US 8,044,209 B2Granted

Pyrrolydine derivatives as IAP inhibitors

AssigneeNovartis AG

InventorsMark G. Charest, Christine Hiu-Tung Chen, Ming Chen, Zhuoliang Chen, Miao Dai, Feng He, Huangshu Lei, Christopher Sean Straub, Run-Ming David Wang, Leigh Zawel

Life of this patent

Estimating the term…

Abstract

The present invention relates to novel IAP inhibitor compounds of: Formula (I).

Claims10

Dependent claims

A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C10 cycloalkyl, where said R1 is unsubstituted or substituted;
R2 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, where said R2 is unsubstituted or substituted;
or
R1 and R2 may be taken together to form a ring or het;
R3 and R3′ are each independently H, CF3, C2F5, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CH2—Z or R2 and R3 taken together with the nitrogen atom to which they are attached form het, wherein said alkyl, said alkenyl, said alkynyl and said het ring are unsubstituted or substituted;
Z is H, OH, F, Cl, CH3, CH2Cl, CH2F or CH2OH;
R4 is C0-10 alkyl, C0-10 alkyl-C3-10 cycloalkyl, C0-10alkyl-C6-10aryl, C0-10alkyl-het, wherein any carbon may be replaced with a heteroatom or group from the list N, O, S(O)r and any atom may be unsubstituted or substituted;
A is a 6 membered heteroaryl ring;
r is 0, 1, or 2;
Q and Y are each independently H, F, Cl, Br, I, C1-C10 alkyl, C1-C10 alkoxy, aryl C1-C10 alkoxy, OH, O—C1-C10-alkyl, (CH2)0-6—C3-C7 cycloalkyl, aryl, aryl C1-C10 alkyl, O—(CH2)0-6 aryl, (CH2)1-6het, het, O—(CH2)1-6het, —OR11, C(O)R11, —C(O)N(R11)(R12), N(R11)(R12), SR11, S(O)R11, S(O)2R11, S(O)2—N(R11)(R12), or NR11—S(O)2—(R12), wherein said alkyl, said cycloalkyl and said aryl are unsubstituted or substituted, independent Q's may be joined to form a 5-10 membered ring;
X is a substituted or unsubstituted aryl, C3-C10 cycloalkyl, or het, where the substituents on said aryl, said C3-C10 cycloalkyl and said het are alkyl, halo, lower alkoxy, NR5R6, CN, NO2 or SR5;
R5 and R6 are each independently H, F, Cl, Br, I, C1-C10 alkyl, C1-C10 alkoxy, aryl C1-C10 alkoxy, OH, O—C1-C10-alkyl, (CH2)0-6—C3-C7 cycloalkyl, aryl, aryl C1-C10 alkyl, O—(CH2)0-6 aryl, (CH2)1-6het, het, O—(CH2)1-6het, —OR11, C(O)R11, —C(O)N(R11)(R12), N(R11)(R12), SR11, S(O)R11, S(O)2R11, S(O)2—N(R11)(R12), or NR11—S(O)2—(R12),
each n is independently 0, 1, 2, 3, 4, 5, 6 or 7;
het is a 5-7 membered monocyclic heterocyclic ring containing 1-4 heteroring atoms selected from N, O and S or an 8-12 membered fused ring system that includes one 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroring atoms selected from N, O and S, where said het is unsubstituted or substituted;
R11 and R12 are each independently H, C1-C10 alkyl, (CH2)0-6—C3-C7cycloalkyl, (CH2)0-6—(CH)0-1(aryl)1-2, C(O)—C1-C10alkyl, —C(O)—(CH2)0-6—C3-C7cycloalkyl, —C(O)—O—(CH2)0-6-aryl, —C(O)—(CH2)0-6—O-fluorenyl, C(O)—NH—(CH2)0-6-aryl, C(O)—(CH2)0-6-aryl, C(O)—(CH2)0-6-het, —C(S)—C1-C10alkyl, —C(S)—(CH2)0-6—C3-C7cycloalkyl, —C(S)—O—(CH2)0-6-aryl, —C(S)—(CH2)0-6—O-fluorenyl, C(S)—NH—(CH2)0-6-aryl, —C(S)—(CH2)0-6-aryl or C(S)—(CH2)0-6-het, C(O)R11, C(O)NR11R12, C(O)OR11, S(O)nR11, S(O)mNR11R12, m=1 or 2, C(S)R11, C(S)NR11R12, C(S)OR11, wherein said alkyl, said cycloalkyl and said aryl are unsubstituted or substituted;
or R11 and R12 together with the nitrogen atom form het;
wherein the alkyl substituents of R11 and R12 may be unsubstituted or substituted by one or more substituents selected from C1-C10alkyl, halogen, OH, O—C1-C6alkyl, CF3 or NR11R12;
substituted cycloalkyl substituents of R11 and R12 are substituted by one or more substituents selected from a C2-C10 alkene, C1-C6alkyl, halogen, OH, O—C1-C6alkyl, S—C1-C6alkyl, CF3, or NR11R12 and
substituted het or substituted aryl of R11 and R12 are substituted by one or more substituents selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, O—C(O)—C1-C4alkyl and C(O)—O—C1-C4-alkyl;
wherein the substituents on R1, R2, R3, R4, Q, and A and X groups are each independently halo, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower alkoxy, aryl, aryl lower alkyl, amino, amino lower alkyl, diloweralkylamino, lower alkanoyl, amino lower alkoxy, nitro, cyano, cyano lower alkyl, carboxy, lower carbalkoxy, lower alkanoyl, aryloyl, lower arylalkanoyl, carbamoyl, N-mono- or N,N-dilower alkyl carbamoyl, lower alkyl carbamic acid ester, amidino, guanidine, ureido, mercapto, sulfo, lower alkylthio, sulfoamino, sulfonamide, benzosulfonamide, sulfonate, sulfanyl lower alkyl, aryl sulfonamide, halogen substituted aryl sulfonate, lower alkylsulfinyl, arylsulfinyl;
aryl-lower alkylsulfinyl, lower alkylarylsulfinyl, lower alkylsulfonyl, arylsulfonyl, aryl-lower alkylsulfonyl, lower aryl alkyl lower alkylarylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, phosphono (—P(═O)(OH)2), hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, (R9)NC(O)—NR10R13, lower alkyl carbamic acid ester or carbamates or —NR8R14, wherein R8 and R14 can be the same or different and are independently H or lower alkyl, or R8 and R14 together with the N atom form a 3- to 8-membered heterocyclic ring containing a nitrogen heteroring atoms and may optionally contain one or two additional heteroring atoms selected from nitrogen, oxygen and sulfur, which heterocyclic ring may be unsubstituted or substituted with lower alkyl, halo, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, nitro, amino, lower alkyl, amino, diloweralkyl amino, cyano, carboxy, lower carbalkoxy, formyl, lower alkanoyl, oxo, carbarmoyl, N-lower or N,N-dilower alkyl carbamoyl, mercapto, or lower alkylthio, and
R9, R10, and R13 are independently hydrogen, lower alkyl, halogen substituted lower alkyl, aryl, aryl lower alkyl, halogen substituted aryl, halogen substituted aryl lower alkyl.

20 more elements

A compound selected from the group consisting of

(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(2,3-dihydro-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((R)-1-Cyclohexyl-2-{(S)-2-[5-(2,3-dihydro-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(3,4-dihydro-2H-quinolin-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(2,3-dihydro-pyrrolo[2,3-b]pyridin-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(5-indol-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(3,4-dihydro-2H-quinolin-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(S)-2-[2-(2-oxo-3,4-dihydro-2H-quinolin-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(6-fluoro-2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[2-(6-Fluoro-2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(2-isoquinolin-4-yl-pyridin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(R)-2-(2-isoquinolin-4-yl-pyridin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(2-indazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(5-Benzofuran-3-yl-pyridin-3-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(2-Benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(3-methyl-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)-2-Methylamino-N—((S)-2-methyl-1-{(S)-2-[2-(3-methyl-indol-1-yl)-pyridin-4-yl]-pyrrolidine-1-carbonyl}-propyl)-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(1H-indol-3-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(2-Benzotriazol-1-yl-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(5-fluoro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(6-fluoro-3,4-dihydro-2H-quinolin-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(1H-indol-2-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(5-fluoro-2,3-dihydro-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(1H-indol-3-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[2-(6-Fluoro-indol-1-yl)-pyridin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(R)-2-[2-(6-fluoro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(6-fluoro-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(S)-2-[5-(2-oxo-benzooxazol-3-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(1,3-dihydro-isoindol-2-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(3,4-dihydro-1H-isoquinolin-2-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(5-Benzoimidazol-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(5-Benzotriazol-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(5-indazol-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-(5-fluoro-3-methyl-indol-1-yl)-pyridin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[2-(5-Fluoro-3-methyl-indol-1-yl)-pyridin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(3-methyl-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(5-fluoro-3-methyl-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(5-fluoro-indol-1-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(5-pyrrolo[2,3-b]pyridin-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(2-Benzoimidazol-1-yl-3-fluoro-pyridin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-[(S)-2-(2-Benzoimidazol-1-yl-pyridin-4-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-2-methylamino-propionamide;
3-(5-{(S)-1-[(S)-2-Cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidin-2-yl}-pyridin-3-yl)-indole-1-carboxylic acid dimethylamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(1-ethyl-1H-indol-3-yl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(5-naphthalen-1-yl-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(6-fluoro-2,3-dihydro-indol-1-yl)-pyridin-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(5-fluoro-2,3-dihydro-indol-1-yl)-pyridin-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-2-{(S)-2-[5-(5-Chloro-2-methoxy-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(5-o-tolyl-pyridin-3-yl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(5-Benzo[1,3]dioxol-5-yl-pyridin-3-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(S)-2-[5-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(3-isopropyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(5-naphthalen-2-yl-pyridin-3-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-2-{(S)-2-[2-Chloro-5-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-2-{(S)-2-[5-(3,5-Bis-trifluoromethyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-oxo-2-{(S)-2-[5-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(3,5-dimethyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-2-{(S)-2-[5-(4-tert-Butyl-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-1-cyclohexyl-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[5-(4-fluoro-phenyl)-pyridin-3-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(5-p-tolyl-pyridin-3-yl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(5-m-tolyl-pyridin-3-yl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-2-{(S)-2-[2,3′]Bipyridinyl-6-yl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—[(S)-2-((S)-2-[3,3′]Bipyridinyl-5-yl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl]-2-methylamino-propionamide;
(S)—N—[(S)-2-((S)-2-[3,4′]Bipyridinyl-5-yl-pyrrolidin-1-yl)-1-cyclohexyl-2-oxo-ethyl]-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(6-fluoro-2,3-dihydro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-2,3-dihydro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(6-indol-1-yl-2-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(6-indol-1-yl-pyrimidin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(2-methyl-6-o-tolyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-oxo-2-[(S)-2-(6-o-tolyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-methyl-6-(3-methyl-indol-1-yl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(6-Benzoimidazol-1-yl-2-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(2-methyl-6-naphthalen-1-yl-pyrimidin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(6-Benzo[1,3]dioxol-5-yl-2-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(3-isopropyl-phenyl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(2,3-dihydro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N-{(S)-1-Cyclohexyl-2-[(S)-2-(2-methyl-6-naphthalen-2-yl-pyrimidin-4-yl)-pyrrolidin-1-yl]-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-2,3-dihydro-indol-1-yl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[6-(5-Fluoro-2,3-dihydro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N-{(S)-2-[(S)-2-(6-Benzofuran-3-yl-2-methyl-pyrimidin-4-yl)-pyrrolidin-1-yl]-1-cyclohexyl-2-oxo-ethyl}-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(1H-indol-3-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(1H-indol-3-yl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[6-(1H-Indol-3-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[6-(5-Fluoro-3-methyl-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-3-methyl-indol-1-yl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
(S)—N—((S)-1-{(S)-2-[6-(5-Fluoro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[6-(5-fluoro-indol-1-yl)-pyrimidin-4-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
3-(6-{(S)-1-[(S)-2-Cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidin-2-yl}-2-methyl-pyrimidin-4-yl)-indole-1-carboxylic acid dimethylamide;
3-(2-Methyl-6-{(S)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-pyrrolidin-2-yl}-pyrimidin-4-yl)-indole-1-carboxylic acid dimethylamide;
3-(6-{(S)-1-[(S)-2-Cyclohexyl-2-((S)-2-methylamino-propionylamino)-acetyl]-pyrrolidin-2-yl}-pyrimidin-4-yl)-indole-1-carboxylic acid dimethylamide;
and
(S)—N—((S)-1-{(S)-2-[6-(6-Fluoro-2,3-dihydro-indol-1-yl)-2-methyl-pyrimidin-4-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-2-methylamino-propionamide;
or a pharmaceutically acceptable salt thereof.

