C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
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Abstract
The present invention provides novel C-linked cyclic compounds and analogues of Formula (I):
or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate form thereof, wherein the variables A, B, D and W are as defined herein. These compounds are selective inhibitors of the human P2Y1 receptor which can be used as medicaments.
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Citations
11 Claims
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1. A compound of Formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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2. A compound according to claim 1, wherein:
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ring B is C6-10 aryl substituted with 0-4 R7, or a 5- to 6-membered heteroaryl comprising;
carbon atoms and 1-4 ring heteroatoms selected from N, NR11, S(O)p, and O, wherein said heteroaryl is substituted with 0-4 R7;
W is —
NHC(O)NH—
, —
NHC(S)NH—
, NR18, O, S, —
NHCOCH═
CH—
, —
NHSO2—
, —
NHSO2CH2—
, or —
NHSO2CH═
CH—
; and
ring D is substituted with 0-5 R6a and selected from;
wherein D1 is a 5- to 7-membered carbocycle or a 5-6-membered heterocycle comprising;
carbon atoms and 0-3 ring heteroatoms selected from N, NR, O, and S(O)p, and 0-2 carbonyl groups, and 0-3 double bonds.
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3. A compound according to claim 1, wherein:
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ring A is substituted with 0-4 R1 and selected from;
phenyl, pyridyl, isoxazolyl, furanyl, thienyl, thiazolyl, benzothiazolyl and benzimidazolyl;
ring B is substituted with 0-3 R7 and selected from;
ring D is substituted with 0-5 R6a and selected from;
wherein D1 is selected from;
cyclopentyl, cylohexyl, piperidinyl, tetrahydropyranyl, phenyl, pyridinyl, pyrimidinyl, thiophenyl, pyrrolyl, furanyl, thiazolyl, imidazolyl, and oxazolyl;
W is —
NHC(O)NH—
, —
NHC(S)NH—
or NH;
R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —
CF2CF3, OCF3, —
OCF2CF2H, —
OCF2CF3, SiMe3, —
(CRfRf)rORc, SRc, CN, NO2, —
(CRfRf)r—
NR12R13, —
(CRfRf)u —
C(O)Rc, —
(CRfRf)r—
CO2Rc, —
(CRfRf)u—
C(O)NR12R13, —
OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, —
(CRfRf)u—
C3-6 carbocycle substituted with 0-2 Rb, or —
(CRfRf)u-5- to 6-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising;
carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-1 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-2 Rb;
R6a is, independently at each occurrence, F, Cl, Br, I, —
(CRiRi)r—
ORc, SRc, CN, CF3, OCF3, —
CF2CF3, —
OCF2CF2H, —
OCF2CF3, —
NR12R13, —
C(O)Rc, —
(CRfRf)r—
C(O)ORc, —
Si(Me)3, C1-4 haloalkyl, C1-4 haloalkyloxy-, C1-4 alkyloxy-, C1-4 alkylthio-, C1-C4 alkyl-C(O)—
, C1-4 alkyl-O—
C(O)—
, C1-4 alkyl-C(O)NH—
, C1-8 alkyl substituted with 0-2 Ra, C2-8 alkenyl substituted with 0-2 Ra, C2-8 alkynyl substituted with 0-2 Ra, —
(CRfRf)r—
C3-10 carbocycle substituted with 0-2 Re, or —
(CRfRf)r-5- to 10-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
alternatively, when two R6a groups are attached to the same carbon atom or silicon atom, together with the carbon atom or silicon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising;
carbon atoms and 0-3 heteroatoms selected from N, NR11, O, Si, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 Rb;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising;
carbon atoms and 0-2 heteroatoms selected from N, NR11, O, Si, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-3 Rb;
R7 is, independently at each occurrence, H, ═
O, F, Cl, Br, I, OCF3, CF3, ORc, SRc, CN, NO2, —
NR12R13, —
C(O)Rc, —
C(O)ORc, —
C(O)NR12R13, —
NR14C(O)Rd, —
S(O)pNR12R13, —
S(O)Rd, —
S(O)2Rd, C1-6 alkyl substituted with 0-2 Ra, —
(CH2)u—
C3-10 carbocycle substituted with 0-3 Rb, or —
(CH2)u-5- to 10-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NR7b, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Rb;
R11 is, independently at each occurrence, H, C1-8 alkyl substituted with 0-2 Ra, —
C(O)(CH2)n(C3-6 cycloalkyl), —
C(O)(CH2)nphenyl, —
C(O)O(C1-8 alkyl), —
C(O)O(CH2)n(C3-6 cycloalkyl), —
C(O)O(CH2)nphenyl, —
C(O)O(CH2)2-4(C1-4 alkyl), —
C(O)NH(C1 -6 alkyl), —
S(O)2(C1-6 alkyl), —
S(O)2(CH2)nphenyl, —
(CRfRf)r—
C3-7 cycloalkyl, —
(CRfRf)r-phenyl, or —
(CRfRf)r-5- to 6-membered heterocycle;
wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 Rb, and said heteroaryl and heterocycle are substituted with 0-2 Rb and comprise;
carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p;
R12 is, independently at each occurrence, H, C1-6 alkyl, —
C(O)(C1-6 alkyl), —
C(O)(CH2)nphenyl, —
C(O)(CH2)n(5- to 6-membered heteroaryl), —
(CH2)nC(O)NH(C1-6 alkyl), —
(CH2)nC(O)NHphenyl, —
(CH2)nC(O)NH(5- to 6-membered heteroaryl), —
S(O)2(C1-6 alkyl), —
S(O)2(CH2)nphenyl, —
S(O)2(CH2)n(5- to 6-membered heteroaryl), —
(CRfRf)n-phenyl, or —
(CRfRf)n-5- to 6-membered heteroaryl;
wherein said alkyl, and aryl are substituted with 0-2 Rg; and
said heteroaryl is substituted with 0-2 Rg and comprises;
carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p; and
R13 is, independently at each occurrence, H, C1-6 alkyl, or —
(CH2)n-phenyl;
alternatively, R12 and R13, when attached to the same nitrogen, combine to form a 5- to 10-membered heterocyclic ring comprising;
carbon atoms and 1-2 additional heteroatoms selected from N, NR11, O, and S(O)p.
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4. A compound according to claim 3, wherein:
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ring B is is substituted with 0-3 R7 and selected from;
W is —
NHC(O)NH—
or NH;
R1 is, independently at each occurrence, F, Cl, Br, I, CF3, —
CF2CF3, OCF3, —
OCF2CF2H, —
OCF2CF3, SiMe3, —
(CH2)r—
ORc, SRc, CN, NO2, —
(CH2)r—
NR12R13, —
(CH2)u—
C(O)Rc, —
(CH2)r—
CO2Rc, —
(CH2)uC(O)NR12R13, —
OP(O)(OEt)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C1-8 alkyl substituted with 0-2 Ra, —
(CH2)u—
C3-6 cycloalkyl substituted with 0-2 Rb, —
(CH2)u-phenyl substituted with 0-2 Rb, or —
(CH2)u-5- to 6-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NR11, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Rb;
alternatively, two R1s on two adjacent carbon atoms are combined with the carbon atoms to which they attached, form a 5- to 7-membered carbocycle or heterocycle comprising;
carbon atoms and 0-3 additional heteroatoms selected from N, NR11, O, and S(O)p, and 0-1 carbonyl groups, wherein said carbocycle or heterocycle is substituted with 0-2 Rb;
R6a is, independently at each occurrence, H, F, Cl, Br, I, CN, —
C(Me)2CN, C1-8 alkyl, C2-8 alkenyl, OH, SMe, S(i-Pr), —
C(Me)2OMe, —
C(Me)2OEt, —
C(Me)2OPr, —
CHMeO(CH2)2OMe, —
C(Me)2O(CH2)2OMe, —
C(Et)2OMe, —
C(Et)2OEt, COPh, —
CH═
CHCO2(t-Bu), CF3, OCF3, C1-4 alkyloxy, CO2Me, —
CH2CO2Me, C3-7 cycloalkyl, Ph, Bn, 1-pyrrolidinyl, 5-isoxazolyl, N-morpholinyl, 4-Bn-piperazinyl, 1-piperidinyl, 1-Bn-piperidin-4-yl, or —
Si(Me)3;
alternatively, when two R6a groups are attached to the same carbon atom, together with the carbon atom to which they are attached, they form a 3- to 7-membered carbocyclic or heterocyclic ring comprising;
carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
alternatively, when two R6a groups are attached to adjacent atoms, together with the atoms to which they are attached they form a 5- to 7-membered carbocyclic or heterocyclic ring comprising;
carbon atoms and 0-2 heteroatoms selected from N, NR11, O, and S(O)p, 0-1 carbonyl and 0-3 ring double bonds, wherein said carbocyclic or heterocyclic ring is substituted with 0-2 Rb;
R7 is, independently at each occurrence, H, Me, Cl, Br, CN, OMe, SMe, or NHMe;
R11 is, independently at each occurrence, C1-6 alkyl, —
CH2CH2OH, —
CH2CH2OMe, —
C(O)(C1-6 alkyl), —
C(O)phenyl, —
C(O)benzyl, —
C(O)O(C1-6 alkyl), —
C(O)Obenzyl, —
CH2CO2H, —
CH2CO2(C1-6 alkyl), —
C(O)NH(C1-6 alkyl), —
C(O)NHbenzyl, —
S(O)2(C1-6 alkyl), —
S(O)2phenyl, —
S(O)2benzyl, phenyl, or benzyl;
Ra is, independently at each occurrence, H, ═
O, F, OCF3, CF3, ORc, SRc, CN, —
NR12R13, —
C(O)Rc, —
C(O)ORc, —
C(O)NR12R13, —
NR14C(O)Rd, —
S(O)pNR12R13, —
S(O)Rd, —
S(O)2Rd, —
(CH2)u—
C3-6 cycloalkyl substituted with 0-2 Re, —
(CH2)u-phenyl substituted with 0-2 Re, or —
(CH2)u-5- to 6-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-2 Re;
Rb is, independently at each occurrence, H, F, Cl, Br, C1-4 alkyl, OH, CO2H, NH2, CF3, OCF3, C1-4 alkyloxy, C3-7 cycloalkyl, phenyl, or benzyl;
Rc is, independently at each occurrence, H, —
OP(O)(OEt)2, C1-8 alkyl substituted with 0-3 Re, C2-4 alkenyl substituted with 0-3 Re, C2-4 alkynyl substituted with 0-3 Re, —
(CH2)u—
C3-8 cycloalkyl substituted with 0-3 Re, —
(CH2)u—
C6-10 aryl substituted with 0-3 Re, or —
(CH2)u-5- to 10-membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Rd is, independently at each occurrence, CF3, OH, C1-4 alkoxy, C1-6 alkyl, —
(CH2)u—
C3-10 carbocycle substituted with 0-3 Re, or —
(CH2)u-5- to 10- membered heterocycle comprising;
carbon atoms and 1-4 heteroatoms selected from N, NRf, O, and S(O)p, wherein said heterocycle is substituted with 0-3 Re;
Re is, independently at each occurrence, H, F, Cl, C1-4 alkyl, OH, CO2H, NH2, CF3, OCF3, or C1-4 alkyloxy;
Rf is, independently at each occurrence, H, or C1-4 alkyl;
n, at each occurrence, is selected from 0, 1, and 2;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and
u, at each occurrence, is selected from 0, 1, and 2.
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5. A compound according to claim 4, wherein:
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ring A is substituted with 0-3 R1 and selected from;
phenyl, pyridyl, isoxazolyl, furanyl, thienyl, pyrrolyl, thiazolyl, benzothizolyl and benzimidazolyl;
ring B is is substituted with 0-2 R7 and selected from;
ring D is substituted with 0-2 R6a and selected from;
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6. A compound according to claim 1, wherein:
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ring A is 4-Me-Ph, 4-t-Bu-Ph, 4-OCF3-Ph, 2,4-diF-Ph, or 4-t-Bu-thiazol-2-yl;
ring B is ring D is;
W is —
NHC(O)NH—
or NH.
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7. A compound according to claim 1, wherein the compound is selected from the exemplified examples of the present invention or a stereoisomer or pharmaceutically acceptable salt, or solvate thereof.
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8. A pharmaceutical composition, comprising:
- a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
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9. A method for treating a thromboembolic disorder, comprising:
- administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.
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10. A method according to claim 9, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
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11. A method according to claim 9, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants, devices, or procedures in which blood is exposed to an artificial surface that promotes thrombosis.
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2. A compound according to claim 1, wherein:
Specification
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Current AssigneeBristol-Myers Squibb Company
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Original AssigneeBristol-Myers Squibb Company
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InventorsSutton, James C., Qiao, Jennifer X., Thibeault, Carl, Ruel, Rejean
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current514/252.03
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CPC Class CodesC07C 2601/02 with a three-membered ringC07C 2601/14 The ring being saturatedC07C 275/34 having nitrogen atoms of ur...C07C 275/42 being further substituted b...C07C 323/44 X or Y being nitrogen atomsC07D 209/14 Radicals substituted by nit...C07D 213/40 Acylated substituent nitrog...C07D 213/61 Halogen atoms or nitro radi...C07D 213/64 attached in position 2 or 6C07D 213/75 Amino or imino radicals, ac...C07D 215/12 with substituted hydrocarbo...C07D 235/14 Radicals substituted by nit...C07D 235/18 with aryl radicals directly...C07D 307/81 Radicals substituted by nit...C07D 307/87 Benzo [c] furans; Hydrogena...C07D 317/58 Radicals substituted by nit...C07D 333/58 Radicals substituted by nit...C07D 401/04 directly linked by a ring-m...C07D 405/04 directly linked by a ring-m...C07D 409/04 directly linked by a ring-m...C07D 417/12 : linked by a chain containin...