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EP-4739683-A1 - 1,6-NAPHTHRIDINE COMPOUNDS AS SMARCA2 INHIBITORS USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS

EP4739683A1EP 4739683 A1EP4739683 A1EP 4739683A1EP-4739683-A1

Abstract

The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC).

Inventors

  • STANSFIELD, IAN
  • LEONARD, KRISTI ANNE
  • WINTERS, MICHAEL PETER
  • BERTHELOT, Didier Jean Claude

Assignees

  • Janssen Pharmaceutica NV

Dates

Publication Date
20260513
Application Date
20230705

Claims (20)

  1. 1. A compound having the structure of Formula (I): or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is selected from the group consisting of: R c is halo, Ci-4alkyl, or OCi-4alkyl; R f is halo, Ci-4alkyl, or O-Ci-4alkyl; R h is Ci-4alkyl; (ii) C 2.3 alkyl substituted wherein R 1 is SO 2 -Ci-4haloalkyl, NH-SO 2 -Ci-4haloalkyl, N(CH 3 )-SO 2 -Ci-4haloalkyl, or SO 2 -N(CH 3 ) 2 , (iii) 5 or 6-membered heteroaryl selected from: wherein R n is SO 2 CH 3 , CH 2 C(OH)(CH 3 ) 2 , CH 2 CH 2 SO 2 CH 3 ; R p is SO 2 CH 3 or CH 2 CH 2 CN; or R q is H or CH 3 ; (iv) C 3 -6cycloalkyl or bridged-C5-7cycloalkyl each substituted with SO 2 Ci-4alkyl, SO 2 -C 3 -6cycloalkyl. CO 2 CH 3 , or NH-SO 2 Ci-4haloalkyl; or, (v) carbon linked pyrrolidine, piperidine, or azepane: each independently substituted with one or two substituents selected from: halo, Ci-4alkyl, Ci-4haloalkyl, CH 2 OH, OH, OCi- 4alkyl, SO 2 Ci-4alkyl, SO 2 Ci-4haloalkyl, SO 2 CH 2 CH 2 OH, and C(=O)Ci-4haloalkyl; or 5- azaspiro[2.5]octane, 6-azaspiro[3.5]nonane, 2-azabicyclo[2.1.1]hexane, and 3- azabicyclo[3.1.0]hexane each independently substituted with SO 2 Ci-4haloalkyl; (vi) R 5 is an optionally substituted 6-membered ring selected from: and X is CH or N.
  2. 2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: (i) R 1 is: (ii) R 1 is: (vi) R 1 is:
  3. 3. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the Formula (IA),
  4. 4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, having the Formula (IB), wherein, R 1 is (i) R 1 is (vi)
  5. 5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof,
  6. 6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is N.
  7. 7. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein: X is CH.
  8. 8. A compound of claim 1 selected from the group consisting of: 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-m ethyl - 3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)-l,6-naphthyridin- 7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((3S,5R)-4-hydroxy-3, 5-dimethylpiperi din-l-yl)pyri din-2 -yl)-l, 6-naphthyri din-7- yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(l- (methylsulfonyl)indolin-6-yl)acetamide; N-(4-methyl-3-(methylsulfonyl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7- yl)acetamide; N-(3-(2-hydroxypropan-2-yl)phenyl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)acetamide; N-(5-(methylsulfonyl)pyridin-3-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l,6-naphthyridin-7- yl)acetamide; N-(l -(methylsulfonyl)indolin-6-yl)-2-(2-(3-(pyridin-4-yl)phenyl)-l, 6-naphthyri din-7- yl)acetamide; 2-(2-(6-((3a, 4a, 5a)-4-hydroxy-3, 5-dimethylpiperi din-l-yl)pyri din-2 -yl)-l, 6-naphthyri din- 7-yl)-N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(3-((2- hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(3-fluoro-5- (methylsulfonyl)phenyl)acetamide; N-(4-chl oro-3 -(methylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2- yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-(4,7-diazaspiro[2.5]octan-7-yl)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrazol-4-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l, 6-naphthyri din-7-yl)-N-(4- (methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l, 1- dioxido-2,3-dihydrobenzo[b]thiophen-6-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- (ethylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(4-fluoro-3- (methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(2-(N, N- dimethylsulfamoyl)ethyl)acetamide; N-(2-(2-oxabicyclo[2.1.1]hexan-l-yl)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(l-(2-cyanoethyl)-5-methyl-lH-pyrazol-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l-(2- (methylsulfonyl)ethyl)-lH-pyrazol-4-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)-4-fluoropyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4- methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrazol-3-yl)acetamide; N-(6,7-dihydro-4H-pyrazolo[5,l-c][l,4]oxazin-2-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; 2-(6-(6-(4, 7 -diazaspiro[2.5 ]octan-7 -yl)pyridin-2-yl)i soquinolin-3 -yl)-N -(4-m ethyl -3 - (methylsulfonyl)phenyl)acetamide; 2-(6-(6-((3a,4P,5a)-4-hydroxy-3,5-dimethylpiperidin-l-yl)pyridin-2-yl)isoquinolin-3-yl)- N-(4-methyl-3-(methylsulfonyl)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(4-methyl-3- (methylsulfonyl)phenyl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 -((2- hydroxyethyl)sulfonyl)-4-methylphenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(5- (methylsulfonyl)pyridin-3-yl)acetamide; N-(3-(cyanomethoxy)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3-methyl- 5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(4-methoxy- 3-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(2,2- dioxido-l,3-dihydrobenzo[c]thiophen-5-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(l, 1- dioxidoisothi azolidin-2 -yl)phenyl)acetamide; N-(3-(cyclopropylsulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3-methoxy- 5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)-lH-pyrrol-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- ((trifluoromethyl)sulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(2 -methyl- 5-(methylsulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(N, N- dimethylsulfamoyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-((2- hydroxyethyl)sulfonyl)phenyl)acetamide; N-(3-(2-cyanopropan-2-yl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)- l,6-naphthyridin-7-yl)acetamide; N-(2,2-dimethylchroman-7-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6- naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3- (tetrahydrofuran-3-yl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-oxo- 2,3,4,5-tetrahydro-lH-benzo[c]azepin-8-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(l-(2- hydroxy -2 -methylpropyl)-lH-pyrazol-4-yl)acetamide; N-(3,3-dimethyl-2,3-dihydrobenzofuran-6-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(2,3-dihydrobenzo[b][l,4]dioxin-6-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2- yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(l -methyl- l-oxido-3H-114-benzo[d]isothiazol-5-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(3-(2,5- dioxopyrrolidin-l-yl)-4-fluorophenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(3-(2- methyloxetan-2-yl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(6- (methylsulfonyl)pyridin-2-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((*R)-l - (methylsulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((* S)-l- (methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3-yl)-N-((*R)-l - (methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((*S)-l- (methylsulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-m ethyl - 3-(S-methylsulfonimidoyl)phenyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)i soquinolin-3 -yl)-N-((3 R,6R)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*S)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((*S)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((*S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*R)- 3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*R)- 3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*R,3*S)- 3-(methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((l*S,3*S)- 3-(methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((3S,6R)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -((3R, 6 S)-6- methyl-l-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(( 1 *R,3 *R)-3 - (methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-((l*S,3*R)-3- (methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(( 1 *R, 3 * S)-3 - (methylsulfonyl)cyclohexyl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N-(( 1 * S, 3 * S)-3 - (methylsulfonyl)cyclohexyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((*R)-l - ((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((* S)-l- ((trifluoromethyl)sulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(l - (methylsulfonyl)pyrrolidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((R)-l - (methylsulfonyl)pyrrolidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((S)-l- (methylsulfonyl)pyrrolidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((ls,3s)-3- (methylsulfonyl)cyclobutyl)acetamide; N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonamido)propyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)propyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((dimethyl(oxo)-16-sulfaneylidene)amino)phenyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonyl)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2 -y 1 )i soquinolin-3 -yl)acetamide; N-(3-((difluoromethyl)sulfonamido)propyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; 2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)-N-(4-(S- methylsulfonimidoyl)phenyl)acetamide; N-(3-((difluoromethyl)sulfonyl)propyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide; N-(3-((dimethyl(oxo)-16-sulfaneylidene)amino)phenyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((S)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((R)-l-(2,2-difluoroacetyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(l-(2,2-difluoroacetyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-(4-(S- methylsulfonimidoyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-(3- ((fluoromethyl)sulfonyl)phenyl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - ((fluoromethyl)sulfonyl)phenyl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyridin-7-yl)-N-((l- (methylsulfonyl)piperidin-4-yl)methyl)acetamide; N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((R)-l-((2- hydroxy ethyl)sulfonyl)piperidin-3-yl)acetamide; N-((R)-l-((3,3-difluoropropyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((S)-l-((2- hydroxyethyl)sulfonyl)piperidin-3-yl)acetamide; N-((3R,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,4R)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((R)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((S)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((R)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((S)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-hydroxypiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(l-((2,2-difluoroethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyri din-2 -yl)-l,6-naphthyri din-7-yl)-N-((3 R,5R)-5- fluoro-l-(methylsulfonyl)piperidin-3-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-((3R,5S)-5- fluoro-l-(methylsulfonyl)piperidin-3-yl)acetamide; N-((3R,5R)-5-(difluoromethyl)-l-(methylsulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(5-((difluoromethyl)sulfonyl)-5-azaspiro[2.5]octan-7-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(6-((difluoromethyl)sulfonyl)-6-azaspiro[3.5]nonan-8-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((S)-l-((difluoromethyl)sulfonyl)-5,5-dimethylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5R)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-(trifluoromethyl)piperidin-3-yl)-2-(2-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(l-(2,2-difluoroethyl)-5-fluoro-6-oxo-l,6-dihydropyridin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(2-((l,l-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lR,2S)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lR,2R)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(5-((difluoromethyl)sulfonamido)bicyclo[3.1.1]heptan-l-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lR,2R)-2-((difluoromethyl)sulfonamido)cyclobutyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(((S)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)methyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(2-((difluoromethyl)sulfonyl)-2-azabicyclo[2.1. l]hexan-4-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lS,2S)-2-((difluoromethyl)sulfonamido)cyclopropyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((l-((difluoromethyl)sulfonyl)piperidin-3-yl)methyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lR,2S)-2-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; 2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)-N-(3-(l,l,2,2- tetrafluoroethoxy)phenyl)acetamide; N-(4-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- yl)-l,6-naphthyridin-7-yl)acetamide; N-((R)-l-(difluoromethyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((lR,5S)-3-((difluoromethyl)sulfonyl)-3-azabicyclo[3.1.0]hexan-l-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; methyl 3-(2-(6-(6-((cis)-2, 6-dimethylmorpholino)pyri din-2 -yl)isoquinolin-3 - yl)acetamido)bicyclo[l .1. l]pentane-l -carboxylate; methyl (ls,3s)-3-(2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3- yl)acetamido)cyclobutane-l -carboxylate; N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-hydroxypyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-(3-(cyclopropylsulfonyl)bicyclo[l.l.l]pentan-l-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(2-((cis)-2,6-dimethylmorpholino)-l-methyl- 6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3-yl)acetamide; N-(3-(S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-phenylisoquinolin-3-yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - (methylsulfonyl)cyclobutyl)acetamide; (R)-N-(l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide; N-(3-(S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-phenylisoquinolin-3-yl)acetamide; (*R)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide; (*S)-N-(l-(methylsulfonyl)piperidin-3-yl)-2-(6-phenylisoquinolin-3-yl)acetamide; (*R)-N-(3-(S-(difluoromethyl)sulfinimidoyl)phenyl)-2-(6-phenylisoquinolin-3- yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-phenylisoquinolin-3-yl)acetamide; N-(3-(cyclopropylsulfonyl)cyclobutyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -( 1 - (methylsulfonyl)piperidin-4-yl)acetamide; N-(l-((difluoromethyl)sulfonyl)piperidin-4-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -( 1 -((2- hydroxyethyl)sulfonyl)piperidin-4-yl)acetamide; N-((3S,4R)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3R,4R)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,5R)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3R,4S)-l-((difluoromethyl)sulfonyl)-4-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,4S)-l-((difluoromethyl)sulfonyl)-4-methoxypyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((3S,5S)-l-((difluoromethyl)sulfonyl)-5-(hydroxymethyl)pyrrolidin-3-yl)-2-(6-(6-((cis)- 2,6-dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; 2-(6-(6-((ci s)-2, 6-dimethylmorpholino)pyridin-2-yl)i soquinolin-3 -yl)-N -(3 - (methylsulfonyl)cyclohexyl)acetamide; N-(3-(cyclopropylsulfonyl)cyclohexyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin-2- y 1 )i soquinolin-3 -yl)acetamide; N-(3-((*R)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; and N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; and pharmaceutically acceptable salts or stereoisomers thereof.
  9. 9. A compound of claim 1 selected from the group consisting of: N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(2-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((difluoromethyl)sulfonyl)phenyl)-2-(6-(6-((cis)-2,6-dimethylmorpholino)pyridin- 2 -y 1 )i soquinolin-3 -yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((*R)-l-((difluoromethyl)sulfonyl)pyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-(2-((difluoromethyl)sulfonamido)ethyl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; N-((R)-l-((difluoromethyl)sulfonyl)azepan-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((R)-l-((difluoromethyl)sulfonyl)-5,5-difluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(3-((*S)-S-(difluoromethyl)sulfonimidoyl)phenyl)-2-(6-(2-((cis)-2,6- dimethylmorpholino)-l-methyl-6-oxo-l,6-dihydropyrimidin-4-yl)isoquinolin-3- yl)acetamide; N-((3R,5R)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-fluoropiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-5-(difluoromethyl)-l-((difluoromethyl)sulfonyl)piperidin-3-yl)-2-(2-(6- ((cis)-2,6-dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpiperidin-3-yl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-(2-((l,l-difluoro-N-methylmethyl)sulfonamido)ethyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; N-((cis)-3-((difluoromethyl)sulfonamido)cyclopentyl)-2-(2-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)-l,6-naphthyridin-7-yl)acetamide; and N-((3R,5S)-l-((difluoromethyl)sulfonyl)-5-methylpyrrolidin-3-yl)-2-(6-(6-((cis)-2,6- dimethylmorpholino)pyridin-2-yl)isoquinolin-3-yl)acetamide; and pharmaceutically acceptable salts and stereoisomers thereof.
  10. 10. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of any one of the preceding claims; and at least one pharmaceutically acceptable excipient.
  11. 11. A compound according to any one of claims 1 to 9 for use in therapy.
  12. 12. A compound according to any one of claims 1 to 9 for use in the treatment of a SMARCA4 deficient cancer.
  13. 13. The compound for the use of claim 12, wherein the SMARCA4 deficient cancer is SMARCA4 deficient non-small cell lung cancer (NSCLC).
  14. 14. A compound according to any one of claims 1 to 9 for use in the treatment of a disease state or condition mediated by the SMARCA2 protein.
  15. 15. The compound for the use of claim 14, wherein the disease state or condition mediated by the SMARCA2 protein is cancer or non-small-cell lung carcinoma (NSCLC).
  16. 16. Use of a compound as defined in any one of claims 1 to 9 for the manufacture of a medicament for the treatment of cancer or NSCLC.
  17. 17. An in vitro method of modulating SMARCA2 activity comprising contacting the SMARCA2 protein, or portion thereof, with a compound, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 9.
  18. 18. A method for the treatment of a SMARCA4 deficient cancer, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 9.
  19. 19. The method of claim 18, wherein the SMARCA4 deficient cancer is SMARCA4 deficient NSCLC.
  20. 20. A method for the treatment of a disease state or condition mediated by the SMARCA2 protein, which method comprises administering to a subject in need thereof, a compound as defined in any one of claims 1 to 9.

Description

1 ,6-NAPHTHRIDINE COMPOUNDS AS SMARCA2 INHIBITORS USEFUL FOR THE TREATMENT OF SMARCA4 DEFICIENT CANCERS FIELD OF THE INVENTION [0001] The invention relates to pharmaceutical compounds and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of the SMARCA2 protein and to their use in the treatment of SMARCA4 deficient cancers, e.g., SMARCA4 deficient non-small cell lung cancer (NSCLC). BACKGROUND OF THE INVENTION [0002] The S witch/ Sucrose Non-Fermentable (SWI/SNF), also known as BAF complex, is a multi-subunit complex that modulates chromatic structure through the activity of two mutually exclusive helicase/ ATPase catalytic subunits: SWI/SNF -Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 2 (SMARCA2, BRAHMA or BRM) and SWI/ SNF -Related, Matrix- Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 (SMARCA4 or BRG1). The core and the regulatory subunits couple ATP hydrolysis to the perturbation of histone-DNA contacts, thereby providing access points to transcription factors and cognate DNA elements that facilitate gene activation and repression. [0003] Mutations in the genes encoding the twenty canonical SWI/SNF subunits are observed in nearly 20% of all cancers with the highest frequency of mutations observed in rhabdoid tumors, female cancers (including ovarian, uterine, cervical, and endometrial), lung adenocarcinoma, gastric adenocarcinoma, melanoma, esophageal, and renal clear cell carcinoma. Despite having a high degree of homology, and their presumed overlapping functions, SMARCA2 and SMARCA4 have been reported as having different roles in cancer. For example, SMARCA4 is frequently mutated in primary tumors, while SMARCA2 inactivation is infrequent in tumor development. In fact, numerous types of cancer have been shown to be SMARCA4-related (e.g., cancers having a SMARCA4-mutation or a SMARCA4-deficiency, such as lack of expression), including, e.g., lung cancer (such as non- small cell lung cancer or NSCLC). [0004] SMARCA2 has been demonstrated as one of the top essential genes in SMARCA4- related or -mutant cancer cell lines. This is because SMARCA4-deficient patient populations or cells depend exclusively on SMARCA2 activity - i.e., there is a greater incorporation of SMARCA2 into the complex to compensate for the SMARCA4 deficiency. Thus, SMARCA2 may be targeted in SMARCA4-related/deficient cancers. The co-occurrence of the deficiency of the expression of two (or more) genes that leads to cell death is known as synthetic lethality. Accordingly, synthetic lethality can be leveraged in the treatment of certain SMARCA2/SMARCA4-related cancers. [0005] There is an ongoing need for effective treatment for diseases that are treatable by inhibiting or degrading SMARCA2 (i.e., BRAHMA or BRM). However, non-specific effects, and the inability to selectively target and modulate SMARCA2 remains an obstacle to the development of effective treatments. As such, small-molecule therapeutic agents that target SMARCA2 would be very useful. [0006] An objective of the present invention is to provide compounds that are selective on SMARCA2 over SMARCA 4. [0007] An objective of the present invention is to provide SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient cancers. [0008] An objective of the present invention is to provide compounds SMARCA2 inhibitors that are effective in the treatment of SMARCA4 deficient NSCLC. SUMMARY OF THE INVENTION [0009] Embodiments of the present invention relate to certain uses and methods of use of 1,6- naphthyridine and isoquinoline chemical entities having SMARCA2 modulating properties, and pharmaceutical compositions comprising these chemical entities, to the use of said chemical entities as inhibitors of the SMARCA2 protein, and to methods of treatment or use in the treatment of SMARCA4 deficient cancers, as described in the claims. [0010] Additional embodiments, features, and advantages of the invention will be apparent from the following detailed description and through practice of the invention. [0011] Embodiments of this invention are uses and methods of treatment using compounds of Formula (I), wherein R1 is selected from the group consisting of: Rc is halo, Ci-4alkyl, or OCi-4alkyl; Rf is halo, Ci-4alkyl, or O-Ci-4alkyl; R1 is SO2-Ci-4haloalkyl, NH-SO2-Ci-4haloalkyl, N(CH3)-SO2-Ci-4haloalkyl, or SO2- N(CH3)2, (iii) 5 or 6-membered heteroaryl selected from: Rn is SO2CH3, CH2C(OH)(CH3)2, CH2CH2SO2CH3; Rp is SO2CH3 or CH2CH2CN; or Rq is H or CH3; (iv) Cs-ecycloalkyl or bridged-Cs-vcycloalkyl each substituted with SO2Ci-4alkyl, SO2-C3-6cycloalkyl. CO2CH3, or NH-SO2Ci-4haloalkyl; or, (v) carbon linked pyrrolidine, piperidine, or azepane: each independently substituted with one or two substituents selected from: halo, Ci-4alkyl, Ci-4haloalkyl, CH2OH, OH, OCi-4alkyl, SO2Ci-4alkyl, SO2Ci-4halo