HK1233620A1

HK1233620A1 - Benzene sulfonamide derivatives and their use as rorc modulators

Info

Publication number: HK1233620A1
Application number: HK17107147.8A
Authority: HK
Inventors: Monique Bodil Van Niel; Benjamin Fauber; Simon Gaines; Jonathan KILLEN; Stuart Ward
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2014-05-23
Filing date: 2015-05-22
Publication date: 2018-02-02

Description

Benzenesulfonamide derivatives and their use as RORC modulators

Technical Field

The present invention relates to compounds that modulate the function of the retinoid receptor-related orphan receptor (rory) and the use of such compounds for the treatment of autoimmune diseases.

Background

T helper cells 17(T helper cells 17) (Th17) are Interleukin (IL) -17 secreting CD4+ T cells involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthritis (spondyloarthritides). Retinoic acid-related orphan receptor gamma (ROR γ or RORc) is recognized as a transcription factor essential for Th17 cell differentiation. RORc is an orphan member of the nuclear hormone receptor subfamily, which includes ROR α (RORa) and ROR β (RORb). RORc controls gene transcription through DNA binding in monomeric form. Selective modulation of RORc has been considered a route to the discovery and development of Th17 cell-associated autoimmune diseases.

Therefore, there is a need for compounds that inhibit RORc for use in the treatment of autoimmune diseases such as rheumatoid arthritis, irritable bowel disease, psoriasis, psoriatic arthritis and spondyloarthritis.

Summary of The Invention

The present invention provides compounds of formula Ia or Ib:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 or 1;

n is 0 to 3;

p is 1 or 2;

q is 1 to 3;

r is 0 to 2;

a is: a bond; -CH₂-；＝CH-；-CH(OH)-；-C(O)-；-C(O)-NH-；-NH-(O)C-；-NR^a-; -O-; -S-; or-SO₂-；

D is: -N-or-CR^g-；

E is: -N-or-CR^h-；

G is: -N-or-CRⁱ-；

X¹、X²、X³And X⁴One or two of which are N, the remainder being CR^b(ii) a Or X¹、X²、X³And X⁴Three of which are N and the other is CR^b(ii) a Or X¹、X²、X³And X⁴Each is CR^b；

Y is: -O-; -S-; -SO₂-；-CR^cR^d-; or-NR^e-；

Z is CR^fOr N;

R¹、R²、R³and R⁴Each independently is: hydrogen; or C_1-6Alkyl, which may be unsubstituted or substituted one or more times by halogen;

or R³And R⁴Together with the atoms to which they are attached may form a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl substituted one or more times and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S;

R⁵the method comprises the following steps: c_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_1-6alkoxy-C_1-6An alkyl group; or hydroxy-C_1-6Alkyl radical, wherein C_1-6Alkyl radical, C_3-6Cycloalkyl and C_3-6cycloalkyl-C_1-6The alkyl radical may be substituted one or more times by halogen;

or R⁵And R³And R⁴One of which, together with the atoms to which they are attached, may form a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl substituted one or more times and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S;

R⁶each independently is: c_1-6An alkyl group; halogen; c_1-6An alkoxy group; or cyano; wherein C is_1-6The alkyl radical may be unsubstituted or substituted one or more times by halogen;

R⁷the method comprises the following steps: hydrogen; c_1-6An alkyl group; a hydroxyl group; or halogen;

R⁸the method comprises the following steps: hydrogen; c_1-6An alkyl group; halogen; a hydroxyl group; or oxo;

or R⁷And R⁸Together with the atoms to which they are attached may form a 4,5, 6 or 7 membered ring;

R⁹each independently is: halogen; a hydroxyl group; c_1-6An alkoxy group; c_1-6Alkyl radicalA sulfonyl group; an amino group; c_1-6An alkyl-amino group; di-C_1-6An alkyl group; -an amino group; a cyano group; or oxo;

R^athe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R^beach independently is: hydrogen; c_1-6An alkyl group; halogen; c_1-6An alkoxy group; or cyano; wherein C is_1-6The alkyl radical may be unsubstituted or substituted one or more times by halogen;

R^cthe method comprises the following steps: hydrogen; halogen; or C_1-6Alkyl, which may be unsubstituted or substituted one or more times by halogen;

R^dthe method comprises the following steps: hydrogen; c_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; halogen; c_1-6Alkyl-carbonyl; c_3-6Cycloalkyl-carbonyl; c_3-6cycloalkyl-C_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6Cycloalkyl-sulfonyl; c_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group; an aminocarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; n, N-di-C_1-6Alkyl-aminosulfonyl; a cyano group; c_1-6An alkoxy group; c_1-6Alkyl-sulfonylamino; an amino group; N-C_1-6An alkyl-amino group; n, N-di-C_1-6An alkyl-amino group; halogen-C_1-6An alkyl group; cyano-C_1-6Alkyl-carbonyl; cyano-C_1-6An alkyl-sulfonyl group; hydroxy-C_1-6Alkyl-carbonyl; c_1-6Alkoxy-carbonyl; a carboxyl group; or a hydroxyl group; wherein C is_1-6The alkyl radical may be unsubstituted or substituted one or more times by halogen; and wherein C_3-6Cycloalkyl and C_3-6cycloalkyl-C_1-6The alkyl radical may be unsubstituted or substituted by R⁹One or more substitutions;

or R^cAnd R^dTo the atom to which they are attachedMay form a 4,5, 6 or 7 membered ring optionally containing a heteroatom selected from O, N and S;

R^ethe method comprises the following steps: hydrogen; c_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; c_1-6Alkyl-carbonyl; c_3-6Cycloalkyl-carbonyl; c_3-6cycloalkyl-C_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6Cycloalkyl-sulfonyl; c_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group; an aminocarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; cyano-C_1-6Alkyl-carbonyl; cyano-C_1-6An alkyl-sulfonyl group; hydroxy-C_1-6Alkyl-carbonyl; c_1-6Alkoxy-carbonyl; a carboxyl group; or N, N-di-C_1-6Alkyl-aminosulfonyl; wherein C is_1-6The alkyl radical may be unsubstituted or substituted one or more times by halogen; and wherein C_3-6Cycloalkyl and C_3-6cycloalkyl-C_1-6The alkyl radical may be unsubstituted or substituted by R⁹One or more substitutions;

or R^eAnd R⁷Together with the atoms to which they are attached may form a 4,5, 6 or 7 membered ring;

R^fthe method comprises the following steps: hydrogen; a hydroxyl group; or C_1-6Alkyl, which may be unsubstituted or substituted one or more times by halogen, or when a is ═ CH-, R^fIs absent;

R^gthe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

or R^gAnd R³And R⁴One of which, together with the atoms to which they are attached, may form a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl substituted one or more times, and wherein the ring may be carbocyclic or wherein one of the ring members may be replaced by a heteroatom selected from O, N and S;

R^hthe method comprises the following steps: hydrogen; or C_1-6An alkyl group; and is

RⁱThe method comprises the following steps: hydrogen; or C_1-6An alkyl group, a carboxyl group,

wherein the compound is selected from:

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

6- (4- (2-cyanoacetyl) piperazin-1-yl) -N- (4-fluorophenyl) -N-isobutylpyridine-3-sulfonamide;

(S) -N- (5-fluoropyridin-2-yl) -4- ((1- (2-hydroxypropionyl) piperidin-4-yl) oxy) -N-isobutylbenzenesulfonamide;

1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) indoline;

(R) -N- (5-fluoropyridin-2-yl) -N-isobutyl-6- ((1- (2-methoxypropionyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

1- (4- (N- (2-chlorophenyl) -N-isobutylsulfamoyl) phenyl) piperidine-4-carboxylic acid;

n- (5- (N- (4-fluorobenzyl) -N-isobutylsulfamoyl) pyridin-2-yl) -1- (methylsulfonyl) piperidine-4-carboxamide;

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

4- (4-acetylpiperazin-1-yl) -N- (5-fluoropyridin-2-yl) -N-isobutylbenzenesulfonamide;

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

N- (4-fluorophenyl) -N-isobutyl-6- (((1- (methylsulfonyl) azetidin-3-yl) methyl) amino) pyridine-3-sulfonamide;

(S) -N- (4-fluorophenyl) -6- (4- (2-hydroxypropionyl) piperazin-1-yl) -N-isobutylpyridine-3-sulfonamide;

n- (4-fluorobenzyl) -N-isobutyl-2- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyrimidine-5-sulfonamide;

n- (4-fluorobenzyl) -N-isobutyl-2- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyrimidine-5-sulfonamide;

n- ((5-cyanopyridin-2-yl) methyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

n- ((6-cyanopyridin-3-yl) methyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

2-ethyl-N- (4-fluorophenyl) -N-methyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

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

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

2-methyl-1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) indoline;

methanesulfonic acid 1- (5- (N- (4-fluorobenzyl) -N-isobutylsulfamoyl) pyrimidin-2-yl) piperidin-4-yl ester;

n- (4-cyanopyridin-2-yl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

4- (4-acetylpiperazin-1-yl) -N- (4-fluorobenzyl) -N-isobutylbenzenesulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (pyridin-3-ylmethyl) benzenesulfonamide;

N-benzyl-N-isobutyl-6- (4- (methylsulfonyl) piperazin-1-yl) pyridine-3-sulfonamide;

6- (4-acetylpiperazin-1-yl) -N- (4-fluorobenzyl) -N-isobutylpyridine-3-sulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (pyridin-4-ylmethyl) benzenesulfonamide;

n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) azetidin-3-yl) oxy) pyridine-3-sulfonamide;

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

n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) azetidin-3-yl) amino) pyridine-3-sulfonamide;

n- (4- (N- (4-fluorobenzyl) -N-isobutylsulfamoyl) phenyl) -1- (methylsulfonyl) piperidine-4-carboxamide;

n- (4-fluorobenzyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine-2-sulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (pyridin-3-yl) benzenesulfonamide;

n-isobutyl-5- (4- (methylsulfonyl) piperazin-1-yl) -N-phenethylpyridine-2-sulfonamide;

n- (5-cyanopyridin-2-yl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

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

n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine-3-sulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (pyridin-2-yl) benzenesulfonamide;

n- (4-fluorobenzyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-2-sulfonamide;

n-isobutyl-6- (4- (methylsulfonyl) piperazin-1-yl) -N-phenethylpyridine-3-sulfonamide;

(S) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) -N- (2-phenylpropyl) benzenesulfonamide;

n- (4-fluorophenyl) -6- ((3-hydroxy-1- (methylsulfonyl) piperidin-4-yl) amino) -N-isobutylpyridine-3-sulfonamide;

1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) -2,3,4, 5-tetrahydro-1H-benzo [ b]Aza derivatives

N- (6-cyanopyridin-3-yl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

N-cyclobutyl-N- (4-fluorobenzyl) -6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

n- (4-fluorobenzyl) -N-isobutyl-6- ((4- (methylsulfonyl) piperazin-1-yl) methyl) pyridine-3-sulfonamide;

n- (4-fluorophenethyl) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (pyridin-2-ylmethyl) benzenesulfonamide;

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

4- (4-acetylpiperazin-1-yl) -N-isobutyl-N- (2- (trifluoromethyl) benzyl) benzenesulfonamide;

n- (4-fluorophenyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-2-sulfonamide;

n- (3-chlorophenyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine-2-sulfonamide;

N-cyclobutyl-N- (4-fluorobenzyl) -6- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine-3-sulfonamide;

n- (4-chlorophenethyl) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

n- (4-cyanopyridin-2-yl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

n- (2-fluorophenethyl) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

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

(S) -N- (1- (4-fluorophenyl) ethyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-2-sulfonamide;

n- (3-fluorophenethyl) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

n- (2-fluorophenyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

3-benzyl-1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) azepane;

N-benzyl-3-fluoro-N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide;

n- (4-chlorobenzyl) -5- ((3-hydroxy-1- (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-1-yl) -N-phenethylbenzenesulfonamide;

N-cyclobutyl-N- (4-fluorobenzyl) -5- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine-2-sulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) amino) -N- (2- (trifluoromethyl) phenyl) benzenesulfonamide;

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

4- (4-acetylpiperazin-1-yl) -N-isobutyl-N- (2- (trifluoromethyl) phenyl) benzenesulfonamide;

n- (5-fluoropyridin-2-yl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

n-isobutyl-4- (methoxy (1- (methylsulfonyl) piperidin-4-ylidene) methyl) -N- (2- (trifluoromethyl) phenyl) benzenesulfonamide;

n- (3-chlorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine-3-sulfonamide;

n- (2-cyanophenyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

4- ((1- ((cyanomethyl) sulfonyl) piperidin-4-yl) oxy) -N- (5-fluoropyridin-2-yl) -N-isobutylbenzenesulfonamide;

n- (4-cyanophenyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

n- (3-cyanophenyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

n-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) -N- (3- (trifluoromethyl) phenyl) benzenesulfonamide;

(R) -N- (1- (4-fluorophenyl) ethyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) benzenesulfonamide;

n- (4-chlorobenzyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) amino) benzenesulfonamide;

n- (4-fluorobenzyl) -N-isobutyl-4- ((1- (methylsulfonyl) piperidin-4-yl) amino) benzenesulfonamide;

n-isobutyl-4- (1- (methylsulfonyl) piperidine-4-carbonyl) -N- (2- (trifluoromethyl) phenyl) benzenesulfonamide;

n-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) -N- (2-phenylpropyl) benzenesulfonamide;

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

n- (4-chlorophenethyl) -N-isobutyl-4- (4- (methylsulfonyl) piperazin-1-yl) benzenesulfonamide; and

n-isobutyl-3- (4- (methylsulfonyl) piperazin-1-yl) -N-phenethylbenzenesulfonamide.

The invention also provides pharmaceutical compositions comprising the compounds, methods of using the compounds, and methods of making the compounds.

Detailed Description

Definition of

Unless otherwise indicated, the following terms used in the present application (including the specification and claims) have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

"alkyl" means a monovalent straight or branched chain saturated hydrocarbon radical consisting only of carbon and hydrogen atoms, having from 1 to 12 carbon atoms. "lower alkyl" refers to alkyl of 1-6 carbon atoms, i.e., C₁-C₆An alkyl group. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.

"alkenyl" means a straight chain monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one double bond, such as vinyl, propenyl, and the like.

"alkynyl" means a straight chain monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched monovalent hydrocarbon group of 3 to 6 carbon atoms containing at least one triple bond, such as ethynyl, propynyl, and the like.

"alkylene" means a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms, such as methylene, ethylene, 2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, and the like.

"alkoxy" and "alkyloxy" are used interchangeably and mean a group of the formula-OR, wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.

"alkoxyalkyl group"Means formula R^a–O–R^bA group of (a) wherein R^aIs alkyl, R^bIs alkylene as defined herein. Exemplary alkoxyalkyl groups include, for example, 2-methoxyethyl, 3-methoxypropyl, 1-methyl-2-methoxyethyl, 1- (2-methoxyethyl) -3-methoxypropyl, and 1- (2-methoxyethyl) -3-methoxypropyl.

"Alkoxyalkoxy" means a group of the formula-O-R-R ', where R is alkylene and R' is alkoxy as defined herein.

"alkylcarbonyl" means a group of formula-c (o) -R, wherein R is alkyl as defined herein.

"alkoxycarbonyl" means a group of the formula-C (O) -R, wherein R is alkoxy as defined herein.

"Alkylcarbonylalkyl" means a group of the formula-R-C (O) -R, wherein R is alkylene and R' is alkyl as defined herein.

"Alkoxycarbonylalkyl" means a group of the formula-R-C (O) -R, wherein R is alkylene and R' is alkoxy as defined herein.

"Alkoxycarbonylalkoxy" means a group of the formula-O-R-C (O) -R ', wherein R is alkylene and R' is alkoxy as defined herein.

"Hydroxycarbonylalkoxy" means a group of the formula-O-R-C (O) -OH, wherein R is alkylene as defined herein.

"Alkylaminocarbonylalkoxy" means a group of the formula-O-R-C (O) -NHR ', wherein R is alkylene and R' is alkyl as defined herein.

"Dialkylaminocarbonylalkoxy" means a group of the formula-O-R-C (O) -NR 'R "wherein R is alkylene and R' and R" are alkyl as defined herein.

"alkylaminoalkoxy" means a group of the formula-O-R-NHR ', wherein R is alkylene and R' is alkyl as defined herein.

"Dialkylaminoalkoxy" means a group of the formula-O-R-NR ' R ', wherein R is an alkylene and R ' and R "are alkyl groups as defined herein.

"alkylsulfonyl" means a radical of the formula-SO₂-R, wherein R is an alkyl group as defined herein.

"Alkylsulfonylalkyl" means a compound of the formula-R' -SO₂A radical of formula-R "wherein R' is alkylene and R" is alkyl as defined herein

"Alkylsulfonylalkoxy" means a compound of the formula-O-R-SO₂A radical of formula-R ', wherein R is alkylene and R' is alkyl as defined herein.

