m, 1H), 3.56 (s, 3H), 3.44-3.39 (m, 2H), 3.24 ( s, 3H), 3.09 (s, 3H). LCMS: 416.0 (M + H) ⁺ .

Example 500: 5- [3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a manner similar to Example 498, but using a different enantiomer, 5-bromo-3- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1, 4-benzodioxin.

¹ H NMR (CDCl3, 400 MHz) δ 7.59 (s, 1H), 7.58 (s, 1H), 7.44 (m, 2H), 4.41-4.37 (m, 2H), 4.20-4.18 (m, 1H), 3.71 -3.63 (m, 5H), 3.44 (s, 3H), 3.07 (s, 3H), 2.24 (s, 3H). LCMS: 380.0 (M + H) ⁺ .

Example 501 4- [2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one.

Stage 1: 5-bromo-2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxine

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a similar manner to Example 497 Step 4 by substituting methylsulfonyl for 2 (methoxymethyl) -6-methylsulfonyl-2,3-dihydro-1,4-benzodioxine -2,3-dihydro-1,4-benzodioxin. LCMS: 359 (M + 23) ⁺ .

3- (methoxymethyl) -6 Stage 2: 4- [2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a similar manner to Example 497 step 5 by substituting 5 bromo-2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4- benzodioxin to 5-bromo-3- (methoxymethyl) 7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin.

1H NMR (DMSO-d6, 400 MHz) δ 8.31 (d, J = 8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.56-7.51 (m, 3H), 7.40 (s, 1H), 7.30- 7.16 (m, 1H), 4.53-4.44 (m, 1H), 4.36-4.28 (m, 1h), 4.12-4.01 (m, 1H), 3.61-3.56 (m, 5H), 3.34 (s, 3H), 3.24 (s, 3H). LCMS: 416.0 (M + H) ⁺ .

Example 502 5- [2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -1,3dimethylpyridin-2-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a manner similar to Example 501 by substituting 1,3-dimethyl-5 (4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl) pyridin-2-one on 2-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isoquinolin-1-one.

1H NMR (CDCl3, 400 MHz) δ 7.48 (m, 3H), 7.41 (d, J = 2.4 Hz, 1H), 4.47-4.34 (m, 2H), 4.19-4.16 (m, 1H), 3.71-3.65 ( m, 5H), 3.45 (s, 3H), 3.05 (s, 3H), 2.22 (s, 3H). LCMS: 380.0 (M + H) +.

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Example 503: 4- [2- (methoxymethyl) -7-methylsulfonyl-2,3-dihydro-1,4-benzodioxin-5-yl] -2methylisoquinolin-1-one

The title compound (single enantiomer, absolute stereochemistry not determined) was prepared in a similar manner to Example 501 by replacing the compound used in step 1 with its enantiomer.

1H NMR (CD3OD, 400 MHz) δ 8.41 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.58-7.54 (m, 2H), 7.48 (s, 1H), 7.42 (s, 1H), 7.33-7.30 (m, 1H), 4.52-4.41 (m, 2H), 4.20-4.12 (m, 1H), 3.67 (s, 3H), 3.47 (m, 2H), 3.193.15 (m, 6H). LCMS: 416.0 (M + n) ⁺ .

Example 504 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6,7-dihydro-5Hcyclopenta [c] pyridin-1-one.

Stage 1: ethyl 6,7-dihydro-5H-cyclopenta [c] pyridine-1-carboxylate

CO ₂ Et

Ethyl 1,2,4-triazine-3-carboxylate (7 g, 45.8 mmol), cyclopentanone (4.9 ml, 55.0 mmol), and pyrrolidine (4.6 ml, 55.0 mmol) in toluene (100 ml) were heated to reflux over 12 h. The mixture was purified by silica gel column chromatography (PE: EYAc = 5: 1) to give the title compound (2.02 g, 25%) as a brown oil. LCMS: 192 (M + 1) +.

Stage 2: 6,7-dihydro-5H-cyclopenta [c] pyridine-1-carboxylic acid

CO ₂ n

2n. a solution of LiOH (50 ml) in water was slowly added to the title compound from step 1 (10 g, 52.4 mmol) in MeOH (250 ml) at 0 ° C. The mixture was left to warm to room temperature and stirred for 30 minutes. MeOH was reduced in vacuo and the residual aqueous solution was washed with EtOAc. The organic phase was re-extracted with water. The combined aqueous extracts were acidified to pH 2 with 1N. HCl. Remove the water and preparative HPLC afforded the title compound (5.4 g, 63%) as a white solid.

1H NMR (CD3OD, 400 MHz): δ 8.45 (d, J = 5.6 Hz, 1H), 7.88 (d, J = 5.6 Hz, 1H), 3.39 (t, J = 8.0, 7.6 Hz, 2H), 3.16 ( d, t, J = 8.0, 7.6 Hz, 2H), 2.16-2.20 (m, 2H).

Stage 3: tert-butyl N- (6,7-dihydro-5H-cyclopenta [c] pyridin-1-yl) carbamate

NHBoc

Ou ^N

The title compound from Step 2 (1.0 g, 6.1 mmol), diphenylphosphorylazide (2.64 ml 12.2 mmol) and triethylamine (1.64 ml, 12.2 mmol) in tBuOH (50 ml) under N2 were heated at 80 ° С for 2 h. Chromatography over silica gel (PE / EtOAc = 5: 1) afforded the title compound (570 mg, 40%) as a white solid.

1H NMR (CDCl ₃ , 300 MHz): δ 8.18 (d, J = 4.8 Hz, 1H), 7.04 (d, J = 4.8 Hz, 1H), 2.90-2.97 (m, 4H), 2.06-2.12 (m, 2H), 1.49 (s, 9H). LCMS: 235 (M + 1) +.

Step 4: 6,7-dihydro-5H-cyclopenta [c] pyridin-1-amine hydrochloride

Anhydrous 1M HCl in DCM (20 ml) was slowly added to the title compound from step 3 (570 mg, 2.43 mmol) in DCM (10 ml) at 0 ° C. After stirring at room temperature for 1.5 h, evaporation of the volatiles gave the title compound (400 mg, 96%) as a white solid.

1H NMR (CD3OD, 300 MHz): δ 7.66 (d, J = 6.6 Hz, 1H), 6.88 (d, J = 6.6 Hz, 1H), 3.04 (t, J = 7.8, 7.2 Hz, 2H), 2.86 ( t, J = 7.8, 7.2 Hz, 2H), 2.17-2.27 (m, 2H). LCMS: 135 (M + 1) +.

Stage 5: 2,5,6,7-tetrahydrocyclopenta [c] pyridin-1-one

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The title compound from step 4 (400 mg, 2.33 mmol) was dissolved in water (6.5 ml) and H ₃ PO ₂ (2 ml, 50% w / w in water, 18.64 mmol) was added. The mixture was cooled to 0 ° C and added dropwise a solution of NaNO ₂ (180 mg, 2.68 mmol) in water (6.5 mL). The mixture was stirred at 0 ° C for 1 hour and then at room temperature overnight. The pH was adjusted to about 7 by the careful addition of NaHCO ₃ . Extraction with ethyl acetate provided the title compound (300 mg, 95%) as a yellow solid.

1H NMR (CDCl3, 300 MHz): δ 12.55 (s, 1H), 7.24 (d, J = 6.3 Hz, 1H), 6.26 (d, J = 6.3 Hz, 1H), 2.84-2.89 (m, 4H), 2.04-2.11 (m, 2H). LCMS: 136 (M + 1) +.

Step 6: 2-methyl-6,7-dihydro-5H-cyclopenta [c] pyridin-1-one

ΑΧ about

The title compound from step 5 (260 mg, 1.93 mmol) was dissolved in DMF (5 ml) and cooled to 0 ° C. NaH (94 mg, 2.31 mmol) was added and the mixture was stirred for 30 min. Methyl iodide (146 μL, 2.31 mmol) was added and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and chromatography on silica gel (PE: EtOAc = 1: 1) gave the title compound (192.6 mg, 67 %) as a brown oil.

¹ H NMR (CDCl3, 300 MHz): δ 7.13 (d, J = 6.6 Hz, 1H), 6.13 (d, J = 6.6 Hz, 1H), 3.53 (s, 3H), 2.79-2.85 (m, 4H) , 2.01-2.11 (m, 2H). LCMS: 150 (M + 1) ⁺ .

Step 7: 4-bromo-2-methyl-6,7-dihydro-5H-cyclopenta [c] pyridin-1-one

Br v about

The title compound from step 6 (140 mg, 1.04 mmol) was dissolved in ACN (5 ml) and NBS (188 mg, 1.06 mmol) was added. After stirring at room temperature for 1.5 h, purification by silica gel chromatography (PE: EtOAc = 1: 1) afforded the title compound (196 mg, 89.5%) as a white solid.

1H NMR (CDCl ₃ , 300 MHz): δ 7.33 (s, 1H), 3.53 (s, 3H), 2.85-2.97 (m, 4H), 2.05-2.13 (m, 2H). LCMS: 228, 230 (M + 1) ⁺ .

Step 8: 4- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methyl-6,7-dihydro-5Hcyclopenta [c] pyridin-1-one

To a solution of the title compound from Step 7 (60 mg, 0.26 mmol), the title compound of Example 90, Step 1 (111.2 mg, 0.32 mmol) and K ₂ CO ₃ (107 mg, 0.78 mmol) in dioxane (4 ml) and water (1 ml) were added Pd (dppf) Cl ₂ (6 mg) under N2. The mixture was heated at 85 ° C overnight. Extraction with EA followed by preparative TLC (DCM / MeOH = 25: 1) afforded the title compound (47 mg, 48%) as a yellow solid.

1H NMR (DMSO-d6, 300 MHz): δ 7.83 (dd, J = 8.7, 2.7 Hz, 1H), 7.66 (d, J = 2.9 Hz, 1H), 7.58 (s, 1H), 7.25 (d, J = 8.7 Hz, 1

H), 3.95 (d, J = 6.9 Hz, 2H), 3.46 (s, 3H), 3.17 (s, 3H), 2.65-2.70 (m, 4H), 1.91-1.97 (m, 2H), 1.13-1.18 (m, 1H), 0.50-0.54 (m, 2H), 0.26-0.30 (m, 2H). LCMS: 374 (M + 1) ⁺ .

Example 505: 4- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -2-methyl-6,7-dihydro-5Hcyclopenta [c] pyridin-1-one

The title compound was prepared in a similar manner to Example 504, step 8, except that 2- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane was replaced with the title compound of Example 90, Step 1.

1H NMR (CD3OD, 400 MHz): δ 7.91 (dd, J = 8.4, 2.0 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 7.56 (s, 1H), 7.27 (d,

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J = 8.4 Hz, 1H), 4.01 (d, J = 6.8 Hz, 2H), 3.66 (s, 3H), 3.23 (q, J = 7.6 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H) , 2.82 (t, J = 7.6

Hz, 2H), 2.08-2.14 (m, 2H), 1.26 (t, J = 7.6 Hz, 3H), 1.08-1.27 (m, 1H), 0.60-0.65 (m, 2H), 0.33-0.37 (m, 2H).

LCMS: 388 (M + 1) +.

Example 506: N- [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta [c] pyridin-4yl) phenyl] methanesulfonamide p_ ^ p V

YY 1J 0®b

O

The title compound was prepared in a similar manner to Example 504, step 8, except N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane-2yl) phenyl] methanesulfonamide was replaced with the title compound of Example 90, Step 1.

¹ H NMR (DMSO-d6, 400 MHz): δ 9.72 (s, 1H), 7.58 (s, 1H), 7.34-7.42 (m, 1H), 7.24-7.10 (m, 2H), 7.007.08 (m , 2H), 6.91 (d, J = 8.4 Hz, 1H), 3.43 (s, 3H), 3.01 (s, 3H), 2.71 (t, J = 7.2 Hz, 2H), 2.65 (t, J = 7.2 Hz , 2H), 1.88-1.96 (m, 2H). LCMS: 447 (M + 1) ⁺ .

Example 507: N- [4- (2,4-difluorophenoxy) -3- (2-methyl-1-oxo-6,7-dihydro-5H-cyclopenta [c] pyridin-4yl) phenyl] ethanesulfonamide

The title compound was prepared in a similar manner to Example 504, step 8, except N- [4- (2,4-difluorophenoxy) -3- (4,4,5,5-tetramethyl-1,3 , 2-dioxaborolane-2yl) phenyl] ethanesulfonamide was replaced with the title compound of Example 90, Step 1.

1H NMR (CDCl3, 400 MHz): δ 7.30 (s, 1H), 7.19 (d, J = 3.2 Hz, 1H), 7.14 (dd, J = 8.8, 3.2 Hz, 1H), 6.89-6.96 (m, 2H ), 6.79-6.85 (m, 1H); 6.77 (d, J = 8.8 Hz, 1H), 6.60 (s, 1H), 3.65 (s, 3H), 3.15 (q, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H), 2.82 (t, J = 7.6 Hz, 2H), 2.02-2.06 (m, 2H), 1.41 (t, J = 7.6 Hz, 3H). LCMS: 461 (M + 1) ⁺ .

Examples 508-511.

Examples 508-511 shown in table. 22 was obtained in three steps. Using conditions similar to those described in WO2005 / 40151 (Preparation 6), 5-bromo-3-methylpyridin-2-ol was N-alkylated with isopropyl bromide to give 5-bromo-3-methyl-1-propan-2-ylpyridin-2-one , which was then reacted with 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane using conditions similar to those described in example 248 , stage 2, to obtain pinacoline ester, 3-methyl-1-propan-2-yl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2- she. This pinacolin ester was then replaced by the pinacolin ester of the example shown in the Synthesis Method column in Table II. 22 and reacted in a similar manner as in the example to provide the title compounds.

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Table 22

Example No. R ¹ Name MS (M + H) Synthesis method MeO ₂ S ^ N 5- (5-butyl-2- 508 σννν methylsulfonylpyrimid in-4-yl) -3 -methyl-1 propan-2-ylpyridin-2- 364 Example 305 he EtO ₂ SHN N F - ^^ F Η Ί Ίτ Η Ν- [5- (2,4- difluorophenoxy) -4- (5 - 509 methyl-6-oxo-1-propan2-ylpyrid in-3 yl) pyrimidin-2yl] ethanesulfonamide 465 Example 169 MeO ₂ S ^ NF ^^^ F Π Ί \ Η 5- [5- (2,4- ΝγΑυ difluorophenoxy) -2- Example 149, stage 4 510 methylsulfonylpyrimid in-4-yl] -3 -methyl-1 propan-2-ylpyridin-2- 436 he EtO ₂ SHN Ν \\ Ί Ν- [5-butyl-4- (5-methyl-6- 511 oxo-1-propane-2 ylpyr idin-3 - 393 Example 2 1 o yl) pyrimidin-2yl] ethanesulfonamide 3 1 and

Examples 512-514.

