IP Library › Granted Patent US 8,372,973

Granted Patent B2

US 8,372,973 · App. 12/970,461 · Granted Feb 12, 2013

Prokineticin 1 receptor antagonists

Inventors: Steven J. Coats (McDonough, GA); Alexey B. Dyatkin (Maple Glen, PA); Wei He (Audubon, PA); Joseph Lisko (Glenmoore, PA); Tamara Miskowski (Chalfont, PA); Janet L. Ralbovsky (Yorktown Heights, NY); Mark Schulz (Skippack, PA)

Assignee: Janssen Pharmaceutica N.V.

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Quick Facts

Patent No.: US 8,372,973
App. No.: 12/970,461
Granted: Feb 12, 2013
Kind: B2

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Abstract

The present invention relates to certain novel compounds of Formula (I): and methods for preparing these compounds, compositions, intermediates and derivatives thereof and for the treatment of prokineticin 1 or prokinetin 1 receptor mediated disorders.

Claims (280)

1. A compound of Formula (I):

wherein:

A 1 is CF 3 , C 1-4 -alkoxy, aryl, aryloxy, benzofused heterocyclyl, or heteroaryl; wherein aryl, aryloxy, and heteroaryl are optionally substituted with pyrazol-1-yl or [1,2,3]thiadiazol-4-yl; or aryl, aryloxy, the benzo portion of benzofused heterocyclyl, and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, hydroxy(C 1-6 )alkyl, C 1-6 alkoxy, halogen, nitro, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, hydroxy, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkoxycarbonylamino, C 1-6 alkylcarbonyl, C 1-6 alkylthiocarbonyl, formyl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfonylamino, aminosulfonyl, C 1-6 alkylaminosulfonyl, and di(C 1-6 alkyl)aminosulfonyl; provided that A 1 is other than 3,5-di-t-butyl-phenyl;

L 1 is —(CH 2 ) r —, —CH 2 C 2-4 alkenyl-, or —CH 2 CH 2 X(CH 2 ) s —, wherein L 1 is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and halogen; and, r is an integer of 1 to 5; such that r is greater than or equal to 4 when A 1 is C 1-4 -alkoxy;

s is an integer of 1 to 3;

X is O or S;

D is -P-A 2 ;

wherein P is —(CH 2 ) 1-2 —or —CH 2 CH═CH— when A 2 is phenyl, benzofused heterocyclyl, heteroaryl, or C 3-8 cycloalkyl; alternatively, P is —(CH 2 ) 3-6 — when A 2 is hydrogen, C 1-4 -alkoxy, or C 1-4 alkoxycarbonyl; and wherein P is optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and halogen;

A 2 is hydrogen, C 1-4 -alkoxy, C 1-4 -alkoxycarbonyl, phenyl, benzofused heterocyclyl, heteroaryl, tetrahydro-pyranyl, piperidinyl, or C 3-8 cycloalkyl; wherein phenyl, heteroaryl, the benzo portion of benzofused heterocyclyl, and C 3-8 cycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, halogen, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, aryl(C 1-6 )alkoxy, phenyl, N-isoindole-1,3-dione, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, cyano, hydroxy, nitro, C 1-6 alkylcarbonyl, C 1-6 alkylthiocarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl, di(C 1-6 alkyl)aminocarbonyl, C 1-6 alkylcarbonylamino, and a non fused C 3-6 cycloalkyloxy; such that no more than two substituents on A 2 are aryl(C 1-6 )alkoxy, phenyl, N-isoindole-1,3-dione, or a non fused C 3-6 cycloalkyloxy;

provided that A 2 is other than 3,5-di-t-butyl-phenyl;

W is C(R W ); wherein R W is H or C 1-2 alkyl;

Q is selected from the group consisting of (a) to (g), wherein

(a) is —NH(CH 2 ) 2 —Ar 1 wherein Ar 1 is pyridinyl optionally substituted one to three C 1-4 -alkyl substituents or a substituent selected from the group consisting of C 1-4 -alkoxy and amino;

provided that when Ar 1 is unsubstituted pyridin-3-yl or unsubstituted pyridin-4-yl, and A 2 is 4-methoxy-phenyl, A 1 is other than unsubstituted phenyl or 3,4-dichloro-phenyl;

(b) is —NHCH(R z )—Ar 2 wherein R Z is H or C 1-3 alkyl; Ar 2 is pyridinyl, pyrimidinyl, pyrazinyl,