"amino" means a group of formula-NRR ', where R and R' are each independently hydrogen or alkyl as defined herein. Thus, "amino" includes "alkylamino" (where one of R and R 'is alkyl and the other is hydrogen) and "dialkylamino" (where both R and R' are alkyl).

"aminocarbonyl" means a group of formula-C (O) -R, wherein R is amino as defined herein.

"Alkoxyamino" means a group of the formula-NR-OR 'where R is hydrogen OR alkyl and R' is alkyl as defined herein.

"alkylthio" means a group of formula-SR, wherein R is alkyl as defined herein.

"aminoalkyl" means a radical-R-R ', wherein R' is amino and R is alkylene as defined herein.

"aminoalkyl" includes aminomethyl, aminoethyl, 1-aminopropyl, 2-aminopropyl and the like. The amino moiety of "aminoalkyl" may be substituted once or twice with alkyl to provide "alkylaminoalkyl" and "dialkylaminoalkyl", respectively. "alkylaminoalkyl" includes methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl, and the like. "dialkylaminoalkyl" includes dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N-ethylaminoethyl, and the like.

"Aminoalkoxy" means a group-OR-R ', where R' is amino and R is alkylene as defined herein.

"Alkylsulfonylamido" means a compound of the formula-NR' SO₂-R, wherein R is alkyl and R' is hydrogen or alkyl.

"Aminocarbonyloxyalkyl" or "carbamoylalkyl" means a group of the formula-R-O-C (O) -NR 'R ", wherein R is alkylene and R', R" are each independently hydrogen or alkyl as defined herein.

"Alkynylalkoxy" means a group of the formula-O-R-R ', wherein R is alkylene and R' is alkynyl as defined herein.

"aryl" means a monovalent cyclic aromatic hydrocarbon group consisting of a monocyclic, bicyclic, or tricyclic aromatic ring. The aryl group may be optionally substituted as defined herein. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylenediphenyl, aminodiphenyl, diphenylthio, diphenylsulfonyl, diphenylisopropylidene, benzodiazepineAlkyl, benzofuranyl, benzodiAlkenyl (benzodioxylyl), benzopyranyl, benzoAzinyl radicals, benzoOxazinonyl, benzopiperidinyl, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like, which may be optionally substituted as defined herein.

"arylalkyl" and "aralkyl" are used interchangeably to mean the group-R^aR^bWherein R is^aIs alkylene, R^bIs aryl as defined herein; for example, phenylalkyl groups such as benzyl, phenethyl, 3- (3-chlorophenyl) -2-methylpentyl and the like are examples of arylalkyl groups.

"arylsulfonyl" means a compound of the formula-SO₂-R, wherein R is aryl as defined herein.

"aryloxy" means a group of formula-O-R, wherein R is aryl as defined herein.

"aralkyloxy" means a group of the formula-O-R-R "wherein R is alkylene and R' is aryl as defined herein.

"carboxy" or "hydroxycarbonyl" are used interchangeably and refer to a group of the formula-C (O) -OH.

"cyanoalkyl" means a group of the formula-R '-R', wherein R 'is alkylene as defined herein, and R' is cyano or nitrile.

"cycloalkyl" means a monovalent saturated carbocyclic group consisting of a single ring or two rings. Particular cycloalkyl groups are unsubstituted or substituted with alkyl. Cycloalkyl groups may be optionally substituted as defined herein. Unless otherwise specified, cycloalkyl groups may be optionally substituted with one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halogen, haloalkyl, amino, monoalkylamino, or dialkylamino. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like, including partially unsaturated (cycloalkenyl) derivatives thereof.

And R "is cycloalkyl as defined herein.

"cycloalkylalkoxy" means a group of the formula-O-R-R ', wherein R is alkylene and R' is cycloalkyl as defined herein.

"heteroaryl" means a monocyclic or bicyclic group of 5 to 12 ring atoms having at least one aromatic ring containing 1,2 or 3 ring heteroatoms selected from N, O or S, the remaining ring atoms being C. "cycloalkylalkyl" means a group of the formula-R ' -R ', where R ' is alkylene. It is understood that the point of attachment of the heteroaryl group is on the aromatic ring. The heteroaryl ring may be optionally substituted as defined herein. Examples of heteroaryl groups include, but are not limited to, optionally substituted imidazolyl,Azolyl radical, isoOxazolyl, thiazolyl, isothiazolyl,Oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thienyl, furyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, benzothienyl, benzothiopyranyl, benzimidazolyl, benzofuranyl, benzothienyl, and the likeAzolyl, benzoOxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azaazanylRadical diazaAn alkyl, an acridinyl, and the like, each of which may be optionally substituted as defined herein.

"heteroarylalkyl" or "heteroaralkyl" means a group of the formula-R-R ', wherein R is alkylene and R' is heteroaryl as defined herein.

"Heteroarylsulfonyl" means a compound of the formula-SO₂-R, wherein R is heteroaryl as defined herein.

"heteroaryloxy" means a group of the formula-O-R, wherein R is heteroaryl as defined herein.

"Heteroaralkyloxy" means a group of the formula-O-R-R "wherein R is alkylene and R' is heteroaryl as defined herein.

The terms "halo", "halogen" and "halide" are used interchangeably to refer to the substituents fluorine, chlorine, bromine or iodine.

"haloalkyl" means an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. Exemplary haloalkyl groups include-CH₂Cl、–CH₂CF₃、–CH₂CCl₃Perfluoroalkyl (e.g., -CF)₃) And the like.

"haloalkoxy" means a group of the formula-OR, wherein R is haloalkyl as defined herein. An exemplary haloalkoxy group is difluoromethoxy.

"Heterocyclylamino" means a saturated ring in which at least one ring atom is N, NH or N-alkyl, the remaining ring atoms forming an alkylene group.

"heterocyclyl" means a monovalent saturated group consisting of 1 to 3 rings incorporating 1,2 or 3 or 4 heteroatoms selected from nitrogen, oxygen or sulfur. The heterocyclyl ring may be optionally substituted as defined herein. Examples of heterocyclyl groups include, but are not limited to, optionally substituted piperidinyl, piperazinyl, morpholineMesityl, thiomorpholinyl, azaAlkyl, pyrrolidinyl, azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl and the like. Such heterocyclyl groups may be optionally substituted as defined herein.

"Heterocyclylalkyl" means a group of the formula-R-R ', where R is alkylene and R' is heterocyclyl as defined herein.

"Heterocyclyloxy" means a group of formula-OR, wherein R is heterocyclyl as defined herein.

"Heterocyclylalkoxy" means a group of the formula-OR-R 'where R is alkylene and R' is heterocyclyl as defined herein.

"Hydroxyalkoxy" means a group of the formula-OR, wherein R is hydroxyalkyl as defined herein.

"Hydroxyalkylamino" means a group of the formula-NR-R ', wherein R is hydrogen or alkyl and R' is hydroxyalkyl as defined herein.

"Hydroxyalkylaminoalkyl" means a radical of the formula-R-NR '-R ", wherein R is alkylene, R' is hydrogen or alkyl, and R" is hydroxyalkyl as defined herein.

"Hydroxycarbonylalkyl" or "carboxyalkyl" means a group of the formula-R- (CO) -OH, wherein R is alkylene as defined herein.

"Hydroxyalkyloxycarbonylalkyl" or "hydroxyalkoxycarbonylalkyl" means a group of the formula-R-C (O) -O-R-OH, wherein each R is alkylene, which may be the same or different.

"hydroxyalkyl" means an alkyl group as defined herein substituted with one or more, e.g., 1,2, or 3, hydroxyl groups, provided that the same carbon atom does not carry more than one hydroxyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1- (hydroxymethyl) -2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2, 3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2, 3-dihydroxybutyl, 3, 4-dihydroxybutyl and 2- (hydroxymethyl) -3-hydroxypropyl.

"Hydroxycycloalkyl" means a cycloalkyl group, as defined herein, wherein 1,2 or 3 of the hydrogen atoms in the cycloalkyl group have been replaced by a hydroxy substituent. Representative examples include, but are not limited to, 2-, 3-, or 4-hydroxycyclohexyl and the like.

"oxo" means a group of formula ═ O (i.e., oxygen having a double bond). Thus, for example, 1-oxo-ethyl is acetyl.

"alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" are used interchangeably to mean an alkyl group, as defined herein, substituted at least once with a hydroxy group and at least once with an alkoxy group. Thus, "alkoxyhydroxyalkyl" and "hydroxyalkoxyalkyl" include, for example, 2-hydroxy-3-methoxy-propan-1-yl and the like.

"urea" or "ureido" means a group of the formula-NR '-C (O) -NR "R'", wherein R ', R "and R'" are each independently hydrogen or alkyl.

"carbamate" means a group of the formula-O-C (O) -NR 'R "wherein R' and R" are each independently hydrogen or alkyl.

"carboxy" means a group of the formula-O-C (O) -OH.

"sulfonamido" means a compound of the formula-SO₂-NR ' R ", wherein R ', R" and R ' "are each independently hydrogen or alkyl.

"optionally substituted" or "optionally substituted with … …" when used in conjunction with "aryl", "phenyl", "heteroaryl", "cycloalkyl" or "heterocyclyl" means that the group may be unsubstituted (i.e., all open valences are occupied by hydrogen atoms) or substituted with specific groups as described herein.

By "leaving group" is meant a group having the meaning normally associated therewith in synthetic organic chemistry, i.e., an atom or group displaceable under substitution reaction conditions. Examples of leaving groups include, but are not limited to, halogen, alkylene-or arylene-sulfonyloxy groups such as methanesulfonyloxy, ethanesulfonyloxy, methylthio, benzenesulfonyloxy, toluenesulfonyloxy, and thienyloxy groups, dihalophosphonooxy groups, optionally substituted benzyloxy, isopropoxy, acyloxy groups and the like.

By "modulator" is meant a molecule that interacts with a target. Such interactions include, but are not limited to, agonists, antagonists, and the like, as defined herein.

"optional," "optionally," or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

"disease" and "disease condition" mean any disease, disorder, symptom, disorder, or sign.

"inert organic solvent" or "inert solvent" means a solvent inert under the reaction conditions in question in connection therewith and includes, for example, benzene, toluene, acetonitrile, tetrahydrofuran, N-dimethylformamide, chloroform, methylene chloride or dichloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, di-butanolAlkanes, pyridines, and the like. Unless stated to the contrary, the solvent used in the reaction of the present invention is an inert solvent.

By "pharmaceutically acceptable" is meant that it can be used in the preparation of pharmaceutical compositions that are generally safe, non-toxic, biologically or otherwise undesirable, including acceptable for veterinary as well as human pharmaceutical use.

By "pharmaceutically acceptable salt" of a compound is meant a pharmaceutically acceptable salt, as defined herein, which possesses the desired pharmacological activity of the parent compound.

It is to be understood that all references to pharmaceutically acceptable salts include the solvate addition forms (solvates) or crystalline forms (polymorphs) as defined herein of the same acid addition salt.

"protecting group" or "protecting group" means a group that selectively blocks one reactive site of a multifunctional compound so that a chemical reaction can proceed at another unprotected reactive site, which has the conventional meaning associated therewith in the art of synthetic chemistry. Certain methods of the invention rely on blocking reactive nitrogen and/or oxygen atoms present in the reactants with a protecting group. For example, the terms "amino-protecting group" and "nitrogen-protecting group" are used interchangeably herein to refer to those organic groups that are used to protect a nitrogen atom from undesirable reactions during synthetic manipulations. Examples of nitrogen protecting groups include, but are not limited to, trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbonylbenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-Butoxycarbonyl (BOC), and the like. The person skilled in the art knows how to select groups which are easy to remove and which are resistant to subsequent reactions.

"solvate" means a solvent addition form containing a stoichiometric or non-stoichiometric amount of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thereby forming solvates. If the solvent is water, the solvate formed is a hydrate, and when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by one or more molecules of water and water in the water to keep the molecular state H of the water₂O, said combination being capable of forming one or more hydrates.

"arthritis" means a disease or condition that causes damage to a joint of the body and the pain associated with the damage to the joint. Arthritis includes rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis and other arthritic conditions.

By "respiratory disease" is meant, but not limited to, Chronic Obstructive Pulmonary Disease (COPD), asthma, bronchospasm, and the like.

"gastrointestinal disorder" ("GI disorder") refers to Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrheic irritable bowel syndrome (diarrhea-dominant IBS), pain associated with GI distention (distension), and the like, but is not limited thereto.

"pain" includes, but is not limited to, inflammatory pain; pain from the operation; visceral pain; toothache; premenstrual pain; central pain; pain due to burn; migraine or cluster headache; nerve damage; neuritis; neuralgia; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infections; post-traumatic injury; or pain associated with irritable bowel syndrome.

By "individual" is meant both mammals and non-mammals. Mammalian means any member of the mammalian class, including but not limited to humans; non-human primates, such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and pigs; domestic animals such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs; and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term "individual" does not denote a particular age or gender.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject to treat a disease state, is sufficient to effect treatment of the disease state. The "therapeutically effective amount" will vary depending upon the compound, the disease state being treated, the severity of the disease being treated, the age and relative health of the individual, the route and form of administration, the judgment of the attending physician or veterinary practitioner, and other factors.

When referring to a variable, the terms "those defined above" and "those defined herein" are meant to encompass the broad definition of the variable as well as the specific definition (if any) of that variable.

"treating" a disease state or "treatment" of a disease state includes, inter alia, inhibiting the disease state (i.e., arresting the development of the disease state or its clinical symptoms) and/or alleviating the disease state (i.e., causing temporary or permanent regression of the disease state or its clinical symptoms).

The terms "treating", "contacting", and "reacting" when referring to a chemical reaction mean adding or mixing two or more reactants under suitable conditions to produce a given and/or desired product. It will be appreciated that the reaction that produces a given and/or desired product need not be directly obtained from the combination of the two reagents initially charged, i.e., one or more intermediates produced in the mixture that ultimately results in the formation of the given and/or desired product may be present.

Naming and Structure

In general, nomenclature and chemical names used in this application are according to chembioof^TMBy Cambridge Soft^TMAnd (4) obtaining the product. Unless otherwise indicated, any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. When the nitrogen-containing heteroaryl ring is shown as having an open valence at the nitrogen atom and the heteroaryl ring is shown with a variable such as R^a、R^bOr R^cWhen such variables are bound or linked to the nitrogen of the open valency. When a chiral center is present in a structure but no specific stereochemistry is given for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. When a structure shown herein can exist in multiple tautomeric forms, the structure encompasses all such tautomers. Book (I)The atoms shown in the structures herein are intended to encompass all naturally occurring isotopes of that atom. Thus, for example, hydrogen atoms shown herein include deuterium and tritium, and carbon atoms include C¹³And C¹⁴An isotope. One or more of the carbon atoms of the compounds of the present invention may be replaced by silicon atoms, it being understood that one or more of the oxygen atoms of the compounds of the present invention may be replaced by sulfur or selenium atoms.

Compounds of the invention

The present invention provides compounds of formula Ia or Ib:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 or 1;

n is 0 to 3;

p is 1 or 2;

q is 1 to 3;

r is 0 to 2;

D is: -N-or-CR^g-；

E is: -N-or-CR^h-；

G is: -N-or-CRⁱ-；

X¹、X²、X³And X⁴One or more ofTwo are N and the remainder are CR^b(ii) a Or X¹、X²、X³And X⁴Three of which are N and the other is CR^b(ii) a Or X¹、X²、X³And X⁴Each is CR^b；

Y is: -O-; -S-; -SO₂-；-CR^cR^d-; or-NR^e-；

Z is CR^fOr N;

R⁹each independently is: halogen; a hydroxyl group; c_1-6An alkoxy group; c_1-6An alkylsulfonyl group; an amino group; c_1-6An alkyl-amino group; di-C_1-6An alkyl group; -an amino group; a cyano group; or oxo;

R^athe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

or R^cAnd R^dTogether with the atoms to which they are attached may form a 4,5, 6 or 7 membered ring optionally containing a heteroatom selected from O, N and S;

R^fthe method comprises the following steps: hydrogen; a hydroxyl group; or C_1-6Alkyl, which may be unsubstituted or substituted one or more times by halogen, orWhen A is ═ CH-, R^fIs absent;

R^gthe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

wherein the compound is selected from:

1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) indoline;

4- (4-acetylpiperazin-1-yl) -N- (4-fluorobenzyl) -N-isobutylbenzenesulfonamide;

In certain embodiments, the compounds of the present invention are compounds of formula Ia.

In certain embodiments, the compounds of the present invention are of formula Ib.

In certain embodiments of formula Ia or Ib, when a is ═ CH-, -NR^awhen-O-or-S-is present, Z is CR^f。

In certain embodiments of formula Ia or Ib, when a is ═ CH-, R^fIs absent.

In certain embodiments of formula Ia or Ib, m is 0.

In certain embodiments of formula Ia or Ib, m is 1.

In certain embodiments of formula Ia or Ib, n is 0.

In certain embodiments of formula Ia or Ib, n is 1.

