WO2018210729A1

WO2018210729A1 - Aromatic sulfonamide derivatives as antagonists or negative allosteric modulators of p2x4 receptor

Info

Publication number: WO2018210729A1
Application number: PCT/EP2018/062344
Authority: WO
Inventors: Stefan Werner; Arwed Cleve
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2017-05-18
Filing date: 2018-05-14
Publication date: 2018-11-22
Anticipated expiration: 2019-11-18

Abstract

Substituted aromatic sulfonamides of formula (I), pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, especially for the treatment of pain.

Description

AROMATIC SULFONAMIDE DERIVATIVES AS ANTAGONISTS

OR NEGATIVE ALLOSTERIC MODULATORS OF P2X4 RECEPTOR

FIELD OF APPLICATION OF THE INVENTION

The invention relates to substituted aromatic sulfonamides of formula (I) as described and defined herein, pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease. The present invention, as described and defined herein, relates to pharmaceutical compositions and combinations comprising an active ingredient which is an antagonist or a negative allosteric modulator of P2X4. The use of such compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular in mammals, such as but not limited to diseases associated with pain, or for the treatment or prophylaxis of pain or neuronal damage and inflammation in the brain or spinal cord or arthritis or spondylitis syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, multiple sclerosis as such, spinal cord or ischemic brain injury as such, as a sole agent or in combination with other active ingredients.

BACKGROUND OF THE INVENTION

Chronic inflammatory pain such as in, but not limited to, conditions of endometriosis and adenomyosis, arises as a consequence of inflammatory responses mounted by the immune system following tissue damage or local cell death and generally persists long after the initial injury has healed. Since a large percentage of patients with inflammatory diseases do not respond adequately to currently available anti-inflammatory treatments or analgesic drugs or suffer from intolerable side effects, investigation of alternative treatments for inflammatory conditions / disorders is warranted.

Adenosine triphosphate ATP is widely recognized as an important neurotransmitter implicated in various physiological and pathophysiological roles by acting through different subtypes of purinergic receptors (Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 201 1 , Prog Neurobiol 95:229-274). To date, seven members of the P2X family have been cloned, comprising P2X1 -7 (Burnstock 2013, Front Cell Neurosci 7:227). The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types largely known to be involved in inflammatory/ immune processes specifically including monocytes, macrophages, mast cells and microglia cells (Wang et al., 2004, BMC Immunol 5:16; Brone et al., 2007 Immunol Lett 1 13:83-89). Activation of P2X4 by extracellular ATP is known, amongst other things, to lead to release of pro-inflammatory cytokines and prostaglandins (PGE2) (Bo et al., 2003 Cell Tissue Res 313:159-165; Ulmann et al., 2010, EMBO Journal 29:2290-2300; de Ribero Vaccari et al., 2012, J Neurosci 32:3058-3066). Numerous lines of evidence in the literature using animal models implicate P2X4 receptor in nociception and pain. Mice lacking the P2X4 receptor do not develop pain hypersensitivity in response to numerous inflammatory challenges such as complete Freunds Adjuvant, carrageenan or formalin (Ulmann et al., 2010, EMBO Journal 29:2290-2300). In addition, mice lacking the P2X4R do not develop mechanical allodynia after peripheral nerve injury, indicating an important role of P2X4 also in neuropathic pain conditions (Tsuda et al., 2009, Mol Pain 5:28; Ulmann et al., 2008, J Neurocsci 28:1 1263- 11268).

Besides the prominent role of P2X4 in acute and chronic pain-related diseases (Trang and Salter, 2012, Purinergic Signalling 8:621 -628; Burnstock , 2013 Eur J Pharmacol 716:24-40), P2X4 is considered as a critically important mediator of inflammatory diseases such as, respiratory diseases (e.g. asthma, COPD), lung diseases including fibrosis, cancer and atherosclerosis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).

EP 2 597 088 A1 describes P2X4 receptor antagonists and in particular a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further disclosed the use of P2X4 receptor antagonist diazepine derivatives represented by the formula (I), (II), (III), or its pharmacologically acceptable salt, which shows P2X4 receptor antagonism, being effective as an agent for prevention or treatment of nociceptive, inflammatory, and neuropathic pain. In more detail, EP 2 597 088 A1 describes P2X4 receptor antagonists being effective as a preventive or therapeutic agent for pain caused by various cancers, diabetic neuritis, viral diseases such as herpes, and osteoarthritis. The preventive or therapeutic agent according to EP 2 597 088 A1 can also be used in combination with other agents such as opioid analgesic (e.g., morphine, fentanyl), sodium channel inhibitor (e.g., novocaine, lidocaine), or NSAIDs (e.g., aspirin, ibuprofen). The P2X4 receptor antagonist used for pain caused by cancers can be also used in combination with a carcinostatic such as a chemotherapic. Further P2X4 receptor antagonists and their use are disclosed in WO2013105608, WO2015005467 and

WO2015005468.

"Discovery and characterization of novel, potent and selective P2X4 receptor antagonists for the treatment of pain" was presented at the Society for Neuroscience Annual Meeting 2014 (Carrie A Bowen et al.; poster N. 241 .1 ) Said poster describes the methods to identify novel, potent and selective small-molecule antagonists that inhibit P2X4 across species, and how to evaluate selected compounds in experimental models of neuropatic and inflammatory pain. In particular a method for human, rat, mouse P2X4R Flipr-based screening, a human P2X4R electrophysiology assay, a suitable mouse neuropathy model and a mouse inflammation model were described.

WO2015/088564 and WO2015/088565 provide P2X4 receptor modulating compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. Said P2X4 receptor modulating compounds are useful for the treatment, prevention, and/or management of various disorders, including but not limited to, chronic pain, neuropathy, inflammatory diseases and central nervous system disorders.

There is no reference in the state of the art about substituted aromatic sulfonamides of general formula (I) as described and defined herein and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, particularly to the use of substituted aromatic sulfonamides of general formula (I) for the treatment or prophylaxis of diseases associated with pain, or for the treatment or prophylaxis of pain syndromes (acute and chronic), inflammatory-induced pain, neuropathic pain, pelvic pain, cancer-associated pain, endometriosis-associated pain as well as endometriosis as such, cancer as such, and proliferative diseases as such like endometriosis, as a sole agent or in combination with other active ingredients.

Therefore, the inhibitors of P2X4 of the current invention represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.

DESCRIPTION OF THE INVENTION

The present invention relates to a compound of formula (I)

in which:

X represents C- R^2a or N ;

R¹ represents a group selected from :

wherein ^* indicates the point of attachment of said group with the rest of the molecule;

R² represents phenyl, heteroaryl or a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said phenyl or heteroaryl groups are substituted once with R¹¹ or once with R^{11 a} and optionally once with Ci-C₂-alkyl; R^2a represents hydrogen, cyano, nitro, halogen, Ci -C₂-alkyl or Ci -C₂-haloalkyl;

R^2b represents hydrogen, halogen, Ci -C2-alkyl or Ci -C2-haloalkyl;

R^2c represents hydrogen, halogen, Ci -C₂-alkyl or Ci -C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH ;

R⁵ represents hydrogen or Ci -C₃-alkyl;

R⁶ represents halogen, cyano, nitro, OH, Ci -C₄-alkyl, Ci -C₄-haloalkyl,

Ci -C₄-alkoxy, Ci -C₄-haloalkoxy or F₃CS-;

R^6a and R^6b are the same or different and represent, independently from each other, respectively

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci -C -alkyl, C3-C₆-cycloalkyl, Ci -C -haloalkyl, Ci -C -alkoxy, Ci -C -haloalkoxy, HO-(C₂-C -alkoxy)-, (Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-, R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci -C -alkyl, C3-C₆-cycloalkyl, Ci -C₄-haloalkyl, Ci -C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-, R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-0-CH₂-CH₂-, -0-CH₂-0- or -0-CH₂-CH₂-0-;

R^7a and R^7b are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci -C -alkyl or Ci -C -haloalkyl;

R⁸ represents, independently from each respective occurence, Ci -C₆-alkyl, Ci -C₄-alkoxy-Ci -C₄-alkyl, Cs-Ce-cycloalkyl or Ci -C₄-haloalkyl;

R⁹ and R¹⁰ are the same or different and represent, independently from each other, hydrogen, Ci -C₄-alkyl, Cs-Ce-cycloalkyl, Ci -C₄-haloalkyl or

(CH₃)₂N-Ci -C₄-alkyl or together with the nitrogen atom to which they are attached form a

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR^a in which R^a represents a Ci -C₆-alkyl or Ci -C₆-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci -C₄-alkyl;

R¹¹ represents R¹²-C(0)-NH-;

R^11a re resents a group selected from:

R¹² represents C₂-C₄-alkenyl, Ci -C₄-hydroxyalkyl or C3-C₆-cycloalkyl,

wherein said Cs-Ce-cycloalkyl groups are substituted one to three times with halogen;

R^13a represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

wherein at least one of R^13a, R^13b, R^13c and R^13d is different from hydrogen;

R^13e represents hydrogen, halogen, methyl or trifluoromethyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

wherein at least one of R^13e, R^13f, R^13g and R^13h is different from hydrogen;

R14 represents hydrogen or halogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In another embodiment the invention relates to a compound of formula (I), in which:

X represents C-R^2a or N;

R¹ represents a group selected from :

wherein * indicates the point of attachment of said group with the rest of the molecule;

R² represents a group selected from:

wherein * indicates the point of attachment of said group with the rest of the molecule and said groups are substituted once with R^{1 1} or once with R^{1 1 a} or

R^2a represents hydrogen, cyano, nitro, halogen, Ci -C₂-alkyl or Ci -C₂-haloalkyl;

R^2b represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl;

R^2c represents hydrogen, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen; R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁵ represents hydrogen or Ci-C₃-alkyl;

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C₄-alkoxy, Ci-C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C₄-alkyl, Cs-Ce-cycloalkyl,

Ci-C -haloalkyl, Ci-C -alkoxy, Ci-C -haloalkoxy, HO-(C₂-C-alkoxy)-, (Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C₄-alkyl, Cs-Ce-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-0-CH₂-CH₂-, -0-CH₂-0- or-0-CH₂-CH₂-0-;

R^7a and R^7b are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C -alkyl or Ci-C-haloalkyl;

R⁸ represents, independently from each respective occurence, Ci-C₆-alkyl, Ci-C -alkoxy-Ci-C -alkyl, C3-C₆-cycloalkyl or Ci-C -haloalkyl;

R⁹ and R¹⁰ are the same or different and represent, independently from each other, hydrogen, Ci-C₄-alkyl, Cs-Ce-cycloalkyl, Ci-C₄-haloalkyl or

(CH₃)₂N-Ci-C₄-alkyl or together with the nitrogen atom to which they are attached form a

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR^a in which R^a represents a Ci-C₆-alkyl or Ci-C₆-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C -alkyl;

R¹¹ represents R¹²-C(0)-NH-;

R^11a represents a group selected from:

R¹² represents C₂-C₄-alkenyl, Ci-C₄-hydroxyalkyl or C₃-C₆-cycloalkyl,

R^13a represents hydrogen or methyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen or methyl;

R^13f represents hydrogen or methyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

wherein at least one of R^13e, R^13f, R¹¾ and R^13h is different from hydrogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a preferred embodiment the invention relates to a compound of formula (I), in which:

X represents C-R^2a or N; represents a group selected from :

R² represents

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said group is substituted once with R¹¹ or once with R^{11 a};

R^2a represents hydrogen, cyano, nitro, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl;

R^2b represents hydrogen, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl;

R^2c represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁵ represents hydrogen or Ci-C₃-alkyl;

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C₄-alkoxy, Ci-C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

Ci-C -haloalkyl, Ci-C -alkoxy, Ci-C -haloalkoxy, HO-(C₂-C -alkoxy)-, (Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-; R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C₄-alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-O-CH2-CH2-, -O-CH2-O- or -0-CH₂-CH₂-0-;

R^7a and R^7b are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C -alkyl or Ci-C -haloalkyl;

R⁸ represents, independently from each respective occurence, Ci-C₆-alkyl, Ci-C₄-alkoxy-Ci-C₄-alkyl, Cs-Ce-cycloalkyl or Ci-C₄-haloalkyl;

R^{1 1} represents R¹²-C(0)-NH-;

R^{1 1 a} represents a group selected from :

wherein * indicates the point of attachment of said group with the rest of the molecule; represents C₂-C₄-alkenyl, Ci-C₄-hydroxyalkyl or Cs-Ce-cycloalkyl,

wherein said C3-C₆-cycloalkyl groups are substituted one to three times with halogen; represents hydrogen or methyl; R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen or methyl;

R^13f represents hydrogen or methyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

In a second aspect, the invention relates in particular to compounds of formula (la),

wherein ^* indicates the point of attachment of said group with the rest of the molecule; represents phenyl, heteroaryl or a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said phenyl or heteroaryl groups are substituted once with R¹¹ or once with R^{11 a} and optionally once with Ci -C2-alkyl;

R^2b represents hydrogen, halogen, Ci -C2-alkyl or Ci -C2-haloalkyl;

R^2c represents hydrogen, halogen, Ci -C₂-alkyl or Ci -C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁶ represents halogen, cyano, nitro, OH, Ci -C₄-alkyl, Ci -C₄-haloalkyl,

Ci -C₄-alkoxy, Ci -C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci -C -alkyl, C3-C₆-cycloalkyl,

Ci -C -haloalkyl, Ci -C -alkoxy, Ci -C -haloalkoxy, HO-(C₂-C -alkoxy)-, (Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci -C₄-alkyl, Cs-Ce-cycloalkyl,

Ci -C₄-haloalkyl, Ci -C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-; or R^6a and R^6b adjacent to each other together represent a group selected from

-O-CH2-CH2-, -O-CH2-O- or-0-CH₂-CH₂-0-;

R^7a and R^7b are the same or different and represent, independently from each other, hydrogen, hydroxy, halogen, Ci-C4-alkyl or Ci-C4-haloalkyl;

R⁸ represents, independently from each respective occurence, Ci-C₆-alkyl, Ci-C4-alkoxy-Ci-C4-alkyl, Cs-Ce-cycloalkyl or Ci-C4-haloalkyl;

R⁹ and R¹⁰ are the same or different and represent, independently from each other, hydrogen, Ci-C4-alkyl, Cs-Ce-cycloalkyl, Ci-C4-haloalkyl or

(CH₃)₂N-Ci-C4-alkyl or together with the nitrogen atom to which they are attached form a

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR^a in which R^a represents a Ci-C₆-alkyl or Ci-C₆-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C4-alkyl;

R^{1 1} represents R¹²-C(0)-NH-;

R^{1 1 a} re resents a group selected from :

wherein * indicates the point of attachment of said group with the rest of the molecule; represents C₂-C₄-alkenyl, Ci-C₄-hydroxyalkyl or C3-C₆-cycloalkyl,

wherein said Cs-Ce-cycloalkyl groups are substituted one to three times with halogen; represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl; R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

_R13d represents hydrogen, methyl or halogen,

_R13e represents hydrogen, halogen, methyl or trifluoromethyl;

R13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

wherein at least one of R^13e, R^13f, R¹¾ and R^13h is different from hydrogen;

R¹⁴ represents hydrogen or halogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a third aspect, the invention relates in particular to compounds of formula (la), supra, in which:

R¹ represents a group selected from :

R² represents a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said groups are substituted once with R¹¹ or once with R^11a or

R^2a represents hydrogen, chloro or cyano;

R^2b represents hydrogen or fluoro;

R^2c represents hydrogen or fluoro;

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C4-alkoxy, Ci-C4-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C₄-alkyl, C3-C₆-cycloalkyl,

Ci-C4-haloalkyl, Ci-C4-alkoxy, Ci-C4-haloalkoxy, HO-(C2-C4-alkoxy)-, (Ci-C₄-alkoxy)-(C2-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C₄-alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C2-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R⁸ represents, independently from each respective occurence, Ci-C₆-alkyl;

R⁹ and R¹⁰ are the same or different and represent, independently from each other, hydrogen, Ci-C₄-alkyl, C3-C₆-cycloalkyl, Ci-C₄-haloalkyl or

4- to 6-membered nitrogen containing heterocyclic ring; represents R¹²-C(0)-NH-;

re resents a group selected from :

R^13a represents hydrogen, halogen or methyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen or methyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

R14 represents halogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a forth aspect, the invention relates in particular to compounds of formula (la), supra, in which:

R¹ represents

R² represents a group selected from:

_R2a represents hydrogen;

_R2b represents hydrogen;

_R2c represents hydrogen;

R³ represents hydrogen;

R⁴ represents hydrogen;

R⁶ represents fluoro or chloro;

R¹¹ represents R¹²-C(0)-NH-;

_R1 1 a represents a group selected from

R¹² represents ethenyl, hydroxypropyl or C3-C₄-cycloalkyl,

wherein said C3-C₄-cycloalkyl groups are substituted two times with fluoro;

R^13a represents hydrogen or methyl;

R^13b represents hydrogen;

R^13c represents hydrogen or fluoro;

R^13d represents hydrogen, methyl or chloro,

R^13e represents hydrogen, chloro or methyl;

R^13f represents hydrogen, chloro or methyl;

R^{1 3}9 represents hydrogen, fluoro or chloro;

R^13h represents hydrogen or methyl,

R¹⁴ represents fluoro; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In a fifth aspect, the invention relates in particular to compounds of formula (lb)

(lb)

in which:

R¹ represents a group selected from :

R² represents phenyl, heteroaryl or a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said phenyl or heteroaryl groups are substituted once with R¹¹ or once with R^{11 a} and optionally once with Ci-C₂-alkyl;

R^2a represents hydrogen, cyano, nitro, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl;

R^2b represents hydrogen, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl; R^2c represents hydrogen, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C₄-alkoxy, Ci-C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-0-CH₂-CH₂-, -0-CH₂-0- or-0-CH₂-CH₂-0-;

R⁹ and R¹⁰ are the same or different and represent, independently from each other, hydrogen, Ci-C -alkyl, C3-C₆-cycloalkyl, Ci-C -haloalkyl or

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR^a in which R^a represents a Ci-Ce-alkyl or Ci-Ce-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C -alkyl;

R¹¹ represents R¹²-C(0)-NH-;

N— * or N— ^*

H wherein * indicates the point of attachment of said group with the rest of the molecule;

R¹² represents C₂-C₄-alkenyl, Ci-C₄-hydroxyalkyl or C3-C₆-cycloalkyl,

wherein said C3-C₆-cycloalkyl groups are substituted one to three times with halogen;

R^13a represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen, methyl or trifluoromethyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

In a sixth aspect, the invention relates in particular to compounds of formula (lb)

represents a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule; represents

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said groups are substituted once with R¹¹ or once with R^11a and optionally once with Ci-C₂-alkyl; R³ represents hydrogen; represents hydrogen; represents chloro or fluoro;

represents R¹²-C(0)-NH-;

re resents a group selected from :

R^13a represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen, methyl or trifluoromethyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

wherein at least one of R^13e, R^13f, R¹¾ and R^13h is different from hydrogen; R¹⁴ represents hydrogen or halogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

In particular the invention refers further to compounds of formula (I), (la) and (lb) as described supra, wherein:

R¹ represents

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C4-alkoxy or Ci-C4-haloalkoxy;

Ci-C₄-haloalkyl, Ci-C₄-alkoxy, Ci-C₄-haloalkoxy, HO-(C₂-C -alkoxy)-, (Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-.

According to a further alternative the invention refers to compounds of formula (I), (la) and (lb) as described supra, in which:

R¹ represents

R⁶ represents halogen, cyano, nitro, OH, Ci -C₄-alkyl, Ci -C₄-haloalkyl,

Ci -C₄-alkoxy or Ci -C₄-haloalkoxy;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci -C₄-alkyl, Cs-Ce-cycloalkyl, Ci -C₄-haloalkyl, Ci -C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-, (Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-, R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-.