1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position; and wherein Ar 2 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, trifluoromethyl, hydroxyl-C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 -alkyl)amino-(C 1-4 )alkyl, di(C 1-4 -alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, C 3-8 cycloalkylamino, amino, (C 1-6 alkyl)amino, and di(C 1-6 alkyl)amino; or Ar 2 is optionally substituted with one amino group and three substituents independently selected from the group consisting of C 1-4 -alkyl and C 1-4 alkoxy;

wherein the C 1-6 alkyl group of (C 1-6 alkyl)amino and di(C 1-6 alkyl)amino is optionally substituted with amino, (C 1-4 -alkyl)amino, di(C 1-4 -alkyl)amino, C 3-8 cycloalkylamino, C 1-4 alkoxy, C 1-4 -alkylthio, hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 membered heterocyclyl; wherein a nitrogen atom of the 5 to 6 membered heterocyclyl is optionally substituted with a C 1-4 -alkyl substituent;

and wherein pyridin-2-yl and pyridin-3-yl are optionally further substituted with N-pyrrolidinyl, N-piperazinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, —CH 2 -O-CH 2 —PH, and phenyl; wherein the phenyl substituent of pyridin-2-yl and pyridin-3-Y1 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), and A 1 is pyridin-4-yl, 4-C 1-6 alkyl-phenyl, 3,4-dichloro-phenyl, or 4-methanesulfonyl-phenyl, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), L 1 is —(CH 2 ) 2 — or —(CH 2 ) 5 —, and A 1 is methoxy, A 2 is other than 4-difluoromethoxy-phenyl or 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), and A 1 is benzotriazol-1-yl, A 2 is other than 4-difluoromethoxy-phenyl;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), L 1 is —(CH 2 ) 3 —, and A 1 is pyrrol-1-yl, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), L 1 is —(CH 2 ) 2 —, and A 1 is 4-nitro-phenyl or ethoxy, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (2-amino-pyridin-3-yl), and A 1 is 4-fluoro-phenyl, A 2 is other than 4-fluoro-phenyl;

provided that when Q is —NHCH 2 (6-amino-pyridin-2-yl), and A 1 is 4-fluoro-phenyl, A 2 is other than 4-trifluoromethoxy-phenyl;

provided that when Q is —NHCH 2 (6-methyl-pyridin-2-yl), and A 1 is 4-methoxy-phenyl, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (imidazo[1,2-a]pyridinyl), and A 1 is 4-fluoro-phenyl, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (pyridin-4-yl), and A 1 is unsubstituted phenyl or 3,4-dichloro-phenyl, A 2 is other than 4-methoxy-phenyl;

provided that when Q is —NHCH 2 (4,6-dimethyl-pyridin-3-yl), and A 1 is 4-methoxy-phenyl, —P-A 2 is other than —(CH 2 )-5-methoxy;

provided that when Q is —NHCH 2 (4,6-dimethyl-pyridin-3-yl), L 1 is —(CH 2 ) 2 —, and A 1 is pyrazol-1-yl, A 2 is other than 4-difluoromethoxy-phenyl;

provided that when Q is —NHCH 2 (4,6-dimethyl-pyridin-3-yl) and A 1 is 4-methoxy-phenyl, A 2 is other than 2-ethyl-phenyl, 4-ethyl-phenyl, 3-methoxy-phenyl, 3-cyano-phenyl, 3-nitro-phenyl, and 3-trifluoromethyl-4-nitro-phenyl;

provided that when Q is —NHCH 2 (4,6-dimethyl-pyridin-3-yl) and A 1 is quinolin-8-yl, benzotriazol-1-yl, 3,5-dimethyl-pyrazolyl, 2-fluoro-phenyl, 2-chloro-phenyl, 2-nitro-phenyl, 2-trifluoromethyl-phenyl, 2-difluoromethoxy-phenyl, 3-difluoromethoxy-phenyl, 2-trifluoromethoxy-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dichloro-phenyl, 2-chloro-4-fluoro-phenyl, 2,6-difluoro-4-methoxy-phenyl, or 4-trifluoromethoxy-phenyl, A 2 is other than 4-difluoromethoxy-phenyl;

and, provided that when Q is —NHCH 2 (4,6-dimethyl-pyridin-3-yl) and A 1 is 3-nitro-4-methoxy-phenyl, 2,6-difluoro-4-methoxy-phenyl, or 3,4-dichloro-phenyl, A 2 is other than 4-methoxy-phenyl;

(c) is —CH 2 NHCH 2 —Ar 3 , wherein W is CH, and Ar 3 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and that the point of attachment to quinolinyl is at the 2, 3, or 4-position; wherein Ar 3 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 -alkyl)amino-(C 1-4 )alkyl, di(C 1-4 -alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, and di(C 1-6 alkyl)amino;

and wherein the C 1-6 alkyl group of (C 1-6 alkyl)amino and di(C 1-6 alkyl)amino is optionally substituted with amino, (C 1-4 -alkyl)amino, di(C 1-4 -alkyl)amino, C 3-8 cycloalkylamino, C 1-4 alkoxy, or hydroxy;