93 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/445,435Filed 10 Oct 2007 · us provisional application
Priority: 12 Oct 2006
Published: US 2011/0015232 A120 Jan 2011
Granted: 25 Oct 2011
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07K 5/06191
Dipeptides: containing heteroatoms different from O, S, or N
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07K
Peptides

Family

Application60/829,234Us provisional application · filed 12 Oct 2006
US 2011/0015232 A1Pre-grant publication · published 20 Jan 2011
US 8,044,209 B2This patent

From the US filing history. Foreign family members aren’t listed.

Timeline

Citations

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A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein
R1 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C10 cycloalkyl, where said R1 is unsubstituted or substituted;
R2 is H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C10 cycloalkyl, where said R2 is unsubstituted or substituted;
or
R1 and R2 may be taken together to form a ring or het;
R3 and R3′ are each independently H, CF3, C2F5, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, CH2—Z or R2 and R3 taken together with the nitrogen atom to which they are attached form het, wherein said alkyl, said alkenyl, said alkynyl and said het ring are unsubstituted or substituted;
Z is H, OH, F, Cl, CH3, CH2Cl, CH2F or CH2OH;
R4 is C0-10 alkyl, C0-10 alkyl-C3-10 cycloalkyl, C0-10alkyl-C6-10aryl, C0-10alkyl-het, wherein any carbon may be replaced with a heteroatom or group from the list N, O, S(O)r and any atom may be unsubstituted or substituted;
A is a 6 membered heteroaryl ring;
r is 0, 1, or 2;
Q and Y are each independently H, F, Cl, Br, I, C1-C10 alkyl, C1-C10 alkoxy, aryl C1-C10 alkoxy, OH, O—C1-C10-alkyl, (CH2)0-6—C3-C7 cycloalkyl, aryl, aryl C1-C10 alkyl, O—(CH2)0-6 aryl, (CH2)1-6het, het, O—(CH2)1-6het, —OR11, C(O)R11, —C(O)N(R11)(R12), N(R11)(R12), SR11, S(O)R11, S(O)2R11, S(O)2—N(R11)(R12), or NR11—S(O)2—(R12), wherein said alkyl, said cycloalkyl and said aryl are unsubstituted or substituted, independent Q's may be joined to form a 5-10 membered ring;
X is a substituted or unsubstituted aryl, C3-C10 cycloalkyl, or het, where the substituents on said aryl, said C3-C10 cycloalkyl and said het are alkyl, halo, lower alkoxy, NR5R6, CN, NO2 or SR5;
R5 and R6 are each independently H, F, Cl, Br, I, C1-C10 alkyl, C1-C10 alkoxy, aryl C1-C10 alkoxy, OH, O—C1-C10-alkyl, (CH2)0-6—C3-C7 cycloalkyl, aryl, aryl C1-C10 alkyl, O—(CH2)0-6 aryl, (CH2)1-6het, het, O—(CH2)1-6het, —OR11, C(O)R11, —C(O)N(R11)(R12), N(R11)(R12), SR11, S(O)R11, S(O)2R11, S(O)2—N(R11)(R12), or NR11—S(O)2—(R12),
each n is independently 0, 1, 2, 3, 4, 5, 6 or 7;
het is a 5-7 membered monocyclic heterocyclic ring containing 1-4 heteroring atoms selected from N, O and S or an 8-12 membered fused ring system that includes one 5-7 membered heterocyclic ring containing 1, 2, or 3 heteroring atoms selected from N, O and S, where said het is unsubstituted or substituted;
R11 and R12 are each independently H, C1-C10 alkyl, (CH2)0-6—C3-C7cycloalkyl, (CH2)0-6—(CH)0-1(aryl)1-2, C(O)—C1-C10alkyl, —C(O)—(CH2)0-6—C3-C7cycloalkyl, —C(O)—O—(CH2)0-6-aryl, —C(O)—(CH2)0-6—O-fluorenyl, C(O)—NH—(CH2)0-6-aryl, C(O)—(CH2)0-6-aryl, C(O)—(CH2)0-6-het, —C(S)—C1-C10alkyl, —C(S)—(CH2)0-6—C3-C7cycloalkyl, —C(S)—O—(CH2)0-6-aryl, —C(S)—(CH2)0-6—O-fluorenyl, C(S)—NH—(CH2)0-6-aryl, —C(S)—(CH2)0-6-aryl or C(S)—(CH2)0-6-het, C(O)R11, C(O)NR11R12, C(O)OR11, S(O)nR11, S(O)mNR11R12, m=1 or 2, C(S)R11, C(S)NR11R12, C(S)OR11, wherein said alkyl, said cycloalkyl and said aryl are unsubstituted or substituted;
or R11 and R12 together with the nitrogen atom form het;
wherein the alkyl substituents of R11 and R12 may be unsubstituted or substituted by one or more substituents selected from C1-C10alkyl, halogen, OH, O—C1-C6alkyl, CF3 or NR11R12;
substituted cycloalkyl substituents of R11 and R12 are substituted by one or more substituents selected from a C2-C10 alkene, C1-C6alkyl, halogen, OH, O—C1-C6alkyl, S—C1-C6alkyl, CF3, or NR11R12 and
substituted het or substituted aryl of R11 and R12 are substituted by one or more substituents selected from halogen, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, nitro, CN, O—C(O)—C1-C4alkyl and C(O)—O—C1-C4-alkyl;
wherein the substituents on R1, R2, R3, R4, Q, and A and X groups are each independently halo, hydroxy, lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower alkoxy, aryl, aryl lower alkyl, amino, amino lower alkyl, diloweralkylamino, lower alkanoyl, amino lower alkoxy, nitro, cyano, cyano lower alkyl, carboxy, lower carbalkoxy, lower alkanoyl, aryloyl, lower arylalkanoyl, carbamoyl, N-mono- or N,N-dilower alkyl carbamoyl, lower alkyl carbamic acid ester, amidino, guanidine, ureido, mercapto, sulfo, lower alkylthio, sulfoamino, sulfonamide, benzosulfonamide, sulfonate, sulfanyl lower alkyl, aryl sulfonamide, halogen substituted aryl sulfonate, lower alkylsulfinyl, arylsulfinyl;
aryl-lower alkylsulfinyl, lower alkylarylsulfinyl, lower alkylsulfonyl, arylsulfonyl, aryl-lower alkylsulfonyl, lower aryl alkyl lower alkylarylsulfonyl, halogen-lower alkylmercapto, halogen-lower alkylsulfonyl, phosphono (—P(═O)(OH)2), hydroxy-lower alkoxy phosphoryl or di-lower alkoxyphosphoryl, (R9)NC(O)—NR10R13, lower alkyl carbamic acid ester or carbamates or —NR8R14, wherein R8 and R14 can be the same or different and are independently H or lower alkyl, or R8 and R14 together with the N atom form a 3- to 8-membered heterocyclic ring containing a nitrogen heteroring atoms and may optionally contain one or two additional heteroring atoms selected from nitrogen, oxygen and sulfur, which heterocyclic ring may be unsubstituted or substituted with lower alkyl, halo, lower alkenyl, lower alkynyl, hydroxy, lower alkoxy, nitro, amino, lower alkyl, amino, diloweralkyl amino, cyano, carboxy, lower carbalkoxy, formyl, lower alkanoyl, oxo, carbarmoyl, N-lower or N,N-dilower alkyl carbamoyl, mercapto, or lower alkylthio, and
R9, R10, and R13 are independently hydrogen, lower alkyl, halogen substituted lower alkyl, aryl, aryl lower alkyl, halogen substituted aryl, halogen substituted aryl lower alkyl.

20 more elements

Facts

Application

12/445,435Filed 10 Oct 2007 · us provisional application

Priority

12 Oct 2006

Published

US 2011/0015232 A120 Jan 2011

Granted

25 Oct 2011

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07K 5/06191
Dipeptides: containing heteroatoms different from O, S, or N
A61P 35/00
Antineoplastic agents
A61P 43/00
Drugs for specific purposes, not provided for in groups a61p1/00-a61p41/00
C07K
Peptides