Examples 512-514 shown in table. 23 was obtained in three steps. Using conditions similar to those described by Malhotra, et al. in Organic Letters 2013, vol. 15, no. 14, p. 3698-3701 (supporting information, compounds 4c and 3a), 3,5-dibromo-1-methylpyridin-2-one was alkylated at position 3 using isopropyl magnesium bromide to give 5-bromo-1-methyl-3-propane-2 -ylpyridin-2-one, which was then reacted with 4,4,5,5-tetramethyl-2- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2 dioxaborolane using conditions similar to described in example 248, step 2, to obtain a pinacolin ester, 1-methyl-3-propan-2-yl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin2-one. This pinacolin ester was then replaced by the pinacolin ester of the example shown in the Synthesis Method in Table II. 23 and reacted in a similar manner as in the example to provide the title compounds.

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Table 23

Example No. R ¹ Name MS (M + H) Synthesis method 512 EtO ₂ SHN N II Ί X- [5-butyl-4- (1-methyl-6oxo-5-propane-2ylpyridin-3yl) pyrimidin-2yl] ethanesulfonamide 393 Example 310 513 MeO ₂ S ^ N Η Ί 5- (5-butyl-2methylsulfonylpyrimid in-4-yl) -1 -methyl-3 propan-2-ylpyridin-2- he 364 Example 305 514 LL R> = ^ζ ζ ω Ο LU Ν- [5- (2,4- difluorophenoxy) -4- (1 methyl-6-oxo-5-propan2-ylpyridin-Zyl) pyrimidin-2yl] ethanesulfonamide 465 Example 169

II. Biological assessment.

Example 1. Assay of inhibition of enzyme action in vitro.

The determination of IC ₅₀ for the derivatives of heterocyclic BRD4 inhibitors of the present invention was performed as follows. His-tagged BRD4 was cloned, expressed and purified to homogeneity (P. Filipakopoulos et al. Nature 468, 1067-1073, 2010). BRD4 binding and inhibition was assessed by monitoring the interaction of biotinylated H4-tetraacetyl peptide (AnaSpec, H4K5 / 8/12/16 (Ac), biotin-labeled) with the target using AlphaScreen technology (Life Technologies). The assay was performed in 384 well plates in DMSO. After 20 min incubation at room temperature, BRD4 (BD1) (2 nM end) in streptavidin plates (Alpha streptavidin donor-well ProxiPlate) was combined with peptide (15 nM end) in 50 mM HEPES (pH 7.3), 10 mM NaCl, 0.25 mM TCEP, 0.1% (w / v) BSA and 0.005% (w / v) Brij-35, either in the presence of DMSO (final 0.4% DMSO) or a series of dilutions of compound granules, and a nickel chelate acceptor was added in the form of granules to final concentration 5 μg / ml. After 2 hours of equilibration, the plates were read with an Envision device and the IC50 was calculated using four points to generate a non-linear curve. Chemical Example 1 (2-methyl-4-phenylisoquinolin-1-one) had an IC ₅₀ value of 2.782 μM in the format of this assay.

The ability of the compounds described herein to inhibit BRD4 activity was quantified and the corresponding IC ₅₀ values were determined. _{The IC 50} values of the various compounds described in this document are given in table. 24.

Example 2. In vitro cell assay.

To assess the ability of the derivatives of heterocyclic BRD4 inhibitors of the present invention to influence the proliferation of cell lines, a colorimetric analysis of cell proliferation (Cell-MTS analysis) was performed.

Analysis principle.

The Cell-MTS assay is a 7-day plate-based colorimetric assay that quantifies the amount of newly formed NADH (nicotinamide adenine dinucleotide) in the presence or absence of a test compound. The NADH level is used to quantify the proliferation of malignant cells.

Analysis technique.

Verified malignant tumor cell lines with a variety of emerging mutations were obtained from the American Type Culture Collection (ATCC) and routinely subcultured according to ATCC protocols. For routine analysis, these cells were plated at densities that allowed for ~ 90% confluence after 7 days of culture. Raji, human Burkitt lymphoma cells (cMYC) were plated at 15,000 cells in a 96-well plate. HL-60, shed cells

- 361 038715 human chemias (NRAS, p16, p53, c-Myc amplified) were seeded in the amount of 5,000 cells per 96-well plate. NCI-H460, human non-small cell lung cancer cells (KRAS, PIK3CA, STLK11, p16) were seeded at 3,000 cells in a 96-well plate. Twenty four hours after seeding, cells were obtained at 11 points of test compound dilution with final concentration ranges from 100 μM to 2.0 nM. The cells were incubated in the presence of the compound for 168 h at 37 ° C and 5% CO2. At the end of this incubation period, 80 μl of medium was removed and 20 μl of CellTiter 96® AQueous Non-Radioactive Cell Proliferation Assay (Promega) was added. The cells were incubated until the optical density OD490 was> 0.6. _{IC 50} values were calculated using IDBS XLfit software and included OD490 background subtraction values and adjustments for control DMSOs. _{Cell proliferation inhibitor IC 50} values were downloaded and archived using the Chem Biography Platform.

Table 24 depicts the results of in vitro assay experiments on enzyme inhibition and in vitro assay experiments using cells performed with the compounds described herein.

Table 24

An example of chemical synthesis Name BRD4 IC50 (μM) Raji IC50 (μM) HL-60 IC50 (μM) Н460 IC50 (μM) one 4- (3-methoxyphenyl) -2- methylisoquinolin-1-one V 2 2-methyl-4-phenylisoquinolin-1-one V 3 4- (2-fluorophenyl) -2- methylisoquinolin-1-one With 4 4- (2-methoxyphenyl) -2- methylisoquinolin-1-one With 5 4- (3 -aminophenyl) -2- methylisoquinolin-1-one v 6 N-cyclopropyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide v 7 2-methyl-4- (3-pyrrolidine-1 ylsulfonylphenyl) isoquinoline-1 - he v A V

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eight N - [[3- (2-methyl-1-oxoisoquinoline4- yl) phenyl] methyl] methanesulfones d V 9 N- [3- (2-methyl-1-oxoisoquinoline-4yl) phenyl] methanesulfonamide A A A WITH 10 N-ethyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide V AND 4- (3-ethylsulfonylphenyl) -2methylisoquinolin-1-one V A V 12 4- [3- (dimethylsulfamoylamino) phenyl] -2-methyl-1-oxoisoquinoline A A A thirteen N- [3- (2-methyl-1-oxoisoquinoline-4yl) phenyl] ethanesulfonamide A A A 14 2-methyl-4- (3-morpholine-4ylsulfonylphenyl) isoquinoline-1 - he V 15 X-benzyl-2-methoxy-5 - (2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide V A V sixteen 2-methoxy-5- (2-methyl-1- OXOISOCHINOLIN-4yl) benzenesulfonamide V 17 X- [2-methyl-5- (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A V A eighteen X-benzyl-2-methoxy-5 - (2-methyl-1 oxoisoquinolin-4-yl) benzamide V V V nineteen 4- (3,4-dihydro-2H-1,4-benzoxazine- 6-yl) -2-methylisoquinolin-1-one v

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twenty 2-methyl-4- (2-oxo-1,3- dihydroindol-6-yl) isoquinoline-1 - he WITH A A 21 3 - (2-methyl-1-oxoisoquinoline-4yl) benzenesulfonamide V V V 22 X- (2-hydroxyethyl) -3 - (2-methyl-1 oxoisoquinoline-4yl) benzenesulfonamide V V v 23 4- (5-amino-2-fluorophenyl) -2methylisoquinolin-1-one v 24 4- (5-amino-2,4-difluorophenyl) -2methylisoquinolin-1-one v 25 4- (3-amino-5-fluorophenyl) -2methylisoquinolin-1-one v 26 4- (3-amino-4-fluorophenyl) -2methylisoquinolin-1-one v 27 N-benzyl-3 - (2-methyl-1 oxoisoquinoline-4yl) benzenesulfonamide v 28 N- [3- (2-methyl-1-oxoisoquinoline-4yl) phenyl] propane-1 -sulfonamide A v v 29 N- [3- (2-methyl-1-oxoisoquinoline-4yl) phenyl] butane-1 -sulfonamide A v v thirty M- [2-methoxy-5- (2-methyl-1- oxoisoquinoline-4- yl) phenyl] methanesulfonamide A v A 31 tert-butyl-X-methyl-X- [3- (2-methyl1-oxoisoquinoline-4yl) phenyl] carbamate V v V

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32 2-methyl-4- [3- (methylamino) phenyl] isoquinoline-1 - he V 33 Ν-μ6τηπ-Ν- [3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A V V 34 Ν- [4-φτορ-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A A A 35 X- [2,4-difluoro-5- (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide V V V 36 Ν- [3-fluoro-5- (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide V V V 37 X- [2-fluoro-5- (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A V v 38 X- [4-chloro-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A v A 39 X- [4-methyl-3 - (2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A v A 40 Ν- [3- (2-methyl-1-oxoisoquinoline-4yl) -5 (trifluoromethyl) phenyl] methanesulfonamide V v V 41 X- [4-fluoro-3- [2-methyl-6- (1methylpyrazol-4-yl) -1 OXOISOCHINOLIN-4yl] phenyl] methanesulfonamide A A A

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42 N- [3 - [2-methyl-6- (1-methylpyrazol4-yl) -1-oxoisoquinoline-4yl] phenyl] methanesulfonamide A A A 43 X- [2,4-difluoro-5- [2-methyl-6- (1methylpyrazol-4-yl) -1 - OXOISOCHINOLIN-4yl] phenyl] methanesulfonamide A A A 44 4- (3-ethylsulfonylphenyl) -2methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one A V A WITH 45 X- [4-chloro-3- [2-methyl-6- (1methylpyrazol-4-yl) -1 OXOISOCHINOLIN-4yl] phenyl] ethanesulfonamide A A A V 46 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2-methyl-6 (1-methylpyrazol-4-yl) isoquinolin1-one A A A With 47 N- [3 - (6-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A A A 48 3 - (6-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) benzenesulfonamide V V V 49 N-ethyl-3 - (6-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide V V V 50 X- [4-chloro-3 - (6-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide A V A v

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51 L- [3- (2-methyl-1-oxo-2,7naphthyridine-4- yl) phenyl] methanesulfonamide V WITH v 52 N- [3- (2-methyl-1-oxo-2,7naphthyridin-4yl) phenyl] ethanesulfonamide V v v 53 N-ethyl-3 - (2-methyl-1-oxo-2,7naphthyridine-4yl) benzenesulfonamide v With With 54 X-benzyl-2-methoxy-5 - (2-methyl-1 oxo-2,7-naphthyride in-4yl) benzenesulfonamide With With v With 55 3- (2-methyl-1-oxo-2,7-naphthyr idin- 4-yl) benzenesulfonamide With 56 2-methoxy-5- (2-methyl-1-oxo-2,7 naphthyridine-4- yl) benzenesulfonamide With 57 H- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-2,7-naphthyr idin-4yl) phenyl] ethanesulfonamide A A A With 58 N- [3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A V A 59 N-ethyl-3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) benzenesulfonamide V v V 60 N-benzyl-5 - (7-fluoro-2-methyl-1 oxoisoquinolin-4-yl) -2methoxybenzenesulfonamide v A v With 61 3 - (7-fluoro-2-methyl-1 OXOISOCHINOLIN-4yl) benzenesulfonamide A V v

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62 N- [3 - (7-fluoro-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide A v A 63 4- (3-ethylsulfonylphenyl) -7-fluoro- 2-methylisoquinolin-1-one V v V WITH 64 5 - (7-fluoro-2-methyl-1 oxoisoquinolin-4-yl) -2methoxybenzenesulfonamide V 65 2-methyl-4- (1-methylpyrazol-4yl) isoquinolin-1-one V 66 4- (furan-2-yl) -2- methylisoquinolin-1-one With 67 2-methyl-4- (1,3-oxazol-2yl) isoquinolin-1-one With 68 2-methyl-4- (1 H-pyrazol-5 yl) isoquinolin-1-one With 69 2-methyl-4- (1-methylimide azole-2yl) isoquinoline-1-one With 70 2-methyl-4-pyridine-2- orisoquinolin-1-one With 71 2-methyl-4-pyrimidin-2ylisoquinolin-1-one With 72 X- [3- [2-methyl-6- (6-methylpyridine- 3 -yl) -1-oxoisoquinoline-4yl] phenyl] ethanesulfonamide A A A v 73 N- [3- (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] ethanesulfonamide V 74 N- [3- (2-methyl-1-oxo-6phenylisoquinoline-4yl) phenyl] methanesulfonamide v V V With

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75 N- [3- (2,6-dimethyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide A A A WITH 76 N- [3- (6-ethyl-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] ethanesulfonamide A 77 N- [3- (6-ethyl-2-methyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A A A WITH 78 N- [3- (2,6-dimethyl-1 - OXOISOCHINOLIN-4yl) phenyl] methanesulfonamide A A A WITH 79 4- (5-ethylsulfonyl-2methoxyphenyl) -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline-1 - he A A A With 80 4- (5-ethylsulfonyl-2hydroxyphenyl) -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline-1 - he A 81 4- (2-ethoxy-5- ethylsulfonylphenyl) -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin1-one A A A A 82 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2-methyl-6 (1-methylpyrazol-4-yl) isoquinolin1-one A A A V 83 4- (5-ethylsulfonyl-2propoxyphenyl) -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline-1 - he A A A A

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84 4- [5-ethylsulfonyl-2- (2- hydroxyethoxy) phenyl] -2-methyl-6 (1-methylpyrazol-4-yl) isoquinolin1-one A V A V 85 4- [2- (2-aminoethoxy) -5- ethylsulfonylphenyl] -2-methyl-6- (1-methylpyrazol-4-yl) isoquinolin1-one A WITH V WITH 86 X- [2-fluoro-4-methoxy-5- [2-methyl-6 (1-methylpyrazol-4-yl) -1 OXOISOCHINOLIN-4yl] phenyl] ethanesulfonamide A A A V 87 N- [3- (2-methyl-1-oxo-6-pyridine-2- ILISOCHINOLIN-4yl) phenyl] ethanesulfonamide V V A With 88 4- [4-fluoro-2-methoxy-5- (methylsulfonylmethyl) phenyl] -2methyl-6- (1-methylpyrazol-4yl) isoquinolin-1-one A A A With 89 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With 90 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6-fluoro-2- methylisoquinolin-1-one A A A 91 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -7-fluoro-2methylisoquinolin-1-one A A A With 92 4- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With

