US 9,040,541 B2Granted

4,6-disubstituted pyrimidines useful as kinase inhibitors

AssigneeCelgene Avilomics Research, Inc.

InventorsJuswinder Singh, Shomir Ghosh, Arthur Kluge, Russell C. Petter, Richland W. Tester

Life of this patent

Estimating the term…

Abstract

The present invention provides 4,6-disubstituted pyrimidine compounds useful as kinase inhibitors, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims24

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O or S, a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from N, O or S;
R1 is selected from the group consisting of:
or
R1 is a warhead group -L-Y selected from the following (a), (b), (c), (h), (i), (l), (m), (n), (o), and (p) combinations of -L- and —Y:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —O—, —N(R)—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) —CH2F, —CH2Cl or —CH2NO2;
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and
Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, or —SO2NH—;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2NO2, or —CH2CN;
or
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
Ry is hydrogen, halogen, CN, lower alkyl, or lower haloalkyl;
W is a bivalent C1-3 alkylene chain wherein one methylene unit of W is replaced by —NR2—, —N(R2)C(O)—, —C(O)N(R2)—, —N(R2)SO2—, —SO2N(R2)—;
R2 is optionally substituted C1-6 aliphatic, wherein R2 and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring;
m is 1, 2, 3 or 4;
each Rx is independently selected from —R, halogen, —OR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)NR2, —NRSO2R, or —N(R)2;
or:
Rx and R1 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with -Q-Z and 0-3 groups independently selected from oxo, halogen, CN, or C1-6 aliphatic;
and
each R group is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

156 more elements

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O or S, a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from N, O or S;
R1 is a warhead group -L-Y, wherein:
-L-Y is
or
L is —C(O)—, —N(R)C(O)—, —NH—, —CH2NH—, —NHCH2—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, —SO2NH—, or a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
Y is
or is selected from the following (i), (ii), (iii), (iv), (v), (vi), (vii), (viii), (ix), (x), (xi), (xii), (xiii), (xiv), (xv), (xvi), or (xvii):
(i) —CH2F, —CH2Cl, —CH2NO2, or —CH2CN;
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
Ry is hydrogen, halogen, CN, lower alkyl, or lower haloalkyl;
W is a bivalent C1-3 alkylene chain wherein one methylene unit of W is replaced by —NR2—, —N(R2)C(O)—, —C(O)N(R2)—, —N(R2)SO2—, —SO2N(R2)—;
R2 is optionally substituted C1-6 aliphatic, wherein R2 and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring;
m is 1, 2, 3 or 4;
each Rx is independently selected from —R, halogen, —OR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)NR2, —NRSO2R, or —N(R)2;
or:
Rx and R1 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with -Q-Z and 0-3 groups independently selected from oxo, halogen, CN, or C1-6 aliphatic;
and
each R group is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
Z is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN.

44 more elements

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O or S, a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from N, O or S;
R1 is a warhead group -L-Y, wherein:
L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two methylene units of L are independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
Y is C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
wherein:
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
Z is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN,
Ry is hydrogen, halogen, CN, lower alkyl, or lower haloalkyl;
W is a bivalent C1-3 alkylene chain wherein one methylene unit of W is replaced by —NR2—, —N(R2)C(O)—, —C(O)N(R2)—, —N(R2)SO2—, —SO2N(R2)—;
R2 is optionally substituted C1-6 aliphatic, wherein R2 and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring;
m is 1, 2, 3 or 4;
each Rx is independently selected from —R, halogen, —OR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)NR2, —NRSO2R, or —N(R)2;
or:
Rx and R1 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with -Q-Z and 0-3 groups independently selected from oxo, halogen, CN, or C1-6 aliphatic;
and
each R group is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/875,755Filed 2 May 2013 · continuation
Priority: 19 Oct 2007
Published: US 2013/0217688 A122 Aug 2013
Granted: 26 May 2015
Term ends: Not estimatedThe source records don’t support an estimate.

