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MXPA00012622A - PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS - Google Patents

PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS

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Publication number
MXPA00012622A
MXPA00012622A MXPA/A/2000/012622A MXPA00012622A MXPA00012622A MX PA00012622 A MXPA00012622 A MX PA00012622A MX PA00012622 A MXPA00012622 A MX PA00012622A MX PA00012622 A MXPA00012622 A MX PA00012622A
Authority
MX
Mexico
Prior art keywords
alkyl
crc6
amino
aryl
acyl
Prior art date
Application number
MXPA/A/2000/012622A
Other languages
Spanish (es)
Inventor
Matthew Frank Brown
Todd Andrew Blumenkopf
Mark Edward Flanagan
Paul Steven Changelian
Original Assignee
Pfizer Products Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pfizer Products Inc filed Critical Pfizer Products Inc
Publication of MXPA00012622A publication Critical patent/MXPA00012622A/en

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Abstract

A compound of formula (I) wherein R1, R2 and R3 are as defined in the description, and are inhibitors of the enzyme protein tyrosine kinases such as Janus Kinase (3) and as such are useful therapy as immunosuppressive agents for organ transplants, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, Leukemia and other autoimmune diseases.

Description

PIRROL COMPOUNDS? R2,3-d, PYRIMIDINE BACKGROUND OF THE INVENTION The present invention relates to pyrrolo [2,3-djpyrimidine compounds which are inhibitors of tyrosine kinase proteins such as the enzyme Janus Kinase 3 (hereinafter referred to as JAK3) and as such, are a useful therapy as immunosuppressive agents for transplants of organs, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other indications in which immunosuppression may be desirable. This invention also relates to a method for using such compounds in the treatment of the above indications in mammals, especially in humans, and to pharmaceutical compositions useful therefor. JAK3 is a member of the Janus family of protein tyrosine kinases. Although the remaining members of this family are expressed essentially by all tissues, the expression of JAK3 is limited to the hematopoietic cells. This is consistent with its essential function in the signaling of IL-2, IL-4, IL-7, IL-9 and IL-15 through the receptors through a non-covalent association of JAK3 with the gamma chain common to these multichannel receptors. . XSCID patient populations have been identified with rather low levels of the JAK3 protein or with genetic defects with respect to the common chain gamma, suggesting that immunosuppression would be the result of blockade of signaling via the JAK3 pathway. Animal studies have suggested that JAK3 not only plays a critical role in the maturation of B and T lymphocytes, but that JAK3 is constitutively required to maintain the function of B cells. The modulation of immune activity by this new mechanism can be useful in the treatment of proliferative disorders of T cells such as the rejection of transplants and autoimmune diseases.
BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula or their pharmaceutically acceptable salts, wherein R 1 is a group of formula where y is O, 1 or 2; R4 is selected from the group consisting of hydrogen, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, C---C4 alkoxy, acyloxy Ci -Cβ, (C 1 -C 6 alkyl) amino, (C 1 -C 4 alkyl) amino, cyano, nitro, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or (C 1 -C 6 acyl) amino; or R4 is C3-C3 cycloalkyl, wherein the cycloalkyl group is optionally substituted by deuterium, hydroxy, amino, trifluoromethyl, acyloxy CrC6, (acyl C? -C6) amino, (alkyl d-Cysamino, (C? -C6 alkyl) 2-amino, cyano, cyano (d-Cß alkyl), trifluoromethyl (d-Cß alkyl), nitro, nitro (C?-C6 alkyl), or (CrC 6) amino; R 5 is selected from the group consisting of trifluoromethyl (Cr C 6 alkyl) ), (CrC 3 alkyl) difluoromethylene (C 1 -C 3 alkyl), C 3 -C 0 cycloalkyl, wherein the cycloalkyl group is optionally substituted by one to five of carboxy, cyano, amino, deuterium, hydroxy, C 1 -C 6 alkyl , C6-C6 alkoxy, halo, C6-C6 acyl, C6-C6 alkyl, amino, C6-C6 alkyl, C6-C6-alkoxy -CO-NH, (C alqu-alkyl) C6) amino-CO-, C2-C6 alkenyl, alkylaryl C2-C6, (C alqu-C6 alkyl) amino, amino (d6C6 alkyl), hydroxy (CrC6 alkyl), (CrC6 alkoxy) (alkyl) C? -C6), (C? -C6 acyloxy) (C? -C6 alkyl), nitro, cyano (CrC6 alkyl), halo (C -? - C6 alkyl), nitro (d-C? Alkyl), trifluoromethyl, trifluoromethyl (alkyl C? -C6), (acyl C? -C6) amino, (acyl Ci-C6) amino (C? -C6 alkyl), (C? -C6 alkoxy) (C -? - C6 acyl) amino, (C? -C6 acyl) amino, amino (acyl CrC6) (C? -C6 alkyl), (C? -C6 alkyl) amino (C? -C6 acyl), (Ci-C6 alkyl) 2 amino (acyl dC6), R15R16N-CO-O-, R15R16N-CO- (alkyl d-C6), (alkyl d-C6) -S (O) m, R15R16NS (O) m, R15R16NS (O) m (alkyl d-C6), R15S (O) mR16N, R15S ( O) mR16N (d-C6 alkyl), where m is 0, 1 or 2 and each of R15 and R16 is selected independently from hydrogen or C-C6 alkyl; or R 5 is (C 3 -C 0 cycloalkyl) (CrC 6 alkyl), (d-C 6 acyloxy) (d-Cß alkyl), (C 2 -C 6 alkoxy) (C 1 -C 6 alkyl), piperazinyl (CrC 6 alkyl), ( acyl C? -C6) amino (C? -C6 alkyl), (aryl Ce-Cio) (C? -C6 alkoxy) (C? -C6 alkyl), (C5-C9 heteroaryl) (C? -C6 alkoxy) ( alkyl d-C6), (C 1 -C 6 alkyl) thio (C -C 6 alkyl), (C 6 -C 6 aryl) thio (C 6 alkyl), (C 6 alkyl) sulfinyl (C 6 -C 6 alkyl), (aryl C6-C? 0) sulfinyl (C? -C6 alkyl), (CrC6 alkyl) sulfonyl (d6C6 alkyl), (C6-C? o aryl) sulfonyl (CrC6 alkyl), amino (d6C6 alkyl) (C 1 -C 4 alkyl) amino (CI-CT alkyl), (C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 4 alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted by one to five of cyano, nitro, halo, deuterium, hydroxy, carboxy, (acyl C? -Ce) amino, (alkoxy d-Cß) (acyl C? -Ce) amino, amino (aci! or d-Cß), (alkyl d-Cß) amino (acyl d-Cß) or (Ci-C6 alkyl) 2amino (acyl d-C6) or R5 is R13CO (C6 alkyl) or R13CO (C3-Cyclocycloalkyl), where R13 is R20O or R20R21N, each one of R20 and R21 independently of the group formed by hydrogen, deuterium, C-C alquilo alkyl, (aryl Ce-Cι) (d-C6 alkyl) or (C5-C9 heteroaryl) (d-C6 alkyl); or R5 is R14, R14-C6-C6 alkyl or R14-C3-C10 cycloalkyl, with R14 (C2-Cg heterocycle) alkyl, (acyl C? -Ce) piperazino, (aryl C6-C? o) piperazino, ( C5-C9 heteroaryl) piperazino, (C 1 -C 6 alkyl) piperazino, (C 6 -C 0 aryl) (C 1 -C 6 alkyl) piperazino, (C 5 -C 9 heteroaryl) (CrCe alkyl) piperazino, morpholino, thiomorpholino, piperidino , pyrrolidino, piperidyl, (alkyl d-C6) piperidinyl, (aryl C6-C? 0) piperidyl, (heteroaryl C5-C9) piperidyl, (aryl C6-C10) (alkyl C? -Ce) piperidyl, (heteroaryl C5-) C9) (C 1 -C 6 alkyl) piperidyl or (C 1 -C 6 acyl) piperidyl; or R5 is a group of formula wherein w is 0, 1 or 2; x is 0, 1, 2 0 3; 0 R5 is a group of formula wherein g, h and j are each independently 0 to 3; F, K and P are each independently oxygen, S (0) d) where d is 0, 1 or 2, NR6 or CR7R8; R6 is selected from the group consisting of hydrogen, d-C6 alkyl, trifluoromethyl, trifluoromethyl (alkyD-Cß), (alkyl d-C6) (difluoromethylene), (C1-C3 alkyl) (difluoromethylene) (C1-C3 alkyl), (C -C6 alkoxy) (C? -C6 acyl), (C? -C6 alkyl) amino (C? -C6 acyl), (C? -C6 alkyl) 2-amino (C? -C6 acyl), C6-C aryl 0 0, C5-C9 heteroaryl, (C6-C6 aryl) (C6-C6 alkyl), (C5-C9 heteroaryl) (d-Cß alkyl), (aryl Ce-Cι) (Ce-Cι aryl), (aryl Ce-Cio) (aryl Ce-C o) (d-C6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (d-C6 alkyl), hydroxy (C2-C6 alkyl), (acyloxy CrC6) (C2-C6 alkyl), (C6-C6 alkoxy) (C2-C6 alkyl), piperazinyl (C6-C6 alkyl), (C6-C6 acyl) amino (C6-C6 alkyl), (C6-aryl) C? 0) (C6-C6 alkoxy) (C6-alkyl), (C5-C9 heteroaryl) (d6-C6 alkoxy) (C6-alkyl), (C6-C6 alkyl) thio (C1-C6 alkyl) ), (aryl C6-C? 0) thio (C? -C6 alkyl), (C? -C6 alkyl) sulfinyl (d-C6 alkyl), (C6-C? o aryl) sulfinyl (C? -C6 alkyl) , (C 1 -C 6 alkyl) sulfonyl (C 1 -C 6 alkyl), (C 6 -C 6 aryl) sulfonyl (C 1 -C 3 alkyl), amin or C Cβ alkyl (C 1 -Ce) alkyl amino (Cr C 6 alkyl), (C 1 -C 6 alkyl) 2 amino (CrC 6 alkyl), R 13 CO (C 1 -C 6 alkyl), where R 13 is R 20 O or R 20 R 21 N, R 20 being selected and R21 each independently of the group consisting of hydrogen, d-C6 alkyl, (C6-C6 aryl) (d6C6 alkyl) or (C5-C9 heteroaryl) (d6C6 alkyl); or R14 (C2-C6 alkyl), where R14 is (acyl C C6) piperazino, (aryl C6-C? 0) piperazino, (heteroaryl C5-C9) p¡perazino, (C1-C6 alkyl) piperazino, (aryl Ce -Cio) (C 1 -C 6 alkyl) piperazin, (C 5 -C 9 heteroaryl) (C 1 -Ce alkyl) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -Ce) alkyl piperidyl, (aryl) C6-C 0) piperidyl, (heteroaryl Cs-Cgjpiperidyl, (aryl Ce-Cι) (C 1 -C 6 alkyl) piperidyl, (C 5 -C 9 heteroaryl) (C 1 -C 6 alky) piperidyl, (C 1 -C 6 alkoxy) ) acyl, (C 1 -C 4 alkyl) aminoaryl, (C 1 -C 6 alkyl) 2aminoacyl or (C 1 -C 6 acyl) piperidyl, R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, amino , hydroxy, C6-C6 alkoxy, (C1-C6 alkyl) amino, (d-C6 alkyl) 2 amino, (acyl CrC6) amino, (acyl dC6) (C1-C6 alkyl) amino, carboxy, (alkoxy) C? -C6) acyl, (C? -C6 alkyl) aminoacyl, (C-alkyl) 2-aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (CI-CT alkyl), (C? -C6 alkyl) (difluoromethylene), (alkyl) C? -C3) difluoromethylene- (C? -alkyl) C3), aryl Cedo), Ce-Cι aryl, C5-C9 heteroaryl, (C6-C10 aryl) (C?-C6 alkyl), (C5-C9 heteroaryl) (d-C6 alkyl), (C6-C aryl) 0) (aryl C6-C? 0), (aryl C6-C? 0) (aryl C6-C? 0) (C? -C6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (C? Alkyl? -C6), hydroxy (d-C6 alkyl), (C6-C6 acyloxy) (C-C6 alkyl), (C6-C6 alkoxy) (C6-C6 alkyl), piperazinyl (C6-C6 alkyl), (C?-C6 acyl) amino (C?-C6 alkyl), piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 6 -C 6 aryl) (dCα alkoxy) (C?-C6 alkyl), (C 5 heteroaryl) -C9) (C?-C6 alkoxy) (C?-C6 alkyl), (C alqu-C6 alkyl) thio (d-C6 alkyl), (C 6 -C 6 aryl) thio (C?-C6 alkyl), (C 1 -C 6 alkyl) sulfinyl (C 1 -C 6 alkyl), (C 6 -C 6 aryl) sulfinyl (dC 6 alkyl), (C 1 -C 6 alkyl) sulfonyl (C 1 -C 6 alkyl), (aryl) C6-C ?o) sulfonyl (Ci-Cß alkyl), amino (Ci-Cß alkyl), (C alqu-C6 alkyl) amino (CrC 6 alkyl), (C 1 -C 6 alkyl) 2amino (C?