AU4054599A

AU4054599A – Pyrrolo(2,3-d)pyrimidine compounds
– Google Patents

AU4054599A – Pyrrolo(2,3-d)pyrimidine compounds
– Google Patents
Pyrrolo(2,3-d)pyrimidine compounds

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Publication number
AU4054599A

AU4054599A
AU40545/99A
AU4054599A
AU4054599A
AU 4054599 A
AU4054599 A
AU 4054599A
AU 40545/99 A
AU40545/99 A
AU 40545/99A
AU 4054599 A
AU4054599 A
AU 4054599A
AU 4054599 A
AU4054599 A
AU 4054599A
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AU
Australia
Prior art keywords
alkyl
aryl
pyrrolo
alkoxy
heteroaryl
Prior art date
1998-06-19
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Application number
AU40545/99A
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AU758427B2
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Inventor
Todd Andrew Blumenkopf
Matthew Frank Brown
Paul Steven Changelian
Mark Edward Flanagan
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Pfizer Products Inc

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Pfizer Products Inc
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1998-06-19
Filing date
1999-06-14
Publication date
2000-01-05

1999-06-14
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2000-01-05
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patent/AU4054599A/en

2003-03-20
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2003-03-20
Publication of AU758427B2
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Critical
patent/AU758427B2/en

2019-06-14
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C—CHEMISTRY; METALLURGY

C07—ORGANIC CHEMISTRY

C07D—HETEROCYCLIC COMPOUNDS

C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 – C07D477/00

C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 – C07D477/00 in which the condensed system contains two hetero rings

C07D487/04—Ortho-condensed systems

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

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A61P11/06—Antiasthmatics

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P17/00—Drugs for dermatological disorders

A61P17/04—Antipruritics

A—HUMAN NECESSITIES

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A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P19/00—Drugs for skeletal disorders

A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

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A61P25/00—Drugs for disorders of the nervous system

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A61P25/00—Drugs for disorders of the nervous system

A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia

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A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P25/00—Drugs for disorders of the nervous system

A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer’s disease or other forms of dementia

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

A—HUMAN NECESSITIES

A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P3/00—Drugs for disorders of the metabolism

A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis

A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE

A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P35/00—Antineoplastic agents

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A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P35/00—Antineoplastic agents

A61P35/02—Antineoplastic agents specific for leukemia

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A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P37/00—Drugs for immunological or allergic disorders

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A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P37/00—Drugs for immunological or allergic disorders

A61P37/02—Immunomodulators

A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

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A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

A61P5/00—Drugs for disorders of the endocrine system

A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

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A61P5/00—Drugs for disorders of the endocrine system