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93 H- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxoisoquinoline-4yl) phenyl] ethanesulfonamide A A A WITH 94 N- [3- (1-methyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide V A WITH 95 N- [3- (1,4-dimethyl-6-oxopyridin3-yl) phenyl] methanesulfonamide V 96 H- [3- (1,5-dimethyl-6-oxopyridin3-yl) phenyl] methanesulfonamide V 97 H- [3- (1,4,5-trimethyl-6oxopyr-idin-3 yl) phenyl] methanesulfonamide v 98 5- [2- (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -1 methylpyridin-2-one v V V WITH 99 M- [4- (2,4-difluorophenoxy) -3 - (1 methyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide A A A WITH one hundred M- [4- (2,4-difluorophenoxy) -3 - (1 methyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A With 101 M- [4- (2,4-difluorophenoxy) -3 - (1,4dimethyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A With 102 H- [4- (2,4-difluorophenoxy) -3- (1,5dimethyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A With 103 M- [4- (2,4-difluorophenoxy) -3 - (1,4,5trimethyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A V A With

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104 3-amino-1-methyl-5- (3 methylsulfonylphenyl) pyrazine-2- he WITH 105 3-amino-5- (3ethylsulfonylphenyl) -1 methylpyrazin-2-one WITH 106 X- [5- (6-amino-4-methyl-5oxopyrazin-2-yl) -2methoxyphenyl] methanesulfonamide WITH 107 3-amino-1-methyl-5- (3 - methylsulfonylphenyl) pyridine-2- he With 108 3-amino-5- (3ethylsulfonylphenyl) -1 methylpyridin-2-one With 109 X- [5- (5-amino-1-methyl-6oxopyr-idin-3-yl) -2methoxyphenyl] methanesulfonamide v WITH With WITH 110 X- [2-methoxy-5- [1-methyl-5 (methylamino) -b-oxopyrid in-3 yl] phenyl] methanesulfonamide A With v With 111 N- [5 - [5 - (ethyl amino) -1 -methyl-6oxopyr-idin-3 -yl] -2methoxyphenyl] methanesulfonamide V 112 X- [5- [5- (cyclopropylmethylamino) 1-methyl-6-oxopyrid in-3-yl] -2methoxyphenyl] methanesulfonamide v FROM X- [5- [5- (dimethylamino) -1-methyl-6oxopyr-idin-3-yl] -2methoxyphenyl] methanesulfonamide A v A v

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114 Ν- [5 - [5 - (diethyl amino) -1-methyl-6oxopyr-idin-3-yl] -2methoxyphenyl] methanesulfonamide V 115 Ν- [3- (5-amino-1-methyl-6oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide A A A WITH 116 3-amino-5- [2- (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -1 methylpyridin-2-one A WITH V With 117 4-ethoxy-3 - (1-methyl-6oxopyr idin-3 yl) benzenesulfonamide A V V With 118 4- (2,4-d ifluorophenoxy) -3 - (1-methyl6-oxopyridin-3 yl) benzenesulfonamide A A A With 119 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one V V V With 120 5- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one V WITH V With 121 5- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one A V A With 122 X- [4- (2,4-difluorophenoxy) -3- (5fluoro-1-methyl-6-oxopyrid in-3 yl) phenyl] ethanesulfonamide A A A With 123 Ν- [3- (2-methyl-1-oxo-2,6naphthyridin-4yl) phenyl] ethanesulfonamide V V V With

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124 N-ethyl-3 - (2-methyl-1-oxo-2,6naphthyridine-4yl) benzenesulfonamide V 125 N- [3- (2-methyl-1-oxo-2,6 naphthyridine-4- yl) phenyl] methanesulfonamide V 126 4- (3-ethylsulfonylphenyl) -2methyl-2,6-naphthyridin-1-one WITH 127 X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-2,6-naphthyr idin-4yl) phenyl] ethanesulfonamide A A A WITH 128 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2-methyl-6 (4-methylpyrazol-1-yl) isoquinolin1-one A A A With 129 X- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxoimidazo [1,5а] pyrazine-5yl) phenyl] ethanesulfonamide A A A With 130 5- [2- (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazin-8-one A V A With 131 7-methyl-5- (3- methylsulfonylphenyl) imidazo [1,5 -а] pyrazin-8-one WITH 132 X- [2-methoxy-5- (7-methyl-8oxoimidazo [1,5-a] pyrazin-5yl) phenyl] methanesulfonamide V WITH V v 133 5 - (3-ethylsulfonylphenyl) -7methylimidazo [1,5-a] pyrazin-8-one With

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134 N- [3- (5-chloro-1-methyl-6oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide A A A V 135 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2methylisoquinolin-1-one A A A V 136 6- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2,4dimethylpyridazin-3-one V WITH V WITH 137 6- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2.5dimethylpyridazin-3-one V 138 X- [4- (2,4-difluorophenoxy) -3 - [1 methyl-6-oxo-5 (trifluoromethyl) pyridin-3 yl] phenyl] ethanesulfonamide A A A With 139 X- [4- (2,4-difluorophenoxy) -3- (4fluoro-1-methyl-6-oxopyrid in-3 yl) phenyl] ethanesulfonamide A A A With 140 N- [3- (5-cyclopropyl-1-methyl-6oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide A A A With 141 X- {4- (2,4-difluorophenoxy) -3- [1 ( ² Hs) methyl-6-oxopyridin-3 yl] phenyl} ethanesulfonamide A 142 X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-5,6,7,8-tetrahydro2,6-naphthyr idin-4yl) phenyl] ethanesulfonamide V

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143 4- [5- (cyclopropylmethoxy) -2 (methyl sulfonyl methyl) pyrimidin-4-yl] -2-methylisoquinolin-1-one A V v With 144 5- [5- (cyclopropylmethoxy) -2 (methyl sulfonyl methyl) pyrimidin-4-yl] -1,3-d-immethylpyrid in-2-one A WITH v With 145 4- [5- (cyclopropylmethoxy) -2 (methyl sulfonyl methyl) pyrimidin-4-yl] -2-methyl-6- (1-methylpyrazol4-yl) isoquinolin-1-one A V A With 146 5- (5- (2,4-difluorophenoxy) -2- (methyl sulfonyl methyl) pyrimidine -4-yl] -3-methoxy-1 -methylpyridine- 2nd A v With 147 5- (5- (2,4-difluorophenoxy) -2- (methyl sulfonyl methyl) pyrimidine -4-yl] -1,3-d imethylpyridin-2-one A v With 148 4- (5- (2,4-difluorophenoxy) -2- (methyl sulfonyl methyl) pyrimidine -4-yl] -2-methylisoquinolin-1-one A With 149 5- (5- (2,4-difluorophenoxy) -2- methylsulfonylpyrimidin-4-yl] 1,3-dimethylpyridin-2-one V With WITH With 150 5- (5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4-yl] 3-methoxy-1-methylpyridin-2-one A v v With 151 4- (5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4-yl] 2-methylisoquinolin-1-one A

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152 X- [5- (cyclopropylmethoxy) -4- (2methyl-1-oxoisoquinoline-4yl) pyrimidin-2yl] methanesulfonamide A A A WITH 153 X- [5- (cyclopropylmethoxy) -4- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] methanesulfonamide A V V WITH 154 X- [5- (cyclopropylmethoxy) -4- [2methyl-6- (1-methylpyrazol-4-yl) -1 oxoisoquinolin-4-yl] pyrimidin2-yl] methanesulfonamide A A A WITH 155 X- [5- (cyclopropylmethoxy) -4- (2methyl-1-oxoisoquinoline-4yl) pyrimidin-2yl] ethanesulfonamide A A A With 156 4- [5- (cyclopropylmethoxy) -2- (1,1-dioxo-1,2-thiazolidin-2yl) pyrimid in-4-yl] -2- methylisoquinolin-1-one A 157 X- [5- (cyclopropylmethoxy) -4- (6fluoro-2-methyl-1-oxoisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide A A A With 158 X- [5- (cyclopropylmethoxy) -4- (7fluoro-2-methyl-1-oxoisoquinoline-4yl) pyrimidin-2yl] methanesulfonamide A A A With 159 X- [5- (cyclopropylmethoxy) -4- (6fluoro-2-methyl-1-oxoisoquinoline-4yl) pyrimidine-2yl] methanesulfonamide A A A With

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160 X- [5- (cyclopropylmethoxy) -4- (7fluoro-2-methyl-1-oxoisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide A A A WITH 161 X- [5- (cyclopropylmethoxy) -4- (2methyl-1-oxoisoquinolin-4yl) pyrimidin-2-yl] -Hethyl methanesulfonamide A A A WITH 162 X- [5- (cyclopropylmethoxy) -4- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-2-yl] -Methyl methanesulfonamide A A A WITH 163 X- [5- (cyclopropylmethoxy) -4- (2methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] methanesulfonamide A A V With 164 X- [5- (cyclopropylmethoxy) -4- (2methyl- 1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide A A V With 165 M- [5- (2,4-difluorophenoxy) -4- (2methyl-1-oxoisoquinolin-4yl) pyrimidin-2yl] methanesulfonamide A V With 166 M- [5- (2,4-difluorophenoxy) -4- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] methanesulfonamide A A A With

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167 L- [5- (2,4-difluorophenoxy) -4- (5methoxy-1-methyl-6-oxopyridin-3 yl) pyrimidin-2yl] methanesulfonamide A V WITH 168 T4- [5- (2,4-difluorophenoxy) -4- (5methoxy-1-methyl-6-oxopyridin-3 yl) pyrimidine-2yl] ethanesulfonamide A A A With 169 M- [5- (2,4-difluorophenoxy) -4- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] ethanesulfonamide A A A With 170 M- [5- (2,4-difluorophenoxy) -4- (2methyl-1-oxoisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide A A A With 171 4- [5- (2,4-difluorophenoxy) -2- (1,1-dioxo-1,2-thiazolidin-2yl) pyrimid in-4-yl] -2- methylisoquinolin-1-one A 172 M- [5- (2,4-difluorophenoxy) -4- (2methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] methanesulfonamide A V V With 173 K- [5- (2,4-difluorophenoxy) -4- (2methyl- 1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) pyrimidine-2yl] ethanesulfonamide A V V With

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174 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-fluoro-2methylisoquinolin-1-one A A A WITH 175 2-methyl-4- [5-methylsulfonyl-2 (oxolan-3- yloxy) phenyl] isoquinolin-1-one A A A WITH 176 2-methyl-4- [5-methylsulfonyl-2 (oxane-4- yloxy) phenyl] isoquinolin-1-one A A A With 177 4- (2-ethoxy-5- methylsulfonylphenyl) -2- methylisoquinolin-1-one A V A With 178 2-methyl-4- (5-methyl sulfonyl-2propoxyphenyl) isoquinoline-1-one A A A With 179 2-methyl-4- [5-methylsulfonyl-2 (oxane-3- yloxy) phenyl] isoquinolin-1-one A A A With 180 4- [2- (trans-4- hydroxycyclohexyl) oxy-5 methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With 181 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenyl] - 2-methylisoquinolin-1-one A A A With 182 4- [2- (trans-4- aminocyclohexyl) oxy-5 methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With 183 4- [2- (cis-4- aminocyclohexyl) oxy-5 methylsulfonylphenyl] -2methylisoquinolin-1-one A WITH V With

-380038715

184 4- (2-but-2-inoxy-5methylsulfonylphenyl) -2methylisoquinolin-1-one A V A V 185 4- (2-but-2-inoxy-5- ethylsulfonylphenyl) -2- methylisoquinolin-1-one A A A WITH 186 6-fluoro-4- [2- (trans-4hydroxycyclohexyl) oxy-5 methylsulfonylphenyl] -2methylisoquinolin-1-one A A A WITH 187 7-fluoro-4- [2- (trans-4hydroxycyclohexyl) oxy-5 methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With 188 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenyl] 6-fluoro-2-methylisoquinolin-1-one A A 189 4- [5-ethylsulfonyl-2- (trans-4hydroxycyclohexyl) oxyphenyl] 7-fluoro-2-methylisoquinoline-1-one A A 190 2-methyl-4- [5-methylsulfonyl-2 (oxolan-3- ylamino) phenyl] isoquinolin-1-one A V V With 191 2-methyl-4- [5-methylsulfonyl-2 (oxane-4- ylamino) phenyl] isoquinolin-1-one A A A With 192 4- [2 - [(trans-4hydroxycyclohexyl) amino] -5 methylsulfonylphenyl] -2methylisoquinolin-1-one A A A With

- 381 038715

193 4- [2- (cyclopropylmethylamino) -5ethylsulfonylphenyl] -2methylisoquinolin-1-one A A A WITH 194 4- [2- (cyclopropylmethylamino) -5methylsulfonylphenyl] -2methylisoquinolin-1-one A A A WITH 195 4- [2- (cyclopropylmethylamino) -5ethylsulfonylphenyl] -7-fluoro-2 methylisoquinolin-1-one A A A WITH 196 4- [2- (cyclopropylmethylamino) -5methylsulfonylphenyl] -7-fluoro-2methylisoquinolin-1-one A A A With 197 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2-methyl-6 (trifluoromethyl) isoquinoline-1-one A V With 198 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6-methoxy- 2-methylisoquinolin-1-one A A A With 199 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] -2methylisoquinolin-1-one A A A With 200 4- [5- (cyclopropylmethoxy) -2methylsulfonylpyridin-4-yl] -2methylisoquinolin-1-one A V A With 201 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] -7fluoro-2-methylisoquinolin-1-one A A A With 202 4- [3 - (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] -6fluoro-2-methylisoquinolin-1-one A A With

- 382 038715

203 4- [5- (cyclopropylmethoxy) -2methylsulphonylpyridin-4-yl] -7fluoro-2-methylisoquinolin-1-one A A A WITH 204 4- (2-ethoxy-5- ethylsulfonylthiophene-3-yl) -2- methylisoquinolin-1-one A V V WITH 205 4- [2- (cyclopropylmethylamino) -5ethylsulfonylthiophen-3-yl] -2methylisoquinolin-1-one A V V WITH 206 4- [3- (cyclopropylmethoxy) -betylsulfonylpyridin-2-yl] -2methylisoquinolin-1-one A A A With 207 4- [5- (cyclopropylmethoxy) -2ethylsulfonylpyridin-4-yl] -2methylisoquinolin-1-one A A A With 208 4- [5- (2-hydroxyethylsulfonyl) -2methoxyphenyl] -2-methyl-6- (1 methylpyrazol-4-yl) isoquinoline-1 - he A V A With 209 X- [4- (cyclopropylmethoxy) -2fluoro-5- [2-methyl-6- (1methylpyrazol-4-yl) -1 OXOISOCHINOLIN-4yl] phenyl] ethanesulfonamide A A A With 210 4- (5-ethylsulfonyl-2methoxyphenyl) -2-methyl-6- (1Hpyrazol-4-yl) isoquinolin-1-one A A A With 211 4- (2-ethoxy-5- methylsulfonylphenyl) -2-methyl-6 (1-methylpyrazol-4-yl) isoquinolin1-one A

