US 12,753,163 B2 · Diaminopyrimidine carboxamide inhibitors of HPK1

Abstract

Compounds of the formula I: or the pharmaceutically acceptable salts thereof, are inhibitors of haematopoietic progenitor kinase 1 (HPK1) useful in the treatment of diseases or disorders associated with HPK1. Also disclosed herein are uses of these compounds in the potential treatment or prevention of an HPK1-associated disease or disorder. Also disclosed herein are compositions comprising one or more of the compounds. Further disclosed herein are uses of these compositions in the potential prevention or treatment of an HPK1-associated disease or disorder.

A compound of the formula (Ib):

wherein:
A is a phenyl, cycloalkyl, or heterocyclyl ring;
R1a, R1b and R1c as are present are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, —O—C1-6alkyl, —NH2, —NH(C1-6alkyl), —N(C1-6alkyl)2, —CN, —(CO)NH(C1-6alkyl), —(CO)NH(C1-6alkyl)2, —(CO)NH(C1-6alkyl-CO2H), phenyl, and fluoro,
(5) —O—C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, methoxy, —(CO)NH(C1-6alkyl), —(CO)O(C1-6alkyl), —CN, and fluoro,
(6) —C3-10cycloalkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, methoxy, —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl, —(CO)NH(C1-6alkyl), —(CO)O(C1-6alkyl), —CN, and fluoro,
(7) C2-6alkynyl,
(8) —NH2,
(9) —NH(C1-6alkyl),
(10) —N(C1-6alkyl)2,
(11) —(CO)(C1-6alkyl),
(12) —(CO)NH2,
(13) —(CO)NH(C1-6alkyl),
(14) —(CO)NH(C3-6cycloalkyl),
(15) —NH(CO)(C1-6alky),
(16) —S—C1-6alkyl,
(17) —SO2—C1-6alkyl,
(18) —SO2NH2,
(19) —CN,
(20) keto,
(21) -phenyl,
(22) -pyridyl,
(23) -diazolyl,
(24) -morpholinyl,
(25) -oxazolyl,
(26) -oxadiazolyl,
(27) -piperazinyl,
(28) -piperidinyl,
(29) -pyrazolyl,
(30) -thiazolyl, and
(31) -triazolyl,
or R1a and R1b may be joined to form a phenyl, 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, oxazolyl, piperidinyl, pyrazolyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydroquinolinyl, or thiazolyl ring, which is unsubstituted or substituted with C1-6alkyl,
or one of R1a, R1b and R1c may be joined by a C3-6alkyl to one of R2a, R2b and R2c;
R2a, R2b and R2c as are present are independently selected from:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) C1-6alkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, fluoro, —(CO)NH(C1-6alkyl), —(CO)O(C1-6alkyl), —SO2—C1-6alkyl, C3-6cycloalkyl, —CN, —O—C1-6alkyl, —(O—C1-6alkyl-)3, —C3-6cycloalkyl, C2-6alkenyl, phenyl, and pyrazolyl which is unsubstituted or substituted with C1-6alkyl,
(5) —O—C1-6alkyl, which is unsubstituted or substituted with fluoro,
(6) —C3-6cycloalkyl, which is unsubstituted or substituted with substituents selected from:
hydroxy, methoxy, —C1-6alkyl, —C1-6alkyl-OH, —(CO)NH(C1-6alkyl), —(CO)O(C1-6alkyl), —CN, and fluoro
(7) —NH2,
(8) —NH(C1-6alkyl),
(9) —N(C1-6alkyl)2,
(10) —(CO)C1-6alkyl,
(10) —(CO)C1-6alkyl-fluoro,
(11) —(CO)C1-6alkyl-O—C1-6alkyl,
(11) —(CO)C1-6alkyl-O—C1-6alkyl-O—C1-6alkyl-O—C1-6alkyl,
(12) —(CO)C3-6cycloalkyl-C1-6alkyl,
(13) —(CO)C3-6cycloalkyl-C1-6alkyl-fluoro,
(14) —(CO)C3-6cycloalkyl-C1-6alkyl-amino,
(15) —(CO)NH2,
(16) —(CO)NH(C1-6alkyl),
(17) —NH(CO)(C1-6alkyl),
(18) —SO2—C1-6alkyl,
(19) —SO2—NH(C1-6alkyl),
(20) —SO2—N(C1-6alkyl)2,
(21) azaspiro[3.3]heptanyl, which is unsubstituted or substituted with —C1-6alkyl or oxetanyl, which is unsubstituted or substituted with —C1-6alkyl,
(22) azetidinyl, which is unsubstituted or substituted with —C1-6alkyl or —(CO)O(C1-6 alkyl),
(23)bicyclopentyl, which is unsubstituted or substituted with —C1-6alkyl or —(CO)O(C1-6alkyl),
(24) oxazolyl,
(25) oxadiazolyl,
(26) oxetanyl, which is unsubstituted or substituted with —C1-6alkyl,
(27) piperidinyl, which is unsubstituted or substituted with —C1-6alkyl or oxetanyl, which is unsubstituted or substituted with —C1-6alkyl,
(28) pyrrolidinyl, which is unsubstituted or substituted with oxo or —C1-6alkyl, and
(29) thiazolyl,
(30) keto,
or R2b and R2c may be joined to form a pyrrolyl, dihydrospiro[1,4′-pyrazolo[1,5-d][1,4]diazepin]-7′(8′H)-one, or dihydro-4H-pyrazolo[1,5-d][1,4]diazepin-one ring, which is unsubstituted or substituted with —C1-6alkyl, —C1-6alkyl-OH or —C3-6cycloalkyl;
R3a and R3b are independently selected from:
(1) hydrogen,
(2) C1-6alkyl, and
(3) —NH2;
or a pharmaceutically acceptable salt thereof.

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Diaminopyrimidine carboxamide inhibitors of HPK1

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Diaminopyrimidine carboxamide inhibitors of HPK1

Life of this patent

Abstract

Claims13