-C6 alkyl), R13CO (alkyl d-C6) or R13CO (C3-C10 cycloalkyl), where R13 is R20O or R20R21N, each one being selected from R20 and R21 independently of the group or formed by hydrogen, CrC6 alkyl, (C6-C10 aryl) (C6 alkyl) or (C5-C9 heteroaryl) (C6-C6 alkyl); R14, R14-d-C6 alkyl or R14-C3-C10 cycloalkyl, with R14 (acyl C-Ce) piperazino, (eril C-C? O) piperazino, (C5-C9 heteroaryl) piperazino, (C? -C6 alkyl) ) piperazino, (aryl Cedo) (C 1 -Ce alkyl) piperazino, (heteroaryl Cs-Cg) (C 1 -Ce alkyl) piperazino, morpholin, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -Ce) alkyl piperidyl, (aryl C6-C? 0) piperidyl, (C5-Cg heteroaryl) piperidyl, (C6-C6aryl aryl) (C1-Ce alkyl) piperidyl, (C5-Cg heteroaryl) (C? -Ce alkyl) piperidyl or ( acyl d-C6) piperidyl; or a group of formula where p is O, 1, 2 or 3; and Z is hydroxy, C-C6 alkoxy or NR1R2, each of R1 and R2 being independently selected from the group consisting of hydrogen, Ci-Cß alkyl, piperidyl, (C alqu-C6 alkyl) piperidyl, (aryl C &-C; ) piperidyl, (C5-Cg heteroaryl) piperidyl, (C6-C6aryl aryl) (C 1 -Ce) alkyl piperidyl, (C 5 -C 6 heteroaryl) (C 1 -C 6 alkyl) piperidyl, (C 1 -C 6 acyl) piperidyl, C6-C6 aryl, C5-C9 heteroaryl, (aryl Ce-Cι) (d-C6 alkyl), (C5-Cg heteroaryl) (Ci-C6 alkyl), (aryl Ce-Cι) (aryl Ce- Cio), (aryl Ce-Cι) (aryl Ce-Cío) (alkyl d-C6), C3-C6 cycloalkyl, (C3-Ce cycloalkyl) (Ci-Cß alkyl), R5 (d-Cß alkyl), (alkyl) C1-C5) (CHR5) (C? -C6 alkyl), where R5 is hydroxy, acyloxy d-Ce, C? -C6 alkoxy, piperazino, (acyl C? -Ce) amino, (C? -Ce) alkyl, (aryl C6-C o) thio, (C1-C6 alkyl) suIfinl, (aryl C6-C or) sulfinyl, (C6-C6 alkyl) sulfonyl, (aryl C6-C? o) sulfonyl, amino, ( alkyl C? -C6) amino, (alkyl dC6) 2amino, (acyl C? -C6) piperazino, (C? -C6 alkyl) piperazino, (aryl Ce-Cio) (CrC6 alkyl) piperazino, (h eteroaryl C5-Cg) (C 1 -C 6 alkyl) piperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C 6 alkyl), (C 1 -C 5 alkyl) (CHR 6) (C 1 -C 6 alkyl), where R 6 is piperidyl, (C 1 -C 6 alkyl) piperidyl, (C 6 -C 6 aryl) piperidyl) (aryl Ce-Cι) (C 1 alky) piperidyl, (C5-Cg heteroaryl) piperidyl or (C5-Cg heteroaryl) (d-C6 alkyl) piperidyl; or R1 is defined as OR9 or S (0) qR9, where q is 0, 1 or 2; and R is selected from the group consisting of trifluoromethyl (d-C6 alkyl), (C 1 -C 3 alkyl) (difluoromethylene) (CrC 3 alkyl), C 3 -C 6 cycloalkyl, the cycloalkyl group being optionally substituted by one to five carboxy, cyano , amino, hydroxy, Ci-Cβ alkoxy, halo, (alkyl C -Ce) S (O) m, where m is 0, 1 or 2; R15R16NS (O) m, where m is 0, 1 or 2 and each of R15 and R16 is independently selected from hydrogen or C? -C6 alkyl; acyl C? -C6, (alkyl d-C6) amino, amino (alkyl d-Cß), alkoxy d-C6-CO-NH, (alkyl CrC6) amino-CO-, R15R16N-CO-0-, R15R16N-CO - (alkyl d-C6), where R15 and R16 are as defined above; C2-C6 alkenyl, C2-C6 alkynyl, (C alqu-C6 alkyl) amino, amino (CrCß alkyl), hydroxy (d-Cß alkyl), (d-Cß alkoxy) (CrC6 alkyl), (C?-C6 acyloxy) ) (C? -C6 alkyl), nitro, cyano (C? -C6 alkyl), nitro (C? -C6 alkyl), trifluoromethyl, trifluoromethyl (C? -C6 alkyl), (C? -C6 acyl) amino, ( C 1 -C 6 alkoxy) (C 1 -C 6 acyl) amino, amino (C 1 -C 5 acyl), (C 1 -C e) amino (d-C ac acyl) or (C 1 -C 6 alkyl) 2 amino (acyl d) C6); C2-C6 alkenyl, C2-C6 alkynyl, (C3-C? o cycloalkyl) (C-C? alkyl), (C6-C6 acyloxy) (C6-C6 alkyl), (C2-C6-alkoxy) (C6-C6 alkyl), piperazinyl (C? C6), (acyl CrCe) amino (CrC6 alkyl), (C6-C6 aryl) (CrC6 alkoxy) (CrC6 alkyl), (C5-Cg heteroaryl) (CrC6 alkoxy) (dCS alkyl), -C6) thio (CrC6 alkyl), (C6-C aryl) thio (CrCe alkyl), (alkyl d-Ce) sulfylnil (CrC6 alkyl), (C6-C6 aryl) sulfinyl (CrC6 alkyl), (alkyl d-C-sulphonyl (CrC6 alkyl), (C6-do) sulfonyl (CrC6 alkyl), amino (CrCß alkyl), (CrCe alkyl) amino (CrC6 alkyl), (CrC6 alkyl) 2 amino, CrCß alkyl, the group being alkyl optionally substituted by one to five of cyano, nitro, hydroxy, carboxy, (acyl dd amino, (alkoxy CrC6) (acyl CrCe) amino, amino (acyl CrC6), (alkyl CrC6) amino (acyl d-C6) or ( alkyl CrC6) 2amino (C6-C6 acyl), R13CO (C6-C6 alkyl) or R13CO (C3-C10 cycloalkyl), where R13 is R20O or R20R21N, each being selected from R20 and R21 independently of the group formed by hydrogen, CrC6 alkyl, (aryl Cedo) (d-C6 alkyl) or (C5-C9 heteroaryl) (CrC6 alkyl); R14, R14-d-C6 alkyl or R14-C3-C10 cycloalkyl, where R14 (C2-Cg heterocycle) is alkyl, (acyl CrC6) piperazino, (aryl C6-C? O) piperazino, (heteroaryl C5-Cg) piperazino, (alkyl d-C6) piperazino, (aryl C-6-C10) (alkyl CrC6) piperazino, (heteroaryl C5-Cg) (alkyl d-C6) p¡perazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (alkyl) CrC? Piperidinyl, (C6-C o aryl) piperidyl, (C5-Cg heteroaryl) piperidyl, (C6-C6aryl) aryl (CrC6 alkyl) piperidyl, (C5-Cg heteroaryl) (CrC? Jpiperidyl alkyl or (CrCl.piperidyl acyl); R9 is a group of formula wherein g, h and j are each independently 0 to 6; F, K and P are each independently oxygen, S (0) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, C2-C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, trifluoromethoxy, CrCß alkyl, d6C6 alkoxy, alkyl or alkoxy groups optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino, (CrC6 alkyl) thio, (C 1 -Ce) amino alkyl, (d-Ce ^ amino alkyl, C5-Cg heteroaryl, (C2-Cg heterocycle) alkyl, C3-C9 cycloaicil or C6-C0 aryl, or each of R2 and R3 is independently C3-C? 0 cycloalkyl, C3-C? 0 cycloalkoxy, (alkyl dC? CrC6) 2amino, (aryl C6-C? O) amino, (alkyl CrC6) thio, (aryl C6-C? O) thio, (alkyl CrCe) sulfinyl, (aryl C6-C? O) sulfinilo, (alkyl) CrC6) sulfonyl, (C6-C6alkyl) sulfonyl, acyl CrC6, (C6-C6alkoxy) -CO-NH-, (CrC6 alkyl) amino-CO-, C5-Cg heteroaryl, (C2-Cg heterocycle) alkyl or aryl C6-C? O, the heteroaryl, heterocycloalkyl and aryl groups being optionally substituted with one at halogen, alkyl d-Ce, (alkyl d-Ce) -CO-NH-, (alkoxy CrC6) -CO-NH-, (alkyl CrC6) -CO-NH- (alkyl d-Ce), (alkoxy d) -C6) -CO-NH- (alkyl d-Ce), (alkoxy CrC6) -CO-NH- (alkoxy d-Cß), carboxy, carboxy (alkyl d-C6), carboxy (alkoxy CrC6), benzyloxycarbonyl (alkoxy) CrC6), (CrC6 alkoxy) carbonyl (d-C alco alkoxy), Ce-Cι aryl, amino, amino (d-Cß alkyl), (CrCe) alkoxy carbonylamino, (aryl Ce-C o) (CrC 6 alkoxy) carbonylamino, ( alkyl CrCe) amino, (CrC6 alkyl) 2amino, (CrC6 alkyl) amino (CrC6 alkyl), (d-C6 alkyl) 2-amino (CrC6 alkyl), hydroxy, CrCß alkoxy, carboxy, carboxy (d-Cß alkyl), (alkoxy) CrCßJcarbonyl, (CrC6 alkoxy) carbonyl (CrC6 alkyl), (CrC6 alkoxy) -CO-NH-, (alkyl d-Ce) -CO-NH-, cyano, (C5-Cg heterocycle) alkyl, amino-CO-NH- , (alkyl CrCe) amino-CO-NH, (alkyl d-Cehamino-CO-NH-, (aryl C6-C10) amino-CO-NH, (heteroaryl C5-C9) amino-CO-NH-, ( alkyl CrC6) amino-CO-NH- (alkyl CrC6), (alkyl d-C6) 2 amino-CO- NH- (alkyl CrC6), (aryl C6-C? 0) amino-CO-NH- (alkyl d) -Ce), (heteroaryl C5-C) 9) amino-CO-NH- (CrC6 alkyl), (CrC6 alkyl) sulfonyl, (alkyl d-sulfonylamino, (CrC6 alkyl) sulfonylamino (CrC6 alkyl), (C6-C6 alkylsulfonyl), (aryl C6-C? o) sulfonylamino, (C6-C6alkylamino) sulfonylamino (CrC6 alkyl), (CrC6 alkyl) sulfonylamino, (CrCe alkyl) sulfonylamino (CrC6 alkyl), C5-Cg heteroaryl or (C2-Cg heterocycle) alkyl; provided that, when R 4 and R 5 is hydrogen, the other of R 4 and R 5 can not be C 6 -C 6 aryl or (C 6 -C 0 aryl), (CrC 6 alkyl); provided that, when R 4 is hydrogen, unsubstituted CrC 6 alkyl or unsubstituted C 3 -C 10 cycloalkyl, R 5 can not be (aryl C 6 -C 0) (alkyl dC 6); R20 and R21 can not be (C5-C9 heteroaryl) (d6C6 alkyl); and R14 can not be (C2-Cg heterocycle) alkyl; morpholino, thiomorpholino, piperidino, pyrrolidino, piperidinyl or (alkyl CrCe) piperidinyl; provided that the sp2 and alkenyl or alkynyl carbons can not be substituted with hydroxy or amino; provided that, when R 4 is hydrogen, R 5 can not be amino (CrC 6 alkyl), CrCß alkylene, (CrC 6 alkyl) amino (CrC 6 alkyl), (CrCe alkyl) 2 amino (d-Cß alkyl), furanyl, ( alkoxy d-Cß) (alkynyl d-Cß) or carboxy (alkyl d-Cß); provided that, R 4 as R 5 can not both be hydroxy (C 1 -C 6 alkyl); provided that, when R 4 is CrCβ alkyl, R 5 can not be (CrCβ alkoxy) (d-C alquilo alkyl) or carboxy (CrC 6 alkyl); and provided that R1 can not be carboxy (alkyl dCS) thio or (C6C6 alkoxy) carbonyl (CrC6 alkyl) thio. The present invention also relates to the pharmaceutically acceptable acid addition salts of the compounds of formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the above-mentioned basic compounds of this invention are those which form salts by the addition of non-toxic acids, that is, salts containing pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate or bitartrate salts, succinate, maleate, fumarate, gluconate , saccharate, benzoate, methanol sulphonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e. 1, 1'-methylene-bis (2-hydroxy-3-naphthoate)]. The invention also relates to the addition salts of bases of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature are those which form base salts. non-toxic with such compounds. Such salts of non-toxic bases include, but are not limited to, those derived from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), ammonium salts or addition of water-soluble amines such as N-methylglucamine (meglumine) and salts of (lower alkanol) ammonium and other pharmaceutically acceptable organic amine bases. The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic radicals or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups in which "alkyl" is as defined above. The term "halo", as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. The compounds of the invention may contain double bonds. When such double bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. Unless indicated otherwise, the alkyl and alkenyl groups herein, as well as the alkyl radicals of other groups mentioned herein (eg, alkoxy) may be linear or branched, and may also be cyclic (eg, example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless indicated otherwise, halogen includes fluorine, chlorine, bromine and iodine. C3-C10 cycloalkyl, when used herein, refers to cycloalkyl groups containing from zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo [3.2.1] octane, norbornanium and the like. (C2-C8 heterocycle) alkyl, when used herein, refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1, 3 tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydrozepinyl, piperazinyl, chromanyl and the like. One of ordinary skill in the art will understand that the connection of said rings (C2-C9 heterocycle) alkyl is through a carbon or a nitrogen heteroatom with sp3 hybridization. C2-C9 heteroaryl, when used herein, refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, midazolyl, 1, 3,5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1,2,3-oxadiazolyl, 1, 3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1, 2,4- triazinyl, 1,2,3-triazinyl, 1,3-triazinyl, pyrazolo [3,4-b] pyridinyl, cinolinyl, pteridyl, purinyl, 6,7-dihydro-5H- [1] pyridinyl, benzo [bichlophenyl, 5,6,7,8-tetrahydroquinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzoisoxazolyl, benzimidazolyl, tianaphtenyl, isothianaphtenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl and the like. One of ordinary skill in the art will understand that the connection of said rings (heterocycle C2-Cg) alkyl is through a carbon or a nitrogen heteroatom with sp3 hybridization. C6-C10 aryl, when used herein, refers to phenyl or naphthyl. The compounds of formula (I) can be administered in acceptable pharmaceutical form alone or in combination with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents. These agents may include, but are not limited to, cyclosporin A (eg, Sandimmune® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxypergualin, mycophenolate (eg Cellcept®), azathiopyrine (eg Imuran® ), daclizumab (for example Zenapax®), OKT3 (for example Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (eg prednisolone or dexamethasone) These agents can be administered as part of the same or in separate forms, by the same or different administration routes, and with the same or different administration patterns according to conventional pharmaceutical practice The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) ) and all optical isomers of the compounds of formula I (for example enantiomers and diastereoisomers), as well as the racemic, diastereomeric and other mixtures of such isomers.
