EA040608B1 - AROMATIC SULFONAMIDE DERIVATIVES - Google Patents

Description

The invention relates to substituted aromatic sulfonamides of formula (I) as described and defined in this patent, to pharmaceutical compositions containing said compounds, and to the use of said compounds for the manufacture of a pharmaceutical composition for the treatment or prevention of diseases. The present invention, as described and defined in this patent, relates to pharmaceutical compositions containing an active ingredient that is an antagonist or negative allosteric modulator of P2X4. Such compounds are useful in the manufacture of a pharmaceutical composition for the treatment or prevention of diseases, particularly in mammals, such as, but not limited to, pain-related diseases, or for the treatment or prevention of pain or neuronal damage and inflammation in the brain or spinal cord, or arthritis. or syndromes of spondylitis (acute and chronic), pain caused by inflammation, neuropathic pain, pelvic pain, pain associated with malignancy, pain associated with endometriosis, as well as endometriosis per se, malignancy per se, multiple sclerosis per se, damage spinal cord or ischemic brain injury as such, as a single agent or in combination with other active ingredients.

Prerequisites for the creation of the invention

Chronic inflammatory pain, such as, but not limited to, in the conditions of endometriosis and adenomyosis, results from inflammatory responses mounted by the immune system due to tissue damage or local cell death, and typically persists long after the initial injury has healed. Because a large percentage of patients with inflammatory diseases do not respond adequately to currently available anti-inflammatory therapies or analgesics, or suffer from intolerable side effects, there is a need to develop alternative treatments for inflammatory conditions/disorders.

ATP adenosine triphosphate is widely recognized as an important neurotransmitter that is involved in various physiological and pathophysiological functions via various purinergic receptor subtypes (Burnstock 1993, Drug Dev Res 28:196-206; Bumstock 2011, Prog Neurobiol 95:229-274). To date, seven members of the P2X family have been cloned, including 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 that are generally known to be involved in inflammatory/immune processes, including but not limited to monocytes, macrophages, mast cells, and microglial cells (Wang et al., 2004, BMC Immunol 5:16; Brone et al., 2007 Immunol Lett 113:83-89). P2X4 activation by extracellular ATP is known to result, among other things, in the release of pro-inflammatory cytokines and prostaglandins (PGE2) (Wo 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 scientific evidence in the literature using animal models implicates the P2X4 receptor in nociception and pain. Mice lacking the P2X4 receptor do not develop pain hypersensitivity in response to multiple inflammatory stimuli such as Freund's complete adjuvant, carrageenan, or formalin (Ulmann et al., 2010, EMBO Journal 29:2290-2300). In addition, mice lacking P2X4R do not develop mechanical allodynia after peripheral nerve injury, indicating an important role for P2X4 in neuropathic pain conditions as well (Tsuda et al., 2009, Mol Pain 5:28; Ulmann et al. , 2008, J Neurocsci 28:11263-11268).

In addition to the important role of P2X4 in diseases associated with acute and chronic pain (Trang and Salter, 2012, Purinergic Signalling 8:621-628; Burnstock, 2013 Eur J Pharmacol 716:24-40), P2X4 is considered to be a critical mediator of inflammatory diseases. eg respiratory diseases (eg asthma, COPD), lung diseases including fibrosis, malignancy and atherosclerosis (Burnstock et al., 2012 Pharmacol Rev. 64:834-868).

EP 2597088 A1 describes P2X4 receptor antagonists and in particular a diazepine derivative of formula (III) or a pharmacologically acceptable salt thereof. Said document further discloses the use of a P2X4 receptor antagonist, a diazepine derivative represented by formulas (I), (II), (III), or a pharmacologically acceptable salt thereof, which exhibits P2X4 receptor antagonism, being effective as an agent for preventing or treating nociceptive , inflammatory and neuropathic pain. In more detail, EP 2597088 A1 describes P2X4 receptor antagonists that are effective as a prophylactic or therapeutic agent for pain caused by various types of malignancies, diabetic neuritis, viral diseases such as herpes and osteoarthritis. The prophylactic or therapeutic agent according to EP 2597088 A1 can also be used in combination with other agents such as an opioid analgesic (eg morphine, fentanyl), a sodium channel inhibitor (eg novocaine, lidocaine), or an NSAID (eg aspirin, ibuprofen). ). A P2X4 receptor antagonist used for cancer pain can also be used in

- 1 040608 combination with a carcinostatic agent such as a chemotherapeutic agent. Further P2X4 receptor antagonists and their use are disclosed in WO 2013105608, WO 2015005467 and WO 2015005468.

A study on the 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 no. 241.1). This poster described methods for identifying novel, potent, and selective small molecule antagonists that inhibit P2X4 in different species, and methods for evaluating selected compounds in experimental models of neuropathic and inflammatory pain. In particular, a Flipr-based screening method for human, rat, and mouse P2X4R, human P2X4R electrophysiological analysis, a suitable mouse model of neuropathy, and a mouse model of inflammation have been described.

WO 2015/088564 and WO 2015/088565 provide P2X4 receptor modulating compounds, methods for their synthesis, pharmaceutical compositions containing these compounds, and methods for using them. These P2X4 receptor modulating compounds are useful in the treatment, prevention, and/or management of a variety of disorders including, but not limited to, chronic pain, neuropathy, inflammatory diseases, and disorders of the central nervous system.

The prior art lacks any information regarding substituted aromatic sulfonamides of general formula (I) as described and defined in this patent, and the use of these compounds for the manufacture of a pharmaceutical composition for the treatment or prevention of diseases, in particular regarding the use of substituted aromatic sulfonamides of general formula (I). formula (I) for the treatment or prevention of diseases associated with pain, or for the treatment or prevention of pain syndromes (acute and chronic), pain caused by inflammation, neuropathic pain, pelvic pain, pain associated with malignancy, pain associated with endometriosis , as well as endometriosis as such, malignant neoplasm as such, and proliferative diseases as such, like endometriosis, as a single agent or in combination with other active components.

Thus, the P2X4 inhibitors of the present invention are 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 CR ^2a or N;

R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ² is phenyl, wherein said phenyl group is optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ substituents, which are, independently of one another, identical or different, or substituted by two adjacent substituents R ¹¹ which together represent a methylenedioxy group to form a 5-membered ring; or

5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, or [5,6]annelated bicyclic heteroaryl, wherein the heteroaryl contains at least one oxygen, nitrogen, or sulfur heteroatom, and wherein said heteroaryl groups are optionally substituted with one three times R ¹¹ substituents, which are independently the same or different, or

- 2 040608 are substituted once by R ^11a and optionally once or twice by R ¹¹ substituents, which are independently the same or different;

R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ -αkyl or C 1 -C ₂ -haloalkyl;

R ^2b is hydrogen, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloαalkyl;

R ^2c represents hydrogen, halogen, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -haloαkyl, where at least one of R ^2a , R ² and R ^2c represents hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine, methyl or OH;

R ⁵ represents hydrogen or C ₁ -C ₃ -alkyl;

R ⁶ is halo, cyano, nitro, OH _{, C1-4} alkyl _{, C1-4} haloalkyl _{, C1-4} alkoxy, _C1-4 haloalkoxy, or F3CS-;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1 -C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -; or

R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-;

R ^7a and R ^7b are the same or different and are, independently of each other, hydrogen, hydroxy, halogen, C ₁ -C ₄ alkyl or C 1 -C ₄ haloalkyl;

R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl;

R ⁹ and R ¹⁰ are the same or different and are independently hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl or (CH3)2N-C1-C4 alkyl, or together with the nitrogen atom to which they are attached form a 4-6-membered nitrogen-containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C ₆ -alkyl or C ₁ -C ₆ -haloalkyl group, and optionally substituted one to three times, independently of each other, halogen or C1-C ₄ -alkyl;

R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C ₁ -C ₄ -alkyl)-S- or (C ₁ -C ₄ -alkyl)-SO ₂ -;

R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino,

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C2-C4-alkyl)-, (C1-C4-haloalkoxy)-(C2-C4-alkyl)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O) -NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

n is 0, 1, 2 or 3;

or an N-oxide, salt or stereoisomer.