A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4

A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones

Description

WO 99/65909 PCT/IB99/01110 -1 5 PYRROLO[2,3-d]PYRIMIDINE COMPOUNDS Background of the Invention The present invention relates to pyrrolo[2,3-d]pyrimidine compounds which are inhibitors of protein tyrosine kinases, such as the enzyme Janus Kinase 3 (hereinafter also referred to as JAK3) and as such are useful therapy as immunosuppressive agents for organ 10 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 indications where immunosuppression would be desirable. This invention also relates to a method of using such compounds in the treatment of 15 the above indications in mammals, especially humans, and the phamaceutical compositions useful therefor. JAK3 is a member of the Janus family of protein tyrosine kinases. Although the other members of this family are expressed by essentially all tissues, JAK3 expression is limited to hematopoetic cells. This is consistent with its essential role in signaling through the receptors 20 for IL-2, IL-4, IL-7, IL-9 and IL-15 by non-covalent association of JAK3 with the gamma chain common to these multichain receptors. XSCID patient populations have been identified with severely reduced levels of JAK3 protein or with genetic defects to the common gamma chain, suggesting that immunosuppression should result from blocking signaling through the JAK3 pathway. Animal studies have suggested that JAK3 not only plays a critical role in B and T 25 lymphocyte maturation, but that JAK3 is constitutively required to maintain T cell function. Modulation of immune activity through this novel mechanism can prove useful in the treatment of T cell proliferative disorders such as transplant rejection and autoimmune diseases. Summary of the Invention The present invention relates to a compound of the formula 30
R
1
R
2 » \ R 3 N N H or the pharmaceutically acceptable salt thereof; wherein
R
1 is a group of the formula WO 99/65909 PCT/IB99/01110 -2 (B) (D)n ( . … IV A -.’ E N 5 wherein the dashed line represents optional double bonds; mis 0, 1, 2 or3; n is 0, 1, 2 or 3; X, B and D are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or 10 CR 7 R»; A and E are each CR 7 R»; and
R
6 is selected from the group consisting of hydrogen, (C 1 -C,)alkyl, trifluoromethyl, trifluoromethyl(C 1
-C
6 )alkyl, (Cl-C 6 )alkyl (difluoromethylene), (Cl-C 3 )alkyl(difluoromethylene)(C,
C
3 )alkyl, (Cl-C 6 )alkoxy(Cl-C 6 )acyl, (C 1
-C
6 )alkylamino(C 1
-C
6 )acyl, ((Cl-Ce)alkyl) 2 amino(C, 15 C 6 )acyl, (C 6 -Co 10 )aryl, (Cs-Cg)heteroaryl, (C 6
-C
1 o)aryl(Cj-C 6 )alkyl, (C 5
-C
9 )heteroaryl(Cl-C 6 )alkyl,
(C
6
-C
1 o)aryl(C 6
-C
1 0 )aryl, (C 6 -Co 10 )aryl(C 6 -Co 10 )aryl(Cl-C 6 )alkyl, (C 3
-C
6 )cycloalkyl, (C3
C
6 )cycloalkyl(C 1 -Cs)alkyl, hydroxy(C 2
-C
6 )alkyl, (Cl-C 6 )acyloxy(C 2
-C
6 )alkyl, (C,-C 6 )alkoxy(C2 Ce)alkyl, piperazinyl(Cl-Ce)alkyl, (Cl-C 6 )acylamino(C,-C 6 )alkyl, (C 6
-C
10 )aryl(Cl-C)alkoxy(Cl C6)alkyl, (C 5 -Cg)heteroaryl(Cl-C 6 )alkoxy(Cl-C 6 )alkyl, (C,-C 6 )alkylthio(C,-C 6 )alkyl, (C6 20 Co 10 )arylthio(C-C 6 )alkyl, (C-C 6 )alkylsulfinyl(Cl-C 6 )alkyl, (C 6 -Co 10 )arylsulfinyl(Cl-C 6 )alkyl, (Cl Ce)alkylsulfonyl(Cl-C 6 )alkyl, (C 6 -Co 10 )arylsulfonyl(Cl-Ce)alkyl, amino(C 1
-C
6 )alkyl, (Ci Ce)alkylamino(Cl-C 6 )alkyl, ((C,-C 6 )alkyl) 2 amino(C-C 6 )alkyl, R1 3 CO(Cl-C)alkyl wherein R 13 is
R
20 0 or R 20
R
2 1 N wherein R 20 and R 21 are each independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl, (C 6 -Co 10 )aryl(C 1
-C
6 )alkyl or (Cs-Cg)heteroaryl(Cl-C 6 )alkyl; or R14( 2 25 Ce)alkyl wherein R 14 is (Cl-C 6 )acylpiperazino, (C 6 -Co 10 )arylpiperazino, (Cs C,)heteroarylpiperazino,
(C,-C
6 )alkylpiperazino, (C 6 -Co)aryl(C-C 6 )alkylpiperazino, (C5 C,)heteroaryl(C 1
-C
6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (Cl-C 6 )alkylpiperidyl, (C 6 -Co 10 )arylpiperidyl, (C 5 -Cg)heteroarylpiperidyl, (C 6
-C
10 o)aryl(C
C
6 )alkylpiperidyl, (C 5 -Cg)heteroaryl(C,-C)alkylpiperidyl, (C 1
-C
6 )alkoxyacyl, (C 1 -Ce)alkylaminoaryl, 30 ((C 1
-C
6 )alkyl 2 aminoacyl or (C-C 6 )acylpiperidyl;
R
7 and RI are each independently selected from the group consisting of hydrogen, deuterium, (Cl-C 6 )alkyl, amino, hydroxy, (C-C 6 )alkoxy, (Cl-C 6 )alkylamino, ((Cl-C 6 )alkyl)amino,
(C
1
-C
6 )acylamino, (C,-C 6 )acyl(C-C 6 )alkylamino, carboxy, (C-C 6 )alkoxyacyl, (C, C6)alkylaminoacyl, ((Cl-C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(Cl- WO 99/65909 PCT/IB99/01110 -3 5 C 6 )alkyl, (Cl-C 6 )alkyl (difluoromethylene), (Cl-C 3 )alkyl(difluoromethylene)(Cl-C 3 )alkyl, (C6 Co 1 0 )aryl, (Cs-C 9 )heteroaryl, (C 6
-C
10 )aryl(C 1
-C
6 )alkyl, (C 5 -Cg)heteroaryl(C 1
-C
6 )alkyl, (C6
C
1 0 )aryl(C 6 -Co 10 )aryl, (C6-Co 10 )aryl(C 6 -Co 10 )aryl(Cl-C 6 )alkyl, (C3-C 6 )cycloalkyl, (C3-C 6 )cycloalkyl(C 1 Ce)alkyl, hydroxy(C 1
-C
6 )alkyl, (C 1 -Ce)acyloxy(C 1
-C
6 )alkyl, (C 1
-C
6 )alkoxy(C,-C 6 )alkyl, piperazinyl(Cl-C 6 )alkyl, (Cl-C 6 )acylamino(Cl-Ce)alkyl, piperidyl, (C 1
-C
6 )alkylpiperidyl, (C6 10 Co 10 )aryl(C 1
-C
6 )alkoxy(Cl-C 6 )alkyl, (C 5 -Cg)heteroaryl(Cl-C 6 )alkoxy(Cl-C,)alkyl, (Cl-Ce)alkylthio(Cl C6)alkyl, (C 6 -Co 10 )arylthio(C 1
-C
6 )alkyl, (Cl-C 6 )alkylsulfinyl(C 1
-C
6 )alkyl, (C-C 10 o)arylsulfinyl(Cl Ce)alkyl, (Cl-C 6 )alkylsulfonyl(Cl-C,)alkyl, (C 6 -Co 0 )arylsulfonyl(Cl-C 6 )alkyl, amino(Cl-C 6 )alkyl, (C1
C
6 )alkylamino(Cl-Ce)alkyl, ((Cl-C 6 )alkyl) 2 amino(Cl-Ce)alkyl, R 13
CO(C
1 -Ce)alkyl or R 13 CO(C3
C
1 0 )cycloalkyl wherein R 13 is R 20 0 or R 2 0
R
21 N wherein R 2 0 and R 21 are each independently 15 selected from the group consisting of hydrogen, (C,-C 6 )alkyl, (C6-Co 10 )aryl(C 1
-C
6 )alkyl or (Cs
C
9 )heteroaryl(C 1
-C
6 )alkyl; R 14 , Ri 4
(C
1
-C
6 )alkyl or R 4
(C
3 -Co 10 )cycloalkyl wherein R1 4 is (0C Ce)acylpiperazino, (C 6 -Clo)arylpiperazino, (C 5
-C
9 )heteroarylpiperazino, (C 1
-C
6 )alkylpiperazino,
(C
6 -Co)aryl(C 1 -Ce)alkylpiperazino, (Cs-C9)heteroaryl(C 1
-C
6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1
-C
6 )alkylpiperidyl, (C 6 -Co 10 )arylpiperidyl, (C5 20 C 9 )heteroarylpiperidyl, (C 6 -Co 10 )aryl(Cl-C 6 )alkylpiperidyl, (C-C, 9 )heteroaryl(C 1 -C)alkylpiperidyl or
(C
1
-C
6 )acylpiperidyl; or a group of the formula O
(CH
2 )p z wherein p is 0, 1, 2 or 3; and 25 Z is hydroxy, (Cl-C 6 )alkoxy or NR 1
R
2 wherein R 1 and R 2 are each independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl, piperidyl, (Cl-C)alkylpiperidyl, (C6
C
1 0 )arylpiperidyl, (Cs-C,)heteroarylpiperidyl, (C6-Clo)aryl(C-C 6 )alkylpiperidyl, (C5
C
9 )heteroaryl(C,-C)alkylpiperidyl, (Cl-C 6 )acylpiperidyl, (C6-Co)aryl, (C 5
-C
9 )heteroaryl, (C 6 C 10 o)aryl(C 1
-C
6 )alkyl, (C 5
-C
9 )heteroaryl(Cl-Ce)alkyl,
(C
6 -Co 0 )aryl(C 6
-C
10 o)aryl, (C 6 -Clo 0 )aryl(C 6 30 Co)aryl(Cl-C 6 )alkyl, (C 3
-C
6 )cycloalkyl, (C 3
-C
6 )cycloalkyl(C,-C 6 )alkyl, R 5
(C-C
6 )alkyl, (Cl Cs)alkyl(CHR’)(C 1
-C
6 )alkyl wherein R’ is hydroxy, (C,-C 6 )acyloxy, (C 1
-C
6 )alkoxy, piperazino, (C,
C
6 )acylamino, (C 1
-C
6 )alkylthio, (C 6 -Co 10 )arylthio, (C 1
-C
6 )alkylsulfinyl, (C6-Co 10 )arylsulfinyl, (Cl
C
6 )alkylsulfoxyl, (C 6 -Co 1 0 )arylsulfoxyl, amino, (C-C,)alkylamino, ((C 1 -Ce)alkyl) 2 amino, (Cl Ce)acylpiperazino, (Cl-C 6 )alkylpiperazino,
(C
6 -Co 10 )aryl(Cl-Ce)alkylpiperazino, (C5 35 C,)heteroaryl(C,-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C1 C 6 )alkyl, (C 1
-C
5 )alkyl(CHR 6 )(Cl-C 6 )alkyl wherein R 6 is piperidyl, (C 1
-C
6 )alkylpiperidyl, (C6
C
1 0 )arylpiperidyl, (C6-C 1 0 )aryl(C 1
-C
6 )alkylpiperidyl, (C 5
-C
9 )heteroarylpiperidyl or (Cs C,)heteroaryl(C 1 -C)alkylpiperidyl; WO 99/65909 PCT/IB99/01110 -4 5 or when n is at least 1, D and E, or D and X, are each CR’R 8 , the adjacent R 7 groups may be taken together, with the carbons to which they are attached, to form groups of the formulas …- (J )a.. G » ‘ L X G M (B)m «)a(B)m A .N M,-*,-L A E N Mor N V VI wherein the dashed lines represent optional double bonds; 10 a is 0, 1 or 2; m, A, B and X are as defined above; and G, J, L and M are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or
CR
7 R’wherein R 6 , R 7 and R 8 are as defined above; or when n is 1, D and E are each CR R 8 and m is 1, A and B are each CR R 8 , the 15 respective adjacent R 7 groups may be taken together, with the carbons to which they are attached, to form a group of the formula R (X)r G I X III s N I wherein the dashed bond represent optional double bonds; a, G, J. L and M are as define above; 20 r is 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or
CR
7
R
8 wherein R 6 , R 7 and R 8 are as defined above;
R
2 and R 3 are each independently selected from the group consisting of hydrogen, 25 deuterium, amino, halo, hydoxy, nitro, carboxy, (C 2
-C
6 )alkenyl, (C 2
-C
6 )alkynyl, trifluoromethyl, WO 99/65909 PCT/IB99/01110 -5 5 trifluoromethoxy, (C 1
-C
6 )alkyl, (C 1
-C
6 )alkoxy wherein the alkyl or alkoxy groups are optionally substittued by one to three groups selected from halo, hydroxy, carboxy, amino (Cl
C
6 )alkylthio, (Cl-C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (Cs-C 9 )heteroaryl, (C2 C,)heterocycloalkyl, (C 3
-C
9 )cycloalkyl or (C 6
-C
1 o)aryl; or R 2 and R 3 are each independently
(C
3 -Co 10 )cycloalkyl, (C 3 -Co 10 )cycloalkoxy, (Cl-C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (Ce 10 Co)arylamino, (Cl-C 6 )alkylthio, (C 6 -Co 10 )arylthio, (C 1
-C
6 )alkylsulfinyl, (C 6 -Co 0 )arylsulfinyl, (Cl
C
6 )alkylsulfonyl, (C,-Co 10 )arylsulfonyl, (Cl-C 6 )acyl, (C 1
-C
6 )alkoxy-CO-NH-, (C,-C 6 )alkyamino CO-, (Cs-C,)heteroaryl, (C 2
-C
9 )heterocycloalkyl or (C 6
-C
10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C-C 6 )alkyl, (Cl-C 6 )alkyl-CO-NH-, (Cl-C 6 )alkoxy-CO-NH-, (Cl-C 6 )alkyl-CO-NH-(Cl-C 6 )alkyl, (C 1
-C
6 )alkoxy 15 CO-NH-(Cl-C 6 )alkyl, (Cl-C 6 )alkoxy-CO-NH-(Cl-C 6 )alkoxy, carboxy, carboxy(C l
-C
6 )alkyl, carboxy(C,-C 6 )alkoxy, benzyloxycarbonyl(Cl-C 6 )alkoxy, (Cl-C 6 )alkoxycarbonyl(C-C 6 )alkoxy,
(C
6 -Co 10 )aryl, amino, amino(Cl-C)alkyl, (Cl-C 6 )alkoxycarbonylamino,
(C
6
-C
10 o)aryl(C 1 Ce)alkoxycarbonylamino, (C,-C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (C-C 6 )alkylamino(C0 Ce)alkyl, ((C 1
-C
6 )alkyl) 2 amino(C 1
-C
6 )alkyl, hydroxy, (Cl-C 6 )alkoxy, carboxy, carboxy(C, 20 C6)alkyl, (Cl-Ce)alkoxycarbonyl, (Cl-C 6 )alkoxycarbonyl(Cl-C 6 )alkyl, (C 1
-C
6 )alkoxy-CO-NH-, (Cl-C 6 )alkyl-CO-NH-, cyano, (Cs-C,)heterocycloalkyl, amino-CO-NH-, (C-C 6 )alkylamino-CO NH-, ((C-C 6 )alkyl) 2 amino-CO-NH-, (C 6
-C
1 )arylamino-CO-NH-, (C 5 -C,)heteroarylamino-CO NH-, (Cl-C)alkylamino-CO-NH-(Cl-C 6 )alkyl, ((C 1
-C
6 )alkyl) 2 amino-CO-NH-(Cl-C 6 )alkyl, (C6
C
0 lo)arylamino-CO-NH-(C-C 6 )alkyl, (C 5 -Cg)heteroarylamino-CO-NH-(Cl-C)alkyl,
(C
1 25 C 6 )alkylsulfonyl, (C 1
-C
6 )alkylsulfonylamino,
(C
l -Ce)alkylsulfonylamino(C-C 6 )alkyl, (C6 Co)arylsulfonyl, (C 6
-C
0 o)arylsulfonylamino, (C,-C 10 )arylsulfonylamino(Cl-C 6 )alkyl, (Cl
C
6 )alkylsulfonylamino, (C 1
-C
6 )alkylsulfonylamino(C -C 6 )alkyl, (C 5 -C,)heteroaryl or (C2
C
9 )heterocycloalkyl; with the proviso that when A, B or X, in formulas V or VI, is defined as NR 6 or CR 7
R
8 , 30 R 2 and/or R 3 must be halo; with the proviso that when R 2 and R 3 are each independently hydrogen or (Cl
C
