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1. (WO2015177325) BENZENE SULFONAMIDE DERIVATIVES AND THEIR USE AS RORC MODULATORS
ملاحظة: نص مبني على عمليات التَعرف الضوئي على الحروف. الرجاء إستخدام صيغ PDF لقيمتها القانونية

CLAIMS

What is claimed is:

1. A compound of formula la or lb:


or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 or 1 ;

n is from 0 to 3;

p is 1 or 2;

q is from 1 to 3;

r is from 0 to 2;

A is: a bond; -CH2-; =CH-; -CH(OH)-; -C(O)-; -C(0)-NH-; -NH-(0)C-; -NRa-; -0-; - S-; or -S02-;

D is: -N- or -CR -;

E is: -N- or -CRh-;

G is: -N- or -CR'-;

one or two of X1, X2, X3 and X4 is N and the others are CRb; or three of X1, X2, X3 and X4 are N and the other is CRb; or each of X1, X2, X3 and X4 is CRb;

Y is: -0-; -S-; -S02-; -CRcRd-; or -NRe-;

Z is CRf or N;

R1, R2, R3 and R4 each independently is: hydrogen; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo;

or R3 and R4 togethjer with the atoms to which they are attached may form a ring of five to seven members which may be unsubstituted or substituted one or more timeswith Ci-6alkyl, and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S;

R5 is: Ci-6alkyl; C3_6cycloalkyl; C3_6cycloalkyl-Ci_6alkyl; Ci_6alkoxy-Ci_6alkyl; or hydroxy-Ci_6alkyl, wherein the Ci_6alkyl, C3_6cycloalkyl and C3_6cycloalkyl-Ci_6alkyl moities may be substituted one or more times with halo;

or R5 together with one of R3 and R4 and the atoms to which they are attached may form a ring of five to seven members which may be unsubstituted or substituted one or more timeswith Ci_6alkyl, and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S;

each R6 is independently: Ci-6alkyl; halo; Ci-6alkoxy; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo;

R is: hydrogen; Ci-6alkyl; hydroxy; or halo;

Q

R is: hydrogen; Ci_6alkyl; halo; hydroxy; or oxo;

7 8

or R and R together with the atoms to which they are attached may form a four, five, six or seven membered ring;

each R9 is independently: halo; hydroxy; Ci-6alkoxy; Ci_6alkylsulfonyl; amino; Ci_ 6alkyl-amino; di-Ci_6alkyl;-amino; cyano; or oxo;

Ra is: hydrogen; or Ci-6alkyl;

each Rb is independently: hydrogen; Ci-6alkyl; halo; Ci-6alkoxy; or cyano; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo;

Rc is: hydrogen; halo; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo;

Rd is: hydrogen; Ci_6alkyl; C3_6cycloalkyl; C3_6cycloalkyl-Ci_6alkyl; halo; Ci_6alkyl-carbonyl; C3_6cycloalkyl-carbonyl; C3_6cycloalkyl-Ci_6alkyl-carbonyl; Ci-6alkyl-sulfonyl; C3_6cycloalkyl-sulfonyl; C3_6cycloalkyl-Ci_6alkyl-sulfonyl; aminocarbonyl; N-Ci_6alkyl-aminocarbonyl; N,N-di-Ci_6alkyl-aminocarbonyl; aminosulfonyl; N-Ci_

6alkyl-aminosulfonyl; N,N-di-Ci_6alkyl-aminosulfonyl; cyano; Ci-6alkoxy; Ci-6alkyl- sulfonylamino; amino; N-Ci_6alkyl-amino; N,N-di-Ci_6alkyl-amino; halo-Ci_6alkyl; cyano-Ci_6alkyl-carbonyl; cyano-Ci_6alkyl-sulfonyl; hydroxy-Ci_6alkyl-carbonyl; Ci_ 6alkyoxy-carbonyl; carboxy; or hydroxyl; wherein the Ci-6alkyl moieties may be unsubstituted or substituted one or more times with halo; and wherein the C3_ 6cycloalkyl, and C3_6cycloalkyl-Ci_6alkyl moieties may be unsubstituted or substituted one or more times with R9;

or Rc and Rd together with the atoms to which they are attached may form a four, five, six or seven membered ring that optionally includes a hetereoatom selected from O, N and S;