In another embodiment, the invention relates to a compound of formula (I) wherein X is CR ^2a or N;

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R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule and these groups are optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different;

R ^2a represents hydrogen, cyano, nitro, halogen, C ₁ -C ₂ -αkyl or C ₁ -C ₂ haloalkyl;

R ^2b is hydrogen, halogen, C1-C ₂ alkyl or C ₁ -C ₂ haloalkyl;

R ^2c represents hydrogen, halogen, C1-C ₂ -alkyl or C ₁ -C ₂ -haloalkyl, where at least one of R ^2a , R ^2b and R ^2c represents hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine, methyl or OH;

R ⁵ represents hydrogen or C ₁ -C ₃ -alkyl;

R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, C1- _C4 haloalkoxy or F3CS-;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl,

C ₁ -C ₄ -haloalkyl, C1-C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy) -, (C ₁ -C ₄ -alkoxy) (C2-C4- alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, HO - (C ₂ - C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C ( O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-; or

R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-;

R ^7a and R ^7b are the same or different and are, independently of one another, hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl;

R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl;

R ⁹ and R ¹⁰ are the same or different and are, independently of one another, hydrogen, C1- _C4 alkyl, _C3 - _C6 cycloalkyl, C1- _C4 haloalkyl, or ( _CH3 ) _2N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times independently with halogen or C 1 -C ₄ alkyl;

R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -,

R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C1-C4 -αkyl)-S- or (C^-alkyl)^-;

R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino,

- 4 040608

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C2-C4-alkyl)-, (C1-C4-haloalkoxy)-(C2-C4-alkyl)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O) -NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

n is 0, 1, 2 or 3;

or an N-oxide, salt or stereoisomer.

In a preferred embodiment, the invention relates to a compound of formula (I) wherein X is CR ^2a or N;

R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two times by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different;

R ^2a represents hydrogen, fluorine, chlorine or cyano;

R ^2b represents hydrogen, fluorine or chlorine;

R ^2c is hydrogen, fluorine or chlorine;

where at least one of R ^2a , R ^2b and R ^2c is hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine or OH;

R ⁵ is hydrogen or methyl;

R ⁶ is fluorine, chlorine, bromine, cyano, nitro, OH, C ₁ -C ₃ alkyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;

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

R ^6a is hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or methoxy;

R ^6b is hydrogen or fluorine;

R ^7a and R ^7b are hydrogen;

R ¹¹ are, independently of each other, cyano, C1-C ₄ -alkyl, difluoromethyl, trifluoromethyl, difluoroethyl, C ₁ -C ₆ -hydroxyalkyl, (C ₁ -C ₃ -alkoxy) -ethyl-, trifluoromethoxyethyl-, F ₂ CH-CH ₂ -NH-CH ₂ -, H3C-C(O)-, H3C-CH2-O-C(O)-;

R ^11a is a group selected from cyclopropyl,

- 5 040608

ci where * denotes the point of attachment of the specified group to the rest of the molecule;

or an N-oxide, salt or stereoisomer.

In a preferred embodiment, the invention relates to a compound of formula (I) wherein X is CR ^2a or N;

R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two substituents R ¹¹ that are, independently of each other, the same or different, or substituted once by the substituent R ^11a and optionally once by the substituent R ¹¹ , being, independently of each other, the same or different;

R ^2a represents hydrogen, fluorine, chlorine or cyano;

R ^2b represents hydrogen, fluorine or chlorine;

R ^2c is hydrogen, fluorine or chlorine;

where at least one of R ^2a , R ^2b and R ^2c is hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ is hydrogen, fluoro or methyl;

R ⁵ is hydrogen or methyl;

R ⁶ is fluorine, chlorine, bromine, cyano, nitro, OH, C ₁ -C ₃ alkyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy;

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

R ^6a is hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl or methoxy;

R ^6b is hydrogen or fluorine;

R ^7a and R ^7b are hydrogen;

R ¹¹ are, independently of each other, fluorine, chlorine, bromine, cyano, methyl, difluoromethyl, trifluoromethyl, difluoroethyl, hydroxypropyl, C ₁ -C ₃ -alkoxy, methoxyethyl-, F ₂ CH-CH ₂ -NH-CH ₂ -, F ₂ CHCH2-NH-, H3C-C(O)-, H3C-CH2-O-C(O)- or H3C-S-;

R ^11a is cyclopropyl; pyridyl or pyrazinyl, or an N-oxide, salt or stereoisomer.

In a second aspect, the invention particularly relates to compounds of formula (Ia)

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(la), in which R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule;

R is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, wherein the heteroaryl contains at least one oxygen, nitrogen, or sulfur heteroatom, and wherein said phenyl , 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with a substituent R ^11a and optionally one or two times R ¹¹ substituents that are independently the same or different, or substituted by two adjacent R ¹¹ substituents which together represent a methylenedioxy group to form a 5-membered ring;

R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ alkyl or C 1 -C ₂ haloalkyl;

R ^2b is hydrogen or halogen;

R ^2c is hydrogen or halogen;

where at least one of R ^2a , R ^2b and R ^2c is hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine, methyl or OH;

R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, C1- _C4 haloalkoxy or F3CS-;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, CrC4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC (O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C _g C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O) -, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-; or

R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-;

R ^7a and R ^7b are the same or different and are, independently of one another, hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl;

R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl;

R ⁹ and R ¹⁰ are the same or different and are, independently of one another, hydrogen, C1- _C4 alkyl, _C3 - _C6 cycloalkyl, C1- _C4 haloalkyl, or ( _CH3 ) _2N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times independently with halogen or C 1 -C ₄ alkyl;

R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C1- C4-alkyl)-8- or (C^-alkyl)^-;

R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino,

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where * denotes the point of attachment of the specified group to the rest of the molecule;

R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -hydroxyalkyl, C1- _C4 -alkoxy, _C1 - _C4 -haloalkoxy, (C1-C4alkoxy)-(C2-C4-alkyl)-, (C1-C4-haloalkoxy)-(C2-C4-alkyl)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl) -SO2-;

n is 0, 1, 2 or 3;

or an N-oxide, salt or stereoisomer.

In a third aspect, the invention specifically relates to compounds of formula (Ia) as described above, in which R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ² is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, in which the heteroaryl contains at least one heteroatom representing oxygen, nitrogen or sulfur, and where the specified phenyl , 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with a substituent R ^11a and optionally one or two substituents R ¹¹ that are, independently of each other, the same or different;

R ^2a is hydrogen, chlorine or cyano;

R ^2b is hydrogen or fluorine;

R ^2c is hydrogen or fluoro;

where at least one of R ^2a , R ^2b and R ^2c is hydrogen;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine, methyl or OH;

R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, _C1 - _C4 haloalkoxy, or F3CS-;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1 -C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ⁸ represents, regardless of the presence in each appropriate case, C ₁ -C ₆ -alkyl;

R ⁹ and R ¹⁰ are the same or different and are, independently of each other, hydrogen, C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl or (CH ₃ ) ₂ N- C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing gete

- 8 040608 rocyclic ring;

R ¹¹ are, independently of one another, halogen, hydroxy, cyano, C1-C4-alkyl, C1-C4 haloalkyl, C1-C6-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, (C1-C4-alkoxy )-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl)-, R ⁹ R ¹⁰ N- , R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C ₁ -C ₄ -alkyl) - S- or (C ₁ -C ₄ -alkyl)-SO ₂ -;

R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino,

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ alkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ haloalkoxy;

n is 0 or 1;

or an N-oxide, salt or stereoisomer.

