US 2019/0315715 A1Published application

Novel pyrimidine carboxamides as inhibitors of vanin-1 enzyme

AssigneePfizer Inc.

InventorsAgustin Casimiro-Garcia, Joseph Walter Strohbach, David Hepworth, Frank Eldridge Lovering, Chulho Choi, Christophe Philippe Allais, Stephen Wayne Wright

Life of this patent

Estimating the term…

Abstract

Compounds, pharmaceutically acceptable salts thereof, are disclosed wherein the compounds have the structure of (I) as defined in the specification. Corresponding pharmaceutical compositions, methods of treatment, methods of synthesis, and intermediates are also disclosed.

Claims40

Dependent claims

A compound of Formula I,

wherein
G is a 6-membered heteroaryl, with one, two or three N, wherein the heteroaryl is optionally substituted with one, two or three substituents selected from C1-C4alkyl, —NR8aC(O)R8b, —NR8aSO2R8b, —(CR6aR6b)tC(O)N(R8a)2, —C(O)OH, halogen, cyano, —N(R8a)2, —(CR6aR6b)tSO2R8b, —(CR6aR6b)tSO2N(R8a)2, C1-C4alkoxy, OH, —S(C1-C3alkyl) or C3-C5cycloalkyl, wherein the alkyl, cycloalkyl and alkoxy are optionally substituted with one, two or three halogen, OH, OCH3, or C3-C5cycloalkyl;
L is NH or O;
Z is a bond;
—(CR5aR5b)q—;
—CH2(CR5aR5b)m—;
or —(CR5aR5b)m—W—(CR5aR5b)n—, wherein W is S, O or NR7;
Ra, Rb, R1a and R1b are each independently hydrogen, C1-C4alkyl, wherein the alkyl is optionally substituted with one, two or three halogen, OH, cyano, —S(C1-C3alkyl) or C1-C4alkoxy, optionally substituted with one, two or three fluoro;
or R1a and R1b, together with the carbon to which they are bonded, form an oxo, C3-C5cycloalkyl, -(4- to 5-membered heterocycloalkyl) wherein said cycloalkyl or heterocycloalkyl are optionally substituted with one, two, three or four halogen, OH, C1-C4alkyl, —S(C1-C3alkyl) C1-C4alkoxy or cyano;
and the heteroatom is selected from one or two N, S or O;
R2a and R2b are each independently hydrogen, —(CR6aR6b)tSO2R8b, OH, halogen, —(CR6aR6b)tC(O)N(R8a)2, —NR8aC(O)R8b, —NR8aC(O)N(R8a)2, —SO2N(R8a)2, C1-C4alkyl, C1-C4alkoxy, S(C1-C3alkyl), —(CR6aR6b)t—(C3-C6cycloalkyl), cyano, —(CR6aR6b)n-(5- to 6-membered heterocycloalkyl) or —(CR6aR6b)n-(5- to 6-membered heteroaryl), wherein said heteroatoms of said heteroalkyl and heteroaryl are selected from one, two or three N, O or S;
wherein said alkyl, cycloalkyl, heterocycloakyl and heteroaryl are optionally substituted with one, two, three or four R9;
or
R2a and R2b together with the carbon to which they are bonded form a C3-C9cycloalkyl or a -(4- to 11-membered heterocycloalkyl), having one to three heteroatoms selected from N, O or S;
wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one, two or three C1-C4alkyl, S(C1-C3alkyl), OH, halogen, oxo, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, C3-C5cycloalkyl or C1-C4alkoxy;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and one of R5a or R5b, together with the respective carbons to which they are bonded, form a C3-C12cycloalkyl, C6-C10aryl, -(5- to 6-membered heteroaryl) or a -(4- to 12-membered heterocycloalkyl), wherein said heteroaryl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and R7, together with the respective atoms to which they are bonded form a -(4- to 12-membered heterocycloalkyl) or a -(5- to 6-membered heteroaryl), wherein said heterocycloalkyl or heteroaryl have one, two to three heteroatoms selected from N, O or S, wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