R¹ represents a roup selected from :

wherein ^* indicates the point of attachment of said group with the rest of the molecule; R^7a and R^7b are the same or different and represent, independently from each other, hydrogen, hydroxy, fluoro, chloro, Ci -C -alkyl, difluoromethyl or trifluoromethyl.

In particular the invention refers further to compounds of formula (I), (la) and (lb) as described supra, wherein: R² represents phenyl, wherein said phenyl group is substituted once with R¹¹ or once with R^11a.

R² represents 5-membered monocyclic heteroaryl, wherein said heteroaryl groups are substituted once with R¹¹ or once with R^{11 a} and optionally once with Ci-C₂-alkyl.

R² represents a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said groups are substituted once with R¹¹ or once with R^11a.

R² represents

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said group is substituted once with R¹¹ or once with R^{11 a}.

According to a further aspect of the present invention compounds of formula (I), (la) and (lb) as described supra are those in which:

R³ represents hydrogen; and

R⁴ represents hydrogen, methyl or OH.

R³ represents hydrogen; and R⁴ represents hydrogen.

R³ represents fluoro; and

R⁴ represents fluoro.

According to a more particular aspect of the present invention compounds of formula (I), (la) and (lb) as described supra are those in which:

R⁵ represents hydrogen.

One aspect of the invention are compounds of formula (I), (la), (lb) as described in the examples, as characterized by their names in the title and their structures as well as the subcombinations of all residues specifically disclosed in the compounds of the examples. Preferred intermediates are the Intermediate Examples as disclosed below.

1 2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

2 N-(2,4-Dimethoxybenzyl)-2-(4-fluoro-1 Ή-1 ,4'-biimidazol-1 '-yl)-5- nitrobenzenesulfonamide

3 2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-fluoro-1 Ή-1 ,4'- biimidazol-1 '-yl)phenyl}acetamide

4 Ethyl 1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4- carboxylate

5 1 -{2-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4-carboxylic acid

6 2-(Trimethylsilyl)ethyl (1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H- pyrazol-4-yl)carbamate

7 2-(Trimethylsilyl)ethyl [1 -(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4- dimethoxybenzyl)sulfamoyl]phenyl)-1 H-pyrazol-4-yl]carbamate

8 N-{4-(4-Amino-1 H-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide

9 N-[4-(4-Amino-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

11 2-{4-[(Cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide

12 tert-Butyl [(2-{4-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-5- {[(2-chlorophenyl)acetyl]amino}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate

13 2-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide 14 N-(4-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-3-[(2,4- dimethoxybenzyl)sulfamoyl]phenyl)-2-(2-chlorophenyl)acetamide

15 N-[4-(4-Bromo-3-methyl-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2- chlorophenyl)acetamide

A further aspect of the invention are compounds of formula (I), (la) and (lb) which are present as their salts.

It is to be understood that the present invention relates to any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), (la) and (lb) supra.

More particularly still, the present invention covers compounds of general formula (I), (la) and (lb) which are disclosed in the Example section of this text, infra.

In accordance with another aspect, the present invention covers methods of preparing compounds of the present invention, said methods comprising the steps as described in the Experimental Section herein.

Another embodiment of the invention are compounds according to the claims as disclosed in the Claims section wherein the definitions are limited according to the preferred or more preferred definitions as disclosed below or specifically disclosed residues of the exemplified compounds and subcombinations thereof.

Definitions

Constituents which are optionally substituted as stated herein, may be substituted, unless otherwise noted, one or more times, independently from one another at any possible position. When any variable occurs more than one time in any constituent, each definition is independent. For example, when R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and/or R¹² occur more than one time in any compound of formula (I) each definition of R¹ , R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and/or R¹² is independent.

Should a constituent be composed of more than one part, e.g. Ci-C₄-alkoxy-Ci-C₄-alkyl-, the position of a possible substituent can be at any of these parts at any suitable position. A hyphen at the beginning of the constituent marks the point of attachment to the rest of the molecule. Should a ring be substituted the substitutent could be at any suitable position of the ring, also on a ring nitrogen atom if suitable.

Furthermore, a constituent composed of more than one part and comprising several chemical residues, e.g. Ci -C₄-alkoxy-Ci -C₄-alkyl or phenvl-Ci-C₄-alkyl, should be read from left to right with the point of attachment to the rest of the molecule on the last part (in the example mentioned previously on the Ci-C -alkyl residue)

The term "comprising" when used in the specification includes "consisting of".

If it is referred to "as mentioned above" or "mentioned above" within the description it is referred to any of the disclosures made within the specification in any of the preceding pages.

"suitable" within the sense of the invention means chemically possible to be made by methods within the knowledge of a skilled person.

The terms as mentioned in the present text have preferably the following meanings:

The term "halogen", "halogen atom", "halo-" or "Hal-" is to be understood as meaning a fluorine, chlorine, bromine or iodine atom, preferably a fluorine or chlorine atom.

The term "Ci-C -alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group having 1 , 2, 3 or 4 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl group, particularly 1 , 2 or 3 carbon atoms ("Ci-C3-alkyl"), e.g. a methyl, ethyl, n-propyl- or iso-propyl group.

The term "C₂-C -alkenyl" means a linear or branched, monovalent hydrocarbon group, which contains one or two double bonds, and which has 2, 3 or 4 carbon atoms, particularly 2 or 3 carbon atoms ("C₂-C3-alkenyl"), it being understood that in the case in which said alkenyl group contains more than one double bond, then it is possible for said double bonds to be isolated from, or conjugated with, each other. Said alkenyl group is, for example, an ethenyl (or "vinyl"), prop-2-en-1 -yl (or "allyl"), prop-1 -en-1 -yl, but-3-enyl, but-2-enyl, but-1 -enyl, prop-1 -en-2-yl (or "isopropenyl"), 2-methylprop-2-enyl,

1 -methylprop-2-enyl, 2-methylprop-1 -enyl, 1 -methylprop-1 -enyl or buta-1 ,3-dienyl group. Particularly, said group is vinyl or allyl. The term "Ci-C₄-haloalkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C₄-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a halogen atom, in identically or differently, i.e. one halogen atom being independent from another.

Particularly, said halogen atom is F. Said Ci-C4-haloalkyl group is, for example,

-CF₃, -CHF₂, -CH₂F, -CF2CF3, or-CH₂CF₃.

The term "Ci-C₄-alkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of formula -O-alkyI, in which the term "alkyl" is defined supra, e.g. a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert- butoxy or sec-butoxy group, or an isomer thereof.

The term "Ci-C₄-haloalkoxy" is to be understood as preferably meaning a linear or branched, saturated, monovalent Ci-C₄-alkoxy group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a halogen atom. Particularly, said halogen atom is F. Said Ci-C -haloalkoxy group is, for example, -OCF₃, -OCHF2, -OCH2F, -OCF2CF3, or -OCH2CF3.

The term "Ci-C -hydroxyalkyl" is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group in which the term "Ci-C₄-alkyl" is defined supra, and in which one or more hydrogen atoms is replaced by a hydroxy group, e.g. a hydroxym ethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1 ,2-dihydroxyethyl, 3-hydroxypropyl, 2- hydroxypropyl, 2,3-dihydroxypropyl, 1 ,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl group.

The term "Ci-C -alkoxy-Ci-C -alkyl" is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group, as defined supra, in which one or more of the hydrogen atoms is replaced, in identically or differently, by a Ci-C₄-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl, propyloxy alkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl, tert-butoxyalkyl or sec-butoxyalkyl group, in which the term "Ci-C -alkyl" is defined supra, or an isomer thereof.

The term "C3-C₆-cycloalkyl" is to be understood as meaning a saturated, monovalent, mono-, or bicyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms ("C3-C6- cycloalkyl"). Said C3-C₆-cycloalkyl group is for example, a monocyclic hydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, or a bicyclic hydrocarbon ring.

The term "4- to 6-membered heterocycloalkyi" or "4- to 6-membered heterocyclic ring", is to be understood as meaning a saturated, monovalent, mono- or bicyclic hydrocarbon ring which contains 3, 4 or 5 carbon atoms, and one or more heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)₂, NH, NR^a, in which R^a represents a Ci-C₆-alkyl- or Ci-Ce-haloalkyl- group ; it being possible for said heterocycloalkyi group to be attached to the rest of the molecule via any one of the carbon atoms or, if present, the nitrogen atom.

Particularly, said heterocycloalkyi can contain 4 or 5 carbon atoms, and one or more of the above-mentioned heteroatom-containing groups (a "5- to 6-membered

heterocycloalkyi").

Particularly, without being limited thereto, said heterocycloalkyi can be a 4-membered ring, such as an azetidinyl, oxetanyl, or a 5-membered ring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl, for example. Optionally, said heterocycloalkyi can be benzo fused.

The term "heteroaryl" is understood as preferably meaning a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 1 1 , 12, 13 or 14 ring atoms (a "5- to 14-membered heteroaryl" group), particularly 5, 6, 9 or 10 ring atoms, and which contains at least one heteroatom which may be identical or different, said heteroatom being such as oxygen, nitrogen or sulfur. In addition said ring system can be benzocondensed. Particularly, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl, and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and benzo derivatives thereof, such as, for example, quinolinyl, quinazolinyl, isoquinolinyl; or azocinyl, indolizinyl, purinyl, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl. In general, and unless otherwise mentioned, the heteroarylic radical include all the possible isomeric forms thereof, e.g. the positional isomers thereof. Thus, for some illustrative non-restricting example, the term pyridyl includes pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl. Preferably, the heteroaryl group is a pyridyl group.

As mentioned supra, said nitrogen atom-containing ring can be partially unsaturated, i.e. it can contain one or more double bonds, such as, without being limited thereto, a 2,5- dihydro-1 H-pyrrolyl, 4H-[1 ,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1 ,4]thiazinyl ring, for example, or, it may be benzo-fused, such as, without being limited thereto, a dihydroisoquinolinyl ring, for example.

The term "Ci-C₄", as used throughout this text, e.g. in the context of the definition of "Ci- C₄-alkyl", "Ci-C₄-haloalkyl", "Ci -C₄-alkoxy", or "Ci-C -haloalkoxy" is to be understood as meaning an alkyl group having a finite number of carbon atoms of 1 to 4, i.e. 1 , 2, 3 or 4 carbon atoms. It is to be understood further that said term "Ci-C " is to be interpreted as any sub-range comprised therein, e.g. Ci-C , C₂-C , C₃-C , C1-C2 , C1-C3 , particularly Ci - C₂ , Ci-C₃ , Ci -C , in the case of "Ci-C₆-haloalkyl" or "Ci -C -haloalkoxy" even more particularly C₁-C₂.

Further, as used herein, the term "C3-C₆", as used throughout this text, e.g. in the context of the definition of "C₃-C6-cycloalkyl", is to be understood as meaning a cycloalkyl group having a finite number of carbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to be understood further that said term "C3-C₆" is to be interpreted as any sub-range comprised therein, e.g. C₃-C₆ , C -C₅ , C3-C5 , C₃-C , C -C₆, C₅-C₆ ; particularly C₃-C₆.

The R⁹R¹⁰N-C(O)- group include, for example, -C(0)NH₂, -C(0)N(H)CH₃, -C(0)N(CH₃)₂, -C(0)N(H)CH₂CH₃, -C(0)N(CH₃)CH₂CH₃ or -C(0)N(CH₂CH₃)₂.

The R⁹R¹⁰N- group includes, for example, -NH₂, -N(H)CH₃, -N(CH₃)₂, -N(H)CH₂CH₃ and -N(CH₃)CH₂CH₃. In the case of R⁹R¹⁰N-, when R⁹ and R¹⁰ together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, NH, NR^a in which R^a represents a Ci-C₆-alkyl- or Ci-C₆-haloalkyl- group, particularly a CH₃, or S and being optionally substituted, one to three times, independently from each other, with halogen or Ci-C₄-alkyl, particularly a CH₃. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic or nonaromatic ring system which, for example, replaces an available hydrogen on the ring system.

As used herein, the term "one or more", e.g. in the definition of the substituents of the compounds of the general formulae of the present invention, is understood as meaning "one, two, three, four or five, particularly one, two, three or four, more particularly one, two or three, even more particularly one or two".

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶CI, ⁸²Br, ¹²³l, ¹²⁴l, ¹²⁵l, ¹²⁹l and ¹³¹1, respectively. Certain isotopic variations of a compound of the invention, for example, those in which one or more radioactive isotopes such as ³H or ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures known by a person skilled in the art such as by the illustrative methods or by the preparations described in the examples hereafter using appropriate isotopic variations of suitable reagents. Where the plural form of the word compounds, salts, polymorphs, hydrates, solvates and the like, is used herein, this is taken to mean also a single compound, salt, polymorph, isomer, hydrate, solvate or the like.

By "stable compound' or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The compounds of this invention may contain one or more asymmetric centre, depending upon the location and nature of the various substituents desired. Asymmetric carbon atoms may be present in the (R) or (S) configuration, resulting in racemic mixtures in the case of a single asymmetric centre, and diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, asymmetry may also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.

Substituents on a ring may also be present in either cis or trans form. It is intended that all such configurations (including enantiomers and diastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or

diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. The purification and the separation of such materials can be accomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation. The optically active bases or acids are then liberated from the separated diastereomeric salts. A different process for separation of optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful. The optically active compounds of this invention can likewise be obtained by chiral syntheses utilizing optically active starting materials.

In order to limit different types of isomers from each other reference is made to lUPAC Rules Section E (Pure Appl Chem 45, 1 1 -30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g. R- or S- isomers, or E- or Z-isomers, in any ratio. Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention may be achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains a pyrazole moiety as a heteroaryl group for example can exist as a 1 H tautomer, or a 2H tautomer, or even a mixture in any amount of the two tautomers, or a triazole moiety for example can exist as a 1 H tautomer, a 2H tautomer, or a 4H tautomer, or even a mixture in any amount of said 1 H, 2H and 4H tautomers, namely:

1 H-tautomer 2H-tautomer 4H-tautomer

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides. The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitates.

The compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example as structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may exist in a

stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri- , tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or can exist in the form of a salt. Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, customarily used in pharmacy.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1 -19.

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethansulfonic, benzenesulfonic, para- toluenesulfonic, methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic,

glycerophosphoric, aspartic, sulfosalicylic, hemisulfuric, or thiocyanic acid, for example. Further, another suitably pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic, is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable cation, for example a salt with N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, dicyclohexylamine, 1 ,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base, 1 -amino-2,3,4- butantriol. Additionally, basic nitrogen containing groups may be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and strearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition salts of the claimed compounds may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.

In the present text, in particular in the Experimental Section, for the synthesis of intermediates and of examples of the present invention, when a compound is mentioned as a salt form with the corresponding base or acid, the exact stoichiometric composition of said salt form, as obtained by the respective preparation and/or purification process, is, in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structural formulae such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCI", "x CF3COOH", "x Na+", for example, are to be understood as not a stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates or example compounds or salts thereof have been obtained, by the preparation and/or purification processes described, as solvates, such as hydrates with (if defined) unknown

stoichiometric composition. The salts include water-insoluble and, particularly, water-soluble salts.

Furthermore, derivatives of the compounds of formula (I) and the salts thereof which are converted into a compound of formula (I) or a salt thereof in a biological system

(bioprecursors or pro-drugs) are covered by the invention. Said biological system is e.g. a mammalian organism, particularly a human subject. The bioprecursor is, for example, converted into the compound of formula (I) or a salt thereof by metabolic processes.

Furthermore, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorphs, or as a mixture of more than one polymorphs, in any ratio.

In the context of the properties of the compounds of the present invention the term "pharmacokinetic profile" means one single parameter or a combination thereof including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration, or magnitude of pharmacological effect, as measured in a suitable experiment. Compounds with improved pharmacokinetic profiles can, for example, be used in lower doses to achieve the same effect, may achieve a longer duration of action, or a may achieve a combination of both effects.

It has now been found, and this constitutes the basis of the present invention, that said compounds of the present invention have surprising and advantageous properties.

In particular, compounds according to the present invention have surprisingly been found to effectively be active as an antagonist or a negative allosteric modulator of P2X4.

An allosteric modulator is a substance which indirectly influences (modulates) the effects of an agonist or inverse agonist at a target protein, for example a receptor. Allosteric modulators bind to a site distinct from that of the orthosteric agonist binding site. Usually they induce a conformational change within the protein structure. A negative modulator (NAM) reduces the effects of the orthosteric ligand, but is inactive in the absence of the orthosteric ligand.

Commercial utility and medical indications

As mentioned supra, the compounds of the present invention have surprisingly been found to effectively be active as an antagonist or a negative allosteric modulator of P2X4. A compound according to the invention is used for the manufacture of a medicament.

A further aspect of the invention is the use of the compounds according to formula (I), (la) or (lb) for the treatment or prophylaxis of a disease

Furthermore, the invention relates to a compound of general formula (I) (la) or (lb), or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, as described and defined herein, for use in the treatment or prophylaxis of a disease.

The invention further relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer to treat mammalian and human disorders and diseases, which include but are not limited to:

genitourinary, gastrointestinal, respiratory, proliferative and pain-related diseases, conditions and disorders;

gynecological diseases including primary and secondary dysmenorrhea, dyspareunia, vulvudynia, endometriosis and adenomyosis; endometriosis- associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular abdominal pain, dysmenorrhea, dyspareunia, dysuria, dyschezia or pelvic hypersensitivity;

urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia;

prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome;

cancer, cancer-related pain and cancer cachexia;

epilepsy, partial and generalized seizures; respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic chough, refractory chronic cough, ideopahtic chronic cough;

gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea- dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like;

fatty liver disorders, in particular NASH (Non-Alcoholic Steato- Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders;

neurodegenerative disorders such as Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, brain ischemia, traumatic brain injury, spinal cord injury; pruritus.

heart disorders including ischemia reperfusion injury, cardiac ischemia,

The present invention further relates to a method for using using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a

pharmaceutically acceptable salt thereof, or a mixture of same, to treat pain-associated mammalian disorders and diseases, which include but not limited to

pain-associated diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus;

impaired wound healing and disease of the skeleton like degeneration of the joints. Furthermore, the present invention relates to a method for using using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a

pharmaceutically acceptable salt thereof, or a mixture of same, to treat mammalian and human disorders and diseases, which are associated with pain or pain syndromes that are in particular:

pain syndromes (including hyperalgesia, allodynia, acute and chronic inflammatory and neuropathic pain), preferably inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis- associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic lower back pain, neck pain phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, fibromyalgia, myofascial disorders, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias, and pain associated with cancer, Morphine-resistant pain, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with diseases or disorders selected from the group consisting of abdominal pain such as functional bowel disorders, irritable bowel syndrome, inflammatory bowl disease and selected from the group of arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis).

Compounds of the invention are thus expected to be useful in the treatment of inflammation. The term "inflammation" is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, fibrotic, allergic and auto-immune disaeses, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, necrosis, endometriosis and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever. The compounds of the present invention may also be useful in the treatment, viral infections (e.g. influenza, common cold, herpes zoster, hepatitis C and HIV), bacterial infections, fungal infections, surgical or dental procedures, malignancies (e.g. melanoma, breast cancer, colon cancer, lung cancer and prostate cancer), arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, diabetes mellitus, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.

Compounds of the invention are also expected to be useful in the treatment of conditions associated or causing bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.