In a fourth aspect, the invention specifically relates to compounds of formula (Ia) as described above, wherein R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ² is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, in which the heteroaryl contains at least one heteroatom representing oxygen, nitrogen or sulfur, and where the specified phenyl , 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with a substituent R ^11a and optionally one or two substituents R ¹¹ that are, independently of each other, the same or different;

R ^2a is hydrogen, chlorine or cyano;

R ^2b is hydrogen or fluorine;

R ^2c is hydrogen or fluoro;

where at least one of R ^2a , R ^2b and R ^2c is hydrogen;

R ³ is hydrogen;

R ⁴ is hydrogen;

R ⁶ is halo, OH, C1- _C4 alkyl, C1- _C4 haloalkyl, _C1 - _C4 alkoxy, or C1-C4 haloalkoxy;

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

R ^6a is hydrogen, halogen, C1- _C4 alkyl, C1- _C4 haloalkyl or C1- _C4 alkoxy;

R ^6b is hydrogen or fluorine;

R ⁸ represents, regardless of the presence in each case, methyl or ethyl;

R ⁹ and R ¹⁰ are the same or different and are independently hydrogen, C1- _C4 alkyl, C1- _C2 haloalkyl or cyclopropyl, or

- 9 040608 together with the nitrogen atom to which they are attached form a 5-membered nitrogen-containing heterocyclic ring;

R ¹¹ are, independently of one another, halogen, cyano, C1- _C4 alkyl, C1- _C4 haloalkyl, _C1 - _C6 hydroxyalkyl, C1- _C4 alkoxy, C1- _C4 haloalkoxy, ( C ₁ -C ₃ -alkoxy)-ethyl-, methoxyethyl-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-, R ⁸ -OC(O)- or R ⁹ R ¹⁰ NC(O)-;

R ^11a is a group selected from C ₃ -C ₅ -cycloalkyl,

where * denotes the point of attachment of the specified group to the rest of the molecule; or an N-oxide, salt or stereoisomer.

In a fifth aspect, the invention specifically relates to compounds of formula (Ib)

ABOUT

R

^R2

RR (Ib), in which R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ² is phenyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, in which the heteroaryl contains at least one heteroatom representing oxygen, nitrogen or sulfur, and where the specified phenyl , 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with a substituent R ^11a and optionally one or two times R ¹¹ substituents that are independently the same or different, or substituted by two adjacent R ¹¹ substituents which together represent a methylenedioxy group to form a 5-membered ring;

R ³ represents hydrogen or fluorine;

R ⁴ represents hydrogen, fluorine, methyl or OH;

R ⁶ is halogen, cyano, nitro, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy or F ₃ CS-;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C1 -C ₄ - haloalkoxy, HO-(C ₂ -C ₄ -alkoxy) -, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O) -, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-; or

R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-;

R ^7a and R ^7b are the same or different and are, independently of each other,

- 10 040608 hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl;

R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl;

R ⁹ and R ¹⁰ are the same or different and are, independently of one another, hydrogen, C1- _C4 alkyl, _C3 - _C6 cycloalkyl, C1- _C4 haloalkyl, or ( _CH3 ) _2N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times independently with halogen or C 1 -C ₄ alkyl;

R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C1- C4-alkyl)-S- or (C1-C4-alkyl)-SO2-;

R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino,

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C2-C4-alkyl)-, (C1-C4-haloalkoxy)-(C2-C4-alkyl)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O) -NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

n is 0, 1, 2 or 3;

or an N-oxide, salt or stereoisomer.

In a sixth aspect, the invention particularly relates to compounds of formula (Ib) as described above, wherein R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ² is a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, wherein the heteroaryl contains at least one oxygen, nitrogen, or sulfur heteroatom, and wherein said 5- membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl, optionally substituted once with R ¹¹ ;

R ³ is hydrogen;

R ⁴ is hydrogen;

R ⁶ is halogen;

R ^6a and R ^6b are hydrogen;

R ¹¹ are, independently of one another, halo, cyano, C1- _C4 alkyl or C1-C4 haloalkyl;

or an N-oxide, salt or stereoisomer.

- 11 040608

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, or _C1 - _C4 haloalkoxy;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C3-C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -haloalkoxy, HO- (C ₂ -C ₄ - alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O) - , R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-.

According to a further alternative, the invention relates to compounds of formulas (I), (Ia) and (Ib) as described above, wherein

R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy or C1- _C4 haloalkoxy;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1 -C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ¹ is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ^7a and R ^7b are the same or different and are, independently of each other, hydrogen, hydroxy, fluorine, chlorine, C1- _C4 alkyl, difluoromethyl or trifluoromethyl.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is phenyl, wherein said phenyl group is optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ substituents, which are, independently of one another, identical or different, or substituted by two adjacent substituents R ¹¹ which together represent a methylenedioxy group to form a 5-membered ring.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

- 12 040608

R ² is a 5-membered monocyclic heteroaryl, wherein said heteroaryl group is optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ which are, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule and these groups are optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule and these groups are optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two times by the R ¹¹ substituents, which are independently the same or different, or substituted once by the R ^11a substituent and optionally once by the substituent

R ¹¹ being, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two substituents R ¹¹ that are, independently of each other, the same or different, or substituted once by the substituent R ^11a and optionally once by the substituent R ¹¹ , being, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is a 6-membered monocyclic heteroaryl, wherein said heteroaryl groups are optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ which are, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

- 13 040608

R ² is a group selected from:

where these groups are optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with R ^11a and optionally one or two times with R ¹¹ substituents that are independently the same or various.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is [5,6]-annelated bicyclic heteroaryl, wherein said heteroaryl group is optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with R ^11a and optionally one two times R ¹¹ substituents, which are, independently of each other, the same or different.

In particular, the invention further relates to compounds of formulas (I), (Ia) and (Ib), as described above, where

R ² is a group selected from:

where * denotes the point of attachment of the specified group to the rest of the molecule.

In accordance with a further aspect of the present invention, the compounds of formulas (I), (Ia) (Ib), as described above, are compounds in which

R ³ is hydrogen; And

R ⁴ is hydrogen, methyl or OH.

In accordance with a further aspect of the present invention, the compounds of formulas (I), (Ia) (Ib), as described above, are compounds in which

R ³ is hydrogen; And

R ⁴ is hydrogen.

In accordance with a further aspect of the present invention, the compounds of formulas (I), (Ia) (Ib), as described above, are compounds in which

R ³ is fluorine; And

R ⁴ is fluorine.

In accordance with a more specific aspect of the present invention, the compounds of formulas (I), (Ia) and (Ib), as described above, are compounds in which

R ⁵ is hydrogen.

According to a further specific form of the invention, the compounds of formulas (Ia) and (Ib) are compounds in which

R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule, and R ⁶ , R ^6a represent, independently of each other, fluorine, chlorine or hydrogen;

R ² is

- 14 040608 where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by the substituent R ^11a and optionally once by the substituent R ¹¹ being, independently of each other, the same or different;

R ^2a , R ^2b and r ^2c are hydrogen.

R ³ , R ⁴ , R ⁵ are hydrogen.

R ⁹ and R ¹⁰ are the same or different and are, independently of each other, hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₂ -haloalkyl or cyclopropyl, or together with the nitrogen atom to which they are attached form 5-membered nitrogen-containing heterocyclic ring;

R ¹¹ are, independently of one another, halogen, cyano, C ₁ -C ₄ alkyl, C 1 -C 4 haloalkyl, C ₁ -C ₆ hydroxyalkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ haloalkoxy, (C ₁ -C ₃ -alkoxy)-ethyl-, methoxyethyl-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-, R ⁸ -OC(O)- or R ⁹ R ¹⁰ NC(O)-;

R ^11a is a group selected from C ₃ -C ₅ -cycloalkyl,

where * denotes the point of attachment of the specified group to the rest of the molecule;

or N-oxides, salts, or stereoisomers.

