C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions

• US 20060293336A1
• Filed: 06/26/2006
• Published: 12/28/2006
• Est. Priority Date: 06/27/2005
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sutton, James C., Qiao, Jennifer X., Thibeault, Carl, Ruel, Rejean
• Granted Patent: US 7,700,620 B2
• Time in Patent Office: Days
• US Class Current: 514/252.03
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07C 275/34 having nitrogen atoms of urea groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 275/42 being further substituted by carboxyl groups
• CPC Class Codes: C07C 323/44 X or Y being nitrogen atoms
• CPC Class Codes: C07D 209/14 Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 213/40 Acylated substituent nitrogen atom
• CPC Class Codes: C07D 213/61 Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/64 attached in position 2 or 6
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 215/12 with substituted hydrocarbon radicals attached to ring carbon atoms
• CPC Class Codes: C07D 235/14 Radicals substituted by nitrogen atoms by nitro radicals C07D235/10
• CPC Class Codes: C07D 235/18 with aryl radicals directly attached in position 2
• CPC Class Codes: C07D 307/81 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/87 Benzo [c] furans; Hydrogenated benzo [c] furans
• CPC Class Codes: C07D 317/58 Radicals substituted by nitrogen atoms nitro radicals C07D317/52
• CPC Class Codes: C07D 333/58 Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links

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.

Claims

1. A compound of Formula (I):

2. A compound according to claim 1, wherein:

ring B is C_6-10 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 R^6a 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.

3. A compound according to claim 1, wherein:

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 R^6a 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, —

(CR^fR^f)_rOR^c, SR^c, CN, NO₂, —

(CR^fR^f)_r—

NR¹²R¹³, —

(CR^fR^f)_u —

C(O)R^c, —

(CR^fR^f)_r—

CO₂R^c, —

(CR^fR^f)_u—

C(O)NR¹²R¹³, —

OP(O)(OEt)₂, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C_1-8 alkyl substituted with 0-2 R^a, —

(CR^fR^f)_u—

C_3-6 carbocycle substituted with 0-2 R^b, or —

(CR^fR^f)_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 R^b;

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 R^b;

R^6a is, independently at each occurrence, F, Cl, Br, I, —

(CRⁱRⁱ)_r—

OR^c, SR^c, CN, CF₃, OCF₃, —

CF₂CF₃, —

OCF₂CF₂H, —

OCF₂CF₃, —

NR¹²R¹³, —

C(O)R^c, —

(CR^fR^f)_r—

C(O)OR^c, —

Si(Me)₃, C_1-4 haloalkyl, C_1-4 haloalkyloxy-, C_1-4 alkyloxy-, C_1-4 alkylthio-, C₁-C₄ alkyl-C(O)—

, C_1-4 alkyl-O—

C(O)—

, C_1-4 alkyl-C(O)NH—

, C_1-8 alkyl substituted with 0-2 R^a, C_2-8 alkenyl substituted with 0-2 R^a, C_2-8 alkynyl substituted with 0-2 R^a, —

(CR^fR^f)_r—

C_3-10 carbocycle substituted with 0-2 R^e, or —

(CR^fR^f)_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 R^e;

alternatively, when two R^6a 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 R^b;

alternatively, when two R^6a 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 R^b;

R⁷ is, independently at each occurrence, H, ═

O, F, Cl, Br, I, OCF₃, CF₃, OR^c, SR^c, CN, NO₂, —

NR¹²R¹³, —

C(O)R^c, —

C(O)OR^c, —

C(O)NR¹²R¹³, —

NR¹⁴C(O)R^d, —

S(O)_pNR¹²R¹³, —

S(O)R^d, —

S(O)₂R^d, C_1-6 alkyl substituted with 0-2 R^a, —

(CH₂)_u—

C_3-10 carbocycle substituted with 0-3 R^b, or —

(CH₂)_u-5- to 10-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^7b, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^b;

R¹¹ is, independently at each occurrence, H, C_1-8 alkyl substituted with 0-2 R^a, —

C(O)(CH₂)_n(C_3-6 cycloalkyl), —

C(O)(CH₂)_nphenyl, —

C(O)O(C_1-8 alkyl), —

C(O)O(CH₂)_n(C_3-6 cycloalkyl), —

C(O)O(CH₂)_nphenyl, —

C(O)O(CH₂)_2-4(C_1-4 alkyl), —

C(O)NH(C_{1 -6} alkyl), —

S(O)₂(C_1-6 alkyl), —

S(O)₂(CH₂)_nphenyl, —

(CR^fR^f)_r—

C_3-7 cycloalkyl, —

(CR^fR^f)_r-phenyl, or —

(CR^fR^f)_r-5- to 6-membered heterocycle;

wherein said alkyl, cycloalkyl, phenyl, and aryl are substituted with 0-2 R^b, and said heteroaryl and heterocycle are substituted with 0-2 R^b and comprise;

carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p;