Re is: hydrogen; Ci-6alkyl; C3_6cycloalkyl; C3_6cycloalkyl-Ci_6alkyl; Ci-6alkyl- carbonyl; C3_6cycloalkyl-carbonyl; C3_6cycloalkyl-Ci_6alkyl-carbonyl; Ci_6alkyl- sulfonyl; C3_6cycloalkyl-sulfonyl; C3_6cycloalkyl-Ci_6alkyl-sulfonyl; aminocarbonyl; N-Ci_6alkyl-aminocarbonyl; N,N-di-Ci_6alkyl-aminocarbonyl; aminosulfonyl; N-Ci_ 6alkyl-aminosulfonyl; cyano-Ci_6alkyl-carbonyl; cyano-Ci_6alkyl-sulfonyl; hydroxy- Ci_6alkyl-carbonyl; Ci_6alkyoxy-carbonyl; carboxy; or N,N-di-Ci_6alkyl- aminosulfonyl; wherein the Ci_6alkyl moieties may be unsubstituted or substituted one or more times with halo; and wherein the C3_6cycloalkyl, and C3_6cycloalkyl-Ci_ 6alkyl moieties may be unsubstituted or substituted one or more times with R9;

or Re and R7 together with the atoms to which they are attached may form a four, five, six or seven membered ring;

R is: hydrogen; hydroxyl; or Ci-6alkyl which may be unsubstituted or substituted one or more times with halo, or R is absent when A is =CH-;

R is: hydrogen; or Ci-6alkyl;

or R together with one of R3 and R4 and the atoms to which they are attached may form a ring of five to seven members which may be unsubstituted or substituted one or more times with Ci-6alkyl, and wherein the ring may be carbocyclic or one of the ring members may be replaced by a heteroatom selected from O, N and S;

Rh is: hydrogen; or Ci-6alkyl; and

R1 is: hydrogen; or Ci_6alkyl

wherein the compound is selected from:

4- (4-((3 -(4-chlorophenyl)pyrrolidin- 1 -yl)sulfonyl)phenoxy)- 1 -(methylsulfonyl)piperidine;

6-(4-(2-cyanoacetyl)piperazin-l-yl)-N-(4-fluorophenyl)-N-isobutylpyridine-3-sulfonamide;

(S)-N-(5-fluoropyridin-2-yl)-4-((l-(2-hydroxypropanoyl)piperidin-4-yl)oxy)-N-isobutylbenzenesulfonamide;

l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)indoline;

(R)-N-(5-fluoropyridin-2-yl)-N-isobutyl-6-((l-(2-methoxypropanoyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

l-(4-(N-(2-chlorophenyl)-N-isobutylsulfamoyl)phenyl)piperidine-4-carboxylic acid;

N-(5-(N-(4-fluorobenzyl)-N-isobutylsulfamoyl)pyridin-2-yl)-l- (methylsulfonyl)piperidine-4-carboxamide;

5- ((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo [b] [ 1 ,4] oxazepine;

4- (4-acetylpiperazin-l-yl)-N-(5-fluoropyridin-2-yl)-N-isobutylbenzenesulfonamide;

1- ((4-((l -(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l, 2,3,5-tetrahydrobenzo[e] [1 ,4] oxazepine;

N-(4-fluorophenyl)-N-isobutyl-6-(((l-(methylsulfonyl)azetidin-3-yl)methyl)amino)pyridine-3-sulfonamide;

