Claims for Patent: 9,035,074

Summary for Patent: 9,035,074

Title:	Pyrrolo[2,3-D]pyrimidine derivatives
Abstract:	Described herein are pyrrolo{2,3-d}pyrimidine derivatives, their use as Janus Kinase (JAK) inhibitors, and pharmaceutical compositions containing them.
Inventor(s):	Brown; Matthew Frank (Stonington, CT), Fenwick; Ashley Edward (Richland, MI), Flanagan; Mark Edward (Gales Ferry, CT), Gonzales; Andrea (Kalamazoo, MI), Johnson; Timothy Allan (Vicksburg, MI), Kaila; Neelu (Lexington, MA), Mitton-Fry; Mark J. (Granville, OH), Strohbach; Joseph Walter (Wentzville, MO), TenBrink; Ruth E. (Labadie, MO), Trzupek; John David (Medford, MA), Unwalla; Rayomand Jal (Bedford, MA), Vazquez; Michael L. (Billerica, MA), Parikh; Mihir D. (Groton, CT)
Assignee:	Pfizer Inc. (New York, NY)
Application Number:	14/183,946
Patent Claims:	1. A compound of formula I having the structure: ##STR00054## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is hydrogen C.sub.1-C.sub.4 alkyl, wherein said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF.sub.3, and C.sub.3-C.sub.6 cycloalkyl; R.sup.2 and R.sup.3 are each independently hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.6 linear or branched chain perfluoroalkyl, C.sub.1-C.sub.6 linear or branched chain alkoxy, C.sub.1-C.sub.6 linear or branched chain perfluoroalkoxy, halogen, cyano, hydroxyl, amino, carboxy, aminocarbonyl, aryl, heteroaryl, (aryl)C.sub.1-C.sub.6 linear or branched chain alkyl, (heteroaryl)C.sub.1-C.sub.6 linear or branched chain alkyl, (heterocyclic)C.sub.1-C.sub.6 linear or branched chain alkyl, (C.sub.1-C.sub.6 linear or branched chain alkyl)aryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)heteroaryl, (C.sub.1-C.sub.6 linear or branched chain alkyl heterocyclic, (C.sub.1-C.sub.6 linear or branched chain alkoxyl)carbonyl, (C.sub.1-C.sub.6 linear or branched chain alkyl)amino-carbonylamino, or (C.sub.1-C.sub.6 linear or branched chain alkyl)aminocarbonyl; R.sup.4 is selected from hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, C.sub.1-C.sub.6 linear or branched chain perfluoroalkyl, aryl, and alkylaryl; X is selected from --NH-- and --CR.sub.aR.sub.b--, where (a) R.sub.a and R.sub.b are independently hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, (aryl)C.sub.1-C.sub.6 linear or branched chain alkyl, heteroaryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)heteroaryl, (heteroaryl)C.sub.1-C.sub.6 linear or branched chain alkyl, (heterocyclic)C.sub.1-C.sub.6 linear or branched chain alkyl, or (b) R.sub.a and R.sub.b together form a chain comprising --(CR.sub.cR.sub.d).sub.j--, where R.sub.c and R.sub.d are independently hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, aryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)aryl, heteroaryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)heteroaryl, halo, CN, CF.sub.3, hydroxyl, CONH.sub.2, or SO.sub.2CH.sub.3; Y is -A-R.sup.5, where A is a bond, --(CH.sub.2).sub.k-- or --(CD.sub.2).sub.k-- and R.sup.5 is C.sub.1-C.sub.6 linear or branched chain alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, or --NR.sub.a'R.sub.b', or is an unsaturated, saturated or partially saturated monocyclic or bicyclic ring structure containing a total of five to eleven atoms having one to three heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur, wherein said alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, or monocyclic or bicyclic ring structure is further optionally substituted with one or more substituents selected from the group consisting of deuterium, halo, C.sub.1-C.sub.6 linear or branched chain alkyl, CN, hydroxyl, CF.sub.3, --OR.sub.e, --NR.sub.eR.sub.f, --S(O).sub.pR.sub.e and C.sub.3-C.sub.6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CONH.sub.2, and SO.sub.2CH.sub.3, where (a) R.sub.a' and R.sub.b' are independently hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, C.sub.3-C.sub.6 cycloalkyl, aryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)aryl, heteroaryl, or (C.sub.1-C.sub.6 linear or branched chain alkyl heteroaryl, where said alkyl and cycloalkyl may be optionally substituted with one or more R.sub.c', or (b) R.sub.a' and R.sub.b' together form a chain comprising --(CR.sub.c'R.sub.d').sub.j--, where R.sub.c' and R.sub.d' are independently hydrogen, deuterium C.sub.1-C.sub.6 linear or branched chain alkyl, aryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)aryl, heteroaryl, (C.sub.1-C.sub.6 linear or branched chain alkyl)heteroaryl, halo, CN, hydroxyl, CF.sub.3, CONH.sub.2, --OR.sub.e, --NR.sub.eR.sub.f, or --S(O).sub.pR.sub.e; where R.sub.e and R.sub.f are independently hydrogen, deuterium, C.sub.1-C.sub.6 linear or branched chain alkyl, or C.sub.3-C.sub.6 cycloalkyl, where said alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halo, CN, hydroxyl, CF.sub.3, and CONH.sub.2; j is 2, 3, 4 or 5; k is 1, 2; 3, or 4; p is 0, 1 or 2; and, n is 1 or 2, said compound being selected from the group consisting of: 4-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl- }pyridine-2-sulfonamide; 2,2,2-trifluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}-ethanesulfonamide; 2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobuty- l}-propane-1-sulfonamide; N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane- -1-sulfonamide; 1-cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cycl- obutyl}-methanesulfonamide; N-{cis-3-[(butylsulfonyl)methyl]cyclobutyl}-N-methyl-7H-pyrrolo[2,3-d]pyr- imidin-4-amine; 