R¹² is, independently at each occurrence, H, C_1-6 alkyl, —

C(O)(C_1-6 alkyl), —

C(O)(CH₂)_nphenyl, —

C(O)(CH₂)_n(5- to 6-membered heteroaryl), —

(CH₂)_nC(O)NH(C_1-6 alkyl), —

(CH₂)_nC(O)NHphenyl, —

(CH₂)_nC(O)NH(5- to 6-membered heteroaryl), —

S(O)₂(C_1-6 alkyl), —

S(O)₂(CH₂)_nphenyl, —

S(O)₂(CH₂)_n(5- to 6-membered heteroaryl), —

(CR^fR^f)_n-phenyl, or —

(CR^fR^f)_n-5- to 6-membered heteroaryl;

wherein said alkyl, and aryl are substituted with 0-2 R^g; and

said heteroaryl is substituted with 0-2 R^g 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, C_1-6 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.

4. A compound according to claim 3, wherein:

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—

OR^c, SR^c, CN, NO₂, —

(CH₂)_r—

NR¹²R¹³, —

(CH₂)_u—

C(O)R^c, —

(CH₂)_r—

CO₂R^c, —

(CH₂)_uC(O)NR¹²R¹³, —

OP(O)(OEt)₂, 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl, C_1-8 alkyl substituted with 0-2 R^a, —

(CH₂)_u—

C_3-6 cycloalkyl substituted with 0-2 R^b, —

(CH₂)_u-phenyl substituted with 0-2 R^b, 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 R^b;

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 R^b;

R^6a is, independently at each occurrence, H, F, Cl, Br, I, CN, —

C(Me)₂CN, C_1-8 alkyl, C_2-8 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, C_1-4 alkyloxy, CO₂Me, —

CH₂CO₂Me, C_3-7 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 R^6a 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 R^b;

alternatively, when two R^6a 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 R^b;

R⁷ is, independently at each occurrence, H, Me, Cl, Br, CN, OMe, SMe, or NHMe;

R¹¹ is, independently at each occurrence, C_1-6 alkyl, —

CH₂CH₂OH, —

CH₂CH₂OMe, —

C(O)(C_1-6 alkyl), —

C(O)phenyl, —

C(O)benzyl, —

C(O)O(C_1-6 alkyl), —

C(O)Obenzyl, —

CH₂CO₂H, —

CH₂CO₂(C_1-6 alkyl), —

C(O)NH(C_1-6 alkyl), —

C(O)NHbenzyl, —

S(O)₂(C_1-6 alkyl), —

S(O)₂phenyl, —

S(O)₂benzyl, phenyl, or benzyl;

R^a is, independently at each occurrence, H, ═

O, F, OCF₃, CF₃, OR^c, SR^c, CN, —

NR¹²R¹³, —

C(O)R^c, —

C(O)OR^c, —

C(O)NR¹²R¹³, —

NR¹⁴C(O)R^d, —

S(O)_pNR¹²R¹³, —

S(O)R^d, —

S(O)₂R^d, —

(CH₂)_u—

C_3-6 cycloalkyl substituted with 0-2 R^e, —

(CH₂)_u-phenyl substituted with 0-2 R^e, or —

(CH₂)_u-5- to 6-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-2 R^e;

R^b is, independently at each occurrence, H, F, Cl, Br, C_1-4 alkyl, OH, CO₂H, NH₂, CF₃, OCF₃, C_1-4 alkyloxy, C_3-7 cycloalkyl, phenyl, or benzyl;

R^c is, independently at each occurrence, H, —

OP(O)(OEt)₂, C_1-8 alkyl substituted with 0-3 R^e, C_2-4 alkenyl substituted with 0-3 R^e, C_2-4 alkynyl substituted with 0-3 R^e, —

(CH₂)_u—

C_3-8 cycloalkyl substituted with 0-3 R^e, —

(CH₂)_u—

C_6-10 aryl substituted with 0-3 R^e, or —

(CH₂)_u-5- to 10-membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^e;

R^d is, independently at each occurrence, CF₃, OH, C_1-4 alkoxy, C_1-6 alkyl, —

(CH₂)_u—

C_3-10 carbocycle substituted with 0-3 R^e, or —

(CH₂)_u-5- to 10- membered heterocycle comprising;

carbon atoms and 1-4 heteroatoms selected from N, NR^f, O, and S(O)_p, wherein said heterocycle is substituted with 0-3 R^e;

R^e is, independently at each occurrence, H, F, Cl, C_1-4 alkyl, OH, CO₂H, NH₂, CF₃, OCF₃, or C_1-4 alkyloxy;

R^f is, independently at each occurrence, H, or C_1-4 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.

5. A compound according to claim 4, wherein:

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 R^6a and selected from;

6. A compound according to claim 1, wherein:

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.

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.

8. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.

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.

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.

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.