Based on the P2X4 antagonising activity the compounds according to the invention are useful for the relief of pain, fever and inflammation of a variety of conditions including rheumatic fever, symptoms associated with influenza or other viral infections, common cold, lowere back and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic treatment), toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, juvenile rheumatoid arthritis, degenerative joint diseases (osteoarthritis), acute gout and ankylosing spondylitis, acute, subacute and chronic musculoskeletal pain syndromes such as bursitis, burns, injuries, and pain following surgical (post-operative pain) and dental procedures as well as the preemptive treatment of surgical pain. The pain may be mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, back pain such as acute visceral pain, neuropathies, acute trauma, chemotherapy— induced

mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy and/ or chemotherapy induced neuropathy), autonomic neuropathy pain states, pheriphaeral nervous system (PNS) lesion or central nervous system (CNS) lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions (such as beriberi, vitamin deficiencies, hypothyroidism, porphyria, cancer, HIV, autoimmune disease such as multiple sclerosis and spinal-cord injury, fibromyalgia, nerve injury, ischaemia, neurodegeneration, stroke, post stroke pain, inflammatory disorders, oesophagitis, gastroeosophagal reflux disorder (GERD), irritable bowel syndrome, inflammatory bowel disease, overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, stomach, duodenal ulcer, muscle pain, pain due to colicky and referred pain. Compounds of thepresent invention may also be useful for the treatment or prevention of hemophilic arthropathy and Parkinson's disease.

The invention relates also to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat conditions treatable by inhibition of prostanoid- induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and hence may be of relevance to use in treatment of dysmenorrhea premature labor and asthma.

The present invention relates to a method for the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat cancer and hyperproliferative disorders. Hyperproliferative discorders include, but are not limited to, for example: psoriasis, keloids, and other hyperplasias affecting the skin, benign prostate hyperplasia (BPH), solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.

Examples of breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ, and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to, brain stem and hypophtalmic glioma, cerebellar and cerebral astrocytoma, medulloblastoma, ependymoma, as well as neuroectodermal and pineal tumour.

Tumours of the male reproductive organs include, but are not limited to, prostate and testicular cancer.

Tumours of the female reproductive organs include, but are not limited to, endometrial, cervical, ovarian, vaginal, and vulvar cancer, as well as sarcoma of the uterus. Tumours of the digestive tract include, but are not limited to, anal, colon, colorectal, oesophageal, gallbladder, gastric, pancreatic, rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to, bladder, penile, kidney, and renal pelvis, ureter, urethral and human papillary renal cancers.

Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancers include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to, laryngeal, hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oral cavity cancer and squamous cell.

Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.

Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.

A preferred embodiment of the present invention relates to a method for using the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a pharmaceutically acceptable salt thereof, or a mixture of same, to treat a gynaecological disease, preferably dysmenorrhea, dyspareunia, vulvodynia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.

Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a urinary tract disease, in particular overactive bladder or cystitis, preferably interstitial cystitis. Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a respiratory disorder, preferably cough, in particular chronic cough.

Another preferred embodiment of the present invention relates to a method for using the compounds of the present invention and compositions thereof, to treat a

neurodegenerative disorders, preferably ischemic brain injury, spinal cord injury and Multiple Sclerosis.

Another preferred embodiment of the present invention relates to a method for using of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer particularly a

pharmaceutically acceptable salt thereof, or a mixture of same, to treat arthritis, in particular rheumatoid arthritis and ankylosing spondylitis (Burnstock et al., 2012

Pharmacol Rev. 64:834-868).

These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals, and can be treated by administering pharmaceutical compositions of the present invention.

The term "treating" or "treatment" as stated throughout this document is used

conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of, etc., of a disease or disorder, such as a gynaecological disease or a disease associated with undesired proliferation like endometriosis or cancer.

Preferably, the diseases treated with said method are gynaecological disorders, more preferably dysmenorrhea, dyspareunia or endometriosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are in particular acute and chonic abdominal pain, dysmenorrhea, dyspareunia, dysuria, or dyschezia.

Further diseases, which can be treated with said method, are osteoarthritis, diabetic neuropathy, burning mouth syndrome, gastroesophageal reflux, migraine disorders, chronic cough, asthma, pruritus, irritable bowel disease, overactive urinary bladder, prostatic hyperplasia, interstitial cystitis.

Preferably, the method of treating the diseases mentioned above is not limited to the treatment of said disease but also includes the treatment of pain related to or associated with said diseases. The compounds of the present invention can be used in particular in therapy and prevention, i.e. prophylaxis, of genitourinary, gastrointestinal, respiratory or pain-related disease, condition or disorder.

Pharmaceutical compositions of the compounds of the invention

This invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be utilised to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purpose of this invention, is a mammal, including a human, in need of treatment for the particular condition or disease.

Therefore, the present invention includes pharmaceutical compositions that are comprised of a pharmaceutically acceptable carrier or auxiliary and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.

Another aspect of the invention is a pharmaceutical composition comprising a

pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable auxiliary for the treatment of a disease mentioned supra, especially for the treatment of haematological tumours, solid tumours and/or metastases thereof.

A pharmaceutically acceptable carrier or auxiliary is preferably a carrier that is non-toxic and innocuous to a patient at concentrations consistent with effective activity of the active ingredient so that any side effects ascribable to the carrier do not vitiate the beneficial effects of the active ingredient. Carriers and auxiliaries are all kinds of additives assisting to the composition to be suitable for administration.

A pharmaceutically effective amount of compound is preferably that amount which produces a result or exerts the intended influence on the particular condition being treated.

The compounds of the present invention can be administered with pharmaceutically- acceptable carriers or auxiliaries well known in the art using any effective conventional dosage unit forms, including immediate, slow and timed release preparations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually, rectally, vaginally, subcutaneously, intra uterine and the like.

For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, troches, lozenges, melts, powders, solutions, suspensions, or emulsions, and may be prepared according to methods known to the art for the manufacture of pharmaceutical compositions. The solid unit dosage forms can be a capsule that can be of the ordinary hard- or soft-shelled gelatine type containing auxiliaries, for example, surfactants, lubricants, and inert fillers such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tableted with conventional tablet bases such as lactose, sucrose and cornstarch in combination with binders such as acacia, corn starch or gelatine, disintegrating agents intended to assist the break-up and dissolution of the tablet following administration such as potato starch, alginic acid, corn starch, and guar gum, gum tragacanth, acacia, lubricants intended to improve the flow of tablet granulation and to prevent the adhesion of tablet material to the surfaces of the tablet dies and punches, for example talc, stearic acid, or magnesium, calcium or zinc stearate, dyes, colouring agents, and flavouring agents such as peppermint, oil of wintergreen, or cherry flavouring, intended to enhance the aesthetic qualities of the tablets and make them more acceptable to the patient. Suitable excipients for use in oral liquid dosage forms include dicalcium phosphate and diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance tablets, pills or capsules may be coated with shellac, sugar or both.

Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above.

Additional excipients, for example those sweetening, flavouring and colouring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents may be (1 ) naturally occurring gums such as gum acacia and gum tragacanth, (2) naturally occurring phosphatides such as soy bean and lecithin, (3) esters or partial esters derived form fatty acids and hexitol anhydrides, for example, sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, for example, polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as, for example, beeswax, hard paraffin, or cetyl alcohol. The suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate ; one or more colouring agents ; one or more flavouring agents ; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, and preservative, such as methyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally, that is, subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly, or interperitoneally, as injectable dosages of the compound in preferably a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid or mixture of liquids such as water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerol ketals such as 2,2-dimethyl-1 ,1 -dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or, a fatty acid glyceride, or an acetylated fatty acid glyceride, with or without the addition of a

pharmaceutically acceptable surfactant such as a soap or a detergent, suspending agent such as pectin, carbomers, methycellulose, hydroxypropylmethylcellulose, or

carboxymethylcellulose, or emulsifying agent and other pharmaceutical adjuvants.

Illustrative of oils which can be used in the parenteral formulations of this invention are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid.

Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include fatty acid alkali metal, ammonium, and triethanolamine salts and suitable detergents include cationic detergents, for example dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates ; anionic detergents, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates ; non-ionic detergents, for example, fatty amine oxides, fatty acid alkanolamides, and poly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxide copolymers ; and amphoteric detergents, for example, alkyl-beta-aminopropionates, and 2-alkylimidazoline quarternary ammonium salts, as well as mixtures.

The parenteral compositions of this invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also be used advantageously. In order to minimise or eliminate irritation at the site of injection, such compositions may contain a non-ionic surfactant having a hydrophile- lipophile balance (HLB) preferably of from about 12 to about 17. The quantity of surfactant in such formulation preferably ranges from about 5% to about 15% by weight. The surfactant can be a single component having the above HLB or can be a mixture of two or more components having the desired HLB.

Illustrative of surfactants used in parenteral formulations are the class of polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

The pharmaceutical compositions may be in the form of sterile injectable aqueous suspensions. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents such as, for example, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia ; dispersing or wetting agents which may be a naturally occurring phosphatide such as lecithin, a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate, a condensation product of ethylene oxide with a long chain aliphatic alcohol, for example, heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxide with a partial ester derived form a fatty acid and a hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents that may be employed are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

A composition of the invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritation excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol.

Controlled release formulations for parenteral administration include liposomal, polymeric microsphere and polymeric gel formulations that are known in the art.

It may be desirable or necessary to introduce the pharmaceutical composition to the patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents is well known in the art. Direct techniques for administration, for example, administering a drug directly to the brain usually involve placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system, used for the transport of agents to specific anatomical regions of the body, is described in US Patent No. 5,01 1 ,472, issued April 30, 1991 .

The compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, generally referred to as carriers or diluents, as necessary or desired. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized.

Such ingredients and procedures include those described in the following references, each of which is incorporated herein by reference: Powell, M.F. et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-31 1 ; Strickley, R.G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1 " PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349 ; and Nema, S. et al., "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51 (4), 166-171 .

Commonly used pharmaceutical ingredients that can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid) ; alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine) ; adsorbents (examples include but are not limited to powdered cellulose and activated charcoa)l ; aerosol propellants (examples include but are not limited to carbon dioxide, CCI₂F₂,

air displacement agents - examples include but are not limited to nitrogen and argon ; antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate) ; antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal) ; antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid,

monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium

formaldehyde sulfoxylate, sodium metabisulfite) ; binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes and styrene- butadiene copolymers) ; buffering agents (examples include but are not limited to potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate); carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection); chelating agents (examples include but are not limited to edetate disodium and edetic acid) ; colourants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red No. 8, caramel and ferric oxide red) ; clarifying agents (examples include but are not limited to bentonite) ; emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyoxyethylene 50 monostearate) ; encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate), flavourants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin) ; humectants (examples include but are not limited to glycerol, propylene glycol and sorbitol) ; levigating agents (examples include but are not limited to mineral oil and glycerin) ; oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil) ; ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment) ; penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, mono-or polyvalent alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas), plasticizers (examples include but are not limited to diethyl phthalate and glycerol) ; solvents (examples include but are not limited to ethanol, corn oil, cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation) ; stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax) ; suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)) ; surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan mono-palmitate) ; suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum) ; sweetening agents (examples include but are not limited to aspartame, dextrose, glycerol, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose) ; tablet anti-adherents (examples include but are not limited to magnesium stearate and talc) ; tablet binders (examples include but are not limited to acacia, alginic acid,

carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinyl pyrrolidone, and pregelatinized starch) ; tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch) ; tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac) ; tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate) ; tablet disinteqrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, cross- linked polyvinylpyrrolidone, sodium alginate, sodium starch glycollate and starch) ; tablet qlidants (examples include but are not limited to colloidal silica, corn starch and talc) ; tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate) ; tablet/capsule opaguants (examples include but are not limited to titanium dioxide) ; tablet polishing agents (examples include but are not limited to carnuba wax and white wax) ; thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin) ; tonicity agents (examples include but are not limited to dextrose and sodium chloride) ; viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth) ; and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can be illustrated as follows:

Sterile i.v. solution: A 5 mg/ml solution of the desired compound of this invention can be made using sterile, injectable water, and the pH is adjusted if necessary. The solution is diluted for administration to 1 - 2 mg/ml with sterile 5% dextrose and is administered as an i.v. infusion over about 60 minutes.

Lyophilised powder for i.v. administration: A sterile preparation can be prepared with (i) 100 - 1000 mg of the desired compound of this invention as a lyophilised powder, (ii) 32- 327 mg/ml sodium citrate, and (iii) 300 - 3000 mg Dextran 40. The formulation is reconstituted with sterile, injectable saline or dextrose 5% to a concentration of 10 to 20 mg/ml, which is further diluted with saline or dextrose 5% to 0.2 - 0.4 mg/ml, and is administered either IV bolus or by IV infusion over 15 - 60 minutes.

Intramuscular suspension: The following solution or suspension can be prepared, for intramuscular injection:

50 mg/ml of the desired, water-insoluble compound of this invention

5 mg/ml sodium carboxymethylcellulose

4 mg/ml TWEEN 80

9 mg/ml sodium chloride

9 mg/ml benzyl alcohol

Hard Shell Capsules: A large number of unit capsules are prepared by filling standard two-piece hard galantine capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft Gelatin Capsules: A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump into molten gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules are washed and dried. The active ingredient can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a water miscible medicine mix.

Tablets: A large number of tablets are prepared by conventional procedures so that the dosage unit is 100 mg of active ingredient, 0.2 mg. of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 1 1 mg. of starch, and 98.8 mg of lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules: These are solid oral dosage forms made by conventional and novel processes. These units are taken orally without water for immediate dissolution and delivery of the medication. The active ingredient is mixed in a liquid containing ingredient such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze drying and solid state extraction techniques. The drug compounds may be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to produce porous matrices intended for immediate release, without the need of water. Dose and administration

Based upon standard laboratory techniques known to evaluate compounds useful for the treatment of disorders and/ or disease, which are influenced by P2X4, by standard toxicity tests and by standard pharmacological assays for the determination of treatment of the conditions identified above in mammals, and by comparison of these results with the results of known medicaments that are used to treat these conditions. The effective dosage of the compounds of this invention can readily be determined for treatment of each desired indication. The amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, "drug holidays" in which a patient is not dosed with a drug for a certain period of time, may be beneficial to the overall balance between pharmacological effect and tolerability. A unit dosage may contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. A preferred oral unit dosage for a administration of the compounds of the present invention includes but is not limited to 0.1 mg/kg to about 10 mg/kg body weight one to three times a day to once a week. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

Combination Therapies

The term "combination" in the present invention is used as known to persons skilled in the art and may be present as a fixed combination, a non-fixed combination or kit of parts.

A "fixed combination" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present together in one unit dosage or in a single entity. One example of a "fixed combination" is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical combination wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.

A non-fixed combination or "kit of parts" in the present invention is used as known to persons skilled in the art and is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit. One example of a non-fixed combination or kit of parts is a combination wherein the said first active ingredient and the said second active ingredient are present separately. The components of the non-fixed combination or kit of parts may be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutical agents where the combination causes no unacceptable adverse effects. The present invention relates also to such combinations.

Those combined pharmaceutical agents can be other agents having antiproliferative, antinociceptive and/or antiinflammatory effects such as for example for the treatment of haematological tumours, solid tumours and/or metastases thereof and/or agents for the treatment of different pain syndromes and/or undesired side effects. The present invention relates also to such combinations. Other anti-hyper-proliferative agents suitable for use with the composition of the invention include but are not limited to those compounds acknowledged to be used in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of

Therapeutics (Ninth Edition), editor Molinoff et al., publ. by McGraw-Hill, pages 1225- 1287, (1996), which is hereby incorporated by reference, especially (chemotherapeutic) anti-cancer agents as defined supra.

For example, the compounds of the present invention can be combined with known hormonal therapeutic agents.

In particular, the compounds of the present invention can be administered in combination or as co-medication with hormonal contraceptives. Hormonal contraceptives can be administered via oral, subcutaneous, transdermal, intrauterine or intravaginal route, for example as Combined Oral Contraceptives (COCs) or Progestin-Only-Pills (POPs) or hormone-containing devices like implants, patches or intravaginal rings.

COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic part is in most of the COCs ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.

Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.

Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol.

POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills.

POPs include but are not limited to Cerazette containing desogestrel; Microlut containing levonorgestrel and Micronor containing norethindrone. Other Progeston-Only forms are intrauterine devices (lUDs), for example Mirena containing levonorgestrel, or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel.

Other hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel, or transdermal systems like contraceptive patches, for example Ortho-Evra containing ethinyl estradiol and norelgestromin or Apleek (Lisvy) containing ethinyl estradiol and gestodene.

A preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms as well as vaginal rings or contraceptive patches as mentioned above.

Furthermore, the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases which are related to or mediated by P2X4.

For the treatment and/ or prophylaxis of urinary tract diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:

Urinary tract disease states including those associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter syndrome

For the treatment and/ or prophylaxis of overactive bladder and symptoms related to overactive bladder, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; β-3 agonists like mirabegron; neurotoxins like onabutolinumtoxin A; or antidepressants like imipramine, duloxetine. For the treatment and/ or prophylaxis of interstitial cystitis, the compounds of the present invention can be administered in combination or as co-medication in addition to behavioral therapy like diet, lifestyle or bladder training with pentosans like elmiron; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine.

For the treatment and/ or prophylaxis of gynaecological diseases, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:

dysmenorrhea, including primary and secondary; dyspareunia; endometriosis;

endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular acute and chronic abdominal pain, dysmenorrhea,

dyspareunia, dysuria, or dyschezia.

For the treatment and/ or prophylaxis of dysmenorrhea, including primary and secondary; dyspareunia; endometriosis and endometriosis-associated pain, the compounds of the present invention can be administered in in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho- Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol.

For the treatment and/ or prophylaxis of diseases, which are associated with pain, or pain syndromes, the compounds of the present invention can be administered in combination or as co-medication with any substance that can be applied as therapeutic agent in the following indications:

pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, viral, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy.

The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions. In addition to well-known medicaments which are already approved and on the market, the compounds of the present invention can be administered in combination with inhibitors of the P2X purinoceptor family (e,g, P2X3 and P2X7), with inhibitors of IRAK4, with inhibitors of PTGES and with antagonists of the prostanoid EP4 receptor.

In particular, the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto- reductase1 C3 (AKR1 C3) and with functional blocking antibodies of the prolactin receptor.

The compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer.

In particular, the compounds of the present invention can be administered in combination with 131 1-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel,

cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib , crisantaspase, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, diclofenac, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, Glucarpidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, 1-125 seeds, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (1231), iomeprol, ipilimumab, irinotecan, Itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna, methadone, methotrexate,

methoxsalen, methylaminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, miltefosine, miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabine, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumab, omacetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel, palifermin, palladium-103 seed, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargase, PEG-epoetin beta (methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pemetrexed, pentazocine, pentostatin, peplomycin, Perflubutane, perfosfamide,

Pertuzumab, picibanil, pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicase, razoxane, refametinib , regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, romidepsin, romiplostim, romurtide, roniciclib , samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium (99mTc) nofetumomab merpentan, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trif luridine + tipiracil, trilostane, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, ubenimex, valatinib , valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer, zoledronic acid, zorubicin.

Furthermore, the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to step II opiods like codeine phosphate, dextropropoxyphene, dihydro-codeine, Tramadol), step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as Dexamethasone and methylprednisolone; bisphosphonates like Etidronate, Clodronate, Alendronate, Risedronate, and Zoledronate; tricyclic antidepressants like Amitriptyline, Clomipramine, Desipramine, Imipramine and Doxepin; class I antiarrhythmics like mexiletine and lidocaine; anticonvulsants like carbamazepine, Gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and

phenobarbital.