In certain embodiments of formula Ia or Ib, n is 2.

In certain embodiments of formula Ia or Ib, n is 3.

In certain embodiments of formula Ia or Ib, p is 1.

In certain embodiments of formula Ia or Ib, p is 2.

In certain embodiments of formula Ia or Ib, q is 1 or 2.

In certain embodiments of formula Ia or Ib, q is 2 or 3.

In certain embodiments of formula Ia or Ib, q is 1.

In certain embodiments of formula Ia or Ib, q is 2.

In certain embodiments of formula Ia or Ib, q is 3.

In certain embodiments of formula Ia or Ib, r is 0 to 2.

In certain embodiments of formula Ia or Ib, r is 0 or 1.

In certain embodiments of formula Ia or Ib, r is 0.

In certain embodiments of formula Ia or Ib, r is 1.

In certain embodiments of formula Ia or Ib, r is 2.

In certain embodiments of formula Ia or Ib, a is a bond; -CH₂-；-C(O)-、-NR^a-; -O-; -S-; or-SO₂-。

In certain embodiments of formula Ia or Ib, a is a bond; -NR^a-; -O-; -S-; or-SO₂-。

In certain embodiments of formula Ia or Ib, a is a bond; -NR^a-; or-O-.

In certain embodiments of formula Ia or Ib, a is a bond.

In certain embodiments of formula Ia or Ib, A is-CH₂-。

In certain embodiments of formula Ia or Ib, a is ═ CH-.

In certain embodiments of formula Ia or Ib, A is-C (O) -.

In certain embodiments of formula Ia or Ib, A is-CH (OH) -.

In certain embodiments of formula Ia or Ib, A is-NR^a-。

In certain embodiments of formula Ia or Ib, a is-O-.

In certain embodiments of formula Ia or Ib, a is-S-.

In certain embodiments of formulas Ia or Ib, A is-SO₂-。

In certain embodiments of formula Ia or Ib, a is-NH- (O) C-.

In certain embodiments of formula Ia or Ib, D is-N-.

In certain embodiments of formula Ia or Ib, D is-CR^g-。

In certain embodiments of formula Ia or Ib, E is: -N-.

In certain embodiments of formula Ia or Ib, E is-CR^h-。

In certain embodiments of formula Ia or Ib, G is: -N-.

In certain embodiments of formula Ia or Ib, G is-CRⁱ-。

In certain embodiments of formula Ia or Ib, X¹、X²、X³And X⁴One or two of which are N, the remainder being CR^b。

In certain embodiments of formula Ia or Ib, X¹、X²、X³And X⁴Three of which are N and the other is CR^b。

In certain embodiments of formula Ia or Ib, X¹、X²、X³And X⁴Each is CR^b。

In certain embodiments of formula Ia or Ib, X¹、X²、X³And X⁴One is N and the others are CR^b。

In certain embodiments of formula Ia or Ib, X¹、X²、X³And X⁴Two of which are N, the remainder being CR^b。

In certain embodiments of formula Ia or Ib, X¹Is N, and X²、X³And X⁴Is CR^b。

In certain embodiments of formula Ia or Ib, X⁴Is N, and X¹、X²And X³Is CR^b。

In certain embodiments of formula Ia or Ib, X¹And X²Is N, and X³And X⁴Is CR^b。

In certain embodiments of formula Ia or Ib, X³And X⁴Is N, and X¹And X²Is CR^b。

In certain embodiments of formula Ia or Ib, X²And X⁴Is N, and X¹And X³Is CR^b。

In certain embodiments of formula Ia or Ib, X¹And X⁴Is N, and X²And X³Is CR^b。

In certain embodiments of formula Ia or Ib, Y is-O-; -CR^cR^d-; or-NR^e-。

In certain embodiments of formula Ia or Ib, Y is-CR^cR^d-; or^–NR^e-。

In certain embodiments of formula Ia or Ib, Y is-O-.

In certain embodiments of formula Ia or Ib, Y is-S-.

In certain embodiments of formulas Ia or Ib, Y is-SO₂-。

In certain embodiments of formula Ia or Ib, Y is-CR^cR^d-。

In certain embodiments of formula Ia or Ib, Y is^–NR^e-。

In certain embodiments of formula Ia or Ib, Z is CR^f。

In certain embodiments of formula Ia or Ib, Z is N.

In certain embodiments of formula Ia or Ib, Z is CH.

In certain embodiments of formula Ia or Ib, R¹、R²、R³And R⁴Is hydrogen.

In certain embodiments of formula Ia or Ib, R¹Is hydrogen.

In certain embodiments of formula Ia or Ib, R¹Is C_1-6Alkyl, which may be unsubstituted or substituted one or more times by halogen.

In certain embodiments of formula Ia or Ib, R¹Is C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R²Is hydrogen.

In certain embodiments of formula Ia or Ib, R²Is C_2-6Alkyl, which may be unsubstituted or substituted one or more times by halogen.

In certain embodiments of formula Ia or Ib, R²Is C_2-6An alkyl group.

In certain embodiments of formula Ia or Ib, R³Is hydrogen.

In certain embodiments of formula Ia or Ib, R³Is C_3-6Alkyl, which may be unsubstituted or substituted one or more times by halogen.

In certain embodiments of formula Ia or Ib, R³Is C_3-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁴Is hydrogen.

In certain embodiments of formula Ia or Ib, R⁴Is C_4-6Alkyl, which may be unsubstituted or substituted one or more times by halogen.

In certain embodiments of formula Ia or Ib, R⁴Is C_4-6An alkyl group.

In certain embodiments of formula Ia or Ib, R³And R⁴Together with the atoms to which they are attached form a 5-7 membered ring, which is unsubstituted or substituted by C_1-6Alkyl is substituted one or more times and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S.

In certain embodiments of formula Ia or Ib, R⁵The method comprises the following steps: c_1-6An alkyl group; c_3-6A cycloalkyl group; or C_3-6cycloalkyl-C_1-6Alkyl radical, wherein C_1-6Alkyl and C_3-6The cycloalkyl radical may be substituted one or more times by halogen.

In certain embodiments of formula Ia or Ib, R⁵Is C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁵Is halogen-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁵Is C_3-6A cycloalkyl group.

In certain embodiments of formula Ia or Ib, R⁵Is C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁵Is C_1-6alkoxy-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁵Is hydroxy-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁵And R³And R⁴One of andthe atoms to which they are attached together form a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl is substituted one or more times and wherein the ring is carbocyclic or wherein one of the ring members is replaced by a heteroatom selected from O, N and S.

In certain embodiments of formula Ia or Ib, R⁶Each independently is: c_1-6An alkyl group; halogen-C_1-6An alkyl group; halogen; c_1-6An alkoxy group; or a cyano group.

In certain embodiments of formula Ia or Ib, R⁶Each independently is: c_1-6An alkyl group; halogen-C_1-6An alkyl group; or a halogen.

In certain embodiments of formula Ia or Ib, R⁶Is C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁶Is a halogen.

In certain embodiments of formula Ia or Ib, R⁶Is C_1-6An alkoxy group.

In certain embodiments of formula Ia or Ib, R⁶Is cyano.

In certain embodiments of formula Ia or Ib, R⁶Is halogen or trifluoromethyl.

In certain embodiments of formula Ia or Ib, R⁷And R⁸Is hydrogen.

In certain embodiments of formula Ia or Ib, R⁷Is hydrogen or C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁷Is hydrogen.

In certain embodiments of formula Ia or Ib, R⁷Is C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁷Is a hydroxyl group.

In certain embodiments of formula Ia or IbIn, R⁷Is a halogen.

In certain embodiments of formula Ia or Ib, R⁸Is hydrogen or C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁸Is hydrogen.

In certain embodiments of formula Ia or Ib, R⁸Is C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R⁸Is a halogen.

In certain embodiments of formula Ia or Ib, R⁸Is a hydroxyl group.

In certain embodiments of formula Ia or Ib, R⁸Is oxo.

In certain embodiments of formula Ia or Ib, R⁷And R⁸Together with the atoms to which they are attached form a 4,5, 6 or 7 membered ring.

In certain embodiments of formula Ia or Ib, R⁹Each independently is: halogen; an amino group; c_1-6An alkyl-amino group; di-C_1-6An alkyl group; -an amino group; or oxo.

In certain embodiments of formula Ia or Ib, R⁹Is a halogen.

In certain embodiments of formula Ia or Ib, R⁹Is a hydroxyl group.

In certain embodiments of formula Ia or Ib, R⁹Is C_1-6An alkoxy group.

In certain embodiments of formula Ia or Ib, R⁹Is C_1-6An alkylsulfonyl group.

In certain embodiments of formula Ia or Ib, R⁹Is an amino group.

In certain embodiments of formula Ia or Ib, R⁹Is C_1-6Alkyl-amino groups.

In certain embodiments of formula Ia or Ib, R⁹Is di-C_1-6An alkyl group; -an amino group.

In certain embodiments of formula Ia or Ib, R⁹Is cyano.

In certain embodiments of formula Ia or Ib, R⁹Is oxo.

In certain embodiments of formula Ia or Ib, R^aIs hydrogen.

In certain embodiments of formula Ia or Ib, R^aIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^cAnd R^dIs hydrogen.

In certain embodiments of formula Ia or Ib, R^bEach independently is: hydrogen; c_1-6An alkyl group; halogen-C_1-6An alkyl group; or a halogen.

In certain embodiments of formula Ia or Ib, R^bEach independently is hydrogen, halogen or halogen-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^bIs hydrogen.

In certain embodiments of formula Ia or Ib, R^bIs a halogen.

In certain embodiments of formula Ia or Ib, R^cThe method comprises the following steps: hydrogen; halogen; c_1-6An alkyl group; or halogen-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^cIs hydrogen.

In certain embodiments of formula Ia or Ib, R^cIs a halogen.

In certain embodiments of formula Ia or Ib, R^cIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^cIs halogenelement-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^dThe method comprises the following steps: hydrogen; c_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; halogen; c_1-6Alkyl-carbonyl; c_3-6Cycloalkyl-carbonyl; c_3-6cycloalkyl-C_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6Cycloalkyl-sulfonyl; c_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group; an aminocarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; n, N-di-C_1-6Alkyl-aminosulfonyl; a cyano group; c_1-6An alkoxy group; c_1-6Alkyl-sulfonylamino; an amino group; N-C_1-6An alkyl-amino group; n, N-di-C_1-6An alkyl-amino group; a hydroxyl group; or halogen-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^dThe method comprises the following steps: an aminocarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; n, N-di-C_1-6Alkyl-aminosulfonyl; or C_1-6Alkyl-sulfonylamino.

In certain embodiments of formula Ia or Ib, R^dIs hydrogen.

In certain embodiments of formula Ia or Ib, R^dIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6A cycloalkyl group.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^dIs a halogen.

In certain embodiments of formula Ia or IbIn the scheme, R^dIs C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6Cycloalkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6cycloalkyl-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^dIs C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6Cycloalkyl-sulfonyl.

In certain embodiments of formula Ia or Ib, R^dIs C_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^dIs aminocarbonyl.

In certain embodiments of formula Ia or Ib, R^dIs N-C_1-6Alkyl-aminocarbonyl.

In certain embodiments of formula Ia or Ib, R^dIs N, N-di-C_1-6Alkyl-aminocarbonyl.

In certain embodiments of formula Ia or Ib, R^dIs an aminosulfonyl group.

In certain embodiments of formula Ia or Ib, R^dIs N-C_1-6Alkyl-aminosulfonyl.

In certain embodiments of formula Ia or Ib, R^dIs N, N-di-C_1-6Alkyl-aminosulfonyl.

In certain embodiments of formula Ia or Ib, R^dIs cyano.

In certain embodiments of formula Ia or Ib, R^dIs C_1-6An alkoxy group.

In certain embodiments of formula Ia or Ib, R^dIs C_1-6Alkyl-sulfonylamino.

In certain embodiments of formula Ia or Ib, R^dIs an amino group.

In certain embodiments of formula Ia or Ib, R^dIs N-C_1-6Alkyl-amino groups. In certain embodiments of formula Ia or Ib, R^dIs N, N-di-C_1-6Alkyl-amino groups.

In certain embodiments of formula Ia or Ib, R^dIs halogen-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^dIs a hydroxyl group.

In certain embodiments of formula Ia or Ib, R^dIs cyano-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^dIs cyano-C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^dIs hydroxy-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^dIs C_1-6Alkoxy-carbonyl.

In certain embodiments of formula Ia or Ib, R^dIs a carboxyl group.

In certain embodiments of formula Ia or Ib, R^cAnd R^dTogether with the atoms to which they are attached form a 4,5, 6 or 7 membered ring optionally containing a heteroatom selected from O, N and S.

In certain embodiments of formula Ia or Ib, R^eThe method comprises the following steps: c_1-6Alkyl-carbonyl; c_3-6Cycloalkyl-carbonyl; c_3-6cycloalkyl-C_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6Cycloalkyl-sulfonyl; c_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group; ammoniaAn alkylcarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; or N, N-di-C_1-6Alkyl-aminosulfonyl.

In certain embodiments of formula Ia or Ib, R^eIs hydrogen.

In certain embodiments of formula Ia or Ib, R^eIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6A cycloalkyl group.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6cycloalkyl-C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^eIs C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6Cycloalkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6cycloalkyl-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^eIs C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6Cycloalkyl-sulfonyl.

In certain embodiments of formula Ia or Ib, R^eIs C_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^eIs aminocarbonyl. In certain embodiments of formula Ia or Ib, R^eIs N-C_1-6Alkyl-aminocarbonyl.

In certain embodiments of formula Ia or Ib, R^eIs N, N-di-C_1-6Alkyl-aminocarbonyl.

In certain embodiments of formula Ia or Ib, R^eIs an aminosulfonyl group.

In certain embodiments of formula Ia or Ib, R^eIs N-C_1-6Alkyl-aminosulfonyl.

In certain embodiments of formula Ia or Ib, R^eIs N, N-di-C_1-6Alkyl-aminosulfonyl.

In certain embodiments of formula Ia or Ib, R^eIs cyano-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^eIs cyano-C_1-6An alkyl-sulfonyl group.

In certain embodiments of formula Ia or Ib, R^eIs hydroxy-C_1-6Alkyl-carbonyl groups.

In certain embodiments of formula Ia or Ib, R^eIs C_1-6Alkoxy-carbonyl.

In certain embodiments of formula Ia or Ib, R^eIs a carboxyl group.

In certain embodiments of formula Ia or Ib, R^eAnd R⁷Together with the atoms to which they are attached form a 4,5, 6 or 7 membered ring.

In certain embodiments of formula Ia or Ib, R^fIs hydrogen.

In certain embodiments of formula Ia or Ib, R^fIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^fIs hydrogen or C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^fIs a hydroxyl group.

In certain embodiments of formula Ia or Ib, R^fIs absent.

In certain embodiments of formula Ia or Ib, R^gIs hydrogen.

In certain embodiments of formula Ia or Ib, R^gIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, R^gAnd R³And R⁴One of which, together with the atoms to which they are attached, forms a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl is substituted one or more times 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.

In certain embodiments of formula Ia or Ib, R^hIs hydrogen.

In certain embodiments of formula Ia or Ib, R^hIs C_1-6An alkyl group.

In certain embodiments of formula Ia or Ib, RⁱIs hydrogen.

In certain embodiments of formula Ia or Ib, RⁱIs C_1-6An alkyl group.

In certain embodiments of formula Ia, the subject compound may be a compound of formulae IIa-IIg:

or a pharmaceutically acceptable salt thereof,

wherein:

s is 0 to 2;

R¹⁰each independently is: c_1-6An alkyl group; halogen; c_1-6An alkoxy group; or halogen-C_1-6An alkyl group; and is

A、Y、Z、m、n、p、q、R、R¹、R²、R³、R¹、R²、R⁴、R⁵、R⁶、R⁷And R⁸As defined herein.

In certain embodiments of formulas IIa-IIg, s is 0 or 1.

In certain embodiments of formulas IIa-IIg, s is 0.

In certain embodiments of formulas IIa-IIg, s is 1.

In certain embodiments of formulas IIa, IIb, IIc, IId, IIe, IIf and IIg, R¹⁰Each independently is: c_1-6An alkyl group; or a halogen.

In certain embodiments of formulas IIa, IIb, IIc, IId, IIe, IIf and IIg, R¹⁰Each independently is: a methyl group; or fluorine.

In certain embodiments, the subject compound is a compound of formula IIa.

In certain embodiments, the subject compounds are of formula IIb.

In certain embodiments, the subject compounds are of formula IIc.

In certain embodiments, the subject compounds are of formula IId.

In certain embodiments, the subject compounds are of formula IIe.

In certain embodiments, the subject compounds are of formula IIf.

In certain embodiments, the subject compound is a compound of formula IIg.