R3 is hydrogen, —(CR6aR6b)tC(O)NH2, or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R3 and Rb, together with the carbon to which they are attached, form an oxo;
R4 is hydrogen, —(CR6aR6b)tC(O)NH2, or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R3 and R4 taken together with the respective carbons to which they are bonded form a -(4- to 11-membered heterocycloalkyl), having one to two heteroatoms selected from N, O or S, wherein the heterocycloalkyl are optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R4 and Ra, together with the carbon to which they are attached, form an oxo;
R5a and R5b are each independently hydrogen, halogen, OH, —(CR6aR6b)tC(O)R8b, —(CR6aR6b)tC(O)NH2, C1-C4alkyl, S(C1-C3alkyl), C1-C4alkoxy, cyano, —(C R6aR6b)t—(C3-C6cycloalkyl) or —(CR6aR6b)t—(C3-C6heterocycloalkyl), wherein said alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9;
and the heteroatom is selected from one or two N, O, or S;
or
R5a and R5b taken together with the carbon to which they are bonded form a C3-C9cycloalkyl or a 4- to 11-membered heterocycloalkyl, wherein the heteroatom is selected from one or two N, S or O, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R3 and either R5a or R5b taken together with the respective carbons to which they are bonded form a C3-C10cycloalkyl or -(4- to 12-membered heterocycloalkyl), wherein the heteroatom is selected from one or two N or O, wherein said cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9 or oxo;
or if substitution is at a N atom, then such N atom is substituted with R7;
R6a and R6b are each independently hydrogen, C1-C4alkyl, S(C1-C3alkyl), OH, C1-C4alkoxy, cyano or halogen;
R7 is hydrogen;
-(4- to 6-membered heterocycloalkyl), having 1 to 2 heteroatoms wherein said heteroatom is selected from O, N and S;
C1-C5alkyl;
S(C1-C3alkyl);
C(O)R8b;
SO2R8b;
SO2N(R8a)2;
C(O)N(R8a)2 or —(C3-C7cycloalkyl), wherein said alkyl, heterocycloalkyl and cycloalkyl are optionally substituted with Ra;
R8a is hydrogen, C1-C4alkyl or —(C3-C7cycloalkyl);
R8b is C1-C4alkyl, —(C3-C7cycloalkyl), (CR6aR6b)tSO2N(R8a)2, —(CR6aR6b)tSO2R8a or —(CR6aR6b)tNHC(O)N(R8a)2;
R9 is hydrogen, C1-C4alkyl, S(C1-C3alkyl), OH, CH2OH, halogen, C1-C4alkoxy, cyano or —C(O)NH2, wherein said alkyl and alkoxy are optionally substituted with OH, halogen, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —S(C1-C4alkyl) or C3-C5cycloalkyl;
or R9 is oxo, provided that it is attached to a non-aromatic group;
R10 is hydrogen or C1-C3alkyl;
m, n and t are each independently 0, 1 or 2;
q is 1, 2 or 3;
and
x is 1 or 2;
or a pharmaceutically acceptable salt thereof.