6 )alkyl, R 1 cannot be unsubstituted piperidinyl; with the proviso that when R 2 and R 3 are each hydrogen, RI cannot be unsubstituted mopholinyl or pyrrolidinyl; 35 with the proviso that when R 2 and R 3 are each hydrogen, R 1 cannot be piperazinyl; and with the proviso that the groups of formuls IV, V, VI or XIII do not contain two or more oxygens, sulfurs or combinations thereof in adjacent positions. The present invention also relates to the pharmaceutically acceptable acid addition salts 40 of compounds of the formula I. The acids which are used to prepare the pharmaceutically WO 99/65909 PCT/IB99/01110 -6 5 acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, 10 benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3 naphthoate)]salts. The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with 15 such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (eg., calcium and magnesium), ammonium or water soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. 20 The term «alkyl», as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term «alkoxy», as used herein, includes O-alkyl groups wherein «alkyl» is defined above. 25 The term «halo», as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. The compounds of this invention may contain double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof. 30 Unless otherwise indicated, the alkyl and alkenyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (eg., alkoxy), may be linear or branched, and they may also be cyclic (e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine. 35 (C3-C 10 )Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc..
(C
2
-C
9 )Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, 40 dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, WO 99/65909 PCT/IB99/01110 -7 5 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, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C 2
-C
9 )heterocycloalkyl rings is through a 10 carbon or a sp 3 hybridized nitrogen heteroatom.
(C
2
-C
9 )Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4 oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4 15 bjpyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2 20 C 9 )heterocycloalkyl rings is through a carbon atom or a sp 3 hybridized nitrogen heteroatom.
(C
6 -Clo)aryl when used herein refers to phenyl or naphthyl. Compounds of formula (I) may be administered in a pharmaceutically acceptable form either alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents. These agents may include but are not limited 25 to cyclosporin A (e.g. Sandimmunel@ or Neoral @, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g. Cellcept(»), azathioprine (e.g. Imuranw’), daclizumab (e.g. Zenapax@. OKT3 (e.g. Orthoclone@), AtGam, aspirin, acetaminophen, ibuprofen, naproxen, piroxicam, and antiinflammatory steroids (e.g. prednisolone or dexamethasone). These agents may be administered as part of the same or separate dosage forms, via the same or different 30 routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice. The compounds of this invention include all configurational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers. This 35 invention also includes all rotamers of compounds of formula I as well as scelemic mixtures. Preferred compounds of formula I include those wherein R 1 is is a group of the formula WO 99/65909 PCT/IB99/01110 -8 x (B). . (D)n IV A E N 5 wherein the dashed line represents optional double bonds; mis 0, 1, 2 or3; n is 0, 1, 2 or 3; 10 X, B and D are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or CR 7
R
8 ; A and E are each independently CR 7 R’or NR 6 ; or when n is 1, D and E are each CR 7
R
8 and m is 1, A and B are each CR 7
R
8 , the respective adjacent R 7 groups may be taken together, with the carbons to which they are 15 attached, to form a group of the formula R N(X)r G
(W)
0 I XIll SN M wherein the dashed bond represent optional double bonds; a, G, J. L and M are as define above; ris 0 or 1; 20 c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or
CR
7
R
8 wherein R 6 , R 7 and R 8 are as defined above. Other preferred compounds of formula I include those wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl, (Cl-C 6 )alkoxy, 25 (C 3 -Clo)cycloalkyl, (C 3 -Co 10 )cycloalkoxy, (C 2
-C
9 )heterocycloalkyl, (Cs-C 9 )heteroaryl or (C
C
1 0 )aryl. Specific preferred compounds of formula I include the following: 5-Fluoro-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1 -yl-5-trifluoromethyl-7H-pyrrolo[2,3-d]pyrimidine; WO 99/65909 PCT/IB99/01110 -9 5 2-{3-Ethyl-4-[methyl-(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; N,N-Dimethyl-N’-[3-(4-piperidin-1 -yl- 7 H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzyl]-ethane 1,2-diamine; 10 2-[1-(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol; 5-(3-Isopropyl-phenyl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(1-Methyl-1 H-imidazol-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(2-Methyl-pyridin-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 15 5-Chloro-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Chloro-4-(octahydro-indol-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine; 5-Ethynyl-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine; and 4-(3,3-Dimethyl-piperidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine. 20 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 from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, Leukemia, and other autoimmune diseases or (b) the inhibition 25 of 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 such 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 30 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 or (b) the inhibition of 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 35 thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable carrier. The present invention also relates to a method for the inhibition of protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically 40 acceptable salt thereof.
WO 99/65909 PCT/IB99/01110 -10 5 The present invention also relates to a method for treating or preventing a disorder or condition selected from organ transplant rejection, 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 in a mammal, including a human, 10 comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, effective in treating such a condition. The present invention also relates to a method for the inhibition of protein typrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of formula I or a pharmaceutically 15 acceptable salt thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents. The present invention also relates to a method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic 20 dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, Leukemia, and other autoimmune diseases in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I or a pharmaceutically acceptable salt thereof, alone or in combination with T-cell immunosuppressant or antiinflammatory agents, effective in treating such a condition.
WO 99/65909 PCT/IB99/01110 -11 5 Detailed Description of the Invention The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated R 1 , R 2 , R 3 and R 9 in the reaction Schemes and the discussion that follow are defined as above. SCHEME 1 CI R 2 N
R
3 XVII N N H N 3 XVI I R N N R 2 R
R
2 N»R3 XV N N R 3 R
R
2 N R3 N N 10 H WO 99/65909 PCT/IB99/01110 -12 5 SCHEME2 CI N XXI N N R CI Cl 2 Y N CIx ‘ ~XIX N R 2 CI R 2 N N R 3 Cl IR2 N R 3 XVI NN\
R
WO 99/65909 PCT/IB99/01110 -13 5 SCHEME 3 CI N XXI N
N
R CI
INR
3 XXII N N R 2 Cl R 2 N
R
3 XVI R
R
WO 99/65909 PCT/IB99/01110 -14 5 SCHEME4 CI y N XX N N R R’ N XXIV N N R R R 2 N- XXIII N N R R
R
2 N R 3 XV N N
R
WO 99/65909 PCT/IB99/01110 -15 5 In reaction 1 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVII is converted to the corresponding compound of formula XVI, wherein R is benzenesulfonyl or benzyl, by treating XVII with benzenesulfonyl chloride, benzylchloride or benzylbromide in the presence of a base, such as sodium hydride or potassium carbonate, and a polar aprotic solvent, such as dimethylformamide or tetrahydrofuran. The reaction 10 mixture is stirred at a temperature between about 0oC to about 700C, preferably about 300C, for a time period between about 1 hour to about 3 hours, preferably about 2 hours. In reaction 2 of Scheme 1, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XVI is converted to the corresponding 4-aminopyrrolo[2,3-d]pyrimidine compound of formula XV by coupling XVI with a compound of the formula R 1 H. The reaction is carried out in an 15 alcohol solvent, such as tert-butanol, methanol or ethanol, or other high boiling organic solvents, such as dimethylformamide, 1,4-dioxane or 1,2-dichloroethane, at a temperature between about 60’C to about 12000, preferably about 800C. Typical reaction times are between 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 20 formula XV, wherein R is benzenesulfonyl, to give the corresponding compound of formula I, is carried out by treating XV with an alkali base, such as sodium hydroxide or potassium hydroxide, in an alcohol 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 time period between about 15 minutes to about 1 hour, preferably 30 minutes. Removal of the 25 protecting group from the compound of formula XV, wherein R is benzyl, is conducted by treating XV with sodium in ammonia at a temperature of about -780C for a time period between about 15 minutes to about 1 hour. In reaction 1 of Scheme 2, the 4-chloropyrrolo[2,3-d]pyrimidine compound of formula XXI, wherein R is hydrogen or benzenesulfonate, is converted to the 4-chloro-5 30 halopyrrolo[2,3-d]pyrimidine compound of formula XX, wherein Y is chloro, bromo or iodo, by reacting XXI with N-chlorosuccinimide, N-bromosuccinimide or N-iodosuccinimide. The reaction mixture is heated to reflux, in chloroform, for a time period between about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, in reaction 1 of Scheme 2, the 4 chloropyrrolo[2,3-d]pyrimidine of formula XXI, wherein R is hydrogen, is converted to the 35 corresponding 4-chloro-5-nitropyrrolo[2,3-d]pyrimidine of formula XX, wherein Y is nitro, by reacting XXI with nitric acid in sulfuric acid at a temperature between about -100C to about 100C, preferably about 000C, for a time period between about 5 minutes to about 15 minutes, preferably about 10 minutes. The compound of formula XXI, wherein Y is nitro, is converted to the corresponding 4-chloro-5-aminopyrrolo[2,3-d]pyrimidine of the formula XX, wherein Y is WO 99/65909 PCT/IB99/01110 -16 5 amino, by reacting XXI under a variety of conditions known to one skilled in the art such as palladium hydrogenolysis 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, wherein R is hydrogen, is converted to the corresponding compound of formula XIX, wherein R 2 is (C 1
-C
6 )alkyl or benzyl, by treating XX with N-butyllithium, at a temperature 10 of about -780C, and reacting the dianion intermediate so formed with an alkylhalide or benzylhalide at a temperature between about -780C to room temperature, preferably room temperature. Alternatively, the dianion so formed is reacted with molecular oxygen to form the corresponding 4 -chloro-5-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XIX, wherein R 2 is hydroxy. The compound of formula XX, wherein Y is bromine or iodine and R is 15 benzenesulfonate, is converted to the compound of formula XIX, wherein R 2 is (C 6
-C
12 )aryl or vinyl, by treating XX with N-butyllithium, at a temperature of about -780C, followed by the addition of zinc chloride, at a temperature of about -78 0 C. The corresponding organo zinc intermediate so formed is then reacted with aryliodide or vinyl iodide in the presence of a catalytic quantity of palladium. The reaction mixture is stirred at a temperature between about 20 500C to about 800C, preferably about 70 0 C, for a time period between 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-butyllithium, lithium diisopropylamine or sodium hydride, at a temperature of about -780C, in the presence of a 25 polar aprotic solvent, puch as tetrahydrofuran. The anionic intermediate so formed is further reacted with (a) alkylhalide or benzylhalide, at a temperature between about -780C to room temperature, preferably -78 oC, when R 3 is alkyl or benzyl; (b) an aldehyde or ketone, at a temperature between about -780C to room temperature, preferably -780C, when R 3 is alkoxy; and (c) zinc chloride, at a temperature between about -780C to room temperature, preferably 30 780C, and the corresponding organozinc intermediate so formed is then reacted with aryliodide or vinyl iodide in the presence of a catalytic quantity of palladium. The resulting reaction mixture is stirred at a temperature between about 500C to about 800C, preferably about 700C, for a time period between about 1 hour to about 3 hours, preferably about 1 hour. Alternatively, the anion so formed is reacted with molecular oxygen to form the corresponding 35 4-chloro-6-hydroxypyrrolo[2,3-d]pyrimidine compound of formula XVI, wherein R 3 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 above in reaction 3 of Scheme 2.
WO 99/65909 PCT/IB99/01110 -17 5 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 10 XXIV, according to the procedure described above in reaction 2 of Scheme 1. In reaction 2 of Scheme 4, the 4 -amino-5-halopyrrolo[2,3-d]pyrimidine compound of formula XXIV, wherein R is benzenesulfonate and Z is bromine or iodine, is converted to the corresponding compound of formula XXIII by reacting XXIV with (a) arylboronic acid, when R 2 is aryl, in an aprotic solvent, such tetrahydrofuran or dioxane, in the presence of a catalytic 15 quantity of palladium (0) at a temperature between about 500C to about 1000C, preferably about 700C, for a time period between about 2 hours to about 48 hours, preferably about 12 hours; (b) alkynes, when R 2 is alkynyl, in the presence of a catalytic quantity of copper (I) iodide and palladium (0), and a polar solvent, such as dimethylformamide, at room temperature, for a time period between about 1 hour to about 5 hours, preferably about 3 20 hours; and (c) alkenes or styrenes, when R 2 is vinyl or styrenyl, in the presence of a catalytic quantity of palladium in dimethylformamide, dioxane or tetrahydrofuran, at a temperature between about 800C to about 1000C, preferably about 1000C, for a time period between 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 25 corresponding compound of formula XV, according to the procedure described above in reaction 3 of Scheme 2. The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often 30 desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a 35 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. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
WO 99/65909 PCT/IB99/01110 -18 5 Those compounds of the present invention that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are 10 those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, 15 preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product. 20 The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention may also be formulated 25 for sustained delivery. For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g.
, pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline 30 cellulose or calcium phosphate); lubricants (e.., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may 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 they may be presented as a dry product for constitution with water or other 35 suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
WO 99/65909 PCT/IB99/01110 -19 5 For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or 10 in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. 15 The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.., 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 delivered in the form of a solution or suspension from a pump 20 spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or 25 nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix 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 30 buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., asthma) is 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. Aerosol formulations for treatment of the conditions referred to above (e.g., rheumatoid arthritis) in the average adult human are preferably arranged so that each metered 35 dose or «puff’ of aerosol contains 20 pg to 1000 pg of the compound of the invention. The overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time. A compound of formula (I) administered in a pharmaceutically acceptable form either 40 alone or in combination with one or more additional agents which modulate a mammlian immune WO 99/65909 PCT/IB99/01110 -20 5 system or with antiinflammatory agents, agents which may include but are not limited to cyclosporin A (e.g. SandimmuneO% or Neoral-k, rapamycin, FK-506 (tacrolimus), leflunomide, deoxyspergualin, mycophenolate (e.g. Cellcept*, azathioprine (e.g. Imuran@) ), daclizumab (e.g. Zenapax-), OKT3 (e.g. Orthocolone@%), AtGam, aspirin, acctaminophen, ibuprofen, naproxen, piroxicam, and antiinflmmatory steroids (e.g. prednisolone or dexamethasone); and such agents 10 may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice. FK506 (Tacrolimus) is given orally at 0.10-0.15 mg/kg body weight, every 12 hours, within first 48 hours postoperative. Does is monitored by serum Tacrolimus trough levels. 15 Cyclosporin A (Sandimmune oral or intravenous formulation, or Neoral,, oral solution or capsules) is given orally at 5 mg/kg body weight, every 12 hours within 48 hours postoperative. Dose is monitored by blood Cyclosporin A trough levels. The active agents can be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in 20 United States Patents 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, consequently, demonstrate their effectiveness for treating disorders or conditions characterized by Janus Kinase 3 is shown by the following in vitro assay tests. 25 Biological Assay JAK3 (JH1:GST) Enzymatic Assay The JAK3 kinase assay utilizes a protein expressed in baculovirus-infected SF9 cells (a fusion protein of GST and the catalytic domain of human JAK3) purified by affinity chromatography on glutathione-Sepaharose. The substrate for the reaction is poly-Glutamic 30 acid-Tyrosine (PGT (4:1), Sigma catalog # P0275), coated onto Nunc Maxi Sorp plates at 100 pg/ml overnight at 37 0 C. The morning after coating, the plates are washed three times and JAK3 is added to the wells containing 100 pl of kinase buffer (50 mM HEPES, pH 7.3, 125 mM NaCI, 24 mM MgCI2)+ 0.2 uM ATP + 1 mM Na orthovanadate.) The reaction proceeds for 30 minutes at room temperature and the plates is washed three more times. The level of 35 phosphorylated tyrosine in a given well is quantitated by standard ELISA assay utilizing an anti-phosphotyrosine antibody (ICN PY20, cat. #69-151-1). DND 39/IL-4 Cellular Assay for JAK3 kinase Inhibitors The DND 39/IL-4 assay is designed to find inhibitors of JAK3 kinase activity which would be prime candidates for immunosupressive and/or allergy. The assay uses a B-cell line 40 called DND39 which has had the luciferase gene driven by the germ line IgE promoter stably WO 99/65909 PCT/IB99/01110 -21 5 integrated into one of the chromosomes. When these cells are stimulated with IL-4, the kinase JAK3, which is associated with the IL-4 receptor, phosphorylates the signal transducer STAT6. STAT6 then blinds to the germline IgE promoter and starts transcription of the luciferase gene. Luciferase is measured in a lysate of these cells using the Promega luciferase assay reagent system. 10 Note: DND39 cells are grown in RPMI 1640 supplemented with 10% heat inactivated FCS, 2 mM L-Glutamine, and 100 units/ml Pen./Strep. The cells are maintained from lx106 to lx106 cells/ml. Split to 1×10 5 on Friday, cells will be at about lx106 on Monday. Then split 1:2 during the week keeping 200 ml in a flask as needed. 3×10 5 DND39 cells are plated in 100 pl of RPMI 1640 supplemented with 1% heat 15 inactivated FCS, 2 mM L-glutamine, and 100 units/mI Pen/Step in a 96 well Vee bottom plate (Nunc). Compounds are diluted serially 1:2 in DMSO starting at 4mM to 1.9pM. In a 96 well polypropylene plate, changing tips after each dilution. Then 5pl of each dilution are added to 500pl of RPMI/1% serum in a 96 tube rack. 125 pL of the compound dilutions are added to the cells and incubated at 37°C, 5% CO2 for one hour. After one hour, 25 pI of 25 ng/ml IL-4 20 is added to the cells and mixed. Final concentration of IL-4 is 2.5 ng/ml and final concentration of compound is from 20 pM to 156 nM. The cells are then incubated overnight 16-18 hours. The plate is then centrifuged at 2500-3000 RPM in a table top centrifuge for 5 minutes. The culture supernatant is carefully removed by aspiration with an 8 well maifold. 100 pl of PBS with calcium and magnesium is added to the pelletted cells. The cells are 25 resuspended in the PBS and transferred to a Packard white OptiPlate. 100 pl of Packard’s LucLite reagent is added to the wells of the OptiPlate. The following Examples illustrate the preparation of the compounds of the present invention but it is not limited to the details thereof. Melting points are uncorrected. NMR data are reported in parts per million (8) and are referenced to the deuterium lock signal from the 30 sample solvent (deuteriochloroform unless otherwise specified). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 5989®, utilizing chemical ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform which uses a 50/50 mixture 35 of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient temperature refers to 20-25 0
C.
WO 99/65909 PCT/IB99/01110 -22 5 EXAMPLE 1 Cyclohexyl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine METHOD A Cyclohexyl-methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine A mixture of 200 mg (1.30 mmol) of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (prepared 10 by the method of Davoll, J. Am. Chem. Soc., (1960), 82, 131), the product from Method A (589 mg/5.21 mmol) and 3 mL of tert-butanol was stirred in a sealed tube at 100 oC for 24 hours. The reaction mixture was added to water, acidified to pH 1 with 1 N hydrochloric acid (aq), washed twice with diethylether (ether) and basified to pH 14 with 1 N sodium hydroxide (NaOH). The resulting precipitate was filtered and dried in vacuo to obtain 263 mg (88%) of 15 the title compound, mp 177-180 oC. 1 H NMR (400 MHz, CDCI 3 ): 5 1.11-1.22 (m, 1H), 1.43 1.63 (m, 4H), 1.73 (br d, 1H, J = 13.3 Hz), 1.83-1.90 (m, 4 H), 3.23 (s, 3H), 4.69 (br, 1H), 6.53 (d, 1H, J = 3.5 Hz), 7.03 (d, 1H, J = 3.5 Hz), 8.30 (s, 1H), 10.6 (br, 1H). LRMS: 231 (M+1). The title compounds of Examples 2-51 were prepared by a method analogous to that 20 described in Example 1. EXAMPLE 2 9
-(
7 H-Pyrrolo[2,3-d]pyrimidin-4-yl)-2,3,4,4a,9,9a-hexahydro- H-carbazole EXAMPLE 3 4
-(
2
,