According to a further specific form of the invention, the compounds of formulas (Ia) and (Ib) are compounds in which

R ¹ is

R

where * denotes the point of attachment of the specified group to the rest of the molecule and R ⁶ , R ^6a represent, independently of each other, fluorine, chlorine or hydrogen;

R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two substituents R ¹¹ that are, independently of each other, the same or different, halogen, cyano, C 1 -C ₄ -alkyl or C 1 -C ₄ -haloalkyl;

R ^2a , R ^2b and R ^2c are hydrogen.

R ³ , R ⁴ , R ⁵ are hydrogen.

R ^6a and R ^6b are hydrogen;

R ¹¹ are, independently of one another, halo, cyano, C1- _C4 alkyl or C1-C4 haloalkyl;

or N-oxides, salts, or stereoisomers.

One aspect of the invention are compounds of formulas (I), (Ia), (Ib) as described in the examples, as characterized by their title names and their structures, as well as subcombinations of all residues specifically disclosed in the examples.

Another aspect of the present invention are intermediates according to formulas 3a, 3b, 4a and 4b

- 15 040608

where R ² , R ^2a , R ^2b and R ^2c are as defined in the description and claims of the present invention.

In a specific embodiment of the present invention, in formulas 3a, 3b, 4a and 4b, the groups R ² , R ^2a , R ^2b and R ^2c are defined as follows:

R ² is

where * denotes the point of attachment of the specified group to the rest of the molecule and the specified group is optionally substituted one or two times by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different;

R ^2a , R ^2b and R ^2c are hydrogen.

In addition, the present invention relates to intermediate compounds in accordance with formula 30 o

2a

R

R ³⁰ where R ¹ , R ^2a , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention, W represents an amino group, which is optionally substituted with a protective group (for example, (dimethylamino) methylene or 2,4-dimethoxybenzyl) and V is chlorine or bromine.

In a specific embodiment of the present invention, the groups of formula 30 are defined as follows:

R ¹ is

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ⁶ is halogen, cyano, nitro, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ haloalkoxy;

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

R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -;

R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, HO - (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-.

R ^2a , R ^2b and R ^2c are hydrogen.

R ³ , R ⁴ , R ⁵ are hydrogen.

Specific intermediates for the synthesis of compounds of formulas (I), (Ia) and (Ib) according to

2-(4-cyano-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide 5amino-2-(4-cyano-1H-pyrazol-1-yl)benzenesulfonamide.

Another aspect of the invention relates to the use of any of the intermediates described herein to obtain a compound of formula (I), as defined herein, or an N-oxide, a salt, or a stereoisomer.

Preferred intermediates are Examples of Intermediates as disclosed below.

An additional aspect of the invention are the compounds of formulas (I), (Ia) and (Ib), which are present in the form of their salts.

It is to be understood that the present invention relates to any subcombination within any embodiment or aspect of the present invention relating to compounds of general formulas (I), (Ia) and (Ib) as defined above.

Even more specifically, the present invention covers compounds of general formulas (I), (Ia) and (Ib), which are disclosed in the Examples section of this text below.

According to another aspect, the present invention encompasses methods for preparing the compounds of the present invention, said methods comprising the steps as described herein in the Experimental section.

Another embodiment of the invention provides compounds according to the claims as disclosed in the Claims section, where the definitions are limited in accordance with the preferred or more preferred definitions as disclosed below, or specifically disclosed definitions of residues given as examples of compounds, and their subcombinations.

Definitions

Structural units that are optionally substituted as described in this application may be substituted, unless otherwise indicated, one or more times, independently of each other in any possible position. When any variable occurs more than once in any structure, each definition is independent. For example, when R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , X and/or Y occur more than once in any compound of formula (I), each definition of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , X and Y is independent.

If the structural component consists of more than one part, for example, as in the case of C ₁ -C ₄ alkoxy-C ₁ -C ₄ -alkyl-, a possible substituent may be in any of these parts in any suitable position. A dash at the beginning of a structural component indicates the point of attachment to the rest of the molecule. If the ring is substituted, the substituent may be at any suitable position on the ring, as well as on the ring nitrogen atom if appropriate.

In addition, a structural component consisting of more than one part and containing several chemical residues, for example, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl or phenyl-C ₁ -C ₄ -alkyl, is read from left to right, and it is believed that the point of attachment to the rest of the molecule is on the last part (in the example mentioned earlier, on the C ₁ -C ₄ alkyl residue).

The term containing as used herein includes consisting of.

If the description is about as mentioned above or as mentioned above, this applies to any of the disclosures made as part of the description on any of the previous pages.

The term suitable in the context of the present invention means the possibility of obtaining chemically using methods within the knowledge of a person skilled in the art.

The terms used in this text preferably have the following meanings:

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

The term C ₁ -C ₄ -alkyl should be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group containing 1, 2, 3 or 4 carbon atoms, for example, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, a tert-butyl group, in particular 1, 2 or 3 carbon atoms (C ₁ -C ₃ alkyl), for example a methyl, ethyl, n-propyl or isopropyl group.

The term C ₁ -C ₄ -haloalkyl should be understood as preferably meaning a linear or branched, saturated, monovalent hydrocarbon group, where the term C ₁ -C ₄ -alkyl is defined above, and in which one or more hydrogen atoms are replaced by halogen atoms, equally or differently, i.e. one halogen atom is independent of the other. In particular, said halogen atom is F. Said C ₁ -C ₄ haloalkyl group is, for example, -CF3, -CHF2, -CH2F, -CF2CF3 or -CH2CF3.

The term C ₁ -C ₄ -alkoxy should be understood as preferably meaning a linear or branched, saturated, monovalent, hydrocarbon group of the formula -O-alkyl, where the term alkyl is defined above, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , isobutoxy, tert-butoxy or sec-butoxy group, or an isomer thereof.

- 17 040608

The term C1- _C4 haloalkoxy is to be understood as preferably meaning a linear or branched, saturated, monovalent C1- _C4 alkoxy group as defined above in which one or more hydrogen atoms are replaced, equally or differently, by halogen atoms. In particular, said halogen atom is F. Said C ₁ -C ₄ haloalkoxy group is, for example, -OCF ₃ , -OCHF2, -OCH2F, -OCF2CF3 or -OCH2CF3.

The term C1- _C4 hydroxyalkyl is to be understood as meaning a linear or branched, saturated, monovalent hydrocarbon group, where the term C1- _C4 alkyl is defined above, and in which one or more hydrogen atoms are replaced by hydroxy groups, e.g., hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl , 1-hydroxy-2-methylpropyl group.

The term C1-C4-alkoxy-C1-C4-alkyl is to be understood as preferably meaning a linear or branched, saturated, monovalent alkyl group as defined above in which one or more hydrogen atoms are replaced, equally or differently, by C1-C4 -alkoxy groups as defined above, for example, methoxyalkyl, ethoxyalkyl, propyloxyalkyl, isopropoxyalkyl, butoxyalkyl, isobutoxyalkyl, t-butoxyalkyl or sec-butoxyalkyl group, in which the term C ₁ -C ₄ -alkyl is defined above, or an isomer thereof.

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

The term 4-6 membered heterocycloalkyl or 4-6 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 groups containing a heteroatom, selected from C(=O), O, S, S(=O), S(=O) ₂ , NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group; wherein said heterocycloalkyl group may be attached to the rest of the molecule via any carbon atom or, if present, a nitrogen atom.