- 383 038715

212 2-methyl-6- (1-methylpyrazol-4-yl) - 4- (5-methyl sulfonyl-2- propoxyphenyl) isoquinoline-1-one A 213 X- [2- [2-methyl-6- (1-methylpyrazol4-yl) -1-oxoisoquinolin-4yl] pyridin-4-yl] ethanesulfonamide A V V WITH 214 [4- (cyclopropylmethoxy) -3 - (2methyl-1-oxoisoquinoline-4yl) phenyl] sulfamate A A A WITH 215 [4- (cyclopropylmethoxy) -3 - (1,5dimethyl-6-oxopyr-idin-3 - yl) phenyl] sulfamate A A A With 216 4- (2-ethoxy-5- methylsulfonylphenyl) -2-methyl- 5,6,7,8-tetrahydroisoquinolin-1-one A 217 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2-methyl5,6,7,8-tetrahydroisoquinolin-1-one A A A With 218 X- [4- (cyclopropylmethoxy) -2fluoro-5- (2-methyl-1-oxo-5,6,7,8tetrahydroisoquinoline-4yl) phenyl] methanesulfonamide A V A With 219 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2-methyl5,6,7,8-tetrahydroisoquinolin-1-one A A A With 220 X- [2- (2-methyl-1-oxoisoquinoline-4yl) -4- methylsulfonylphenyl] cyclopropa ncarboxamide V WITH WITH With

- 384 038715

221 X- [2- (2-methyl-1-oxoisoquinoline-4yl) -4methylsulfonylphenyl] propanes e WITH WITH With WITH 222 N- [2- (2-methyl-1-oxoisoquinoline-4- yl) -4- methyl sulfonyl phenyl] acetamide WITH WITH With WITH 223 4- [2- (cyclopropylmethylamino) -5methylsulfonylphenyl] -2-methyl5,6,7,8-tetrahydroisoquinolin-1-one A V A With 224 8- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6-methyl-2 (1-methylpyrazol-4-yl) pyrid o [4,3 d] pyrimidin-5-one A A A With 225 8- (5-ethylsulfonyl-2propoxyphenyl) -6-methyl-2- (1 methylpyrazol-4-yl) pyrido [4,3 d] pyrimidin-5-one A A A With 226 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-methyl-2 (1-methylpyrazol-4-yl) pyrid o [4,3 d] pyrimidin-5-one A A A With 227 8- (2-ethoxy-5- ethylsulfonylphenyl) -6-methyl-2 (1-methylpyrazol-4-yl) pyrid o [4,3 d] pyrimidin-5-one A V A With 228 6-methyl-2- (1-methylpyrazol-4-yl) 8- (5-methylsulfonyl-2propoxyphenyl) pyrido [4,3 - d] pyrimidin-5-one A V A With

- 385 038715

229 X- [4- (2,4-difluorophenoxy) -3- (1,5dimethyl-6-oxopyr-idin-3 yl) phenyl] -Amethylmethanesulfonamide A A A With 230 X- [4- (2,4-difluorophenoxy) -3- (1,5dimethyl-6-oxopyridin-3 yl) phenyl] -N- (oxetan-3 yl) methanesulfonamide A A A With 231 8- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6methylpyrido [4,3-d] pyrimid in-5 - he V 232 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6methylpyrido [4,3-d] pyrimid in-5 - he A 233 8- [2- (2,4-difluorophenoxy) -5methylsulfonylphenyl] -6methylpyrido [4,3 -d] pyrimid in-5 - he V 234 8- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -6methylpyrido [4,3-d] pyrimid in-5 - he V 235 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -7-methyl [1,2,4] triazolo [4,3-a] pyrazin-8-one WITH WITH WITH With 236 X- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxo [1,2,4] triazolo [4,3а] pyrazine-5yl) phenyl] ethanesulfonamide A WITH V With

- 386 038715

237 7- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -5-methyl [1,3] oxazolo [4,5-c] pyrid in-4-one A 238 7- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2.5dimethyl- [1,3] oxazolo [4.5 s] pyrid IN-4-OH A V A With 239 5-methyl-7- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] - [1,3] oxazolo [4,5 -s] pyrid in-4-one A 240 PM- [4- (2,4-difluorophenoxy) -3- (5methyl-4-oxo [1,3] oxazolo [4.5 s] pyridine-7yl) phenyl] ethanesulfonamide A A A With 241 X- [4- (2,4-difluorophenoxy) -3- (2,5dimethyl-4-oxo [1,3] oxazolo [4.5 s] pyridine-7yl) phenyl] ethanesulfonamide A A A With 242 5- [2- (cyclopropylmethoxy) -5methyl sulfonyl phenyl] -1 (cyclopropylmethyl) -3 methylpyridin-2-one A V A With 243 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3-methyl-1 (2-methylpropyl) pyridin-2-one V WITH V With 244 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -1- (2methoxyethyl) -3 - methylpyridin-2 - he V With V With

-387 038715

245 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3 -methyl-1 (oxetane-3 -ylmethyl) pyrid in-2-one V WITH WITH WITH 246 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3 -methyl-1 (1,3-oxazol-4-ylmethyl) pyridin-2 - he V WITH WITH WITH 247 M- [3- [1- (cyclopropylmethyl) -5methyl-6-oxopyridin-3-yl] -4- (2,4difluorophenoxy) phenyl] ethanesulfonamide A A A WITH 248 M- [4- [1- (cyclopropylmethyl) -5methyl-6-oxopyridin-3 -yl] -5 - (2,4difluorophenoxy) pyrimidin-2yl] methanesulfonamide A A A With 249 K- [4- [1- (cyclopropylmethyl) -5methyl-6-oxopyridin-3 -yl] -5 - (2,4difluorophenoxy) pyrimidin-2yl] ethanesulfonamide A A A With 250 1- (cyclopropylmethyl) -5- [4- (2,4difluorophenoxy) -1 (methylsulfonylmethyl) -boxopyr-idin-3-yl] -3 methylpyridin-2-one A V A With 251 1 -cyclopropyl-5 - [2 (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3methylpyridin-2-one A V A With 252 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6- methylfuro [2,3-c] pyridin-7-one A A A With

- 388 038715

253 Ch- [4- (2,4-difluorophenoxy) -3- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) phenyl] ethanesulfonamide A A A WITH 254 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one A A A WITH 255 Ch- [4- (cyclopropyl methoxy) -3 - (6methyl-7-oxofuro [2,3-c] pyridin4-yl) phenyl] ethanesulfonamide A A A WITH 256 Ch- [6- (2,4-difluorophenoxy) -5- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) pyridin-3yl] ethanesulfonamide A A A With 257 Ch- [6- (cyclopropylmethoxy) -5- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) pyrid in-3 yl] ethanesulfonamide A A A With 258 6-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] furo [2,3с] pyride IN-7-OH A V A v 259 4- [3- (cyclopropylmethoxy) -bmethylsulfonylpyridin-2-yl] -6methylfuro [2,3-c] pyridin-7-one A V A With 260 2-chloro-4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one A A A v 261 Ch- [6- (cyclopropylmethoxy) -5- (2fluoro-6-methyl-7-oxofuro [2,3с] pyridin-4-yl) pyridin-3 yl] ethanesulfonamide A A A With

- 389 038715

262 X- [5- (2,4-difluorophenoxy) -4- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) pyrimidin-2yl] methanesulfonamide A A A WITH 263 X- [5- (2,4-difluorophenoxy) -4- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) pyrimidin-2yl] ethanesulfonamide A A A WITH 264 X- [5- (cyclopropylmethoxy) -4- (6methyl-7-oxofuro [2,3-c] pyridin4-yl) pyrimidin-2yl] ethanesulfonamide A A A WITH 265 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-methyl-7 oxothieno [2,3-c] pyridine-2 carboxamide A A A With 266 4- [2- (cyclopropylmethoxy) -5 (ethylsulfonylamino) phenyl] -6methyl-7-oxothieno [2,3-c] pyridine 2-carboxamide A A A With 267 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6-methyl-7oxothieno [2,3-c] pyridine-2 carboxamide A V A With 268 4- [2- (cyclopropylmethoxy) -5 (ethylsulfonylamino) pyridin-3 yl] -6-methyl-7-oxothieno [2,3 - c] pyrid yn-2-carboxamide A V A With 269 X- [4- (2,4-difluorophenoxy) -3- (2,6dimethyl-7-oxofuro [2,3с] pyridin-4yl) phenyl] ethanesulfonamide A A A With

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270 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2,6dimethylfuro [2,3-c] pyridin-7-one A A A V 271 M- [4- (2,4-difluorophenoxy) -3- (5fluoro-1-methyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A WITH 272 3-chloro-5- [2- (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -1 methylpyridin-2-one A A A WITH 273 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4-yl] 1 -methyl-3-propan-2-ylpyridin-2- he V 274 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-fluoro-1 methylpyridin-2-one A V V With 275 3-chloro-5- [2 (cyclopropylmethylamino) -5 ethyl sulfonyl phenyl] -1 methylpyridin-2-one A A A With 276 5- [2- (2,4-difluorophenoxy) -5 (methanesulfonylmethyl) phenyl] -3 ( ² H ₃ ) methyl-1-methyl-1,2-dihydropyridin-2-one A A 277 M- [4- (2,4-difluorophenoxy) -3- [5 ( ² H ₃ ) methyl-1-methyl-6-oxo-1,6 dihydropyridin-3 yl] phenyl] methanesulfonamide A A

-391 038715

278 T4- [4- (2,4-difluorophenoxy) -3- [5 ( ² H ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyrid in-3-yl] phenyl] ethane 1-sulfonamide A A 279 N- [3- (5-cyclopropyl-1-methyl-6oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide A A A WITH 280 3-cyclopropyl-5 - [2 (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -1 methylpyridin-2-one A A A With 281 H- [4- (2,4-difluorophenoxy) -3 - (1methyl-6-oxo-5-pyrrolidin-1 ylpyridin-3- yl) phenyl] methanesulfonamide V 282 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 -methyl-3 pyrrolidin-1 -ylpyridin-2-one V 283 H- [4- (2,4-difluorophenoxy) -3- (5ethynyl-1-methyl-6-oxopyrid in-3 yl) phenyl] ethanesulfonamide A V A With 284 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-ethynyl-1methylpyridin-2-one A V V With 285 5- [2- (cyclopropylmethoxy) -5methylsulphonylphenyl] -3-ethynyl- 1-methylpyridin-2-one V 286 H- [4- (2,4-difluorophenoxy) -3- (5ethynyl-1-methyl-6-oxopyrid in-3 yl) phenyl] methanesulfonamide A V With

- 392 038715

287 5- [2- (cyclopropylmethoxy) -5- ethylsulfonylphenyl] -3- (difluoro methoxy) -1-methylpyridin2-one A V A With 288 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 -methyl-3 (2,2,2-trifluoroethoxy) pyridin-2-one A V 289 N- [3 - [5 - (difluoro methoxy) -1 -methyl6-oxopyridin-3-yl] -4- (2,4difluorophenoxy) phenyl] ethanesulfonamide A A A With 290 X- [4- (2,4-difluorophenoxy) -3 - [1 methyl-6-oxo-5- (2,2,2trifluoroethoxy) pyridin-3 yl] phenyl] ethanesulfonamide A A A With 291 3- (difluoromethoxy) -5- [2- (2,4- difluorophenoxy) -5 (ethylsulfonylmethyl) phenyl] -1 - methylpyridin-2-one A A A With 292 5- [2- (2,4-difluorophenoxy) -5 (ethylsulfonylmethyl) phenyl] -1 methyl-3- (2,2,2- trifluoroethoxy) pyridin-2-one A V A With 293 5- [2- (cyclopropylmethoxy) -5methyl sulfonylphenyl] -1 -methyl-3 - (1-methylpyrazole-4- yl) oxypyridin-2-one A V V With 294 5- [2- (cyclopropylmethoxy) -5methyl sulfonylphenyl] -1 -methyl-3 (1-propan-2-ylpyrazol-4yl) oxypyridin-2-one A WITH V With

- 393 038715

295 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -1 -methyl-3 phenoxypyridin-2-one A V V V 296 N- [4- (l-butyl-5-methyl-6oxopyridin-3-yl) -5- (2,4 difluorophenoxy) pyrimidin-2yl] methanesulfonamide A 297 N- [4- (l-butyl-5-methyl-6oxopyridin-3-yl) -5- (2,4difluorophenoxy) pyrimidin-2yl] ethanesulfonamide A 298 X- [4- [1- (cyclobutylmethyl) -5methyl-6-oxopyridin-3-yl] -5 - (2,4difluorophenoxy) pyrimidin-2yl] methanesulfonamide V 299 X- [4- [1- (cyclobutylmethyl) -5methyl-6-oxopyridin-3-yl] -5- (2,4difluorophenoxy) pyrimidin-2yl] ethanesulfonamide V 300 N- [5-ethyl-4- (2-methyl-1 oxoisoquinolin-4-yl) pyrimidin2-yl] ethanesulfonamide A 301 2-methyl-4- (2-methylsulfonyl-5propylpyrimidin-4yl) isoquinolin-1-one 302 5- (5-ethyl-2- methylsulfonylpyrimidin-4-yl) 1,3-dimethylpyridin-2-one 303 1,3-dimethyl-5 - (2-methyl sulfonyl- 5-propylpyrimidin-4yl) pyridin-2-one

- 394 038715

304 4- (5-butyl-2- methylsulfonylpyrimidin-4-yl) - 2-methylisoquinolin-1-one A 305 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) 1,3-dimethylpyridin-2-one A 306 X- [4- (2-methyl-1-oxoisoquinoline-4yl) -5-propylpyrimidin-2yl] ethanesulfonamide A 307 X- [4- (1,5-dimethyl-6-oxopyridin3-yl) -5-ethylpyrimidin-2yl] ethanesulfonamide A A A WITH 308 B1- [4- (1,5-dimethyl-6-oxopyridin3-yl) -5-propylpyrimidin-2yl] ethanesulfonamide A A A With 309 X- [5-butyl-4- (2-methyl-1- oxoisoquinolin-4-yl) pyrimidin2-yl] ethanesulfonamide A A A With 310 X- [5-butyl-4- (1,5-dimethyl-6oxopyr-idin-3-yl) pyrimid in-2yl] ethanesulfonamide A A A With 311 4- [5- (cyclopropylmethoxy) -2methylsulfonylpyrimidin-4-yl] - 2-methylisoquinolin-1-one A 312 5- (2-ethyl-5 methylsulfonylphenyl) -1 methylpyridin-2-one V WITH WITH With 313 1-methyl-5 - (5-methyl sulfonyl-2propylphenyl) pyridin-2-one V WITH V With 314 2-methyl-4- (5-methyl sulfonyl-2propylphenyl) isoquinolin-1-one A