55 more elements

A compound of formula Ia, Ib, Ic, Id, Ie, If or Ig,

wherein
G is a triazinyl, pyridazinyl, pyridonyl, pyridinyl, pyrazinyl or pyrimidinyl, optionally substituted with one, two or three substituents selected from halogen, OH, cyano, C1-C4alkyl, —NR8aC(O)R8b, —NR8aSO2R8b, —(CR6aR6b)tC(O)N(R8a)2, C(O)OH, —N(R8a)2, —(CR6aR6b)tSO2R8b, —(CR6aR6b)tSO2N(R8a)2, C1-C4alkoxy, S(C1-C3alkyl) or C3-C5cycloalkyl, wherein the alkyl, cycloalkyl and alkoxy are optionally substituted with one, two or three halogen, OH, OCH3, or C3-C5cycloalkyl;
L is NH or O;
Ra, Rb, R1a and R1b are each independently hydrogen, C1-C4alkyl, wherein the alkyl is optionally substituted with one, two or three halogen, OH, cyano or C1-C4alkoxy (optionally substituted with one, two or three fluoro);
or R1a and R1b, together with the carbon to which they are bonded, form an oxo, C3-C5cycloalkyl, -(4- to 5-membered heterocycloalkyl) wherein said cycloalkyl or heterocycloalkyl are optionally substituted with one, two, three or four halogen, OH, C1-C4alkyl, C1-C4alkoxy or cyano;
R2a and R2b are each independently hydrogen, halogen, C1-C4alkyl, —(CR6aR6b)tSO2R8b, —(CR6aR6b)tC(O)N(R8a)2, —NR8C(O)R8b, —SO2N(R8a)2, —NR8C(O)N(R8a)2, S(C1-C3alkyl), cyano, —(CR6aR6b)t(C3-C6cycloalkyl), OH, C1-C4alkoxy, —(CR6aR6b)n(5- to 6-membered heterocycloalkyl), having one to three heteroatoms selected from N, O or S, —(CR6aR6b)n-(5- to 6-membered heteroaryl), having one to three heteroatoms selected from N, O or S, wherein said alkyl, cycloalkyl, heterocycloakyl and heteroaryl are optionally substituted with one, two, three or four R9;
or
R2a and R2b together with the carbon to which they are bonded form a C3-C7cycloalkyl or a -(4- to 12-membered heterocycloalkyl), having one to three heteroatoms selected from N, O or S;
wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one, two or three C1-C4alkyl, S(C1-C3alkyl), OH, halogen, oxo, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C3-C5cycloalkyl or C1-C4alkoxy;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and one of R5a or R5b, together with the respective carbons to which they are bonded, form a C3-C12cycloalkyl, C6-C10aryl, -(5- to 6-membered heteroaryl) or a -(4- to 12-membered heterocycloalkyl), wherein said heteroaryl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and R7, together with the respective atoms to which they are bonded form a -(4- to 12-membered heterocycloalkyl) or a -(5- to 6-membered heteroaryl), wherein said heterocycloalkyl or heteroaryl have one, two to three heteroatoms selected from N, O or S, wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, three or four R9;
R3 is hydrogen, —(CR6aR6b)tC(O)NH2 or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R3 and Rb, together with the carbon to which they are attached, form an oxo;
R4 is hydrogen, —(CR6aR6b)tC(O)NH2 or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R4 and Ra, together with the carbon to which they are attached, form an oxo;
or
R3 and R4 taken together with the respective carbons to which they are bonded form a -(4- to 12-membered heterocycloalkyl), having one to two heteroatoms selected from N, O or S, wherein the heterocycloalkyl are optionally substituted with one, two, three or four R9;
R5a and R5b are each independently hydrogen, halogen, OH, —(CR6aR6b)tC(O)R8b, —(CR6aR6b)tC(O)NH2, C1-C4alkyl, S(C1-C3alkyl), C1-C4alkoxy, cyano, —(CR6aR6b)t—(C3-C6cycloalkyl) or —(CR6aR6b)t—(C3-C6heterocycloalkyl) (having one, to two heteroatoms selected from N, O or S), wherein said alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9;
or
R5a and R5b taken together with the carbon to which they are bonded form a C3-C6cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the heteroatom is selected from one or two N, S or O, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or
R3 and either R5a or R5b taken together with the respective carbons to which they are bonded form a C3-C7cycloalkyl or -(4- to 12-membered heterocycloalkyl), wherein the heteroatom is selected from one or two N or O, wherein said cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9 or oxo;
R6a and R6b are each independently hydrogen, C1-C4alkyl, S(C1-C3alkyl), OH, C1-C4alkoxy, —S(C1-C4alkyl), cyano or halogen;
R7 is hydrogen;
-(4- to 6-membered heterocycloalkyl), having 1 to 2 heteroatoms wherein said heteroatom is selected from O, N and S;
C1-C5alkyl;
S(C1-C3alkyl);
C(O)R8b;
SO2R8b;
SO2N(R8a)2;
C(O)N(R8a)2 or —(C3-C7cycloalkyl), wherein said alkyl, heterocycloalkyl and cycloalkyl are optionally substituted with Ra;
R8a is hydrogen, C1-C4alkyl or —(C3-C7cycloalkyl);
R8b is C1-C4alkyl, —(C3-C7cycloalkyl), —(CR6aR6b)tSO2N(R8a)2, —(CR6aR6b)tSO2R8a or —(CR6aR6b)tNHC(O)N(R8a)2;
R9 is hydrogen, C1-C4alkyl, S(C1-C3alkyl), oxo, OH, CH2OH, halogen, C1-C4alkoxy, cyano or C(O)NH2, wherein said alkyl and alkoxy are optionally substituted with OH, halogen, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, —S(C1-C4alkyl) or C3-C5cycloalkyl;
R10 is hydrogen or C1-C3alkyl;
m, n and t are each independently 0, 1 or 2;
q is 1, 2 or 3;
and
x is 1 or 2;
or a pharmaceutically acceptable salt thereof.

