IP Library › Granted Patent US 10,059,695

Granted Patent B2

US 10,059,695 · App. 15/634,314 · Granted Aug 28, 2018

Cot modulators and methods of use thereof

Inventors: Gayatri Balan (Bellevue, WA); Chien-Hung Chou (Dublin, CA); Musong Kim (Bellevue, WA); Thorsten A. Kirschberg (San Carlos, CA); John O. Link (San Francisco, CA); Gary Phillips (Issaquah, WA); Roland D. Saito (San Mateo, CA); Neil H. Squires (San Francisco, CA); James G. Taylor (Burlingame, CA); William J. Watkins (Saratoga, CA); Nathan E. Wright (Foster City, CA)

Assignee: GILEAD SCIENCES, INC.

C07D403/12 C07D401/14 C07D405/14 C07D417/14

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Quick Facts

Patent No.: US 10,059,695
App. No.: 15/634,314
Granted: Aug 28, 2018
Kind: B2

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Abstract

The present disclosure relates generally to modulators of Cot (cancer Osaka thyroid) and methods of use and manufacture thereof.

Claims (176)

1. A compound of Formula I:

wherein

R 1 is C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, heteroaryl, or C 6-10 aryl;

wherein each C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, heteroaryl, and C 6-10 aryl may be optionally substituted with one to four Z 1 ;

R 2 is hydrogen, —C(O)—R 7 , —C(O)O—R 7 , —C(O)N(R 7 ) 2 , or C 1-9 alkyl;

R 3 is heterocyclyl or heteroaryl;

wherein each heterocyclyl or heteroaryl is optionally substituted with one to four Z 3 ;

R 4 is aryl, heterocyclyl, or heteroaryl;

wherein each aryl, heterocyclyl, or heteroaryl is optionally substituted with one to four Z 4 ;

R 5 is hydrogen, halo, cyano, —NO 2 , —O—R 7 , —N(R 8 )(R 9 ), —S(O)—R 7 , —S(O) 2 R 7 , —S(O) 2 N(R 7 ) 2 , —C(O)R 7 , —OC(O)—R 7 , —C(O)O—R 7 , —OC(O)O—R 7 , —OC(O)N(R 10 )(R 11 ), —C(O)N(R 7 ) 2 , —N(R 7 )C(O)(R 7 ), C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-9 alkylthio, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-9 alkylthio, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 5 ;

R 6 is hydrogen, —C(O)—R 7 , —C(O)O—R 7 , —C(O)N(R 7 ) 2 , C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 6 ;

each R 7 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 7 ;

R 8 and R 9 at each occurrence are independently hydrogen, —S(O) 2 R 10 , —C(O)—R 10 , —C(O)O—R 10 , —C(O)N(R 10 )(R 11 ), C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl may be optionally substituted with one to four Z 8 ;

R 10 and R 11 at each occurrence are independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl,

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl optionally is substituted with one to four Z 1b ;

each Z 1 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 is independently hydrogen, oxo, halo, —NO 2 , —N 3 , cyano, thioxo, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —N(R 12 )C(O)—R 12 , —N(R 12 )C(O)O—R 12 , —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —NR 12 S(O) 2 N(R 13 )(R 14 ), —NR 12 S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)—N(R 13 )(R 14 ), —P(O)(OR 12 ) 2 , —OP(O)(OR 12 ) 2 , —CH 2 P(O)(OR 12 ) 2 , —OCH 2 P(O)(OR 12 ) 2 , —C(O)OCH 2 P(O)(OR 12 ) 2 , —P(O)(R 12 )(OR 12 ), —OP(O)(R 12 )(OR 12 ), —CH 2 P(O)(R 12 )(OR 12 ), —OCH 2 P(O)(R 12 )(OR 12 ), —C(O)OCH 2 P(O)(R 12 )(OR 12 ), —P(O)(N(R 12 ) 2 ) 2 , —OP(O)(N(R 12 ) 2 ) 2 , —CH 2 P(O)(N(R 12 ) 2 ) 2 , —OCH 2 P(O)(NR 12 ) 2 ) 2 , —C(O)OCH 2 P(O)(N(R 12 ) 2 ) 2 , —P(O)(N(R 12 ) 2 )(OR 12 ), —OP(O)(N(R 12 ) 2 )(OR 12 ), —CH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —C(O)OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —P(O)(R 12 )(N(R 12 ) 2 ), —OP(O)(R 12 )(N(R 12 ) 2 ), —CH 2 P(O)(R 12 )(N(R 12 ) 2 ), —OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —C(O)OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each Z 1a is independently oxo, halo, thioxo, —NO 2 , cyano, —N 3 , C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)R 12 , —C(O)O—R 12 , —C(O)N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + —N(R 12 )—C(O)R 12 , —N(R 12 )C(O)O(R 12 ), —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —N(R 12 )S(O) 2 —N(R 13 )(R 14 ), —N(R 12 )S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)OR 12 , —OC(O)—N(R 13 )(R 14 ), —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each R 12 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl,

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

R 13 and R 14 at each occurrence are each independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl;

wherein any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one to four Z 1b groups, or R 13 and R 14 together with the nitrogen to which they are attached form a heterocyclyl, wherein said heterocyclyl is optionally substituted with one to four Z 1b groups;

each Z 1b is independently oxo, thioxo, hydroxy, halo, —NO 2 , —N 3 , cyano, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O(C 1-9 alkyl), —O(C 2-6 alkenyl), —O(C 2-6 alkynyl), —O(C 3-15 cycloalkyl), —O(C 1-8 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), —NH 2 , —NH(C 1-9 alkyl), —NH(C 2-6 alkenyl), —NH(C 2-6 alkynyl), —NH(C 3-15 cycloalkyl), —NH(C 1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C 1-9 alkyl) 2 , —N(C 3-15 cycloalkyl) 2 , —N(C 2-6 alkenyl) 2 , —N(C 2-6 alkynyl) 2 , —N(C 3-15 cycloalkyl) 2 , —N(C 1-8 haloalkyl) 2 , —N(aryl) 2 , —N(heteroaryl) 2 , —N(heterocyclyl) 2 , —N(C 1-9 alkyl)(C 3-15 cycloalkyl), —N(C 1-9 alkyl)(C 2-6 alkenyl), —N(C 1-9 alkyl)(C 2-6 alkynyl), —N(C 1-9 alkyl)(C 3-15 cycloalkyl), —N(C 1-9 alkyl)(C 1-8 haloalkyl), —N(C 1-9 alkyl)(aryl), —N(C 1-9 alkyl)(heteroaryl), —N(C 1-9 alkyl)(heterocyclyl), —C(O)(C 1-9 alkyl), —C(O)(C 2-6 alkenyl), —C(O)(C 2-6 alkynyl), —C(O)(C 3-15 cycloalkyl), —C(O)(C 1-8 haloalkyl), —C(O)(aryl), —C(O)(heteroaryl), —C(O)(heterocyclyl), —C(O)O(C 1-9 alkyl), —C(O)O(C 2-6 alkenyl), —C(O)O(C 2-6 alkynyl), —C(O)O(C 3-15 cycloalkyl), —C(O)O(C 1-8 haloalkyl), —C(O)O(aryl), —C(O)O(heteroaryl), —C(O)O(heterocyclyl), —C(O)NH 2 , —C(O)NH(C 1-9 alkyl), —C(O)NH(C 2-6 alkenyl), —C(O)NH(C 2-6 alkynyl), —C(O)NH(C 3-15 cycloalkyl), —C(O)NH(C 1-8 haloalkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)NH(heterocyclyl), —C(O)N(C 1-9 alkyl) 2 , —C(O)N(C 3-15 cycloalkyl) 2 , —C(O)N(C 2-6 alkenyl) 2 , —C(O)N(C 2-6 alkynyl) 2 , —C(O)N(C 3-15 cycloalkyl) 2 , —C(O)N(C 1-8 haloalkyl) 2 , —C(O)N(aryl) 2 , —C(O)N(heteroaryl) 2 , —C(O)N(heterocyclyl) 2 , —NHC(O)(C 1-9 alkyl), —NHC(O)(C 2-6 alkenyl), —NHC(O)(C 2-6 alkynyl), —NHC(O)(C 3-15 cycloalkyl), —NHC(O)(C 1-8 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C 1-9 alkyl), —NHC(O)O(C 2-6 alkenyl), —NHC(O)O(C 2-6 alkynyl), —NHC(O)O(C 3-15 cycloalkyl), —NHC(O)O(C 1-8 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C 1-9 alkyl), —NHC(O)NH(C 2-6 alkenyl), —NHC(O)NH(C 2-6 alkynyl), —NHC(O)NH(C 3-15 cycloalkyl), —NHC(O)NH(C 1-8 haloalkyl), —NHC(O)NH(aryl), —NHC(O)NH(heteroaryl), —NHC(O)NH(heterocyclyl), —SH, —S(C 1-9 alkyl), —S(C 2-6 alkenyl), —S(C 2-6 alkynyl), —S(C 3-15 cycloalkyl), —S(C 1-8 haloalkyl), —S(aryl), —S(heteroaryl), —S(heterocyclyl), —NHS(O)(C 1-9 alkyl), —N(C 1-9 alkyl)(S(O)(C 1-9 alkyl), —S(O)N(C 1-9 alkyl) 2 , —S(O)(C 1-9 alkyl), —S(O)(NH)(C 1-9 alkyl), —S(O)(C 2-6 alkenyl), —S(O)(C 2-6 alkynyl), —S(O)(C 3-15 cycloalkyl), —S(O)(C 1-8 haloalkyl), —S(O)(aryl), —S(O)(heteroaryl), —S(O)(heterocyclyl), —S(O) 2 (C 1-9 alkyl), —S(O) 2 (C 2-6 alkenyl), —S(O) 2 (C 2-6 alkynyl), —S(O) 2 (C 3-15 cycloalkyl), —S(O) 2 (C 1-8 haloalkyl), —S(O) 2 (aryl), —S(O) 2 (heteroaryl), —S(O) 2 (heterocyclyl), —S(O) 2 NH(C 1-9 alkyl), or —S(O) 2 N(C 1-9 alkyl) 2 ;

wherein any alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl is optionally substituted with one to four halo, C 1-9 alkyl, C 1-8 haloalkyl, —OH, —NH 2 , —NH(C 1-9 alkyl), —NH(C 3-15 cycloalkyl), —NH(C 1-8 haloalkyl), —NH(aryl), —NH(heteroaryl), —NH(heterocyclyl), —N(C 1-9 alkyl) 2 , —N(C 3-15 cycloalkyl) 2 , —NHC(O)(C 3-15 cycloalkyl), —NHC(O)(C 1-8 haloalkyl), —NHC(O)(aryl), —NHC(O)(heteroaryl), —NHC(O)(heterocyclyl), —NHC(O)O(C 1-9 alkyl), —NHC(O)O(C 2-6 alkynyl), —NHC(O)O(C 3-15 cycloalkyl), —NHC(O)O(C 1-8 haloalkyl), —NHC(O)O(aryl), —NHC(O)O(heteroaryl), —NHC(O)O(heterocyclyl), —NHC(O)NH(C 1-9 alkyl), —S(O)(NH)(C 1-9 alkyl), —S(O) 2 (C 1-9 alkyl), —S(O) 2 (C 3-15 cycloalkyl), —S(O) 2 (C 1-8 haloalkyl), —S(O) 2 (aryl), —S(O) 2 (heteroaryl), —S(O) 2 (heterocyclyl), —S(O) 2 NH(C 1-9 alkyl), —S(O) 2 N(C 1-9 alkyl) 2 , —O(C 3-15 cycloalkyl), —O(C 1-8 haloalkyl), —O(aryl), —O(heteroaryl), —O(heterocyclyl), or —O(C 1-9 alkyl);

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein:

R 1 is C 1-9 alkyl or C 3-15 cycloalkyl;

wherein each C 1-9 alkyl and C 3-15 cycloalkyl may be optionally substituted with one to four Z 1 ;

R 2 is hydrogen, —C(O)—R 7 , —C(O)O—R 7 , —C(O)N(R 7 ) 2 , or C 1-9 alkyl;

R 3 is heterocyclyl or heteroaryl;

wherein each heterocyclyl or heteroaryl is optionally substituted with one to four Z 3 ;

R 4 is aryl, heterocyclyl, or heteroaryl;

wherein each aryl, heterocyclyl, or heteroaryl is optionally substituted with one to four Z 4 ;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-9 alkylthio, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 5 ;

R 6 is hydrogen, —C(O)—R 7 , —C(O)O—R 7 , —C(O)N(R 7 ) 2 , C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 6 ;

each R 7 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to four Z 7 ;

wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl may be optionally substituted with one to four Z 8 ;

R 10 and R 11 at each occurrence are independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl, wherein each C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl optionally is substituted with one to four Z 1b ;

each Z 1 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 and Z 8 is independently hydrogen, oxo, halo, —NO 2 , —N 3 , cyano, thioxo, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —N(R 12 )C(O)—R 12 , —N(R 12 )C(O)O—R 12 , —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —NR 12 S(O) 2 N(R 13 )(R 14 ), —NR 12 S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)—N(R 13 )(R 14 ), —P(O)(OR 12 ) 2 , —OP(O)(OR 12 ) 2 , —CH 2 P(O)(OR 12 ) 2 , —OCH 2 P(O)(OR 12 ) 2 , —C(O)OCH 2 P(O)(OR 12 ) 2 , —P(O)(R 12 )(OR 12 ), —OP(O)(R 12 )(OR 12 ), —CH 2 P(O)(R 12 )(OR 12 ), —CH 2 P(O)(R 12 )(OR 12 ), —C(O)OCH 2 P(O)(R 12 )(OR 12 ), —P(O)(N(R 12 ) 2 ) 2 , —OP(O)(N(R 12 ) 2 ) 2 , —CH 2 P(O)(N(R 12 ) 2 ) 2 , —OCH 2 P(O)(N(R 12 ) 2 ) 2 , —C(O)OCH 2 P(O)(N(R 12 ) 2 ) 2 , —P(O)(N(R 12 ) 2 )(OR 12 ), —OP(O)(N(R 12 ) 2 )(OR 12 ), —CH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —C(O)OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —P(O)(R 12 )(N(R 12 ) 2 ), —OP(O)(R 12 )(N(R 12 ) 2 ), —CH 2 P(O)(R 12 )(N(R 12 ) 2 ), —OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —C(O)OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each Z 1a is independently oxo, halo, thioxo, —NO 2 , cyano, —N 3 , C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)R 12 , —C(O)O—R 12 , —C(O)N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —N(R 12 )—C(O)R 12 , —N(R 12 )C(O)O(R 12 ), —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —N(R 12 )S(O) 2 —N(R 13 )(R 14 ), —N(R 12 )S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)OR 12 , —OC(O)—N(R 13 )(R 14 ), —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each R 12 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl,

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

R 13 and R 14 at each occurrence are each independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , having the structure of Formula II:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , having the structure of Formula IIA:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , having the structure of Formula IIIA:

wherein

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

n is 1, 2, or 3;

each Z 3 is independently hydrogen, oxo, halo, —NO 2 , —N 3 , cyano, thioxo, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —N(R 12 )C(O)—R 12 , —N(R 12 )C(O)O—R 12 , —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —NR 12 S(O) 2 N(R 13 )(R 14 ), —NR 12 S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)—N(R 13 )(R 14 ), —P(O)(OR 12 ) 2 , —OP(O)(OR 12 ) 2 , —CH 2 P(O)(OR 12 ) 2 , —OCH 2 P(O)(OR 12 ) 2 , —C(O)OCH 2 P(O)(OR 12 ) 2 , —P(O)(R 12 )(OR 12 ), —OP(O)(R 12 )(OR 12 ), —CH 2 P(O)(R 12 )(OR 12 ), —OCH 2 P(O)(R 12 )(OR 12 ), —C(O)OCH 2 P(O)(R 12 )(OR 12 ), —P(O)(N(R 12 ) 2 ) 2 , —OP(O)(N(R 12 ) 2 ) 2 , —CH 2 P(O)(N(R 12 ) 2 ) 2 , —OCH 2 P(O)(N(R 12 ) 2 ) 2 , —C(O)OCH 2 P(O)(N(R 12 ) 2 ) 2 , —P(O)(NR 12 ) 2 )(OR 12 ), —OP(O)(N(R 12 ) 2 )(OR 12 ), —CH 2 P(O)(NR 12 ) 2 )(OR 12 ), —OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —C(O)OCH 2 P(O)(N(R 12 ) 2 )(OR 12 ), —P(O)(R 12 )(N(R 12 ) 2 ), —OP(O)(R 12 )(N(R 12 ) 2 ), —CH 2 P(O)(R 12 )(N(R 12 ) 2 ), —OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —C(O)OCH 2 P(O)(R 12 )(N(R 12 ) 2 ), —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each Z 1a is independently oxo, halo, thioxo, —NO 2 , cyano, —N 3 , C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, aryl, heteroaryl, heterocyclyl, —O—R 12 , —C(O)R 12 , —C(O)O—R 12 , —C(O)N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —N(R 12 )—C(O)R 12 , —N(R 12 )C(O)O(R 12 ), —N(R 12 )C(O)N(R 13 )(R 14 ), —N(R 12 )S(O) 2 (R 12 ), —N(R 12 )S(O) 2 —N(R 13 )(R 14 ), —N(R 12 )S(O) 2 O(R 12 ), —OC(O)R 12 , —OC(O)OR 12 , —OC(O)—N(R 13 )(R 14 ), —C(O)N(R 12 )—S(O) 2 R 12 , —Si(R 12 ) 3 , —S—R 12 , —S(O)R 12 , —S(O)(NH)R 12 , —S(O) 2 R 12 or —S(O) 2 N(R 13 )(R 14 );

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

each R 12 is independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl;

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

R 13 and R 14 at each occurrence are each independently hydrogen, C 1-9 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, heteroaryl or heterocyclyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 , wherein W is N, X is N—Z 3 , and Y is C—Z 3 , or a pharmaceutically acceptable salt thereof.

7. The compound of claim 6 , wherein Z 3 is hydrogen, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, aryl, or heterocyclyl, may be optionally substituted with one to four substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)—R 12 , —OC(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —S(O) 2 —R 12 , —Si(R 12 ) 3 , C 1-9 alkyl, C 1-9 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl; and

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O(C 1-9 alkyl), —C(O)N(C 1-9 alkyl) 2 , C 1-9 alkyl, and heterocyclyl, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 6 , wherein Z 3 is hydrogen or C 1-9 alkyl;

wherein said C 1-9 alkyl may be optionally substituted with one to four substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)—R 12 , —OC(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —S(O) 2 —R 12 , —Si(R 12 ) 3 , C 1-9 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl; and

wherein said C 3-15 cycloalkyl, aryl, heterocyclyl, or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O(C 1-9 alkyl), —C(O)N(C 1-9 alkyl) 2 , C 1-9 alkyl, and heterocyclyl, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 6 , wherein Z 3 is hydrogen or C 1-9 alkyl optionally substituted with one to four substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)O—R 12 , —OC(O)—R 12 , —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , C 1-9 haloalkyl, heterocyclyl, and heteroaryl, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 6 , wherein Z 3 is C 3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

11. The compound of claim 6 , wherein Z 3 is C 3-15 cycloalkyl optionally substituted with one to four substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)O—R 12 , —OC(O)—R 12 , —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , C 1-9 alkyl, C 1-9 haloalkyl, heterocyclyl, and heteroaryl, or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein the compound is represented by Formula IVA:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 12 , wherein:

Z 3 is hydrogen, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, aryl, or heteroaryl may be optionally substituted with one to four substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)—R 12 , —OC(O)—R 12 , —C(O)O—R 12 , —C(O)—N(R 13 )(R 14 ), —N(R 13 )(R 14 ), —N(R 13 ) 2 (R 14 ) + , —S(O) 2 —R 12 , —Si(R 12 ) 3 , C 1-9 alkyl, C 1-9 haloalkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, aryl, heterocyclyl, and heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O(C 1-9 alkyl), —C(O)—N(C 1-9 alkyl) 2 , C 1-9 alkyl, and heterocyclyl;

R 1 is C 1-9 alkyl;

wherein said C 1-9 alkyl may be optionally substituted with one to three substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —N(R 13 )(R 14 ), —N(R 12 )C(O)OR 12 , —S(O) 2 —R 12 , —Si(R 12 ) 3 , C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, aryl, and heteroaryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, aryl, or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —N(R 13 )(R 14 ), C 1-9 alkyl, C 3-15 cycloalkyl, and aryl;

R 4 is aryl, heterocyclyl, or heteroaryl;

wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with one to three substituents independently selected from the group consisting of cyano, halo, —O—R 12 , —C(O)—R 12 , —C(O)O—R 12 , —S(O) 2 —R 12 , —N(R 12 )C(O)—R 12 , —N(R 12 )S(O) 2 R 12 , —C(O)N(R 13 )(R 14 ), —N(R 13 )(R 14 ), C 1-9 alkyl, heterocyclyl, aryl, and heteroaryl;

wherein said C 1-9 alkyl, or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O—R 12 , —N(R 13 )(R 14 ), C 1-9 alkyl, and heterocyclyl;

R 5 is cyano, halo, —O—R 7 , —C(O)R 7 , —N(R 8 )C(O)(R 7 ), —C(O)N(R 8 )(R 9 ), C 1-9 alkyl, C 2-6 alkynyl, C 3-15 cycloalkyl, aryl, or heteroaryl;

wherein said C 1-9 alkyl, aryl, or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O—R 12 , and C 1-9 alkyl;

each R 7 is independently hydrogen, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, —O—R 12 , —N(R 13 )(R 14 ), C 1-9 alkyl, aryl, and heteroaryl;

each R 12 is independently hydrogen, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy, —O(C 1-9 alkyl), —N(C 1-9 alkyl) 2 , C 1-9 alkyl, aryl, and heteroaryl; and

each R 13 and R 14 are independently hydrogen, C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl;

wherein said C 1-9 alkyl, C 3-15 cycloalkyl, heterocyclyl, or aryl may be optionally substituted with one to three substituents independently selected from the group consisting of halo, hydroxy, —O(C 1-9 alkyl), —N(C 1-9 alkyl) 2 , C 1-9 alkyl, aryl, and heteroaryl, or a pharmaceutically acceptable salt thereof.

14. The compound of claim 12 , wherein Z 3 is cyclopropyl optionally substituted with C 1-9 haloalkyl, or a pharmaceutically acceptable salt thereof.

15. The compound of claim 12 , wherein Z 3 is cyclopropyl, 1-(fluoromethyl)cyclopropyl, 1-(difluoromethyl)cyclopropyl, 1-(trifluoromethyl)cyclopropyl, 1-cyanocyclopropyl, bicyclo[1.1.1]pentan-1-yl, or carboxymethyl, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein R 1 is C 1-9 alkyl optionally substituted with one to four substituents independently selected the group consisting of cyano, aryl and heterocyclyl, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 , wherein R 1 is C 1-9 alkyl optionally substituted with one to two substituents independently selected the group consisting of cyano, phenyl and tetrahydro-2H-pyran, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 1 , wherein R 1 is 2,2-dimethylpropyl, (4-methyltetrahydro-2H-pyran-4-yl)methyl, or 3-cyano-1-phenylpropyl, or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1 , wherein R 4 is aryl or heteroaryl, wherein said aryl or heteroaryl may be optionally substituted with one to three substituents independently selected from the group consisting of cyano, halo and C 1-9 alkyl, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , wherein R 4 is 6-fluoro-2-methylpyridin-3-yl, 2-chlorophenyl, 4-fluorophenyl, 3-cyanophenyl, 6-fluoro-2-methylpyridin-3-yl, 2-methyl-1-oxo-1,2-dihydroisoquinolin-5-yl, or benzo[d]thiazol-7-yl, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wherein R 5 is hydrogen, cyano, or halo, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1 , wherein R 5 is hydrogen, cyano, chloro, or bromo, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 , wherein R 6 is hydrogen or C 1-9 alkyl, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1 , wherein R 6 is hydrogen or ethyl, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 , wherein R 6 is hydrogen, or a pharmaceutically acceptable salt thereof.

26. A compound selected from Table 1A or 1B, or a pharmaceutically acceptable salt thereof;

TABLE 1A

Cmpd

Structure

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-8

I-9

I-10

I-11

I-12

I-13

I-14

I-15

I-16

I-17

I-18

I-19

I-20

I-21

I-22

I-23

I-24

I-25

I-26

I-27

TABLE 1B

Cmpd

Structure

II-1

II-2

II-3

II-4

II-5

II-6

II-7

II-8

II-9

II-10

II-11

III-1

III-2

III-3

III-4

III-5

III-6

27. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

28. A composition comprising a mixture of stereoisomers of a compound of Formula I:

wherein the mixture comprises compounds of Formula IA and IB in a ratio of at least about 3:1:

wherein m, R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 .

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 11, 2017

From: BALAN, GAYATRI; CHOU, CHIEN-HUNG; KIM, MUSONG; KIRSCHBERG, THORSTEN A.; LINK, JOHN O.; PHILLIPS, GARY; SAITO, ROLAND; SQUIRES, NEIL H.; TAYLOR, JAMES G.; WATKINS, WILLIAM J.; WRIGHT, NATHAN E.

To: GILEAD SCIENCES, INC.

Reel/Frame 042977/0740 →

Continuity (2)

Provisional Application 62356926 · Jun 30, 2016

Related Publication 20180002316A1 · Jan 4, 2018

Cited By (3)

US 12,365,666 US 12,398,160 US 12,486,252