(d) is —(CH 2 ) 2 —Ar 4 , wherein Ar 4 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position; wherein Ar 4 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 alkyl)amino-(C 1-4 )alkyl, di(C 1-4 -alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, halogen, and aminocarbonyl;

(e) is —CH═CH—Ar 5 ; wherein Ar 5 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position; wherein Ar 5 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 alkyl)amino-(C 1-4 )alkyl, di(C 1-4 -alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, halogen, and aminocarbonyl;

(f) is —O—CH(R 1 )—Ar 6 when W is CH; or (f) is —S—CH(R 1 )—Ar 6 and W is CH; wherein R 1 is hydrogen or C 1-4 -alkyl, and Ar 6 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position;

wherein Ar 6 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 alkyl)amino-(C 1-4 )alkyl, di(C 1-4 alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, halogen, and aminocarbonyl;

and wherein the C 1-6 alkyl group of (C 1-6 alkyl)amino and di(C 1-6 alkyl)amino is optionally substituted with amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, C 3-8 cycloalkylamino, C 1-4 alkoxy, or hydroxy;

provided that when Q is —O—CH(R 1 )—Ar 6 , A 1 and A 2 are 4-methoxy-phenyl, and R 1 is hydrogen, Ar 6 is other than unsubstituted pyridin-2-yl or 2-amino-pyridin-4-yl;

and

(g) is —X 1 -(CH(R x )) 2 —Ar 7 when W is CH; wherein X 1 is O or S, R x is H or C 1-4 -alkyl, and Ar 7 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position;

wherein Ar 7 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, amino(C 1-4 )alkyl, (C 1-4 alkyl)amino-(C 1-4 )alkyl, di(C 1-4 alkyl)amino-(C 1-4 )alkyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, halogen, and aminocarbonyl;

provided that when Q is −0(CH 2 ) 2 —Ar 7 and A 1 and A 2 are 4-methoxy-phenyl, Ar 7 is other than unsubstituted pyridin-2-yl or unsubstituted pyridin-3-yl;

wherein a nitrogen atom of Ar 1 , Ar 2 , Ar 3 , Ar 4 , Ar 5 , Ar 6 , and Ar 7 is optionally substituted with oxo;

and an enantiomer, a diastereomer, a tautomer, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein A 1 is aryl, heteroaryl, or a benzofused heterocyclyl selected from the group consisting of benzo[1,3]dioxalyl and 2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 alkoxy, nitro, fluoro, chloro, iodo, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, and C 1-4 alkylthio; provided that A 1 is other than 3,5-di-t-butyl-phenyl.

3. The compound of claim 1 wherein A 1 is substituted phenyl, benzotriazolyl, benzofuranyl, benzo[1,3]dioxalyl, or 2,3-dihydro-benzofuranyl; wherein phenyl is substituted with, and benzotriazolyl and benzofuranyl are optionally substituted with, one to three substituents independently selected from the group consisting of C 1-4 -alkyl, C 1-4 alkoxy, nitro, fluoro, chloro, iodo, halogenated C 1-4 alkyl, halogenated C 1-4 alkoxy, and C 1-4 alkylthio; provided that A 1 is other than 3,5-di-t-butyl-phenyl.

4. The compound of claim 2 wherein A 1 is aryl, heteroaryl, or a benzofused heterocyclyl selected from the group consisting of benzo[1,3]dioxalyl and 2,3-dihydro-benzofuranyl; wherein aryl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-3 alkyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, and methylthio.

5. The compound of claim 4 wherein A 1 is substituted phenyl, heteroaryl, or a benzofused heterocyclyl selected from the group consisting of benzo[1,3]dioxalyl and 2,3-dihydro-benzofuranyl; wherein substituted phenyl and heteroaryl are optionally substituted with one to three substituents independently selected from the group consisting of C 1-3 alkyl, methoxy, fluoro and methylthio.

6. The compound of claim 5 wherein A 1 is substituted phenyl, benzotriazolyl, benzofuranyl, benzo[1,3]dioxalyl, or 2,3-dihydro-benzofuranyl; wherein phenyl is substituted at the 4-position with methoxy, fluoro, or methylthio; and wherein A 1 other than substituted phenyl is optionally substituted with one to two substituents independently selected from the group consisting of methyl, methoxy, fluoro and methylthio.

7. The compound of claim 1 wherein L 1 is —(CH 2 ) r —, wherein L 1 is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 -alkyl and C 2-4 alkenyl and r is 1 or 2.

8. The compound of claim 7 wherein L 1 is —CH 2 —.

9. The compound of claim 1 wherein P is —(CH 2 ) 1-2 — when A 2 is phenyl, benzofused heterocyclyl, heteroaryl, or C 3-8 cycloalkyl; alternatively, P is —(CH 2 ) 4-6 —when A 2 is hydrogen, C 1-4 -alkoxy, or C 1-4 -alkoxycarbonyl.

