	US 7,579,356 B2
	Thia-tetraazaacenaphthylene kinase inhibitors
Kathleen A. Battista, Williamstown, N.J. (US); Gilles C. Bignan, Bridgewater, N.J. (US); Peter J. Connolly, New Providence, N.J. (US); Stuart Hayden, Point Pleasant, N.J. (US); Sigmond G. Johnson, Flemington, N.J. (US); Ronghui Lin, East Brunswick, N.J. (US); Niranjan B. Pandey, White Marsh, Md. (US); and Mark T. Powell, Newtown, Pa. (US)
Assigned to Janssen Pharmaceutica NV, Beerse (Belgium)
Filed on Apr. 10, 2006, as Appl. No. 11/401,339.
Claims priority of provisional application 60/677542, filed on May 04, 2005.
Prior Publication US 2007/0265264 A1, Nov. 15, 2007
Int. Cl. A01N 43/54 (2006.01); A61K 31/515 (2006.01); C07D 239/00 (2006.01); C07D 471/00 (2006.01); C07D 487/00 (2006.01); C07D 491/00 (2006.01)

U.S. Cl. 514—267 [544/251]

27 Claims

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein

L¹is selected from the group consisting of hydrogen, —N(R₁R₂), —C(O)N(R₁R₂), —C(O)O(R₁), —S(C_1-4alkyl), NO₂, —(CH₂)_p—Ar¹, —C(O)—(CH₂)_p—Ar¹, —N(R₁)—(CH₂)_p—Ar¹, —N(R₁)C(O)—(CH₂), —Ar¹, -N(R₁)C(O)N(R₂)—(CH₂)_p—Ar₁and -C(O)N(R₁)-(CH2)_p—Ar¹,

R₁is selected from the group consisting of hydrogen, C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl, amino-C_1-8alkoxy-C_1-8alkyl and C_1-8alkyl-amino-C_1-8alkoxy-C_1-8alkyl;

R₂is selected from the group consisting of hydrogen, C_1-8alkyl, C_1-8alkoxy-C_1-8alkyl, hydroxy-C_1-8alkyl, amino-C_1-8alkyl, C_1-8alkyl-amino-C_1-8alkyl and C_1-8alkoxy-carbonyl-amino-C_1-8alkyl;

p is 0, 1, 2, 3 or 4,

L²is selected from the group consisting of —(C_1-8alkyl)-, —N(R₁)— and a bond,

Ar¹is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl, each optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(1)C_1-8alkyl,

(2)C_2-8alkenyl,

(3)C_2-8alkynyl,

(4)C_1-8alkoxy,

wherein each (1), (2), (3) and (4) is optionally substituted with one, two or three substituents independently selected from the group consisting of

(i) C_3-8cycloalkyl,

(ii) aryl,

(iii) heteroaryl,

(iv)heterocyclyl,

wherein each (i), (ii), (iii) and (iv) is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy,

(d) halo-C_1-8alkyl,

(e) hydroxy-C_1-8alkyl,

(f) C_1-8alkoxy-carbonyl,

(g) amino optionally mono or disubstituted with C_1-8alkyl or C_1-8alkoxy-carbonyl,

(h) cyano,

(i) halogen,

(j) hydroxy,

(k) amino-C_1-8alkyl optionally mono or disubstituted on amino with C_1-8alkyl,

(l) C_3-8cycloalkyl,

(m) C_3-8cycloalkyl-C_1-8alkyl,

(n) heterocyclyl optionally substituted with one or two C_1-8alkyl substituents, and

(o) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(v) amino optionally mono or disubstituted with a substituent independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy-C_1-8alkyl,

(d) C_3-8cycloalkyl,

(e) heterocyclyl optionally substituted with one or two C_1-8alkyl substituents, and

(f) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(vi) hydroxy,

(vii) halogen, and

(viii) C_1-8alkoxy-carbonyl,

(5) amino optionally mono or disubstituted with a substituent independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy-C_1-8alkyl,

(iii) amino-C_1-8alkyl optionally mono or disubstituted on amino with C_1-8alkyl,

(iv) hydroxy-C_1-8alkyl,

(v) C_3-8cycloalkyl, (vi) heterocyclyl optionally substituted with one or two C_1-8alkyl substituents, and (vii) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(6) cyano,

(7) halogen,

(8) hydroxy,

(9) C_3-8cycloalkyl,

(10) aryl,

(11) heteroaryl,

(12) heterocyclyl,

(13) —O— substituted with a substituent selected from the group consisting of

(i) CF₃,

(ii) C_3-8cycloalkyl,

(iii) aryl,

(iv) heteroaryl, and

(v) heterocyclyl,

(14) heterocyclyl-SO₂optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(15) C(O) substituted with a substituent selected from the group consisting of

(i) hydrogen,

(ii) hydroxy,

(iii) C_1-8alkyl,

(iv) C_1-8alkoxy, and

(v) amino optionally mono or disubstituted with a substituent independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy-C_1-8alkyl,