- 395 038715

315 5 - [2- (2-cyclopropylethyl) -5 methyl sulfonyl phenyl] -1 methylpyridin-2-one A 316 4- (2-ethyl-5 - methylsulfonylphenyl) -2- methylisoquinolin-1-one A 317 5- (2-butyl-5methylsulfonylphenyl) -1 methylpyridin-2-one A 318 4- (2-butyl-5- methylsulfonylphenyl) -2- methylisoquinolin-1-one A 319 4- [2- (2-cyclopropylethyl) -5methylsulfonylphenyl] -2methylisoquinolin-1-one A 320 X- [6- (cyclopropylmethoxy) -5- (2methyl-1-oxoisoquinoline-4yl) pyridin-3-yl] ethansul phonamide A A A WITH 321 4- [2- (cyclopropylmethoxy) -5methylsulfonylpyr idin-3-yl] -2methylisoquinolin-1-one A A A WITH 322 4- [2- (cyclopropylmethoxy) -5ethylsulfonylpyrid in-3-yl] -2methylisoquinolin-1-one A A A WITH 323 5 - [3 - [(4-methoxyphenyl) methoxy] -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A 324 1,3-dimethyl-5 - (3-methyl sulfonyl5-phenylmethoxyphenyl) pyridine-2one A V A With

- 396 038715

325 5- [3- (cyclopropylmethoxy) -5methyl sulfonylphenyl] -1,3dimethylpyridin-2-one A V v WITH 326 1,3-dimethyl-5 - [3-methyl sulfonyl5- (2-phenylethoxy) phenyl] pyridin2-one A V v With 327 5- [3- (2-cyclopropylethoxy) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A V v With 328 1,3-dimethyl-5 - [3-methyl sulfonyl- 5- (2,2,2- trifluoroethoxy) phenyl] pyridine-2one A 329 1,3-dimethyl-5 - [3 - [(3-methyloxetan3-yl) methoxy] -5- methylsulfonylphenyl] pyridine-2- he A 330 1,3-dimethyl-5 - [3-methyl sulfonyl- 5- (feast idin-2 - ylmethoxy) phenyl] pyrid in-2-one A 331 5 - [3 - [(2,6-dimethylphenyl) methoxy] - 5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A v A With 332 5 - [3 - [(2-chlorophenyl) methoxy] -5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A 333 5- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5methyl sulfonyl phenyl] -1,3- dimethylpyridin-2-one A v A With

- 397 038715

334 2 - [[3- (1,5-dimethyl-6-oxopyridin3-yl) -5- methylsulfonylphenoxy] methyl] benzonitrile A V A WITH 335 5- [3 - [(2,4-difluorophenyl) methoxy] 5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A 336 1,3-dimethyl-5 - [3-methyl sulfonyl 5- (1-phenylethoxy) phenyl] pyridin2-one A V A WITH 337 5- [3 - [(2,3-dichlorophenyl) methoxy] -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one V 338 1,3-dimethyl-5 - [3-methyl sulfonyl- 5- (pyridine-3 - ylmethoxy) phenyl] pyrid in-2-one A 339 3 - [[3 - (1,5-d-immethyl-6-oκcopyridin3-yl) -5- methylsulfonylphenoxy] methyl] benzonitrile A 340 5 - (3-but-2-inoxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one A 341 1,3-dimethyl-5 - [3-methyl sulfonyl 5- (1-phenylethoxy) phenyl] pyridin2-one A A A With 342 X- [3- (2,4-difluorophenoxy) -5- (1,5dimethyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide A A A v 343 4- [3 - [(4-methoxyphenyl) methoxy] -5methylsulfonylphenyl] -2methylisoquinolin-1-one V

- 398 038715

344 2-methyl-4- (3-methylsulfonyl-5 phenylmethoxyphenyl) isoquinoline- 1st A 345 4- [3- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2methylisoquinolin-1-one A 346 X- [4- (2,4-difluorophenoxy) -6- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-2yl] ethanesulfonamide V 347 X- [2- (2,4-difluorophenoxy) -6- (1,5dimethyl-6-oxopyridin-3 yl) pyrimidin-4yl] ethanesulfonamide V 348 4- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one A A A V 349 6-methyl-4- (3-methylsulfonyl-5 phenylmethoxyphenyl) furo [2,3с] pyrid IN-7-OH A A A WITH 350 4- [3- (cyclopropylmethoxy) -5methylsulfonylphenyl] -6methylfuro [2,3-c] pyridin-7-one A 351 1-methyl-5- (2-methylsulfonyl-5propylpyrimidin-4-yl) pyridin2-one 352 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) - 1-methylpyridin-2-one

- 399 038715

353 3-chloro-1 -methyl-5 - (2methyl sulfonyl- 5 propylpyrimidin-4-yl) pyridine- 2nd 354 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) - 3-chloro-1-methylpyridin-2-one 355 3-methoxy-1-methyl-5- (2methyl sulfonyl-5 - propylpyrimidin-4-yl) pyridine- 2nd 356 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) - 3-methoxy-1-methylpyrid in-2-one 357 N- [4- (l -methyl-6-oxopyr-idin-3 yl) -5-propylpyrimidin-2yl] ethanesulfonamide A 358 X- [5-butyl-4- (1-methyl-6oxopyr-idin-3-yl) pyrimid in-2yl] ethanesulfonamide A 359 M- [4- (5-chloro-1-methyl-6oxopyr-idin-3-yl) -5 propylpyrimidin-2yl] ethanesulfonamide A 360 X- [5-butyl-4- (5-chloro-1-methyl-6oxopyr-idin-3-yl) pyrimid in-2yl] ethanesulfonamide A 361 X- [4- (5-methoxy-1-methyl-6oxopyr-idin-3-yl) -5 propylpyrimidin-2yl] ethanesulfonamide A

- 400 038715

362 X- [5-butyl-4- (5-methoxy-1-methyl6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide A 363 B1- [5-butyl-4- (1,5-dimethyl-6oxopyr-idin-3-yl) pyrimid yn-2yl] methanesulfonamide A 364 4- [2- (cyclopropylmethoxy) -5propan-2-ylsulfonylphenyl] -2- methylisoquinolin-1-one A 365 8- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -6-methyl-4Hpyrido [4,3-b] [1,4] oxazine-3,5-dione A A A WITH 366 8- [2- (cyclopropylmethoxy) -5- ethylsulfonylphenyl] -6-methyl-3,4-dihydro-2H-pyrido [4,3 - b] [1,4] oxazin-5-one A 367 X- [4- (2,4-difluorophenoxy) -3- (7methyl-8-oxoimidazo [1,5а] pyrazine-5- yl) phenyl] methanesulfonamide A A A WITH 368 5- [2- (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -7- methylimidazo [1,5-a] pyrazin-8-one A A A v 369 5- [2- (2,4-difluorophenoxy) -5 (ethyl sulfonyl methyl) phenyl] -7methylimidazo [1,5-a] pyrazin-8-one A V A With 370 7-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] imide azo [1,5а] pyrazin-8-one A V V With

- 401 038715

371 5- [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -7methylimidazo [1,5-a] pyrazin-8-one V V V WITH 372 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -7methylimidazo [1,5-a] pyrazin-8-one A A A WITH 373 5- [2- (4,4-difluorocyclohexyl) oxy- 5-ethylsulfonylphenyl] -7methylimidazo [1,5-a] pyrazin-8-one A V A WITH 374 5 - (2-cyclopentyloxy-5 ethylsulfonylphenyl) -7methylimidazo [1,5-a] pyrazin-8-one A A A With 375 5 - [2- (cyclopropylmethylamino) -5 ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazin-8-one A 376 5- [2- (2,4-difluorophenoxy) -5ethyl sulfonyl phenyl] -7methylimidazo [1,5-a] pyrazin-8-one A V A With 377 7- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -5 methylfuro [3,2-c] pyridin-4-one A A A With 378 7- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -5 - methylfuro [3,2-c] pyridin-4-one A A A v 379 H- [4- (2,4-difluorophenoxy) -3- (5methyl-4-oxofuro [3,2-c] pyridin7-yl) phenyl] ethanesulfonamide A A A With 380 N- [4- (2,4-difluorophenoxy) -3- (5methyl-4-oxofuro [3,2-c] pyridin7-yl) phenyl] methanesulfonamide A A A With

- 402 038715

381 4- (cyclopropylmethoxy) -5 - (1 methyl-6-oxopyr-idin-3 -yl) -1 (methylsulfonylmethyl) pyridine-2- he A WITH V WITH 382 5- [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyridin-3-yl] -1,3dimethylpyridin-2-one A V A WITH 383 4- [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyr-idin-3-yl] -7-fluoro-2methylisoquinolin-1-one A V A WITH 384 4- [4- (cyclopropylmethoxy) -1 (methylsulfonylmethyl) -boxopyr-idin-3-yl] -2methylisoquinolin-1-one A v A With 385 5- [4- (2,4-difluorophenoxy) -1 (methylsulfonylmethyl) -boxopyridin-3-yl] -1,3dimethylpyridin-2-one A A A With 386 4- (2,4-difluorophenoxy) -5- (1-methyl6-oxopyridin-3-yl) -1 - (methylsulfonylmethyl) pyridine-2one A V V With 387 4- [4- (2,4-difluorophenoxy) -1 (methylsulfonylmethyl) -boxopyr idin-3-yl] -2methylisoquinolin-1-one A A A With 388 5 - (2-but-2-inoxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one A A A With

-403 038715

389 5 - (2-but-2-inoxy-5 ethylsulfonylphenyl) -3 -methoxy- 1-methylpyridin-2-one A V A WITH 390 5 - (5-ethylsulfonyl-2-pent-2inoxyphenyl) -3-methoxy-1 methylpyridin-2-one A 391 5 - [2- (3-cyclopropylprop-2inoxy) -5-ethylsulfonylphenyl] -3 methoxy-1-methylpyridin-2-one A V A WITH 392 5- [2- (2,4-difluorophenoxy) -5ethylsulfonylphenyl] -1 -methyl-3 (trifluoromethyl) pyridin-2-one V 393 4- [2- (cyclopropylmethoxy) -5propan-2-ylsulfonylphenyl] -6methoxy-2-methylisoquinolin-1-one A 394 5- [2- (cyclopropylmethoxy) -5propan-2-ylsulfonylphenyl] -1,3dimethylpyridin-2-one A 395 N- [3 - (1,5-d imethyl-6-oxopyridine- 3-yl) -5- phenylmethoxyphenyl] ethanesulfone Ministry of Foreign Affairs A 396 5- [2- (2,4-difluoroanilino) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A WITH 397 5- [2 - [(4.4- difluorocyclohexyl) amino] -5 ethylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A With 398 5- [2- (2,4-difluoroanilino) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A V A With

-404038715

399 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -3-methoxy- 1-methylpyridin-2-one A A A WITH 400 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -3 methoxy-1-methylpyridin-2-one A A A WITH 401 5- [2- (4-hydroxycyclohexyl) oxy5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A V A WITH 402 X- [4- (2,4-difluorophenoxy) -3 - (1 methyl-5-methylsulfanyl-6oxopyr-idin-3 yl) phenyl] ethanesulfonamide A A A With 403 5- [2- (cis-4- aminocyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A 404 5- [2- (trans-4aminocyclohexyl) oxy-5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A WITH A With 405 1,3-d imethyl-5 - [5 -methyl sul lf onyl2- (3,3,3- trifluoropropoxy) phenyl] pyridin2-one A 406 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 (2-hydroxyethyl) -3-methylpyridine- 2nd A

-405 038715

407 5- [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -1- (2hydroxyethyl) -3 - methylpyr idin-2 - he V 408 5 - [2- (cyclopropylmethylamino) -5 ethylsulfonylphenyl] -1 -methyl-3 (methylamino) pyridin-2-one A 409 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1 -methyl-3 (methylamino) pyridin-2-one A 410 M- [4- (2,4-difluorophenoxy) -3 - [1 methyl-5- (methylamino) -6oxopyridin-3yl] phenyl] ethanesulfonamide A 411 5- [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -1,3dimethylpyridin-2-one A 412 X- [4- (2,4-difluorophenoxy) -3 - [1 methyl-5- (methylamino) -6oxopyridin-3 - yl] phenyl] methanesulfonamide A 413 5- [2 - [(4.4- difluorocyclohexyl) amino] -5 methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A 414 5 - [2- (cyclopropylmethylamino) -5 ethylsulfonylphenyl] -3-methoxy- 1-methylpyridin-2-one A 415 5- [2- (4,4-difluorocyclohexyl) oxy5-methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A A A WITH

- 406 038715

416 5- [2- (cyclopentylamino) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A WITH 417 5- [2- (cyclopentylamino) -5methyl sulfonyl phenyl] -1,3 dimethylpyridin-2-one A A A WITH 418 3-chloro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he A V A With 419 5 - (2-cycle opentiloxy-5 methylsulfonylphenyl) -1,3dimethylpyridin-2-one A V A With 420 1,3-d imethyl-5 - [5 -methyl sul lf onyl2- (oxan-4-yloxy) phenyl] pyridin2-one A v A With 421 3-fluoro-1 - methyl- 5 - [5 (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he A 422 5 - [2- (cyclopropylmethylamino) -5 methylsulfonylphenyl] -1,4dimethylpyridin-2-one V 423 5 - [2- (cyclopropylmethylamino) -5 ethylsulfonylphenyl] -1,4dimethylpyridin-2-one V 424 N- [4- (l -methyl-6-oxopyr-idin-3 yl) -5-phenylthiophen-2yl] ethanesulfonamide WITH 425 1,3-d imethyl-5 - [5 -methyl sul lf onyl- 2- (oxolan-3- ylamino) phenyl] pyridin-2-one A

