US 7,601,714 B2
Pyrimidine derivatives useful as inhibitors of PKC-theta
Antonio J. M. Barbosa, Jr., Middlebury, Conn. (US); Steven Richard Brunette, New Milford, Conn. (US); Eugene Richard Hickey, Danbury, Conn. (US); Jin Mi Kim, Sandy Hook, Conn. (US); Michael David Lawlor, Seymour, Conn. (US); René Marc Lemieux, Plantsville, Conn. (US); Bryan McKibben, New Milford, Conn. (US); Matt Aaron Tschantz, Newtown, Conn. (US); and Hui Yu, New Milford, Conn. (US)
Assigned to Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Conn. (US)
Filed on Jul. 06, 2005, as Appl. No. 11/175,476.
Claims priority of provisional application 60/586289, filed on Jul. 08, 2004.
Prior Publication US 2006/0025433 A1, Feb. 02, 2006
This patent is subject to a terminal disclaimer.
Int. Cl. C07D 239/48 (2006.01); C07D 403/12 (2006.01); A61K 31/505 (2006.01)
U.S. Cl. 514—235.8  [514/255.05; 514/275; 544/122; 544/295; 544/323; 544/324] 9 Claims
 
1. A compound of the following formula (I):

OG Complex Work Unit Drawing
X is C1-6 alkyl wherein one or two of the methylene units can be replaced by an oxygen or sulfur atom, and wherein the C1-6alkyl group is optionally and independently substituted with:
(A) oxo,
(B) C1-6alkyl which is optionally substituted with one or more of the following groups:
(i) hydroxyl,
(ii) C1-3alkyloxy,
(iii) halogen,
(C) C1-6alkyloxy,
(D) C1-6alkylthio,
(E) aryl
(F) —COR6, wherein R6 is:
(i) C1-6alkyl,
(ii) C1-6alkyloxy,
(iii) —NR7R8, wherein R7 and R8 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) aryl,
(d) heteroaryl,
(iv) —OH,
(G) halogen,
(H) —NR9R10, wherein R9 and R10 are each independently selected from:
(i) hydrogen,
(ii) C1-6alkyl,
(iii) C1-6alkylcarbonyl,
(iv) C1-6alkylsylfonyl,
(v) aryl,
(vi) heteraoaryl;
Y is —NH—, —O— or —S—;
R1 is:
(A) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(i) C1-6alkyl, which is optionally substituted one or more of the following:
(a) halogen,
(b) NH2
(ii) C1-6alkoxy, which is optionally substituted with halogen,
(iii) C1-6alkylthio, which is optionally substituted with halogen,
(iv) C1-6alkylsulfonyl,
(v) cyano,
(vi) halogen,
(vii) hydroxyl,
(viii) nitro,
(ix) —COR11, wherein R11 is:
(a) C1-6alkyl,
(b) C1-6alkyloxy,
(c) —OH,
(d) —NR12R13, wherein R12 and R13 are each independently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(III) aryl,
(IV) heteroaryl,
(x) —NR14R15, wherein R14 and R15 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) C1-6alkylcarbonyl,
(d) C1-6alkylsulfonyl,
or wherein R14 and R15 together constitute an alkylene bridge which together with the nitrogen atom between them forms a five to seven-membered ring,
(xi) arylthio, arylsulfonyl or aryloxy, each optionally and independently substituted with one or more of the following groups:
(a) C1-6alkyl,
(b) C1-6alkoxy,
(c) C1-6alkylthio,
(d) C1-6alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR16R17, wherein R16 and R17 are each independently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(III) C1-6alkylcarbonyl,
(IV) C1-6alkylsulfonyl,
(B) C3-6cycloalkyl which is optionally and independently substituted with one or more of the following groups:
(i) C1-6alkyl, which is optionally substituted with halogen,
(ii) C1-6alkoxy, which is optionally substituted with halogen,
(iii) C1-6alkylthio, which is optionally substituted with halogen,
(iv) C1-6alkylsulfonyl,
(v) halogen,
(vi) hydroxyl,
(vii) —NR18R19, wherein R18 and R19 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) C1-6alkylcarbonyl,
(d) C1-6alkylsulfonyl,
(viii) —COR20, wherein R20 is:
(a) C1-6alkyl,
(b) C1-6alkyloxy,
(c) —OH,
(d) NR21R22, wherein R21 and R22 are each independently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(C) —COR23, wherein R23 is:
(i) C1-6alkyloxy,
(ii) —NR24R25, wherein R24 and R25 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
or wherein R24 and R25 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four to six-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(a) C1-6alkyloxy,
(b) C1-6alkyl, which is optionally substituted with halogen,
(c) hydroxyl,
(d) halogen,
(e) COR26, wherein R26 is:
(I) C1-6alkyloxy,
(II) NR27R28, wherein R27 and R28 are each independently selected from:
 a. hydrogen,
 b. C1-6alkyl,
 c. aryl,
 d. heteroaryl,
(D) is:

OG Complex Work Unit Drawing
which is optionally substituted with halogen;
(E) is selected from the following:

OG Complex Work Unit Drawing
R2 is selected from the following groups:
(A) CF3,
(B) cyano,
(C) halogen,
(D) nitro,
(E) C1-6alkylalkynyl,
(F) arylalkynyl which is optionally substituted with one or more of the following groups:
(i) halogen,
(ii) C1-6alkyl, which is optionally substituted with halogen,
R3 is selected from the following groups:

OG Complex Work Unit Drawing
R4 and R5 are each independently selected from:
(A) hydrogen,
(B) C1-6alkyl, optionally and independently substituted with one or more of the following groups:
(i) oxo,
(ii) C3-6cycloalkyl,
(iii) C1-6alkyloxy,
(iv) C1-6alkylthio,
(v) —COR29, wherein R29 is:
(a) C1-6alkyl,
(b) C1-6alkyloxy,
(c) —OH,
(vi) —CONR30R31, wherein R30 and R31 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) aryl,
(d) heteroaryl,
(vii) halogen,
(viii) hydroxyl,
(ix) —NR32R33, wherein R32 and R33 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) C1-6alkylcarbonyl,
(d) C1-6alkylsulfonyl,
(e) aryl,
(f) heteroaryl,
(x) aryl or heteroaryl, each optionally and independently substituted with one or more of the following groups:
(a) C1-6alkyl, which is optionally substituted with halogen,
(b) C1-6alkoxy, which is optionally substituted with halogen,
(c) C1-6alkylthio, which is optionally substituted with halogen,
(d) C1-6alkylsulfonyl,
(e) cyano,
(f) halogen,
(g) nitro,
(h) —NR34R35, wherein R34 and R35 are each independently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(III) C1-6alkylcarbonyl,
(IV) C1-6alkylsulfonyl,
(i) —COR36, wherein R36 is:
(I) C1-6alkyl,
(II) C1-6alkyloxy,
(III) —OH,
(j) —CONR37R38, wherein R37 and R38 are each independently selected from:
(I) hydrogen,
(II) C1-6alkyl,
(III) aryl,
(IV) heteroaryl,
(C) C1-6alkylsulfonyl,
(D) arylsulfonyl,
(E) aryl-C1-6alkylsulfonyl,
(F) heteroarylsulfonyl,
(G) C1-6alkylcarbonyl,
(H) arylcarbonyl,
(I) aryl-C1-6alkylcarbonyl,
(J) heteroarylcarbonyl,
(K) C1-6alkylaminocarbonyl, or
(L) heteroaryl,
or wherein R4 and R5 together constitute an alkylene bridge which together with the nitrogen atom between them forms a four- to seven-membered ring, wherein one of the methylene groups is optionally replaced by an oxygen, sulfur or NH group, and which ring is optionally and independently substituted with one or more of the following groups:
(A) C1-6alkyl, which is optionally substituted with halogen,
(B) C1-6alkoxy, which is optionally substituted with halogen,
(C) C1-6alkylthio, which is optionally substituted with halogen,
(D) C1-6alkylsulfonyl,
(E) halogen,
(F) —NR39R40, wherein R39 and R40 are each independently selected from:
(i) hydrogen,
(ii) C1-6alkyl,
(iii) C1-6alkylcarbonyl,
(iv) C1-6alkylsulfonyl,
(v) arylcarbonyl,
(vi) arylsulfonyl
(vii) heteroarylcarbonyl,
(viii) heteroarylsulfonyl,
(G) —COR41, wherein R41 is:
(i) C1-6alkyl,
(ii) C1-6alkyloxy,
(iii) —NR42R43, wherein R42 and R43 are each independently selected from:
(a) hydrogen,
(b) C1-6alkyl,
(c) aryl,
(d) heteroaryl,
(iv) hydroxyl,
(H) —OR44, wherein R44 is selected from:
(i) hydrogen,
(ii) C1-6alkylcarbonyl,
(iii) C1-6alkylsulfonyl
(I) oxo,
or wherein NR4R5 constitutes a 5-membered heteroaryl ring containing a total of 2 nitrogen hetero atoms in the ring;
or a tautomer or pharmaceutically acceptable salt thereof or a corresponding compound having at least one amine group protected by an amino-protecting group.