10. The compound of claim 9 wherein P is —CH 2 — when A 2 is phenyl, benzofused heterocyclyl, heteroaryl, or C 3-8 cycloalkyl; alternatively, P is —(CH 2 ) 4-6 — when A 2 is hydrogen, C 1-4 -alkoxy, or C 1-4 -alkoxycarbonyl.

11. The compound of claim 1 wherein A 2 is hydrogen, C 1-4 -alkoxy, C 1-4 alkoxycarbonyl, phenyl, benzofused heterocyclyl, heteroaryl other than pyridin-4-yl, or C 3-8 cycloalkyl; wherein phenyl, heteroaryl, and C 3-8 cycloalkyl are optionally substituted with one to two substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, fluoro, chloro, halogenated C 1-6 alkoxy, phenyl, N-isoindole-1,3-dione, C 1-6 alkylthio, C 1-6 alkylsulfonyl, C 1-6 alkoxycarbonyl, nitro, hydroxy, and C 1-6 alkylcarbonylamino; provided that no more than one substituent of A 2 is phenyl or N-isoindole-1,3-dione; and provided that A 2 is other than 3,5-di-t-butyl-phenyl.

12. The compound of claim 11 wherein A 2 is C 1-4 -alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl other than pyridin-4-yl; wherein phenyl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 -alkyl, C 1-4 alkoxy, fluoro, chloro, halogenated C 1-4 -alkoxy, N-isoindole-1,3-dione, C 1-4 -alkylthio, C 1-4 -alkylsulfonyl, C 1-4 -alkoxycarbonyl, nitro, hydroxy, and C 1-4 alkylcarbonylamino; provided that no more than one substituent of A 2 is N-isoindole-1,3-dione; and provided that A 2 is other than 3,5-di-t-butyl-phenyl.

13. The compound of claim 12 wherein A 2 is C 1-4 -alkoxy, phenyl, benzofused heterocyclyl, or a heteroaryl other than pyridin-4-yl; wherein phenyl and heteroaryl are optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 -alkoxy, fluoro, halogenated C 1-4 alkoxy, C 1-4 -alkylthio, C 1-4 alkylsulfonyl, C 1-4 alkoxycarbonyl, nitro, and hydroxy.

14. The compound of claim 13 wherein A 2 is C 1-4 alkoxy, phenyl, 2,3-dihydro-benzofuranyl, indolyl, benzofuranyl, pyridin-3-yl, or benzothiophenyl; wherein A 2 other than C 1-4 -alkoxy is optionally substituted with one to two substituents independently selected from the group consisting of C 1-4 -alkoxy, fluoro, fluorinated C 1-4 -alkoxy, C 1-4 alkylthio, C 1-4 -alkylsulfonyl, C 1-4 -alkoxycarbonyl, nitro, and hydroxy.

15. The compound of claim 1 wherein Q is selected from the group consisting of (a)-(g) wherein:

(a) is —NH(CH 2 ) 2 —Ar 1 wherein Ar 1 is pyridinyl substituted with one to three C 1-4 -alkyl substituents or a substituent selected from the group consisting of C 1-4 -alkoxy and amino;

(b) is —NHCH 2 —Ar 2 wherein Ar 2 is pyridinyl, pyrimidinyl, 1,2,3,4-tetrahydro-[1,8]naphthyridinyl, imidazo[1,2-a]pyridinyl, or quinolinyl; such that the point of attachment to 1,2,3,4-tetrahydro-[1,8]naphthyridinyl is at the 6 or 7 position, and the point of attachment to quinolinyl is at the 2, 3, or 4-position; and wherein Ar 2 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 alkyl, trifluoromethyl, C 1-4 -alkoxy, amino, (C 1-6 alkyl)amino, and di(C 1-6 alkyl)amino;

wherein the C 1-6 alkyl group of (C 1-6 alkyl)amino and di(C 1-6 alkyl)amino is optionally substituted with (C 1-4 -alkyl)amino, di(C 1-4 -alkyl)amino, C 1-4 -alkoxy, C 1-4 -alkylthio, hydroxy, a 5 to 6 membered heteroaryl, or a 5 to 6 membered heterocyclyl; wherein a nitrogen atom of the 5 to 6 membered heterocyclyl is optionally substituted with a C 1-4 alkyl substituent;

and wherein pyridin-2-yl and pyridin-3-yl are optionally further substituted with N-pyrrolidinyl, N-piperazinyl, N-piperidinyl, N-morpholinyl, N-thiomorpholinyl, and phenyl; wherein the phenyl substituent of pyridin-2-yl and pyridin-3-Y1 is optionally substituted with one to three substituents independently selected from the group consisting of C 1-4 -alkyl, C 1-4 -alkoxy, and halogen;