- 407 038715

426 1,3-d imethyl-5 - [5 -methyl sul lf onyl- 2- (oxolan-3- yloxy) phenyl] pyridin-2-one A V V WITH 427 1,3-d imethyl-5 - [5 - (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] pyridine-2- he A A A WITH 428 5 - [2- (cyclopropylmethylamino) -5 methylsulfonylphenyl] -1-ethyl-3 methylpyridin-2-one A V V With 429 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 ethyl-3-methylpyridin-2-one A A A With 430 N- [3 - (1,5-d imethyl-6-oxopyridin3-yl) -4- (trans-4- hydroxycyclohexyl) oxyphenyl] etansu lf onamide A A A With 431 N- [3 - (1,5-d imethyl-6-oxopyridin3-yl) -4- (cis-4- hydroxycyclohexyl) oxyphenyl] etansu lf onamide A V A With 432 N- [4- (l -methyl-6-oxopyridin-3 yl) - 5 - (2-methylphenyl) thiophene-2yl] ethanesulfonamide WITH 433 N- [3 - (1,5-d-immethyl-6-oκcopyridin3-yl) -4- (tranc-4- hydroxycyclohexyl) oxyphenyl] m ethanesulfonamide A A A With 434 N- [3 - (1,5-d-immethyl-6-oκcopyridin3-yl) -4- (cis-4- hydroxycyclohexyl) oxyphenyl] m ethanesulfonamide A V V With

- 408 038715

435 M- [5- (2-ethylphenyl) -4- (1-methyl-6oxopyr-idin-3-yl) thiophene-2yl] ethanesulfonamide WITH 436 1,3-d imethyl-5 - [5 -methyl sul lf onyl- 2- (oxane-4- ylamino) phenyl] pyridin-2-one A V A WITH 437 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -3 fluoro-1-methylpyridin-2-one A A A WITH 438 5 - [2- (cyclopropylmethylamino) -5 methylsulfonylphenyl] -3- (dimethylamino) -1-methylpyridin2-one A A A WITH 439 N- [3 - (1,5-d imethyl-6-oxopyridine- 3 -yl) -4- (oxane-4- yloxy) phenyl] methanesulfonamide A A A With 440 5 - [2- (cyclopropylmethylamino) -5 ethylsulfonylphenyl] -3- (dimethylamino) -1-methylpyridin2-one A A A With 441 N- [3 - (1,5-d imethyl-6-oxopyridin3-yl) -4- (oxane-4yloxy) phenyl] ethanesulfonamide A A A With 442 X- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A With 443 X- [4- (2,4-difluorophenoxy) -3- (5methoxy-1-methyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide A A A With 444 N- [3 - (1,5-d imethyl-6-oxopyridin3-yl) -4- (oxolan-3 yloxy) phenyl] methanesulfonamide A A A With

- 409 038715

445 N- [3 - (1,5-dimethyl-6-oxopyridin3-yl) -4- (oxolan-3 yloxy) phenyl] ethanesulfonamide A A A WITH 446 N- [3 - (1,5-dimethyl-6-oxopyridin3-yl) -4- (oxane-3 yloxy) phenyl] methanesulfonamide A A A WITH 447 L [4- (4,4-difluorocyclohexyl) oxy3- (1,5-dimethyl-6-oxopyridin-3 yl) phenyl] methanesulfonamide A A A WITH 448 N- [3 - (1,5-d imethyl-6-oxopyridin3-yl) -4- (oxane-3 yloxy) phenyl] ethanesulfonamide A A A With 449 L [4- (4,4-difluorocyclohexyl) oxy3- (1,5-dimethyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide A A A With 450 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A With 451 L [4- (2,4-difluorophenoxy) -3- (5-hydroxy-1-methyl-6-oxopyridin3-yl) phenyl] ethanesulfonamide A ND A With 452 4- (cyclopropylmethylamino) -3 (1,5-d-immethyl-6-oxopyrid in-3 yl) benzenesulfonamide V ND V With 453 4- (cyclopropylmethylamino) -3 - (1 methyl-6-oxopyridin-3 yl) benzenesulfonamide WITH WITH WITH With 454 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1,4dimethylpyridin-2-one A A A With

- 410 038715

455 5- (2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1,3dimethylpyridin-2-one A A A WITH 456 5- (2-ethoxy-5-ethylsulfonylphenyl) -1 - ( ² H ₃ ) methyl-4-methylpyridin-2-one A 457 5- [2- (cyclopropylmethoxy) -5ethyl sulfonyl phenyl] -1 ( ² H ₃ ) methyl-4-methylpyridin-2-one A A 458 5- (2-ethoxy-5- ethylsulfonylphenyl) -1,4dimethylpyridin-2-one A 459 5 - [2- (cyclobutylmethoxy) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A WITH 460 5 - [2- (cyclobutylmethoxy) -5 methylsulfonylphenyl] -1 methylpyridin-2-one A 461 5 - (5-ethylsulfonyl-2methoxyphenyl) -3-hydroxy-1 methylpyridin-2-one V 462 5 - [2- (cyclopropylmethylamino) -5 methylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A WITH 463 X- [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyr idin-3 - yl] phenyl] methanesulfonamide A A A With 464 X- [4- (2,4-difluorophenoxy) -3- [5 (dimethylamino) -1 -methyl-6oxopyridin-3yl] phenyl] ethanesulfonamide A A A With

-411 038715

465 5 - [2- (cyclopropylmethylamino) -5 ethylsulfonylphenyl] -1,3dimethylpyridin-2-one A A A WITH 466 5- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -1,4dimethylpyridin-2-one A A A WITH 467 N- [3- (5-hydroxy-1-methyl-6oxopyr idin-3 - yl) phenyl] methanesulfonamide V WITH WITH WITH 468 5 - [2- (cyclopropylmethylamino) -5 methyl sulfonyl phenyl] -1 methylpyridin-2-one A WITH V With 469 3- (dimethylamino) -5- (2-ethoxy-5ethylsulfonylphenyl) -1 methylpyridin-2-one A A A With 470 5- [2- (2,4-difluorophenoxy) -5 (methylsulfonylmethyl) phenyl] -1 methylpyridin-2-one A A A v 471 N- [3- (1-methyl-6-oxo-5 phenylmethoxypyridin-3 yl) phenyl] methanesulfonamide WITH 472 X- [4- (2,4-difluorophenoxy) -3- (1,5dimethyl-6-oxopyridin-3 yl) phenyl] ethanesulfonamide A A A With 473 5 - [2- (cyclopropylmethylamino) -5 ethyl sulfonyl phenyl] -1 methylpyridin-2-one A V A With 474 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3 (dimethylamino) -1 -methylpyridine- 2nd A A A With

- 412 038715

475 5- [4-fluoro-2-methoxy-5 (methylsulfonylmethyl) phenyl] -1 - methylpyridin-2-one V 476 5- [2- (cyclopropylmethoxy) -5methylsulphonylphenyl] -1,3dimethylpyridin-2-one A V A WITH 477 5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -1,4dimethylpyridin-2-one A v A WITH 478 N- [6- [3- (methanesulfonamido) phenyl] -4methyl-3-oxopyrazine-2- sludge] acetamide WITH 479 X- [3- (1,4-dimethyl-6oxopyridazin-3 yl) phenyl] ethanesulfonamide WITH 480 N- [3- (l, 5-dimethyl-6oxopyridazin-3 yl) phenyl] ethanesulfonamide V 481 N- [5- [3- (methanesulfonamido) phenyl] -1 methyl-2-oxopyr idin-3 - sludge] propanamide With 482 N- [5- [3- (methanesulfonamido) phenyl] -1 methyl-2-oxopyr idin-3 - sludge] acetamide With 483 1-cyclobutyl-5- [2 (cyclopropylmethoxy) -5methylsulphonylphenyl] -3 methylpyridin-2-one A

- 413 038715

484 M- [3- (1-cyclobutyl-5-methyl-6oxopyr-idin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide A 485 1-benzyl-5- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -3methylpyridin-2-one V 486 1,3-dimethyl-5 - (2-methyl-5 methylsulfonyl-2,3-dihydro-1 benzofuran-7-yl) pyridin-2-one V WITH V WITH 487 4- [5- (ethylsulfonylmethyl) -2 (2,2,2-trifluoroethoxy) phenyl] -2methylisoquinolin-1-one A A A WITH 488 2-methyl-4- [5- (methylsulfonylmethyl) -2- (2,2,2trifluoroethoxy) phenyl] isoquinolin1-one A A A WITH 489 1,3-dimethyl-5 - (7-methyl sulfonyl- 2,3-dihydro-1,4-benzodioxin-5 yl) pyridin-2-one V 490 N - [2-ethyl- 8 - (2-methyl-1 oxoisoquinolin-4-yl) -3,4-dihydro2H-chromene-6yl] methanesulfonamide A 491 N - [2-ethyl- 8 - (2-methyl-1 oxoisoquinolin-4-yl) -3,4-dihydro2H-chromen-6-yl] ethanesulfonamide A 492 K- [8- (1,5-dimethyl-6-oxopyridin3-yl) -2-ethyl-3,4-dihydro-2Hchromen-6-yl] ethanesulfonamide A

- 414 038715

493 4- (2-cyclopropyl-5methylsulfonyl-2,3-dihydro-1 benzofuran-7-yl) -2methylisoquinolin-1-one A 494 4- (2-ethyl-5-methyl sulfonyl-2,3 dihydro-1-benzofuran-7-yl) -2methylisoquinolin-1-one A V 495 N- [7- (1,5-d-immethyl-6-oxopyridin3-yl) -2-propyl-2,3-dihydro-1 benzofuran-5-yl] ethanesul phonamide A 496 X- [2-cyclopropyl-7- (1,5-dimethyl6-oxopyr-idin-3-yl) -2,3-dihydro1-benzofuran-5yl] ethanesulfonamide A A 497 4- [3 - (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -2methylisoquinolin-1-one A V V With 498 5 - [3 - (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -1,3- dimethylpyridin-2-one A WITH v With 499 4- [3 - (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -2methylisoquinolin-1-one A 500 5 - [3 - (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -1,3- dimethylpyridin-2-one A

- 415 038715

501 4- [2- (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -2methylisoquinolin-1-one A V V WITH 502 5 - [2- (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -1,3- dimethylpyridin-2-one A 503 4- [2- (methoxymethyl) -7methylsulfonyl-2,3-dihydro-1,4benzodioxin-5 -yl] -2methylisoquinolin-1-one A 504 4- [2- (cyclopropylmethoxy) -5methylsulfonylphenyl] -2-methyl6,7-dihydro-5H- cyclopenta [c] pyridin-1-one A A 505 4- [2- (cyclopropylmethoxy) -5ethylsulfonylphenyl] -2-methyl-6,7 dihydro-5H- cyclopenta [c] pyridin-1-one A 506 M- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-6,7-dihydro-5Hcyclopenta [c] pyridin-4yl) phenyl] methanesulfonamide A 507 X- [4- (2,4-difluorophenoxy) -3- (2methyl-1-oxo-6,7-dihydro-5Hcyclopenta [c] pyridin-4yl) phenyl] ethanesulfonamide A 508 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) 3-methyl-1-propan-2-ylpyridin-2one A

-416038715

509 T4- [5- (2,4-difluorophenoxy) -4- (5methyl-6-oxo-1-propan-2 ylpyr-idin-3-yl) pyrimidin-2yl] ethanesulfonamide A A 510 5- [5- (2,4-difluorophenoxy) -2methylsulfonylpyrimidin-4-yl] 3-methyl-1-propan-2-ylpyrid yn-2- he V 511 N- [5-butyl-4- (5-methyl-6-oxo-1propan-2-ylpyr idin-3 yl) pyrimidin-2yl] ethanesulfonamide A A 512 N- [5-butyl-4- (1-methyl-6-oxo-5propan-2-ylpyr idin-3 yl) pyrimidin-2yl] ethanesulfonamide A A 513 5- (5-butyl-2- methylsulfonylpyrimidin-4-yl) 1-methyl-3-propan-2-ylpyridin-2one A 514 H- [5- (2,4-difluorophenoxy) -4- (1methyl-6-oxo-5-propane-2ylpyr-idin-3-yl) pyrimidin-2yl] ethanesulfonamide A

Note: IC ₅₀ values are in the following ranges:

A: <0.5 μM;

B:> 0.5 to <5.0 μM;

C:> 5.0 μM.

Example 3. In vivo xenographic study - antitumor efficacy in xenographic models of NUT carcinoma (NMC).

In this study, xenographic mouse models were used. Cohorts of matched tumor-bearing mice were randomly selected for treatment with a test compound or vehicle administered by daily intraperitoneal injection. Before randomization and after 4 days of therapy, mice were evaluated by positron emission tomography using a fluorodeoxyglucose radiopharmaceutical ( ¹⁸ F-fluorodeoxyglucose (FDG) -PET imaging). Tumor volume was also measured as well as the numerical indicators of toxicity or weight loss. Tumors were removed and sectioned and examined by immunohistochemistry for BRD4-NUT oncoprotein, cell proliferation, keratin expression, nuclear Ki67 and TUNEL staining (terminal deoxyuridine end-labeling). Pairwise matched individuals from treated and untreated mice were prepared for surgery and analyzed using standard protocols and commercially available software (ie, ImageScopt; Aperio Technologies).

Example 4. In vivo xenographic study - antitumor efficacy in xenographic models of MCF-7 breast cancer cells.

Nu / nu mice were subcutaneously implanted with sustained release beads containing 0.72 mg of 17-β estradiol. MCF-7 cells were grown in RPMI medium containing 10% FBS at 5% CO2 and 37 ° C. Cells were pelleted and resuspended in 50% RPMI (serum free) and 50% Matrigel at 1 x 10 ⁷ cells / ml. MCF-7 cells were injected subcutaneously in mice (100 μl / animal) in the right flank 2-3 days after implantation of the beads, and tumor volume (length x width 2/2) was monitored twice a week. When the tumors reached an average volume of ~ 200 mm ³ , animals were selected at random and treatment was started. The animals were treated with the test compound or vehicle daily for 4 weeks. Tumor volume and body weight were monitored every two weeks throughout the study. At the end of the treatment period, plasma and tumor samples were taken for pharmacokinetic and pharmacodynamic analyzes, respectively.

- 417 038715

Example 5. Xenographic study in vivo - antitumor efficacy in a xenographic model of Raji cells of human Burkitt's lymphoma.

Methodology: Female SCID (Severe Combined Immunodeficiency) CB17 mice (6-8 weeks old, Charles River Laboratories) were inoculated subcutaneously in the right flank area of Raji cells (3.5x10 ⁶ cells / mouse) and tumors were allowed to grow to approximately 150 mm ³ . Mice were then randomly assigned to cohorts (N = 8) for therapy and administered orally once a day with vehicle control or test compound for 21 days. The test compound was administered as a suspension in 1% Tween 80, 40% PEG400 and either: 59% 0.5% HPMC or 9% DMSO + 50% 0.5% HPMC. The length and width of the tumor was measured in millimeters three times a week. Tumor volumes were calculated using the formula V = LxWxW / 2. Tumor growth inhibition (TGI) was calculated using the formula:

TGI = 100- (mean tumor volume of the therapeutic group / mean tumor volume of the control group receiving vehicle) x 100.