In certain embodiments of formula Ia, the subject compound may be a compound of formula III:

or a pharmaceutically acceptable salt thereof,

wherein A, Y, Z, n, p, q, R, s, R⁵、R⁶、R⁷、R⁸And R¹⁰As defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula IV:

or a pharmaceutically acceptable salt thereof,

wherein Y, Z, n, p, q, R, s, R⁵、R⁶、R⁷、R⁸And R¹⁰As defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula V:

or a pharmaceutically acceptable salt thereof,

wherein A, Y, Z, n, R, s, R⁵、R⁶、R⁷、R⁸And R¹⁰As defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula VI:

or a pharmaceutically acceptable salt thereof,

wherein Y, Z, n, R, s, R⁵、R⁶、R⁷、R⁸And R¹⁰As defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula VII:

or a pharmaceutically acceptable salt thereof,

wherein n, R, s, R⁵、R⁶、R⁷、R⁸、R¹⁰And R^eAs defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula VIII:

or a pharmaceutically acceptable salt thereof,

wherein n, R, s, R⁵、R⁶、R⁷、R⁸、R¹⁰And R^eAs defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula IX:

or a pharmaceutically acceptable salt thereof,

wherein n, R, s, R⁵、R⁶、R⁷、R⁸、R¹⁰And R^eAs defined herein.

In certain embodiments of formula Ia, the subject compound may be a compound of formula X:

wherein

s is: 0; or 1;

t is: 1; or 2;

j is: -CR^jR^k-；-NR^m-; -O-; or-S-; and is

R^j；R^kAnd R^mEach independently is: hydrogen; or C_1-6An alkyl group.

In certain embodiments of formula X, s is 0.

In certain embodiments of formula X, s is 1.

In certain embodiments of formula X, t is 1.

In certain embodiments of formula X, t is 2.

In certain embodiments of formula X, J is-CR^jR^k-。

In certain embodiments of formula X, J is-NR^m-。

In certain embodiments of formula X, J is-O-.

In certain embodiments of formula X, J is-S-.

In certain embodiments of formula X, R^jIs hydrogen.

In certain embodiments of formula X, R^jIs C_1-6An alkyl group.

In certain embodiments of formula X, R^kIs hydrogen.

In certain embodiments of formula X, R^kIs C_1-6An alkyl group.

In certain embodiments of formula X, R^mIs hydrogen.

In certain embodiments of formula X, R^mIs C_1-6An alkyl group.

The present invention also provides a method for treating a disease or disorder mediated by or associated with the RORc receptor, comprising administering to a subject in need thereof an effective amount of a compound of the present invention.

The disease may be arthritis such as rheumatoid arthritis, osteoarthritis, psoriasis, muscle sclerosis, lupus, sjogren's disease, asthma or COPD.

The disease may be arthritis, such as rheumatoid arthritis or osteoarthritis.

The disease may be psoriasis, muscle sclerosis, lupus or sjogren's disease.

The disease may be asthma or COPD.

The disease may be psoriasis.

The disease may be muscle sclerosis.

Representative compounds for use in the methods of the invention are shown in the experimental examples below.

Synthesis of

The compounds of the present invention can be prepared by various methods depicted in the illustrative synthetic reaction schemes shown and described below.

The starting materials and Reagents used in preparing these compounds are generally available from commercial suppliers such as aldrich chemical co, or prepared by methods known to those skilled in the art according to the procedures set forth in the references, e.g., Fieser and Fieser's Reagents for Organic Synthesis; wiley & Sons, New York,1991, Vol.1-15; rodd's Chemistry of carbon Compounds, Elsevier Science Publishers,1989, Vol.1-5 and suppl.A; and Organic Reactions, Wiley & Sons: New York,1991, volumes 1-40. The following synthetic reaction schemes are merely illustrative of some of the methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made, as will be apparent to those skilled in the art in light of the disclosure contained herein.

If desired, starting materials and intermediates in the synthetic reaction schemes can be isolated and purified using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. The materials may be characterized using conventional methods including physical constants and spectral data.

Unless stated to the contrary, the reactions described herein may be carried out under an inert atmosphere, at atmospheric pressure, at a reaction temperature range of from about-78 ℃ to about 150 ℃, e.g., from about 0 ℃ to about 125 ℃, or conveniently at about room temperature (ambient temperature), e.g., about 20 ℃.

Scheme A below illustrates one synthetic procedure that may be used to prepare a particular compound of formula Ia, where X is a leaving group and may be the same or different at each occurrence, and m, n, r, X¹、X²、X³、X⁴、Y、Z、R¹、R²、R³、R⁴、R⁵、R⁵、R⁶、R⁷And R⁸As defined herein.

Scheme A

In step 1 of scheme A, an aryl or arylalkyl sulfonyl halide compoundaWith aryl or arylalkyl aminesbReaction to give the arylsulfonyl groupAmine compoundc. The reaction of step 1 may be carried out in a polar aprotic solvent in the presence of a tertiary amine.

In step 2, the N-alkylation is carried out by using an alkylating agentd(which may be, for example, an alkyl halide or an alkyl triflate) treating compoundcTo obtain aryl sulfonamide compoundse. As an example, the reaction may be carried out under polar aprotic solvent conditions.

Then the compound in step 3aeWith cyclic aminesfCan give arylsulfonamidesgWhich are compounds of formula I of the present invention. The reaction of step 3a may be carried out in a non-polar solvent in the presence of a suitable palladium catalyst.

Alternatively, alcohol compounds may be used in step 3bhTreatment compoundseTo obtain aryl sulfonamide compoundsiWhich are compounds of formula I of the present invention. The reaction of step 3b may be carried out in a polar solvent, under anhydrous conditions and in the presence of an alkali metal hydride base.

In another alternative, the compoundeCan be reacted with cyclic aminesjReacting to obtain aryl sulfonamide compoundkWhich are compounds of formula I of the present invention. The reaction of step 3c may be carried out in a non-polar solvent in the presence of a suitable palladium catalyst.

Many variations of the operation of scheme a are possible and may suggest themselves to those skilled in the art. For example, in certain embodiments, a reagent may be used prior to step 1dReacting an amine compoundbAnd (4) alkylation. Different protecting group strategies can be used for the reaction of scheme a. Specific details for the production of the compounds of the present invention are set forth in the examples below.

Administration and pharmaceutical compositions

The present invention includes pharmaceutical compositions comprising at least one compound of the present invention, or an individual isomer, racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable carrier, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of the present invention are administered in therapeutically effective amounts by any of the conventional modes of administration for substances of similar efficacy. Suitable dosage ranges are typically from 1 to 500mg per day, preferably from 1 to 100mg per day, most preferably from 1 to 30mg per day, depending on factors such as the severity of the disease to be treated, the age and relative health of the individual, the potency of the compound used, the route and form of administration, the indication for which administration is intended, and the preference and experience of the medical practitioner involved. One of ordinary skill in the art of treating such diseases will be able to determine, without undue experimentation and depending on personal knowledge and the disclosure of the present application, a therapeutically effective amount of a compound of the present invention for a given disease.

The compounds of the present invention may be administered in the form of pharmaceutical formulations including those suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The particular mode of administration will generally be oral, and will be adjusted to the degree of affliction, using an appropriate daily dosage regimen.

One or more compounds of the present invention may be formulated in pharmaceutical compositions and unit dosage forms together with one or more conventional adjuvants, carriers or diluents. The pharmaceutical compositions and unit dosage forms can contain conventional ingredients in conventional proportions, with or without additional active compounds or ingredients, and the unit dosage forms can contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical compositions may be applied in the form of a solid such as a tablet or filled capsule, a semi-solid, a powder, a sustained release formulation or a liquid such as a solution, suspension, emulsion, elixir or filled capsule for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of a sterile injectable solution for parenteral use. Thus, formulations containing about one (1) milligram of active ingredient per tablet or, more broadly, about 0.01 to about one hundred (100) milligrams of active ingredient are suitable representative unit dosage forms.

The compounds of the present invention may be formulated into various dosage forms for oral administration. Pharmaceutical compositions and dosage forms may contain one or more compounds of the invention or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutically acceptable carrier may be a solid or a liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is typically a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is generally mixed with a carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain from about one percent (1%) to about seventy percent (70%) of the active compound. Suitable carriers include, but are not limited to, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low melting wax, cocoa butter, and the like. The term "formulation" includes preparations of an active compound that contain an encapsulating material as the carrier to provide a capsule in which the active component, with or without a carrier, is surrounded by the carrier in association therewith. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be solid forms suitable for oral administration.

Other forms suitable for oral administration include: liquid form preparations, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are converted into liquid form preparations immediately before use. Emulsions may be prepared in solutions such as aqueous propylene glycol or may contain emulsifying agents such as lecithin, sorbitan monooleate or acacia. Aqueous solutions can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers, and thickening agents. Aqueous suspensions may be formulated by dispersing the finely divided active component in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. Liquid form preparations include solutions, suspensions and emulsions, which may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.

The compounds of the invention may be formulated for parenteral administration (e.g., by injection, such as bolus injection or continuous infusion) and may be presented in unit dosage form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous media, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous vehicles, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preservatives, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic packaging of a sterile solid or by lyophilisation of a solution for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.

The compounds of the present invention may be formulated for topical application to the epidermis in the form of an ointment, cream or lotion, or in the form of a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated for administration in the form of suppositories. The low melting wax, such as a fatty acid glyceride mixture or cocoa butter, can be melted first and the active ingredient dispersed homogeneously therein, for example by stirring. The molten homogeneous mixture is then poured into a suitably sized mold, allowed to cool and solidify.

The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

The subject compounds may be formulated for nasal administration. The solution or suspension can be applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or nebulizer. The formulations may be in single or multiple dose form. For a dropper or pipette multi-dose form, this may be achieved by the patient administering an appropriate, predetermined volume of solution or suspension. For a nebulizer, this can be achieved, for example, by a metered atomizing spray pump.

The compounds of the invention may be formulated for aerosol administration, particularly to the respiratory tract, including intranasal administration. The compounds generally have a small particle size, for example on the order of five (5) microns or less. The particle size may be obtained by methods known in the art, for example by micronization. The active ingredient is provided in pressurized packs with a suitable propellant, such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may suitably also contain a surfactant such as lecithin. The dosage of the medicament may be controlled by a metering valve. Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder compositions may be presented in unit dosage form, for example in capsules or cartridges of, for example, gelatin or in blister packs, from which the powder may be administered by means of an inhaler.

If desired, the formulations may be prepared with enteric coatings suitable for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention may be formulated as transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with the treatment regimen is critical. The compounds in transdermal delivery systems are often attached to a skin-adherent solid support. The compound of interest may also be combined with a penetration enhancer such as lauryl nitrogenKetones (1-dodecylazacycloheptane-2-one) are used in combination. The sustained release delivery system may be inserted subcutaneously into the subcutaneous layer by surgery or injection. Subcutaneous implants encapsulate compounds in lipid soluble membranes such as silicone rubber or biodegradable polymers such as polylactic acid.

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

Other suitable pharmaceutical carriers and their formulation are described in the following documents: remington the science and Practice of Pharmacy 1995, edited by e.w. martin, Mack Publishing Company, 19 th edition, Easton, Pennsylvania. Representative pharmaceutical formulations containing the compounds of the present invention are described below.

Utility of

In general, the compounds of the invention are useful for the treatment of immunological disorders. The compounds are useful for the treatment of arthritis, including rheumatoid arthritis, osteoarthritis, psoriatic arthritis, septic arthritis, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus and juvenile arthritis, osteoarthritis and other arthritic conditions.

The compounds are useful for treating respiratory disorders such as Chronic Obstructive Pulmonary Disease (COPD), asthma, bronchospasm, and the like.

The compounds are useful for treating gastrointestinal disorders ("GI disorders"), such as Irritable Bowel Syndrome (IBS), Inflammatory Bowel Disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-predominant IBS, pain associated with GI distention (displacement), and the like.

The compounds are useful for treating pain disorders, such as inflammatory pain; pain in arthritis; pain from the operation; visceral pain; toothache; premenstrual pain; central pain; pain due to burn; migraine or cluster headache; nerve damage; neuritis; neuralgia; poisoning; ischemic injury; interstitial cystitis; cancer pain; viral, parasitic or bacterial infections; post-traumatic injury; or pain associated with irritable bowel syndrome.

Examples

The following preparations and examples are given to enable those skilled in the art to more clearly understand and practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Unless otherwise indicated, all temperature units including melting point (i.e., MP) are degrees celsius (° c). It will be appreciated that the reaction which produces the indicated and/or the desired product need not necessarily result directly from the combination of the two reagents initially charged, i.e., there may be one or more intermediates produced in the mixture which ultimately results in the formation of the indicated and/or the desired product. The following abbreviations may be used in the preparations and examples.

General experiments

LCMS method:

high performance liquid chromatography-mass spectrometry (LCMS) experiments for determination of Retention Time (RT) and associated mass ions were performed using one of the following methods:

the method A comprises the following steps: compounds were analyzed using the following conditions: experiments were performed using a Waters ZMD single quadrupole mass spectrometer connected to a Hewlett Packard HP1100LC system with a UV diode array detector and a 100-position autosampler. The mass spectrometer has an electrospray source operating in positive and negative ion modes. The system used a phenomenex luna 3 μm C18(2)30x 4.6mm column at ambient temperature and a flow rate of 2.0 mL/min. The starting solvent system was: the first 0.5 minutes, 95% water containing 0.1% formic acid (solvent a) and 5% acetonitrile containing 0.1% formic acid (solvent B), then a gradient to 5% solvent a and 95% solvent B was made over the next 4 minutes. It was maintained for 1 minute and then returned to 95% solvent a and 5% solvent B over the next 0.5 minutes. The total run time was 6 minutes.

The method B comprises the following steps: compounds were analyzed using the following conditions: experiments were performed using a Waters Micromass ZQ2000 quadrupole mass spectrometer connected to a Waters acquityupplc system with PDA UV detector. The mass spectrometer has an electrospray source operating in positive and negative ion modes. The system used an Acquity BEH C181.7 μm 100X 2.1mm column maintained at 40 ℃ or an Acquity BEH Shield RP 181.7 μm 100X 2.1mm column maintained at 40 ℃ and a flow rate of 0.4 mL/min. The starting solvent system was: for the first 0.4 minutes, 95% water containing 0.1% formic acid (solvent a) and 5% acetonitrile containing 0.1% formic acid (solvent B) were then graded to 5% solvent a and 95% solvent B over the next 5.6 minutes. It was maintained for 0.8 minutes and then returned to 95% solvent a and 5% solvent B in the next 1.2 minutes. The total run time was 8 minutes.

NMR method:

say thatAs will be apparent from the above description,¹h NMR spectra were recorded at ambient temperature or at 80 ℃ using the following machine: a Varian Unity Inova (400MHz) spectrometer with a triple resonant 5mm probe; bruker Avance DRX 400(400MHz) with triple resonant 5mm probe; equipped with means for detecting¹H and¹³c BrukerAvance DPX300(300MHz) from a standard 5mm dual frequency probe; bruker AVIII (400MHz) using a BBI Broad Band Inverse 5mm probe; or Bruker AVIII (500MHz) using QNP (Quad Nucleus detection) 5mm probe. Chemical shifts are expressed in ppm relative to tetramethylsilane (ppm 0.00) as an internal standard. The following abbreviations are used: br ═ broad peak signal, s ═ singlet, d ═ doublet, dd ═ doublet, t ═ triplet, q ═ quartet, m ═ multiplet, or any combination thereof.

A microwave reactor:

use ofThe microwave reaction was carried out in a vial suitable for reaction scale at the temperatures and times described in the detailed description of the experiments.

Purification equipment:

application of Teledyne ISCO Using Pre-filled silica gel columnsOrIsoleraOr purification using compressed air with external pressure applied. The solvents and gradients shown in the experimental detailed description were used.

Reverse phase High Pressure Liquid Chromatography (HPLC) was used to purify the indicated compounds. Separation was performed on a phenomenex gemini C18 column (250x 21.2mm,5 microns) as the stationary phase using gradient elution and using the mobile phase shown, operating at a flow rate of 18mL/min, using a Gilson UV/Vis-155 dual channel detector and a Gilson GX-271 automated liquid handler.

The phase separation column is composed ofTo be provided withProvided in the form of a phase separation column.