(d) hydroxy-C_1-8alkyl,

(e) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C₁alkyl substituents,

(f) C_3-8cycloalkyl, and

(g) aryl; and

(16) amino-SO₂optionally mono or disubstituted on amino with a substituent independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) C_1-8alkoxy-C_1-8alkyl,

(iii) amino-C_1-8alkyl optionally mono or disubstituted on amino with C_1-8alkyl,

(iv) hydroxy-C_1-8alkyl,

(v) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(vi) C_3-8cycloalkyl, and

(vii) aryl; and 2

Ar²is selected from the group consisting of aryl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl, each optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(1) C_1-8alkyl,

(2) C_2-8alkenyl,

(3) C_2-8alkynyl,

(4) C_1-8alkoxy,

wherein each (1), (2), (3) and (4) is optionally substituted with one, two or three substituents independently selected from the group consisting of

(i) C_1-8alkoxy,

(ii) cyano,

(iii) halogen,

(iv) hydroxy,

(v) C_3-8cycloalkyl,

(vi) aryl,

(vii) heteroaryl,

(viii) heterocyclyl,

wherein each (v), (vi), (vii) and (viii) is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy,

(d) amino optionally mono or disubstituted with C_1-8alkyl,

(e) cyano,

(f) halogen,

(g) halo-C_1-8alkyl,

(h) hydroxy,

(i) hydroxy-C_1-8alkyl,

(j) C_3-8cycloalkyl, and

(k) heterocyclyl optionally substituted with one or two C_1-8alkyl substituents,

(ix) amino optionally mono or disubstituted with a substituent independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy-C_1-8alkyl,

(d) C_3-8cycloalkyl,

(e) heterocyclyl optionally substituted with one or two C₁alkyl substituents, and

(f) heterocyclyl-C₁alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents, and

(x) C(O)amino optionally mono or disubstituted with a substituent independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy-C_1-8alkyl,

(d) C_3-8cycloalkyl,

(e) aryl optionally substituted with one to three halogen substituents,

(f) heterocyclyl optionally substituted with one or two C_1-8alkyl substituents, and

(g) heterocyclyl-C_1-8alkyl optionally substituted on heterocyclyl with one or two C_1-8alkyl substituents,

(5) NH, NHC(O), N, S, S(O), SO₂or 0 substituted with one or two substituents independently selected from the group consisting of

(i) hydrogen,

(ii) C_1-8alkyl,

(iii) C_1-8alkoxy-C_1-8alkyl,

(iv) amino-C_1-8alkyl optionally mono or disubstituted on amino with C_1-8alkyl,

(v) hydroxy-C_1-8alkyl,

(vi) aryl,

(vii) heteroaryl,

(viii) benzofused heteroaryl,

(ix) C_3-8cycloalkyl,

(x) heterocyclyl,

xi) benzofused heterocyclyl,

(xii) aryl-C_1-8alkyl,

(xiii) heteroaryl-C_1-8alkyl,

(xiv) benzofused heteroaryl-C_1-8alkyl,

(xv) C_3-8cycloalkyl-C_1-8alkyl,

(xvi) heterocyclyl-C_1-8alkyl, and

(xvii) benzofused heterocyclyl-C_1-8alkyl,

wherein each aryl, C_3-8cycloalkyl, heteroaryl, benzofused heteroaryl, heterocyclyl and benzofused heterocyclyl in one or more of from (vi) to (xvii) is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(a) C_1-8alkyl,

(b) C_1-8alkoxy,

(d) amino optionally mono or disubstituted with C_1-8alkyl, and

(e) halogen,

(6) C(O) substituted with a substituent independently selected from the group consisting of

(i) hydrogen,

(ii) C_1-8alkyl optionally substituted with one, two or three substituents independently selected from the group consisting of

(a) cyano,

(b) halogen, and

(iii) C_1-8alkoxy,

(iv) hydroxy, and

(v) C_1-8alkoxy-C_1-8alkoxy,

(7) cyano,

(8) halogen,

(9) hydroxy,

(10) nitro,

(11) C_3-8cycloalkyl,

(12) aryl,

(13) heteroaryl,

(14) benzofused heteroaryl,

(15) heterocyclyl, and

(16) benzofused heterocyclyl;

wherein each (11), (12), (13), (14), (15) and (16) is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of

(i) C_1-8alkyl,

(ii) cyano,

(iii) halogen,

(iv) hydroxy,

(v) nitro,

(vi) C_3-8cycloalkyl,

(vii) C_3-8cycloalkyl-C_1-8alkyl,

(viii) aryl,

(ix) aryl-C_1-8alkyl,

(x) heteroaryl,

(xi) heteroaryl-C_1-8alkyl,

(xii) heterocyclyl, and

(xiii) heterocyclyl-C_1-8alkyl.