TGI measurements were carried out until the tumor volume in the control group reached 3,000 mm ³ . Statistical analysis was performed using the two-tailed paired Student's test. P values <0.05 were considered statistically significant.

Preliminary results: from table. 1, seven compounds were selected and administered at a dose range of 5 mg / kg to 50 mg / kg. TGI was determined in the range from 42 to 80%. Results are preliminary and do not reflect optimized dosing regimens.

III. Obtaining pharmaceutical dosage forms.

Example. Tablet for oral administration.

A tablet is prepared by mixing 48% by weight of a compound of formula (I) or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose and 2% by weight of magnesium stearate.

The tablets are obtained by direct compression. The total weight of the compressed tablets is maintained at 250-500 mg.

Claims (55)

CLAIM 1. The compound of formula (II) or a pharmaceutically acceptable salt thereof r ^a X5 ^ X6 R ⁶ R ² ° formula (II) where R ² is a C1-C4 alkyl optionally substituted with an OH or F group, 3-4 membered cycloalkyl, methoxy, -SO2R ⁵ , oxetanyl, phenyl or 5-membered heteroaryl containing 1-2 heteroatoms selected from O or N; 3-4 membered cycloalkyl, CH2D, CHD2, or CD3; X6 is CH or N; X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH; R ⁵ is hydrogen, halogen, —OH, —CN, —OR ⁶¹ , —NHR ⁶¹ , —N (R ⁶¹ ) ₂ , C ₁ -C ₄ alkyl, where each R ⁶¹ is phenyl optionally substituted with halogen; R ⁶ is hydrogen, halogen, -OH, -CN, -CD3, C ₁ -C ₄ -alkyl optionally substituted with halogen or ethynyl, cyclopropyl, amino, (C ₁ -C ₂ -alkyl) amino, di (C ₁ -C ₂ -alkyl) amino, cyclopropyl (C ₁ -C ₄ -alkyl) amino, C ₁ -C ₂ -alkoxy optionally substituted with halogen, -S-methyl, 3-4 membered cycloalkyl-C ₁ -C ₄ - alkoxy, pyrrolidinyl, phenyl C ₁ -C ₄ alkyloxy, 5-membered heteroaryloxy containing 2 heteroatoms selected from N, phenoxy, C ₂ -C ₄ alkynyloxy, or —N (H) COC ₁ -C ₄ alkyl; R ^a represents ^{X2 R} ; X2 is N or CR ¹² , where R ¹² is hydrogen; R ¹³ represents -YZ; Y is selected from a bond, —CH ₂ - or —CH (C ₁ -C ₄ -alkyl) -; Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -COR ²¹ , -OC (O) N (R ²² ) 2, -OSO ₂ N (R ²² ) 2 or —N (R ²² ) SO3R ²¹ ; X3 is N or CR ¹⁴ , where R ¹⁴ is hydrogen, halogen, —CN, C ₁ -C ₄ alkyl, or methoxy; X4 is N or CR ¹⁵ , where R ¹⁵ is hydrogen, halogen, —CN, C ₁ -C ₄ -alkyl, C ₁ -C ₂ -alkoxy optionally substituted with halogen or ethynyl, phenoxy optionally substituted with halogen, phenyl- C ₁ -C ₄ alkyloxy optionally substituted with methyl, halogen, CN or methoxy, cyclopropyl C ₁ -C ₄ alkyloxy, 4-membered heterocyclyloxy containing 1 heteroatom, selected - 418 038715 from O, a 6-membered _{heteroaryl-C1-C4} alkyloxy, containing 1 heteroatom selected from N, or butynyloxy; R ¹⁶ is hydrogen, halogen, —N (H) COX or —WX, where W is a bond, —O—, —S—, or —NH— and X is selected from C ₁ -C ₄ alkyl optionally substituted with halogen , phenyl, phenyl-C ₁ -C ₄ -alkyl, optionally substituted with a methoxy group, 5-6-membered cycloalkyl, optionally substituted with halogen or OH, 3-4-membered cycloalkyl-C ₁ -C ₄ -alkyl, C ₄ -C ₅ -alkynyl optionally substituted with cyclopropyl, 3-4 membered cycloalkyl-C ₂ -C ₄ alkynyl or 5-6 membered heterocyclyl containing 1 heteroatom selected from O; each R ^{21 is} independently selected from C ₁ -C ₄ alkyl; and each R ^{22 is} independently selected from hydrogen, C ₁ -C ₄ alkyl, or oxetanyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof represented by formula (IIa) r ^a Hb N _x R ⁶ R ^{2 0} formula (Pa) where R ² is CH3, CH2CF3, CH2F, CHF2, CF3, CH2D, CHD2 or CD3; X6 is CH or N; X5 is CR ⁵ or N; with the proviso that if X6 is N then X5 is CR ⁵ and if X5 is N then X6 is CH; R ⁵ is hydrogen; R ⁶ is hydrogen; R ¹ % X4. R ^a represents ^{X2 R} L X2 is N or CR ¹² , where R ¹² is hydrogen; R ¹³ represents -YZ; Y is selected from a bond or -CH2-; Z is selected from -SO2R ²¹ , -N (R ²² ) SO2R ²¹ , -SO2N (R ²² ) 2, -N (R ²² ) SO2N (R ²² ) 2, -CON (R ²² ) 2, -N (R ²² ) CO2R ²¹ , -N (R ²² ) CON (R ²² ) 2, -N (R ²² ) COR ²¹ , -OC (O) N (R ²² ) 2, -OSO2N (R ²² ) 2 or -N (R ²² ) SO3R ²¹ ; X3 is N or CR ¹⁴ where R ¹⁴ is hydrogen; X4 is N or CR ¹⁵ where R ¹⁵ is hydrogen; R ¹⁶ is hydrogen, halogen or -WX, where W is a bond, -O-, -S-, or —NH— and X is selected from C ₁ -C ₄ alkyl or 3-membered cycloalkyl C ₁ -C ₄ alkyl; each R ^{21 is} independently selected from C ₁ -C ₄ alkyl; and each R ^{22 is} independently selected from hydrogen or C ₁ -C ₄ alkyl; and with the proviso that when X6 is N, then R ⁵ and R ⁶ are not hydrogen. 3. A compound according to any one of claims 1, 2, wherein X6 is CH. 4. A compound according to any one of claims 1, 2, wherein X6 is N. 5. A compound according to any one of claims 1-4, wherein X5 is CR ⁵ . 6. A compound according to any one of claims 1-4, wherein X5 is N. 7. A compound according to any one of claims 1 and 3, 4, wherein R ⁵ is hydrogen, halogen or C1-C4 alkyl. 8. A compound according to any one of claims 1 and 3-7, wherein R ⁶ is hydrogen, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₂ alkoxy. 9. A compound according to any one of claims 1-8, wherein Y is a bond. 10. A compound according to any one of claims 1-8, wherein Y is —CH2—. 11. A compound according to any one of claims 1-10, wherein Z is —SO2R ²¹ . 12. A compound according to any one of claims 1-10, wherein Z is —N (R ²² ) SO ₂ R ²¹ . 13. A compound according to any one of claims 1-10, wherein Z is —SO ₂ N (R ²² ) ₂ . 14. A compound according to any one of claims 1-10, wherein Z is —N (R ²² ) SO2N (R ²² ) 2. 15. A compound according to any one of claims 1-10, wherein Z is —CON (R ²² ) ₂ . 16. A compound according to any one of claims 1-10, wherein Z is —N (R ²² ) CO ₂ R ²¹ . 17. A compound according to any one of claims 1-10, wherein Z is —N (R ²² ) CON (R ²² ) ₂ . 18. A compound according to any one of claims 1-12 and 16, wherein R ²¹ is C ₁ -C ₄ alkyl. 19. A compound according to any one of claims 1-10 and 12-18, wherein R ²² is C ₁ -C ₄ alkyl. 20. A compound according to any one of claims 1 and 3-19, wherein R ¹⁴ is hydrogen, halogen or C1-C4 alkyl. 21. A compound according to any one of claims 1-20, wherein X4 is CR ¹⁵ . 22. A compound according to any one of claims 1-19, wherein X3 is N. - 419 038715 23. A compound according to any one of claims 1 to 22, wherein X2 is N. 24. A compound according to any one of claims 1-19, wherein X2 and X3 are N and X4 is S-N. 25. A compound according to any one of claims 1-24, wherein W is —O—. 26. A compound according to any one of claims 1-24, wherein W is —NH—. 27. A compound according to any one of claims 1-24, wherein W is a bond. 28. A compound according to any one of claims 1 to 27, wherein X is C ₁ -C 4 alkyl. 29. A compound according to any one of claims 1 and 3-27, wherein X is phenyl. 30. A compound according to any one of claims 1 and 3-27, wherein X is 3-4 membered cycloalkyl-C ₁ -C 4 alkyl. 31. A compound according to any one of claims 1-24, wherein W is —O— and X is Ci — C ₄ alkyl. 32. A compound according to any one of claims 1 and 3-24, wherein W is —O— and X is phenyl. 33. A compound according to any one of claims 1 and 3-24, wherein W is —O— and X is 34 membered cycloalkyl C 1 -C 4 alkyl. 34. A compound according to any one of claims 1-24, wherein W is a bond and X is C1C4 alkyl. 35. A compound according to any one of claims 1 and 3-24, wherein W is a bond and X is phenyl. 36. A compound according to any one of claims 1 and 3-24, wherein W is a bond and X is 3 to 4 membered cycloalkyl C ₁ -C 4 alkyl. 37. A compound according to any one of claims 1 to 36, wherein R ⁶ is CD3. 38. A compound or a pharmaceutically acceptable salt thereof selected from: N- [3- (1,4-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; N- [3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; N- [3- (1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one; N- [4- (2,4-difluorophenoxy) -3- (1,4-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; N- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; N- [4- (2,4-difluorophenoxy) -3- (1,4,5-trimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; 3-amino-1-methyl-5- (3-methylsulfonylphenyl) pyrazin-2-one; 3-amino-5- (3-ethylsulfonylphenyl) -1-methylpyrazin-2-one; N- [5- (6-amino-4-methyl-5-oxopyrazin-2-yl) -2-methoxyphenyl] methanesulfonamide; 3-amino-1-methyl-5- (3-methylsulfonylphenyl) pyridin-2-one; 3-amino-5- (3-ethylsulfonylphenyl) -1-methylpyridin-2-one; N- [5- (5-amino-1-methyl-6-oxopyridin-3-yl) -2-methoxyphenyl] methanesulfonamide; N- [2-methoxy-5- [1-methyl-5- (methylamino) -6-oxopyridin-3-yl] phenyl] methanesulfonamide; N- [5- [5- (ethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide; N- [5- [5- (cyclopropylmethylamino) -1-methyl-6-oxopyridin-3-yl] -2methoxyphenyl] methanesulfonamide; N- [5- [5- (dimethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide; N- [5- [5- (diethylamino) -1-methyl-6-oxopyridin-3-yl] -2-methoxyphenyl] methanesulfonamide; N- [3- (5-amino-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide; 3-amino-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one; 4-ethoxy-3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide; 4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5-methylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one; 6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,4-dimethylpyridazin-3-one; 6- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2,5-dimethylpyridazin-3-one; N- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (trifluoromethyl) pyridin-3yl] phenyl] ethanesulfonamide; N- [4- (2,4-difluorophenoxy) -3- (4-fluoro-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; N- [3- (5-cyclopropyl-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] ethanesulfonamide; N- {4- (2,4-difluorophenoxy) -3- [1 - ⁽² N ₃₎ -methyl-6-oksopiridin-3-yl] phenyl} ethanesulphonamide; 5- [5- (cyclopropylmethoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3-dimethylpyridin-2-one; 5- [5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -3-methoxy-1-methylpyridin2-one; 5- [5- (2,4-difluorophenoxy) -2- (methylsulfonylmethyl) pyrimidin-4-yl] -1,3-dimethylpyridin-2-one; - 420 038715 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1,3-dimethylpyridin-2-one; 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3-methoxy-1-methylpyridin-2-one; K- [5- (cyclopropylmethoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide; K- [5- (cyclopropylmethoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] -Kethylmethanesulfonamide; K- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide; K- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] methanesulfonamide; K- [5- (2,4-difluorophenoxy) -4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2yl] ethanesulfonamide; K- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; [4- (cyclopropylmethoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] sulfamate; K- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] -K-methylmethanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] -K- (oxetane-3yl) methanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1- (cyclopropylmethyl) -3-methylpyridin-2one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (2-methylpropyl) pyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1- (2-methoxyethyl) -3-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (oxetan-3-ylmethyl) pyridin-2one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methyl-1- (1,3-oxazol-4-ylmethyl) pyridin2-one; K- [3- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -4- (2,4 difluorophenoxy) phenyl] ethanesulfonamide; K- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2yl] methanesulfonamide; K- [4- [1- (cyclopropylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2yl] ethanesulfonamide; 1- (cyclopropylmethyl) -5- [4- (2,4-difluorophenoxy) -1- (methylsulfonylmethyl) -6-oxopyridin-3-yl] -3methylpyridin-2-one; 1-cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-methylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (5-fluoro-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; 3-chloro-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-fluoro-1-methylpyridin-2-one; 3-chloro-5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methanesulfonylmethyl) phenyl] -3- ( ² H ₃ ) methyl-1-methyl-1,2-dihydropyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- [5- ( ² H ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyridine-3yl] phenyl] methanesulfonamide; K- [4- (2,4-difluorophenoxy) -3 - [5- ( ² H ₃ ) methyl-1-methyl-6-oxo-1,6-dihydropyridin-3-yl] phenyl] ethane-1 sulfonamide; K- [3- (5-cyclopropyl-1-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide; 3-cyclopropyl-5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (1-methyl-6-oxo-5-pyrrolidin-1-ylpyridin-3yl) phenyl] methanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3-pyrrolidin-1-ylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (5-ethynyl-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-ethynyl-1-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-ethynyl-1-methylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (5-ethynyl-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3- (difluoromethoxy) -1-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3- (2,2,2-trifluoroethoxy) pyridin-2one; K- [3- [5- (difluoromethoxy) -1-methyl-6-oxopyridin-3-yl] -4- (2,4 difluorophenoxy) phenyl] ethanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- [1-methyl-6-oxo-5- (2,2,2-trifluoroethoxy) pyridin-3yl] phenyl] ethanesulfonamide; 3- (difluoromethoxy) -5- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -1-methylpyridin-2- 421 038715 one; 5- [2- (2,4-difluorophenoxy) -5- (ethylsulfonylmethyl) phenyl] -1-methyl-3- (2,2,2trifluoroethoxy) pyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3- (1-methylpyrazol-4yl) oxypyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3- (1-propan-2-ylpyrazol-4yl) oxypyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1-methyl-3-phenoxypyridin-2-one; K- [4- (1-butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidine-2yl] methanesulfonamide; K- [4- (1-butyl-5-methyl-6-oxopyridin-3-yl) -5- (2,4-difluorophenoxy) pyrimidin-2yl] ethanesulfonamide; K- [4- [1- (cyclobutylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2yl] methanesulfonamide; K- [4- [1- (cyclobutylmethyl) -5-methyl-6-oxopyridin-3-yl] -5- (2,4-difluorophenoxy) pyrimidin-2yl] ethanesulfonamide; 