In particular, said heterocycloalkyl may contain 4 or 5 carbon atoms and one or more of the aforementioned groups containing a heteroatom (5-6 membered heterocycloalkyl).

In particular, without limitation, said heterocycloalkyl may be, for example, a 4-membered ring such as 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. Optionally, said heterocycloalkyl may be benzofused.

The term heteroaryl should be understood as preferably meaning a monovalent, monocyclic, bicyclic or tricyclic aromatic ring system which contains 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms (5-14 membered heteroaryl group) , in particular 5, 6, 9 or 10 ring atoms, and which contains at least one heteroatom, which, if there are several, may be the same or different, said heteroatoms being oxygen, nitrogen or sulfur. In addition, said ring system may be benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia4H-pyrazolyl and their benzo derivatives, such as, for example, benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and their benzo derivatives such as, for example, quinolinyl, quinazolinyl, isoquinolinyl; or azocinyl, indolizinyl, purinyl and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naftpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl.

In general, and unless otherwise indicated, a heteroaryl radical includes all possible isomeric forms thereof, for example, its positional isomers. Thus, for a separate illustrative non-limiting 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 above, said ring containing a nitrogen atom may be partially unsaturated, ie. it may contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5dihydrooxazolyl, or 4H-[1,4] a thiazinyl ring, or it may be benzo-fused, such as, but not limited to, a dihydroisoquinolinyl ring.

The term C ₁ -C ₄ used throughout this text, for example, in the context of the definition of C ₁ C ₄ -alkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, or C ₁ -C ₄ -haloalkoxy, should be understood as

- 18 040608 meaning an alkyl group containing a finite number of carbon atoms from 1 to 4, i.e. 1, 2, 3 or 4 carbons. In addition, it should be understood that the specified term C ₁ -C ₄ should be interpreted as any subrange contained therein, for example, C ₁ -C ₄ , C ₂ -C ₄ , C ₃ -C ₄ , C ₁ -C ₂ , C ₁ -C ₃ , in particular C ₁ C ₂ , C ₁ -C ₃ , C ₁ -C ₄ , in the case of C ₁ -C ₆ haloalkyl or C ₁ -C ₄ haloalkoxy, even more specifically C1 -C2.

In addition, the term C ₃ -C ₆ used throughout this text, for example, in the context of the definition of C ₃ -C ₆ -cycloalkyl, should be understood as meaning a cycloalkyl group containing a finite number of carbon atoms from 3 to 6, i.e. 3, 4, 5 or 6 carbons. In addition, it should be understood that the specified term C ₃ -C ₆ should be interpreted as any subrange contained therein, for example, C ₃ -C ₆ , C ₄ -C ₅ , C ₃ -C ₅ , C3-C4, C ₄ - C ₆ , C ₅ -C ₆ ; in particular C ₃ -C ₆ .

The group R ⁹ R ¹⁰ NC(O)- includes, for example, -C(O)NH ₂ , -C(O)N(H)CH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O )N(H)CH2CH3, -C(O)N(CH3)CH2CH3 or -C(OMSSCHCH3)2.

The R ⁹ R ¹⁰ N- group includes, for example, -NH2, -N(H)CH3, -I(CH3)2, -M(H)CHCH3 and -N(CH3)CH2CH3. In the case of R ⁹ R ¹⁰ N-, when R ⁹ and R ¹⁰ together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, said ring optionally contains one additional heteroatom selected from O, NH, NR ^a , where R ^a is a C1-C6 alkyl or C1-C ₆ haloalkyl group, in particular CH ₃ or S, and is optionally substituted once three times, independently of each other, with halo or C1-C ₄ alkyl, in in particular, CH ₃ .

The term "substituted" means that one or more hydrogen atoms on the designated atom are replaced by substituents selected from the specified group, provided that the normal valency of the designated atom under existing circumstances is not exceeded and that the substitution results in a stable compound. Only such combinations of substituents and/or variables are allowed that result in stable compounds.

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

A ring system substituent means a substituent attached to an aromatic or non-aromatic ring system that, for example, replaces an available hydrogen in the ring system.

As used in this application, the term one or more, for example, in the definition of substituents of compounds of the general formulas of the present invention, is understood to mean one, two, three, four or five, in particular one, two, three or four, more specifically one, two or three, more specifically one or two.

The invention also includes all suitable isotopic variants of a compound of the invention. An isotopic variant 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 that normally or predominantly found in nature. Examples of isotopes that can be introduced into the compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ² H (deuterium), ³ H (tritium), ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁷ 0 ^{, 18} O, ³² P, 33 P, ³³ S, 34 S, ³⁵ S, ³⁶ S, ¹⁸ F, ³⁶ Cl, ⁸² Br, ¹²³ I, ^{124 I, 125 I} , ¹²⁹ I and ¹³¹ I, respectively. Certain isotopic variants of a compound of the invention, for example those incorporating one or more radioactive isotopes such as ³ H or ¹⁴ C, are useful for drug and/or substrate tissue distribution studies. Labeled with tritium and carbon-14, i.e. ¹⁴ C isotope, the compounds are particularly preferred because of their ease of preparation and ability to be detected. In addition, substitution with isotopes such as deuterium may result in certain therapeutic benefits as a result of greater metabolic stability, eg, increased in vivo half-life or reduced doses required, and may therefore be preferred in some circumstances. Isotopic variants of a compound of the invention can generally be prepared using conventional techniques known to those skilled in the art, for example, by using the illustrative methods or by using the syntheses described in the examples below, using the appropriate isotopic variants of the appropriate reagents.

If the present invention uses the plural form of the word compounds, salts, polymorphs, hydrates, solvates, and the like, then this should also be understood as a single compound, salt, polymorph, isomer, hydrate, solvate, or the like.

By stable compound or structure is meant a compound that is sufficiently stable to withstand isolation to a suitable degree of purity from a reaction mixture and formulation into an effective therapeutic agent.

The compounds of the invention may contain one or more asymmetric centers, depending on 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 center, and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also be present due to limited rotation around a given bond, such as the central bond adjacent to the two substituted aromatic rings of the specified compounds.

- 19 040608

Ring substituents may also be present in either cis or trans form. All such configurations (including enantiomers and diastereomers) are intended to be included within the scope of the present invention.

Preferred compounds are those that produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such substances can be carried out using standard methods known in the art.

Optical isomers can be obtained by separating racemic mixtures according to conventional methods, for example by forming diastereomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereomers based on their physical and/or chemical differences by methods known in the art, such as chromatography or fractional crystallization. Optically active bases or acids are then released from the separated diastereomeric salts. Another method for separating optical isomers involves the use of chiral chromatography (eg, chiral HPLC columns), with or without conventional derivatization optimally chosen to maximize separation of the enantiomers. Suitable chiral HPLC columns are available from Diacel, such as Chiracel OD and Chiracel OJ, among many others commonly chosen. Enzymatic separation methods, with or without derivatization, are also suitable. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

For the purpose of distinguishing between different types of isomers, reference is made to the IUPAC rules, section E (Pure Appl Chem 45, 11-30, 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, for example R or S isomers, or E or Z isomers, in any ratio. Isolation of a single stereoisomer, eg a single enantiomer or a single diastereomer, of a compound of the present invention can be achieved by any suitable prior art method such as, for example, chromatography, especially chiral chromatography.

In addition, the compounds of the present invention may exist as tautomers. For example, any compound of the present invention which contains, for example, a pyrazole moiety as a heteroaryl group, may exist as a 1H-tautomer or 2H-tautomer, or even a mixture of any amounts of two such tautomers, and which contains, for example, a triazole moiety as 1H-tautomer, 2H-tautomer or 4H-tautomer, or even mixtures of any amounts of the indicated 1H-, 2H- and 4H-tautomers, namely:

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

Moreover, the compounds of the present invention may exist as N-oxides, which are defined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

The present invention also relates to suitable forms of the compounds disclosed in this application, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and co-precipitation products.

The compounds of the present invention may exist as a hydrate, or as a solvate, where the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol, for example, as a structural element of the crystal lattice of the compounds. The amount of polar solvents, in particular water, may be in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example a hydrate, hemi- (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. are possible. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

In addition, the compounds of the present invention may exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or may exist in the form of a salt. Said salt may be any salt, or an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt commonly used in the pharmaceutical art.

The term "pharmaceutically acceptable salt" refers to a relatively non-toxic addition salt.

- 20 040608 inorganic or organic acid to the 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, for example, in a chain or ring, which is sufficiently basic, such as an addition salt with an inorganic acid, such as, for example hydrochloric, hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric or nitric acid, or with an organic acid such as, for example, formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4hydroxybenzoyl)-benzoic, camphoric, cinnamon, cyclopentanepropionic, digluconic, 3hydroxy-2-naphthoic, nicotinic, pamoic, pectinic, supersulphuric, 3-phenylpropionic, picric, pivalic, 2-hydroxyethanesulfonic, itaconic, sulfamic, trifluoromethanesulfonic, dodecylsulfuric, ethanesulfonic, benzenesulfonic, para-tolu olsulfonic acid, methanesulfonic acid, 2naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic, mandelic, ascorbic, glucoheptanoic, glycerosulfonic phosphoric, asparalytic phosphoric , hemisulfuric or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of a compound of the present invention which is sufficiently acidic is an alkali metal salt, such as a sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, an ammonium salt, or a salt with an organic base. , which gives a physiologically acceptable cation, for example, a salt with N-methylglucamine, dimethylglucamine, ethylglucamine, lysine, dicyclohexylamine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, trishydroxymethylaminomethane, aminopropanediol, Sovak's base, 1-amino-2, 3,4-butanetriol. In addition, groups containing a basic nitrogen can be quaternized with reagents such 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 stearyl chlorides, bromides and iodides; aralkyl halides like benzyl and phenethyl bromides, and others.

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

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

In the present text, in particular in the experimental part, in the case of describing the synthesis of intermediate compounds and compounds - examples of the present invention, when the compound is mentioned in the form of a salt with the corresponding base or acid, the exact stoichiometric composition of the indicated salt form, obtained using the corresponding method of obtaining and/or purification, in most cases is not disclosed, i. is unknown.

Unless otherwise indicated, suffixes in chemical names or structural formulas, such as hydrochloride, trifluoroacetate, sodium salt, or xHCl, x CF3COOH, x Na ⁺ , should not be understood as a stoichiometric characteristic, but solely as an indication of the form of salt .

This applies similarly to cases in which synthetic intermediates or exemplary compounds or salts thereof have been prepared by the described preparation and/or purification processes as solvates such as hydrates of (if of a certain type) unknown stoichiometric composition.

Salts include water-insoluble and in particular water-soluble salts.

In addition, the invention covers derivatives of compounds of formula (I) and their salts, which are converted into compounds of formula (I) or their salts in a biological system (bioprecursors or prodrugs). Said biological system is, for example, an organism of a mammal, in particular a human. Bioprecursors, for example, are converted into compounds of formula (I) or salts thereof by metabolic processes.

In addition, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph, 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 combination of parameters, including permeability, bioavailability, exposure, and pharmacodynamic parameters such as duration or magnitude of pharmacological action measured in a suitable experiment. Connections with improved

- 21 040608 pharmacokinetic profile, for example, may be used at lower doses to achieve the same effect, may provide a longer effect, or may provide a combination of both effects.

It has now been found, and this forms the basis of the present invention, that said compounds of the present invention have unexpected and useful properties.

In particular, it has surprisingly been found that the compounds of the present invention are effective as an antagonist or negative allosteric modulator of P2X4.

An allosteric modulator is a substance that indirectly influences (modulates) the actions of an agonist or inverse agonist on a target protein, such as a receptor. Allosteric modulators bind to a site other than the orthosteric agonist binding site. They usually induce a conformational change in the structure of the protein. The negative modulator (NAM) attenuates the actions of the orthosteric ligand but is inactive in the absence of the orthosteric ligand.

Industrial applicability and medical indications

As mentioned above, it has surprisingly been found that the compounds of the present invention are effective as an antagonist or negative allosteric modulator of P2X4.

The compound according to the invention is used for the manufacture of a medicinal product.

An additional aspect of the invention is the use of compounds according to formula (I), (Ia) or (Ib) for the treatment or prevention of diseases.

In addition, the invention relates to a compound of general formula (I), (Ia) or (Ib), or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said N-oxide, or a stereoisomer, in particular its pharmaceutically acceptable salt , or mixtures thereof, as described and defined in this patent, for use in the treatment or prevention of a disease.

The invention further relates to a method of using a compound of general formula (I), (Ia) or (Ib), or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said N-oxide, or a stereoisomer, for the treatment of disorders and diseases in mammals and a person, which include, but are not limited to, the following:

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

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

painful conditions of the urinary tract, including conditions associated with obstruction of the bladder outlet; urinary incontinence conditions such as reduced bladder capacity, increased frequency of urination, urge incontinence, stress urinary incontinence, or overreactive bladder; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms associated with overactive bladder, where these symptoms are, in particular, increased frequency of urination, nocturia, urge to urinate or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease as hyperprostaglandin E syndrome, classic Bartter's syndrome;

cancer, pain associated with cancer and tumor cachexia;

epilepsy, partial and generalized seizures;

respiratory disorders including asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic cough, refractory chronic cough, idiopathic chronic cough;

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

fatty liver disorders, in particular NASH (non-alcoholic steatohepatitis); fibrotic diseases including pulmonary fibrosis, cardiac fibrosis, renal fibrosis, and fibrosis of other organs; metabolic syndrome, including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinemia and obesity, diabetes mellitus, in particular type II diabetes, myocardial infarction; atherosclerosis; lipid metabolism disorders;

neurodegenerative disorders such as Alzheimer's disease, multiple sclerosis, Parkinson's disease, cerebral ischemia, traumatic brain injury, spinal cord injury;

- 22 040608 itching;

cardiac disorders, including ischemia-reperfusion injury, cardiac ischemia.

In addition, the present invention relates to a method of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said Noxide, or a stereoisomer, in particular its pharmaceutically acceptable salt , or mixtures thereof, for the treatment of pain-related disorders and diseases in mammals, which include, but are not limited to, the following:

pain-related 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 headache, nerve injury, traumatic nerve injury, post-traumatic injury (including bone and sports injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, malignancy, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and associated neuralgia, HIV- and HIV-treated neuropathy, pruritus; wound healing disorders; and skeletal disease like joint degeneration.

In addition, the present invention relates to a method of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said Noxide, or a stereoisomer, in particular its pharmaceutically acceptable salt , or mixtures thereof, for the treatment of disorders and diseases in mammals and humans that are associated with pain or pain syndromes, which, in particular, are:

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, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain caused by burning mouth syndrome, pain caused by burns, pain caused by migraine, cluster headache, pain caused by nerve damage, pain caused by neuritis, neuralgia, pain caused by poisoning, pain caused by ischemic disease, pain caused by interstitial cystitis, pain associated with malignancy, pain caused by viral, parasitic or bacterial infections, pain caused by traumatic nerve injury, pain caused by post-traumatic injuries (including bone and sports injuries), pain caused by neuralgia trigeminal nerve pain associated with nevi small fiber ropathy, pain associated with diabetic neuropathy, postherpetic neuralgia, chronic low back pain, neck pain, phantom pain in amputees, pelvic pain syndrome, chronic pelvic pain, neuroma pain, complex regional pain syndrome, fibromyalgia, myofascial disorders, pain associated with gastrointestinal bloating, chronic arthritis pain and associated neuralgia, and pain associated with malignant neoplasm, morphine-resistant pain, pain associated with chemotherapy, induced by HIV and HIV treatment 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 bowel disease, and selected from the group of arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis).

Thus, the compounds of the invention are expected to be useful in the treatment of inflammation. The term inflammation should also be understood to include any inflammatory disease, disorder or condition as such, any condition that has an inflammatory component associated with it, and/or any condition that is characterized by inflammation as a symptom, including but not limited to acute, chronic , ulcerative, fibrotic, allergic and autoimmune diseases, infection by pathogens, immune responses due to hypersensitivity, foreign bodies, mechanical trauma, necrosis, endometriosis and other forms of inflammation known to those skilled in the art. Thus, for the purposes of the present invention, the term also includes inflammatory pain, general pain and/or fever. The compounds of the present invention may also be useful in the treatment of viral infections (eg, influenza, common cold, herpes zoster, hepatitis C, and HIV), bacterial infections, fungal infections, surgical or dental procedures, and treatment of malignancies (eg, melanoma, breast cancer). colon cancer, lung cancer, and prostate cancer), arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis , iritis, scleritis, uveitis, for wound healing, for the treatment of dermatitis, eczema, stroke, diabetes mellitus, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderate ulcerative colitis, family hell

- 23 040608 nomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.

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

Because of their P2X4 antagonizing activity, the compounds of the invention are useful in relieving pain, fever, and inflammation in a number of conditions, including rheumatic fever, symptoms associated with influenza or other viral infections, the common cold, lower back pain, and neck pain, dysmenorrhea, headache, migraine (acute and prophylactic), toothache, sprains and congestion, 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, trauma, and pain following surgical (postoperative pain) and dental procedures, as well as for the proactive management 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, pain due to acute trauma, chemotherapy-induced mononeuropathic pain conditions, conditions polyneuropathic pain (such as diabetic peripheral neuropathy and/or chemotherapy-induced neuropathy), autonomic neuropathic pain conditions, pain conditions that are associated with peripheral nervous system (PNS) or central nervous system (CNS) damage or disease, polyradiculopathy of the cervical, lumbar, or lumbosacral type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain conditions related to various conditions of polyneuritis, which are based on various infections, chemical injuries, radiation exposure, underlying diseases or deficiency states (such as beriberi, vitamin deficiency, hypothyroidism, porphyria), malignancy, HIV, autoimmune disease such as multiple sclerosis and spinal cord injury, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, post-stroke pain, inflammatory disorders, esophagitis, gastroesophageal reflux disease (GERD), irritable bowel syndrome, inflammatory bowel disease, overactive bladder, pelvic hypersensitivity, urinary incontinence, cystitis, gastric ulcer, duodenal ulcer, muscle pain, pain caused by colic and repercussion pain. The compounds of the present invention may also be useful in the treatment or prevention of haemophilus arthropathy and Parkinson's disease.

The invention also relates to a method of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said N-oxide, or a stereoisomer, in particular its pharmaceutically acceptable salt, or mixtures thereof, for the treatment of conditions that are treatable by inhibition of prostanoid-induced smooth muscle contraction by preventing the synthesis of contractile prostanoids and, therefore, the method may be of value for use in the treatment of dysmenorrhea, the prevention of preterm labor and the treatment of asthma.

The present invention relates to a method of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said N-oxide, or a stereoisomer, in particular its pharmaceutically acceptable salt, or mixtures thereof, for the treatment of cancer and hyperproliferative disorders. Hyperproliferative disorders include, but are not limited to, e.g., psoriasis, keloids, and other hyperplasias affecting the skin, benign prostatic hyperplasia (BPH), solid tumors such as cancer of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid cancer, parathyroid cancer and their distant metastases. Such disorders also include lymphomas, sarcomas, and leukemias.

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

Examples of types of respiratory tract cancer 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 cancer types include, but are not limited to, brain stem and hypophthalmic glioma, cerebellar and brain astrocytoma, medulloblastoma, ependymoma, and neuroectodermal tumor and pineal tumor.

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

Tumors of the female reproductive organs include, but are not limited to, cancer

- 24 040608 endometrium, cervix, ovary, vagina and vulva, as well as uterine sarcoma.

Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, cancer of the esophagus, gallbladder, stomach, pancreas, rectal cancer, and cancer of the small intestine and salivary gland.

Tumors of the urinary tract include, but are not limited to, cancer of the bladder, penis, kidney, and cancer of the renal pelvis, ureter, urethra, and human papillary kidney cancer.

Ocular types of cancer include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer types include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinomas with or without fibrolamellar variant), cholangiocarcinoma (carcinoma of the intrahepatic bile ducts), and mixed hepatocellular cholangiocarcinoma.

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

Types of head and neck cancer include, but are not limited to, laryngeal, subesophageal, nasopharyngeal, oropharyngeal, lip and oral cavity, and squamous cell carcinoma.

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

Sarcomas include, but are not limited to, soft tissue sarcoma, 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 of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt, or a stereoisomer of said compound, or a salt of said N-oxide, or a stereoisomer, in particular its pharmaceutical an acceptable salt, or mixture thereof, for the treatment of a gynecological disorder, preferably dysmenorrhea, dyspareunia, vulvodynia or endometriosis, pain associated with endometriosis, or other symptoms associated with endometriosis, 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 of using the compound of the present invention and its composition for the treatment of urinary tract disease, in particular overactive bladder or cystitis, preferably interstitial cystitis.

Another preferred embodiment of the present invention relates to a method of using the compound of the present invention and its composition for the treatment of a respiratory disorder, preferably cough, in particular chronic cough.

Another preferred embodiment of the present invention relates to a method of using the compound of the present invention and its composition for the treatment of neurodegenerative disorders, preferably ischemic brain injury, spinal cord injury and multiple sclerosis.

Another preferred embodiment of the present invention relates to a method of using a compound of general formula (I), (Ia) or (Ib) or an N-oxide, a salt or a stereoisomer of said compound, or a salt of said N-oxide or a stereoisomer, in particular its a pharmaceutically acceptable salt, or mixture thereof, for the treatment of 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 the pharmaceutical compositions of the present invention.

The term treat or treat as used herein is conventionally used, for example, to mean the management or care of a patient for the purpose of combating, alleviating, reducing, relieving, ameliorating, etc., a disease or disorder such as a gynecological disease or disease associated with unwanted proliferation, like endometriosis or malignancy.

Preferably, the diseases treated by said method are gynecological disorders, more preferably dysmenorrhea, dyspareunia or endometriosis, pain associated with endometriosis, or other symptoms associated with endometriosis, where said symptoms are, in particular, acute and chronic abdominal pain. , dysmenorrhea, dyspareunia, dysuria or dyschezia.

- 25 040608

Further diseases that can be treated in this way are osteoarthritis, diabetic neuropathy, burning mouth syndrome, gastroesophageal reflux, migraine disorders, chronic cough, asthma, pruritus, irritable bowel disease, overactive bladder, prostatic hyperplasia, interstitial cystitis.

Preferably, the method of treating the diseases mentioned above is not limited to the treatment of these diseases, but also includes the treatment of pain related to or associated with these diseases.

The compounds of the present invention can be used, in particular, for therapy and prevention, i. prevention, genitourinary disease, gastrointestinal disease, respiratory or pain-related disease, condition or disorder.