Preferred compounds of formula I include those in which R1 is NR4R5. Other preferred compounds of formula I include those in which R 4 is hydrogen, CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted with hydroxy, amino, trifluoromethyl, acyloxy CrCβ, (alkyl) d-Cβ) amino, (alkyl dC 6) amino or (acyl CrC 6) amino; or R 4 is C 3 -C 10 cycloalkyl, the cycloalkyl group being optionally substituted by hydroxy, trifluoromethyl or acyloxy CrC 6. Other preferred compounds of formula I include those in which R5 is C3-C10 cycloalkyl, the cycloalkyl group being optionally substituted by one to five of deuterium, hydroxy, trifluoromethyl, halo, alkyl Cr C6, hydroxy (CrC6 alkyl), CrC6 acyl, (CrC6 alkyl) amino (CrC6 acyl), (alkyl) CrC6) 2amino (acyl CrC6), (acyl CrC6) amino, (alkoxy d-Ce) -CO-NH, (alkyl d- C6) amino-CO-, alkenyl d-Cß, alkynyl C2-C6, halo (alkyl C ? -C6), (acyl dC6) amino (C? -C6 alkyl), R15S (O) mR16N, R15S (O) mR16N (alkyl dC6) where m is 0, 1 or 2 and each of R15 and R16 is independently selected from hydrogen or d-Cß alkyl. Other preferred compounds of formula I include those in which R2 and R3 are each independently selected from the group consisting of hydrogen, halo, CrCß alkyl, C2-C6 alkenyl, C2 alkynyl -C6, CrC6 alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, (C2-Cg heterocycle) alkyl, Cs-Cg heteroaryl or Ce-Cio aryl. The specific compounds of formula I include the following: 2-. { 4-Methyl-3- [methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} -propan-2-ol; 2-. { 3 - [(2-Hydroxy-ethyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -4-methyl-cyclohexyl} -propan-2-ol; 2 - [(5-lsopropenyl-2-methyl-cyclohexyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; (5-lsopropenyl-2-methyl-cyclohexyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) - (2,2,2-trifluoro-ethyl) -amine; 2-. { 4-MetiI-3 - [(7H-pyrrolo [2,3-d] pyrimidin-4-yl) - (2,2,2-trifluoro-ethyl) amino] -cyclohexyl} -propan-2-ol; 2-. { 4-Methyl-5- [meth] - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclohex-3-enyl} -propan-2-ol; 2- [1 - (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -azetidin-3-yl] -propan-2-ol; 2- [1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -azetidin-2-yl] -propan-2-ol; (5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) - (5-isopropenyl-2-methyl-cyclohexyl) -methyl-amine; 2-. { 3 - [(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-cyclohexyl} -propan-2-ol; (2-Ethyl-4-isopropenyl-cyclopentyl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; 2-. { 3-Ethyl-4- [meth] - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclopentyl} -propan-2-ol; 2-. { 3-Ethyl-4 - [(2-hydroxy-ethyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] -cyclopentyl} -propan-2-ol; 2 - [(2-Ethyl-4-isopropenyl-cyclopentyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -aminohetanol; (5- (S) -lsopropenyl-2-methyl-cyclohexyl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; 3-Methyl-8- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -8-aza-bicyclo [3.2.1] octan-3-ol; 2- [Cycloheptyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; 2- [Cyclooctyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; Bicyclo- [2.2.1] hept-2-yl-methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; and 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] -pyrimidine. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, arthritis, rheumatoid, psoriasis, type I diabetes and complications of diabetes, cancer , asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in said disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or ( b) inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with immunosuppressive agents of cells T or anti-inflammatories, effective in said disorders or conditions and a pharmaceutically acceptable vehicle. The present invention also relates to a method for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or one of its pharmaceutically acceptable salts. The present invention also relates to a method for treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis. , autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of formula or one of its pharmaceutically salts acceptable, effective to treat such disorder. The present invention also relates to a method for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, which comprises administering to said mammal an effective amount of a compound of formula I or one of its pharmaceutically acceptable salts, alone or combined with immunosuppressive agents of T cells or anti-inflammatories. The present invention also relates to a method for treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis. , autoimmune disorders of the thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being, comprising administering to said mammal an amount of a compound of formula I or one of its salts pharmaceutically acceptable, alone or combined with immunosuppressive agents of T cells or anti-inflammatory, effective to treat said disorder.
DETAILED DESCRIPTION OF THE INVENTION The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless indicated otherwise, R1, R2, R3 and R9 in the following reaction and description schemes are as defined above.
SCHEME 1 SCHEME 2 twenty SCHEME 3 15 SCHEME 4 XXIII SCHEMES SCHEME 6 XXVI In reaction 2 of scheme 1, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVI is converted to the corresponding compound of 4-aminopyrrolo [2,3-d] pyrimidine of formula XV coupling XVI with an amine of formula HNR4R5. The reaction is carried out in an alcohol as solvent, such as tert-butanol, methanol or ethanol, or other high-boiling organic solvent, such as dimethylformamide, 1,4-dioxane or 1,2-dichloroethane, at a temperature of about 60 ° C to about 120 ° C, preferably about 80 ° C. Typical reaction times vary from about 2 hours to about 48 hours, preferably about 16 hours. In reaction 3 of scheme 1, removal of the protecting group from the compound of formula XV, where R is benzenesulfonyl, to give the corresponding compound of formula I, is carried out by treating XV with an alkaline base, such as sodium hydroxide or potassium hydroxide. , in an alcohol as a solvent, such as methanol or ethanol, or mixed solvents, such as alcohol / tetrahydrofuran or alcohol / water. The reaction is carried out at room temperature for a period of about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the protecting group of the compound of formula XV, where R is benzyl, is carried out by treating XV with sodium in ammonia at a temperature of about -78 ° C for a period of about 15 minutes to about 1 hour.
In reaction 1 scheme 2, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XXI, wherein R is hydrogen or benzenesulfonate, is converted into the 4-chloro-5-halopyrrolo compound [2, 3-d] pyrimidine of formula XX, probe Y is chlorine, bromine or iodine, by reacting XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated to reflux in chloroform, for a period of from about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of scheme 2, the compound of 4-chloropyrrolo [2,3-d] pyrimidine of formula XXI, where R is hydrogen, is converted to the compound 4-chloro-5-nitropyrrolo [2,3-d] pyrimidine of formula XX, where Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature of about -10 ° C to about 10 ° C, preferably about 0 ° C, during the period from about 5 minutes to about 15 minutes, preferably about 10 minutes. The compound of formula XXI, where Y is nitro, is converted to the corresponding 4-chloro-5-aminopyrrolo [2,3-d-pyrimidine of formula XX, where Y is amino, by reacting XXI under a series of conditions known to an expert in the art, such as hydrogenolysis with palladium or tin (IV) chloride and hydrochloric acid. In reaction 2 of scheme 2, the 4-chloro-5-halopyrrolo [2,3-d] pyrimidine compound of formula XX, where R is hydrogen, is converted to the corresponding compound of formula XIX, where R2 is CrC6 alkyl , or benzyl, treating XX with N-butyl lithium at a temperature of about -78 ° C, and reacting the dianion intermediate thus formed with an alkyl halide or benzyl halide at a temperature of about -78 ° C up to temperature environment, preferably room temperature. Alternatively, the dianion thus formed is reacted with molecular oxygen to form the corresponding 4-cioro-5-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XIX, where R2 is hydroxy. The compound of formula XX, where Y is bromine or iodine and R is benzenesulfonate, is converted to the compound of formula XIX, where R 2 is C 6 -C 2 aryl or vinyl, treating XX with N-butyllithium at a temperature of about -78 ° C, followed by the addition of zinc chlorine, at a temperature of about -78 ° C. The corresponding organo-zinc intermediate thus formed is then reacted with aryl iodide or vinyl iodide in the presence of a catalytic amount of palladium. The reaction mixture is stirred at a temperature of about 50 ° C to about 80 ° C, preferably about 70 ° C, for a period of about 1 hour to about 3 hours, preferably about 1 hour. In reaction 3 of scheme 2, the compound of formula XIX is converted to the corresponding compound of formula XVI by treating XIX with N-butyl lithium, lithium diisopropylamide or sodium hydride, at a temperature of about -78 ° C, in the presence of a polar aprotic solvent, such as tetrahydrofuran. The anionic intermediate thus formed is further reacted with (a) alkyl halide or benzyl halide, at a temperature of about -78 ° C to room temperature, preferably -78 ° C, when R3 is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature of about -78 ° C at room temperature, preferably -78 ° C, when R3 is alkoxy; and (c) zinc chloride, at a temperature of about -78 ° C to room temperature, preferably -78 ° C, and the corresponding organo-zinc intermediate thus formed is then reacted with aryl iodide or vinyl iodide in presence of a catalytic amount of palladium. The resulting reaction mixture is stirred at a temperature of about 50 ° C to about 80 ° C, preferably about 70 ° C, for a period of about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, the anion thus formed is reacted with molecular oxygen to form the corresponding 4-chloro-6-hydroxypyrrolo [2,3-d] pyrimidine compound of formula XVI, wherein R3 is hydroxy. In reaction 1 of scheme 3, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XXI is converted to the corresponding compound of formula XXII, according to the procedure described before reaction 3 of scheme 2. In reaction 2 of scheme 3, the compound of formula XXII is converted to the corresponding compound of formula XVI, according to the procedures described above in reactions 1 and 2 of scheme 3.
In reaction 1 of scheme 4, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XX is converted to the corresponding 4-aminopyrrolo [2,3-d] pyrimidine compound of formula XXIV, according to the procedure described above in the reaction of scheme 1 .. In reaction 2 of scheme 4, the 4-amino-5-halopyrrolo [2,3-d] pyrimidine compound of formula XXIV is converted, where R is benzenesulfonate and Z is bromine or iodine, in the corresponding compound of formula XXIII by reacting XXIV with (a) arylboronic acid, when R2 is aryl, in an aprotic solvent such as tetrahydrofuran or dioxane, in the presence of a catalytic amount of palladium (0) at a about 50 ° C to about 100 ° C, preferably about 70 ° C, for a period of about 2 hours to about 48 hours, preferably about 12 hours, (b) alkynes, when R 2 is alkynyl, in the presence of a catalytic amount of copper iodide (I) and palladium (0), and a polar solvent, such as dimethylformamide, at room temperature for a period of from about 1 hour to about 5 hours, preferably 3 hours; and (c) alkenes or styrenes, when R2 is vinyl or styrenyl, in the presence of a catalytic amount of palladium in dimethylformamide, dioxane or tetrahydrofuran, at a temperature of about 80 ° C to about 100 ° C, preferably about 100 ° C, for a period of from about 2 hours to about 48 hours, preferably about 48 hours.
In reaction 3 of scheme 4, the compound of formula XXIII is converted to the corresponding compound of formula XV, according to the procedure described above in reaction 3 of scheme 2. In reaction 1 of scheme 5, the compound of 4-chloropyrrolo [2,3-d] pyrimidine of formula XVII in the corresponding compound of formula XVI, wherein R is defined as above, according to the procedure described above in reaction 1 of the scheme. In reaction 2 of scheme 5, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVI is converted to the corresponding compound of formula XXV by coupling XVI with a compound of formula R9OH, in the presence of sodium hydroxide. . The reaction is carried out in a polar aprotic solvent, such as tetrahydrofuran, and heated to reflux for a period of from about 2 hours to about 4 hours, preferably about 3 hours. The removal of the protecting group is carried out according to the procedure described above in reaction 3 of scheme 1. In reaction 1 of scheme 6, the 4-chloropyrrolo [2,3-d] pyrimidine compound of formula XVII is converted to the corresponding compound of formula XXVI coupling compound XVII with a compound of formula SR9, in the presence of potassium tert-butoxide and a polar aprotic solvent such as tetrahydrofuran. The resulting reaction mixture is heated to reflux for a period of from about 2.5 hours to about 5 hours, preferably about 3.5 hours. The compound of formula XXVI can be further reacted with an oxidizing agent known to one of ordinary skill in the art, such as hydrogen peroxide, ozone, 3-chloroperoxybenzoic acid or tere-butyl peroxide to generate the 4-R9-sulfin compounds Corresponding pyrrolo [2,3-d] pyrimidine or 4-R9-sulfonylpyrrolo [2,3-d] pyrimidine. The compounds of the present invention which are basic in nature can form a wide range of different salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the above into the compound of free base by treatment with an alkaline reagent, and subsequently converting the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treatment of the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After carefully evaporating the solvent, the desired solid salt is obtained. The salt of the desired acid can also be precipitated in a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
The compounds of the present invention which are acidic in nature can form base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal and alkaline earth metal salts and in particular, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases that are used as reagents for preparing the pharmaceutically acceptable base salts of this invention are those that form non-toxic base salts with the acidic compounds of the present invention. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, magnesium and the like. These salts are readily prepared by treating the corresponding acidic compounds as an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, these can also be prepared by mixing solutions in lower alkanes of the acidic compounds and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as before. In any case, stoichiometric amounts of the reagents are preferably employed in order to ensure completion of the reaction and obtaining the maximum product yield. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention can be formulated for oral, sublingual, intranasal, parenteral (eg, intravenous, intramuscular or subcutaneous) or rectal administration, or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention can also be formulated for sustained release. For oral administration, the pharmaceutical compositions may take the form, for example, of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients as binding agents (eg, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (for example, lactose, microcrystalline cellulose or calcium phosphate); lubricants (for example, magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or these may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives as suspending agents (eg, sorbitol, syrup, methylcellulose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid). For sublingual administration, the composition may take the form of tablets or tablets formulated in conventional manner. The active compounds of the invention can be formulated for parenteral administration by injection, including the use of conventional catheterization or infusion techniques. Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with the addition of a preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending agents, stabilizers and / or dispersion. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use. The active compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently released in the form of a solution or suspension from a pump spray container that is compressed or pumped by the patient or as an aerosol spray presentation from a container. under pressure or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dose unit can be determined by providing the container with a valve that releases a measured quantity. The pressure pack or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, of gelatin) can be formulated for use in an inhaler or insufflator, containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or sublingual administration to an average adult human for the treatment of the above-mentioned disorders (e.g., rheumatoid arthritis) ranges from 0.1 to 1000 mg of active ingredient per unit dose which could be administered, for example, 1 to 4 times a day. Aerosol formulations for the treatment of the above-mentioned disorders (e.g., asthma) in an average adult human are preferably arranged such that each metered dose or "application" of aerosol contains from 20 μg to 1000 μg of the compound of the invention . The total daily dose with an aerosol will vary in the range of 0.1 mg to 1000 mg. The administration can be carried out several times a day, for example. 2, 3, 4 or 8 times, administering for example 1, 2 or 3 doses each time.
A compound of formula (I) is administered in a pharmaceutically acceptable form alone or in combination with one or more additional agents that modulate a mammalian immune system or with anti-inflammatory agents which may include, but are not limited to cyclosporin A (eg, Sandimmune ® or Neoral®, rapamycin, FK-506 (tacrolimus), leflunomide, deoxypergualin, mycophenolate (for example Cellcept®), azathioprine (for example Imuran®), declizumab (for example Zenapax®), OKT3 (for example Orthoclone®), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam and anti-inflammatory steroids (eg, prednisolone or dexamethasone) and such agents can be administered as part of the same form or in separate forms, by the same or by different routes of administration, and with the same or different administration guidelines according to conventional pharmaceutical practice FK506 (Tacrolimus) is administered orally at 0.1-0.15 mg / kg of weight, every 12 hours, and n the first 48 hours postoperatively. The dose is controlled by serum levels of Tracrolimus valley. Ciclosporin A (formulation of oral or intravenous Sandimmune®, or Neoral®, oral solution or capsules) is administered orally at 5 mg / kg of weight, every 12 hours in the first 48 hours after surgery. The dose is controlled by the blood levels of cycloperine A. The active agents can be formulated for sustained release according to procedures well known to those skilled in the art. Examples of such formulations can be found in U.S. Patent Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3, 492,397. The ability of the compounds of formula I or their pharmaceutically acceptable salts to inhibit Janus Kinase 3 and, therefore, demonstrate efficacy in treating disorders or conditions characterized by Janus Kinase 3 is shown by the following in vitro assays.
BIOLOGICAL ASSAY JAK3 Enzyme Assay (JH1: GST) The JAK3 Enzyme Enzyme Assay uses a protein expressed in baculovirus-infected SF9 cells (a GST fusion protein and the catalytic domain of human JAK3) purified by glutathione-Sepharose affinity chromatography . The substrate for the reaction is poly-glutamic acid-tyrosine (PC (4: 1), Sigma, catalog number P0275), coated on Nunc Maxi Sorp plates at 100 μg / ml overnight at 37 ° C. The morning after the coating, the plates are washed three times and JAK3 is added to the wells containing 100 μl of kinase buffer (HEPES 50 mm, pH 7.3, NaCl 125 mm, MgCl 2, 24 mm) + Atp 0.2 uM + sodium orthovanadate 1 mm). The reaction proceeds for 30 minutes at room temperature and the plates are washed three more times. The level of tyrosine phosphorylated in a given well is quantified by normalized ELISA using an anti-phosphotyrosine antibody (ICN PY20, catalog number 69-151-1).
DND39 / IL-4 cell assay for kinase inhibitors JAK3 The DND 39 / IL-4 assay is designed to find inhibitors of JAK3 kinase activity that would be the main candidates for immunosuppression and / or allergy. The assay uses a cell line B called DND39 which has received the luciferase gene driven by the germline IgE promoter stably integrated into one of the chromosomes. When these cells are stimulated with IL-4, the JAK3 kinase that is associated with the IL-4 receptor, phosphorylates the transducer of the STAT6 signal. STAT6 then binds to the germline IgE promoter and initiates transcription of the luciferase gene. Luciferase is measured in a lysate of these cells using the Promega luciferase assay reagent system. Note: DND 39 cells are reproduced in RMPI 1640 supplemented with 10% heat inactivated FCS, 2 mm L-glutamine and 100 units / ml Penicillin / streptomycin cells are maintained from 1 × 10 5 to 1 × 10 6 cells / ml . By dividing up to 1 x 105 on Friday, the cells will become 1 x 106 on Monday. Then divide 1: 2 during the week keeping 200 ml in a flask if necessary. DND 39 to 3 x 105 cells are seeded in 100 μl of RPMI 1640 supplemented with 1% heat-activated FCS, 2 mm L-glutamine and 100 units / ml of Penicillin / Streptomycin in a 96-well V-bottom plate. wells (Nunc.). The compounds are serially diluted 1: 2 in DMSO, starting at 4 mm to 1.9 μM. In a 96-well polypropylene plate, the tips are changed after each dilution. Then 5 μl of each dilution is added to 500 μl of RPMI / 1% serum in a 96-tube rack. 125 μl of the dilutions of the compounds are added to the cells and incubated at 37 ° C, 5% C02 for one hour. One hour later, 25 μl of 25 ng / ml IL-4 is added to the cells and mixed. The final concentration of IL-4 is 2.5 ng / ml and the final concentration of the compound ranges from 20 μM to 156 nM. The cells are then incubated overnight 16-18 hours. The plate is then centrifuged at 2500-3000 rpm in a tabletop centrifuge for 5 minutes. The culture supernatant is carefully removed by aspiration with an 8-well collector. 100 μl of PBS with calcium and magnesium are added to the sedimented cells. The cells are resuspended in PBS and transferred to a Packard White OptiPlate plate. 100 μl of Packard LucLite reagent is added to the wells of the OptiPlate plate. The following examples illustrate the preparation of the compounds of the present invention although it is not limited to the details thereof. The melting points are uncorrected. The NMR data are expressed in parts per million (d) and are referenced to the deuterium stabilization signal of the sample solvent (deuteriochloroform, unless otherwise indicated). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. The Low Resolution Mass Spectrums (LRMS) were recorded in a Hewlett Packard 5989®, using chemical ionization (ammonium) or in a platform of Atmospheric Pressure Chemical Ionization (APCI) Fisons (or Micro Mass) that uses a mixture 50 / 50 acetonitrile / water with 0.1% formic acid as the ionization agent. Ambient temperature refers to 20-25 ° C.
EXAMPLE 1 Cyclohexyl-methyl- (7H-pyrrolor-2,3-d.-pyrimidin-4-yl) amine PROCEDURE A Cyclohexylmethylamine 2.0 ml of a 2 M solution of methylamine in methanol was added to a solution of cyclohexanone (98 mg / 1 mmol) and acetic acid (120 mg, 2 mmol) dissolved in 2.0 ml of 1,2-dichloroethane and the resulting mixture stirred at room temperature for 4 hours. Polymer-supported borohydride (1 g, 2.5 mmol) was added and the mixture was stirred at room temperature for 1 hour and then filtered and concentrated to dryness in vacuo, yielding 66 mg (40%) of the title compound as the acetate salt . NMR of H (400 mHz) (CD3OD) d: 1.17-1.37 (m, 5H), 1.67 (broad d, 1 H, J = 1.25 Hz), 1.83 (broad d, 2H, J = 18.7 Hz), 1.86 ( s, 3H), 2.04 (broad d, 2H, J = 10.2 Hz), 2.60 (s, 3H), 2.86-2.92 (m, 1 H).
PROCEDURE B Cyclohexylmethyl- (7H-pyrrolo [2,3-dlp] rmidn-4-yl) amine A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (prepared by the procedure of Davoll, J. AM.Chem.Soc. (1960), 82, 131 was stirred. ), the product of procedure A (589 mg / 5.21 mmoles) and 3 ml of tert-butanol, in a sealed tube at 100 ° C for 24 hours. The reaction mixture was added to water, acidified to pH 14 with 1N sodium hydroxide (NaOH), washed twice with diethyl ether (ether) and basified to pH 14 with 1N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of the title compound, m.p. 177-180 ° C. NMR of H (400 MHz, CDCl 3): d 1.1 1-1.22 (m, 1 H), 1.43-1.63 (m, 4H), 1.73 (broad d, 1 H, J = 13.3 Hz), 1.83-1.90 (m, 4H), 3.23 (s, 3H), 4.69 (width, 1 H), 6.53 (d, 1 H, J = 3.5 Hz), 7.03 (d, 1 H, J = 3.5 Hz), 8.30 (s) , 1 H), 10.6 (width, 1 H). LRMS: 231 (M + 1). The title compounds of Examples 2 to 84 were prepared by a procedure analogous to that described in Example 1.
EXAMPLE 2 Benzyl-ethyl-7H-pyrrolor-2,3-d.pyrimidin-4-yl) -amine Benzylethylamine Melting point: 170-172 ° C; LRMS: 252.3.
EXAMPLE 3 Methyl-fS) - (1-phenyl-etin- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine Methyl- (S) -1-phenylethylamine. Melting point. 131 ° C; LRMS: 253.
EXAMPLE 4 Cyclopentyl-methy1-, 7H-pyrrolo.2.3-d1-pyrimidine-4-H, -amine Cyclopentyl amine LRMS. 217.3.
EXAMPLE 5 AliI-cyclohexi- (7H-pyrrolo [2,3-dlpyrimidin-4-yl) -amine Allylcyclohexylamine. LRMS: 257.
EXAMPLE 6 Allyl-cyclopenti! - (7H-pyrrolo.2,3-d1-pyrimidin-4-yl, -amine Allylcyclopentylamine. Melting point. 173-175 ° C; LRMS: 243.
EXAMPLE 7 Allyl-cyclopentyl-, 7H-pyrrolor2,3-d, pyrimidin-4-yl, -amine Cyclohexylethylamine. LRMS. 245.3.
EXAMPLE 8 (1-Cyclohexyl-ethyl) -methyl- (7H-pyrrolof2,3-d1pyrimidn-4-yl) -amine (1-Cyclohexyl-ethyl) methylamine. LRMS: 259.4.
EXAMPLE 9 Cycloheptyl-methyl-, 7H-pyrrolor2, 3-d-pyrimidin-4-yl. -amine Cycloheptylmethylamine. Melting point: 177-178 ° C; LRMS: 245.3.
EXAMPLE 10 Cyclooctyl-methyl-, 7H-pyrrolo.2,3-d1-pyrimidin-4-yl) -amine Cyclooctylmethylamine. Melting point: 188-189 ° C; LRMS: 259.4.
EXAMPLE 11 Methyl- (3-methyl-cyclohexyl) - (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine Methyl- (3-methylcyclohexyl) amine. LRMS: 245.3.
EXAMPLE 12 Methyl- (4-methyl-cyclohexyl) - (7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amine Methyl- (4-methyl-cyclohexyl) -amine. LRMS: 245.3.
EXAMPLE 13 Methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) - (3,3,5-trimethyl-cyclohexyl) -amine Methyl- (3,3,5-trimethylcyclohexyl) -amine. LRMS: 273.4.
EXAMPLE 14 CyclohTPtil-Ttil-f7H-pyrrolor-2,3-dlpyrimidin-4-yl-amine Cycloheptylethylamine. Melting point: 168-169 ° C; LRMS: 259.4.
EXAMPLE 15 Cyclooctyl-ethyl- (7H-pyrrolor-2-d1-pyrimidin-4-yl) -amine Cyclooctylethylamine. Melting point: 155-156 ° C; LRMS: 273.4.
EXAMPLE 16 ri- (4-Chloro-phenyl) -propin-methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine [1- (4-Chlorophenyl) -propyl] methylamine. LRMS: 301.7.
EXAMPLE 17 r2- (2-Methoxy-phenyl) -1-methyl-etip-methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine [2- (2-Methoxy-phenyl) -1-methyl-ethyl] -methylamine. LRMS: 297.4.
EXAMPLE 18 (Decahdrone-naphthalen-1-l) -methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine Decahydronaphthalen-1-yl-methylamine. LRMS: 285.4.
EXAMPLE 19 Cyclodecyl-methyl- (7H-pyrrolor-2,3-d.-pyrimidin-4-yl, -amine Cyclodecylmethylamine. LRMS: 287.1.
EXAMPLE 20 CyClononyl-methyl-.7H-pyrrolo.2,3-d, pyrimidin-4-iD-amine Ciclononllmetil. LRMS: 273.1 EXAMPLE 21 2-r Cyclopentyl-f7H-pyrrolof2.3-d1-pyrimidin-4-yl) -amino-1-ethanol 2-Cyclopentylaminoethanol. Melting point: 156-158 ° C; LRMS: 247.3.
EXAMPLE 22 Cycloheptyl- (2-methoxy-ethyl) - (7H-pyrroxy [2,3-d1-pyrimidin-4-yl] -amine) Cycloheptyl- (2-methoxy-ethyl) amine. LRMS: 289 EXAMPLE 23 Cycloheptyl-cyclopropyl- (7H-pyrrolof2,3-dlpyrimidin-4-yl) -amine Cycloheptylcyclopropylamine. LRMS: 217.4.
EXAMPLE 24 Cycloheptyl-cyclopropyl-7H-pyrrolof2,3-dlpyrimidin-4-ip-amino-1-ethanol Cyclohexylaminoethanol. Melting point: 200-201 ° C; LRMS: 261.3 EXAMPLE 25 Cyclooctyl- (2-methoxy-ethyl) - (7H-pyrrolor-2,3-d-pyrimidin-p-amine Cyclooctyl- (2-methoxy-ethyl) amine. LRMS: 303.
EXAMPLE 26 Sec-butyl-methyl- (7H-pyrrolor-2,3-d, pyrimidin-4-yl, -amine Sec-butyl-methylamine. Melting point: 146-148 ° C; LRMS: 205.
EXAMPLE 27 2-rMethyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amino-1-phenyl-propan-1-ol 2-Methyl-1-phenyl-propan-1-ol. LRMS: 283,265.
EXAMPLE 28 r2- (4-Chloro-phenoxy) -1-methyl-ethyl-methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine [2- (4-Chlorophenoxy) -1-methylethyl-methylamine. Melting point: 139-141 ° C; LRMS: 319, 317, 189.
EXAMPLE 29 N-Cyclohexyl-N,. N, -dimethyl-N- (7 H -Drolor 2,3-dlpyrimidin-4-n-propane-1,3-diamine N-Cyclohexyl-N ', N'-dimethyl propane-1,3-diamine. LRMS: 302.4.
EXAMPLE 30 N-f2-rCyclohexyl-f7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amino-1-ethyl > -acetamide N-Cyclohexylaminoethyl acetamide. LRMS: 302.4.
EXAMPLE 31 2-rCycloheptyl-, 7H-pyrrolo.213-d1-pyrimid-4-yl) -amino-1-ethanol 2-Cyclohexylaminoethanol. Melting point: 69-72 ° C; LRMS: 275.4.
EXAMPLE 32 2-rCyclooctyl- (7H-pyrrolor2,3-d1-pyrimidin-4-ip-amino-1-ethanol 2-Cyclooctylaminoethanol. Melting point: 66-77 ° C; LRMS: 289.4.
EXAMPLE 33 (3,5-Dimethyl-cyclohexyl) -methyl- (7H-pyrr> lo-2,3-d1-pyridin-4-y!) -amine (3,5-Dimethylcyclohexyl) methylamine. LRMS: 259.4.
EXAMPLE 34 2-rBenzyl-, 7H-pyrrolof2,3-d1-pyrimidin-4-yl) -amino.-ethanol 2-Benzylaminoethanol. LRMS: 269,251.
EXAMPLE 35 2-rCyclopentiK7H-pyrrolor2,3-d1pyrimidin- -iD-amino1-propan-1 -ol 3-Cyclopentyl-propane-1-ol. Melting point 162-164 ° C; LRMS: 261.3.
EXAMPLE 36 3- [Cycloheptyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amino-1-propan-1-yl 3-Cycloheptylaminopropan-1 -ol Melting point: 62-66 ° C; LRMS: 289.4.
EXAMPLE 37-r (Decahydro-naphthalen-2-yl) - (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amino-1-ethanol 2-Decahydronaphthalen-2-yl-aminoethanol. Melting point: 75 ° C; LRMS: 315.
EXAMPLE 38 2-r (1-Ethyl-propyl) - (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amino-1-ethanol 2- (1-Ethylpropyl) amine ethanol. Melting point: 49 - 53 ° C; LRMS: 249.3.
EXAMPLE 39 1-rCyclohexyl- (7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amino-1-but * in-2-ol Cyclohexylamino-butan-2-ol. LRMS: 289 EXAMPLE 40 Biciclor2.2.nhept-2-yl-methyl (7H-pyrrolor2.3-d1-pyrimidin-4-yl) -amine Bicyclo [2.2.1] hept-2-yl-methylamine. LRMS: 243.
EXAMPLE 41 2 (SH, Cyclohexyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amino-1-methyl) -cyclohexanol 2- (Cyclohexylamine) methylcyclohexanol. LRMS: 329 EXAMPLE 42 2 (R-Cyclohexyl- (7H-pyrrolor2.3-d1pyrimidin-4-in-amino-1-methyl-cyclohexanol 2- (Cyclohexylamine) methylcyclohexanol. LRMS: 329 EXAMPLE 43, 2-Ethyl-cyclopentyl, -methyl- (7H-pyrrolo [2,3-dlpyrimidin-4-M) -amine (2-Ethylcyclopentyl) methylamine. LRMS: 287 EXAMPLE 44 Ciclononyl-methyl-.7H-pyrrolor-2,3-d.-pyrimidin-4-yl. -amine Cyclononylmethylamine. LRMS: 273 EXAMPLE 45 Methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) - (2,4,4-trimethyl-cyclopentip-amine) Methyl ^^^ - trimethyl-cyclopentyl-J-amine. LRMS: 259.
EXAMPLE 46 (3-Ethyl-cyclopentyl) -methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine (3-Ethyl-cyclopentyl) methylamine. LRMS: 245.
EXAMPLE 47 (2,5-Dimethyl-cyclohexyl) -methyl- (7H-pyrroori-2,3-d1-pyrimidin-4-yl) -amine (2,5-Dimethylcyclohexyl) methylamine. LRMS: 259.
EXAMPLE 48 (3,4-Dimethyl-cyclohexyl) -methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (3,4-D-methylcyclohexyl) methylamine. LRMS: 259 EXAMPLE 49 (4-lsopropyl-cyclohexyl) -methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl, -amine (4-Isopropylcyclohexyl) methylamine. LRMS: 273.
EXAMPLE 50 (Decahydro-naphthalen-1-yl) -methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (Decahydronaphthalen-1-yl) methylamine. LRMS: 285 EXAMPLE 51 (2,2-Dimethyl-cyclohexin-methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (2,2-Dimethylcyclohexyl) methylamine. LRMS: 259.
EXAMPLE 52 (2-lsopropyl-5-methyl-cyclohexyl) -methyl- (7H-pyrrolor-2, 3-d. Pyrimidine-4-p. -amine (2-lsopropyl-5-methylcyclohexyl) methylamine. LRMS: 287 EXAMPLE 53 Met.l-, 3-methyl-cyclopentylH7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amine Methyl- (3-methyl-cyclopentyl) amine. LRMS: 231.
EXAMPLE 54 (1-Benzyl-piperidin-4-yl) -methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (1-Benzylpiperidin-4-yl) methylamine. LRMS: 322.
EXAMPLE 55 (4-tert-Butyl-cyclohexyl-methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine (4-tert-Butylcyclohexyl) methylamine. LRMS: 287.
EXAMPLE 56 lndan-1-yl-methyl- (7H-pyrrolo [2,3-d1pyrimidin-4-yl, -amine] lndan-1-l-methylamine. LRMS: 265.
EXAMPLE 57 (4-Ethyl-cyclohexyl) -methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (4-Ethylcyclohexyl) methylamine. LRMS: 259.
EXAMPLE 58 Methyl- (7H-pyrrolor-2,3-dlpyrimidin-4-yn- (1,2,3,4-tetrahydro-naphthalen-2-yl) -amine Methyl-1, 2,3,4-tetrahydro-naphthalen-2-yl) -amine.
LRMS: 279 EXAMPLE 59 Bicyclo3.2.noct-2-yl-methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine Bicyclo [3.2.1] oct-2-yl-methylamine. LRMS: 257.
EXAMPLE 60 Methyl- (octahydro-4,7-methano-inden-5-ip-f7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine Methyl- (octahydro-4,7-methano-inden-5-yl) amine. LRMS: 283.
EXAMPLE 61 Bicyclo2.3.1.hept-2-yl-methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine Bicyclo [2.2.1] hept-2-yl-methylamine. LRMS: 243.
EXAMPLE 62 (5-Chloro-indan-1 -yl) -methyl- (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine (5-Chloro-indan-1-yl) methylamine. LRMS: 299.
EXAMPLE 63 Adamantan-2-yl-methy1- (7H-pyrrolof213-d.pyrimidin-4-yl. -amine Adamantan-2-yl-methylamine. LRMS: 283.
EXAMPLE 64 (Decahydro-naphthalen-2-ip-methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (Decahydro-naphthalen-2-yl) methylamine. LRMS: 285.
EXAMPLE 65 (3,5-Dimethyl-cyclohexin-methyl-f 7 H -pyrrolor-2,3-dl-pyrimidin-4-n-amine (S.S.-Dimethyl-1-methoxy-methylamine.) LRMS: 259.
EXAMPLE 66 Bicyclo3.3.nnon-9-yl-methyl- (7H-pyrrolor-2-d1-pyrimidin-4-yl) -amine Bicyclo [3.3.1] non-9-yl-methylamine. LRMS: 271.
EXAMPLE 67 (1-lsopropyl-4-methyl-bicichlor3.1.0lhex-3-yl) -methyl- (7H-pyrrolor-2-d1-pyrimidin-4-yl) -amine (1-lsopropyl-4-methylbicyclo [3.1.0] hext-3-yl) -methylamine. LRMS: 285.
EXAMPLE 68 Cyclobutyl-methyl-.7H-pyrro! Or2,3-d, pyrimidin-4-yl-amine Cyclobutylmethylamine. LRMS: 203.
EXAMPLE 69 (2,2-Dimethyl-cyclopentyl) -methyl- (7H-pyrrolof2,3-d1-pyrimidin-4-yl) -amine (2,2-Dimethyl-cyclopentyl) methylamine.
LRMS: 245.
EXAMPLE 70 Ethyl 4-rmethyl-, 7H-pyrrolor-2,3-d.-pyrimidin-4-yl) -amino-1-cyclohexanecarboxylic acid ethyl ester 4- [Methylamino] cyclohexanecarboxylic acid. LRMS: 303.
EXAMPLE 71 (2-lsopropyl-5-methyl-cyclohexyl) -methyl- (7H-pyrrolo [2,3-d1-pyrimidin-4-yl] -amine) (2-lsopropyl-5-methyl-cyclohexyl) methylamine. LRMS: 287.
EXAMPLE 72 (3,3-Dimethyl-cyclohexyl) -methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine (3,3-Dimethyl-cyclohexyl) methylamine. LRMS: 259.
EXAMPLE 73 1 (S) -r Cyclohexyl- (7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amino-1-propan-2-ol 1- [Cyclohexylamino] -propan-2-ol. LRMS: 275.4.
EXAMPLE 74 1 (R) -r Cyclohexyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-p-aminol-propan-2-ol 1- [Cyclohexylamino] -propan-2-ol. LRMS: 275.4.
EXAMPLE 75 3-r Cyclohexyl- (7H-pyrrolor-2,3-dlp8rimidin-4-yl) -aminol-propan-1,2-diol 3- [Cyclohexylamino] -propane-1,2-diol. LRMS: 291.4.
EXAMPLE 76 2-r (Decahydro-naphthalen-1-yl) - (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amino-1-ethanol 2 - [(Decahydro-naphthalen-1-yl) -amino] -ethanol. LRMS: 315.4.
EXAMPLE 77 Tert-butyl ester of acid. { 2-, cycloheptyl- (7H-pyrrolor-2,3-dlpyrimidin-4-yl) -amino-ethyl) -carbamic 2 - [(Cycloheptylamino) ethyl] carbamic acid. LRMS: 374.5.
EXAMPLE 78 Methyl-, 3-methyl-cyclohexyl) -. 7H-pyrrolor-2,3-d.pyrimidin-4-yl, -amine Methyl- (3-methylcyclohexyl) amine. LRMS: 359.4.
EXAMPLE 79 Methyl- (2-methyl-cyclohexyl) - (7H-pyrrolor-2,3-d1-pyridin-4-yl) -amine Methyl- (2-methylcyclohexyl) amine. LRMS: 359.4.
EXAMPLE 80.2-Ethyl-cyclohexyl-met81- (7H-pyrrolor2.3-d.pyrimidin-4-yl-amine (2-Ethyl-cyclohexyl) methylamine.
LRMS: 373.4.
EXAMPLE 81 Methyl- (2-propyl-cyclohexyl) - (7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine Methyl- (2-propylcyclohexyl) amine. LRMS: 387.4.
EXAMPLE 82 (2,4-Dimethyl-cyclohexyl-methyl-, 7H-pyrrolo [2,3-d.pyramidin-4-yl) -amine (2,4-Dimethylcyclohexyl) methylamine. LRMS: 373.4.
EXAMPLE 83 Methyl- (7H-pyrrolor-2,3-d1-pyrimidin-4-yl) - (2,515-trimethyl-cyclo-ethyl) -amine Methyl- (2,5,5-trimethylcyclohexyl) -amine. LRMS: 387.4.
EXAMPLE 84 Methyl- (7H-pyrrolor213-d1-pyrimidin-4-yl) - (2,2,5,5-tetramethyl-cyclohexyl) -amine Methyl- (2,2,5,5-tetramethylcyclohexyl) -amine. LRMS: 401.
EXAMPLE 85 Cyclohexyl-methyl- (6-phenyl-7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine Cyclohexylmethylamine.
PROCEDURE C 7-Benzenesulfonyl-4-chloro-7H-pyrrolor-2,3-dlpyrimidine In a flame-dried flask under nitrogen, 780 mg of 60% sodium hydride (19.5 mmol) in mineral oil was added to 30 nl of dimethylformamide (DMF) and the resulting mixture was cooled to 0 ° C. A solution of 2.0 g (13.0 mmoles) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine in 10 ml of DMF was added slowly over a period of 5 minutes. The reaction was stirred for 10 minutes, at which time the generation of hydrogen (H2) ceased. Benzenesulfonyl chloride (1.7 ml / 13.0 mmol) was added, the reaction was warmed to room temperature and stirred for 1 hour. Water was added and the resulting precipitate was filtered and dried in vacuo to obtain 3.4 g (89%) of the title compound as a crystalline solid, m.p. 163-167 ° C.
PROCEDURE P 7-Benzenesulfonyl-4-cioro-6-phenyl-7H-pyrrolor 2,3-d. pyrimidine In a flame-dried flask and under nitrogen, 0.53 ml (3.79 mmoles) of diisopropylamine was dissolved in 5 ml of tetrahydrofuran (THF) and the solution was cooled to -78 ° C. N-Butyl lithium (3.75 mmol as a 2.5 M solution in hexanes) was added and the resulting mixture was brought to 0 ° C with continuous stirring for 10 minutes. The reaction mixture was again cooled to -78 ° C and to this mixture a solution of 1.0 g (3.40 mmol) of the product from procedure C in 10 ml of THF was added over a period of 10 minutes. The reaction mixture was stirred for 1 hour at -78 ° C, at which time 8.2 ml (4.10 mmol) of a 0.5 M solution of zinc chloride in THF was added, the reaction mixture was brought to room temperature and stirred for 1 hour. Iodobenzene (0.46 ml / 4.1 1 mmol) and a suspension of 197 mg of tetrakis (triphenylphosphine) palladium in 2 ml of THF were added. The resulting mixture was stirred under reflux for 3 hours, cooled to room temperature and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 N HCl and extracted twice with dichloromethane. The dichloromethane layers were combined, washed with 1 N HCl and brine, dried over magnesium sulfate (MgSO), filtered and concentrated in vacuo to obtain the title compound. LRMS: 370, 372 (M + 2).
PROCEDURE E 4-Chloro-6-phenyl-7H-pyrrolor-2,3-dlpyrimidine The product of procedure D was dissolved in 10 ml of THF and 5.0 ml of methanol and 1.0 g of NaOH were added to this solution. The reaction mixture was stirred for 15 minutes, concentrated in vacuo and partitioned between a saturated aqueous solution of ammonium chloride (NH4CI) and ethyl acetate. The resulting aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with brine, dried over MgSO, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate: hexane 1: 5), obtaining 0.59 g (76%) of the title compound as a pale yellow solid, m.p. 145 ° C (dec.). LRMS: 230, 232 (M + 2).
PROCEDURE F Cyclohexyl-methyl- (6-phenyl-7H-pyrrolor-2,3-d.-pyrimidin-4-yl, -amine The product of procedure E (50 mg / 0.218 mmol) was reacted with 0.12 ml of N-methylcyclohexylamine (0.920 mmol) as described in procedure B. The reaction mixture was concentrated in vacuo, methanol and methanol were added. The resulting precipitate was filtered to give 7 mg (10%) of the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl 3) d: 1.18-1.25 (m, 1 H), 1.47-1.66 (m, 4 H), 1.75-1.90 (m, 5 H), 3.30 (s, 3 H), 4.74 (Width, 1 H), 6.79 (s, 1 H), 7.32-7.36 (m, 1 H), 7.47-7.51 (m, 2 H), 7.77 (d, 2 H, J = 7.9 Hz), 8.33 (s, 1 H) . LRMS: 307 (M + 1). The compound of Example 86 was prepared by a procedure analogous to that described in Example 85.
EXAMPLE 86 H-lndol-5-yl) - (6-phenyl-7H-pyrrolor-2,3-dlpyrimidin-4-yn-amine 1 H-lndolamine. LRMS: 326.4 EXAMPLE 87 Cyclohexyl-methyl- (6-methyl-7H-pyrrolof2,3-d1-pyrimidin-4-yl) -amine Cyclohexylmethylamine.
PROCEDURE G 7-Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolor-2,3-d1-pyrimidine A 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 ml of dry THF were charged to a flame-dried flask under nitrogen. The solution was cooled to -78 ° C and 1.63 ml (4.08 mmol) of a 2.5 solution was added.
M of n-butyl lithium in hexanes. The resulting mixture was brought to 0 ° C and stirred for 10 minutes. After cooling the mixture back to -78 ° C, a solution of 1.0 g (3.40 mmol) of the crude product of procedure C in 10 ml of dry THF was added over a period of 10 minutes. The resulting mixture was stirred for 1 hour, at which point it was added 0. 28 ml (4.50 mmol) of iodomethane. The reaction mixture was stirred for 2 hours, quenched with saturated NH 4 Cl solution and warmed to room temperature. The mixture was stirred for 5 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (m + 2).
PROCEDURE H 4-Chloro-6-methyl-7H-pyrrolor-2,3-d-pyrimidone The product of procedure G was deprotected as described in procedure E. The crude product was purified by trituration with hexanes and dichloromethane to obtain 250 mg (44%) of the title compound as a yellow solid. Melting point 205 ° C (dec.). LRMS: 168, 170 (M + 2).
PROCEDURE I Cyclohexyl-methyl-, 6-methyl-7H-pyrrolor-2,3-d.pyrimidin-4-yl) -amine The product of procedure H was reacted (50 mg / 0.298 mmol) with 100 mg (0.883 mmol) of N-methylcyclohexylamine as described in procedure B. The reaction mixture was treated as in procedure B with the exception of that ethyl acetate was used instead of ether. The title compound (42 mg, 58% yield) was obtained as a white solid. Melting point 221 ° C (dec.). 1 H NMR (400 MHz, CDCl 3) d: 1.15-1.25 (m, 1 H), 1.43-1.62 (m, 4H), 1.73 (broad s, 1 H, J = 13.7 Hz), 1.82-1.90 ( m, 4H), 2.41 (d, 3H, J = 0.8 Hz), 3.21 (s, 3H), 4.63 (s, 1 H), 6.20 (s, 1 H), 8.22 (s, 1 H), 10.1 (s wide, 1 H). LRMS: 245 (M + 1). The title compound of Example 88 was prepared by a procedure analogous to that described in Example 87.
EXAMPLE 88 Cyclohexyl- (6-methyl-7H-pyrrolor2,3-d, pyrimidin-4-8l) -amine Cyclohexylamine. LRMS: 231.3.
EXAMPLE 89 4-Cyclohexyloxy-7H-pyrrolor-2,3-d.pyrimidine PROCEDURE L 7-Benzyl-4-chloro-7H-pyrrolor-2,3-d1pyrimidine 676 mg (4.89 mmol) of potassium carbonate was added to a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (250 mg / 1.63 mmol) in 12 ml of DMF and the resulting mixture was stirred under stirring. room temperature for 20 minutes. Benzyl chloride (310 mg / 2.45 mmol) was added and the new mixture was stirred at room temperature for 24 hours, then filtered, concentrated and the residue was purified by chromatography on silica gel (hexane: ethyl acetate 3: 1), providing 318 mg (80%) of the title compound. LRMS: 244.1 (M + 1).
PROCEDURE M 7-Benzyl-4-cyclohexyloxy-7H-pyrrolof2,3-d1pyrimidine 84 mg (2.10 mmol) of 60% sodium hydride in mineral oil and 3.0 ml of THF were charged into a flame-dried flask under nitrogen and the mixture was cooled to 0 ° C. Cyclohexanol (0.18 ml, 1.70 mmol) was added and the reaction mixture was stirred for 5 minutes. A solution of 102 mg (0.419 mmol) of the product of procedure L in 1.0 ml of THF was added and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2N HCl and concentrated in vacuo. The resulting residue was then suspended in ethyl acetate, filtered and the filtrate was concentrated in vacuo to give 76 mg (59%) of the title compound as an oil. LRMS: 308 (M + 1).
PROCEDURE N 4-Cyclohexyloxy-7H-pyrrolo.2,3-d1pyrimidine 33 mg (1.43 mmol) of metallic sodium was added to liquid ammonia (6.0 ml) at -78 ° C and the resulting dark blue solution was stirred at -78 ° C for 10 minutes. A solution of 75 mg (0.244 mmol) of the product of procedure M in 3.0 ml of ether was added dropwise over a period of 5 minutes. The resulting solution was stirred at -78 ° C for 1 hour, followed by quenching after the addition of 500 mg of solid ammonium chloride. After evaporating at room temperature, the residual solid was triturated with 25 ml of ethyl acetate containing 1 ml of acetic acid for 1 hour. Filtration and concentration in vacuo afforded the crude material which was purified by preparative thin layer chromatography (silica gel; ethyl acetate: hexanes 2: 1) yielding 5 mg of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 1.27-1.35 (m, 6H), 1.62-1.67 (m, 4H), 5.30-5.36 (m, 1 H), 8.55 (d, 1 H, J = 3.2 Hz), 7.11 (d, 1 H, J = 3.2 Hz), 8.37 (s wide, 1 H) . LRMS: 218.2 (M + 1).
EXAMPLE 90 4-Cyclohexylsulfanyl-7H-pyrrolor 2,3-d-pyrimidine 0.10 ml (0.818 mmoles) of cyclohexyl mercaptan and 100 mg (0.847 mmoles) of 95% potassium tert-butoxide were added to a solution of 100 mg (0.651 mmoles) of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine dissolved in 3.0 ml of THF and the mixture was heated to reflux for 3.5 hours. After cooling to room temperature, the reaction mixture was acidified to pH 1 with 2N HCl and concentrated in vacuo. The residue was then partitioned between ethyl acetate and 1 N HCl. The aqueous layer was extracted with ethyl acetate, the ethyl acetate layers were combined, washed with brine, dried over MgSO, filtered and evaporated in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate: hexanes 1: 3) to give 34 mg (22%) of the title compound as a white solid. Melting point 162-163 ° C. 1 H NMR (400 MHz) d: 1.22-1.36 (m, 1 H), 1.45-1.64 (m, 5H), 1.75-1.79 (m, 2H), 2.12-2.14 (m, 2H), 4.18- 4.20 (m, 1 H), 6.50 (d, 1 H, J = 3.7 Hz), 7.19 (d, 1 H, J = 3.5 Hz), 8.61 (s, 1 H), 10.0 (s wide, 1 H) . LRMS: 234 (M + 1).
EXAMPLE 91 5-Chloro-4-piperidin-1-yl-7H-pyrrolo [2,3-d1-pyrimidine PROCEDURE R 4,5-Dichloro-7H-pyrrolor 2,3-d. pyrimidine 4-Chloro-7H-pyrrolo [2,3-d] pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 dry dichloromethane in a flame-dried flask and N-chlorosuccinimide (147 mg, 1.1) was added to this mixture. mmoles) in one portion. The resulting mixture was stirred at room temperature for 18 hours, at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration, affording 137 mg (72%) of the title compound as a gray solid, mp 224-227 ° C (dec.). LRMS: 188 (M + 1).
PROCEDURE S 5-Chloro-4-piperidin-1-yl-7H-pyrrolor-2,3-d-pyrimidine The product of procedure R (57 mg, 0.3 mmol) was suspended in 3.0 ml of tert-butanol and piperidine (90 μl, 0.9 mmol) was added to this mixture and the resulting system was heated to reflux for 1 hour. The reaction mixture was cooled to room temperature and water (4.0 ml) was added. The solution was adjusted to pH 1 with. 1 N HCl and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2N NaOH. The solution was then extracted with 2 x 15 ml of dichloromethane and the combined organics were washed with water and then brine and dried over MgSO. Evaporation of the solvent gave 45 mg of a yellow solid which was purified by silica gel chromatography (ethyl acetate: hexanes 3: 1), providing 23 mg (32%) of the title compound as a light yellow solid. Melting point 170-172 ° C. 1 H NMR (400 MHz, CDCl 3) d: 1.67-1.74 (m, 6H), 3.65-3.67 (m, 4H), 7.10 (s, 1 H), 8.31 (s, 1 H). LRMS: 237 (M + 1). The title compounds of Examples 92 to 94 were prepared by a procedure analogous to that described in Example 91.
EXAMPLE 92 (5-Chloro-7H-pyrrolor-2,3-dlpyrimidin-4-8l) - (3-ethynyl-phenyl) -amine 3-Ethynylphenylamine. Melting point: 240 ° C.
EXAMPLE 93 (5-Chloro-7H-pyrrolof2,3-d1-pyrimidin-4-ip-cycloheptyl-methyl-amine Cycloheptylmethylamine. Melting point: 152-153 ° C; LRMS: 279.8.
EXAMPLE 94 (5-Chloro-7H-pyrrolor-2,3-dlpyrimidin-4-ip-coclooctyl-methyl-amine Cyclooctylmethylamine. Melting point: 151-153 ° C; LRMS: 293.8.
EXAMPLE 95 5-Phenyl-4-piperidin-1-yl-7H-pyrrolor2.3-d. pyrimidine PROCEDURE T 5-Bromo-4-chloro-7H-pyrrolor213-dlpyrimidine To a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g / 0.02 mole) dissolved in 75 ml of chloroform was added 3.5 g (0.02 mole) of N-bromosuccinimide and the resulting mixture was led to reflux for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure to give 4.1 g (89%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 7.93 (d, 1 H, J = 2.8 Hz), 8.60 (s, 1 H).
PROCEDURE U 7-Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolor2,3-d, pyrimidine 1.0 g (0.025 mole) of 60% sodium hydride in mineral oil was added to a suspension of the product of procedure T (4.1 g / 0.018 mole) in DMF (15 ml) and cooled to 0 ° C and the resulting mixture was stirred at 0 ° C for 15 minutes. Benzenesulfonyl chloride (3.2 g / 0.018 mol) was added, the reaction mixture was warmed to room temperature and stirred for 2 hours. Water (15 ml) was then added and the resulting solid was removed by filtration and dried in vacuo to give 5.9 g (89%) of the title compound.
PROCEDURE V 7-Benzenesulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolor2,3-d. pyrimidine A mixture of 2.0 g (5.37 mmoles) of the product of procedure U and 1.1 g (13.4 mmoles) of piperidine in 10 ml of tert-butanol was heated at 60 ° C with stirring for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 ml) and water (25 ml). The dichloromethane layer was dried over sodium sulfate (Na2SO) and concentrated to dryness in vacuo affording 2.2 g (97%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 1.63-1.72 (m, 6H), 3.54-3.57 (m, 4H), 7.53 (t, 2H, J = 2.0 Hz), 7.60 (s, 1 H), 7.61 (T, 1 H, J = 2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1 H). LRMS: 422.7, 420.7 (M + 1).
PROCEDURE W 5-Phenyl-p -peridin-1-yl-7H-pyrrolor-2,3-d. pyrimidine 32 mg (0.261 mmoles) of phenylboronic acid and 75 mg (0.356 mmoles) of tribasic potassium phosphate were added, followed by 7 mg (0.006 mmoles) of tetrakis (triphenylphosphine) palladium, to a stirred solution of the process product. V (100 mg, 0.237 mmol) in 1.0 ml of dioxane. The resulting mixture was degassed with nitrogen and stirred at 100 ° C for 48 hours. After cooling to room temperature, 1.0 ml of methanol was added, followed by 50 mg of NaOH and the new mixture was stirred at room temperature for 1 hour. The resulting mixture was then partitioned between dichloromethane and water, the dichloromethane layer was dried over MgSO4 and concentrated to dryness in vacuo. The crude product was purified by chromatography over that of silica (2: 1 ethyl acetate: hexanes) to give 13 mg (20%) of the title compound. 1 H NMR (400 MHz) (CDCl 3) d: 1.33-1.34 (m, 4 H), 1.43-1.44 (m, 2 H), 3.26-3.28 (m, 4 H), 7.12 (s, 1 H), 7.27 (t , 1 H, J = 7.2 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 0.8 Hz), 8.42 (s, 1 H). LRMS: 279.2 (M + 1). The title compounds of Examples 96-99 were prepared by a procedure analogous to that described in Example 95.
EXAMPLE 96 Cyclohexyl-methyl- (5-phenyl-7H-pyrrolor-2,3-d-pyrimidin-4-yl) -amine Cyclohexylamine. Melting point: 200 ° C; LRMS: 307.4.
EXAMPLE 97 Cyclohexyl-r5- (4-fluoro-phenyl) -7H-pyrrolor-2,3-d1-pyrimidin-4-yl) -amine Cyclohexylmethylamine. Melting point: 220 ° C LRMS: 325.4.
EXAMPLE 98 Bichloro.2.2.phept-2-yl- (5-phenyl-7H-pyrrolor-2,3-cnpyrimidin-4-in-amine Bicyclo [2.2.1] hept-2-yl-amine. LRMS: 305.4.
EXAMPLE 99 T5- (3-Chloro-pheny8) -7H-pyrrolor-2,3-cpprimidin-4-ip-cyclohexyl-methyl-amine Cyclohexylmethylamine. LRMS: 455.9.
EXAMPLE 100 PROCEDURE X 4-Piperidin-1-yl-7H-pyrrolor-2,3-dlpyrimidine-5-carbonitrile Piperidine (59 μL, 0.60 mmol) was added to a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine-5-carbonitrile (54 mg, 0.3 mmol) (prepared by the Townsend procedure, et al. al., J. Am. Chem. Soo, 1969, 91, 2102), suspended in 3.0 ml of tert-butanol. The resulting mixture was then heated to reflux for 2.5 hours and after cooling to room temperature, it was transferred to a separatory funnel and diluted with ether (20 ml). The solution was extracted with 2 x 10 ml of 1 N HCl, the combined aqueous layers were adjusted to pH 7 with 2N potassium hydroxide solution (KOH) forming a precipitate which was collected by filtration, washed with water and dried under pressure reduced by providing 29 mg (42%) of the title compound as a colorless solid. Melting point 209-211 ° C; 1 H NMR (400 MHz) (acetone-d 6) d: 1.72-1.74 (m, 6H), 3.72-3.79 (m, 4H), 8.12 (s, 1 H), 8.29 (s, 1 H). LRMS: 228 (M + 1).
EXAMPLE 101 5-Ethyl-4-piperidin-1-yl-7H-pyrrolor2.3-cppirimidin Procedure and 4-Chloro-5-vodo-7H-pyrrolor-2,3-d-pyrimidine 4.5 g (0.02 mole) of N-iodosuccinimide was added to a stirred solution of 4-chloro-7H-pyrrolo [2,3-d] pyrimidine (30 g, 0.02 mole) dissolved in 80 ml of chloroform and the resulting mixture was heated at reflux for 1 hour. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure to give 4.6 g (82%) of the title compound.
PROCEDURE Z 7-Benzenesulfonyl-4-chloro-5-vodo-7H-pyrrolor 2,3-d, pyrimidine The title compound was prepared as described above in procedure U using the product of procedure X, providing 5.4 g (80%) of the material. LRMS: 419.6 (M + 1), 279.7 PROCEDURE AA 7-Benzenesuifonyl-5-vodo-4-piperidin-1-yl-7H-pyrrolor-2,3-d1pyrimidine The title compound was prepared by the procedure described in procedure V using the product of procedure Z to provide the title compound. LRMS: 469 (M + 1), 329.1.
PROCEDURE BB 7-Benzenesulfonyl-4-piperidin-1-l-5-tr-ethylsilanylethynyl-7H-pyrrolor2.3-d.pyrimidine Charged in a flame-dried flask under nitrogen were 211 mg (0.5 mmol) of the product of procedure AA, 19 mg, (0.1 mmol) of copper iodide (I) and 58 mg (0.05 mmol) of tetrakis (triphenylphosphine) palladium . To this mixture were added 0.14 ml (1.0 mmol) of triethylamine and 0.27 ml (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 ml of dry DMF. The resulting mixture was stirred at room temperature for 3 hours, at which time 5.0 ml of water was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over MgSO 4 and concentrated in vacuo. The resulting crude product was then purified by chromatography on silica gel (hexanes: ethyl acetate 7: 1) to give 194 mg (89%) of the title compound. LRMS: 481 (M + 1), 341.
PROCEDURE CC 5-Ethyl-4-piperidin-1-yl-7H-pyrrolo.2,3-d1pyrimidine 0.4 ml (0.4 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF were added dropwise to a stirred solution of the product from the procedure BB (194 mg, 0.40 mmol) dissolved in 2.0 ml of dry THF. The resulting mixture was stirred at room temperature for 10 minutes, then transferred to a methanolic solution (3.0 ml) containing 1 g of KOH, the new mixture was stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, the ethyl acetate layer was washed with water and brine, dried over MgSO4 and concentrated to dryness in vacuo. The crude product was purified by chromatography on silica gel (ethyl acetate: hexanes 2: 1) to give 72 mg (64% of the title compound) as a white crystalline solid. Melting point: 179-181 ° C. 1 H NMR (400 MHz) (CDCl 3) d: 1.72 (broad s, 6H), 3.20 (s, 1 H), 3.82-3.83 (m, 4H), 7.47 (s, 1 H), 8.35 (s, 1 H). LRMS: 227 (M + 1).

Claims (10)

NOVELTY OF THE INVENTION CLAIMS
1. - A compound of the formula or their pharmaceutically acceptable salts; where R1 is a group of formula where y is 0, 1, or 2; R4 is selected from the group consisting of hydrogen, CrC6 alkyl, C2-C6 alkenyl, alky.No C2-C6, the alkyl, alkenyl and alkynyl groups being optionally substituted with deuterium, hydroxy, amino, trifluoromethyl, alkoxy CrC, acyloxy CrC? ( alkyl d-Ce.amino, (d-C6 alkyl) 2 amino, cyano, nitro, C2-C6 alkenyl, C2-C6 alkynyl or (acyl CrCe) amino, or R4 is C3-C3 cycloalkyl, the cycloalkyl group optionally being substituted by deuterium, hydroxy, amino, trifluoromethyl, acyloxy CrCβ, (acyl d-C6) amino, (alkyl CrC6) amino, (alkyl d-Ce amino, cyano, cyano (Cr C6 alkyl), trifluoromethyl (CrCe alkyl) nitro, nitro (CrC6 alkyl), or (acyl CrC6) amino; R5 is selected from the group consisting of trifluoromethyl (alkyl dd), (alkyl dC3) difluoromethylene (CrC3 alkyl), C3-C6 cycloalkyl, the cycloalkyl group being optionally substituted by one to five carboxy, cyano, amino , deuterium, hydroxy, CrC6 alkyl, CrC6 alkoxy, halo, CrC6 acyl, (d-C6 alkyl) amino, amino (dd alkyl), (CrCe alkoxy) -CO-NH, (CrC6 alkyl) amino-CO-, C2 alkenyl -C6, C2-C6 alkynyl, (CrC6 alkyl) amino, amino (CrC6 alkyl), hydroxy (dd alkyl), (CrC6 alkoxy) (CrC6 alkyl), (CrC6 acyloxy) (CrC6 alkyl), nitro, cyano (CrC6 alkyl), halo (dd alkyl), nitro (dd alkyl), trifluoromethyl, trifluoromethyl (CrC6 alkyl), (CrC6 acyl) amino, (acyl dCe) amino (dd alkyl), (CrC6 alkoxy) (CrC6 acyl) amino, amino (acyl CrC6), amino (acyl CrC6) (alkyl dd), (alkyl CrCe) amino (acyl CrC6), (alkyl d-C6) 2amino (acyl C? -Cß), R15R16N-CO-0- , R15R16N-CO- (alkyl d-C6), (alkyl CrC6) -S (0) m, R15R16NS (0) m, R15R16NS (0) m (alkyl d-Ce), R15S (0) mR16N, R15S (O ) mR16N (alkyl dd), m, 0, 1 or 2 being and each of R15 and R16 being independently selected from hydrogen or d-d alkyl; or R5 is (C3-C10 cycloalkyl) (alkyl dd), (acyloxy CrC6) (alkyl d-dMalkoxyC2-Ce) (alkyl dd), piperazinyl (alkyl dd), (acyl CrC6) amino (aIcyl dd), (aryl) Ce-Cio) (CrC6 alkoxy) (dd alkyl), (C5-C9 heteroaryl) (CrC6 alkoxy) (C? -C6 alkyl), (CrC6 alkyl) thio (d-Ce alkyl), (C6-C aryl) ) tio (CrC6 alkyl), (dC6 alkyl) sulfinyl (CrC6 alkyl), (aryl C6C) sulfinyl (d1 alkyl), (dC6 alkyl) sulfonyl (dd alkyl) ), (aryl C6-C? 0) sulfonyl (dd alkyl), amino (d-C6 alkyl), (CrC6 alkyl) amino (CrC6 alkyl), (CrC6 alkyl) 2 amino, CrC6 alkyl, C2-C6 alkenyl, C2 alkynyl -C6, the alkyl, alkenyl and alkynyl groups being optionally substituted with one to five of cyano, nitro, halo, deuterium, hydroxy, carboxy, (acyl CrC6) amino, (alkoxy dd) (acyl CrC6) amino, amino (acyl CrC6) ), (CrC6 alkyl) amino (acyl dd) or (alkyl d-C6) 2-amino (acyl CrC6); or R5 is R13CO (CrC6 alkyl) or R13CO (C3-C10 cycloalkyl), wherein R13 is R20O or R20R21N, each of R20 and R21 being independently selected from the group consisting of hydrogen, deuterium, dd alkyl, (aryl d-Cio) ( CrC6 alkyl) or (C5-C9 heteroaryl) (d-Ce alkyl); or R 5 is R 14, R 14-CrC 6 alkyl or R 14-C 3 -C 0 cycloalkyl, wherein R 14 (C 2 -Cg heterocycle) is alkyl, (acyl CrC 6) piperazino, (arylCio) piperazino, (heteroaryl C 5 -Cg) piperazino, (C 1 -Ce alkyl) piperazino, (C 6 -C 6 aryl) (CrC 6 alkyl) piperazino, (heteroaryl dCg) (Crdjpiperazino alkyl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 alkyl) piperidinyl, (aryl C6-C? o) piperidyl, (heteroaryl d-C9) piperidyl, (aryl C6-C or) (alkyl Crdjpiperidyl, (heteroaryl C5-Cg) (alkyl C? -6) piperidyl or (acyl) d-piperidyl, or R5 is a group of formula wherein w is 0, 1 or 2; x is 0, 1, 2 or 3; or R5 is a group of formula wherein g, h and j are each independently 0 to 3, b F, K and P are each independently oxygen, S (O) d, where d is 0, 1 or 2, NR6 or CR7R8; R6 is selected from the group consisting of hydrogen alkyl d-d, trifluoromethyl, trifluoromethyl (alkyl d-d), (alkyl CrdXdifluoromethylene), (alkyl d-C3) (difluoromethylene) (alkyl dd), (alkoxy Crd) (acllo CrC6), (alkyl d-C6) amino (acyl dd), (alkyl CrC6) 2amino (acyl CrC6), aryl C6 -C? 0, C5-C9 heteroaryl, (C6-C6 aryl) (CrC6 alkyl), (C5-C9 heteroaryl) (CrC6 alkyl), (C6-C6 aryl) (C6-C6 aryl) , (aryl C6-C? 0) (aryl C6-C? 0) (alkyl dd), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (CrC6 alkyl), hydroxy (C2-C6 alkyl), (acyloxy d-) C6) (C2-C6 alkyl), (CrC6 alkoxy) (C2-C6 alkyl), piperazinyl (CrC6 alkyl), (CrC6 acyl) amino (CrC6 alkyl), (C6-C6 aryl) (CrC6 alkoxy) (alkyl CrC6), (C5-Cg heteroaryl) (CrC6 alkoxy) (dd alkyl), (CrC6 alkyl) tio (CrC6 alkyl), (C6-C6 o aryl) thio (CrC6 alkyl), (CrCe alkyl) sulfinyl ( alkyl dd), (C 6 -C 0 aryl) sulfinyl (CrCβ alkyl), (CrCe alkyl) sulfonyl (dd alkyl), (C 6 -C 6 aryl) sulfonyl (CrC 6 alkyl), dd aminoalkyl, (CrCe alkyl) amino (alkyl dC6), (alkyl CrC6) 2 amino (alkyl dd), R13CO (alkyl CrC6), where R13 is R20O or R20R21N, R20 and R21 being selected each independently of the group consisting of hydrogen, alkyl d-d, (aryl C6-C? o) (alkyl d-d) or (heteroaryl C5-C9) (alkyl d-C6); or R14 (C2-C6 alkyl), where R14 is (acyl d-djpiperazino, (aryl C6-C? o) piperazino, (heteroaryl d-djpiperazino, (alkyl d-C6) piperazino, (aryl C6-C? or) (alkyl Crdjpiperazino, (C5-C9 heteroaryl) (alkyl d-C6) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (alkyl Crdjpiperidilo, (aryl C6-C? o) piperidilo, (heteroaril C5-Cg) piperidyl, (C 6 -C 6 aryl) (CrC 6 alkyl) piperidyl, (C 5 -Cg heteroaryl) (C 1 -Ce) alkyl piperidyl, (C 6 alkoxy) acyl, (Crkaminoaryl alkyl, (CrCe) 2aminoacyl alkyl or ( acyl d-Ce) piperidyl, R7 and R8 are each independently selected from the group consisting of hydrogen, dd alkyl, amino, hydroxy, dd alkoxy, (d-C6 alkyl) amino, (Crd ^ amino alkyl, (acyl CrC6) amino , (acyl CrC6) (alkyl d-C6) amino, carboxy (alkoxy Crdjacilo, (alkyl CrCe) aminoacyl, (alkyl Cr d ^ aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl (alkyl dd), (alkyl CrdXdifluoromethylene), (alkyl CrC3) difluoromethylene (C1-C3 alkyl), aryl Cedo, C5-Cg heteroaryl, (C6-aryl) C? O) (CrC6 alkyl), (C5-Cg heteroaryl) (C6-alkyl), (C6-C6 aryl) (Ce-Cio aryl), (C6-C6 aryl) (C6-C aryl) 0) (CrC6 alkyl), C3-C6 cycloalkyl, (C3-C6 cycloalkyl) (CrC6 alkyl), hydroxy (CrC6 alkyl), (acyloxy d-dXalkyl dd), (CrCe alkoxy) (Crd alkyl), piperazinyl (alkyl) dd), (acyl CrC6) amino (alkyl dd), piperidyl, (C 1 -C e) piperidyl, (aryl dC 0) (alkoxy dCe) (CrCβ alkyl), (C 5 -Cg heteroaryl) (alkoxy) d-dXalkyl d-C6), (C 1 -C 6 alkyl) thio (CrC 6 alkyl), (C 6 -C 6 aryl) thio (CrC 6 alkyl), (C 1 alky) sulfinyl (dd alkyl), (C 6 aryl) C 0) sulfonyl (CrC6 alkyl), (d-C6 alkyl) sulfonyl (alkyl dd), (aryl C6-C? 0) sulfonyl (alkyl dd), amino (alkyl d-C6), (CrC6 alkyl) ) amino (CrC6 alkyl), (CrC6 alkyl) 2a ino (CrC6 alkyl), R13CO (CrC6 alkyl) or R 3CO (C3-C? 0 cycloalkyl), where R13 is R20O or R20R21N, each selected from R20 and R21 independently of the group consisting of hydrogen, alkyl dd, (aryl dCioXalkho dd) or (C5-C9 heteroaryl) (CrC6 alkyl); R14, R14-alkyl d-Ce or R14-cycloalkylene C3-C10, with R14 (acyl CrCe) piperazino, (aryl C6-C? 0) piperazino, (heteroaryl C5-C9) piperazino, (alkyl CrC6) piperazino, (aryl) C6-C? 0) (alkyl CrC6) piperazino, (heteroaryl C5-Cg) (alkyl CrC6) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (alkyl CrCe) piperidiIo, (aryl C6-C? O) piperidil, (C5-C9 heteroaryl) piperidyl, (C6-C6alkyl) (C? -Ce) alkyl piperidyl, (C5-Cg heteroaryl) (d-C6 alkyl) piperidyl or (acyl Crdjpiperidyl; or a group of formula wherein p is 0, 1, 2 or 3; and Z is hydroxy, alkoxy dd or NR1R2, each of R1 and R2 being independently selected from the group consisting of hydrogen, alkyl dd, piperidyl, (alkyl d-djpiperidyl, (aryl dC? o) piperidyl, (heteroaryl C5-Cg) piperidyl) (aryl C6-C? o) (alkyl CrCe) piperidyl, (heteroaryl C5-Cg) (alkyl CrC6) piperidyl, (acyl CrCe) piperidyl, aryl C6-C? o, heteroaryl C5-Cg, (aryl C6) -C? 0) (alkyl dd), (C5-Cg heteroaryl) (CrC6 alkyl), (C6-C6 aryl) (C6-C? O aryl), (C6-C6 aryl) (C6-aryl) C? 0) (CrC6 alkyl), C3-cycloalkyl, (C3-C6 cycloalkyl) (CrC6 alkyl), R5 (dd alkyl), (d-C5 alkyl) (CHR5) (CrC6 alkyl), where R5 is hydroxy, acyloxy dd, alkoxy CrC6, piperazino, (acyl CrC6) amino, (alkyl CrCe) thio, (aryl C6-C? o) thio, (alkyl Cr Ce) sulfinyl, (aryl C6-C? o) sulfinyl, (alkyl Crdjsulfonyl, (aryl C6-C10) sulfonyl, amino, (alkyl d-CßJamino, (alkyl CrC6) 2amino, (acyl Crd) piperazino, (alkyl CrCe) piperazino, (aryl C6-C or) (alkyl CrC6) piperazino, ( heteroaryl C5-Cg) (alkyl CrC6) piperazino, morfol ino, thiomorpholino, piperidino or pyrrolldino; Realkyl dC6), (CrC5 alkyl) (CHR6) (alkyl dd), where R6 is piperidyl, (C6 alkyl) piperidyl, (aryl Ce-C? O) piperidyl, (aryl C6-C? 0) (alkyl C ? -Ce) piperidyl, (C5-Cg heteroaryl) piperidyl or (C5-Cg heteroaryl) (C? -Ce alkyl) piperidyl; or R1 is defined as OR9 or S (O) qR9, where q, 1 or 2; and R 9 is selected from the group consisting of trifluoromethyl (CrC 6 alkyl), (C 1 -C 3 alkyl) (difluoromethylene) (C 3 alkyl), C 3 -C 6 cycloalkyl, the cycloalkyl group being optionally substituted by one to five carboxy, cyano, amino, hydroxy, alkoxy dd, halo, (CrC6 alkyl) S (O) m, where m is 0, 1 or 2; R15R16NS (O) m, where m is 0, 1 or 2 and each of R15 and R16 is selected independently of hydrogen or alkyl d-d; acyl dd, (CrC6 alkyl) amino, amino (CrC6 alkyl), alkoxy d-Ce-CO-NH, (CrC6 