6 -Dimethyl-morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine 25 2,6-Dimethylmorpholine. LRMS: 233.3. EXAMPLE 4 4 -Morpholin-4-yl-7H-pyrrolo[2,3-d]pyrimidine 4-Morpholine. LRMS: 205. EXAMPLE 5 30 4-(2,5-Dimethyl-pyrrolidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine 2,5-Dimethylpyrrolidine. Melting Point: 227 – 2290C; LRMS: 216.3. EXAMPLE 6 4-(4-Benzyl-piperidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine 4-Benzylpiperidine. Melting Point: 188 – 1900C; LRMS: 292.4. 35 EXAMPLE 7 4-Phenyl-I -(7H-pyrrolo[2,3-d]lpyrimidin-4-yl)-piperidin-4-ol 4-Phenylpiperidin-4-ol. Melting Point: 201 – 2020C; LRMS: 294.4.
WO 99/65909 PCT/IB99/01110 -23 5 EXAMPLE 8 1-[1-(7H-Pyrrolo [2,3-d]pyrimidin-4-yI)-pi peridin-4-y ]-1,3-dihydro-benzoimidazo
I
2-one Piperidin-4-yl-1,3-dihydrobenzoimidazole. Melting Point: 182 – 1840C; LRMS: 334.4. EXAMPLE 9 10 1 -Phenyl-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,3,8-triaza-spiro[4.5]decan-4-one 1-Phenyl-1,3,8-triaza-spiro[4.5]decan-4-one. Melting Point: 232 – 2340C. EXAMPLE 10 4-(3-Methyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 3-Methylpiperidine. Melting Point: 176 – 1780C; LRMS: 217.1. 15 EXAMPLE 11 4-(3,5-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 3,5-Dimethylpiperidine. Melting Point: 258 – 260°C; LRMS: 231. EXAMPLE 12 4-(2-Methyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 20 2-Methyl-piperidine. Melting Point: 144 – 1460C; LRMS: 217.1. EXAMPLE 13 4-(2-Ethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 2-Ethylpiperidine. Melting Point: 112 – 1140C; LRMS: 231. EXAMPLE 14 25 (1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl]-methanol Piperidine-2-yl-methanol. Melting Point: 135 – 1360C; LRMS: 232.9. EXAMPLE 15 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylic acid diethylamide Piperidine-3-carboxylic acid diethylamide. LRMS: 302.1. 30 EXAMPLE 16 2-(1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-2-yl]-ethanol Piperidin-2-yl-ethanol. Melting Point: 139 – 1400C. EXAMPLE 17 4-Azocan-1-yl-7H-pyrrolo[2,3-d]pyrimidine 35 Azapane. Melting Point: 225 – 2260C; LRMS: 231.3. EXAMPLE 18 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylic acid amide Piperidine-3-carboxylic acid amide. Melting Point: 283 – 2850C.
WO 99/65909 PCT/IB99/01110 -24 5 EXAMPLE19 Dimethyl-[1 -( 7 H-pyrrolo[2,3-d]pyrimidin-4.yl)-pyrrolidin-3.-yl]-amine Dimethylpyrrolidin-3-yl-amine. Melting Point: 210 – 2120C; LRMS: 232.2. EXAMPLE 20 N-Ethyl-N-[l -( 7 H-pyrrolo[ 2
,
3 -d]pyrimidin-4-yl)-pyrrolidin-3-yl]-acetamide 10 N-Ethylpyrrolidin-3-yl-acetamide. Melting Point: 197 – 1990C; LRMS: 274.3. EXAMPLE 21 4-(2-Methoxymethyl-pyrrolidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 2-Methoxymethylpyrrolidine. Melting Point: 134 – 1350C; LRMS: 233.2. EXAMPLE 22 15 [1-( 7 H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol Pyrrolidin-2-yl-methanol. Melting Point: 188 – 1890C; LRMS: 219.3. EXAMPLE 23 N-[1-( 7 H-Pyrrolo[ 2 ,3-d]pyrimidin-4-yl)-pyrrolidin-3-yl]-acetamide Pyrrolidin-3-yl-acetamide. Melting Point: 260 – 2610C; LRMS: 246.3. 20 EXAMPLE24 4-(2-Propyl-piperidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine Propylpiperidine. Melting Point: 106 – 1070C; LRMS: 245.3. EXAMPLE 25 4-(4-Methyl-piperazin-l1-yl)-7H-pyrrolo[2,3-d]pyrimidine 25 4-Methylpiperazine. Melting Point: 141 – 1420C. EXAMPLE 26 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine Piperazine. Melting Point: 164 – 1660C. EXAMPLE 27 30 4-Azepan-1-yl-7H-pyrrolo[2,3-d]pyrimidine Azapane. Melting Point: 2100C; LRMS: 217.3. EXAMPLE 28 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yi)-pyrrolidin-3-ol Pyrrolidin-3-ol. Melting Point: 220 – 2250C; LRMS: 205.2. 35 EXAMPLE 29 [1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl].methanol Piperidine-3-yl-methanol. Melting Point: 161.5 – 163.50C; LRMS: 234.3.
WO 99/65909 PCT/IB99/01110 -25 5 EXAMPLE30 1 -( 7 H-Pyrrolo[ 2 ,3-d]pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester Piperidine-4-carboxylic acid ethyl ester. Melting Point: 139 – 1410C; LRMS: 275.3. EXAMPLE 31 1-( 7 H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester 10 Piperidine-3-carboxylic acid ethylester. Melting Point: 139.5 – 141.5 0 C; LRMS: 275.3. EXAMPLE 32 2-[1-( 7 H-Pyrrolo[2,3-d]pyrimidin-.4-yl)-piperidin-4-yl]-ethanol Piperidin-4-yl-ethanol. Melting Point: 129 – 1310C; LRMS: 265.3. EXAMPLE 33 15 4-(4-Phenyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 4-Phenylpiperidine. Melting Point: 1950C; LRMS: 279. EXAMPLE 34 4-(4-Trifluoromethyl-piperidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine 4-Trifluoromethylpiperidine. Melting Point: 1980C; LRMS: 271. 20 EXAMPLE35 4-[4-(3-Phenyl-propyl)-piperidin-1-yl]-7H-pyrrolo[2,3-d]pyrimidine 4-(3-Phenylpropyl)piperidine. Melting Point: 1340C; LRMS: 321. EXAMPLE 36 4-(3,3-Dimethyl-piperidin-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine 25 3,3-Dimethylpiperidine. Melting Point: 2040C; LRMS: 231. EXAMPLE 37 1-( 7 H-Pyrrolo[2,3-d]pyrimidin-4.-yl)-piperidine-3-carboxylic acid Piperidine-3-carboxylic acid. Melting Point: 159 – 1600C; LRMS: 307.3. EXAMPLE 38 30 1-Methyl-1 0-oxa-4-aza-tricyclo[S.2.1.0%2,6&]decane 1-MethylA-4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1 0-oxa-4-aza-tricyclo[5.2. 1]decane. Melting Point: 251 – 2520C; LRMS: 271.3. EXAMPLE 39 1-(5-Chloro- 7 H-pyrrolo[2,3-d]pyrimidin4.-yl)-decahydro-quinoline 35 Decahydroquinoline. Melting Point: 190 – 1920C; LRMS: 291.8. EXAMPLE 40 3-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propionic acid ethyl ester Piperidin-3-yl-propionic acid ethyl ester. Melting Point: 101 – 1031C; LRMS: 303.4.
WO 99/65909 PCT/IB99/01110 -26 5 EXAMPLE 41 3-[1-( 7 H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin.3-yl]-propionic acid Piperidine-3-yl-propionic acid. Melting Point: 217 – 2190C; LRMS: 275.3. EXAMPLE 42 1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-ol 10 Piperidin-3-ol. Melting Point: 152 – 1540C; LRMS: 219.3. EXAMPLE 43 3-[1-( 7 H-Pyrrolo( 2 ,3-d]pyrimidin-4-yl)-piperidin-3-yl]-propionamide Piperidin-3-yl-propionamide. Melting Point: 212 – 2140C; LRMS: 274.3. EXAMPLE 44 15 4-(2,6-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 2,6-Dimethylpiperidine. LRMS: 231. EXAMPLE 45 2-fl1-( 7 H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-3-yli]-propan-2-ol Piperidin-3-yl-propan-2-ol. Melting Point: 182.8- 183.60C; LRMS: 261. 20 EXAMPLE 46 2-[1 -(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-propan-2-ol Piperidin-4-yl-propan-2-ol. Melting Point: 170.1 – 171.30C; LRMS: 261. EXAMPLE 47 4-Methyl-1 -( 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ol 25 4-Methylpiperdin4-ol. Melting Point: 163.8 – 165.10C; LRMS: 233.1. EXAMPLE 48 3-Methyl-8-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-aza-bicyclo[3.2.1]octan-3-ol 3-Methyl-8-aza-bicyclo[3.2.1]octan-3-ol. Melting Point: 142.1 – 143.80C; LRMS: 259.1. 30 EXAMPLE 49 2-[1-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-pyrrolidin-2-yl]-propan-2-ol Pyrrolidin-2-yl-propan-2-ol. Melting Point: 173 dec; LRMS: 247.1. EXAMPLE 50 3-Methyl-l-(7H-pyrrolo[2,3-d]pyrimidin-4-yl).-pyrrolidin-3-ol 35 3-Methylpyrrolidin-3-ol. LRMS: 219. EXAMPLE 51 4-Pyrazol-1 -yl-7H-pyrrolo[2,3-d]pyrimidine Pyrazole. LRMS: 186.2.
WO 99/65909 PCT/IB99/01110 -27 5 EXAMPLE52 Cyclohexyl-methyl-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine Cyclohexylmethylamine. METHOD B 7 -Benzenesulfonyl-4-chloro-7H-pyrrolo[2,3-d]pyrimidine 10 In a flame-dried flask under nitrogen, 780 mg of 60 % sodium hydride ( 19.5 mmol) in mineral oil was added to 30 mL of dimethylformamide (DMF) and the resulting mixture cooled to 0 oC. A solution of 2.0 g (13.0 mmol) of 4 -chloro-7H-pyrrolo[2,3-d]pyrimidine in 10 mL of DMF was added slowly over a 5 minute period. The reaction was stirred for 10 min at which time generation of hydrogen (H 2 ) ceased. Benzenesulfonylchloride (1.7 mL/13.0 mmol) was 15 added, the reaction 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 grams (89%) of the title compound as a crystalline solid, mp 163-167 oC. METHOD C 7 -Benzenesulfonyl-4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine 20 In a flame-dried flask under nitrogen, 0.53 mL (3.79 mmol) of diisopropylamine were dissolved in 5 mL of tetrahydrofuran (THF) and the solution cooled to -78 OC. n-Butyllithium (3.75 mmol as a 2.5 M solution in hexanes) was added and the resulting mixture brought to 0 oC with continued stirring for 10 minutes. The reaction mixture was again cooled to -78 oC and to this mixture added a solution of 1.0 grams (3.40 mmol) of the product from Method B 25 in 10 mL of THF over a 10 min period. The reaction mixture was stirred for 1 hour at -78 oC, 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. lodobenzene (0.46 mL/4.11 mmol) and a suspension of 197 mg of tetrakis(triphenylphosphine) palladium in 2 mL of THF were added. The resulting mixture was stirred at reflux for 3 hours, cooled to room 30 temperature, and partitioned between dichloromethane and water. The aqueous layer was acidified with 1 N HCI and extracted twice with dichloromethane. The dichloromethane layers were combined, washed with 1 N HCI and brine, dried over magnesium sulfate (MgSO 4 ), filtered and concentrated in vacuo to obtain the title compound. LRMS: 370, 372 (M+2). METHOD D 35 4-Chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine The product from Method C was dissolved in 10 mL of THF and to this solution was added 5.0 mL of methanol and 1.0 grams of NaOH. 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 40 twice with ethyl acetate. The ethylacetate layers were combined, washed with brine, dried WO 99/65909 PCT/IB99/01110 -28 5 over MgSO 4 , filtered and concentrated in vacuo. The crude product was purified by silica-gel chromatography (1:5 ethyl- acetate/hexane) to obtain 0.59 grams (76 %) of the title compound as a pale yellow solid, mp 145 ‘C (dec). LRMS: 230, 232 (M+2). METHOD E Cyclohexyl-methyl-(6-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 10 The product from Method D (50 mg/0.218 mmol) was reacted with 0.12 mL of N methylcyclohexylamine (0.920 mmol) as described in Method A. The reaction mixture was concentrate in vacuo, methanol was added, and the resulting precipitate filtered to provide 7 mg (10%) of the title compound as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) 8:1.18-1.25 (m, 1H), 1.47-1.66 (m, 4H), 1.75-1.90 (m, 5H), 3.30 (s, 3H), 4.74 (br, 1H), 6.79 (s, 1H), 7.32-7.36 15 (m, 1H), 7.47-7.51 (m, 2H), 7.77 (d, 2H, J = 7.9 Hz), 8.33 (s, 1H). LRMS: 307 (M+1). The title compounds of Examples 53-58 were prepared by a method analogous to that described in Example 52. EXAMPLE 53 1-(6-Phenyl- 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-decahydro-quinoline 20 Decahydroquinoline. LRMS: 333.4. EXAMPLE 54 4-(2-Ethyl-piperidin-1-yl)- 6 -phenyl-7H-pyrrolo[2,3-d]pyrimidine 2-Ethylpiperidine. LRMS: 307.4. EXAMPLE 55 25 4-(3,3-Dimethyl-piperidin-1-yl)-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine 3,3-Dimethylpiperidine. LRMS: 307.4. EXAMPLE 56 6-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 279.4. 30 EXAMPLE 57 4-Piperidin-1 -yl-6-thiophen-3-yl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 285.4. EXAMPLE 58 4-Piperidin-1-yl- 6 -thiophen-2-yl-7H-pyrrolo[2,3-d]pyrimidine 35 Piperidine. LRMS: 285.4. EXAMPLE 59 Cyclohexyl-methyl-(6-methyl-7H-pyrrolo[2,3.-d]pyrimidin-4-yl)-amine Cyclohexylmethylamine.
WO 99/65909 PCT/IB99/01110 -29 5 METHOD F 7 -Benzenesulfonyl-4-chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine To flame-dried flask under N 2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to -78 oC and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0 oC and 10 stirred for 10 minutes. After cooling the mixture again to -78 oC, a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 minute period. The resulting mixture was stirred for 1 hour, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 hours, quenched with a saturated solution of NH 4 CI and warmed to room temperature. The mixture was stirred for 5 15 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO 4 , filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2). METHOD G 4 -Chloro-6-methyl-7H-pyrrolo[2,3-d]pyrimidine 20 The product from Method F was deprotected as described in Method 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. Mp 2050C dec. LRMS 168, 170 (M+2). METHOD H Cyclohexyl-methyl-(6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine 25 The product from Method G (50 mg/0.298 mmol) was reacted with 100 mg (0.883 mmol) of N-methylcyclohexylamine as described in Method A. The reaction mixture was worked up as in Method A with the exception that ethyl acetate was used in place of ether. The title compound (42 mg, 58 % yield) was obtained as a white solid. Mp 221 oC dec. 1 H NMR (400 MHz, CDCI 3 ) 8: 1.15-1.25 (m, 1H), 1.43-1.62 (m, 4H), 1.73 (br s, 1H, J = 13.7 Hz), 30 1.82-1.90 (m, 4H), 2.41 (d, 3H, J = 0.8 Hz), 3.21 (s, 3H) 4.63 (br s, 1H), 6.20 (s, 1H), 8.22 (s, 1H), 10.1 (brs, 1H). LRMS: 245 (M+1). The title compound of Example 60 was prepared by a method analogous to that described in Example 59. EXAMPLE 60 35 6-Methyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 217.3. EXAMPLE 61 5-Chloro-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine WO 99/65909 PCT/IB99/01110 -30 5 METHODI 4 ,5-Dichloro-7H-pyrrolo[2,3-d]pyrimidine 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (154 mg, 1.0 mmol) was suspended in 6.0 mL of dry dichloromethane in a flame-dried flask and to this mixture was added N-chlorosuccinimide (147 mg, 1.1 mmol) in one portion. The resulting mixture stirred at room temperature for 18 h, 10 at which time the solvent was removed under reduced pressure. The residue was triturated with water and isolated by filtration to afford 137 mg (72%) of the title compound as a gray solid, mp 224-227 OC(dec). LRMS: 188 (M+1). METHOD J 5-Chloro-4-piperidin-1 -yl-7H-pyrrolo[2,3-d] pyrimidine 15 The product from Method I (57 mg, 0.3 mmol) was suspended in 3.0 mL of tert butanol and to this solution was added piperidine (90pL, 0.9 mmol) and the resulting system heated at reflux for 1 hour. The reaction mixture was cooled to room temperature and water was added (4.0 mL). The solution was adjusted to pH 1 with 1 N HCI and then washed with ether. The aqueous layer was removed and adjusted to pH 12 with 2 N NaOH. The solution 20 was then extracted 2 x 15 mL with dichloromethane and the combined organics washed with water then brine and dried over MgSO 4 . Evaporation of solvent afforded 45 mg of a yellow solid that was purified by silica-gel chromatography (3:1 ethyl acetate/hexanes) to yield 23 mg (32%) of the title compound as a light yellow solid. Mp 170 – 172 oC. ‘H NMR (400 MHz,
CDCI
3 ) 8:1.67 – 1.74 (m, 6H), 3.65 – 3.67 (m, 4H), 7.10 (s, 1H), 8.31 (s, 1H). LRMS: 237 (M + 25 1). The title compounds of Examples 62-63 were prepared by a method analogous to that described in Example 61. EXAMPLE 62 5-Chloro-4-(octahydro-indol-1-yl)-7H-pyrrolo[2,3-d]pyrimidine 30 Octahydroindole. Melting Point: 1930C; LRMS: 277.8. EXAMPLE 63 1-(5-Chloro- 7 H-pyrrolo[2,3-d]pyrimidin-4-yl)-decahydro-quinoline Decahydroquinoline. Melting Point: 190 – 1920C; LRMS: 291.8. EXAMPLE 64 35 5-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine METHOD K 5-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4 -chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 75 mL of chloroform was added 3.5 grams (0.02 mol) of N-bromosuccinamide and the 40 resulting mixture refluxed for 1 hour. After cooling to room temperature, the precipitate was WO 99/65909 PCT/IB99/01110 -31 5 removed by filtration and dried under reduced pressure affording 4.1 grams (89%) of the title compound. 1 H NMR (400 MHz) (CDCl 3 ) 8:7.93 (d, 1H, J = 2.8 Hz), 8.60 (s, 1H). METHOD L 7 -Benzenesulfonyl-5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine To a slurry of the product from Method K (4.1 g/0.018 mol) in DMF (15 mL) and 10 cooled to 0 oC was added 1.0 g (0.025 mol) of 60% sodium hydride in mineral oil and the resulting mixture stirred at 0 oC for 15 minutes. Benzenesulfonyl chloride (3.2 g/0.018 mol) was added, the reaction mixture warmed to room temperature and stirred for 2 hours. Water was then added (15 mL) and the resulting solid removed by filtration and dried in vacuo affording 5.9 grams (89%) of the title compound. 15 METHOD M 7-Benzenesulfonyl-5-bromo-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine A mixture of 2.0 g (5.37 mmol) of the product from Method L and 1.1 grams (13.4 mmol) of piperidine in 10 mL of tert-butanol was heated with stirring at 60 oC for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane 20 (25 mL) and water (25 mL). The dichloromethane layer was dried over sodium sulfate (Na 2
SO
4 ) and concentrated to dryness in vacuo affording 2.2 grams (97%) of the title compound. ‘H NMR (400 MHz) (CDCI 3 ) 8:1.63 – 1.72 (m, 6H), 3.54 – 3.57 (m, 4H), 7.53 (t, 2H, J = 2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, J = 2.0 Hz), 8.17 – 8.20 (m, 2H), 8.43 (s, 1H). LRMS: 422.7, 420.7 (M+1). 25 METHOD N 5-Phenyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of the product from Method M (100 mg/0.237 mmol) in 1.0 mL of dioxane was added 32 mg (0.261 mmol) of phenylboronic acid and 75 mg (0.356 mmol) of tribasic potassium phosphate followed by 7 mg (0.006 mmol) of tetrakis(triphenylphosphine) 30 palladium. The resulting mixture was degassed with nitrogen and stirred at 100 oC 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 stirred at room temperature for 1 hour. The resulting mixture was then partitioned between dichloromethane and water, the dichloromethane layer dried over MgSO 4 and concentrated to dryness in vacuo. The crude product was purified by silica 35 gel chromatography (2:1 ethyl acetate/hexanes) affording 13 mg ( 20%) of the title compound. 1 H NMR (400 MHz) (CDCl 3 ) 8:1.33 – 1.34 (m, 4H), 1.43 – 1.44 (m, 2H), 3.26 3.28 (m, 4H), 7.12 (s, 1H), 7.27 (t, 1H, J = 7.2 Hz), 7.38 (t, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 0.8 Hz), 8.42 (s, 1H). LRMS:279.2 (M+1). The title compounds of Examples 65-77 were prepared by a method analogous to that 40 described in Example 64.
WO 99/65909 PCT/1B99/01 10 -32 5 EXAMPLE 65 5-(3-Chloro-4-fluoro-phenyl)-4-piperidin.1 -yl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 331.8. EXAMPLE 66 5-(4-Fluoro-phenyl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine 10 Piperidine. LRMS: 297. EXAMPLE 67 5-(4-Ch lo ro-phenyl)-4-pi perid in-1 -y 1-7 H-py rrolo[2,3-d] py rimid ine Piperidine. LRMS: 313. EXAMPLE 68 15 5-(3,5-Bis-trifluoromethyl-phenyl)4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 415.4. EXAMPLE 69 4-Piperidin-1 -yl-5-o-tolyl-7H-pyrrolo[2,3-dlpyrimidine Piperidine. LRMS: 293.4. 20 EXAMPLE 70 4-Piperidin-1 -yI-5-p-tolyl-7H-pyrrolo[2,3-d]pyrimidine Piperidine. LRMS: 293.4. EXAMPLE 71 5-(4-Meth oxy-p he nyl)-4-pi period in -1 -yl-7H-py rrolo [2,3-d] pyri mid in e 25 Piperidine. LRMS: 309.4. EXAMPLE 72 4-Piperidin-1 -yi-5-(3-trifluoromethyl-phenyl)-7H-pyrrolo[2,3-d~pyrimidine Piperidine. LRMS: 347.4. EXAMPLE 73 30 5-(3-Ch lo ro-phenylI)-4-pi pe rid in-I -yl-7 H-pyrrolo [2,3-d] py rim id ine Piperidine. LRMS: 427.8. EXAMPLE 74 3-(4-Piperidin-1 -yl-7H-pyrrolo[2,3-dlpyrimidin-5-yI)-benzoic acid ethyl ester Piperidine. LRMS: 465.4. 35 EXAMPLE 75 2-[3-(4-Piperidin-1 -yi-7H-pyrrolo[2,3-d]pyrimidin-5-yi)-phenyl1-propan-2oI Piperidine. LRMS: 451.4.
WO 99/65909 PCT/IB99/01110 -33 5 EXAMPLE 76 4-(2-Methyl-piperidin-1 -yl)- 5 -m-tolyl-7H-pyrrolo[2,3-d]pyrimidine 2-methylpiperidine. LRMS: 307.2. EXAMPLE 77 4-Azepan-1 -yl- 5 -m-tolyl-7H-pyrolo[2,3-d]pyrimidine 10 Azepane. LRMS: 307.2. EXAMPLE 78 METHOD O 4-Piperidin-1 -yl- 7 H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile (54 mg/0.3 15 mmol) (prepared by the method of Townsend, et. al., J. Am. Chem. Soc., 1969, 91, 2102) suspended in 3.0 mL tert-Butanol was added piperidine (59 pL/0.60 mmol). The resulting mixture was then heated at reflux for 2.5 h and after cooling to room temperature, was transferred to a separatory funnel and diluted with ether (20 mL). The solution was extracted 2 x 10 mL with 1N HCI, the combined aqueous layers were adjusted to pH 7 with 2 N 20 potassium hydroxide (KOH) solution forming a precipitate which was collected by filtration, washed with water and dried under reduced pressure to give 29 mg (42%) of the title compound as a colorless solid. Mp 209 – 211 oC; ‘H NMR (400 MHz) (acetone-d6) 8:1.72 1.74 (m, 6H), 3.72 – 3.79 (m, 4H), 8.12 (s, 1H), 8.29 (s, 1H). LRMS: 228 (M + 1). EXAMPLE 79 25 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine METHOD P 4-Chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 80 mL of chloroform was added 4.5 grams (0.02 mol) of N-iodosuccinimide and the 30 resulting mixture heated at reflux for 1 hour. After cooling to room temperature, the percipitate was removed by flitration and dried under reduced pressure affording 4.6 grams (82%) of the title compound. METHOD Q 7-Benzenesulfonyl-4-chloro-5-iodo-7H-pyrrolo[2,3-d]lpyrimidine 35 The title compound was prepared as previously described in Method L using the product from Method O affording 5.4 grams (80%) of material. LRMS: 419.6 (M+1), 279.7.
WO 99/65909 PCT/IB99/01110 -34 5 METHOD R 7-Benzenesulfonyl-5-iodo-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine The title compound was prepared by the procedure described in Method M using the product from Method Q to produce the title compound. LRMS: 469 (M+1), 329.1. METHOD S 10 7-Benzenesulfonyl-4-piperidin-1-yl-5-triethylsilanylethynyl-7H-pyrrolo[2,3 d]pyrimidine To a flamed-dried flask under nitrogen was charged 211 mg (0.5 mmol) of the product from Method R, 19 mg (0.1 mmol) of copper (I) iodide and 58 mg (0.05 mmol) of tetrakis(triphenylphosphine)palladium. To this mixture was then added 0.14 mL (1.0 mmol) of 15 triethylamine and 0.27 mL (1.5 mmol) of triethylsilylacetylene as a solution in 1.5 mL of dry DMF. The resulting mixture stirred at room temperature for 3 hours, at which time, 5.0 mL of water were added and the mixture extracted with ethylacetate. The ethyl acetate extract was dried over MgSO 4 and concentrated in vacuo. The resulting crude product was then purified by silica-gel chromatography (7:1 hexanes/ethyl acetate) affording 194 mg (89%) of the title 20 compound. LRMS: 481 (M+1), 341. METHOD T 5-Ethynyl-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine To a stirred solution of the product from Method S (194 mg/0.40 mmol) dissolved in 2.0 mL of dry THF was added dropwise 0.4 mL (0.4 mmol) of a 1 M solution of 25 tetrabutylammonium fluoride in THF. The resulting mixture stirred at room temperature for 10 minutes, then was transferred to a methanol solution (3.0 mL) containing 1 gram of KOH, the new mixture stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, the ethyl acetate layer washed with water and brine, dried over MgSO 4 and concentrated to dryness in vacuo. The crude product 30 was purified by silica-gel chromatography (2:1 ethyl acetate/hexanes) affording 72 mg (64%) of the title compound as a white crystalline solid. Mp 179 – 181 oC. 1 H NMR (400 MHz)
(CDCI
3 ) d: 1.72 (br s, 6H), 3.20 (s, 1H), 3.82 – 3.83 (m, 4H), 7.47 (s, 1H), 8.35 (s, 1H). LRMS: 227 (M+1).

Claims (10)

1. A compound of the formula R R 2 NR3 N N H or the pharmaceutically acceptable salt thereof; wherein R’ is a group of the formula x (B). (D)n IV A E N 10 wherein the dashed line represents optional double bonds; m is 0, 1, 2 or 3; nis 0, 1, 2or3; X, B and D are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or 15 CR 7 R»; A and E are each CR 7 R 8 ; and R 6 is selected from the group consisting of hydrogen, (C 1 -Ce)alkyl, trifluoromethyl, trifluoromethyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl (difluoromethylene), (C ,-C 3 )alkyl(difluoromethylene)(C, C 3 )alkyl, (Cl-C 6 )alkoxy(C l -C 6 )acyl, (C 1 -Ce)alkylamino(C,-C,)acyl, ((Cl-Ce)alkyl) 2 amino(Cl 20 C,)acyl, (C 6 -Co 1 0 )aryl, (Cs-C,)heteroaryl, (C 6 -Cjo)aryl(C 1 -C 6 )alkyl, (Cs-Cg)heteroaryl(C,-C 6 )alkyl, (C 6 -C 1 o)aryl(C 6 -C 1 O)aryl, (C 6 -Co 1 0 )aryl(C 6 -Co 10 )aryl(Cl-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 C 6 )cycloalkyl(Cl-C 6 )alkyl, hydroxy(C 2 -C 6 )alkyl, (Cl-C 6 )acyloxy(C 2 -C 6 )alkyl, (Cl-C 6 )alkoxy(C 2 Cs)alkyl, piperazinyl(C 1 -C 6 )alkyl, (C 1 -C 6 )acylamino(Cl-C 6 )alkyl, (C 6 -Co 10 )aryl(C 1 -C 6 )alkoxy(Cj Ce)alkyl, (C 5 -C 9 )heteroaryl(Cl-C 6 )alkoxy(Cl-C 6 )alkyl, (C,-C 6 )alkylthio(C 1 -C 6 )alkyl, (C 6 25 Co 10 )arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(Cl-C 6 )alkyl, (C 6 -Co 1 0 )arylsulfinyl(Cl-Ce)alkyl, (Cf Cs)alkylsulfonyl(Cl-C 6 )alkyl, (C 6 -Co 10 )arylsulfonyl(Cl-C 6 )alkyl, amino(Cl-C 6 )alkyl, (Cf Ce)alkylamino(Cl-C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino(C 1 -C 6 )alkyl, R 13 CO(C 1 -C 6 )alkyl wherein R 13 is R 20 0 or R 20 R 21 N wherein R 2 0 and R21 are each independently selected from the group consisting of hydrogen, (Cl-C 6 )alkyl, (C 6 -Co 10 )aryl(C 1 -C 6 )alkyl or (C 5 -C,)heteroaryl(Cl-C 6 )alkyl; or R14(C 30 Cs)alkyl wherein R 14 is (Cl-Ce)acylpiperazino, (C 6 -Co 10 )arylpiperazino, (C 5 – WO 99/65909 PCT/IB99/01110 -36 5 C 9 )heteroarylpiperazino, (Cl-C 6 )alkylpiperazino, (C 6 -Co 10 )aryl(C 1 -C 6 )alkylpiperazino, (Cs C 9 )heteroaryl(C 1 -C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -C 10 )arylpiperidyl, (C 5 -C 9 )heteroarylpiperidyl, (C 6 -C 10 )aryl(C1 C 6 )alkylpiperidyl, (Cs-C 9 )heteroaryl(Cl-C 6 )alkylpiperidyl, (C 1 -C 6 )alkoxyacyl, (C 1 -C 6 )alkylaminoaryl, ((C 1 -C 6 )alkyl 2 aminoacyl or (C 1 -C 6 )acylpiperidyl; 10 R 7 and R 8 are each independently selected from the group consisting of hydrogen, deuterium, (C 1 -C 6 )alkyl, amino, hydroxy, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl)amino, (C 1 -C 6 )acylamino, (C 1 -C 6 )acyl(Cj-C 6 )alkylamino, carboxy, (C 1 -C 6 )alkoxyacyl, (C, C 6 )alkylaminoacyl, ((Cl-C 6 )alkyl) 2 aminoacyl, aminoacyl, trifluoromethyl, trifluoromethyl(Cl C6)alkyl, (C 1 -C 6 )alkyl (difluoromethylene), (C, 1 -C 3 )alkyl(difluoromethylene)(C 1 -C 3 )alkyl, (C6 15 C 1 0 )aryl, (C 5 -C 9 )heteroaryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl, (C 5 -C 9 )heteroaryl(C-C 6 )alkyl, (C6 C 0 lo)aryl(C 6 -Co 0 )aryl, (C 6 -Clo)aryl(C 6 -Co 10 )aryl(Cl-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 C 6 )alkyl, hydroxy(C,-C 6 )alkyl, (C,-C 6 )acyloxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy(C,-C 6 )alkyl, piperazinyl(C 1 -C 6 )alkyl, (Cj-C 6 )acylamino(C 1 -C 6 )alkyl, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 CIo)aryl(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, (Cs-C,)heteroaryl(Cl-C)alkoxy(C-C 6 )alkyl, (C 1 -C 6 )alkylthio(Cl 20 Ce)alkyl, (C 6 -C 1 o)arylthio(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylsulfinyl(Cl-C 6 )alkyl, (C 6 -C 10 )arylsulfinyl(Cl C 6 )alkyl, (Cl-C 6 )alkylsulfonyl(Cl-C 6 )alkyl, (C 6 -C 1 o)arylsulfonyl(Cl-C 6 )alkyl, amino(C 1 -C 6 )alkyl, (C, Ce)alkylamino(C 1 -C 6 )alkyl, ((C1-C 6 )alkyl) 2 amino(Cl-C 6 )alkyl, R 13 CO(Cl-C 6 )alkyl or R 13 CO(C 3 C 1 0 )cycloalkyl wherein R 13 is R 20 0 or R 20 R 21 N wherein R 20 and R 21 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 25 C 9 )heteroaryl(Cl-C 6 )alkyl; R 1 4 , R 14 (C 1 -C 6 )alkyl or R 14 (C 3 -Co 10 )cycloalkyl wherein R 14 is (C, C 6 )acylpiperazino, (C 6 -Clo)arylpiperazino, (C 5 -C 9 )heteroarylpiperazino, (Cl-Ce)alkylpiperazino, (C 6 -Co 10 )aryl(C-C 6 )alkylpiperazino, (Cs-C,)heteroaryl(C,-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C 1 -C 6 )alkylpiperidyl, (C 6 -Co 1 0 )arylpiperidyl, (C5 C,)heteroarylpiperidyl, (C 6 -C 1 o)aryl(Cl-C 6 )alkylpiperidyl, (Cs-C 9 )heteroaryl(C,-C 6 )alkylpiperidyl or 30 (C 1 -C 6 )acylpiperidyl; or a group of the formula O (CH 2 )p z I wherein p is 0, 1, 2 or 3; and Z is hydroxy, (C 1 -C 6 )alkoxy or NR 1 R 2 wherein R 1 and R 2 are each independently 35 selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, piperidyl, (Cl-C 6 )alkylpiperidyl, (C6 Co)arylpiperidyl, (C.-C,)heteroarylpiperidyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkylpiperidyl, (Cs C 9 )heteroaryl(C 1 -C 6 )alkylpiperidyl, (C 1 -C 6 )acylpiperidyl, (C 6 -Clo)aryl, (C 5 -C 9 )heteroaryl, (C6 C 1 0 )aryl(C 1 -C 6 )alkyl, (Cs-C 9 )heteroaryl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 6 -C 1 o)ary, (C 6 -C 10 )aryl(C 6 – WO 99/65909 PCT/IB99/01110 -37 5 Co 10 )aryl(C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 6 )alkyl, R 5 (C 1 -C 6 )alkyl, (Cl C 5 )alkyl(CHR 5 )(Cl-C 6 )alkyl wherein R 5 is hydroxy, (Cl-C 6 )acyloxy, (C 1 -C 6 )alkoxy, piperazino, (C, C 6 )acylamino, (C 1 -C 6 )alkylthio, (C,-C 1 o)arylthio, (Cl-C 6 )alkylsulfinyl, (C 6 -Co 1 0 )arylsulfinyl, (Cl C,)alkylsulfoxyl, (C 6 -Co 1 0 )arylsulfoxyl, amino, (Cl-C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (Cl Ce)acylpiperazino, (Cl-C 6 )alkylpiperazino, (Ce-C 1 o)aryl(Cl-C 6 )alkylpiperazino, (C 5 10 Cg)heteroaryl(C-C 6 )alkylpiperazino, morpholino, thiomorpholino, piperidino or pyrrolidino; R 6 (C 1 Ce)alkyl, (Cl-Cs)alkyl(CHR 6 )(Cl-C,)alkyl wherein R 6 is piperidyl, (C 1 -C 6 )alkylpiperidyl, (C6 C 1 0 )arylpiperidyl, (C 6 -Co 1 0 )aryl(Cl-Ce)alkylpiperidyl, (C 5 -Cg)heteroarylpiperidyl or (C5 Cg)heteroaryl(C-C 6 )alkylpiperidyl; or when n is at least 1, D and E, or D and X, are each CR 7 R 8 , the adjacent R 7 groups 15 may be taken together, with the carbons to which they are attached, to form groups of the formulas G «» L x G ‘M (B)m ()(B)m A N , LA E or N V VI wherein the dashed lines represent optional double bonds; ais 0, 1 or2; 20 m, A, B and X are as defined above; and G, J, L and M are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or CR 7 R’wherein R’, R 7 and R 8 are as defined above; or when n is 1, D and E are each CR 7 R 8 and m is 1, A and B are each CR 7 R 8 , the respective adjacent R 7 groups may be taken together, with the carbons to which they are 25 attached, to form a group of the formula WO 99/65909 PCT/IB99/01110 -38 R (X), G (W)~ ‘(J) a I XIII Y L 5 wherein the dashed bond represent optional double bonds; a, G, J. L and M are as define above; r isO or 1; c is 0, 1 or 2; and 10 R, W, Y and S are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or CR 7 R 8 wherein R 6 , R 7 and R 8 are as defined above; R 2 and R 3 are each independently selected from the group consisting of hydrogen, deuterium, amino, halo, hydoxy, nitro, carboxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy wherein the alkyl or alkoxy groups are optionally 15 substittued by one to three groups selected from halo, hydroxy, carboxy, amino (C, C 6 )alkylthio, (C 1 -C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (C 5 -Cg)heteroaryl, (C 2 C,)heterocycloalkyl, (C 3 -C 9 )cycloalkyl or (C 6 -C 1 0 )aryl; or R 2 and R 3 are each independently (C 3 -C 1 0 )cycloalkyl, (C 3 -Clo)cycloalkoxy, (Cl-C 6 )alkylamino, ((C,-C 6 )alkyl) 2 amino, (C6 C 1 0 )arylamino, (C 1 -C 6 )alkylthio, (C 6 -Co 10 )arylthio, (C 1 -C 6 )alkylsulfinyl, (C 6 -Co 10 )arylsulfinyl, (C 1 20 C 6 )alkylsulfonyl, (C 6 -Co 10 )arylsulfonyl, (Cl-C 6 )acyl, (C 1 -C 6 )alkoxy-CO-NH-, (C 1 -C 6 )alkyamino CO-, (Cs-C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl or (C 6 -C 10 )aryl wherein the heteroaryl, heterocycloalkyl and aryl groups are optionally substituted by one to three halo, (C 1 -C 6 )alkyl, (C,-C 6 )alkyl-CO-NH-, (C l -C 6 )alkoxy-CO-NH-, (C 1 -C 6 )alkyl-CO-NH-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy CO-NH-(C 1 -C 6 )alkyl, (Cl-C 6 )alkoxy-CO-NH-(Cl-C 6 )alkoxy, carboxy, carboxy(Cl-C 6 )alkyl, 25 carboxy(Cl-C 6 )alkoxy, benzyloxycarbonyl(Cl-C 6 )alkoxy, (C,-C 6 )alkoxycarbonyl(C 1 -C 6 )alkoxy, (C 6 -C 10 )aryl, amino, amino(Cl-C 6 )alkyl, (Cl-C 6 )alkoxycarbonylamino, (C 6 -Co 10 )aryl(Cl C 6 )alkoxycarbonylamino, (Cl-C 6 )alkylamino, ((Cl-C 6 )alkyl) 2 amino, (C,-C 6 )alkylamino(C 1 C 6 )alkyl, ((C,-C 6 )alkyl) 2 amino(C,-C 6 )alkyl, hydroxy, (C,-C 6 )alkoxy, carboxy, carboxy(Cl C 6 )alkyl, (Cl-C 6 )alkoxycarbonyl, (Cl-C 6 )alkoxycarbonyl(Cl-C 6 )alkyl, (Cl-C 6 )alkoxy-CO-NH-, 30 (C 1 -C 6 )alkyl-CO-NH-, cyano, (C . -C 9 )heterocycloalkyl, amino-CO-NH-, (Cl-C 6 )alkylamino-CO NH-, ((Cl-C 6 )alkyl) 2 amino-CO-NH-, (C 6 -C 1 Io)arylamino-CO-NH-, (C 5 -C,)heteroarylamino-CO NH-, (C 1 -C 6 )alkylamino-CO-NH-(C-C 6 )alkyl, ((C 1 -C 6 )alkyl) 2 amino-CO-NH-(C 1 -C 6 )alkyl, (C6 Co)arylamino-CO-NH-(C l -C 6 )alkyl, (Cs-Cg)heteroarylamino-CO-NH-(C,-C 6 )alkyl, (C 1 C 6 )alkylsulfonyl, (Cl-C 6 )alkylsulfonylamino, (Cl-C 6 )alkylsulfonylamino(Cl-C 6 )alkyl, (C6 35 Co 10 )arylsulfonyl, (C 6 -C 1 o)arylsulfonylamino, (C 6 -Co 10 )arylsulfonylamino(C,-C 6 )alkyl, (C,- WO 99/65909 PCT/IB99/01110 -39 5 C 6 )alkylsulfonylamino, (C,-C 6 )alkylsulfonylamino(C,-C)alkyl, (Cs-C 9 )heteroaryl or (C 2 C 9 )heterocycloalkyl; with the proviso that when A, B or X, in formulas V or VI, is defined as NR 6 or CR 7 R 8 , R 2 and/or R 3 must be halo; with the proviso that when R 2 and R 3 are each independently hydrogen or (C 1 10 C 6 )alkyl, R’ cannot be unsubstituted piperidinyl; with the proviso that when R 2 and R 3 are each hydrogen, R 1 cannot be unsubstituted mopholinyl or pyrrolidinyl; with the proviso that when R 2 and R 3 are each hydrogen, R 1 cannot be piperazinyl; and 15 with the proviso that the groups of formuls IV, V, VI or XIII do not contain two or more oxygens, sulfurs or combinations thereof in adjacent positions.

