# US 9,040,543 B2 · Compositions and methods for inhibition of the JAK pathway

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- Number: US 9,040,543 B2
- Document ID: US9040543B2
- Status: Granted
- Kind: B2
- Application number: 14/247,878
- Filed: 2014-04-08
- Published: 2014-08-21
- Granted: 2015-05-26
- Earliest claimed: 2006-10-19
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Hui Li; Ankush Argade; Sambaiah Thota; David Carroll; Arvinder Sran; Robin Cooper; Rajinder Singh; Kin Tso; Somasekhar Bhamidipati
- Web page: https://patentgrep.com/patent/US9040543B2

## CPC

- C07D 239/48: Two nitrogen atoms
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention encompasses compounds having formula I and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases are therapeutically useful.

## Claims

### Claim 1

A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of a compound effective to inhibit an activity of the JAK kinase, wherein the compound is a compound of formula I
or pharmaceutically acceptable salt thereof, wherein:
ring A is heteroaryl;
p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3, 4, or 5 when ring A is bi- or tricyclic;
q is 0,1,2 or 3;
X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl;
Y is selected from the group consisting of hydrogen, alk1-SO2N(R4)R5 and alk1-N(R4)SO2R5;
W is selected from the group consisting of alk2-SO2N(R6)R7 and alk2-N(R6)SO2R7;
alk1 and alk2 are each independently a bond, straight or branched chain C1-6 alkylene group, cycloalkylene or substituted cycloalkylene wherein:
if W is alk2-SO2N(R6)R7 and alk2 is a bond, then Y is alk1-N(R4)SO2R5 and alk1 is a bond;
R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl;
each R2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro, halo and oxo;
wherein if R2 is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A; or
R4 and one of R2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A; or
R5 and one of R2 together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A;
Z1, Z2, and Z3 each independently is carbon or nitrogen, wherein 0 or 1 of Z1, Z2, and Z3 is N; and
W is not attached to Z1, Z2 or Z3 when said Z1, Z2 or Z3 is nitrogen;
each R3 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro, halo, and aminosulfonyl; or
R6 and one of R3, together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to the ring containing Z1, Z2 and Z3; or
R7 and one of R3, together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to the ring containing Z1, Z2 and Z3; or
R4 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M+, wherein M+ is a counterion selected from the group consisting of K+, Na+, Li+ and +N(R8)4, wherein R8 is hydrogen or alkyl, and the nitrogen of —SO2N(R4)R5 or —N(R4)SO2R5 is N−; or
R4 and R5 together with the intervening atom or atoms bound thereto form a heterocyclic or substituted heterocyclic group; or
R5 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and acyl; or
R4 and R5 together with the intervening atom or atoms bound thereto form a heterocyclic or a substituted heterocyclic group;
R6 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, carboxyl, carboxyl ester, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M+, wherein M+ is a counterion selected from the group consisting of K+, Na+, Li+ or +N(R8)4, wherein R8 is hydrogen or alkyl, and the nitrogen of —SO2N(R6)R7 or —N(R6)SO2R7 is N−; or
R6 and R7 together with the intervening atom or atoms bound thereto, form a heterocyclic or a substituted heterocyclic group; or
if W is alk2-SO2N(R6)R7, then R6 and R7 together with the nitrogen atom bound thereto optionally form —N═C(OR9)2 wherein each R9 independently is an alkyl group; and
R7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester, and acyl;
provided that when X is hydrogen, ring A is not benzimidazolyl or indazolyl.

### Claim 2 (depends on 1)

The method of claim 1 which is carried out in vitro.

### Claim 3 (depends on 1)

The method of claim 1 which is carried out in vivo.

### Claim 4 (depends on 3)

The method of claim 3, wherein the compound is administered to a subject suffering from a T-cell mediated autoimmune disease.

### Claim 5 (depends on 4)

The method of claim 4 in which the compound is administered in combination with, or adjunctively to, a compound that inhibits Syk kinase with an IC50 in the range of at least 10 μM.

### Claim 6 (depends on 4)

The method of claim 4, wherein the subject is a transplant recipient suffering from or predisposed to an allograft transplant rejection.

### Claim 7 (depends on 6)

The method of claim 6, wherein the compound is administered to a tissue or an organ prior to transplanting the tissue or organ in the transplant recipient.

### Claim 8 (depends on 6)

The method of claim 6 in which the rejection is acute rejection.

### Claim 9 (depends on 6)

The method of claim 6 in which the rejection is chronic rejection.

### Claim 10 (depends on 6)

The method of claim 6 in which the rejection is mediated by HVGR or GVHR.

### Claim 11 (depends on 6)

The method of claim 6 in which the allograft transplant is selected from a kidney, a heart, a liver or a lung.

### Claim 12 (depends on 6)

The method of claim 6 in which the compound is administered in combination with, or adjunctively to, another immunosuppressant.

### Claim 13 (depends on 12)

The method of claim 12 in which the immunosuppressant is selected from cyclosporine, tacrolimus, sirolimus, an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil, an anti-T-Cell antibody or OKT3.

### Claim 14 (depends on 3)

The method of claim 3, wherein the compound is administered to a subject suffering from or predisposed to develop a Type IV hypersensitivity reaction.

### Claim 15 (depends on 14)

The method of claim 14 wherein the compound is administered prophylactically.

### Claim 16 (depends on 1)

The method of claim 1, wherein the method inhibits a signal transduction cascade in which JAK3 kinase plays a role.

### Claim 17 (depends on 4)

The method of claim 4, wherein the compound is selected from:
IV-5 N2-(3-Aminosulfonylmethylenephenyl)-5-fluoro-N4-[2-(2-N-morpholinoethylaminoacarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine;
IV-2 N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4methyl-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;
IV-3 N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine;
IV-4 N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-cyanomethylene-1H-indol-5-yl)-5-5-fluoro-2,4-pyrimidinediamine;
IV-1 N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;
III-3 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
V-1 N2-(4-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;
V-2 N2-(3-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;
V-3 N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;
V-4 N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-N2-[3,3-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;
V-5 N2-(3-Benzyl-cyclopropanesulfonamide-)-N4-(3,4-dihydroquinolin-1H-6-yl)-5-methyl-2,4-pyrimidinediamine; or
III-4 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-(prop-2-ynyloxy)phenyl)-5-fluoro-2,4-pyrimidinediamine.