alkyl) amino-CO-, R15R16N-CO-0-, R15R16N-CO- (alkyl dd), R15 and R16 as defined above; C2-C6 alkenyl, C2-alkynyl, (CrC6 alkyl) amino, amino (CrC6 alkyl), hydroxy (CrC6 alkyl), (CrC6 alkoxy) (CrC6 alkyl), (CrC6 acyloxy CrC 6), nitro, cyano (dd alkyl) , nitro (d-Cß alkyl), trifluoromethyl, trifluoromethyl (alkyl dd), (acyl d-Ce) amino, (alkoxy CrCe) (acyl CrCe) amino, amino (acyl dd) (alkyl d-C6) amino (acyl CrC6) ) or (alkyl CrCe) 2-amino (acyl dd); alkenyl dd, C2-C6 alkynyl, (C3-C3 cycloalkyl) (dd alkyl), (acyloxy CrCe) (d6C6 alkyl), (d6CX alkoxy CrC6), piperazinyl (dd alkyl), (acyl d- C6) amino (CrC6 alkyl), (C6-C0 aryl) (CrCe alkoxy) (CrC6 alkyl), (C3-C9 heteroaryl) (CrC6 alkoxy) (CrC6 alkyl), (CrC6 alkyl) thio (dd alkyl), (aryl C6-C? o) thio (CrC6 alkyl), (CrCe alkyl) sulfinyl (dd alkyl), (C6-C? o aryl) sulfinyl (CrC6 alkyl), (CrC6 alkyl) sulfonyl (CrC6 alkyl), (C6-C aryl) sulfonyl (CrC6 alkyl), amino (dd alkyl), (CrCe alkyl) amino (dC6 alkyl), (CrC6 alkyl) 2 amino, dd alkyl, the alkyl group being optionally substituted by one to five of cyano, nitro, hydroxy, carboxy, (acyl CrC6) amino, (alkoxy CrC6) (acyl CrC6) amino, amino (acyl dd), (alkyl Cr C6) amino (acyl CrC6) or (alkyl CrCe) 2amino ( acyl dd); R13CO (Cr C6 alkyl) or R13CO (C3-C10 cycloalkyl), wherein R13 is R20O or R20R21N, each being selected from R20 and R21 independently of the group consisting of hydrogen, alkyl dd, (aryl C6-C? 0) (CrC6 alkyl ) or (C5-C9 heteroaryl) (dd alkyl); R14, R14-alkyl dC6 or R4-cycloalkyl C3-C? O, where R14 (C2-Cg heterocycle) alkyl, (acyl CrCe) piperazino, (aryl C6-C? O) piperazino, (heteroaryl C5-Cg) ) piperazino, (CrCe alkyl) piperazino, (C6-C6 aryl) (Cr C6 alkyl) piperazino, (C5-Cg heteroaryl) (C 1 -C e alkyl) piperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl (alkyl Crdjpiperidinium, (aryl C6-C? o) piperidyl, (C5-Cg heteroaryl) p.peridyl, (aryl d-CioXalkyl CrCe) piperidyl, (C5-Cg heteroaryl) (alkyl CrCe) piperidyl or (acyl Crdjpiperidyl; or R9 is a group of formula where g, h and j are each independently 0 to 6; F, K and P are each independently oxygen, S (0) d, where d is 0, 1 or 2, NR6 or CR7R8, where R6, R7 and R8 are as defined above; R2 and R3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydroxy, nitro, carboxy, alkenyl dd, C2-d 'alkynyl trifluoromethyl, trifluoromethoxy, alkyl dd, alkoxy dd, the alkyl or alkoxy groups being optionally substituted with one to three groups selected from halo, hydroxy, carboxy, amino (alkyl d-dXio, (alkyl CrCe) samino, (alkyl d-C6) 2 amino, heteroaryl C5-Cg, (heterocycle C2-Cg) alkyl, cycloalkyl C3-Cg or aryl-Cio, or each of R2 and R3 is independently C3-C3 cycloalkyl, or C3-C10 cycloalkoxy, (d-djamino alkyl, (CrCe) 2amino alkyl, (aryl dC? O) amino, ( alkyl CrC6) thio, aryl (Ce-C? o) thio, (alkyl CrC6) sulfinyl, (aryl C6-C? 0) sulfinyl, (alkyl CrC6) sulfonyl, (aryl C6-C? 0) sulfonyl , acyl dd, (CrC6 alkoxy) -CO-NH-, (CrC6 alkyl) amino-CO-, C5-Cg heteroaryl, (C2-Cg heterocycle) C6-C6 alkyl or aryl, wherein the heteroaryl, heterocycloalkyl and aryl optionally substituted with one to three halo, alkyl dd, (Crc alkyl) -CO-NH-, (CrC6 alkoxy) -CO-NH-, (CrC6 alkyl) -CO-NH- (d-C6 alkyl), (CrC6 alkoxy) -CO-NH- (alkyl) d-C6), (CrC6 alkoxy) -CO-NH- (alkoxy. CrC6), carboxy, carboxy (alkyl dd), carboxy (alkoxy dd), benzyloxycarbonyl (alkoxy CrC6), (alkoxy C? -Ce) carbonyl (alkoxy dd), aryl C6-C? Or, amino, amino (alkyl CrC6) , (alkoxy d-dicarbonylamino, (aryl C6-C? 0) (alkoxy CrCe) carbonylamino, (alkyl Crdjamino, (alkyl CrC6) 2amino, (alkyl CrCe) amino (alkyl dd), (alkyl d-C6) 2amino (alkyl) dd), hydroxy alkoxy dd), carboxy, carboxy (CrC6 alkyl), (CrCe alkoxy) carbonyl, (CrCe alkoxy) carbonyl (d-Ce alkyl), (CrC6 alkoxy) -CO-NH-, (d-C6 alkyl) -CO-NH-, cyano (C5-Cg heterocycle) alkyl, amino-CO-NH-, (CrC6 alkyl) amino-CO-NH, (alkyl Crhamino-CO-NH-, (aryl C6-C? 0) amino) -CO-NH, (C5-C9 heteroaryl) amino-CO-NH-, (CrC6 alkyl) amino-CO-NH- (dd alkyl), (CrC6 alkyl) 2 amino- CO- NH- (d-C6 alkyl), (aryl C6-C? o) amino-CO-NH- (CrC6 alkyl), (C5-Cg heteroaryl) amino-CO-NH- (dd alkyl), (d-alkylsulfonyl, alkyl (CrCe) sulfonylamino, (alkyl) C? -Ce) sulfonylamino (alkyl dd), (aryl C6-C? O) sulfonyl, (aryl C6-C? 0) sulfonylamino, (aryl C6-C? O) sulfonylam no (alkyl d-d), (alkyl d-Ce) sulfonylamino, (alkyl CrCe) sulfonylamino (alkyl d-d), heteroaryl C5-C9 or heterocycle C2-Cg) alkyl; provided that, when R 4 and R 5 is hydrogen, the other of R 4 and R 5 can not be aryl C 6 -C 0 0 or (aryl C 6 -C 0) (alkyl d-d); provided that, when R 4 is hydrogen, unsubstituted d-d alkyl or unsubstituted or unsubstituted C 3 -C 6 cycloalkyl, R 5 can not be (aryl C 6 -C 0) (alkyl d-d); R 20 and R 21 can not be (heteroaryl Cs-Cg) (alkyl d-d); and R14 can not be (C2-Cg heterocycle) alkyl, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidinyl or (alkyl d-piperidinyl; provided that the sp2 and alkenyl or alkynyl carbons can not be substituted with hydroxy or amino provided that, when R 4 is hydrogen, R 5 can not be amino (d-C 6 alkyl), dd alkyl, (C 1 -C e alkyl) amino (dd alkyl), (d 6 alkyl) 2 amino (dd alkyl) , furanyl, (alkoxy d-CeXalkyl CrC6) or carboxy (alkyl dd), provided that, R4 as R5 can not both be hydroxy (CrC6 alkyl), provided that, when R4 is alkyl dd, R5 can not be (CrC6 alkoxy) (CrC6 alkyl) or carboxy (CrC6 alkyl), and provided that R1 can not be carboxy (CrC6 alkyl) thio or (CrCe alkoxy) carbonyl (alkyl dCe) thio.
2. The compound according to claim 1, wherein R1 is NR4R5.
3. The compound according to claim 1, wherein R4 is hydrogen, alkyl dd, C2-C6 alkenyl, C2-C6 alkynyl, the alkyl, alkenyl and alkynyl groups being optionally substituted with hydroxy, amino, trifluoromethyl, acyloxy dd, (CrC6 alkyl) amino, (alkyl dd ^ amino or (acyl d-djamino, or R4 is C3-C10 cycloalkyl, the cycloalkyl group being optionally substituted by hydroxy, trifluoromethyl or acyloxy dd.)
4. The compound in accordance with Claim 1, wherein R5 is C3-C6 cycloalkyl, wherein the cycloalkyl group is optionally substituted by one to five of deuterium, hydroxy, trifluoromethyl, halo, d-C6 alkyl, hydroxy (dd alkyl), acyl dd, ( alkyl CrC6) amino (aciIo CrC6), (alkyl CrC6.2amino (acllo dd), (acyl Crdíamino, (alkoxy CrC6) -CO-NH, (alkyl d-C6) amino-CO-, alkenyl C2-C6, C2-C6 alkynyl, halo (CrC6 alkyl), (CrC6 acyl) amino (C6-6 alkyl), R15S (0) mR16N, R15S (0) mR16N (d6C6 alkyl) where m is 0, 1 or 2 and each of R15 and R16 is independently selected from hydrogen or alkyl dd-
5. The compound according to claim 1, wherein R2 and R3 are each independently selected from the group consisting of hydrogen, halo, dd alkyl, C2-C6 alkenyl, C2-C6 alkynyl, alkoxy dd, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, (C2-Cg heterocycle) alkyl, C5-C9 heteroaryl or aryl -Cio.
6. - The compound according to claim 1, said compound being selected from the group consisting of; 2-. { 4-Methyl-3- [methyI- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclohexyl} -propan-2-ol; 2-. { 3 - [(2-Hydroxy-ethyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -4-methyl-cyclohexyl} -propan-2-ol; 2 - [(5-lsopropenyl-2-methyl-cyclohexyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; (5-lsopropenyl-2-methyl-cyclohexyl) - (7H-pyrrolo [2,3-dipyrimidin-4-yl) - (2,2,2-trifluoro-ethyl) -amine; 2-. { 4-Methyl-3 - [(7H-pyrrolo [2,3-d] pyrimidin-4-yl) - (2,2,2-trifluoro-ethyl) -amino] -cyclohexyl} -propan-2-ol; 2-. { 4-Methyl-5- [meth] - (7H-pyrrolo [2,3-d] pyridin-4-yl) -amino] -cyclohex-3-enyl) -propan-2-ol; 2- [1- (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -azetidin-3-yl] -propan-2-ol; 2- [1 - (7H-Pyrrolo [2,3-d] pyrimidin-4-yl) -azetidin-2-yl] -propan-2-ol; (5-Fluoro-7H-pyrroIo [2,3-d] pyrimidin-4-yl) - (5-isopropenyl-2-methyl-cyclohexyl) -methyl-amine; 2-. { 3 - [(5-Fluoro-7H-pyrrolo [2,3-d] pyrimidin-4-yl) -methyl-amino] -4-methyl-cyclohexyl} -propan-2-ol; (2-Ethyl-4-isopropenyl-cyclopentyl) -methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; 2-. { 3-Ethyl-4- [meth] - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -cyclopentyl} -propan-2-ol; 2-. { 3-Ethyl-4 - [(2-hydroxy-ethyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl-amino] -cyclopentyl] -propan-2-ol; 2 - [( 2-Ethyl-4-isopropenyl-cyclopentyl) - (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; (5- (S) -lsopropenyl-2-methyl-cyclohexyl) - methyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amine; 3-Methyl-8- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -8- aza-bicyclo [3.2.1] octan-3-ol; 2- [Cycloheptyl- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; 2- [Cyclooctyl- ( 7H-pyrrolo [2,3-d] pyrimidin-4-yl) -amino] -ethanol; Bicyclo [2.2.1] hept-2-yl-methyl- (7H-pyrrolo [2,3-d] pyrimidin-4) -yl) -amine; and 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo [2,3-d] -pyrimidine.
7. - A pharmaceutical composition for (a) treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, disorders autoimmune thyroid, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or (b) inhibit tyrosine kinases or Janus Kinase 3 (JAK3) proteins in a mammal, including a human being, comprising a quantity of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, effective in said disorders or conditions and a pharmaceutically acceptable carrier.
8. The pharmaceutical composition for (a) treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases or ( b) inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, alone or combined with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents, effective in said disorders or conditions and a pharmaceutically acceptable carrier.
9. - The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human .
10. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof for the manufacture of medicament for treating or preventing a disorder or condition selected from rejection of organ transplantation, lupus, multiple sclerosis , rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human. 1. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, alone or combined with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents for the manufacture of a medicament for inhibiting the protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human. 12. The use of a compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents that modulate an immune system of a mammal or with anti-inflammatory agents for manufacturing of a drug to treat or prevent a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, type I diabetes and complications of diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn's disease, Alzheimer's disease, leukemia and other autoimmune diseases in a mammal, including a human being.
MXPA/A/2000/012622A 1998-06-19 2000-12-15 PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS MXPA00012622A (en)

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US60/089,866 1998-06-19
US60/104,787 1998-10-19

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MXPA00012622A true MXPA00012622A (en) 2001-07-31

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