2. A compound according to claim 1, wherein R 1 is a group of the formula X (B )m ………………… (D ) n IV A .. N wherein the dashed line represents optional double bonds; 20 m is 0, 1, 2 or 3; n is 0, 1, 2 or

3; X, B and D are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or CR 7 R»; A and E are each independently CR 7 R 8 or NR 6 ; 25 or when n is 1, D and E are each CR 7 R 8 and m is 1, A and B are each CR 7 R 8 , the respective adjacent R 7 groups may be taken together, with the carbons to which they are attached, to form a group of the formula R (X)r G (W)C Ma XIll y S N M, .5.L Xl S Ll wherein the dashed bond represent optional double bonds; WO 99/65909 PCT/IB99/01110 -40 5 a, G, J. L and M are as define above; ris 0 or 1; c is 0, 1 or 2; and R, W, Y and S are each independently oxygen, S(O)d wherein d is 0, 1 or 2, NR 6 or CR 7 R 8 wherein R 6 , R 7 and R 8 are as defined above. 10 3. A compound according to claim 1, wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl, (C 3 -Co 10 )cycloalkoxy, (C 2 -C 9 )heterocycloalkyl, (Cs-C,)heteroaryl or (C 6 -Co 1 0 )aryl.

4. A compound according to claim 1, wherein said compound is selected from the group consisting of: 15 5-Fluoro-4-piperidin-1-yl-7H-pyrrolo[2,3-d]pyrimidine; 4-Piperidin-1 -yl-5-trifluoromethyl-7H-pyrrolo[2,3-d]pyrimidine; 2-{3-Ethyl-4-[methyl-(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; 20 N,N-Dimethyl-N’-[3-(4-piperidin-1-yl- 7 H-pyrrolo[2,3-d]pyrimidin-5-yl)-benzyl]-ethane 1,2-diamine; 2-[1-(5-m-Tolyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-ethanol;

5-(3-Isopropyl-phenyl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(3-Methyl-3H-imidazol-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 25 5-(1-Methyl-I H-imidazol-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-(2-Methyl-pyridin-4-yl)-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Chloro-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 5-Chloro-4-(octahydro-indol-1 -yl)-7H-pyrrolo[2,3-d]pyrimidine; 5-Ethynyl-4-piperidin-1 -yl-7H-pyrrolo[2,3-d]pyrimidine; 30 4-Piperidin-1-yl-5-m-tolyl-7H-pyrrolo[2,3-d]pyrimidine; and 4-(3,3-Dimethyl-piperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidine. 5. 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 from diabetes, cancer, asthma, atopic 35 dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in such disorders or conditions and a pharmaceutically acceptable carrier. WO 99/65909 PCT/IB99/01110 -41 5

6. 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 from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, Alzheimer’s disease, leukemia and other autoimmune diseases or (b) the inhibition of protein tyrosine 10 kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, effective in such disorders or conditions and a pharmaceutically acceptable carrier. 15

7. A method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. A method for treating or preventing a disorder or condition selected from organ transplant rejection, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I 20 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 in a mammal, including a human, comprising administering to said mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, effective in treating such a condition. 25

9. A method for the inhibition of protein tyrosine kinases or Janus Kinase 3 (JAK3) in a mammal, including a human, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents. 30

10. A method for treating or preventing a disorder or condition selected from organ transplant rejection, 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 in a mammal, including a human, comprising administering to said 35 mammal an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, alone or in combination with one or more additional agents which modulate a mammalian immune system or with antiinflammatory agents, effective in treating such a condition.

AU40545/99A
1998-06-19
1999-06-14
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