(S)-N-(4-fluorophenyl)-6-(4-(2-hydroxypropanoyl)piperazin-l-yl)-N-isobutylpyridine-3-sulfonamide;

N-(4-fluorobenzyl)-N-isobutyl-2-((l-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-sulfonamide;

N-(4-fluorobenzyl)-N-isobutyl-2-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyrimidine- 5- sulfonamide;

N-((5-cyanopyridin-2-yl)methyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

N-((6-cyanopyridin-3-yl)methyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

2- ethyl-N-(4-fluorophenyl)-N-methyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

1- ((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l, 2,3,4-tetrahydroquinoline;

9-((4-((l -(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l ,2,3,4-tetrahydro- 1 ,4-epiminonaphthalene;

2- methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)indoline;

1- (5-(N-(4-fluorobenzyl)-N-isobutylsulfamoyl)pyrimidin-2-yl)piperidin-4-yl methanesulfonate;

N-(4-cyanopyridin-2-yl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

4-(4-acetylpiperazin-l-yl)-N-(4-fluorobenzyl)-N-isobutylbenzenesulfonamide;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(pyridin-3-ylmethyl)benzenesulfonamide;

N-benzyl-N-isobutyl-6-(4-(methylsulfonyl)piperazin-l-yl)pyridine-3-sulfonamide; 6-(4-acetylpiperazin-l-yl)-N-(4-fluorobenzyl)-N-isobutylpyridine-3-sulfonamide; N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(pyridin-4-ylmethyl)benzenesulfonamide;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)azetidin-3-yl)oxy)pyridine-3-sulfonamide;

3- methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l, 2,3,4-tetrahydroquinoline;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)azetidin-3-yl)amino)pyridine-3-sulfonamide;

N-(4-(N-(4-fluorobenzyl)-N-isobutylsulfamoyl)phenyl)-l-(methylsulfonyl)piperidine- 4- carboxamide;

N-(4-fluorobenzyl)-N-isobutyl-5-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine- 2- sulfonamide;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(pyridin-3-yl)benzenesulfonamide;

N-isobutyl-5-(4-(methylsulfonyl)piperazin-l-yl)-N-phenethylpyridine-2-sulfonamide;

N-(5-cyanopyridin-2-yl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

2- methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l, 2,3,4-tetrahydroquinoline;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine- 3- sulfonamide;

2- methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-l, 2,3,4-tetrahydroquinoline;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(pyridin-2-yl)benzenesulfonamide;

N-(4-fluorobenzyl)-N-isobutyl-5-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-2-sulfonamide;

N-isobutyl-6-(4-(methylsulfonyl)piperazin-l-yl)-N-phenethylpyridine-3-sulfonamide;

(S)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)-N-(2-phenylpropyl)benzenesulfonamide;

N-(4-fluorophenyl)-6-((3-hydroxy-l-(methylsulfonyl)piperidin-4-yl)amino)-N-isobutylpyridine-3-sulfonamide;

l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3,4,5-tetrahydro-lH-benzo[b]azepine;

N-(6-cyanopyridin-3-yl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-cyclobutyl-N-(4-fluorobenzyl)-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine- 3- sulfonamide;

N-(4-fluorobenzyl)-N-isobutyl-6-((4-(methylsulfonyl)piperazin-l-yl)methyl)pyridine- 3- sulfonamide;

N-(4-fluorophenethyl)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(pyridin-2-ylmethyl)benzenesulfonamide;

6-fluoro-2-methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-1 ,2,3,4-tetrahydroquinoline;

4- (4-acetylpiperazin-l-yl)-N-isobutyl-N-(2-(trifluoromethyl)benzyl)benzenesulfonamide;

N-(4-fluorophenyl)-N-isobutyl-5-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-2-sulfonamide;

N-(3-chlorophenyl)-N-isobutyl-5-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine- 2- sulfonamide;

N-cyclobutyl-N-(4-fluorobenzyl)-6-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine-3-sulfonamide;