Classification45 codes

C07D 239/48
Two or more oxygen, sulphur or nitrogen atoms: two nitrogen atoms
A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol

Family

Application60/981,432Us provisional application · filed 19 Oct 2007
Application61/052,002Us provisional application · filed 9 May 2008
Application12/253,424Parent of this continuation · filed 17 Oct 2008
Application13/018,624Parent of this continuation · filed 1 Feb 2011
US 7,982,036 B2Parent of this continuation · filed 11 Jul 2011
US 2013/0217688 A1Pre-grant publication · published 22 Aug 2013
US 8,445,498 B2Parent of this continuation
US 2009/0137588 A1Published application
US 2011/0230494 A1Published application
US 9,040,541 B2This patent

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

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Abstract

The present invention provides 4,6-disubstituted pyrimidine compounds useful as kinase inhibitors, pharmaceutically acceptable compositions thereof, and methods of using the same.

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is an optionally substituted group selected from phenyl, an 8-10 membered bicyclic partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ring B is phenyl, a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from N, O or S, a 5-6 membered saturated heterocyclic ring having 1-2 heteroatoms independently selected from N, O or S, or an 8-10 membered bicyclic partially unsaturated or aryl ring having 1-3 heteroatoms independently selected from N, O or S;
R1 is selected from the group consisting of:
or
R1 is a warhead group -L-Y selected from the following (a), (b), (c), (h), (i), (l), (m), (n), (o), and (p) combinations of -L- and —Y:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by —C(O)—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —O—, —N(R)—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) —CH2F, —CH2Cl or —CH2NO2;
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and
Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, or —SO2NH—;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2NO2, or —CH2CN;
or
(ii) C2-6 alkenyl substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, diazonium, or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C1-6 saturated or unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, or —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
Ry is hydrogen, halogen, CN, lower alkyl, or lower haloalkyl;
W is a bivalent C1-3 alkylene chain wherein one methylene unit of W is replaced by —NR2—, —N(R2)C(O)—, —C(O)N(R2)—, —N(R2)SO2—, —SO2N(R2)—;
R2 is optionally substituted C1-6 aliphatic, wherein R2 and a substituent on Ring A are taken together with their intervening atoms to form a 4-6 membered saturated ring;
m is 1, 2, 3 or 4;
each Rx is independently selected from —R, halogen, —OR, —CN, —NO2, —SO2R, —SOR, —C(O)R, —CO2R, —C(O)N(R)2, —NRC(O)R, —NRC(O)NR2, —NRSO2R, or —N(R)2;
or:
Rx and R1 are taken together with their intervening atoms to form a 5-7 membered saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with -Q-Z and 0-3 groups independently selected from oxo, halogen, CN, or C1-6 aliphatic;
and
each R group is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

156 more elements

Facts

Application

13/875,755Filed 2 May 2013 · continuation

Priority

19 Oct 2007

Published

US 2013/0217688 A122 Aug 2013

Granted

26 May 2015

Term ends

Not estimatedThe source records don’t support an estimate.

Classification45 codes

C07D 239/48
Two or more oxygen, sulphur or nitrogen atoms: two nitrogen atoms
A61K 31/505
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrimidines; Hydrogenated…
A61K 31/506
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: not condensed and containing further heterocyclic rings
A61K 31/5377
1,4-Oxazines, e.g. morpholine: not condensed and containing further heterocyclic rings, e.g. timolol

Family

Application60/981,432Us provisional application · filed 19 Oct 2007

Application61/052,002Us provisional application · filed 9 May 2008

Application12/253,424Parent of this continuation · filed 17 Oct 2008

Application13/018,624Parent of this continuation · filed 1 Feb 2011

US 7,982,036 B2Parent of this continuation · filed 11 Jul 2011

US 2013/0217688 A1Pre-grant publication · published 22 Aug 2013

US 8,445,498 B2Parent of this continuation

US 2009/0137588 A1Published application

US 2011/0230494 A1Published application

US 9,040,541 B2This patent

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