US 2021/0070748 A1Published application

Inhibitors of brutons tyrosine kinase

AssigneePharmacyclics, Inc.

InventorsGordana B. Atallah, Wei Chen, Zhaozhong J. Jia, Alfonso Pozzan, Luca F. Raveglia, Riccardo Zanaletti

Life of this patent

Estimating the term…

Abstract

Disclosed herein are reversible and irreversible inhibitors of Bruton's tyrosine kinase (Btk). Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the Btk inhibitors are described, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, and inflammatory diseases or conditions.

Claims21

Dependent claims

-54. (canceled)

A compound of Formula (I) having the structure:

wherein:
Q is
ring A is substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
X1 and X2 are both N or are both C(R2);
or X1 is N and X2 is C(R2);
Y is a bond, or is —CH2O—, —OCH2—, —OCH2CH2O—, —O—, —N(R3)—, —C(O)—, —N(R3)C(O)—, —C(O)N(R3)—, —N(R3)C(O)N(R3)—, —S(O)—, —S(O)2—, —N(R3)S(O)2—, —S(O)2N(R3)—, —C(═NH)—, —C(═NH)N(R3)—, —C(═NH)N(R3)—, or substituted or unsubstituted C1-C4alkylene;
Z is H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
L is a bond, or is NR11;
R1 is substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted cyclohexyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
or R1 is substituted or unsubstituted isoindolinyl or CN;
or R1 and R10 together with the -L-C(O)—N-between them form a substituted or unsubstituted C1-C12heteroaryl or a substituted or unsubstituted C2-C7heterocycloalkyl optionally fused with a substituted or unsubstituted phenyl ring, which C2-C7heterocycloalkyl is other than
(wherein Sub represents H or a substituent);
and further wherein, when m is 1, R1 may also be substituted or unsubstituted C1-C4alkyl;
each R2 is independently H, —CN, halogen, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
each R3 is independently H, or substituted or unsubstituted C1-C4alkyl;
each R4 is independently halogen, —CN, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
or two R4 form a C1-C4alkylene;
R5 is H, halogen, —CN, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
or R5 together with one R4 form a C1-C4alkylene;
R10 and R11 are independently H, or substituted or unsubstituted C1-C4alkyl;
or R10 and R11 connect to form a C1-C4alkylene;
m is 0 or 1;
n is 0, 1, 2 or 3;
and
p is 0, 1, 2 or 3;
or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, and/or pharmaceutically acceptable prodrug thereof;
provided that:
(1) when Q is Q1, m is 0, R1 is substituted or unsubstituted C2-C4alkenyl, and X1 is N, then X2 is other than C(Et);
(2) when Q is Q1, and m is 0, then -A-Y—Z is other than
(3) when Q is Q1, and m is 0, then R1 is other than
(4) when Q is Q2, R1 is substituted or unsubstituted C2-C4alkenyl, A is substituted or unsubstituted phenyl, R7 is H, the group
and the group
are attached to the same carbon atom or attached to carbon atoms that are adjacent to each other, and X1 is N, then X2 is other than CH or C(Et);
(5) when Q is Q3, and m is 0, then -A-Y—Z is other than
(6) when Q is Q3, m is 0, A is quinolinyl, X1 is N and X2 is CH, then R1 is other than Me;
(7) when Q is Q3, R1 is substituted or unsubstituted C1-C4alkyl or substituted or unsubstituted C2-C4alkenyl, m is 0, and X1 is N, then X2 is CH or N;
and
(8) the compound is other than:
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(5-fluoropyridin-3-ylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(p-tolylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(m-tolylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(3-(pyrimidin-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-3-(3-(4-tert-butylbenzamido)piperidin-1-yl)-5-(4-(oxazol-2-yl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R)-5-(3-(4-tert-butylbenzamido)piperidin-1l-yl)-3-(3-methylisothiazol-5-ylamino)picolinamide;
(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(4-tert-butylbenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(4-fluorobenzamido)piperidin-1-yl)-3-(4-(1-methylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
5-((2R,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
5-((2S,3R)-3-benzamido-2-methylpiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chlorophenyl)-2-oxoimidazolidin-1-yl)piperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-benzamidopiperidin-1-yl)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
00518SUSCi1 (R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(nicotinamido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(5-fluoronicotinamido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(2-oxopyrrolidin-1-yl)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(1-oxoisoindolin-2-yl)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-5-(3-(4-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-chlorobenzamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(5-chloronicotinamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(5-chlorothiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(benzo[b]thiophene-2-carboxamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-5-(3-(2-naphthamido)piperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-biphenyl-4-ylcarboxamidopiperidin-1-yl)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopropylpiperidin-4-yl)phenylamino)-5-(3-(6-phenylnicotinamido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-(3-(4-fluorobenzamido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)-3-(phenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-fluorophenylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(4-(1-cyanocyclopropyl)phenyl amino)pyrazine-2-carboxamide;
(R)-3-(4-(1-carbamoylcyclopropyl)phenylamino)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)—N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)imidazo[1,2-a]pyridine-6-carboxamide;
(R)—N-(1-(5-carbamoyl-6-(4-(tetrahydro-2H-pyran-4-yl)phenylamino)pyrazin-2-yl)piperidin-3-yl)-5-hydroxyimidazo[1,2-a]pyridine-6-carboxamide;
(R)-3-(cyclopropylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-3-(cyclopentylamino)-5-(3-(3-methyl-3-phenylureido)piperidin-1-yl)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(cyclopropylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(3-chloro-5-(trifluoromethyl)phenyl)-3-methylureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide;
(R)-5-(3-(3-(tetrahydro-2H-pyran-4-yl)ureido)piperidin-1-yl)-3-(tetrahydro-2H-pyran-4-ylamino)pyrazine-2-carboxamide;
5-[[trans-4-(acetylamino)cyclohexyl]amino]-6-ethyl-3-[[3-methyl-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]amino]-2-pyrazinecarboxamide;
(R)-3-(1-but-2-ynoylpiperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-phenoxyphenylamino)pyrazine-2-carboxamide;
or
(R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide.

82 more elements

A compound with the structure of Formula (B-I), (B-IA) or (B-IB):

wherein:
ring A is substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
X1 and X2 are both N or are both C(R2);
or X1 is N and X2 is C(R2);
Y is optionally present and when present is —CH2O—, —OCH2—, —OCH2CH2O—, —O—, —N(R3)—, —C(O)—, —N(R3)C(O)—, —C(O)N(R3)—, —N(R3)C(O)N(R3)—, —S(O)—, —S(O)2—, —N(R3)S(O)2—, —S(O)2N(R3)—, —C(═NH)—, —C(═NH)N(R3)—, —C(═NH)N(R3)—, or substituted or unsubstituted C1-C4alkylene;
Z is optionally present and when present is H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
R1 is substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
or R1 is NR5R11 or CN;
or R1 and R10 together with the —C(O)—N— moiety between them form a substituted or unsubstituted C1-C12heteroaryl or substituted or unsubstituted C2-C7heterocycloalkyl optionally fused with a substituted or unsubstituted phenyl ring;
each R2 is independently H, —CN, halogen, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
each R3 is independently H, or substituted or unsubstituted C1-C4alkyl;
each R4 is independently halogen, —CN, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
R5 is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C6-C7cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
R7 is H, or substituted or unsubstituted C1-C4alkyl or C(O)—(C2-C4alkenyl);
R10 and R11 are independently H, or substituted or unsubstituted C1-C4alkyl;
or R10 and R11 connect to form a C1-C4alkylene;
m is 1, 2, or 3;
n is 0, 1, 2 or 3;
and
p is 0, 1, 2 or 3;
or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof;
provided that
(1) when R1 is substituted or unsubstituted C2-C4alkenyl, A is substituted or unsubstituted phenyl, R7 is H, the group
and the group
are attached to the same carbon atom or attached to carbon atoms that are adjacent to each other, and X1 is N, then X2 is other than CH or C(Et);
and
(2) the compound is other than 5-[[trans-4-(acetylamino)cyclohexyl]amino]-6-ethyl-3-[[3-methyl-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]amino]-2-pyrazinecarboxamide.