43 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/316,688Filed 7 Jul 2017
Priority: 14 Jul 2016
Published: 17 Oct 2019
Term ends: Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis

Family

Application62/362,098Us provisional application · filed 14 Jul 2016
US 10,906,888 B2Related patent
US 2019/0315715 A1This patent

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

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Abstract

A compound of Formula I,

wherein
G is a 6-membered heteroaryl, with one, two or three N, wherein the heteroaryl is optionally substituted with one, two or three substituents selected from C1-C4alkyl, —NR8aC(O)R8b, —NR8aSO2R8b, —(CR6aR6b)tC(O)N(R8a)2, —C(O)OH, halogen, cyano, —N(R8a)2, —(CR6aR6b)tSO2R8b, —(CR6aR6b)tSO2N(R8a)2, C1-C4alkoxy, OH, —S(C1-C3alkyl) or C3-C5cycloalkyl, wherein the alkyl, cycloalkyl and alkoxy are optionally substituted with one, two or three halogen, OH, OCH3, or C3-C5cycloalkyl;
L is NH or O;
Z is a bond;
—(CR5aR5b)q—;
—CH2(CR5aR5b)m—;
or —(CR5aR5b)m—W—(CR5aR5b)n—, wherein W is S, O or NR7;
Ra, Rb, R1a and R1b are each independently hydrogen, C1-C4alkyl, wherein the alkyl is optionally substituted with one, two or three halogen, OH, cyano, —S(C1-C3alkyl) or C1-C4alkoxy, optionally substituted with one, two or three fluoro;
or R1a and R1b, together with the carbon to which they are bonded, form an oxo, C3-C5cycloalkyl, -(4- to 5-membered heterocycloalkyl) wherein said cycloalkyl or heterocycloalkyl are optionally substituted with one, two, three or four halogen, OH, C1-C4alkyl, —S(C1-C3alkyl) C1-C4alkoxy or cyano;
and the heteroatom is selected from one or two N, S or O;
R2a and R2b are each independently hydrogen, —(CR6aR6b)tSO2R8b, OH, halogen, —(CR6aR6b)tC(O)N(R8a)2, —NR8aC(O)R8b, —NR8aC(O)N(R8a)2, —SO2N(R8a)2, C1-C4alkyl, C1-C4alkoxy, S(C1-C3alkyl), —(CR6aR6b)t—(C3-C6cycloalkyl), cyano, —(CR6aR6b)n-(5- to 6-membered heterocycloalkyl) or —(CR6aR6b)n-(5- to 6-membered heteroaryl), wherein said heteroatoms of said heteroalkyl and heteroaryl are selected from one, two or three N, O or S;
wherein said alkyl, cycloalkyl, heterocycloakyl and heteroaryl are optionally substituted with one, two, three or four R9;
or
R2a and R2b together with the carbon to which they are bonded form a C3-C9cycloalkyl or a -(4- to 11-membered heterocycloalkyl), having one to three heteroatoms selected from N, O or S;
wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one, two or three C1-C4alkyl, S(C1-C3alkyl), OH, halogen, oxo, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, C3-C5cycloalkyl or C1-C4alkoxy;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and one of R5a or R5b, together with the respective carbons to which they are bonded, form a C3-C12cycloalkyl, C6-C10aryl, -(5- to 6-membered heteroaryl) or a -(4- to 12-membered heterocycloalkyl), wherein said heteroaryl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R2a or R2b, and R7, together with the respective atoms to which they are bonded form a -(4- to 12-membered heterocycloalkyl) or a -(5- to 6-membered heteroaryl), wherein said heterocycloalkyl or heteroaryl have one, two to three heteroatoms selected from N, O or S, wherein said heterocycloalkyl and heteroaryl are optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