Methods of testing for a particular pharmacological or pharmaceutical property are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

As will be appreciated by persons skilled in the art, the invention is not limited to the particular embodiments described herein, but covers all modifications of said

embodiments that are within the spirit and scope of the invention as defined by the appended claims.

The following examples illustrate the invention in greater detail, without restricting it. Further compounds according to the invention, of which the preparation is not explicitly described, can be prepared in an analogous way.

The compounds, which are mentioned in the examples and the salts thereof represent preferred embodiments of the invention as well as a claim covering all subcombinations of the residues of the compound of formula (I) as disclosed by the specific examples.

The term "according to" within the experimental section is used in the sense that the procedure referred to is to be used "analogously to". SYNTHESIS OF COMPOUNDS

The following schemes and general procedures illustrate general synthetic routes to the compounds of general formula (I), (la) and (lb) of the invention and are not intended to be limiting. It is obvious to the person skilled in the art that the order of transformations as exemplified in schemes 1 to 7 can be modified in various ways. The order of

transformations exemplified in schemes 1 to 7 is therefore not intended to be limiting. In addition, interconversion of substituents, for example of residues R¹ , R², R^2a, R^2b, R^2c, R³, R⁴, R⁵, R⁶, R^6a, R^6b, R^7a, R^7b, R⁸, R⁹, R¹⁰, R¹¹ , R^11a, R¹², R^13a, R^13b, R^13c, R^13d, R^13e, R^13f, Ri 3g Ri 3h _or R14 _{can De} achieved before and/or after the exemplified transformations. These modifications can be such as the introduction of protecting groups, cleavage of protecting groups, reduction or oxidation of functional groups, halogenation, metallation, substitution or other reactions known to the person skilled in the art. These

transformations include those which introduce a functionality which allows for further interconversion of substituents. Appropriate protecting groups and their introduction and cleavage are well-known to the person skilled in the art (see for example T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). All reagents used for the preparation of the compounds of the invention are commercially available, known in the literature or can be prepared as described.

^• 5: W = : NHPG or NPG 4 deprotection |

6: W= I NH₂ Scheme 1: General procedures for the preparation of compounds of general formula (I) and (la) corresponding to formula 6; R¹, R^2a, R^2b- R^2c, R³, and R⁴ are as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g., (dimethylamino) methylene, 2,4-dimethoxybenzyl); V corresponds to LG, chloride or bromide; LG corresponds to a leaving group (e.g. chloride, fluoride, tosyl); R² is a heteroaromatic system with a nucleophilic nitrogen (e.g. pyrazole, imidazole, triazole) and undergoes a nucleophilic aromatic substitution at this nitrogen atom.

Compounds of general formula 6 can by synthesized as depicted in Scheme 1 . The person skilled in the art will be able to convert sulfonyl chlorides 1 to the protected sulfonyl amides 2 and will be able to select a protecting group PG that is suitable for the following steps. Examples for suitable protecting groups PG are 2,4-dimethoxybenzyl or

(dimethylamino)methylene. In case V corresponds to a leaving group LG (e.g. fluoride, chloride, tosyl) compounds 2 can be converted in a nucleophilic aromatic substitution reaction in a suitable solvent (e.g. acetonitrile) and in presence of a suitable base (e.g. potassium carbonate, cesium carbonate, ...) with a heteroaromatic system R²H that contains a nucleophilic nitrogen (e.g. pyrazole, imidazole, triazole, ...) to compounds 3 while forming a new C-N-bond. In case V corresponds to chloride or bromide, compounds 3 can be formed in a metal-catalyzed C-N coupling reaction with a nitrogen-containing heteroaromatic system (e.g. 1 ,2,3-triazoles) and in the presence of a suitable catalytic system (e.g. tris(dibenzylideneacetone)dipalladium / di-fert-butyl(2',4',6'-triisopropyl- 3,4,5,6-tetramethyl-[1 ,1 '-biphenyl]-2-yl)phosphine / potassium phoasphate / toluene). In the next step, nitro compounds 3 can be converted to the corresponding anilines 4 by reduction under hydrogenation conditions, in polar solvents such as ethanol, methanol, dioxane or tetrahydrofuran in the presence of for example Pd-, Pt- , Fe- or Sn- based catalysts. Anilines 4 can be converted to the corresponding amides 5 for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. In the last step, amides 5 are deprotected to the desired sulfonamides 6. Deprotection conditions depend on the used protecting group (e.g.

TFA/dichloromethane in case of 2,4-dimethoxybenzyl or aqueous ammonia/methanol in case of (dimethylamino)methylene).

nucleophilic

aromatic

itution

deprotection

depro

Scheme 2: General procedure for the preparation of compounds of general formula (I) and (lb) corresponding to formula 13; R¹, R^2b- R^2c, R³, and R⁴ are as defined in the description and claims of this invention; W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g. (dimethylamino) methylene); Ar is aryl; R² is a heteroaromatic system with a nucleophilic nitrogen (e.g. pyrazole, imidazole, triazole) and undergoes a nucleophilic aromatic substitution at this nitrogen atom.

Compounds of general formula 13 can by synthesized as depicted in Scheme 2. The person skilled in the art will be able to convert sulfonyl chlorides 7 to the protected sulfonyl amides 8 and will be able to select a protecting group PG that is suitable for the following steps. Example for a suitable protecting group PG is (dimethylamino)methylene (reaction of sulfonylchlorides 7 with ammonia, then reaction with 1 ,1 -dimethoxy-N,/V- dimethylmethanamine in DMF). Using protection and deprotection strategies, Buchwald amination of 8 in the presence of suitable catalysts (see for example WO201 1 120026A1 ) leads to intermediates 9. Nucleophilic aromatic substitution reaction in a suitable solvent (e.g. acetonitrile) and in presence of a suitable base (e.g. potassium carbonate, ...) with a heteroaromatic system R²H that contains a nucleophilic nitrogen (e.g. pyrazole, imidazole, triazole, ...) leads to pyridines 10. Deprotection of 10 (under acidic conditions in case Y = - N=CAr₂) is followed by conversion of the resulting anilines 11 to amides 12 for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acids in the presence of a coupling reagent e.g. HATU. In the last step, amide 12 is deprotected to the desired sulfonamides 13. Deprotection conditions depend on the used protecting group (e.g. aqueous ammonia/methanol in case of (dimethylamino)methylene).

acylation/ acylation/ peptide coupling peptide coupling

Scheme 3: General procedures for the preparation of compounds of general formula (I) and (la) corresponding to formula 19; R¹, R², R^2a, R^2b- R^2c, R³ and R⁴ are as defined in the description and claims of this invention, B(0Z)₂ corresponds to B(0H)₂ or B(0₂CeH₁₂) or a mixture of both and W corresponds to either an amine with hydrogen and /or a protecting group PG (e.g., (dimethylamino)methylene, 2,4-dimethoxybenzyl). Compounds of general formula 19 can by synthesized as depicted in Scheme 3. Starting from corresponding sulfonyl chlorides 14 (with V being either bromide or chloride) C- connected aryl and heteroaryl derivatives can be prepared via e.g. Suzuki cross-coupling reactions known to the person skilled in the art. Transformation of the protected sulfonamides 15 into aryl/heteroaryl compounds with general formula 16 can be achieved by reaction with the corresponding boronic acid (or ester or a mixture of both) under palladium catalysis in protic (e.g. isopropanol) or aprotic solvents. The corresponding amines 17 can be obtained from intermediates 16 by reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pd-, Pt- , Fe- or Sn- based catalysts. Subsequent acylation to the corresponding amides 16 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. For W equals a protecting group subsequent deprotection with e.g. trifluoroacetic acid (TFA), results in compounds of general formula 19.

Alternatively, starting from intermediates 15 with V = Br, reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran in the presence of for example Pt- , Fe- or Sn- based catalysts yields amines 20. The corresponding amides 21a can be obtained by reaction with acyl chlorides or by standard peptide bond formation using all known procedures. Subsequent arylation / heteroarylation using e.g. palladium catalyzed cross-couplings gives access to intermediates 18. Alternatively bromides 21a can be converted into the corresponding boronic acid/ ester intermediates 22 (B(OZ)₂ = B(OH)₂ or B(0₂C₆Hi2)) and further reacted using e.g. palladium catalysis known to the person skilled in the art to obtain intermediates 18 which after deprotection yield final products with general formula 19.

9 (Y= -N=CAr₂) acylation / peptide coupling

dep

Scheme 4: General procedure for the preparation of compounds of general formula (I) and (lb) corresponding to formula 26; R¹, R², R^2b- R^2c, R³, R⁴ are as defined in the description and claims of this invention, W corresponds to either amine with hydrogen and /or a protecting group PG (e.g., (dimethylamino)methylene, 2,4-dimethoxybenzyl); Ar is aryl.

Compounds of general formula 26 can by synthesized as depicted in Scheme 4. Starting from intermediate 9 C-coupled aryl and heteroaryl derivatives 23 can be prepared via e.g. palladium cross-couplings, e.g. Suzuki reactions, known to the person skilled in the art (see for example US 20110281865). Deprotection under e.g. acidic condition yields amines 24. Subsequent acylation to the corresponding amides can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. For W equals a protected amino function subsequent deprotection (with e.g. aqueous ammonia in case of (dimethylamino)methylene as protection group), results in compounds of general formula 26.

PG

Scheme 5: General procedure for the preparation of compounds of formula 21a; R¹, R³ and R⁴ are as defined in the description and claims of this invention, R^2a, R^2b and R^2c are hydrogen, W corresponds to either an amine with hydrogen and /or a protecting group PG (e.g., (dimethylamino)methylene, 2,4-dimethoxybenzyl).

Compounds of general formula 21a can by synthesized as depicted in Scheme 5. Starting from the corresponding aniline 27, bromination (e.g. with NBS in DMF) leads to

bromoaniline 28. Subsequent acylation to the corresponding amides 29 can be achieved for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent e.g. HATU. Subsequent protection of the sulfonamide moiety (e.g. with 1 ,1 -dimethoxy-N,N-dimethylmethanamine in DMF) leads to protected amides 21a that then can be further transformed e.g. using Suzuki chemistry as described in Scheme 3.

t , 30: W = NH₂ I 32: W = NHPG / NPG protection deprotectic

31 : W = NHPG / NPG 33: W = NH₂

Scheme 6: General procedure for the preparation of compounds of general formula (I) and (la) corresponding to formula 33; R¹, R^2a, R^2b, R^2c, R³ and R⁴ are as defined in the description and claims of this invention, Q corresponds to hydrogen, methyl or ethyl, W corresponds to either an amine with hydrogen and /or a protecting group PG (e.g., (dimethylamino)methylene, 2,4-dimethoxybenzyl). Compounds of general formula 33 can by synthesized as depicted in Scheme 6. After protection of the sulfonamide moiety of bromopyrazoles 30 (e.g. with a

(dimethylamino)methylene group), these can be transformed e.g. via Suzuki cross- coupling reactions known to the person skilled in the art to compounds 32. For W equals a protecting group subsequent deprotection with e.g. aqueous ammonia in an alcohol (e.g. methanol, ethanol, propanol) results in compounds of general formula 33.

Scheme 7: General procedure for the preparation of compounds of general formula (I) and (la) corresponding to formula 41; R¹, R^2a, R^2b, R^2c, R³, R⁴ and R¹² are as defined in the description and claims of this invention, W corresponds to either an amine with hydrogen and/or a protecting group PG (e.g., (dimethylamino)methylene, 2,4- dimethoxybenzyl); V corresponds to LG, chloride or bromide; LG corresponds to a leaving group (e.g. chloride, fluoride, tosyl); R' corresponds to Ci-C_e alkyl; PG' corresponds to another protecting group (e.g. CH₂CH₂SiMe3). Compounds of general formula 41 can by synthesized as depicted in Scheme 7. As already described in Scheme 1 nitro compounds 2 can be converted into the

corresponding pyrazoles 34. Hydrolysis, followed by a Curtius reaction known to the person skilled in the art (e.g. with diphenyl phosphorazidate or another azide source under basic conditions in a suitable solvent like e.g. dioxane) and scavenging with a protecting group PG' containing alcohol (e.g. HOCH CH SiMes) leads to carbamates 36. Amides 38 can be generated via reduction and acylation as already described in Scheme 1. These can be deprotected at the amine and the sulfonamide (e.g. with TBAF and TFA) to aminopyrazoles 40 which can be further acylated for example by reaction with acyl chlorides or by standard peptide bond formation using all known procedures, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent (e.g. HATU) at the aminopyrazole moiety to yield target compoudns 41.

In addition, example compounds can be further derivatized by late-stage functionalization chemistry (e.g. Bioorg. Med. Chem. Lett. 2012, 22, 1255-1262, Chem. Soc. Rev. 2016, 45(3), 546-476, Chem. Rev. 2016, 116(2), 422-518; Chem Rev. 2014, 114(4), 2432- 2506), as known to a person skilled in the art. These can be for example fluorination, difluoromethylation, trifluoromethylation, cyanation, methoxylation, oxidation or alkylation reactions (for oxidation examples see Org. Lett. 2015, 17, 6066-6069, Adv. Synth. Catal. 2004, 346, 171 -184, Science 2007, 318(5851), 783-7, Org. Lett., 2005, 7(1), 79-82, J. Organomet. Chem., 2015 , 793, 217-231 ).

The compounds according to the invention are isolated and purified in a manner known per se, e.g. by distilling off the solvent in vacuo and recrystallizing the residue obtained from a suitable solvent or subjecting it to one of the customary purification methods, such as chromatography on a suitable support material. Furthermore, reverse phase preparative HPLC of compounds of the present invention which possess a sufficiently basic or acidic functionality, may result in the formation of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. Salts of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays.

Additionally, the drying process during the isolation of compounds of the present invention may not fully remove traces of cosolvents, especially such as formic acid or trifluoroacetic acid, to give solvates or inclusion complexes. The person skilled in the art will recognise which solvates or inclusion complexes are acceptable to be used in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base, solvate, inclusion complex) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

Salts of the compounds of formula (I), (la) and (lb) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example a ketone such as acetone, methylethylketone or methylisobutylketone, an ether such as diethyl ether, tetrahydrofuran or dioxane, a chlorinated hydrocarbon such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol such as methanol, ethanol or isopropanol) which contains the desired acid or base, or to which the desired acid or base is then added. The acid or base can be employed in salt preparation, depending on whether a mono- or polybasic acid or base is concerned and depending on which salt is desired, in an equimolar quantitative ratio or one differing therefrom. The salts are obtained by filtering, reprecipitating, precipitating with a non-solvent for the salt or by evaporating the solvent. Salts obtained can be converted into the free compounds which, in turn, can be converted into salts. In this manner, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in the manufacturing on an industrial scale, can be converted into pharmaceutically acceptable salts by processes known to the person skilled in the art. Especially preferred are hydrochlorides and the process used in the example section.

Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained e.g. by asymmetric synthesis, by using chiral starting compounds in synthesis and by splitting up enantiomeric and diasteriomeric mixtures obtained in synthesis.

Enantiomeric and diastereomeric mixtures can be split up into the pure enantiomers and pure diastereomers by methods known to a person skilled in the art. Preferably, diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated e.g. by forming diastereomers with a chiral auxilliary agent, resolving the diastereomers obtained and removing the chiral auxilliary agent. As chiral auxilliary agents, for example, chiral acids can be used to separate enantiomeric bases such as e.g. mandelic acid and chiral bases can be used to separate enantiomeric acids by formation of diastereomeric salts. Furthermore, diastereomeric derivatives such as diastereomeric esters can be formed from enantiomeric mixtures of alcohols or enantiomeric mixtures of acids, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxilliary agents. Additionally, diastereomeric complexes or diastereomeric clathrates may be used for separating enantiomeric mixtures. Alternatively, enantiomeric mixtures can be split up using chiral separating columns in chromatography. Another suitable method for the isolation of enantiomers is the enzymatic separation.

One preferred aspect of the invention is the process for the preparation of the compounds of general formula (I) (la) or (lb) or an N-oxide, a salt, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer according to the examples, as well as the intermediates used for their preparation.

Optionally, compounds of the formula (I), (la) and (lb) can be converted into their salts, or, optionally, salts of the compounds of the formula (I), (la) and (lb) can be converted into the free compounds. Corresponding processes are customary for the skilled person.

EXPERIMENTAL PART

Abbreviations

The following table lists the abbreviations used in this paragraph and in the Intermediate Examples and Examples section as far as they are not explained within the text body.

Abbreviation Meaning

AcOH acetic acid (ethanoic acid)

aq. aqueous

boc t-butoxycarbonyl

br broad

CI chemical ionisation

d doublet

DAD diode array detector

DBU 1 ,8-Diazabicyclo(5.4.0)undec-7-ene

DCM dichloromethane

dd double-doublet

DIPEA diisopropylethylamine

DMF N,/V-dimethylform amide

DMSO dimethyl sulfoxide

ELSD Evaporative Light Scattering Detector

EtOAc ethyl acetate

EtOH ethanol

eq. equivalent

ESI electrospray (ES) ionisation HATU 1 -[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate

HPLC high performance liquid chromatography

LC-MS liquid chromatography mass spectrometry

m multiplet

MeCN acetonitrile

MeOH methanol

MS mass spectrometry

MTBE methyl tert-butylether

NMR nuclear magnetic resonance spectroscopy : chemical shifts (δ) are given in ppm. The chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise stated.

PDA Photo Diode Array

PoraPak™; a HPLC column obtainable from Waters

q quartet

r.t. or rt room temperature

Rt retention time (as measured either with HPLC or UPLC) in minutes

s singlet

SM starting material

SQD Single-Quadrupol-Detector

t triplet

td dublett of a triplet

dt triplett of a dublet

TBAF tetrabutyl ammonium fluoride

TEA triethylamine

TFA trifluoro acetic acid

THF tetrahydrofuran

UPLC ultra performance liquid chromatography

Other abbreviations have their meanings customary per se to the skilled person.

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. Specific Experimental Descriptions

NMR peak forms in the following specific experimental descriptions are stated as they appear in the spectra, possible higher order effects have not been considered. Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. from Separtis such as Isolute® Flash silica gel or Isolute® Flash NH₂ silica gel in combination with a Isolera® autopurifier (Biotage) and eluents such as gradients of e.g. hexane/ethyl acetate or DCM/methanol. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. In some cases, purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g. salt, free base etc) of a compound of the present invention as isolated as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

The percentage yields reported in the following examples are based on the starting component that was used in the lowest molar amount. Most reaction conditions were not optimized for yield. Air and moisture sensitive liquids and solutions were transferred via syringe or cannula, and introduced into reaction vessels through rubber septa. Commercial grade reagents and solvents were used without further purification. The term "concentrated in vacuo" refers to use of a Buchi rotary evaporator at a minimum pressure of approximately 15 mm of Hg. All temperatures are reported uncorrected in degrees Celsius (^<C).

In order that this invention may be better understood, the following examples are set forth. These examples are for the purpose of illustration only, and are not to be construed as limiting the scope of the invention in any manner. All publications mentioned herein are incorporated by reference in their entirety.

Analytical LC-MS and UPLC-MS conditions

LC-MS and UPLC-MS data given in the subsequent specific experimental descriptions refer (unless otherwise noted) to the following conditions:

Method A

Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μιη, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm.

Method B

Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μιη, 50x2.1 mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B:

acetonitrile; gradient: 0-1 .6 min 1 -99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min;

temperature: 60 ^<C; DAD scan: 210-400 nm.

Method C

Instrument: Waters Acquity UPLC-MS SingleQuad; Column: Acquity UPLC BEH C18 1 .7 μιη, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: methanol;

gradient: 0-1 .6 min 1 -99% B, 1 .6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 Ό; DAD scan: 210-400 nm.

Method D

Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IA 5μιη 100x4.6mm; Eluent A: C0₂, Eluent B: Methanol 0.2 Vol-% Diethylamine (99%); isocratic: 28%B; low 4.0 ml/min; temperature: 37.5^<C; BPR: 100bar; M WD @ 254nm. Method E

Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μ 100x4, 6mm; eluent A: MTBE + 0.1 % vol. diethylamine (99%), eluent B: ethanol; isocratic: 90%A + 10%B; flow 1 .4 imL/min; temperature: 25 Ό; injection: 5 μΙ; DAD @ 254 nm.

Method F

Instrument: Agilent: 1260, Aurora SFC-Modul; Column: Chiralpak IA 5μιη 100x4.6mm;

Eluent A: C0₂, Eluent B: Methanol; isocratic: 26%B;

low 4.0 ml/in; temperature: 37.5Ό; BPR: 100bar; MW D @ 254nm.

Flash column chromatography conditions

"Purification by (flash) column chromatography" as stated in the subsequent specific experimental descriptions refers to the use of a Biotage Isolera purification system. For technical specifications see "Biotage product catalogue" on www.biotage.com.

General Experimental Procedures

General Procedure GP1.1

Sulfonamide A (e.g.1 .29 mmol) was dissolved in acetonitrile (15 mL in case of 1 .29 mmol scale) and finely powdered potassium carbonate (3.0 eq) and the corresponding azole (1.5 eq) were added. Stirring was continued at 100 - 1 10Ό until TLC showed

consumption of starting material. The solvent was removed under reduced pressure, followed by addition of water and dichloromethane. Afterwards, the phases were separated, the organic phase was dried and it was concentrated in vacuo. The crude was either used without further purification or purified as indicated in the examples.

General Procedure GP2.1

Crude nitro compound B (e.g. 1 .29 mmol) was dissolved in dioxane (15 mL in case of 1.29 mmol scale) and tin(ll)chloride dihydrate (3.0 eq) was added and the reaction mixture was stirred for 2h at 70Ό. After cooling to room t emperature the reaction mixture was filtered and concentrated in vacuo. The filtrate was either used without further purification or purified as indicated in the examples.

General Procedure GP2.2

Crude nitro compound B (e.g. 1 .29 mmol) was dissolved in dioxane (15 mL in case of 1.29 mmol scale) and tin(ll)chloride dihydrate (5.0 eq) was added and the reaction mixture was stirred for 2h at 70Ό. After cooling to room t emperature the reaction mixture was filtered and concentrated in vacuo. The filtrate was either used without further purification or purified as indicated in the examples.

General Procedure GP2.3

Crude nitro compound B (e.g. 1 .29 mmol) was dissolved in methanol/dioxane (15 mL in case of 1.29 mmol scale) and Pd/C (10% loading, 50 mg) was added. The flask was evacuated three times and flushed with hydrogen (1 bar) and stirring was continued at room temperature. After completion of the reaction, the mixture was filtered and concentrated in vacuo. The crude was used without further purification.

General Procedure GP2.4

Crude nitro compound B (e.g. 1 .29 mmol) was dissolved in methanol/dioxane (15 mL in case of 1.29 mmol scale) and Pt/C (10% loading, 50 mg) was added. The flask was evacuated three times and flushed with hydrogen (1 bar) and stirring was continued at room temperature. After completion of the reaction, the mixture was filtered and concentrated in vacuo. The crude was used without further purification.

General procedure GP3.1

Crude substituted aniline C (1.29 mmol) was dissolved in dimethylformamide (10 mL in case of 1.29 mmol scale) followed by the addition of the corresponding acid (amount as indicated in examples), N,/V-diisopropylethylamine (2.7 eq based on acid) and HATU (1 .0 eq based on acid). The reaction mixture was either stirred overnight at room temperature or heated at 50Ό until TLC showed consumption of s tarting material. After cooling to room temperature the reaction mixture was concentrated in vacuo. Ethyl acetate and water were added, the organic phase was dried and concentrated in vacuo. The crude was used without further purification.

General procedure GP3.2

D E

General procedure GP4.1

Crude amide D (e.g. 1.29 mmol) was dissolved in dichloromethane (5-10 mL in case of 1 .29 mmol scale), trifluoroacetic acid (50 eq) was added and the reaction mixture was stirred at room temperature until TLC showed consumption of starting material. The reaction mixture was concentrated in vacuo, ethyl acetate and water were added to the crude and the organic phase was dried and the solvent was removed under reduced pressure. The resulting residue was purified as indicated in the examples. Purification without aqueous extraction was also possible but made the HPLC purification more difficult.

General procedure GP4.2

Crude amide D (e.g. 1.29 mmol) was dissolved in dichloromethane/trifluoroacetic acid 2/1 (6 mL in case of 1.29 mmol scale) and the reaction mixture was stirred at room temperature until TLC showed consumption of starting material. The reaction mixture was concentrated in vacuo, ethyl acetate and water were added to the crude and the organic phase was dried and the solvent was removed under reduced pressure. The resulting residue was purified as indicated in the examples. Purification without aqueous extraction was also possible but made the HPLC purification more difficult.

General procedure GP4.3

Crude amide D (e.g. 1.29 mmol) was dissolved in dichloromethane/trifluoroacetic acid 1/1 (6 mL in case of 1.29 mmol scale) and the reaction mixture was stirred at room temperature until TLC showed consumption of starting material. The reaction mixture was concentrated in vacuo, ethyl acetate and water were added to the crude and the organic phase was dried and the solvent was removed under reduced pressure. The resulting residue was purified as indicated in the examples. Purification without aqueous extraction was also possible but made the HPLC purification more difficult.

General procedure GP5.1

Bromopyrazole F (amount as indicated in examples) was dissolved in dimethylformamide (20 mL in case of 3.19 mmol scale), 1 ,1 -dimethoxy-N,N-dimethylmethanamine (2 eq) was added and it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, extracted with dichloromethane/water and the organic phase was washed with brine solution, dried over sodium sulfate and concentrated.

The crude from the previous step was redissolved in methanol (100 mL in case of 3.19 mmol scale), it was degassed twice with nitrogen, followed by addition of

bis(pinacolato)diboron (2.5 eq), mesylate[(di(1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1 ,1 '-biphenyl)]palladium(ll) (cataCXium® A Pd G3, 0.05 eq) and diisopropylethylamine (2.5 eq). The reaction mixture was stirred at 50Ό for one hour. Then, the catalyst was removed by filtration and the solution was concentrated in vacuo. Normally these two steps were performed on larger scale (0.57 mmol to 3.2 mmol scale) and then an aliquot was used for the next step.

An aliquot of the crude from the previous step was redissolved in dioxane (5 mL in case of 0.44 mmol scale), followed by addition of the corresponding bromohetaryl (amount as indicated in examples) and 2 M potassium carbonate solution (3 eq based on

bromohetaryl). It was flushed with argon for 5 min, followed by addition of [1 ,1 ' - bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.2 eq based on bromohetaryl). It was flushed again with argon, followed by stirring for 18 hours at 80Ό. Then, any precipitate was removed by filtration and the filtrate was concentrated in vacuo. The crude was redissolved in methanol (10 mL in case of 0.44 mmol scale), aqueous 33% ammonium hydroxide solution (10 mL in case of 0.44 mmol scale) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and purified as indicated in the examples. General procedure GP5.2

Bromopyrazole F (amount as indicated in examples) was dissolved in dimethylformamide (25 mL in case of 4.13 mmol scale), 1 ,1 -dimethoxy-N,N-dimethylmethanamine (2 eq) was added and it was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo, extracted with dichloromethane/water and the organic phase was washed with brine solution, dried over sodium sulfate and concentrated.

The crude from the previous step was redissolved in methanol (25 mL in case of 4.12 mmol scale), it was degassed twice with nitrogen, followed by addition of

bis(pinacolato)diboron (2.5 eq), mesylate[(di(1 -adamantyl)-n-butylphosphine)-2-(2'-amino- 1 ,1 '-biphenyl)]palladium(ll) (cataCXium® A Pd G3, 0.05 eq) and diisopropylethylamine (2.5 eq). The reaction mixture was stirred at 50Ό for one hour. Then, the catalyst was removed by filtration and the solution was concentrated in vacuo. Normally these two steps were performed on larger scale (up to 4.1 mmol scale) and then an aliquot was used for the next step.

An aliquot of the crude from the previous step was redissolved in THF (3 mL in case of 0.51 mmol scale), followed by addition of the corresponding bromohetaryl (amount as indicated in examples) and 2 M potassium carbonate solution (2 eq based on

bromohetaryl). It was flushed with argon for 5 min, followed by addition of second generation XPhos precatalyst (0.2 eq based on bromohetaryl). It was flushed again with argon, followed by stirring for 2 hours at 45Ό. Th en, any precipitate was removed by filtration and the filtrate was concentrated in vacuo. The crude was redissolved in methanol (10 mL in case of 0.51 mmol scale), aqueous 33% ammonium hydroxide solution (10 mL in case of 0.51 mmol scale) was added, followed by stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and purified as indicated in the examples.

Synthesis of Intermediates

Intermediate 1

2-Chloro-A-(2,4-dimethox benzyl)-5-nitrobenzenesulfonamide

To a solution of 2-chloro-5-nitrobenzenesulfonylchloride (10.8 g, 42.2 mmol) in dichloromethane (108 mL) was added sodium bicarbonate (7.09 g, 84.4 mmol) and 1 -(2,4- dimethoxyphenyl)methanamine (7.05 g, 42.2 mmol). The mixture was stirred overnight. The reaction mixture was concentrated in vacuo, followed by addition of water (75 mL) and ethyl acetate (75 mL). After stirring for 10 min the resulting precipitate was separated by filtration and it was dried at 4CC overnight in vacuo to yield the title compound (14.1 g, 36.5 mmol, 86 % yield).

LC-MS (Method A): Rt = 1 .17 min; MS (ESIneg): m/z = 385 [M-H]-

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.56 (s, 3H), 3.61 (s, 3H), 4.08 (s, 2H), 6.10 (d, 1 H), 6.26 (dd, 1 H), 7.04 (d, 1 H), 7.79 (d, 1 H), 8.19 (d, 1 H), 8.28 (dd, 1 H), 8.45 (s, 1 H).

Intermediate 2

Af-(2,4-Dimethoxybenzyl)-2-(4-fluoro-1 ,4'-biimidazol-1 '-yl)-5- nitrobenzenesulfonamide

To a solution of 2-chloro-/V-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (800 mg,

1.97 mmol, 95% purity) in acetonitrile (15 mL) were added 4-fluoro-1 /-/-imidazole (423 mg, 4.91 mmol, CAS-RN 30086-17-0) and powdered potassium carbonate (815 mg, 5.89 mmol). The mixture was irradiated for 5h at 120Ό in the microwave. The reaction mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography to yield the title compound (305 mg, 21 % yield, 66% purity).

LC-MS (Method B): Rt = 1 .03 min; MS (ESIpos): m/z = 503 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.60 (s, 3H), 3.68 (s, 3H), 4.04 (d, 2H), 6.32 (d, 1 H), 6.35 (dd, 1 H), 7.02 (d, 1 H), 7.40 (d, 1 H), 7.71 (d, 1 H), 7.83 (d, 1 H), 7.89 (d, 1 H), 7.92 (dd, 1 H), 8.44 (d, 1 H), 8.49 (dd, 1 H), 8.60 (t, 1 H).

Intermediate 3

2-(2-Chlorophenyl)-A^{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-fluoro-1 'H-1 ,4'- biimidazol-1 '-yl)phen l}acetamide

Tin(ll) chloride dihydrate (685 mg, 3.04 mmol) was added to a solution of N-(2,4-dimeth- oxybenzyl)-2-(4-fluoro-1 'A7-1 ,4'-biimidazol-1 '-yl)-5-nitrobenzenesulfonamide (305 mg, 401 μιηοΙ, 66% purity) in dioxane (7.8 mL) and stirred for 4 h at 70Ό. The reaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted three times with ethyl acetate. The combined organic phases were filtered over Celite, washed with brine, dried using a Whatman filter, and concentrated in vacuo to give 312 mg crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1 '/-/-1 ,4'-biimidazol-1 '-yl)ben- zenesulfonamide that was used without further purification in the next step.

Crude material from the previous step (310 mg) was dissolved in DMF (9 mL) followed by the addition of (2-chlorophenyl)acetic acid (157 mg, 919 μιηοΙ), N,N-diisopropylethylamine (400 μΙ_, 2.30 mmol) and HATU (349 mg, 919 μιηοΙ). The reaction mixture was stirred at room temperature for 4h. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give the title compound that was used without further purification (287 mg, 70% purity, 80% yield over 2 steps).

LC-MS (Method B): Rt = 1 .21 min; MS (ESIpos): m/z = 625 [M+H]⁺ Intermediate 4

Ethyl 1-{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4- carboxylate

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (5 g, 12.9 mmol) in acetonitrile (250 mL) were added ethyl 1 /-/-pyrazole-4-carboxylate (2.72 g, 19.4 mmol, CAS-RN 37622-90-5) and powdered potassium carbonate (5.36 g, 38.8 mmol) and it was heated for 19h to 90Ό. The reaction mix ture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine and dried using a Whatman filter. Concentration under reduced pressure led to the title compound that was used without further purification (7.8 g, 98% yield, 80% purity).

LC-MS (Method A): Rt = 1 .27 min; MS (ESIpos): m/z = 491 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 1 .30 (t, 3H), 3.51 (s, 3H), 3.63 (s, 3H), 4.14 (s, 2H), 4.29 (q, 2H), 6.17 (d, 1 H), 6.28 (dd, 1 H), 7.07 (d, 1 H), 7.91 (d, 1 H), 8.05 (br s, 1 H), 8.24 (d, 1 H), 8.29 (s, 1 H), 8.46 (dd, 1 H), 8.84 (s, 1 H).

Intermediate 5

1-{2-[(2,4-Dimethoxybenz l)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4-carboxylic acid

To a solution of ethyl 1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 /-/-pyrazole-4- carboxylate (7.8 g, 12.9 mmol, 80% purity) in tetrahydrofuran (129 mL) was added a solution of lithium hydroxide (1 .55 g, 64.6 mmol) in water (1 1.6 mL) and it was stirred for 18h at room temperature. The solvent was evaporated and the crude was suspended in water (15 mL), and acidified to a pH of 5 using aq. HCI (55 mL, 1.0 M). The slurry was stirred for 30 min, and filtered. The precipitate was dried at 50Ό in vacuo to yield the title compound (5.7 g, 91 % yield, 95% purity).

LC-MS (Method A): Rt = 1 .08 min; MS (ESIpos): m/z = 463 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.50 (s, 3H), 3.62 (s, 3H), 4.14 (d, 2H), 6.16 (d, 1 H), 6.28 (dd, 1 H), 7.07 (d, 1 H), 7.90 (d, 1 H), 8.12 (t, 1 H), 8.22 (d, 1 H), 8.24 (s, 1 H), 8.45 (dd, 1 H), 8.76 (s, 1 H), 12.82 (br s, 1 H).

Intermediate 6

2-(Trimethylsilyl)ethyl (1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H- pyrazol-4-yl)carbamate

To a solution of 1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 /-/-pyrazole-4- carboxylic acid (5.7 g, 1 1 .7 mmol, 95% purity) and triethylamine (2.45 mL, 17.6 mmol) in dioxane (59 mL) was added diphenyl phosphorazidate (6.45 g, 23.4 mmol), and the solution was heated to 50Ό for 75 min. Then, 2-(tr imethylsilyl)ethanol (8.39 mL, 58.5 mmol) was added, and the mixture was stirred at 100Ό for 3h. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution and with brine. The organic phase was dried using a Whatman filter and evaporated in vacuo. Purification by flash chromatography yielded the title compound (6.5 g, 86% yield, 89% purity).

LC-MS (Method A): Rt = 1 .46 min; MS (ESIpos): m/z = 578 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.07 (s, 9H), 1 .03 (m, 2H), 3.46 (s, 3H), 3.63 (s, 3H), 4.18 (d, 2H), 4.21 (m, 2H), 6.14 (d, 1 H), 6.29 (dd, 1 H), 7.10 (d, 1 H), 7.81 (d, 1 H), 7.88 (s, 1 H), 8.17 (t, 1 H), 8.20 (d, 1 H), 8.21 (s, 1 H), 8.40 (dd, 1 H), 9.74 (s, 1 H). Intermediate 7

2-(Trimethylsilyl)ethyl [1-(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4- dimethoxybenz l)sulfamoyl]phenyl)-1 H-pyrazol-4-yl]carbamate

Tin(ll) chloride dihydrate (1 1.1 g, 50.3 mmol) was added to a solution of 2- (trimethylsilyl)ethyl (1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 /-/-pyrazol-4- yl)carbamate (6.5 g, 89% purity, 10.1 mmol) in dioxane (129 mL), followed by stirring for 4h at 7CC and overnight at room temperature. The r eaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was neutralized with 5% aqueous sodium hydroxide solution, then extracted three times with ethyl acetate. The combined organic phases were filtered over Celite, dried over a Whatman filter, and concentrated in vacuo to give 5.5 g crude 2-(trimethylsilyl)ethyl (1 -{4-amino-2-[(2,4-dimethoxybenzyl)sul- famoyl]phenyl}-1 /-/-pyrazol-4-yl)carbamate that was used without further purification in the next step.

Crude material from the previous step (5.5 g) was dissolved in DMF (154 mL) followed by the addition of (2-chlorophenyl)acetic acid (2.74 g, 16.1 mmol), N,/V-diisopropylethylamine (5.6 mL, 32.1 mmol) and HATU (6.1 1 g, 16.1 mmol). The reaction mixture was stirred for 17h at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give the title compound that was used without further purification (10.55 g, 50% purity, 75% yield over 2 steps).

LC-MS (Method B): Rt = 1 .49 min; MS (ESIpos): m/z = 700 [M+H]⁺ Intermediate 8

/V-{4-(4-Amino-1 H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide

To a solution of 2-(trimethylsilyl)ethyl [1 -(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4- dimethoxybenzyl)sulfamoyl]phenyl)-1 /-/-pyrazol-4-yl]carbamate (10.55 g, 7.53 mmol) in tetrahydrofuran (4 mL), a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (15.1 mL, 15.1 mmol) was added, and the mixture was heated for 2.5h to 50Ό. Additional 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.77 mL, 3.77 mmol) was added, and heating to 5CC was continued for 3h. Th e reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were washed with brine and dried using a Whatman filter. Concentration under reduced pressure led to the title compound that was purified by flash chromatography (2.9 g, 55% yield, 80% purity). LC-MS (Method B): Rt = 1 .18 min; MS (ESIpos): m/z = 556 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.56 (s, 3H), 3.63 (s, 3H), 3.84 (s, 2H), 3.95 (d, 2H), 4.13 (s, 2H), 6.30 (dd, 1 H), 6.31 (d, 1 H), 7.02 (d, 1 H), 7.24 (s, 1 H), 7.28 (s, 1 H), 7.30 (m, 2H), 7.36 (d, 1 H), 7.42 (m, 2H), 7.77 (t, 1 H), 7.87 (dd, 1 H), 8.02 (d, 1 H), 10.57 (s, 1 H).

Intermediate 9

Λ^[4-(4- Amino- 1 /¾ⁱpyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

N-{4-(4-Amino-1 /-/-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2-chloro- phenyl)acetamide (403 mg, 435 μιηοΙ, 60% purity) was dissolved in dichloromethane (5.6 mL) and treated with trifluoroacetic acid (1.7 mL, 22 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (28 mg, 16% yield, 100% purity).