1-cyclopropyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cycl- obutyl}-azetidine-3-sulfonamide; 3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl- }-azetidine-1-sulfonamide; (1R,5S)--N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobuty- l}-6-oxa-3-azabicyclo[3.1.1]heptane-3-sulfonamide; (3R)-3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclo- butyl}-pyrrolidine-1-sulfonamide; (3S)-3-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclo- butyl}-pyrrolidine-1-sulfonamide; N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-(oxe- tan-3-yl)methane-sulfonamide; 1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-- yl)amino]cyclobutyl}methane-sulfonamide; trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)am- ino]-cyclobutyl}cyclo-butanesulfonamide; cis-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amin- o]-cyclobutyl}cyclobutane-sulfonamide; N-[cis-3-({[(3,3-difluorocyclobutyl)methyl]sulfonyl}methyl)cyclobutyl]-N-- methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; (1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide; (1R,5R)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide; (3R)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}- meth-yl)sulfonyl]pyrrolidine-3-carbonitrile; 1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methy- l)sulfonyl]-4-(trifluoromethyl)piperidin-4-ol; N-(cis-3-{[(4,4-difluoropiperidin-1-yl)sulfonyl]methyl}cyclobutyl)-N-meth- yl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; (3S)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}- meth-yl)sulfonyl]pyrrolidine-3-carbonitrile; N-(cis-3-{[(3-chloro-4-fluorophenyl)sulfonyl]methyl}cyclobutyl)-N-methyl-- 7H-pyrrolo[2,3-d]pyrimidin-4-amine; N-(cis-3-{[(2-cyclopropylethyl)sulfonyl]methyl}cyclobutyl)-N-methyl-7H-py- rrolo[2,3-d]pyrimidin-4-amine; N-methyl-N-[cis-3-({[1-(propan-2-yl)pyrrolidin-3-yl]sulfonyl}methyl)cyclo- butyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclo- butyl}cyclobutane-sulfonamide; 1-[3-(cyanomethyl)oxetan-3-yl]-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidi- n-4-yl)amino]cyclobutyl}-methanesulfonamide; cis-3-(cyanomethyl)-3-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-- 4-yl)amino]cyclobutyl}-cyclobutanesulfonamide; trans-3-(cyanomethyl)-3-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidi- n-4-yl)amino]cyclobutyl}cyclobutanesulfonamide; N-(2-cyanoethyl)-N-methyl-N'-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-- yl)amino]cyclobutyl}sulfuric diamide; N-{(1S,3R)-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclopentyl}pr- opane-1-sulfonamide; 3-(2-hydroxypropan-2-yl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl- )amino]cyclobutyl}benzene-sulfonamide; N-(cyclopropylmethyl)-N'-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)a- mino]cyclobutyl}sulfuric diamide; N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-4-(1H-- pyrazol-3-yl)piperidine-1-sulfonamide; 2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobuty- l}-2,6-dihydropyrrolo[3,4-c]pyrazole-5(4H)-sulfonamide; N-cyclopropyl-1-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}methane-sulfonamide; 2-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}methy- l)sulfonyl]pyridine-4-carbonitrile; (1S,3S)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobut- yl}methylysulfonyl]cyclopentanecarbonitrile; (1R,3R)-3-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobut- yl}methyl)sulfonyl]cyclopentanecarbonitrile; 1-cyclopropyl-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}methane sulfonamide; 3-cyano-N-{trans-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobut- yl}pyrrolidine-1-sulfonamide; N-methyl-N-{trans-3-[(propylsulfonyl)methyl]cyclobutyl}-7H-pyrrolo[2,3-d]- pyrimidin-4-amine; and, 2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobuty- l}-1,3-thiazole-5-sulfonamide; or, a pharmaceutically acceptable salt thereof. 2. A compound of claim 1 wherein the compound is 2-methyl-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobuty- l}-1,3-thiazole-5-sulfonamide, or a pharmaceutically acceptable salt thereof. 3. A compound of claim 1 wherein the compound is N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propan- e-1-sulfonamide, or a pharmaceutically acceptable salt thereof. 4. A compound of claim 1 wherein the compound is trans-3-(cyanomethyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)am- ino]cyclobutyl}cyclobutanesulfonamide or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1 wherein the compound is 1-(3,3-difluorocyclobutyl)-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-- yl)amino]cyclobutyl}methanesulfonamide or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1 wherein the compound is N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-1-(oxe- tan-3-yl)methanesulfonamide or a pharmaceutically acceptable salt thereof. 7. A compound of claim 1 wherein the compound is (3R)-1-[({cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}- methyl)sulfonyl]pyrrolidine-3-carbonitrile or a pharmaceutically acceptable salt thereof. 8. A compound of claim 1 wherein the compound is 3,3-difluoro-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclo- butyl}cyclobutanesulfonamide or a pharmaceutically acceptable salt thereof. 9. A compound of claim 1 wherein the compound is (1S,5S)-1-cyano-N-{cis-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cy- clobutyl}-3-azabicyclo[3.1.0]hexane-3-sulfonamide or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical or a veterinary composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.