R3 is hydrogen, —(CR6aR6b)tC(O)NH2, or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R3 and Rb, together with the carbon to which they are attached, form an oxo;
R4 is hydrogen, —(CR6aR6b)tC(O)NH2, or C1-C4alkyl, wherein said alkyl is optionally substituted with one, two, three or four R9;
or
R3 and R4 taken together with the respective carbons to which they are bonded form a -(4- to 11-membered heterocycloalkyl), having one to two heteroatoms selected from N, O or S, wherein the heterocycloalkyl are optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R4 and Ra, together with the carbon to which they are attached, form an oxo;
R5a and R5b are each independently hydrogen, halogen, OH, —(CR6aR6b)tC(O)R8b, —(CR6aR6b)tC(O)NH2, C1-C4alkyl, S(C1-C3alkyl), C1-C4alkoxy, cyano, —(C R6aR6b)t—(C3-C6cycloalkyl) or —(CR6aR6b)t—(C3-C6heterocycloalkyl), wherein said alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9;
and the heteroatom is selected from one or two N, O, or S;
or
R5a and R5b taken together with the carbon to which they are bonded form a C3-C9cycloalkyl or a 4- to 11-membered heterocycloalkyl, wherein the heteroatom is selected from one or two N, S or O, wherein said cycloalkyl or heterocycloalkyl is optionally substituted with one, two, three or four R9;
or if substitution is at a N atom, then such N atom is substituted with R7;
or
R3 and either R5a or R5b taken together with the respective carbons to which they are bonded form a C3-C10cycloalkyl or -(4- to 12-membered heterocycloalkyl), wherein the heteroatom is selected from one or two N or O, wherein said cycloalkyl and heterocycloalkyl are optionally substituted with one, two, three or four R9 or oxo;
or if substitution is at a N atom, then such N atom is substituted with R7;
R6a and R6b are each independently hydrogen, C1-C4alkyl, S(C1-C3alkyl), OH, C1-C4alkoxy, cyano or halogen;
R7 is hydrogen;
-(4- to 6-membered heterocycloalkyl), having 1 to 2 heteroatoms wherein said heteroatom is selected from O, N and S;
C1-C5alkyl;
S(C1-C3alkyl);
C(O)R8b;
SO2R8b;
SO2N(R8a)2;
C(O)N(R8a)2 or —(C3-C7cycloalkyl), wherein said alkyl, heterocycloalkyl and cycloalkyl are optionally substituted with Ra;
R8a is hydrogen, C1-C4alkyl or —(C3-C7cycloalkyl);
R8b is C1-C4alkyl, —(C3-C7cycloalkyl), (CR6aR6b)tSO2N(R8a)2, —(CR6aR6b)tSO2R8a or —(CR6aR6b)tNHC(O)N(R8a)2;
R9 is hydrogen, C1-C4alkyl, S(C1-C3alkyl), OH, CH2OH, halogen, C1-C4alkoxy, cyano or —C(O)NH2, wherein said alkyl and alkoxy are optionally substituted with OH, halogen, —C(O)NH2, —C(O)NHCH3, —C(O)N(CH3)2, —S(C1-C4alkyl) or C3-C5cycloalkyl;
or R9 is oxo, provided that it is attached to a non-aromatic group;
R10 is hydrogen or C1-C3alkyl;
m, n and t are each independently 0, 1 or 2;
q is 1, 2 or 3;
and
x is 1 or 2;
or a pharmaceutically acceptable salt thereof.

55 more elements

Facts

Application

16/316,688Filed 7 Jul 2017

Priority

14 Jul 2016

Published

17 Oct 2019

Term ends

Not estimatedThe source records don’t support an estimate.

Classification29 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis