Cot modulators and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10577352-B2
Application number	US-201816045518-A
Country	US
Kind code	B2
Filing date	Jul 25, 2018
Priority date	Jun 30, 2016
Publication date	Mar 3, 2020
Grant date	Mar 3, 2020

Abstract

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

First claim

The invention claimed is:

1. A method for inhibiting cancer Osaka thyroid (Cot) comprising administering, to a human patient in need thereof, an effective amount of 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)(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 1 (R 2 )(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 4 ), —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 3-5 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),

Assignees

• Gilead Sciences Inc

Inventors

• Balan Gayatri
• Chou Chienhung
• Kim Musong
• Kirschberg Thorsten A
• Link John O
• Phillips Gary
• Saito Roland D
• Squires Neil H
• Taylor James G
• Watkins William J
• Wright Nathan E

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title