List of abbreviations

AcOH acetic acid

AIBN 2, 2' -azobis (2-methylpropanenitrile)

Atm. atmospheric pressure

BOC tert-butoxycarbonyl

(BOC)₂Di-tert-butyl O dicarbonate

CDCl₃Deuterated chloroform

DavePhos 2-dicyclohexylphosphino-2' - (N, N-dimethylamino) biphenyl

DCM dichloromethane/methylene chloride

DMA N, N-dimethylacetamide

DIAD diisopropyl azodicarboxylate

DIPEA DIPEA

DMAP 4-dimethylaminopyridine

DME 1, 2-dimethoxyethane

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

DPPF 1,1' -bis (diphenylphosphino) ferrocene

ES electrospray ionization

Et₂O Ether

Et₃N-Triethylamine

EtOH ethanol/Ethyl alcohol

EtOAc ethyl acetate

HATU 2- (1H-7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethylureaAmmonium methyl hexafluorophosphate

HBTU O-benzotriazole-1-yl-N, N, N ', N' -tetramethylureaHexafluorophosphates

HCl hydrochloric acid

HOBT 1-hydroxybenzotriazole

HPLC high pressure liquid chromatography

RP HPLC reversed-phase high-pressure liquid chromatography

IBX 2-iodoxybenzoic acid

Methylated alcohol for IMS industry

K₂CO₃Potassium carbonate

i-PrOH Isopropanol/isopropyl alcohol/propan-2-ol

LCMS liquid chromatography/mass spectrometry

MeOH methanol/methyl alcohol

MW microwave

NaH sodium hydride

NaOH sodium hydroxide

Na₂SO₄Sodium sulfate

Na₂CO₃Sodium carbonate

NaHCO₃Sodium bicarbonate

NBS N-bromosuccinimide

NH₄Cl ammonium chloride

NMP 1-methyl-2-pyrrolidone

Pd₂(dba)₃Tris (dibenzylideneacetone) dipalladium (0)

PSI PSI

RT Room temperature

sat, saturated

SCX-2 Pre-populationAdsorbent with chemically bound propanesulfonic acid functional groups of silica

TBDMS tert-butyldimethylsilyl group

TFA trifluoroacetic acid

THF tetrahydrofuran

TIPS Triisopropylsilyl radical

TLC thin layer chromatography

XantPhos 4, 5-bis (diphenylphosphino) -9, 9-dimethylxanthene

Example 1: 1- (4- (4-acetylpiperazin-1-yl) phenyl) -N- (3-chlorophenyl) -N-isobutylmethanesulfonamide

Step 1: thioacetic acid S- (4-bromo-benzyl) ester

To a solution of 4-bromobenzyl alcohol (2g,10.7mmol) in DCM (30mL) was added Et at 0 deg.C₃N (2.2mL,16.0mmol) followed by methanesulfonyl chloride (910. mu.L, 11.8mmol) was added. The reaction was warmed to room temperature, stirred for 2 hours, and then quenched with water. Adding saturated NaHCO₃The aqueous solution was extracted with DCM and the combined organic extracts were filtered through a phase separation column and concentrated to give 4-bromo-benzyl methanesulfonate (2.67g,10mmol, 94%). A solution of the crude product (2.67g,10mmol) in DMSO (40mL) was stirred at room temperature with potassium thioacetate (1.26g,11mmol) for 16 h. The reaction was treated with water, extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give S- (4-bromo-benzyl) thioacetate (1.81g,7.39mmol, 69%).¹H NMR(300MHz,CDCl₃)：7.41(d,2H),7.16(d,2H),4.05(s,2H),2.35(s,3H).

Step 2: (4-bromo-phenyl) -methanesulfonyl chloride

To a solution of N-chlorosuccinimide (3.95g,29.6mmol) in acetonitrile (11.6mL) and 1MHCl (2.31mL) was slowly added a solution of S- (4-bromo-benzyl) thioacetate (1.81g,7.39mmol) in acetonitrile (6.3mL) over 60 minutes while the reaction was warmed to 15 ℃. The remaining solution was added and the reaction was allowed to warm to room temperature for 10 minutes. The mixture was cooled to 0 ℃ and stirred for 1 hour. Water was added and the product was extracted with EtOAc, washed with brine and Na₂SO₄Dried and concentrated to give (4-bromo-phenyl) -methanesulfonyl chloride (2.6g,9.6 mmol).¹H NMR(300MHz,CDCl₃)：7.60(d,2H),7.36(d,2H),4.81(s,2H).

And step 3: c- (4-bromo-phenyl) -N- (3-chloro-phenyl) -methanesulfonamide

To a solution of (4-bromo-phenyl) -methanesulfonyl chloride (1.4g,5.2mmol) in DCM (20mL) was added pyridine (1.26mL,15.6mmol) followed by 3-chloroaniline (1.1mL,10.4mmol) at room temperature and the reaction was stirred at room temperature for 3 h. Adding1M aqueous HCl was added, followed by extraction with DCM, filtration through a separator, concentration, drying the load onto silica gel and purification by silica gel column chromatography (0-100% DCM in cyclohexane) gave C- (4-bromo-phenyl) -N- (3-chloro-phenyl) -methanesulfonamide (0.61g,1.68 mmol).¹H NMR(300MHz,CDCl₃)：7.49(d,2H),7.26(m,1H),7.13-7.15(m,4H),6.96-6.98(m,1H),6.31(s,1H),4.31(s,2H).

And 4, step 4: c- (4-bromo-phenyl) -N- (3-chloro-phenyl) -N-isobutyl-methanesulfonamide

To the solution of C- (4-bromo-phenyl) -N- (3-chloro-phenyl) -methanesulfonamide (0.61g,1.68mmol) and K₂CO₃(464mg,3.4mmol) to a mixture in dimethylformamide (5mL) was added 1-iodo-2-methylpropane (584. mu.L, 5.0 mmol). The mixture was heated in a microwave reactor at 100 ℃ for 3 hours. Water was added, the reaction was extracted with EtOAc, washed with brine and Na₂SO₄Dried, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give C- (4-bromo-phenyl) -N- (3-chloro-phenyl) -N-isobutyl-methanesulfonamide (423mg,1.0mmol, 60%). LCMS (m/z, method A) ES⁺415.8[M+1]⁺.

And 4, step 4: 1- (4- (4-acetylpiperazin-1-yl) phenyl) -N- (3-chlorophenyl) -N-isobutylmethanesulfonamide

N-chloro-3-chloro-phenyl-C- (4-bromo-phenyl) -N- (4-chloro-phenyl) -N-isobutyl-methanesulfonamide (150mg, 361. mu. mol), 1-methanesulfonylpiperazine (59.2mg, 361. mu. mol), Pd were given with nitrogen₂(dba)₃A mixture of (33mg, 36. mu. mol), XantPhos (20.9mg, 36. mu. mol) and sodium tert-butoxide (104mg,1.08mmol) in toluene (3mL) was degassed and then heated in a microwave reactor at 120 ℃ for 30 min. Water was added, the reaction was extracted with EtOAc, washed with brine and Na₂SO₄Drying, concentration, purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by lyophilization afforded the title compound (22.4 mg).¹HNMR(400MHz,DMSO)：7.33-7.34(m,4H),7.22(d,J＝8.5Hz,2H),6.95(d,J＝8.5Hz,2H),4.37(s,2H),3.45(d,J＝7.3Hz,2H),3.22-3.27(m,8H),2.92(s,3H),1.44-1.46(m,1H),0.82(d, J ═ 6.6Hz,6H). LCMS (m/z, method B) ES⁺499.9[M+1]⁺.

Example 2: n- (4-fluoro-benzyl) -N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylamino) -benzenesulfonamide

Step 1: 4-bromo-N-isobutyl-benzenesulfonamides

To a solution of 4-bromobenzenesulfonyl chloride (2g,7.8mmol) in DCM (40mL) was added pyridine (1.9mL,23.5mmol) followed by isobutylamine (1.56mL,15.7mmol) and the reaction was stirred at rt for 16 h. 1M aqueous HCl was added, the reaction was extracted with DCM, filtered through a phase separator and concentrated to give 4-bromo-N-isobutyl-benzenesulfonamide (1.99 g). LCMS (m/z, method A) ES⁺294[M+1]⁺

Step 2: 4-bromo-N- (4-fluoro-benzyl) -N-isobutyl-benzenesulfonamide

To a solution of 4-bromo-N-isobutyl-benzenesulfonamide (0.25g,856 μmol) in anhydrous dimethylacetamide (5mL) was added NaH (60% dispersion in mineral oil, 37.7mg,942 μmol) and the mixture was stirred at room temperature for 15 minutes. 4-Fluorobenzyl bromide (117. mu.L, 942. mu. mol) was added and the reaction was heated at 90 ℃ for 2 hours. The reaction was cooled to room temperature, water was added, then extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give 4-bromo-N- (4-fluoro-benzyl) -N-isobutyl-benzenesulfonamide (267mg, 78%)¹H NMR(300MHz,CDCl₃)：7.65-7.66(m,4H),7.23(m,2H),6.99(t,2H),4.27(s,2H),2.89(d,2H),1.64(dt,1H),0.74(d,6H).

And step 3: 4- {4- [ (4-fluoro-benzyl) -isobutyl-sulfamoyl]-phenylamino } piperidine-1-carboxylic acid tert-butyl ester

Feeding 4-bromo-N- (4-fluoro) gas with nitrogen-benzyl) -N-isobutyl-benzenesulfonamide (200mg, 500. mu. mol), 4-amino-1-boc-piperidine (120mg, 600. mu. mol), Pd₂(dba)₃A mixture of (46mg, 50. mu. mol), XantPhos (29mg, 50. mu. mol) and sodium tert-butoxide (106mg,1.1mmol) in toluene (5mL) was degassed and then heated in a microwave reactor at 125 ℃ for 30 min. Water was added, followed by extraction with EtOAc, washing with brine, and Na₂SO₄Drying, concentration and purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) afforded 4- {4- [ (4-fluoro-benzyl) -isobutyl-sulfamoyl]-phenylamino } -piperidine-1-carboxylic acid tert-butyl ester (208mg, 80%). LCMS (m/z, method A) ES^-518[M-1]^-.

And 4, step 4: n- (4-fluoro-benzyl) -N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylamino) -benzenesulfonamide

To 4- {4- [ (4-fluoro-benzyl) -isobutyl-sulfamoyl]To a solution of tert-butyl-phenylamino } -piperidine-1-carboxylate (208mg) in DCM (9mL) was added TFA (1mL) and the reaction was stirred at room temperature for 30 min. Concentration reaction, purification by SCX column, 2M NH₃Elution of a solution in MeOH afforded N- (4-fluoro-benzyl) -N-isobutyl-4- (piperidin-4-ylamino) -benzenesulfonamide. To a solution of the crude product (149mg) in DCM (5mL) was added DIPEA (124. mu.L, 711. mu. mol) followed by methanesulfonyl chloride (28. mu.L, 356. mu. mol), and the reaction was stirred at room temperature for 30 min. Water was then added, passed through a phase separator, re-extracted by the phase separator, concentrated, and purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) to give the title compound (139 mg).¹H NMR (400MHz, DMSO): 7.51(d, J ═ 8.7Hz,2H),7.4(dd, J ═ 8.5,5.6Hz,2H),7.15(t, J ═ 8.8Hz,2H),6.71(d, J ═ 8.7Hz,2H),6.55(d, J ═ 7.8Hz,1H),4.15(s,2H),3.48-3.53(m,3H),2.93(d, J ═ 11.6Hz,2H),2.89(s,3H),2.76(d, J ═ 7.4Hz,2H),1.99(m,2H),1.44-1.49(m,3H),0.65(d, J ═ 6.6Hz,6H), s (m/z), method B) ES (ES)⁺498.0[M+1]+.

Example 3: n- (4-fluoro-phenyl) -N-isobutyl-4- (1-methanesulfonyl-piperidin-4-yloxy) -benzenesulfonamide

Step 1: 4-fluoro-N- (4-fluoro-phenyl) -benzenesulfonamides

A solution of 4-fluorobenzenesulfonyl chloride (2g,10.3mmol) was stirred at room temperature with pyridine (2.49mL,30.8mmol) and 4-fluoroaniline (1.95mL,20.6mmol) for 2 hours. The reaction was quenched with 1M aqueous HCl, then extracted with DCM, filtered through a phase separator, and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give 4-fluoro-N- (4-fluoro-phenyl) -benzenesulfonamide (2.15g, 78%). LCMS (m/z, method A) ES⁺270[M+1]⁺.

Step 2: 4-fluoro-N- (4-fluoro-phenyl) -N-isobutyl-benzenesulfonamide

To 4-fluoro-N- (4-fluoro-phenyl) -benzenesulfonamide (1.0g,3.7mmol) and K₂CO₃(1.03g,7.4mmol) to a mixture in dimethylformamide (5mL) was added 1-bromo-2-methylpropane (1.21mL,11.2 mmol). The mixture was heated in a microwave reactor at 100 ℃ for 3 hours. Water was added, followed by extraction with EtOAc, washing with brine, and Na₂SO₄Dried and then concentrated. The crude product was redissolved in cyclohexane and then concentrated to give 4-fluoro-N- (4-fluoro-phenyl) -N-isobutyl-benzenesulfonamide (1.05g, 86%).¹H NMR(300MHz,CDCl₃)：7.56-7.57(m,2H),7.12-7.13(m,2H),7.00(d,4H),3.28(d,2H),1.54(m,1H),0.91(d,6H).

And step 3: (N- (4-fluoro-phenyl) -N-isobutyl-4- (1-methanesulfonyl-piperidin-4-yloxy) -benzenesulfonamide)

To a solution of 1-methanesulfonyl-piperidin-4-ol (61mg) in anhydrous tetrahydrofuran (5mL) was added NaH (60% dispersion in mineral oil, 15mg,369 μmol) at room temperature, and the reaction was stirred at room temperature for 30 minutes. 4-fluoro-N- (4-fluoro-phenyl) -N-isobutyl-benzenesulfonamide (100mg, 308. mu. mol) was added and the reaction was heated at 90 ℃ for 3 hours. The reaction was cooled to room temperature, water was added, and the mixture was usedEtOAc extraction, concentration, purification by preparative reverse phase HPLC, followed by lyophilization afforded the title compound (51.8 mg).¹H NMR (400MHz, DMSO): 7.44(d, J ═ 8.8Hz,2H),7.13-7.14(m,7H),4.69(t, J ═ 3.8Hz,1H),3.35(d, J ═ 10.8Hz,4H),3.28(d, J ═ 7.4Hz,3H),3.12-3.14(m,2H),2.91(s,3H),2.03(br s,3H),1.71-1.79(m,3H),1.41(t, J ═ 6.8Hz,1H),0.84(d, J ═ 6.6Hz,6H) LCMS (m/z, method B) ES⁺484.9[M+1]⁺.

Example 4: N-cyclobutyl-N- (3-fluoro-phenyl) -4- (1-methanesulfonyl-piperidin-4-yloxy) -benzenesulfonamide

Step 1: cyclobutyl- (3-fluoro-phenyl) -amines

3-Fluoroiodobenzene (1.0g,4.5mmol), cyclobutylamine (320. mu.L, 3.8mmol), Pd were given with nitrogen₂(dba)₃A mixture of (34mg, 38. mu. mol), XantPhos (54mg, 94. mu. mol) and sodium tert-butoxide (541mg,5.6mmol) in toluene (10mL) was degassed and then heated in a microwave reactor at 120 ℃ for 30 min. Adding saturated NaHCO₃Aqueous solution, then extracted with EtOAc, washed with brine, and Na₂SO₄Dried, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give cyclobutyl- (3-fluoro-phenyl) -amine (447mg, 71%). LCMS (m/z, method A) ES⁺166[M+1]⁺.

Step 2: N-cyclobutyl-4-fluoro-N- (3-fluoro-phenyl) -benzenesulfonamides

To a solution of cyclobutyl- (3-fluoro-phenyl) -amine (447mg,2.7mmol) in DCM (8mL) was added pyridine (438 μ L,5.4mmol) followed by 4-fluorobenzenesulfonyl chloride (633mg,3.3mmol) in DCM (3mL) and the reaction was stirred at rt for 2 h. The reaction was allowed to stand at room temperature for 64 hours. 1M aqueous HCl was added, followed by extraction with DCM, filtration through a phase separator, and then passage throughPurification by silica gel column chromatography (0-50% DCM in cyclohexane) gave N-cyclobutyl-4-fluoro-N- (3-fluoro-phenyl) -benzenesulfonamide (756mg,2.3mmol, 85%). LCMS (m/z, method A) ES⁺324[M+1]⁺.

And step 3: 4- {4- [ cyclobutyl- (3-fluoro-phenyl) -sulfamoyl]-phenoxy } -piperidine-1-carboxylic acid tert-butyl ester

To a solution of tert-butyl-4-hydroxy-1-piperidinecarboxylic acid ester (137mg, 681. mu. mol) in anhydrous THF (5mL) was added NaH (60% dispersion in mineral oil, 30mg, 743. mu. mol), and the reaction was stirred at room temperature for 15 minutes. N-cyclobutyl-4-fluoro-N- (3-fluoro-phenyl) -benzenesulfonamide (200mg, 619. mu. mol) was added and the reaction was heated at 90 ℃ for 4 hours. The reaction was kept cool to room temperature, water was added, extracted with EtOAc, washed with brine and Na₂SO₄Dried, then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4- {4- [ cyclobutyl- (3-fluoro-phenyl) -sulfamoyl]-phenoxy } -piperidine-1-carboxylic acid tert-butyl ester (330 mg). LCMS (m/z, method A) ES⁺527[M+23]⁺.

And 4, step 4: (N-cyclobutyl-N- (3-fluoro-phenyl) -4- (1-methanesulfonyl-piperidin-4-yloxy) -benzenesulfonamide)

To 4- {4- [ cyclobutyl- (3-fluoro-phenyl) -sulfamoyl]To a solution of tert-butyl-phenoxy } -piperidine-1-carboxylate (330mg, 655. mu. mol) in DCM (9mL) was added TFA (1mL), and the reaction was stirred at room temperature for 30 min. The reaction was concentrated and then purified by SCX using 2M NH₃Elution of a solution in MeOH afforded N-cyclobutyl-N- (3-fluoro-phenyl) -4- (piperidin-4-yloxy) -benzenesulfonamide (195mg,483 μmol). To a solution of N-cyclobutyl-N- (3-fluoro-phenyl) -4- (piperidin-4-yloxy) -benzenesulfonamide in DCM (10mL) were added DIPEA (168 μ L,965 μmol) and methanesulfonyl chloride (41 μ L,531 μmol), and the reaction was stirred at room temperature for 30 min. Water was added, then extracted with DCM, filtered through a phase separator and concentrated. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) followed by preparative reverse phase HPLC gave the title compound (169mg).¹H NMR(DMSO)：7.46(2H,dJ8.8 Hz),7.38-7.39(1H, m),7.16-7.17(3H, m),6.77-6.78(2H, m),4.69-4.71(1H, m),4.20-4.22(1H, m),3.33-3.38(4H, m),3.13(2H, ddd, J12.1, 8.09,3.4Hz),2.91(3H, s),2.03-2.06(4H, m),1.77-1.81(4H, m),1.53-1.56(2H, m) LCMS (m/z, method B) ES⁺482.9[M+1]⁺.

Example 5: n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine- 3-sulfonamides

Step 1: (4-fluoro-phenyl) -isobutyl-amine

To a solution of 4-fluoroaniline (1g,9mmol) in DCM (20mL) was added isobutyraldehyde (985. mu.L, 10.8mmol) at room temperature, followed by addition of sodium triacetoxyborohydride (2.86g,13.5mmol) in portions, and the reaction was stirred at room temperature for 64 hours. The reaction was concentrated, then dissolved in DCM and MeOH, dried to load onto silica gel, then purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give (4-fluoro-phenyl) -isobutyl-amine (817mg, 54%). LCMS (M/z, method A) ES +168[ M +1] +.

Step 2: 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide

To a solution of (4-fluoro-phenyl) -isobutyl-amine (250mg,1.5mmol) in DCM (5mL) was added pyridine (242 μ L,3.0mmol) followed by 6-chloropyridine-3-sulfonyl chloride (379mg,1.8mmol) and the reaction was stirred at rt for 2 h. Adding water and saturated NaHCO₃Then extracted with DCM, filtered through a phase separator and then purified by silica gel column chromatography (0-20% EtOAC in cyclohexane) to give chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (411mg, 80%) LCMS (m/z, method a) ES⁺343[M+1]⁺.

And step 3: (6- (1-Methylsulfonyl-piperidin-4-yloxy) -pyridine-3-sulfonic acidAcid (4-fluoro-phenyl) -isobutyl-acyl Amine)

To a solution of 1-methanesulfonyl-piperidin-4-ol (86mg, 482. mu. mol) in anhydrous THF (5mL) at room temperature was added NaH (60% dispersion in mineral oil, 21mg, 526. mu. mol), and the reaction was stirred at room temperature for 15 minutes. Chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (150mg,439 μmol) was added, and the reaction was stirred at room temperature for 45 minutes, then heated at 80 ℃ for 2 hours. Adding water and saturated NaHCO₃Then extracted with EtOAc, washed with brine, washed with Na₂SO₄Dried and then concentrated and purified by silica gel column chromatography (0-25% EtOAc in cyclohexane) to give the title compound (137 mg).¹H NMR (400MHz, DMSO): 8.30(dd, J ═ 2.6,0.67Hz,1H),7.75(dd, J ═ 8.8,2.60Hz,1H),7.19-7.20(m,4H),6.97(dd, J ═ 8.8,0.7Hz,1H),5.23-5.25(m,1H),3.39(d, J ═ 8.8Hz,4H),3.13(ddd, J ═ 12.2,8.56,3.46Hz,2H),2.91(s,3H),2.04-2.09(m,2H),1.78-1.80(m,2H),1.44(dd, J ═ 13.6,6.9Hz,1H),0.85(d, J ═ 6.6, 6H), 6H, s (m/z), method B (z), and method (s, z)⁺485.9[M+1]⁺.

Example 6: n- (4-fluorophenyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine- 2-sulfonamides

Step 1: (4-fluoro-phenyl) -isobutyl-amine

To a solution of 4-fluoroaniline (1g,9mmol) in DCM (20mL) was added isobutyraldehyde (985. mu.L, 10.8mmol) at room temperature, followed by addition of sodium triacetoxyborohydride (2.86g,13.5mmol) in portions, and the reaction was stirred at room temperature for 64 hours. The reaction was concentrated, then dissolved in DCM and MeOH, dried to load onto silica gel, then purified by silica gel column chromatography (0-25% DCM in cyclohexane) to give (4-fluoro-phenyl) -isobutyl-amine (817mg, 54%). LCMS (m/z, method A) ES⁺168[M+1]⁺.

Step 2: 5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide

To a solution of 5-bromo-pyridine-2-sulfonyl chloride (330mg,1.29mmol) in DCM (10mL) was added pyridine (208 μ L,2.57mmol) followed by a solution of (4-fluoro-phenyl) -isobutyl-amine (215mg,1.29mmol) in DCM (10mL) and the reaction was stirred at rt for 16 h. Adding water and saturated NaHCO₃Aqueous solution, then extracted with DCM, filtered through a phase separator and then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (414mg, 78%). LCMS (m/z, method A) ES⁺387/389[M+1]⁺.

And step 3: 5- (1-methanesulfonyl-piperidin-4-ylamino) -pyridine-2-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide

5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (150mg, 388. mu. mol), 4-amino-1-methanesulfonylpiperidine (82.8mg, 465. mu. mol), Pd, was given with nitrogen₂(dba)₃A mixture of (36mg, 39. mu. mol), XantPhos (22mg, 39. mu. mol) and sodium tert-butoxide (82mg, 853. mu. mol) in toluene (4mL) was degassed and then heated in a microwave reactor at 125 ℃ for 30 minutes. Adding saturated NaHCO₃Aqueous solution, then extracted with EtOAc, washed with brine, concentrated and purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) to give the title compound (103 mg).¹H NMR (400MHz, DMSO-d 6): 8.10(d,1H),7.36(d,1H),7.15(d,4H),6.96(dd,1H),6.81(d,1H),3.50-3.52(m,5H),2.89(s,5H),1.99(s,2H),1.43-1.47(m,3H),0.83(d,6H). LCMS (m/z, method A) ES⁺484.9[M+1]⁺.

Example 7: n- (4-fluorophenyl) -N-isobutyl-6- ((1- (methylsulfonyl) piperidin-4-yl) amino) pyridine- 3-sulfonamides

Step 1: (4-fluoro-phenyl) -isobutyl-amine

Step 2: 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide

To a solution of (4-fluoro-phenyl) -isobutyl-amine (250mg,1.5mmol) in DCM (5mL) was added pyridine (242 μ L,3.0mmol) followed by 6-chloropyridine-3-sulfonyl chloride (379mg,1.8mmol) and the reaction was stirred at rt for 2 h. Adding water and saturated NaHCO₃Aqueous solution, then extracted with DCM, filtered through a phase separator, concentrated, then purified by silica gel column chromatography (0-20% EtOAc in cyclohexane) to give 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (411mg, 67%). LCMS (m/z, method A) ES⁺343[M+1]⁺.

And step 3: 4- {5- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-pyridin-2-ylamino } -piperidine-1-carboxylic acid tert-butyl ester Butyl ester

To a solution of 6-chloro-pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (150mg, 439. mu. mol) and 4-amino-1-boc piperidine (114mg, 570. mu. mol) in acetonitrile (3mL) was added DIPEA (115. mu.l, 658. mu. mol), and the reaction was heated in a microwave reactor at 160 ℃ for 2.5 hours. EtOAc and saturated NaHCO were added₃Aqueous solution, extraction, washing with brine, and Na₂SO₄Dried, then concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give 4- {5- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-pyridin-2-ylamino } -piperazinePyridine-1-carboxylic acid tert-butyl ester (69mg, 31%). LCMS (M/z, method A) ES-506[ M-1]-.

And 4, step 4: (6- (1-methanesulfonyl-piperidin-4-ylamino) -pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-acyl Amine)

To 4- {5- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-pyridin-2-ylamino } -piperidine-1-carboxylic acid tert-butyl ester (66mg, 130. mu. mol) in DCM (8mL) was added TFA (2mL) and the reaction stirred at room temperature for 30 min. Concentration reaction, purification by SCX column, 2M NH₃Elution of a solution in MeOH afforded 6- (piperidin-4-ylamino) -pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (41mg,101 μmol). To a solution of 6- (piperidin-4-ylamino) -pyridine-3-sulfonic acid (4-fluoro-phenyl) -isobutyl-amide (41mg,101 μmol) in DCM (5mL) was added DIPEA (35 μ L,202 μmol) followed by methanesulfonyl chloride (1mL of 78 μ L,1mmol in 10mL DCM) and the reaction was stirred at rt for 30 min. Then water and saturated NaHCO were added₃Extraction, filtration through a phase separator, concentration, purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) gave the title compound (49 mg).¹H NMR (400MHz, DMSO): 8.03(d, J ═ 2.52Hz,1H),7.54(d, J ═ 7.47Hz,1H),7.35(dd, J ═ 8.95,2.54Hz,1H),7.17(t, J ═ 8.01Hz,4H),6.51(d, J ═ 8.98Hz,1H),3.91 (brs,1H), 3.51(d, J ═ 11.88Hz,2H),3.25(d, J ═ 7.31Hz,2H),2.86(m,5H),1.97(d, J ═ 12.65Hz,2H),1.44-1.49(m,2H),0.82(d, J ═ 6.63Hz,6H), s (m/z, method B) ES⁺485.0[M+1]⁺.

Example 8: n- (4-chlorobenzyl) -4- ((+/-) trans-3-hydroxy-1- (methylsulfonyl) piperidin-4-yl) oxy Yl) -N-isobutylbenzenesulfonamides

Step 1: n-isobutyl-4-methoxy-benzenesulfonamides

To a solution of 4-methoxybenzenesulfonyl chloride (1g,4.8mmol) in DCM (20mL) was added pyridine (1.17mL,14.5mmol) followed by isobutylamine (961 μ L,9.7mmol), and the reaction was stirred at rt for 16 h. 1M aqueous HCl was added, extracted with DCM, filtered through a phase separator, concentrated, and purified by silica gel column chromatography (100% DCM) to afford N-isobutyl-4-methoxy-benzenesulfonamide (1.03g, 88%). LCMS (m/z, method A) ES^-242[M-1]^-.

Step 2: n- (4-chloro-benzyl) -N-isobutyl-4-methoxy-benzenesulfonamide

To a solution of N-isobutyl-4-methoxy-benzenesulfonamide (1.03g,4.2mmol) in anhydrous dimethylacetamide (20mL) was added NaH (60% dispersion in mineral oil, 186mg,4.6mmol) at 0 ℃ until no more gas was evolved, then stirred for a further 10 minutes. 4-chlorobenzyl bromide (951mg,4.6mmol) was added and the reaction was heated at 90 ℃ for 2 hours. The reaction was cooled to room temperature, water was added, extracted with DCM, filtered through a phase separator, concentrated and then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N- (4-chloro-benzyl) -N-isobutyl-4-methoxy-benzenesulfonamide (1.03g, 67%). LCMS (m/z, method A)) ES⁺368[M+1]⁺.

And step 3: n- (4-chloro-benzyl) -4-hydroxy-N-isobutyl-benzenesulfonamide

To a solution of N- (4-chloro-benzyl) -N-isobutyl-4-methoxy-benzenesulfonamide (1.03g,2.8mmol) in DCM (25mL) was added tetrabutylammonium iodide (1.14g,3.1mmol) and the reaction was cooled to-78 ℃. Boron trichloride (4.2mL,4.2mmol of a 1M solution in DCM) was added to the solution over a 2 minute period, followed by stirring for an additional 5 minutes. The reaction was allowed to warm to 0 ℃ and stirred for an additional 2 hours. Adding water and saturated NaHCO₃Aqueous solution, extracted with DCM, filtered through a phase separator, concentrated and then purified by silica gel column chromatography (0-30% EtOAc in cyclohexane) to give N- (4-chloro-benzyl) -4-hydroxy-N-isobutyl-benzenesulfonamide (629mg, 64%). LCMS (m/z, method A) ES^-352[M-1]^-.

Step (ii) of4: (+/-) trans-4- {4- [ (4-chloro-benzyl) -isobutyl-sulfamoyl ] -4]-phenoxy } -3-hydroxy-piperazine Pyridine-1-carboxylic acid tert-butyl ester

To 7-oxa-3-aza-bicyclo [4.1.0]To a solution of tert-butyl heptane-3-carboxylate (354mg,1.8mmol) in EtOH (5mL) was added K₂CO₃(246mg,1.8mmol) and a solution of N- (4-chloro-benzyl) -4-hydroxy-N-isobutyl-benzenesulfonamide (629mg,1.78mmol) in EtOH (5mL), the reaction was heated at 95 ℃ for 16 h. The reaction was cooled to room temperature and concentrated. Water and EtOAc were added, extracted, washed with brine, and Na₂SO₄Dried, then concentrated and purified by silica gel column chromatography (0-100% EtOAc in cyclohexane) to give (+/-) trans-4- {4- [ (4-chloro-benzyl) -isobutyl-sulfamoyl]-phenoxy } -3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (259mg, 26%). LCMS (m/z, method A) ES⁺553[M+1]⁺.

And 5: n- (4-chloro-benzyl) -4- ((+/-) trans-3-hydroxy-piperidin-4-yloxy) -N-isobutyl-benzenesulfonate Amides of carboxylic acids

To (+/-) trans-4- {4- [ (4-chloro-benzyl) -isobutyl-sulfamoyl]To a solution of tert-butyl-phenoxy } -3-hydroxy-piperidine-1-carboxylate (222mg, 402. mu. mol) in DCM (8mL) was added TFA (2mL) and the reaction was stirred at room temperature for 30 min. Concentration reaction, purification by SCX column, 2M NH₃Elution of a solution in MeOH gave N- (4-chloro-benzyl) -4- ((+/-) -trans-3-hydroxy-piperidin-4-yloxy) -N-isobutyl-benzenesulfonamide (202mg, 447. mu. mol). LCMS (m/z, method A) ES⁺453[M+1]⁺.

Step 6: n- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-3-triisopropylsilanyloxy-piperidine- 4-yloxy) -benzenesulfonamides

To a solution of N- (4-chloro-benzyl) -4- ((+/-) trans-3-hydroxy-piperidin-4-yloxy) -N-isobutyl-benzenesulfonamide (202mg, 447. mu. mol) in DCM (10mL) was added triethylamine (187. mu.L, 1.34mmol) followed by triisopropylsilyl triflate (132. mu.L, 492. mu. mol), and the reaction was stirred at room temperature for 1 hour. Et was added to the reaction₃N (187. mu.L, 1.34mmol), triisopropylsilyl trifluoromethanesulfonate (132. mu.L, 492. mu. mol) was then added and the reaction was stirred at room temperature for a further 30 minutes. Water was added and the mixture was extracted with DCM, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-10% MeOH in DCM) to give N- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-3-triisopropylsilanyloxy-piperidin-4-yloxy) -benzenesulfonamide (189mg, 70%). LCMS (m/z, method A) ES⁺609[M+1]⁺.

And 7: n- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-1-methanesulfonyl-3-triisopropylsilyl Oxy-piperidin-4-yloxy) -benzenesulfonamides

To a solution of N- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-3-triisopropylsilanyloxy-piperidin-4-yloxy) -benzenesulfonamide (185mg, 304. mu. mol) in DCM (5mL) was added DIPEA (106. mu.L, 609. mu. mol) followed by methanesulfonyl chloride (1mL of a 231. mu.L solution of 3mmol in 10mL DCM), and the reaction was stirred at room temperature for 1 hour. Adding saturated NaHCO₃The aqueous solution was extracted with DCM, filtered through a phase separator and concentrated to give N- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy) -benzenesulfonamide (271mg, 100%). LCMS (m/z, method A) ES⁺709[M+23]⁺.

And 8: (N- (4-chloro-benzyl) -4- ((+/-) -trans-3-hydroxy-1-methanesulfonyl-piperidin-4-yloxy) -N- Isobutyl-benzenesulfonamide

To a solution of N- (4-chloro-benzyl) -N-isobutyl-4- ((+/-) trans-1-methanesulfonyl-3-triisopropylsilanyloxy-piperidin-4-yloxy) -benzenesulfonamide (271mg) in THF (5mL) was added 1M tetrabutylammonium fluoride in THF (609. mu.L, 609. mu. mol), and the reaction was stirred at room temperature for 30 minutes. Water was added, followed by extraction with EtOAc, washing with brine, and Na₂SO₄Drying, then concentration, purification by silica gel column chromatography (0-75% EtOAc in cyclohexane) and lyophilization afforded the title compound (107 mg).¹H NMR(400MHz,DMSO)：776(d,2H),7.36-7.37(m,4H),7.20(d,2H),5.54(d,1H),4.41(td,1H),4.23(s,2H),3.70-3.72(m,1H),3.52(dd,1H),3.42(d,1H),3.04-3.08(m,1H),2.94(s,3H),2.90(dd,1H),2.83(d,2H),2.12-2.19(m,1H),1.57-1.59(m,2H),0.67(d,6H). LCMS (m/z, method B) ES⁺531[M+1]

Example 9: 4- (4-acetyl-piperazin-1-yl) -N-isobutyl-N- (2-trifluoromethyl-benzyl) -benzenesulfonamide

Step 1: 4-fluoro-N-isobutyl-benzenesulfonamides

A solution of isobutylamine (6.64mL,66.8mmol) and pyridine (6.24mL,77.1mmol) in DCM (100mL) was treated with 4-fluorobenzenesulfonyl chloride (10.0g,51.4mmol) and stirred at RT for 18 h. The mixture was diluted with DCM and diluted with 1N HCl aqueous solution, saturated NaHCO₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Trituration with pentane gave 4-fluoro-N-isobutyl-benzenesulfonamide (10.48g, 88%) as a pale yellow solid.¹H NMR (400MHz, DMSO)7.88-7.81(m,2H),7.63(t, J ═ 6.1Hz,1H),7.47-7.39(m,2H),2.54(t, J ═ 6.5Hz,2H),1.67-1.55(m,1H),0.80(d, J ═ 6.7Hz,6H)⁺232.0[M+1]⁺.

Step 2: n-isobutyl-4-piperazin-1-yl-benzenesulfonamides

To a microwave vial was added 4-fluoro-N-isobutyl-benzenesulfonamide (1.0g,4.32mmol), piperazine (1.86g,21.60mmol), and water (20mL), and heated at 150 ℃ for 1 hour using a microwave reactor. The solid was collected from the reaction mixture by filtration, washed with water, and dried to give N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.15g, 90%).¹H NMR(300MHz,CDCl₃)7.70(d,J＝9.0Hz,2H),6.90(d,J＝9.0Hz,2H),4.33(t,J＝6.5Hz,1H),3.32-3.25(m,4H),3.05-2.99(m,4H),2.73(t,J＝6.6Hz,2H),1.78-1.65(m,1H),0.87(d, J ═ 6.7Hz,7H), LCMS (m/z, method a) ES⁺298.2[M+1]⁺.

And step 3: 4- (4-acetyl-piperazin-1-yl) -N-isobutyl-benzenesulfonamide

N-isobutyl-4-piperazin-1-yl-benzenesulfonamide (1.14g,3.83mmol) and Et were treated with acetyl chloride (340. mu.L, 4.79mmol)₃A solution of N (795. mu.L, 5.75mmol) in DCM (25mL) was stirred at room temperature for 30 min. The mixture was diluted with DCM and saturated aqueous HCl 1N, NaHCO₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (60-75% EtOAc/DCM) gave 4- (4-acetyl-piperazin-1-yl) -N-isobutyl-benzenesulfonamide (1.23g, 95%) as a white solid.¹H NMR (400MHz, DMSO)7.58(d, J ═ 8.8Hz,2H),7.27(t, J ═ 6.2Hz,1H),7.04(d, J ═ 8.8Hz,2H),3.62-3.54(m,4H),3.38-3.26(m,8H),2.49-2.43(m,2H),2.04(s,3H),1.65-1.54(m,1H),0.80(d, J ═ 6.7Hz,6H), LCMS (m/z, method B) ES⁺340.0[M+1]⁺.

And 4, step 4: (4- (4-acetyl-piperazin-1-yl) -N-isobutyl-N- (2-trifluoromethyl-benzyl) -benzenesulfonamide)

A solution of 4- (4-acetyl-piperazin-1-yl) -N-isobutyl-benzenesulfonamide (100mg,0.295mmol) in DMA (2mL) was treated with NaH (60% as a dispersion in mineral oil, 18mg,0.443mmol) and stirred at room temperature for 30 minutes. 2- (trifluoromethyl) benzyl bromide (141mg,0.590mmol) was added and the mixture was heated at 90 ℃ for 1 h. The cooled mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc/DCM) gave the title compound (110mg, 75%).¹H NMR (400MHz, DMSO)7.81(d, J ═ 7.9Hz,1H),7.69 to 7.71(m,4H),7.50(t, J ═ 7.6Hz,1H),7.08(d, J ═ 8.8Hz,2H),4.36(s,2H),3.59(d, J ═ 5.26Hz,4H),3.38(dd, J ═ 26.2,5.0Hz,4H),2.86(d, J ═ 7.2Hz,2H),2.05(s,3H),1.36(t, J ═ 6.7Hz,1H),0.70(d, J ═ 6.6Hz,6H), s (m/z method B) ES⁺498.1[M+1]⁺.

Example 10: n- (4-fluorobenzyl) -N-isobutyl-5- ((1- (methylsulfonyl) piperidin-4-yl) oxy) pyridine- 2-sulfonamides

Step 1: 4- (6-chloro-pyridin-3-yloxy) -piperidine-1-carboxylic acid tert-butyl ester

A solution of 2-chloro-5-hydroxypyridine (5.00g,38.60mmol), 1-Boc-4-hydroxypiperidine (9.32g,46.31mmol) and triphenylphosphine (15.19g,57.90mmol) in THF (200mL) was treated dropwise with diisopropyl azodicarboxylate (11.14mL,57.90mmol) at 0 deg.C. The mixture was stirred at rt for 18 h, diluted with EtOAc, washed with water and brine, and Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (25-40% EtOAc in petrol (40-60 ℃) afforded 4- (6-chloro-pyridin-3-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (5.70g, 47%) as a pale yellow residue.¹HNMR(300MHz,CDCl₃)8.06(d, J ═ 2.8Hz,1H),7.23-7.16(m,2H),4.51-4.41(m,1H),3.75-3.64(m,2H),3.40-3.29(m,2H),1.99-1.86(m,2H),1.83-1.67(m,2H),1.47(s,9H), LCMS (m/z, method a) ES⁺311.1[M+1]⁺.

Step 2: 2-chloro-5- (piperidin-4-yloxy) -pyridines

A solution of 4- (6-chloro-pyridin-3-yloxy) -piperidine-1-carboxylic acid tert-butyl ester (5.68g,18.16mmol) in DCM (2mL) was treated with TFA (25mL) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo, dissolved in 1N aqueous HCl and washed with EtOAc. Basified the aqueous phase with ammonium hydroxide and extracted into EtOAc. With Na₂SO₄The combined extracts were dried and concentrated in vacuo to give 2-chloro-5- (piperidin-4-yloxy) -pyridine (4.58g) as a yellow solid.¹H NMR(300MHz,DMSO)8.54(brs,1H),8.18(d,J＝3.1Hz,1H),7.60-7.53(m,1H),7.45(d,J＝8.8Hz,1H),4.76-4.65(m,1H),3.30-3.19(m,2H),3.11-3.00(m,2H),2.15-2.03(m,2H),1.89-1.74(m,2H).LCMS(m/z, method A) ES⁺213.1[M+1]⁺.

And step 3: 2-chloro-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine

Treatment of 2-chloro-5- (piperidin-4-yloxy) -pyridine (4.55g,21.39mmol) and Et with methanesulfonyl chloride (2.48mL,32.09mmol)₃A solution of N (5.92mL,42.8mmol) in DCM (50mL) was stirred at room temperature for 2 h. The mixture was diluted with DCM and saturated aqueous NaHCO with 1N HCl₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-70% EtOAc in cyclohexane) afforded 2-chloro-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (3.19g, 51%).¹H NMR(300MHz,CDCl₃)8.07(d, J ═ 2.9Hz,1H),7.28-7.16(m,2H),4.58-4.49(m,1H),3.44-3.28(m,4H),2.83(s,3H),2.13-1.92(m,4H) LCMS (m/z, method a) ES⁺290.9[M+1]⁺.

And 4, step 4: 2-benzylsulfanyl-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine

A suspension of NaH (60% dispersion in mineral oil, 413mg,10.32mmol) in dry DMF (12mL) was treated dropwise at 0 deg.C with benzyl mercaptan (1.21mL,10.32 mmol). After addition, the mixture was stirred at room temperature for 15 minutes. 2-chloro-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (1.00g,3.44mmol) was added, and the mixture was stirred at room temperature for 18 hours, heated at 80 ℃ for another 8 hours, and cooled overnight. The mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (30-50% EtOAc in cyclohexane) afforded 2-benzylsulfanyl-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (659mg, 51%).¹H NMR(300MHz,CDCl₃)8.20(brs,1H),7.40-7.34(m,2H),7.32-7.18(s,4H),7.14-7.05(m,2H),4.52-4.43(m,1H),4.39(s,2H),3.36(t, J ═ 5.6Hz,4H),2.82(s,3H),2.08-1.91(m,4H) LCMS (m/z, method a) ES (m/z, method a)⁺379.1[M+1]⁺.

And 5: 5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine-2-sulfonyl chlorides

A suspension of 2-benzylsulfanyl-5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine (650mg,1.72mmol) in acetic acid (8mL) and water (4mL) was treated with N-chlorosuccinimide (917mg,6.87mmol) at 0 deg.C and stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and the aqueous phase was extracted with EtOAc. With saturated NaHCO₃The combined extracts were washed with aqueous solution, water and brine, and Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) afforded 5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine-2-sulfonyl chloride (269mg, 44%).¹H NMR(300MHz,CDCl₃)8.43(d, J ═ 2.8Hz,1H),8.08(d, J ═ 8.8Hz,1H),7.38(dd, J ═ 8.8,2.9Hz,1H),4.79-4.71(m,1H),3.50-3.33(m,4H),2.85(s,3H),2.21-1.99(m,4H), LCMS (m/z, method a) ES⁺355.1[M+1]⁺.

Step 6: (5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine-2-sulfonic acid (4-fluoro-benzyl) -isobutyl-acyl Amine)

A solution of (4-fluorobenzyl) -isobutylamine (53mg,0.295mmol) and pyridine (34. mu.L, 0.423mmol) in DCM (3mL) was treated with 5- (1-methanesulfonyl-piperidin-4-yloxy) -pyridine-2-sulfonyl chloride (75mg,0.211mmol) and stirred at room temperature for 18 h. The mixture was diluted with DCM and saturated NaHCO with 1M aqueous citric acid₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) followed by silica gel column chromatography (0-10% EtOAc in DCM) gave the title compound (39mg, 37%).¹H NMR (400MHz, DMSO)8.45(d, J ═ 2.8Hz,1H),7.89(d, J ═ 8.7Hz,1H),7.66(dd, J ═ 8.8,2.9Hz,1H),7.38-7.32(m,2H),7.17-7.09(m,2H),4.84-4.76(m,1H),4.39(s,2H),3.43-3.34(m,2H),3.18-3.10(m,2H),3.00(d, J ═ 7.5Hz,2H),2.92(s,3H),2.11-2.01(m,2H),1.84-1.73(m,2H),1.63-1.52(m,1H),0.68(d, J ═ 6.6H, 6 ES (m, 6H), B/z method (B, z)⁺499.9[M+1]⁺.

Example 11: 1-methanesulfonyl-piperidine-4-carboxylic acid {4- [ isobutyl- (2-trifluoromethyl-phenyl) -sulfamoyl Base of]-phenyl } -amides

Step 1: 4-nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamides

A solution of 2- (trifluoromethyl) aniline (1.51g,9.37mmol) and pyridine (1.08mL,13.38mmol) in DCM (30mL) was treated with 4-nitrobenzenesulfonyl chloride (1.48g,6.69mmol) and stirred at room temperature for 18 h. The mixture was diluted with DCM and saturated NaHCO with 1M aqueous HCl₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Trituration with pentane gave 4-nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (1.91g, 82%).¹H NMR(300MHz,CDCl₃)8.31-8.23(m,2H),7.95-7.85(m,3H),7.64-7.50(m,2H),7.31(t, J ═ 7.7Hz,1H),6.89(brs,1H), LCMS (m/z, method a) ES⁺347.1[M+1]⁺.

Step 2: N-isobutyl-4-nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide

4-Nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (1.90g,5.49mmol), 1-bromo-2-methylpropane (1.19mL,10.97mmol) and K₂CO₃A mixture of (1.51g,10.97mmol) in DMF (20mL) was heated at 100 ℃ for 18 h. The cooled mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-30% EtOAc in cyclohexane) afforded N-isobutyl-4-nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (1.69g, 77%).¹H NMR(300MHz,CDCl₃)8.34(d, J ═ 8.8Hz,2H),7.88(d, J ═ 8.8Hz,2H),7.78-7.70(m,1H),7.61-7.47(m,2H),7.23-7.16(m,1H),3.48-3.31(m,2H),1.76-1.60(m,1H),0.88(dd, J ═ 10.1,6.6Hz,6H), LCMS (m/z, method a) no ES determination⁺And (4) mass ions.

And step 3: 4-amino-N-isobutyl-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide

A partial solution of N-isobutyl-4-nitro-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (1.68g,4.19mmol) in EtOH (IMS grade, 50mL) and water (15mL) was treated with iron powder (. about.325 mesh, 936mg,16.76mmol) and ammonium chloride (896mg,16.76mmol) and heated at reflux for 1 h. The cooled mixture was filtered through celite, the filter cake was washed with EtOH, and the filtrate was concentrated to a small volume in vacuo. The resulting residue was diluted with water and extracted into DCM. With Na₂SO₄The combined extracts were dried and concentrated in vacuo. Purification by silica gel column chromatography (0-75% EtOAc in cyclohexane) afforded 4-amino-N-isobutyl-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (1.53g, 98%).¹H NMR(300MHz,CDCl₃)7.72(dd, J ═ 7.5,2.1Hz,1H),7.54-7.39(m,4H),7.14(d, J ═ 7.7Hz,1H),6.70-6.63(m,2H),3.35(dd, J ═ 13.5,8.3Hz,1H),3.15(dd, J ═ 13.5,5.3Hz,1H),1.71-1.55(m,1H),0.88(d, J ═ 6.5Hz,3H),0.77(d, J ═ 6.7Hz,3H), LCMS (m/z, method a) ES (m/z, method a)⁺373.1[M+1]⁺.

And 4, step 4: (1-methanesulfonyl-piperidine-4-carboxylic acid {4- [ isobutyl- (2-trifluoromethyl-phenyl) -sulfamoyl]- Phenyl } -amide)

A solution of 4-amino-N-isobutyl-N- (2-trifluoromethyl-phenyl) -benzenesulfonamide (100mg,0.268mmol), 1- (methylsulfonyl) -4-piperidinecarbonyl chloride (108mg,0.48mmol) and DIPEA (138. mu.L, 0.804mmol) in DCM (8mL) was stirred at room temperature for 3 hours. The mixture was diluted with DCM and saturated aqueous NaHCO with 1N HCl₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) with Et₂Trituration of O/pentane together gave the title compound (98mg, 65%).¹H NMR(400MHz,DMSO10.42(s,1H),7.85(d,J＝8.8Hz,2H),7.82(dd,J＝7.7,1.9Hz,1H),7.62-7.63(m,1H),7.58(d,J＝8.8Hz,2H),6.99(d,J＝7.8Hz,1H),3.63(d,J＝11.8Hz,2H),3.38-3.39(m,1H),3.11(dd,J＝13.4,4.7Hz,1H),2.90(s,3H),2.76-2.78(m,2H),1.95(d,J＝13.5Hz,2H),1.63-1.68(m,2H),1.44-1.48(m,1H),1.09(t, J ═ 7.0Hz,1H),0.88(d, J ═ 6.5Hz,3H),0.71(d, J ═ 6.7Hz,3H), LCMS (m/z, method B) ES⁺562.0[M+1]⁺.

Example 12: 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-N- (1-methanesulfonyl-piperidin-4-yl) -benzene Carboxamides

Step 1: 4- (4-fluoro-phenylsulfamoyl) -benzoic acid methyl ester

A solution of 4-fluoroaniline (484. mu.L, 5.11mmol) and pyridine (688. mu.L, 8.52mmol) in DCM (20mL) was treated with methyl 4- (chlorosulfonyl) benzoate (1.00g,4.26mmol) and stirred at room temperature for 3 h. The mixture was diluted with DCM and saturated aqueous NaHCO with 1N HCl₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Trituration with pentane gave 4- (4-fluoro-phenylsulfamoyl) -benzoic acid methyl ester (1.02g, 77%).¹H NMR(300MHz,CDCl₃)8.10(d, J ═ 8.4Hz,2H),7.78(d, J ═ 8.4Hz,2H),7.07-6.99(m,2H),6.98-6.88(m,2H),6.75(brs,1H),3.94(s,3H), LCMS (m/z, method a) ES⁺310.0[M+1]⁺.