5- (5-ethyl-2-methylsulfonylpyrimidin-4-yl) -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1,3-dimethylpyridin-2-one; K- [4- (1,5-dimethyl-6-oxopyridin-3-yl) -5-ethylpyrimidin-2-yl] ethanesulfonamide; K- [4- (1,5-dimethyl-6-oxopyridin-3-yl) -5-propylpyrimidin-2-yl] ethanesulfonamide; K- [5-butyl-4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; 5- (2-ethyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one; 1-methyl-5- (5-methylsulfonyl-2-propylphenyl) pyridin-2-one; 5- [2- (2-cyclopropylethyl) -5-methylsulfonylphenyl] -1-methylpyridin-2-one; 5- (2-butyl-5-methylsulfonylphenyl) -1-methylpyridin-2-one; 5- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- (3-methylsulfonyl-5-phenylmethoxyphenyl) pyridin-2-one; 5- [3- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5- (2-phenylethoxy) phenyl] pyridin-2-one; 5- [3- (2-cyclopropylethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5- (2,2,2-trifluoroethoxy) phenyl] pyridin-2-one; 1,3-dimethyl-5- [3 - [(3-methyloxetan-3-yl) methoxy] -5-methylsulfonylphenyl] pyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5- (pyridin-2-ylmethoxy) phenyl] pyridin-2-one; 5- [3 - [(2,6-dimethylphenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [3 - [(2-chlorophenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [3 - [[2- (difluoromethoxy) phenyl] methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 2 - [[3- (1,5-dimethyl-6-oxopyridin-3-yl) -5-methylsulfonylphenoxy] methyl] benzonitrile; 5- [3 - [(2,4-difluorophenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5 - (1-phenylethoxy) phenyl] pyridin-2-one; 5- [3 - [(2,3-dichlorophenyl) methoxy] -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5- (pyridin-3-ylmethoxy) phenyl] pyridin-2-one; 3 - [[3- (1,5-dimethyl-6-oxopyridin-3-yl) -5-methylsulfonylphenoxy] methyl] benzonitrile; 5- (3-but-2-inoxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [3-methylsulfonyl-5 - (1-phenylethoxy) phenyl] pyridin-2-one; K- [3- (2,4-difluorophenoxy) -5- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; 4- [3 - [(4-methoxyphenyl) methoxy] -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one; 2-methyl-4- (3-methylsulfonyl-5-phenylmethoxyphenyl) isoquinolin-1-one; 4- [3- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -2-methylisoquinolin-1-one; K- [4- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; K- [2- (2,4-difluorophenoxy) -6- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-4-yl] ethanesulfonamide; 1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1-methylpyridin-2-one; 3-chloro-1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-chloro-1-methylpyridin-2-one; 3-methoxy-1-methyl-5- (2-methylsulfonyl-5-propylpyrimidin-4-yl) pyridin-2-one; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-methoxy-1-methylpyridin-2-one; K- [4- (1-methyl-6-oxopyridin-3-yl) -5-propylpyrimidin-2-yl] ethanesulfonamide; K- [5-butyl-4- (1-methyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; K- [4- (5-chloro-1-methyl-6-oxopyridin-3-yl) -5-propylpyrimidin-2-yl] ethanesulfonamide; K- [5-butyl-4- (5-chloro-1-methyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; K- [4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) -5-propylpyrimidin-2-yl] ethanesulfonamide; - 422 038715 K- [5-butyl-4- (5-methoxy-1-methyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; K- [5-butyl-4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] methanesulfonamide; 5- (2-but-2-inoxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one; 5- (2-but-2-inoxy-5-ethylsulfonylphenyl) -3-methoxy-1-methylpyridin-2-one; 5- (5-ethylsulfonyl-2-pent-2-inoxyphenyl) -3-methoxy-1-methylpyridin-2-one; 5- [2- (3-cyclopropylprop-2-inoxy) -5-ethylsulfonylphenyl] -3-methoxy-1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5-ethylsulfonylphenyl] -1-methyl-3- (trifluoromethyl) pyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-propan-2-ylsulfonylphenyl] -1,3-dimethylpyridin-2-one; N- [3- (1,5-dimethyl-6-oxoiridin-3-yl) -5-phenylmethoxyphenyl] ethanesulfonamide; 5- [2- (2,4-difluoroanilino) -5-ethylsulfonylphenyl] -1,3-dimethyliridin-2-one; 5- [2 - [(4,4-difluorocyclohexyl) amino] -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (2,4-difluoroanilino) -5-methylsulfonylphenyl] -1,3-dimethyliridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -3-methoxy-1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -3-methoxy-1-methyliridin-2-one; 5- [2- (4-hydroxycyclohexyl) oxy-5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (1-methyl-5-methylsulfanyl-6-oxopyridin-3yl) phenyl] ethanesulfonamide; 5- [2- (4-aminocyclohexyl) oxy-5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [5-methylsulfonyl-2- (3,3,3-trifluoropropoxy) phenyl] pyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1- (2-hydroxyethyl) -3-methylpyridin-2one; 5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1- (2-hydroxyethyl) -3-methylpyridin-2one; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1-methyl-3- (methylamino) pyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1-methyl-3- (methylamino) pyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- [1-methyl-5- (methylamino) -6-oxopyridin-3yl] phenyl] ethanesulfonamide; 5- [5- (ethylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] -1,3-dimethylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- [1-methyl-5- (methylamino) -6-oxopyridin-3yl] phenyl] methanesulfonamide; 5- [2 - [(4,4-difluorocyclohexyl) amino] -5-methylsulfonylphenyl] -1,3-dimethyliridin-2-one; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -3-methoxy-1-methylpyridin-2-one; 5- [2- (4,4-difluorocyclohexyl) oxy-5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (cyclopentylamino) -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (cyclopentylamino) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 3-chloro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] pyridin-2-one; 5- (2-cyclopentyloxy-5-methylsulfonylphenyl) -1,3-dimethylpyridin-2-one; 1,3-dimethyl-5- [5-methylsulfonyl-2- (oxan-4-yloxy) phenyl] pyridin-2-one; 3-fluoro-1-methyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] pyridin-2-one; 5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -1,4-dimethylpyridin-2-one; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1,4-dimethylpyridin-2-one; 1,3-dimethyl-5- [5-methylsulfonyl-2- (oxolan-3-ylamino) phenyl] pyridin-2-one; 1,3-dimethyl-5- [5-methylsulfonyl-2- (oxolan-3-yloxy) phenyl] pyridin-2-one; 1,3-dimethyl-5- [5- (methylsulfonylmethyl) -2- (2,2,2-trifluoroethoxy) phenyl] iridin-2-one; 5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -1-ethyl-3-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1-ethyl-3-methylpyridin-2-one; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (4-hydroxycyclohexyl) oxyphenyl] ethanesulfonamide; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (4-hydroxycyclohexyl) oxyphenyl] methanesulfonamide; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (4-hydroxycyclohexyl) oxyphenyl] methanesulfonamide; 1,3-dimethyl-5- [5-methylsulfonyl-2- (oxane-4-ylamino) phenyl] pyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -3-fluoro-1-methylpyridin-2-one; 5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -3- (dimethylamino) -1-methylpyridin-2one; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (oxane-4-yloxy) phenyl] methanesulfonamide; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -3- (dimethylamino) -1-methylpyridin-2-one; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (oxane-4-yloxy) phenyl] ethanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- (5-methoxy-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- (5-methoxy-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (oxolan-3-yloxy) phenyl] methanesulfonamide; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (oxolan-3-yloxy) phenyl] ethanesulfonamide; K- [3- (1,5-dimethyl-6-oxopyridin-3-yl) -4- (oxan-3-yloxy) phenyl] methanesulfonamide; K- [4- (4,4-difluorocyclohexyl) oxy-3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; - 423 038715 N- [3- (1,5-dimethyl-6-oxonyridin-3-yl) -4- (oxane-3-yloxy) phenyl] ethanesulfonamide; K- [4- (4,4-difluorocyclohexyl) oxy-3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- (5-hydroxy-1-methyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; 4- (cyclopropylmethylamino) -3- (1,5-dimethyl-6-oxopyridin-3-yl) benzenesulfonamide; 4- (cyclopropylmethylamino) -3- (1-methyl-6-oxopyridin-3-yl) benzenesulfonamide; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1,4-dimethylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1,3-dimethylpyridin-2-one; 5- (2-ethoxy-5-ethylsulfonylphenyl) -1- ( ² H ₃ ) methyl-4-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1- ⁽² N ₃₎ methyl-4-methylpyridin-2-one; 5- (2-ethoxy-5-ethylsulfonylphenyl) -1,4-dimethylpyridin-2-one; 5- [2- (cyclobutylmethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (cyclobutylmethoxy) -5-methylsulfonylphenyl] -1-methylpyridin-2-one; 5- (5-ethylsulfonyl-2-methoxyphenyl) -3-hydroxy-1-methylpyridin-2-one; 5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; K- [4- (2,4-difluorophenoxy) -3- [5- (dimethylamino) -1-methyl-6-oxopyridin-3yl] phenyl] methanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- [5- (dimethylamino) -1-methyl-6-oxopyridin-3yl] phenyl] ethanesulfonamide; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-ethylsulfonylphenyl] -1,4-dimethylpyridin-2-one; K- [3- (5-hydroxy-1-methyl-6-oxopyridin-3-yl) phenyl] methanesulfonamide; 5- [2- (cyclopropylmethylamino) -5-methylsulfonylphenyl] -1-methylpyridin-2-one; 3- (dimethylamino) -5- (2-ethoxy-5-ethylsulfonylphenyl) -1-methylpyridin-2-one; 5- [2- (2,4-difluorophenoxy) -5- (methylsulfonylmethyl) phenyl] -1-methylpyridin-2-one; K- [3- (1-methyl-6-oxo-5-phenylmethoxypyridin-3-yl) phenyl] methanesulfonamide; K- [4- (2,4-difluorophenoxy) -3- (1,5-dimethyl-6-oxopyridin-3-yl) phenyl] ethanesulfonamide; 5- [2- (cyclopropylmethylamino) -5-ethylsulfonylphenyl] -1-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3- (dimethylamino) -1-methylpyridin-2-one; 5- [4-fluoro-2-methoxy-5- (methylsulfonylmethyl) phenyl] -1-methylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1,3-dimethylpyridin-2-one; 5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -1,4-dimethylpyridin-2-one; K- [6- [3- (methanesulfonamido) phenyl] -4-methyl-3-oxopyrazin-2-yl] acetamide; K- [3- (1,4-dimethyl-6-oxopyridazin-3-yl) phenyl] ethanesulfonamide; I- [3- (1,5-dimethyl-6-oxopyridazin-3-yl) phenyl] ethanesulfonamide; K- [5- [3- (methanesulfonamido) phenyl] -1-methyl-2-oxopyridin-3-yl] propanamide; K- [5- [3- (methanesulfonamido) phenyl] -1-methyl-2-oxopyridin-3-yl] acetamide; 1-cyclobutyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin-2-one; K- [3- (1-cyclobutyl-5-methyl-6-oxopyridin-3-yl) -4- (2,4-difluorophenoxy) phenyl] methanesulfonamide; 1-benzyl-5- [2- (cyclopropylmethoxy) -5-methylsulfonylphenyl] -3-methylpyridin-2-one; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -3-methyl-1-propan-2-ylpyridin-2-one; K- [5- (2,4-difluorophenoxy) -4- (5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl) pyrimidin-2yl] ethanesulfonamide; 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -3-methyl-1-propan-2-ylpyridin-2one; K- [5-butyl-4- (5-methyl-6-oxo-1-propan-2-ylpyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; K- [5-butyl-4- (1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide; 5- (5-butyl-2-methylsulfonylpyrimidin-4-yl) -1-methyl-3-propan-2-ylpyridin-2-one; K- [5- (2,4-difluorophenoxy) -4- (1-methyl-6-oxo-5-propan-2-ylpyridin-3-yl) pyrimidin-2yl] ethanesulfonamide or 5- [5- (2,4-difluorophenoxy) -2-methylsulfonylpyrimidin-4-yl] -1-methyl-3-propan-2-ylpyridin-2one. 39. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the compound is K- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidine-2 -yl] methanesulfonamide. 40. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the compound is K- [5- (2,4-difluorophenoxy) -4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidine-2 -yl] ethanesulfonamide. 41. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the compound is K- [5-butyl-4- (1,5-dimethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide. 42. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein the compound is K- [5-butyl-4- (5-chloro-1-methyl-6-oxopyridin-3-yl) pyrimidin-2-yl] ethanesulfonamide ... - 424 038715 43. The compound according to i.38, or a pharmaceutically acceptable salt thereof, wherein the compound is K- [5-butyl-4- (1,5-dimmethyl-6-oxopyridin-3-yl) pyrimidin-2-yl] methanesulfonamide. 44. A pharmaceutical composition for the treatment of cancer or neoplastic disease, comprising a compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 45. The pharmaceutical composition of claim 44, wherein the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma. 46. Use of a compound of formula (II) according to claim 1 for the regulation of gene transcription in a cell. 47. Use of a compound of formula (II) according to claim 1 for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein. 48. Use of a compound of formula (II) according to claim 1, or a pharmaceutically acceptable salt thereof, for the treatment of cancer in a patient. 49. The use of claim 48, wherein the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma. 50. A pharmaceutical composition for the treatment of cancer or neoplastic disease, comprising a compound according to claim 38, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 51. The pharmaceutical composition of claim 50, wherein the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma. 52. Use of a compound according to claim 38 for regulating gene transcription in a cell. 53. Use of a compound according to claim 38 for inhibiting bromodomain-mediated recognition of the acetyllysine region of a protein. 54. Use of a compound according to claim 38, or a pharmaceutically acceptable salt thereof, for the treatment of cancer in a patient in need thereof. 55. The use of claim 54, wherein the cancer is midline NUT carcinoma, Burkitt's lymphoma, prostate cancer, breast cancer, lung cancer, bladder cancer, or melanoma.