LC-MS (Method A): Rt = 0.74 min; MS (ESIpos): m/z = 406 (M+H)⁺ ¹ H-NMR (400MHz, DMSO-de) δ [ppm] 3.88 (s, 2H), 4.14 (s, 2H), 7.30 (d, 1 H), 7.32 (m, 2H), 7.35 (d, 1 H), 7.44 (m, 2H), 7.45 (d, 1 H), 7.48 (s, 2H), 7.94 (dd, 1 H), 8.32 (d, 1 H), 10.70 (s, 1 H).

Intermediate 10

/V-(Cyclopropylmethyl)-1 H-pyrazol-4-amine and A ,/V-bis(cyclopropylmethyl)-1 H- pyrazol-4-amine

To a solution of 1 /-/-pyrazol-4-amine (1 g, 95% purity, 1 1 .4 mmol) in acetonitrile (57 mL) were added (bromomethyl)cyclopropane (1 .65 ml, 17.1 mmol, CAS-RN 7051 -34-5), powdered potassium carbonate (3.95 g, 28.6 mmol), and triethylamine (2.39 mL, 17.1 mmol). The mixture was heated to 90Ό for 4h a nd stirred at room temperature overnight. For work-up, it was filtered, and the solid was rinsed with ethyl acetate. Concentration of the filtrate in vacuo followed by flash chromatography led to N- (cyclopropylmethyl)-l /-/-pyrazol-4-amine (416 mg, 24% yield, 90% purity).

LC-MS (Method B): Rt = 0.54 min; MS (ESIpos): m/z = 138 (M+H)⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.16 (m, 2H), 0.42 (m, 2H), 0.99 (m, 1 H), 2.68 (m, 2H), 4.23 (m, 1 H), 7.03 (s, 2H), 12.01 (s, 1 H).

As additional fraction, N,N-bis(cyclopropylmethyl)-1 /-/-pyrazol-4-amine was isolated (657 mg, 27% yield, 90% purity).

LC-MS (Method B): Rt = 0.97 min; MS (ESIpos): m/z = 192 (M+H)⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.06 (m, 4H), 0.33 (m, 4H), 0.84 (m, 2H), 2.82 (d, 4H), 7.07 (s, 2H), 12.07 (s, 1 H).

Intermediate 11

2-{4-[(Cyclopropylmethyl)amino]-1 H-pyrazol-1-yl}-Ai-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (547 mg, 1 .35 mmol, 95% purity) in acetonitrile (14 mL) were added N-(cyclopropylmethyl)-1 /-/- pyrazol-4-amine (410 mg, 2.69 mmol, 90% purity) and powdered potassium carbonate (138 mg, 4.03 mmol) and it was irradiated for 12h at 12CC in the microwave. The reaction mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography (232 mg, 32% yield, 90% purity).

LC-MS (Method A): Rt = 1 .22 min; MS (ESIneg): m/z = 486 [M-H]-

¹ H-NMR (400MHz, DMSO-d₆) 6 [ppm]: 0.21 (m, 2H), 0.47 (m, 2H), 1 .07 (m, 1 H), 2.80 (dd, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 4.16 (d, 2H), 5.09 (t, 1 H), 6.08 (d, 1 H), 6.25 (dd, 1 H), 7.08 (d, 1 H), 7.60 (s, 1 H), 7.65 (s, 1 H), 7.73 (d, 1 H), 8.16 (d, 1 H), 8.28 (t, 1 H), 8.34 (dd, 1 H).

Intermediate 12

ferf-Butyl [(2-{4-[(ferf-butoxycarbonyl)(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-5- {[(2-chlorophenyl)acet l]amino}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate

To a solution of 2-{4-[(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-N-(2,4-dimethoxyben- zyl)-5-nitrobenzenesulfonamide (175 mg, 359 μιηοΙ) in dichloromethane (3.6 mL), di-iert- butyl dicarbonate (125 mg, 574 μιηοΙ) and 4-(dimethylamino)pyridine (2.19 mg, 18 μιηοΙ) were added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure yielding crude tert-butyl [(2-{4-[(fert-butoxycarbonyl)(cyclopropylmethyl)- amino]-1 /-/-pyrazol-1 -yl}-5-nitrophenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate that was used without further purification (1 19 mg).

Tin(ll) chloride dihydrate (189 mg, 836 μιηοΙ) was added to a solution of the crude di-boc compound (1 15 mg) in dioxane (1 .1 mL) and stirred for 4 h at 70Ό. The reaction mixture was concentrated in vacuo. Water was added to the residue and the mixture was extracted three times with ethyl acetate. The combined organic phases were filtered over Celite, washed with brine, dried using a Whatman filter, and concentrated in vacuo to give 108 mg crude fert-butyl [(5-amino-2-{4-[(ferf-butoxycarbonyl)(cyclopropylmethyl)amino]- 1 /-/-pyrazol-1 -yl}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate that was used without further purification in the next step.

The crude material from the previous step (105 mg) was dissolved in DMF (3 mL) followed by the addition of (2-chlorophenyl)acetic acid (41 mg, 282 μιηοΙ), N,N-diisopropylethyl- amine (160 μί, 940 μιηοΙ) and HATU (107 mg, 239 μιηοΙ). The reaction mixture was stirred overnight at room temperature and for 1 h at 40Ό. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give the title compound that was used without further purification (127 mg).

LC-MS (Method B): Rt = 1 .62 min; MS (ESIpos): m/z = 810 [M+H]⁺ Intermediate 13

2-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1-yl}-/V-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (623 mg, 1.53 mmol, 95% purity) in acetonitrile (14 mL) were added N,/V-bis(cyclopropylmethyl)-1 H- pyrazol-4-amine (650 mg, 3.06 mmol, 90% purity) and powdered potassium carbonate (634 mg, 4.59 mmol) and it was irradiated for 12h at 12CC in the microwave. The reaction mixture was filtered, concentrated in vacuo, and the residue was purified by flash chromatography to yield the title compound (383 mg, 42% yield, 90% purity).

LC-MS (Method A): Rt = 1 .48 min; MS (ESIpos): m/z = 542 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 0.23 (m, 4H), 0.47 (m, 4H), 1 .04 (m, 2H), 3.08 (d, 2H), 3.39 (s, 3H), 3.59 (s, 3H), 4.16 (d, 2H), 6.09 (d, 1 H), 6.26 (dd, 1 H), 7.08 (d, 1 H), 7.78 (d, 1 H), 7.80 (s, 1 H), 7.82 (s, 1 H), 8.18 (d, 1 H), 8.29 (t, 1 H), 8.35 (dd, 1 H).

Intermediate 14

Ai-(4-{4-[Bis(cyclopropylmethyl)amino]-1 W-pyrazol-1-yl}-3-[(2,4- dimethoxybenzyl)sulfamo l]phenyl)-2-(2-chlorophenyl)acetamide

Tin(ll) chloride dihydrate (189 mg, 836 μιηοΙ) was added to a solution of 2-{4- [bis(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)-5-nitrobenzene- sulfonamide (380 mg, 631 μιηοΙ, 90% purity) in dioxane (8.1 mL) and stirred for 4 h at 70Ό. The reaction mixture was concentrated in vacu o. Water was added to the residue and the mixture was extracted three times with ethyl acetate. The combined organic phases were filtered over Celite, washed with brine, dried using a Whatman filter, and concentrated in vacuo to give 333 mg crude 5-amino-2-{4-[bis(cyclopropylmethyl)amino]- 1 /-/-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)benzenesulfonamide that was used without further purification in the next step.

The crude material from the previous step (330 mg) was dissolved in DMF (6 mL) followed by the addition of (2-chlorophenyl)acetic acid (157 mg, 919 μιηοΙ), N,N-diisopropylethyl- amine (427 μί, 2.45 mmol) and HATU (349 mg, 919 μιηοΙ). The reaction mixture was stirred overnight at room temperature and for 1 h at 40Ό. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give the title compound that was used without further purification (535 mg, 66% yield, 50% purity). LC-MS (Method A): Rt = 1 .37 min; MS (ESIpos): m/z = 664 [M+H]⁺ Intermediate 15

A-[4-(4-Bromo-3-methyl-1 H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2- chlorophenyl)acetamide

According to general procedures GP1 .1 , GP2.4, GP3.2 and GP4.1 , 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (3.90 g, 10.1 mmol), 4-bromo-3-methyl-1 H- pyrazole (2.43 g, 15.1 mmol) and (2-chlorophenyl)acetic acid (1 .06 g, 6.23 mmol) were converted without purification of intermediates to the title compound which was purified by column chromatography.

LC-MS (Method A): Rt = 1 .20 min; MS (ESIpos): m/z = 483/485 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.23 (s, 3H), 3.90 (s, 2H), 7.30 - 7.54 (m, 7H), 7.95

(dd, 1 H), 8.25 (s, 1 H), 8.35 (d, 1 H), 10.77 (s, 1 H).

Synthesis of Examples

Example 1

2-(2-Chlorophenyl)-Af-[4-(4-f luoro-1 ,4'-biimidazol-1 '-yl)-3- sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-fluoro-1 '/-/-1 ,4'-biimidazol- 1 '-yl)phenyl}acetamide (286 mg, 320 μιηοΙ, 70% purity) was dissolved in dichloromethane (9.2 mL) and treated with trifluoroacetic acid (1 .8 mL, 23.0 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (86 mg, 57% yield, 100% purity). LC-MS (Method A): Rt = 0.95 min; MS (ESIpos): m/z = 475 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 3.91 (s, 2H), 7.33 (m, 2H), 7.37 (d, 1 H), 7.46 (m, 2H), 7.52 (d, 1 H), 7.65 (d, 1 H), 7.65 (s, 2H), 7.78 (d, 1 H), 7.88 (d, 1 H), 7.92 (dd, 1 H), 8.42 (d, 1 H), 10.82 (s, 1 H).

Example 2

Ai-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4-yl]-3,3- difluorocyclobutanecarboxamide

A mixture of N-{4-(4-amino-1 /-/-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (195 mg, 350 μιηοΙ), N,N-diisopropylethylamine (305 μΙ_, 1.75 mmol), and 3,3-difluorocyclobutanecarbonyl chloride (108 mg, 700 μιηοΙ, CAS-RN 946488-78-4) was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give crude N-[1 -(4-{[(2-chlorophenyl)ace- tyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1 /-/-pyrazol-4-yl]-3,3-difluorocyclobu- tanecarboxamide (344 mg) that was deprotected immediately by stirring with trifluoroacetic acid (1 .35 mL, 17.5 mmol) in dichloromethane (7 mL) for 4h at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (38 mg, 21 % yield, 99% purity).

LC-MS (Method A): Rt = 1 .06 min; MS (ESIpos): m/z = 524 (M+H)⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 2.79 (m, 4H), 3.06 (m, 1 H), 3.90 (s, 2H), 7.33 (m, 2H), 7.42 (s, 2H), 7.45 (m, 2H), 7.55 (d, 1 H), 7.81 (d, 1 H), 7.96 (dd, 1 H), 8.20 (d, 1 H), 8.36 (d, 1 H), 10.37 (s, 1 H), 10.76 (s, 1 H).

Example 3, Example 4 (Enantiomer A) and Example 5 (Enantiomer B)

Example 3

Ai-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide

A mixture of N-{4-(4-amino-1 /-/-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (216 mg, 350 μmol, 90% purity), N,N-diisopropylethylamine (305 μί, 1 .75 mmol), and (±)-2,2-difluorocyclopropanecarbonyl chloride (98 mg, 700 μιηοΙ, CAS-RN 130340-05-5) was stirred at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give crude (±)-Λ/-[1 -(4-{[(2- chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1 /-/-pyrazol-4-yl]- 2,2-difluorocyclopropanecarboxamide (31 1 mg) that was deprotected immediately by stirring with trifluoroacetic acid (1.35 mL, 17.5 mmol) in dichloromethane (7 mL) for 3h at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (1 14 mg, 64% yield, 99% purity).

LC-MS (Method A): Rt = 1 .02 min; MS (ESIpos): m/z = 510 (M+H)⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 2.00 (m, 2H), 2.77 (m, 1 H), 3.90 (s, 2H), 7.33 (m, 2H), 7.42 (s, 2H), 7.45 (m, 2H), 7.54 (d, 1 H), 7.82 (d, 1 H), 7.95 (dd, 1 H), 8.19 (d, 1 H), 8.36 (d, 1 H), 10.67 (s, 1 H), 10.76 (s, 1 H).

106 mg of the racemic compound were separated into the enantiomers by chiral phase HPLC (Instrument: Sepiatec: Prep SFC100; Column: Chiralpak IA 5μιη 250x30mm; Eluent A: C0₂, Eluent B: methanol; isocratic: 26%B; flow 100.0 mL/min; temperature: 4CC; BPR: 150bar; MWD @ 254nm) yielding the following two isomers:

Example 4

/V-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide (Enantiomer A)

22 mg, 100% purity.

LC (Method F): Rt = 2.66 min.

Example 5

Ai-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide (Enantiomer B) 22 mg, 100% purity.

LC (Method F): Rt = 5.06 min.

Example 6

/V-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4-yl]-4- hydroxybutanamide

A mixture of N-[4-(4-amino-1 /-/-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)aceta- mide (40 mg, 98 μιηοΙ), N,/V-diisopropylethylamine (47 μΙ_, 269 μιηοΙ), and 4-bromo- butanoyl chloride (12 μΙ_, 108 μηιοΙ, CAS-RN 927-58-2) in THF (1 mL) was stirred at 50Ό overnight. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo and purified by HPLC to give the title compound (4 mg, 7% yield, 95% purity).

LC-MS (Method A): Rt = 0.77 min; MS (ESIpos): m/z = 492 (M+H)⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 1 .73 (tt, 2H), 2.32 (t, 2H), 3.43 (td, 2H), 3.90 (s, 2H), 4.52 (t, 1 H), 7.33 (m, 2H), 7.42 (s, 2H), 7.45 (m, 2H), 7.53 (d, 1 H), 7.77 (d, 1 H), 7.95 (dd, 1 H), 8.16 (d, 1 H), 8.35 (d, 1 H), 10.12 (s, 1 H), 10.75 (s, 1 H).

Example 7

Ai-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazol-4- yl]acrylamide

A mixture of N-{4-(4-amino-1 /-/-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2- (2-chlorophenyl)acetamide (200 mg, 288 μιηοΙ, 80% purity), N,N-diisopropylethylamine (150 μΙ_, 863 μιηοΙ), 3-bromopropanoyl chloride (35 μΙ_, 345 μιηοΙ, CAS-RN 15486-96-1 ), and THF (0.5 mL) was vigorously stirred at room temperature for 4 days. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. Then all organic phases were combined, washed with brine, dried over a Whatman filter and concentrated in vacuo to give crude 2-(2- chlorophenyl)-/V-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[4-(2-oxoazetidin-1 -yl)-1 H-pyrazol-

1 - yl]phenyl}acetamide (245 mg) that was further reacted immediately by stirring with trifluoroacetic acid (1.48 mL, 14.4 mmol) in dichloromethane (3.7 mL) for 210min at room temperature. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (36 mg, 26% yield, 96% purity).

LC-MS (Method A): Rt = 0.97 min; MS (ESIpos): m/z = 460 (M+H)⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm] 3.90 (s, 2H), 5.74 (dd, 1 H), 6.23 (dd, 1 H), 6.38 (dd, 1 H), 7.33 (m, 2H), 7.43 (s, 2H), 7.46 (m, 2H), 7.55 (d, 1 H), 7.85 (d, 1 H), 7.96 (dd, 1 H), 8.25 (d, 1 H), 8.37 (d, 1 H), 10.44 (s, 1 H), 10.77 (s, 1 H).

Example 8

2- (2-Chlorophenyl)-Ai-(4-{4-[(cyclopropylmethyl)amino]-1 W-pyrazol-1-yl}-3- su If amoyl phenyl)acetamide

Crude fert-butyl [(2-{4-[(fert-butoxycarbonyl)(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-5- {[(2-chlorophenyl)acetyl]amino}phenyl)sulfonyl](2,4-dimethoxybenzyl)carbamate (127 mg, 94.2 μιηοΙ, 60% purity) was dissolved in dichloromethane (2 mL) and treated with trifluoroacetic acid (604 μΙ_, 7.84 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (10 mg, 23% yield, 95% purity).

LC-MS (Method A): Rt = 0.90 min; MS (ESIpos): m/z = 460 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 0.20 (m, 2H), 0.45 (m, 2H), 1 .05 (m, 1 H), 2.77 (m, 2H), 3.89 (s, 2H), 4.74 (m, 1 H), 7.33 (m, 2H), 7.36 (d, 1 H), 7.42 (d, 1 H), 7.45 (m, 2H), 7.47 (d, 1 H), 7.49 (s, 2H), 7.95 (dd, 1 H), 8.33 (d, 1 H), 10.78 (s, 1 H).

Example 9

A^(4-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1-yl}-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide

Crude N-(4-{4-[bis(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-3-[(2,4-dimethoxybenzyl)- sulfamoyl]phenyl)-2-(2-chlorophenyl)acetamide (530 mg, 479 μmol, 60% purity) was dissolved in dichloromethane (6 mL) and treated with trifluoroacetic acid (1 .84 ml_, 23.9 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (100 mg, 40% yield, 99% purity).

LC-MS (Method A): Rt = 1 .04 min; MS (ESIpos): m/z = 514 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm] 0.45 (m, 4H), 0.84 (m, 4H), 1 .01 (m, 2H), 3.02 (d, 4H), 3.89 (s, 2H), 7.33 (m, 2H), 7.45 (m, 2H), 7.50 (s, 2H), 7.51 (d, 1 H), 7.52 (d, 1 H), 7.57 (d, 1 H), 7.95 (dd, 1 H), 8.32 (d, 1 H), 10.71 (s, 1 H).

Example 10 and Example 11

According to general procedures GP1 .1 , GP2.1 , GP3.2 and GP4.1 , 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1 .29 mmol), 2,4,5,6- tetrahydrocyclopenta[c]pyrazole (210 mg, 1 .94 mmol) and (2-chlorophenyl)acetic acid (328 mg, 1.94 mmol) were converted without purification of intermediates to the title compounds which were purified and separated at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by preparative SFC (Sepiatec: Prep SFC100; Saule: Chiralpak IA 5μιη 250x30mm, C0₂/methanol + 0.2% aqueous ammonia (32%)).

Example 10

2-(2-Chlorophenyl)-A-[4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-3- su If amoyl phenyl]acetamide

35 mg, 0.0812 mmol, 6 % yield over 4 steps, 96 % purity

LC (Method D): Rt = 3.39 min;

LC-MS (Method A): Rt = 1 .12 min; MS (ESIpos): m/z = 431 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.34 - 2.43 (m, 2H), 2.62 - 2.73 (m, 4H), 3.89 (s, 2H), 7.29 - 7.36 (m, 2H), 7.41 - 7.56 (m, 5H), 7.69 (s, 1 H), 7.95 (dd, 1 H), 8.33 (d, 1 H), 10.73 (s, 1 H).

Example 11

2-(2-Chlorophenyl)-A-[4-(5,6-dihydrocyclopenta[c]pyrazol-1 (4H)-yl)-3- su If amoyl phenyljacetamide

20 mg, 0.0464 mmol, 4 % yield over 4 steps, 96 % purity

LC (Method D): Rt = 2.64 min;

LC-MS (Method A): Rt = 1 .12 min; MS (ESIpos): m/z = 431 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.48 - 2.52 (m, 2H, overlapped by solvent signal), 2.61 - 2.72 (m, 4H), 3.89 (s, 2H), 7.30 - 7.37 (m, 2H), 7.42 - 7.49 (m, 5H), 7.53 (d, 1 H), 7.97 (dd, 1 H), 8.33 (d, 1 H), 10.76 (s, 1 H).

Example 12 and Example 13

According to general procedures GP1 .1 , GP2.1 , GP3.2 and GP4.1 , 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1 .29 mmol), 2,4,5,6- tetrahydrocyclopenta[c]pyrazole (210 mg, 1 .94 mmol) and (2-fluorophenyl)acetic acid (297 mg, 1.94 mmol) were converted without purification of intermediates to the title compounds which were purified and separated at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by preparative SFC (Sepiatec: Prep SFC100; Saule: Chiralpak IA 5μιη 250x30mm, C0₂/methanol + 0.2% aqueous ammonia (32%)).

Example 12 A-[4-(5,6-Dihydrocyclopenta[c]pyrazol-2(4H)-yl)-3-sulfamoylphenyl]-2-(2- fluorophenyl)acetamide

30 mg, 0.0724 mmol, 4 % yield over 6 steps, 96 % purity

LC (Method D): Rt = 4.17 min;

LC-MS (Method A): Rt = 1 .08 min; MS (ESIpos): m/z = 415 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.35 - 2.43 (m, 2H), 2.62 - 2.73 (m, 4H), 3.79 (s, 2H), 7.14 - 7.22 (m, 2H), 7.29 - 7.36 (m, 1 H), 7.41 (td, 1 H), 7.44 - 7.56 (m, 3H), 7.69 (s, 1 H), 7.94 (dd, 1 H), 8.32 (d, 1 H), 10.71 (s, 1 H).

Example 13

A-[4-(5,6-Dihydrocyclopenta[c]pyrazol-1 (4H)-yl)-3-sulfamoylphenyl]-2-(2- fluorophenyl)acetamide

20 mg, 0.0483 mmol, 4 % yield over 4 steps, 96 % purity

LC (Method D): Rt = 2.85 min;

LC-MS (Method A): Rt = 1 .08 min; MS (ESIpos): m/z = 415 [M+H]⁺

1 H-NMR (600MHz, DMSO-d₆) δ [ppm]: 2.48 - 2.54 (m, 2H. overlapped by solvent signal), 2.62 - 2.71 (m, 4H), 3.79 (s, 2H), 7.16 - 7.23 (m, 2H), 7.31 - 7.36 (m, 1 H), 7.41 (td, 1 H), 7.43 - 7.48 (m, 3H), 7.54 (d, 1 H), 7.97 (dd, 1 H), 8.33 (d, 1 H), 10.75 (s, 1 H).

Example 14

2-(2-Chlorophenyl)-A-{4-[4-(6-methylpyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.532 mmol) and 2-bromo-6- methylpyridine (75.2 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (5 mg, 0.0104 mmol, 2 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 0.85 min; MS (ESIpos): m/z = 482 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: Me probably overlapped by solvent signal, 3.91 (s, 2H), 7.10 (d, 1 H), 7.28 - 7.37 (m, 2H), 7.42 - 7.51 (m, 4H), 7.55 - 7.74 (m, 3H), 8.00 (dd, 1 H), 8.30 (d, 1 H), 8.38 (d, 1 H), 8.61 (d, 1 H), 10.80 (s, 1 H).

Example 15

2-(2-Chlorophenyl)-A-{4-[4-(3-methylpyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 H-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.532 mmol) and 2-bromo-3- methylpyridine (75.2 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (8 mg, 0.0167 mmol, 3 % yield over 4 steps, 98 % purity).

LC-MS (Method A): Rt = 0.85 min; MS (ESIpos): m/z = 482 [M+H]⁺

Ή-NMR (400MHz, DMSO-d₆) δ [ppm]: Me probably overlapped by solvent signal, 3.92 (s, 2H), 7.20 (dd, 1 H), 7.30 - 7.37 (m, 2H), 7.44 - 7.53 (m, 4H), 7.64 - 7.71 (m, 2H), 8.00 (dd, 1 H), 8.28 (d, 1 H), 8.40 (d, 1 H), 8.45 (dd, 1 H), 8.53 (d, 1 H), 10.80 (s, 1 H). Example 16

2-(2-Chlorophenyl)-A-{4-[4-(6-chloropyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.532 mmol) and 2-bromo-6- chloropyridine (84.1 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (18 mg, 0.0358 mmol, 7 % yield over 4 steps, 95 % purity).

LC-MS (Method A): Rt = 1 .16 min; MS (ESIpos): m/z = 502 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.28 - 7.38 (m, 3H), 7.42 - 7.50 (m, 4H), 7.64 (d, 1 H), 7.80 (d, 1 H), 7.89 (t, 1 H), 7.99 (dd, 1 H), 8.33 (s, 1 H), 8.39 (d, 1 H), 8.70 (s, 1 H), 10.81 (s, 1 H).

Example 17

2-(2-Chlorophenyl)-A-{4-[4-(4-methylpyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 3-bromo-4- methylpyridine (60.2 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (XBridge C18 5μ 100x30mm, methanol/water + 0.1 % formic acid) (7.9 mg, 0.0164 mmol, 4 % yield over 4 steps, 95 % purity). LC-MS (Method C): Rt = 1 .09 min; MS (ESIpos): m/z = 482 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.45 (s, 3H), 3.92 (s, 2H), 7.28 - 7.37 (m, 3H), 7.43 - 7.52 (m, 4H), 7.65 (d, 1 H), 8.01 (dd, 1 H), 8.15 (d, 1 H), 8.36 (br d, 1 H), 8.40 (d, 1 H), 8.47 (d, 1 H), 8.67 (s, 1 H), 10.81 (s, 1 H).

Example 18

2-(2-Chlorophenyl)-A-{4-[4-(2-methylpyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 3-bromo-2- methylpyridine (60.2 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (9 mg, 0.0187 mmol, 4 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 0.81 min; MS (ESIpos): m/z = 482 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.63 (s, 3H), 3.91 (s, 2H), 7.26 - 7.37 (m, 3H), 7.43 - 7.52 (m, 4H), 7.65 (d, 1 H), 7.87 (dd, 1 H), 8.00 (dd, 1 H), 8.12 (d, 1 H), 8.37 - 8.41 (m, 2H), 8.44 (d, 1 H), 10.80 (s, 1 H).

Example 19

2-(2-Chlorophenyl)-A-{4-[4-(6-methylpyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 5-bromo-2- methylpyridine (60.2 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (1 mg, 0.00207 mmol, 1 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 0.79 min; MS (ESIpos): m/z = 482 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.48 (s, 3H), 3.91 (s, 2H), 7.26 - 7.37 (m, 3H), 7.42 - 7.52 (m, 4H), 7.63 (d, 1 H), 7.97 (dd, 1 H), 8.01 (dd, 1 H), 8.30 (s, 1 H), 8.38 (d, 1 H), 8.65 (d, 1 H), 8.82 (d, 1 H), 10.80 (s, 1 H).

Example 20

2-(2-Chlorophenyl)-A -{4-[4-(5-fluoropyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.532 mmol) and 2-bromo-5- fluoropyridine (83.7 mg, 0.48 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), folloeed by another preparative HPLC (Waters XBridge C18 5μ 100x30mm, methanol/water + 0.1 % formic acid) (4.4 mg, 0.00905 mmol, 2 % yield over 4 steps, 95 % purity).

LC-MS (Method A): Rt = 1 .34 min; MS (ESIpos): m/z = 486 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.91 (s, 2H), 7.30 - 7.37 (m, 2H), 7.42 - 7.49 (m, 2H), 7.63 (d, 1 H), 7.81 (dd, 1 H), 7.87 (dd, 1 H), 8.00 (dd, 1 H), 8.31 (s, 1 H), 8.39 (d, 1 H), 8.56 (d, 1 H), 8.66 (s, 1 H), 10.82 (s, 1 H), 2H very broad between 7.0 and 7.6

Example 21

2-(2-Chlorophenyl)-A -{4-[4-(5-fluoropyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 3-bromo-5- fluoropyridine (61 .5 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (1 mg, 0.00206 mmol, 1 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 1 .04 min; MS (ESIpos): m/z = 486 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.30 - 7.35 (m, 2H), 7.43 - 7.50 (m, 4H), 7.63 (d, 1 H), 8.02 (dd, 1 H), 8.1 1 (dt, 1 H), 8.38 - 8.42 (m, 2H), 8.45 (d, 1 H), 8.77 (s, 1 H), 8.85 - 8.89 (m, 1 H), 10.82 (s, 1 H).

Example 22

2-(2-Chlorophenyl)-A-{4-[4-(2-chloropyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 3-bromo-2- chloropyridine (67.3 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (Labomatic XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (12.2 mg, 0.0239 mmol, 7 % yield over 4 steps, 95 % purity).

LC-MS (Method A): Rt = 1 .10 min; MS (ESIpos): m/z = 502 [M+H]⁺ ¹ H-NMR (400MHz, DMSO-de) δ [ppm]: 3.92 (s, 2H), 7.30 - 7.37 (m, 2H), 7.43 - 7.54 (m, 5H), 7.64 (d, 1 H), 8.00 (dd, 1 H), 8.19 (dd, 1 H), 8.30 (d, 1 H), 8.35 (dd, 1 H), 8.40 (d, 1 H), 8.65 (d, 1 H), 10.81 (s, 1 H).

Example 23

2-(2-Chlorophenyl)-A-(3-sulfamoyl-4-{4-[3-(trifluoromethyl)pyridin-2-yl]-1 H-pyrazol- 1-yl}phenyl)acetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.54 mmol) and 2-bromo-3- (trifluoromethyl)pyridine (98.8 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (19 mg, 0.0355 mmol, 8 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 1 .15 min; MS (ESIpos): m/z = 536 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.29 - 7.69 (m, 8H), 7.99 (br d, 1 H), 8.17 (s, 1 H), 8.27 (br d, 1 H), 8.41 (s, 1 H), 8.48 (s, 1 H), 8.89 (br d, 1 H), 10.81 (s, 1 H).

Example 24

2-(2-Chlorophenyl)-A-{4-[4-(4-chloropyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 3-bromo-4- chloropyridine (67.3 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Chromatorex C- 18 10μιη, 125x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (2.6 mg, 0.00518 mmol, 1 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 1 .07 min; MS (ESIpos): m/z = 502 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.29 - 7.38 (m, 2H), 7.42 - 7.55 (m, 4H), 7.84 (s, 1 H), 7.65 (d, 1 H), 8.00 (dd, 1 H), 8.33 (s, 1 H), 8.41 (d, 1 H), 8.45 (d, 1 H), 8.69 (s, 1 H), 8.92 (s, 1 H), 10.84 (s, 1 H).

Example 25

2-(2-Chlorophenyl)-A-(3-sulfamoyl-4-{4-[4-(trifluoromethyl)pyridin-3-yl]-1 H-pyrazol- 1-yl}phenyl)acetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.54 mmol) and 3-bromo-4- (trifluoromethyl)pyridine (98.8 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (Waters Phenomenex Kinetex EVO C18 5μ 100x30mm, acetonitrile/water + 0.1 % trifluoroacetic acid) (2.6 mg, 0.00485 mmol, 1 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 1 .14 min; MS (ESIpos): m/z = 536 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.91 (s, 2H), 7.29 - 7.37 (m, 2H), 7.42 - 7.51 (m, 4H), 7.63 (d, 1 H), 7.84 (d, 1 H), 8.00 (dd, 1 H), 8.02 (s, 1 H), 8.41 (d, 1 H), 8.45 (s, 1 H), 8.81 (d, 1 H), 8.92 (s, 1 H), 10.82 (s, 1 H).

Example 26

2-(2-Chlorophenyl)-A-{4-[4-(5-chloropyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.54 mmol) and 3-bromo-5- chloropyridine (168 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (Waters Phenomenex Kinetex EVO C18 5μ 100x30mm, acetonitrile/water + 0.1 % trifluoroacetic acid) (4.3 mg, 0.00916 mmol, 2 % yield over 4 steps, 95 % purity).

LC-MS (Method A): Rt = 1 .13 min; MS (ESIpos): m/z = 502 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.30 - 7.37 (m, 2H), 7.43 - 7.50 (m, 4H), 7.62 (d, 1 H), 8.01 (dd, 1 H), 8.31 (t, 1 H), 8.39 (d, 1 H), 8.42 (s, 1 H), 8.49 (d, 1 H), 8.78 (s, 1 H), 8.95 (d, 1 H), 10.82 (s, 1 H).

Example 27

2-(2-Chlorophenyl)-A-{4-[4-(3-chloropyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to general procedures GP1 .1 , GP2.3, GP3.1 and GP4.3, 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (250 mg, 0.65 mmol), 3-chloro-2-(4/-/- pyrazol-4-yl)pyridine (174 mg, 0.97 mmol) and (2-chlorophenyl)acetic acid (166 mg, 0.97 mmol) were converted without purification of intermediates to the title compound which was purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (33 mg, 0.0657 mmol, 10 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 1 .13 min; MS (ESIpos): m/z = 502 [M+H]⁺ ¹ H-NMR (400MHz, DMSO-de) δ [ppm]: 3.92 (s, 2H), 7.30 - 7.38 (m, 3H), 7.43 - 7.52 (m, 4H), 7.66 (d, 1 H), 7.96 - 8.03 (m, 2H), 8.41 (d, 1 H), 8.44 (d, 1 H), 8.59 (dd, 1 H), 8.78 (d, 1 H), 10.81 (s, 1 H).

Example 28

A -{4-[4-(3-Chloropyridin-2-yl)-1 H-pyrazol-1-yl]-3-sulfamoylphenyl}-2-(2- fluorophenyl)acetamide

According to general procedures GP1 .1 , GP2.3, GP3.1 and GP4.3, 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (250 mg, 0.65 mmol), 3-chloro-2-(4/-/- pyrazol-4-yl)pyridine (174 mg, 0.97 mmol) and (2-fluorophenyl)acetic acid (150 mg, 0.97 mmol) were converted without purification of intermediates to the title compound which was purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (18 mg, 0.0370 mmol, 6 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 1 .09 min; MS (ESIpos): m/z = 486 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.81 (s, 2H), 7.16 - 7.23 (m, 2H), 7.31 - 7.38 (m, 2H), 7.42 (td, 1 H), 7.49 (s, 2H), 7.65 (d, 1 H), 7.96 - 8.03 (m, 2H), 8.40 (d, 1 H), 8.43 (d, 1 H), 8.59 (dd, 1 H), 8.78 (d, 1 H), 10.79 (s, 1 H).

Example 29

2-(2-Chlorophenyl)-A -(4-{4-[3-(difluoromethyl)pyridin-2-yl]-1 H-pyrazol-1-yl}-3- su If amoyl phenyl)acetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (200 mg, 0.43 mmol) and 2-bromo-3- (difluoromethyl)pyridine (72.7 mg, 0.35 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid), followed by another preparative HPLC (Waters XBridge C18 5μ 100x30mm, methanol/water + 0.1 % formic acid) (5.8 mg, 0.01 12 mmol, 3 % yield over 4 steps, 90 % purity).

LC-MS (Method C): Rt = 1 .36 min; MS (ESIpos): m/z = 518 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.92 (s, 2H), 7.14 - 7.58 (m, 8H), 7.68 (d, 1 H), 8.00 (dd, 1 H), 8.13 (d, 1 H), 8.20 (s, 1 H), 8.41 (d, 1 H), 8.43 (s, 1 H), 8.79 (d, 1 H), 10.81 (s, 1 H).

Example 30

2-(2-Chlorophenyl)-A ^3-sulfamoyl-4-{4-[2-(trifluoromethyl)pyridin-3-yl]-1 H-pyrazol- 1-yl}phenyl)acetamide

According to the general procedure GP5.1 , N-[4-(4-bromo-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (250 mg, 0.54 mmol) and 3-bromo-2- (trifluoromethyl)pyridine (98.8 mg, 0.44 mmol) were converted without purification of intermediates to the title compound and were purified at the end twice by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (10.5 mg, 0.0196 mmol, 4 % yield over 4 steps, 97 % purity).

LC-MS (Method A): Rt = 1 .15 min; MS (ESIpos): m/z = 536 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 3.91 (s, 2H), 7.29 - 7.38 (m, 2H), 7.43 - 7.50 (m, 4H), 7.61 (d, 1 H), 7.80 (dd, 1 H), 7.99 (s, 1 H), 8.00 (dd, 1 H), 8.12 (dd, 1 H), 8.38 - 8.43 (m, 2H), 8.71 (dd, 1 H), 10.81 (s, 1 H).

Example 31

2-(2-Chlorophenyl)-A-{4-[4-(5-fluoropyridin-3-yl)-3-methyl-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.2, N-[4-(4-bromo-3-methyl-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (300 mg, 0.62 mmol) and 3-bromo-5- fluoropyridine (90.2 mg, 0.51 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (18 mg, 0.0360 mmol, 6 % yield over 4 steps, 85 % purity).

LC-MS (Method A): Rt = 1 .12 min; MS (ESIpos): m/z = 500 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.48 (s, 3H, partly overlapped by DMSO signal), 3.91 (s, 2H), 7.31 - 7.37 (m, 2H), 7.43 - 7.50 (m, 2H), 7.53 (s, 2H), 7.61 (d, 1 H), 7.92 (ddd, 1 H), 8.00 (dd, 1 H), 8.38 (d, 1 H), 8.50 (d, 1 H), 8.56 (s, 1 H), 8.70 (t, 1 H), 10.79 (s, 1 H).

Example 32

2-(2-Chlorophenyl)-A-{4-[3-methyl-4-(3-methylpyridin-2-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.2, N-[4-(4-bromo-3-methyl-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (300 mg, 0.62 mmol) and 2-bromo-3- methylpyridine (88.1 mg, 0.51 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (14 mg, 0.0282 mmol, 5 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 0.88 min; MS (ESIpos): m/z = 496 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.36 (s, 3H), 2.38 (s, 3H), 3.91 (s, 2H), 7.22 (dd, 1 H), 7.31 - 7.37 (m, 2H), 7.43 - 7.48 (m, 2H), 7.55 (s, 2H), 7.60 (d, 1 H), 7.69 (ddd, 1 H), 7.99 (dd, 1 H), 8.33 (s, 1 H), 8.39 (d, 1 H), 8.48 (ddd, 1 H), 10.78 (s, 1 H). Example 33

2-(2-Chlorophenyl)-A-{4-[3-methyl-4-(6-methylpyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.2, N-[4-(4-bromo-3-methyl-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (300 mg, 0.62 mmol) and 5-bromo-2- methylpyridine (88.1 mg, 0.51 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (13 mg, 0.0262 mmol, 4 % yield over 4 steps, 90 % purity).

LC-MS (Method A): Rt = 0.84 min; MS (ESIpos): m/z = 496 [M+H]⁺

1 H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.42 (s, 3H), second methyl group overlapped by solvent signal, 3.91 (s, 2H), 7.30 - 7.36 (m, 3H), 7.43 - 7.48 (m, 2H), 7.55 (s, 2H), 7.61 (d, 1 H), 7.84 (dd, 1 H), 7.99 (dd, 1 H), 8.37 (d, 1 H), 8.43 (s, 1 H), 8.65 (d, 1 H), 10.77 (s, 1 H).

Example 34

2-(2-Chlorophenyl)-A-{4-[3-methyl-4-(4-methylpyridin-3-yl)-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.2, N-[4-(4-bromo-3-methyl-1 /-/-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (300 mg, 0.62 mmol) and 3-bromo-4- methylpyridine (88.1 mg, 0.51 mmol) were converted without purification of intermediates to the title compound and were purified at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (14 mg, 0.0282 mmol, 5 % yield over 4 steps, 85 % purity).