24 more elements

A compound of Formula (C-I) having the structure:

wherein:
ring A is substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
X1 and X2 are both N or are both C(R2);
or X1 is N and X2 is C(R2);
Y is a bond, or is —CH2O—, —OCH2—, —OCH2CH2O—, —O—, —N(R3)—, —C(O)—, —N(R3)C(O)—, —C(O)N(R3)—, —N(R3)C(O)N(R3)—, —S(O)—, —S(O)2—, —N(R3)S(O)2—, —S(O)2N(R3)—, —C(═NH)—, —C(═NH)N(R3)—, —C(═NH)N(R3)—, or substituted or unsubstituted C1-C4alkylene;
Z is H, substituted or unsubstituted C1-C3alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
R1 is substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
or R1 is —NR7R10 or CN;
each R2 is independently H, —CN, halogen, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
each R3 is independently H, or substituted or unsubstituted C1-C4alkyl;
each R4 is independently halogen, —CN, —OH, substituted or unsubstituted C1-C4alkoxy, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C6heterocycloalkyl, or —N(R3)2;
R5 is H, or substituted or unsubstituted C1-C4alkyl or C(O)—(C2-C4alkenyl);
R7 is independently substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C2-C4alkenyl, substituted or unsubstituted C2-C4alkynyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C2-C7heterocycloalkyl, substituted or unsubstituted C6-C12aryl, or substituted or unsubstituted C1-C12heteroaryl;
R10 is H, or substituted or unsubstituted C1-C4alkyl;
m is 0 or 1;
n is 0, 1, 2 or 3;
and
p is 0, 1, 2 or 3;
or a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof;
provided that
(1) when m is 0, then -A-Y—Z is other than
(2) when A is quinolinyl, m is 0, X1 is N and X2 is CH, then R1 is other than Me;
(3) when R1 is substituted or unsubstituted C1-C4alkyl or substituted or unsubstituted C2-C4alkenyl, m is 0, and X1 is N, then X2 is CH or N;
(4) the compound is other than
(R)-3-(1-but-2-ynoylpiperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(dimethylamino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)piperidin-3-ylamino)-5-(4-(methylsulfonyl)phenylamino)-1,2,4-triazine-6-carboxamide;
(R,E)-5-((1-(4-(dimethylamino)but-2-enoyl)piperidin-3-yl)(methyl)amino)-3-(4-phenoxyphenylamino)pyrazine-2-carboxamide;
or
(R)-3-(5-carbamoyl-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-N,N-dimethylazepane-1-carboxamide;
and a pharmaceutically acceptable solvate, pharmaceutically acceptable salt, or pharmaceutically acceptable prodrug thereof.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/514,544Filed 17 Jul 2019
Priority: 2 Jun 2015
Published: 11 Mar 2021
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…
A61P 19/02
Drugs for skeletal disorders: for joint disorders, e.g. arthritis, arthrosis
A61P 19/10
For bone diseases, e.g. rachitism, Paget's disease: for osteoporosis
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents

Family

Application62/169,935Us provisional application · filed 2 Jun 2015
Application62/169,945Us provisional application · filed 2 Jun 2015
Application62/169,941Us provisional application · filed 2 Jun 2015
Application62/249,336Us provisional application · filed 1 Nov 2015
Application62/249,338Us provisional application · filed 1 Nov 2015
Application62/249,340Us provisional application · filed 1 Nov 2015
Application15/579,142Continuation · filed 1 Dec 2017
Application16/514,544Continuation
US 2018/0305348 A1Published application
US 2021/0070748 A1This patent

From the US filing history. Foreign family members aren’t listed.

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