Step 2: 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-benzoic acid methyl ester

4- (4-fluoro-phenylsulfamoyl) -benzoic acid methyl ester (1.00g,3.23mmol), 1-bromo-2-methylpropane (527. mu.L, 4.85mmol) and K₂CO₃A mixture of (891mg,6.46mmol) in DMF (10mL) was heated at 90 ℃ for 18 h. The cooled mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) afforded 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-methyl benzoate (1.69g, 77%).¹H NMR(300MHz,CDCl₃)8.12(d, J ═ 8.3Hz,2H),7.63(d, J ═ 8.3Hz,2H),6.99(d, J ═ 6.5Hz,4H),3.96(s,3H),3.31(d, J ═ 7.3Hz,2H),1.58-1.56(m,1H),0.92(d, J ═ 6.7Hz,6H), LCMS (m/z, method a) ES⁺366.1[M+1]⁺.

And step 3: 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-benzoic acid

Treatment of 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl with 1M aqueous NaOH solution (8.6mL,8.60mmol)]A solution of methyl benzoate (1.05g,2.87mmol) in MeOH (40mL) was stirred at room temperature for 2.5 hours. MeOH was removed in vacuo, the aqueous phase diluted with water, washed with EtOAc and acidified to pH 1-2 with 1N aqueous HCl. The acidic aqueous phase was extracted with EtOAc. With Na₂SO₄The combined extracts were dried and concentrated in vacuo to give 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-benzoic acid (914mg, 91%).¹H NMR (300MHz, DMSO)13.48(br s,1H),8.10(d, J ═ 8.3Hz,2H),7.65(d, J ═ 8.3Hz,2H),7.25-7.05(m,4H),3.35(d, J ═ 7.3Hz,2H),1.51-1.33(m,1H),0.85(d, J ═ 6.6Hz,6H), LCMS (m/z, method a) ES (m/z, method a)⁺352.0[M+1]⁺.

And 4, step 4: 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl]-N- (1-methanesulfonyl-piperidin-4-yl) -benzoyl Amines as pesticides

Treatment of 4- [ (4-fluoro-phenyl) -isobutyl-sulfamoyl with HATU (162mg,0.428mmol)]A solution of benzoic acid (100mg,0.285mmol), 4-amino-1-methanesulfonylpiperidine (66mg,0.370mmol) and DIPEA (146. mu.L, 0.855mmol) in DMF (2mL) was stirred at room temperature for 18 h. The mixture was diluted with EtOAc and diluted with 1N aqueous HCl, saturated NaHCO₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-50% EtOAc in DCM), extraction with Et₂Trituration with O afforded the title compound (124mg, 85%).¹H NMR (400MHz, DMSO)8.60(d, J ═ 7.6Hz,1H),8.00(d, J ═ 8.3Hz,2H),7.63(d, J ═ 8.3Hz,2H),7.20(t, J ═ 8.7Hz,2H),7.11(dd, J ═ 8.8,5.0Hz,2H),3.93-3.95(m,1H),3.58(d, J ═ 11.8Hz,2H),2.88(s,5H),1.93(s,1H),1.90(s,2H),1.58-1.61(m,2H),1.42-1.44(m,1H),0.85(d, J ═ 6.6Hz,6H), s (m/z), method s (m/z, methodB)ES⁺511.8[M+1]⁺.

Example 13: n-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -N- (2-trifluoromethyl-benzyl) - Benzenesulfonamides

Step 1: 4-bromomethyl-N-isobutyl-benzenesulfonamide

A solution of isobutylamine (1.10mL,11.14mmol) and pyridine (600. mu.L, 7.42mmol) in DCM (60mL) was treated with 4- (bromomethyl) benzenesulfonyl chloride (2.00g,7.42mmol) and stirred at room temperature for 1.5 h. The mixture was diluted with DCM and saturated aqueous NaHCO with 1N HCl₃Aqueous solution, water and brine, washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-50% EtOAc in cyclohexane) afforded 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08g, 48%).¹H NMR(300MHz,CDCl₃)7.83(d, J ═ 8.1Hz,2H),7.53(d, J ═ 8.1Hz,2H),4.50(s,2H),4.43(t, J ═ 6.4Hz,1H),2.78(t, J ═ 6.6Hz,2H),1.81-1.65(m,1H),0.88(d, J ═ 6.7Hz,6H), LCMS (m/z, method a) ES (m/z, method a)⁺308.0[M+Na]⁺.

Step 2: bromination of 4-isobutylsulfamoyl-benzyl-

A mixture of 4-bromomethyl-N-isobutyl-benzenesulfonamide (1.08g,3.53mmol) and triphenylphosphine (1.39g,5.29mmol) in toluene (20mL) was heated at reflux for 18 h. The precipitate was collected from the cooled mixture, washed with toluene and air dried to give 4-isobutylsulfamoyl-benzyl bromide-(1.88g,94％)。¹H NMR(300MHz, DMSO)7.96-7.88(m,2H),7.79-7.56(m,15H),7.20-7.13(m,2H),5.29(d, J ═ 16.1Hz,2H),2.53-2.46(m,2H),1.64-1.48(m,1H),0.77(d, J ═ 6.7Hz,6H), LCMS (m/z, method a) ES⁺488.1[M+Na]⁺.

And step 3: n-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -benzenesulfonamide

4-Isobutylsulfamoyl-benzyl-A solution of (1.87g,3.29mmol) in DMF (10mL) was stirred at room temperature for 1 hour. 1- (methylsulfonyl) piperidin-4-one (758mg,4.28mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) afforded N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -benzenesulfonamide (392mg, 31%).¹HNMR(300MHz,CDCl₃)7.81(d, J ═ 8.2Hz,2H),7.31(d, J ═ 8.2Hz,2H),6.43(s,1H),4.40(t, J ═ 6.5Hz,1H),3.37(t, J ═ 5.7Hz,2H),3.25(t, J ═ 5.8Hz,2H),2.82-2.76(m,5H),2.60(t, J ═ 5.7Hz,2H),2.53(t, J ═ 5.7Hz,2H),1.80-1.66(m,1H),0.88(d, J ═ 6.7Hz,6H), LCMS (m/z, method a) ES (m/z), method a) ES⁺523.1[M+Na]⁺.

And 4, step 4: (N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -N- (2-trifluoromethyl-benzyl) -benzene Sulfonamides)

N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -benzenesulfonamide (375mg,0.97mmol), 2- (trifluoromethyl) benzyl bromide (289mg,1.22mmol) and K₂CO₃A mixture of (201mg,1.46mmol) in DMF (5mL) was heated at 110 ℃ for 6 h. The cooled mixture was diluted with EtOAc, washed with water and brine, and washed with Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) from Et₂The residue was concentrated in O to give the title compound(290mg,55％)。¹H NMR (400MHz, DMSO)7.83(d, J ═ 8.3Hz,2H),7.70-7.73(m,3H),7.49(t, J ═ 8.1Hz,3H),6.51(s,1H),4.46(s,2H),3.22(dt, J ═ 30.4,5.7Hz,4H),2.96(d, J ═ 7.3Hz,2H),2.89(s,3H),2.49-2.50(m,4H),1.39-1.40(m,1H),0.70(d, J ═ 6.6Hz,6H) LCMS (m/z, method B) ES⁺544.9[M+1]⁺.

Example 14: 4- (hydroxy (1- (methylsulfonyl) piperidin-4-yl) methyl-N-isobutyl-N- (2- (trifluoromethyl) sulfonyl) Yl) benzyl) benzenesulfonamide

A solution of N-isobutyl-4- (1-methanesulfonyl-piperidin-4-ylidenemethyl) -N- (2-trifluoromethyl-benzyl) -benzenesulfonamide (1.05g,1.93mmol) in THF (5mL) was treated with borane THF complex (1.0M in THF, 15.4mL,15.4mmol) under a nitrogen atmosphere and stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 ℃ and quenched by the addition of 95% ethanol (IMS grade), 2M aqueous NaOH (10mL) and hydrogen peroxide (50 wt% solution in water, 10 mL). The mixture was stirred for 1 hour with saturated NH₄Dilute aqueous Cl and extract with EtOAc. The combined extracts were washed with brine, Na₂SO₄Drying and vacuum concentrating. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) followed by preparative reverse phase HPLC (gradient of 0.1% formic acid in 30-98% acetonitrile in water) followed by silica gel column chromatography (0-20% EtOAc in DCM) gave the title compound (75mg, 7%).¹H NMR (400MHz, DMSO)7.83(d, J ═ 8.2Hz,2H),7.70-7.69(m,3H),7.55(d, J ═ 8.1Hz,2H),7.52-7.47(m,1H),5.52(d, J ═ 4.5Hz,1H),4.50-4.43(m,3H),3.61-3.49(m,2H),2.94(m,2H),2.81(s,3H),2.64-2.53(m,2H),1.83-1.75(m,1H),1.67-1.56(m,1H),1.44-1.20(m,4H),0.69(d, J ═ 6.6Hz,6H), s (m/z), method B) ES⁺563.0[M+1]⁺.

Using the above procedure, prepareThe compounds of the invention are shown in Table 1 below, which also shows the RORc IC of selected compounds as determined by the assay described below₅₀(micromolar) data. Where stereoisomers of a compound are isolated, but stereochemistry is not specified, the terms "stereoisomer a" and "stereoisomer B" are used.

TABLE 1

Example 15 in vitro RORc ligand binding assay

By measuring Ki_app、IC₅₀Or percent inhibition value, and the potency of a compound to inhibit RORc activity is determined using this assay. The consumables used in this example are shown in table 2 below.

By measuring Ki_app、IC₅₀Or percent inhibition value, which determines the inhibition of a compound

TABLE 2

Filter plate preparation

On the day of assay, 100uL of 0.05% CHAPS (in deionized H) was added₂O) were added to all wells of the GFB Unifilter plate and allowed to soak for 1 h. Preparation of 50mM HEPES (pH7.4), 150mM NaCl and 5mM MgCl₂To wash the filter plate. To prepare the assay buffer, BSA was added to the wash buffer to bring the concentration to 0.01% and DTT was added to bring the concentration to 1 mM.

Compound (I)

For IC₅₀Mode, 10mM compound stock was serially diluted in DMSO with DMSO to yield a final concentration of 20 × required in DMSO (15uL compound +30uL DMSO), 20 × compound stock was diluted 4-fold in DMSO with assay buffer to reach a final test concentration of 5 × in 25% DMSO (10uL compound +30uL assay buffer), the solutions were mixed by several aspirations using a pipette set to a volume of 50 uL.

For two-point screening, 10mM stock compound solutions were diluted in DMSO to obtain 200uM (20 × high assay concentration) and then further diluted 10-fold to 20uM (20 × low assay concentration). The 20 × stock solution was diluted 4-fold with assay buffer (10uL compound +30uL assay buffer) to 5 × assay concentration (50uM and 5uM), and 10uL was added to duplicate wells of both assay plates. For each concentration tested on 2 plates, 4 assay plates (1uM and 10uM, n-2) were used for each group of 80 compounds.

Non-specific binding (NSB) samples, Total Binding (TB) samples, and receptor-free (R-free) samples

25-hydroxycholesterol (1uM) was prepared in DMSO as described above for compounds for determination of NSB signal levels, and then diluted in assay buffer to give a final concentration of 5 uM. For 25-hydroxycholesterol in 25% DMSO/75% assay buffer; 10uL per well was used for NSB samples. The wells used for the total binding and no receptor sample assays contained 10uL of 25% DMSO/75% assay buffer per well.

Radioligand (25-, [ solution of a nucleic acid sequence ] ³ H]Hydroxycholesterol) preparation

Will 25-, is³H]Hydroxycholesterol was diluted in assay buffer to obtain a concentration of 15nM and vortexed. To all wells 20uL was added to reach a final concentration of 6nM in the assay.

Receptor preparation

The optimal concentration of RORc receptor was found to be 0.6 ug/mL. Stock acceptor solution was diluted in assay buffer to obtain a concentration of 1.5ug/mL in assay buffer. Add 20uL to all wells. For the receptor-free samples, 20uL of assay buffer was used instead of the receptor solution.

Adding samples to the plate and incubation

The assay plate is a 96-well polypropylene V-plate.A solution of 10uL 5 × compound in 25% DMSO/75% assay buffer is added to the test wells.A 10uL 25% DMSO/75% assay wash is added to either the total binding wells or the no receptor wells.A solution of 10uL 5uM 25-hydroxycholesterol in 25% DMSO/75% assay wash is added to the NSB wells.20 uL of 15nM 25-, "prepared in assay buffer is added to all wells³H]A hydroxycholesterol. To the hole adding 20uL 1.5ug/mL RORc receptor (or to the no R hole adding 40uL determination buffer). After addition to the wells, the plates were incubated at 25 ℃ for 3 h.

Filtration

After transfer of the incubated sample the filter plates were washed 4 times with a Packard Filtermate Harvester. The plate was thoroughly dry filtered (2h at 50 ℃ C. or overnight at room temperature). To all wells 50uL Microscint 0 was added and read on a Topcountprotocol insert.

Final concentration

The final concentrations were as follows: 50mM HEPES buffer (pH 7.4); 150mM NaCl; 1mM DTT; 5mM MgCl₂(ii) a 0.01% BSA; 5% DMSO; 0.6ug/mL RORc receptor; 6nM 25-³H]A hydroxycholesterol. For the NSB well, 1uM 25-hydroxycholesterol was also present.

While the invention has been described with reference to specific embodiments thereof, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process step or steps, to the objective spirit and scope of the present invention. All such variations are within the scope of the appended claims.

Claims

1. A compound of formula Ia or Ib:

or a pharmaceutically acceptable salt thereof,

wherein:

m is 0 or 1;

n is 0 to 3;

p is 1 or 2;

q is 1 to 3;

r is 0 to 2;

D is: -N-or-CR^g-；

E is: -N-or-CR^h-；

G is: -N-or-CRⁱ-；

Y is: -O-; -S-; -SO₂-；-CR^cR^d-; or-NR^e-；

Z is CR^fOr N;

or R⁵And R³And R⁴One of which, together with the atoms to which they are attached, may form a 5-7 membered ring, which may be unsubstituted or substituted by C_1-6Alkyl is substituted one or more times and wherein the ring is carbocyclic or a combination thereofOne of the ring members is replaced with a heteroatom selected from O, N and S;

R^athe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

R^dthe method comprises the following steps: hydrogen; c_1-6An alkyl group; c_3-6A cycloalkyl group; c_3-6cycloalkyl-C_1-6An alkyl group; halogen; c_1-6Alkyl-carbonyl; c_3-6Cycloalkyl-carbonyl; c_3-6cycloalkyl-C_1-6Alkyl-carbonyl; c_1-6An alkyl-sulfonyl group; c_3-6Cycloalkyl-sulfonyl; c_3-6cycloalkyl-C_1-6An alkyl-sulfonyl group; an aminocarbonyl group; N-C_1-6Alkyl-aminocarbonyl; n, N-di-C_1-6Alkyl-aminocarbonyl; an aminosulfonyl group; N-C_1-6Alkyl-aminosulfonyl; n, N-di-C_1-6Alkyl-aminosulfonyl; a cyano group; c_1-6An alkoxy group; c_1-6Alkyl-sulfonyl radicalAn amino group; an amino group; N-C_1-6An alkyl-amino group; n, N-di-C_1-6An alkyl-amino group; halogen-C_1-6An alkyl group; cyano-C_1-6Alkyl-carbonyl; cyano-C_1-6An alkyl-sulfonyl group; hydroxy-C_1-6Alkyl-carbonyl; c_1-6Alkoxy-carbonyl; a carboxyl group; or a hydroxyl group; wherein C is_1-6The alkyl radical may be unsubstituted or substituted one or more times by halogen; and wherein C_3-6Cycloalkyl and C_3-6cycloalkyl-C_1-6The alkyl radical may be unsubstituted or substituted by R⁹One or more substitutions;

R^gthe method comprises the following steps: hydrogen; or C_1-6An alkyl group;

wherein the compound is selected from:

1- ((4- ((1- (methylsulfonyl) piperidin-4-yl) oxy) phenyl) sulfonyl) indoline;

4- (4-acetylpiperazin-1-yl) -N- (4-fluorobenzyl) -N-isobutylbenzenesulfonamide;

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

wherein

s is: 0; or 1;

t is: 1; or 2;

j is: -CR^jR^k-；-NR^m-; -O-; or-S-; and is

R^j；R^kAnd R^mEach independently is: hydrogen; or C_1-6An alkyl group.

3. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to 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. Use of a compound according to claim 1 or 2 for the treatment of arthritis.

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

8. Use of a compound according to claim 1 or 2 in the manufacture of a medicament for the treatment of arthritis.

9. The invention as hereinbefore described.