LC-MS (Method A): Rt = 0.83 min; MS (ESIpos): m/z = 496 [M+H]⁺ ¹ H-NMR (400MHz, DMSO-de) δ [ppm]: 2.20 (s, 3H), 2.28 (s, 3H), 3.91 (s, 2H), 7.31 (m, 3H), 7.43 - 7.49 (m, 2H), 7.52 (s, 2H), 7.60 (d, 1 H), 7.99 (dd, 1 H), 8.20 (s, 1 H), 8.45 (m, 3H), 10.78 (s, 1 H).

Example 35

2-(2-Chlorophenyl)-A ^4-[4-(5-fluoropyridin-2-yl)-3-methyl-1 H-pyrazol-1-yl]-3- su If amoyl phenyl Jacetamide

According to the general procedure GP5.2, N-[4-(4-bromo-3-methyl-1 H-pyrazol-1 -yl)-3- sulfamoylphenyl]-2-(2-chlorophenyl)acetamide (300 mg, 0.62 mmol) and 2-bromo-5- fluoropyridine (90.1 mg, 0.51 mmol) were converted without purification of intermediates to the title compound and were purified at the end twice by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid) (9 mg, 0.0180 mmol, 3 % yield over 4 steps, 99 % purity).

LC-MS (Method A): Rt = 1 .18 min; MS (ESIpos): m/z = 500 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.54 (s, 3H), 3.91 (s, 2H), 7.30 - 7.37 (m, 2H), 7.43 - 7.49 (m, 2H), 7.54 (br s, 2H), 7.61 (d, 1 H), 7.78 (dd, 2H), 8.00 (dd, 1 H), 8.37 (d, 1 H), 8.57 - 8.61 (m, 2H), 10.79 (s, 1 H).

Example 36 and Example 37

According to general procedures GP1 .1 , GP2.2, GP3.1 and GP4.2, 2-chloro-N-(2,4- dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1 .29 mmol), 2,4,6,7- tetrahydropyrano[4,3-c]pyrazole (241 mg, 1 .94 mmol) and (2-chlorophenyl)acetic acid (219 mg, 1.28 mmol) were converted without purification of intermediates to the title compounds which were purified and separated at the end by preparative HPLC (Waters XBridge C18 5μ 100x30mm, acetonitrile/water + 0.1 % formic acid).

Example 36

2-(2-Chlorophenyl)-A-[4-(6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)-3- su If amoyl phenyl]acetamide

10 mg, 0.0224 mmol, 2 % yield over 4 steps, 97 % purity).

LC-MS (Method E): Rt = 2.17 min; MS (ESIpos): m/z = 447 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.75 (t, 2H), 3.88 - 3.93 (m, 4H), 4.67 (s, 2H), 7.30 - 7.36 (m, 2H), 7.42 - 7.53 (m, 5H), 7.82 (s, 1 H), 7.96 (dd, 1 H), 8.35 (d, 1 H), 10.76 (s, 1 H).

Example 37

2-(2-Chlorophenyl)-A-[4-(6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl)-3- su If amoyl phenyljacetamide

3 mg, 0.00671 mmol, 1 % yield over 4 steps, 96 % purity).

LC-MS (Method E): Rt = 3.19 min; MS (ESIpos): m/z = 447 [M+H]⁺

¹ H-NMR (400MHz, DMSO-d₆) δ [ppm]: 2.52 - 2.55 (m, 2H), 3.80 (t, 2H), 3.91 (s, 2H), 4.64 (s, 2H), 7.25 (s, 2H), 7.30 - 7.36 (m, 2H), 7.43 - 7.48 (m, 2H), 7.53 (d, 1 H), 7.56 (s, 1 H), 7.98 (dd, 1 H), 8.36 (d, 1 H), 10.81 (s, 1 H).

BIOLOGICAL ASSAYS

The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.

Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average (avg) values or as median values, wherein

- the average value, also referred to as the arithmetic mean value, represents the sum of the obtained values divided by the number of values obtained, and

- the median value represents the middle number of the group of obtained values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

When no meaningful calculation of average values or median values is possible due to the existence of measurement values falling outside the detection range of the assay (indicated by < or > in the tables below) all individual measurement values are indicated. Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.

IN VITRO STUDIES

Human P2X4 HEK Cell FLIPR Assay

HEK293 cells stably expressing human P2X4 were plated in poly-D-lysine-coated 384- well plates at a seeding density of 30000 cells/well and incubated overnight. P2X4 function was assessed by measuring intracellular calcium changes using the calcium- chelating dye Fluo8-AM (Molecular Devices) on a fluorescent imaging plate reader (FLEX/FLIPR station; Molecular Devices). On the day of the assay, the medium was removed and the cells were incubated for 30 min at 37Ό and 5% CO ₂ in 30 μΙ_ of dye buffer (Hank's balanced salt solution, 10 mM HEPES, 1 .8 mM CaCI₂, 1 mM MgCI₂ , 2 mM probenecid, 5mM D-glucose monohydrate, 5μΜ Fluo8-AM, pH=7.4). Compounds diluted in probenecid buffer (Hank's balanced salt solution, 10 mM HEPES, 1 .8 mM CaCI₂, 1 mM MgCI₂ , 2 mM probenecid, 5mM D-glucose monohydrate, pH=7.4) were added in a volume of 10 μΙ_ and allowed to incubate for 30 min at room temperature. The final assay DMSO concentration was 0.5%. The agonist, Bz-ATP (Tocris), was added in a volume of 10 μΙ_ at a concentration representing the EC₈o value. The EC₈o value of Bz-ATP was determined each assay day prior to compound profiling. The fluorescence was measured for an interval of 120 sec at 2 sec intervals. The excitation and emission wavelengths used to monitor fluorescence were 470-495 nm and 515-575 nm, respectively. The data was analyzed based on the increase in peak relative fluorescence units (RFU) compared to the basal fluorescence and the data was normalized to the agonist control. The compounds were tested in triplicates per plate and mean values were plotted in Excel XLFit to determine IC₅o values, percentage of maximal inhibition and the Hill coefficients.

Human P2X4 HEK Human P2X4 HEK

Example Number Cells (FLIPR Assay) Cells (FLIPR Assay) avg ICso [nM] avg Efficacy [%] 1 45 85

2 323 65

3 191 78

4 69 87

5 209 86

6 488 87

7 17 74

8 73 89

9 861 90

10 82 68

1 1 182 83

12 220 79

13 692 82

14 70 94

15 69 88

16 1 19 80

17 8 95

18 75 91

19 50 74

20 23 77

21 157 88

22 713 70

23 1270 84

24 126 78

25 487 96

26 146 96

27 9424 60

28 12528 58

29 8336 61

30 >25000 41

31 1 1 1 93

32 38 99 34 19 105

35 641 84

36 1 65

37 46 91

Claims

1. A compound of formula (I)

(I) characterised in that:

X represents C-R^2a or N;

R¹ represents a group selected from :

R² represents phenyl, heteroaryl or a group selected from:

R^2b represents hydrogen, halogen, Ci -C2-alkyl or Ci -C2-haloalkyl;

R^2c represents hydrogen, halogen, Ci -C₂-alkyl or Ci -C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁵ represents hydrogen or Ci -C₃-alkyl;

R⁶ represents halogen, cyano, nitro, OH, Ci -C₄-alkyl, Ci -C₄-haloalkyl,

Ci -C₄-alkoxy, Ci -C₄-haloalkoxy or F₃CS-;

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci -C -alkyl, C3-C₆-cycloalkyl,

Ci -C₄-haloalkyl, Ci -C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci -C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci -C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-0-CH₂-CH₂-, -0-CH₂-0- or -0-CH₂-CH₂-0-;

R¹¹ represents R¹²-C(0)-NH-;

R^11a re resents a group selected from:

R^13a represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen, methyl or trifluoromethyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

2. A compound according to claim 1 of formula (la),

wherein * indicates the point of attachment of said group with the rest of the molecule; R² represents phenyl, heteroaryl or a group selected from :

wherein * indicates the point of attachment of said group with the rest of the molecule and said phenyl or heteroaryl groups are substituted once with

R^{1 1} or once with R^{1 1 a} and optionally once with Ci-C₂-alkyl; R^2a represents hydrogen, cyano, nitro, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl;

R^2b represents hydrogen, halogen, Ci-C2-alkyl or Ci-C2-haloalkyl;

R^2c represents hydrogen, halogen, Ci-C₂-alkyl or Ci-C₂-haloalkyl,

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH;

R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C₄-alkoxy, Ci-C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl, Ci-C -haloalkyl, Ci-C -alkoxy, Ci-C -haloalkoxy, HO-(C₂-C-alkoxy)-, (Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-, R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl, Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-, R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-; or

R^6a and R^6b adjacent to each other together represent a group selected from

-0-CH₂-CH₂-, -0-CH₂-0- or-0-CH₂-CH₂-0-;

4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR^a in which R^a represents a Ci-Ce-alkyl or Ci-Ce-haloalkyl group and being optionally substituted, one to three times, independently from each other, with halogen or Ci -C₄-alkyl; represents R¹²-C(0)-NH-;

re resents a group selected from :

N— * or N— *

R¹² represents C2-C4-alkenyl, Ci -C4-hydroxyalkyl or Cs-Ce-cycloalkyl,

R^13a represents hydrogen, halogen, methyl, difluoromethyl or trifluoromethyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen, methyl or trifluoromethyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

3. A compound according to claim 1 of formula (la) characterised in that:

R¹ represents a group selected from :

R² represents a group selected from:

R^2a represents hydrogen, chloro or cyano;

R^2b represents hydrogen or fluoro;

R^2c represents hydrogen or fluoro;

wherein not less than one of R^2a, R^2b and R^2c represents hydrogen;

R³ represents hydrogen or fluoro;

R⁴ represents hydrogen, fluoro, methyl or OH; R⁶ represents halogen, cyano, nitro, OH, Ci-C₄-alkyl, Ci-C₄-haloalkyl,

Ci-C₄-alkoxy, Ci-C₄-haloalkoxy or F₃CS-;

R^6a hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-alkoxy, Ci-C₄-haloalkoxy, HO-(C2-C₄-alkoxy)-, (Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R^6b hydrogen, halogen, hydroxy, nitro, cyano, Ci-C -alkyl, C3-C₆-cycloalkyl,

Ci-C₄-haloalkyl, Ci-C₄-haloalkoxy, HO-(C₂-C₄-alkoxy)-,

(Ci-C₄-alkoxy)-(C₂-C₄-alkoxy)-, R⁹R¹⁰N-, R⁸-C(0)-NH-, R⁸-C(0)-,

R⁸-0-C(0)-, R⁹R¹⁰N-C(O)- or (Ci-C₄-alkyl)-S0₂-;

R⁸ represents, independently from each respective occurence, Ci-C₆-alkyl;

4- to 6-membered nitrogen containing heterocyclic ring;

R¹¹ represents R¹²-C(0)-NH-;

R^11a re resents a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule; represents C₂-C -alkenyl, Ci-C -hydroxyalkyl or C3-C₆-cycloalkyl,

wherein said C3-C₆-cycloalkyl groups are substituted one to three times with halogen; R^13a represents hydrogen, halogen or methyl;

R^13b represents hydrogen;

R^13c represents hydrogen or halogen;

R^13d represents hydrogen, methyl or halogen,

R^13e represents hydrogen, halogen or methyl;

R^13f represents hydrogen, halogen, methyl or trifluoromethyl;

R^{1 3}9 represents hydrogen or halogen;

R^13h represents hydrogen or methyl,

R¹⁴ represents halogen; or an N-oxide, a salt, a hydrate, a solvate, a tautomer or a stereoisomer of said compound, or a salt of said N-oxide, tautomer or stereoisomer.

4. A compound according to claim 1 of formula (la) characterised in that:

R¹ represents

R² represents a group selected from:

wherein ^* indicates the point of attachment of said group with the rest of the molecule and said groups are substituted once with R¹¹ or once with R^11a or R^2a represents hydrogen;

R^2b represents hydrogen;

R^2c represents hydrogen;

R³ represents hydrogen;

R⁴ represents hydrogen;

R⁶ represents fluoro or chloro;

R¹¹ represents R¹²-C(0)-NH-;

R^11a represents a group selected from:

R¹² represents ethenyl, hydroxypropyl or C3-C₄-cycloalkyl,

wherein said C3-C₄-cycloalkyl groups are substituted two times with fluoro;

R^13a represents hydrogen or methyl;

R^13b represents hydrogen;

R^13c represents hydrogen or fluoro;

R^13d represents hydrogen, methyl or chloro,

wherein at least one of R ^3a, R ^3b, R ^3c and R^13d is different from hydrogen;

R^13e represents hydrogen, chloro or methyl;

R^13f represents hydrogen, chloro or methyl; R^{1 3}9 represents hydrogen, fluoro or chloro;

R^13h represents hydrogen or methyl,

A compound according to claim 1 to 15 selected from the following list:

2-(2-Chlorophenyl)-N-[4-(4-fluoro-1 ΉΛ ,4'-biimidazol-1 '-yl)-3- sulfamoylphenyl]acetamide

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4-yl]-3,3- difluorocyclobutanecarboxamide

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide (Enantiomer A)

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4-yl]-2,2- difluorocyclopropanecarboxamide (Enantiomer B)

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4-yl]-4- hydroxybutanamide

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 /-/-pyrazol-4- yl]acrylamide

2-(2-Chlorophenyl)-N-(4-{4-[(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-3- sulfamoylphenyl)acetamide

N-(4-{4-[Bis(cyclopropylmethyl)amino]-1 /-/-pyrazol-1 -yl}-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide

2-(2-Chlorophenyl)-N-[4-(5,6-dihydrocyclopenta[c]pyrazol-2(4H)-yl)-3- sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-[4-(5,6-dihydrocyclopenta[c]pyrazol-1 (4H)-yl)-3- sulfamoylphenyl]acetamide N-[4-(5,6-Dihydrocyclopenta[c]pyrazol-2(4H)-yl)-3-sulfamoylphenyl]-2-(2- fluorophenyl)acetamide

N-[4-(5,6-Dihydrocyclopenta[c]pyrazol-1 (4H)-yl)-3-sulfamoylphenyl]-2-(2- fluorophenyl)acetamide

2-(2-Chlorophenyl)-N-{4-[4-(6-methylpyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(3-methylpyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(6-chloropyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(4-methylpyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(2-methylpyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(6-methylpyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(5-fluoropyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(5-fluoropyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-{4-[4-(2-chloropyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{4-[3-(trifluoromethyl)pyridin-2-yl]-1 /-/-pyrazol 1 -yl}phenyl)acetamide

2-(2-Chlorophenyl)-/V-{4-[4-(4-chloropyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{4-[4-(trifluoromethyl)pyridin-3-yl]-1 /-/-pyrazol 1 -yl}phenyl)acetamide

2-(2-Chlorophenyl)-/V-{4-[4-(5-chloropyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide 2-(2-Chlorophenyl)-N-{4-[4-(3-chloropyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

N-{4-[4-(3-Chloropyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3-sulfamoylphenyl}-2-(2- fluorophenyl)acetamide

2-(2-Chlorophenyl)-N-(4-{4-[3-(difluoromethyl)pyridin-2-yl]-1 /-/-pyrazol-1 -yl}-3- sulfamoylphenyl)acetamide

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{4-[2-(trifluorom

1 -yl}phenyl)acetamide

2-(2-chlorophenyl)-N-{4-[4-(5-fluoropyridin-3-yl)-3-methyl-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-chlorophenyl)-/V-{4-[3-methyl-4-(3-methylpyridin-2-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-/V-{4-[3-methyl-4-(6-methylpyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-/V-{4-[3-methyl-4-(4-methylpyridin-3-yl)-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-/V-{4-[4-(5-fluoropyridin-2-yl)-3-methyl-1 /-/-pyrazol-1 -yl]-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-/V-[4-(6,7-dihydropyrano[4,3-c]pyrazol-2(4H)-yl)-3- sulfamoylphenyljacetamide

2-(2-Chlorophenyl)-/V-[4-(6,7-dihydropyrano[4,3-c]pyrazol-1 (4H)-yl)-3- sulfamoylphenyl]acetamide

6. A compound of general formula I, or a stereoisomer, a tautomer, an N oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 5, for use in the treatment or prophylaxis of a disease.

7. Use of a compound of general formula I, or a stereoisomer, a tautomer, an N

oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 5, for the prophylaxis or treatment of a disease. Use of a compound of general formula I, or a stereoisomer, a tautomer, an N oxide, a hydrate, a solvate, or a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, according to any one of claims 1 to 5, for the preparation of a medicament for the prophylaxis or treatment of a disease.

Use according to claims 7 to 8, wherein said disease is a genitourinary, gastrointestinal, proliferative or pain-related disease, condition or disorder; cancer; fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; gynaecological diseases including dysmenorrhea, dyspareunia, endometriosis and adenomyosis; endometriosis-associated pain; endometriosis- associated symptoms, wherein said symptoms are in particular endometriosis- associated, dysmenorrhea, dyspareunia, dysuria, or dyschezia; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis; idiopathic bladder hypersensitivity; gastrointestinal disorders including irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS, gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like; Parkinson's disease; Alzheimer's disease; myocardial infarction; atherosclerosis; lipid disorders; and pain-associated diseases selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), arthritis (such as osteoarthritis and rheumatoid arthritis), burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, traumatic nerve-injury, post-traumatic injuries (including fractures and sport injuries), trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints, ankylosing spondylitis, a gynaecological disease, dysmenorrhea, dyspareunia, endometriosis, adenomyosis, endometriosis-associated pain, or other endometriosis-associated symptoms, wherein said symptoms are endometriosis- associated, dysmenorrhea, dyspareunia, dysuria, or dyschezia; a disease associated with pain syndromes (including acute, chronic, inflammatory and neuropathic pain), inflammatory pain, low back pain, surgical pain, visceral pain, dental pain, premenstrual pain, endometriosis-associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post-traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, chronic lower back pain, phantom limb pain, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal distension, chronic arthritic pain and related neuralgias, and pain associated with cancer, pain associated with chemotherapy, HIV and HIV treatment-induced neuropathy; and pain associated with diseases or disorders selected from the group consisting of hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis and rheumatoid arthritis).

10. A pharmaceutical composition comprising at least one compound according to any one of the claims 1 to 5, together with at least one pharmaceutically acceptable auxiliary.

11 . A compound with the following formula:

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

N-(2,4-Dimethoxybenzyl)-2-(4-fluoro-1 Ή-1 ,4'-biimidazol-1 '-yl)-5- nitrobenzenesulfonamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-fluoro-1 'H-1 ,4'- biimidazol-1 '-yl)phenyl}acetamide

Ethyl 1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4- carboxylate

1 - {2-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H-pyrazole-4-carboxylic acid

2- (Trimethylsilyl)ethyl (1 -{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1 H- pyrazol-4-yl)carbamate

2-(Trimethylsilyl)ethyl [1 -(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4- dimethoxybenzyl)sulfamoyl]phenyl)-1 H-pyrazol-4-yl]carbamate

N-{4-(4-Amino-1 H-pyrazol-1 -yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2- chlorophenyl)acetamide N-[4-(4-Amino-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

N-(Cyclopropylmethyl)-1 H-pyrazol-4-amine and N,N-bis(cyclopropylmethyl)-1 H- pyrazol-4-amine

2-{4-[(Cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide

tert-Butyl [(2-{4-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}- 5-{[(2-chlorophenyl)acetyl]amino}phenyl)sulfonyl](2,4- dimethoxybenzyl)carbamate

2-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-N-(2,4-dimethoxybenzyl)-5- nitrobenzenesulfonamide

N-(4-{4-[Bis(cyclopropylmethyl)amino]-1 H-pyrazol-1 -yl}-3-[(2, 4- dimethoxybenzyl)sulfamoyl]phenyl)-2-(2-chlorophenyl)acetamide

N-[4-(4-Bromo-3-methyl-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2- chlorophenyl)acetamide