N-(4-chlorophenethyl)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

N-(4-cyanopyridin-2-yl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine- 3- sulfonamide;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

N-(2-fluorophenethyl)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

5-methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3,4,5-tetrahydro- 1 H-benzo [b] azepine;

(S)-N-(l-(4-fluorophenyl)ethyl)-N-isobutyl-5-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-2-sulfonamide;

N-(3-fluorophenethyl)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

N-(2-fluorophenyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

3-benzyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)azepane;

N-benzyl-3-fluoro-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)benzenesulfonamide;

N-(4-chlorobenzyl)-5-((3-hydroxy-l-(methylsulfonyl)piperidin-4-yl)oxy)-N-isobutylpyridine-2-sulfonamide;

2-fluoro-N-isobutyl-4-(4-(methylsulfonyl)piperazin- 1 -yl)-N-phenethylbenzenesulfonamide;

3-fluoro-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)-N-phenethylbenzenesulfonamide;

(S)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)-N-(2-phenylpropyl)benzenesulfonamide;

N-cyclobutyl-N-(4-fluorobenzyl)-5-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine-2-sulfonamide;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)amino)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide;

3- methyl-l-((4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)sulfonyl)-2,3,4,5-tetrahydro- 1 H-benzo [b] azepine;

4- (4-acetylpiperazin-l-yl)-N-isobutyl-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide;

N-(5-fluoropyridin-2-yl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-isobutyl-4-(methoxy(l-(methylsulfonyl)piperidin-4-ylidene)methyl)-N-(2-(trifluoromethyl)phenyl)benzenesulfonamide;

N-(3-chlorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3-sulfonamide;

N-(2-cyanophenyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

4-((l-((cyanomethyl)sulfonyl)piperidin-4-yl)oxy)-N-(5-fluoropyridin-2-yl)-N-isobutylbenzenesulfonamide;

N-(4-cyanophenyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-(3-cyanophenyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)-N-(3-(trifluoromethyl)phenyl)benzenesulfonamide;

(R)-N-(l-(4-fluorophenyl)ethyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)benzenesulfonamide;

N-(4-chlorobenzyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4- yl)amino)benzenesulfonamide;

N-(4-fluorobenzyl)-N-isobutyl-4-((l-(methylsulfonyl)piperidin-4- yl)amino)benzenesulfonamide;

N-(4-fluorophenyl)-N-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)oxy)pyridine-3- sulfonamide;

N-isobutyl-4-(l-(methylsulfonyl)piperidine-4-carbonyl)-N-(2- (trifluoromethyl)phenyl)benzenesulfonamide;

N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)-N-(2- phenylpropyl)benzenesulfonamide;

N-isobutyl-4-(4-(methylsulfonyl)piperazin-l-yl)-N-phenethylbenzenesulfonamide; N-(4-chlorophenethyl)-N-isobutyl-4-(4-(methylsulfonyl)piperazin-l- yl)benzenesulfonamide; and

N-isobutyl-3-(4-(methylsulfonyl)piperazin-l-yl)-N-phenethylbenzenesulfonamide.

2. The compound of claim 1, wherein said compound is of formula X


wherein

s is: 0; or 1;

t is: 1; or 2;

J is: -CRjRk-; -NRm-; -0-; or -S-; and

R^; Rk and Rm each independently is: hydrogen; or Ci_6alkyl.

3. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound of claim 1 or 2.

4. A method for treating arthritis, said method comprising administering to a subject in need thereof an effective amount of a compound of claim 1 or 2.

5. A compound according to claim 1 or 2 for use as therapeutically active substance.

6. The use of a compound according to claim 1 or 2 for the treatment arthritis.

7. A compound according to claim 1 or 2 for the treatment arthritis.

8. The use of a compound according to claim 1 or 2 for the preparation of a medicament for the treatment arthritis.

9. The invention as hereinbefore described.

I l l