Pharmaceutical compositions of the compounds of the invention

The present invention also relates to pharmaceutical compositions containing one or more compounds of the present invention. These compositions can be used to achieve the desired pharmacological effect by administration to a patient in need thereof. A patient, for the purposes of the present invention, is a mammal, including a human, who is in need of treatment for a specific condition or disease.

Therefore, the present invention includes pharmaceutical compositions which contain a pharmaceutically acceptable carrier or adjuvant and a pharmaceutically effective amount of a compound, or salt thereof, of the present invention.

Another aspect of the invention is a pharmaceutical composition containing a pharmaceutically effective amount of a compound of formula (I) and a pharmaceutically acceptable adjuvant for the treatment of the disease mentioned above, especially for the treatment of hematological tumors, solid tumors and/or their metastases.

The pharmaceutically acceptable carrier or adjuvant is preferably one that is non-toxic and harmless to the patient at concentrations appropriate to the effective activity of the active ingredient so that any side effects attributed to the carrier do not interfere with the beneficial effects of the active ingredient. Carriers and adjuvants are all types of additives that help the composition to be suitable for administration.

A pharmaceutically effective amount of a compound is preferably that amount which results in or is expected to have an effect on the specific condition being treated.

The compounds of the present invention may be administered with pharmaceutically acceptable carriers or auxiliaries well known in the art, using any effective conventional unit dosage form, including immediate, sustained and sustained release formulations, orally, parenterally, topically, nasally, ophthalmically, optically, sublingually. , rectally, vaginally, subcutaneously, intrauterine, etc.

For oral administration, the compounds may be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, lozenges, molten forms, powders, solutions, suspensions, or emulsions, which may be prepared according to methods known in the art for preparing pharmaceutical formulations. compositions. Solid dosage forms may be a capsule, which may be of the standard gelatin type, hard or soft shell, containing excipients such as surfactants, lubricants, and excipients such as lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of the present invention may be tabletted with conventional tablet bases such as lactose, sucrose and corn starch in combination with binders such as acacia, corn starch or gelatin, disintegrants designed to promote disintegration and dissolution. tablets after injection, such as potato starch, alginic acid, corn starch and guar gum, gum tragacanth, acacia, lubricants designed to improve flow during tablet granulation and to prevent sticking of the tablet substance on the surface of the tablet press and punches, such as, for example, talc, stearic acid or magnesium, calcium or zinc stearate, coloring agents, coloring agents and flavoring agents such as mint, wintergreen oil or cherry flavor, designed to enhance the aesthetic qualities of tablets and make l 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 such as ethanol, benzyl alcohol and polyethylene alcohols, with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Various other substances may be present as shells or otherwise modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both.

- 26 040608

Dispersible powders and granules are suitable for formulating 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 adjuvants may also be present, such as the sweetening, flavoring and coloring agents described above.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil such as liquid paraffin or a mixture of vegetable oils. Suitable emulsifying agents can be (1) natural gums such as gum arabic and gum tragacanth, (2) natural phosphatides such as soybean phosphatides and lecithin, (3) esters or partial esters derived from fatty acids and hexitol anhydrides eg sorbitan monooleate, (4) condensation products of said partial esters with ethylene oxide, eg polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening and flavoring agents.

Oil suspensions can be formulated by suspending the active ingredient in a vegetable oil such as, for example, peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent such as, for example, wax, paraffin wax or cetyl alcohol. Suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate; one or more colorants; one or more aromatics; and one or more sweeteners such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweeteners such as, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain an emollient and a preservative such as methyl and propyl parabens, and flavoring and coloring agents.

The compounds of the present invention may also be administered parenterally, i.e., subcutaneously, intravenously, intraocularly, intrasynovially, intramuscularly or intraperitoneally, as injectable dosages of the compound in a preferably physiologically acceptable diluent with a pharmaceutical carrier, which may be a sterile liquid or mixture of liquids such as water. , saline, aqueous solutions of dextrose and related sugars, alcohol such as ethanol, isopropyl alcohol or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, glycerine 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 fatty acid glyceride, or an acetylated fatty acid glyceride with the addition of a pharmaceutically acceptable surfactant such as soap or detergent, a suspending agent such as as pectin, carbomers, methylcell yulose, hydroxypropylmethylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants, or without them.

Examples of oils that can be used in the parenteral formulations of the present invention are those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petroleum jelly 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 alkali metal fatty acid ammonium and triethanolamine salts, and suitable detergents include cationic detergents, for example, dimethyldialkylammonium halides, alkylpyridinium halides and alkylamine acetates; anionic detergents such as 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(oxyethyleneoxypropylene)s or copolymers of ethylene oxide or propylene oxide; and amphoteric detergents, for example alkyl beta-amino propionates and quaternary ammonium salts of 2-alkylimidazoline, as well as mixtures.

Parenteral compositions of the present invention will typically contain from about 0.5% to about 25% by weight of the active ingredient in solution. Preservatives and buffers may also advantageously be used. To minimize or eliminate irritation at the injection site, such compositions may contain a non-ionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably about 12 to about 17. The amount of surfactant in such a formulation preferably ranges from about 5 to about 15% by weight. The surfactant may be a single component having the aforementioned HLB, or may be a mixture of two or more components having the desired HLB.

Examples of surfactants used in parenteral formulations are the class of polyethylenesorbitan fatty acid esters such as sorbitanmo

- 27 040608 nooleate, and 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, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic; dispersing or wetting agents, which may be a natural phosphatide such as lecithin, a condensate of alkylene oxide with a fatty acid, for example polyoxyethylene stearate, a condensate of ethylene oxide with a long chain aliphatic alcohol, for example from a fatty acid and hexitol, such as polyoxyethylene sorbitan monooleate, or a condensation product of ethylene oxide with a partial ester derived from fatty acid and hexitol anhydride, such as 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 can be used are, for example, water, Ringer's solution, isotonic sodium chloride solutions and isotonic glucose solutions. In addition, sterile fixed oils have traditionally been used as solvents or suspending media. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

The composition of the invention can 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-irritating 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 substances are, for example, cocoa butter and polyethylene glycol.

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

It may be desirable or necessary to administer the pharmaceutical composition to a patient via a mechanical delivery device. The design and use of mechanical delivery devices for the delivery of pharmaceuticals is well known in the art. Direct methods of administration, such as those that allow the drug to be administered directly to the brain, typically involve the placement of a drug delivery catheter into the patient's ventricular system to bypass the blood-brain barrier. One such implantable delivery system used to transport agents to specific anatomical locations in the body is described in US Pat. No. 5,011,472 issued April 30, 1991.

The compositions of the invention may also contain other conventional pharmaceutically acceptable ingredients, generally referred to as carriers or diluents, as needed or desired. Conventional techniques may be used to prepare such compositions in suitable dosage forms.

Such components and techniques include those described in the following references, each of which is incorporated by reference by the authors: Powell, M.F. et al., Compendium of Excipients for Parenteral Formulations PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; 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 may be used as suitable for formulating a 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);

alkalizing 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 charcoal);

aerosol propellants (examples include, but are not limited to, carbon dioxide, CCl2F2, F2ClC-CClF2, and CClT ₃ ), air displacing agents (examples include, but are not limited to, nitrogen and argon);

- 28 040608 antifungal preservatives (examples include, but are not limited to, benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate);

antibacterial 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, hypophosphoric acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite);

binders (examples include, but are not limited to, block copolymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones, polysiloxanes, and styrene-butadiene copolymers);

buffer agents (examples include, but are not limited to, potassium metaphosphate, dipotassium phosphate, sodium acetate, sodium citrate anhydrous, and sodium citrate dihydrate), carrier 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 for injection and bacteriostatic water for injection), chelating agents (examples include, but are not limited to, disodium edetate and edetic acid), colors (examples include, but are not limited to, FD&C Red #3, FD&C Red #20, FD&C Yellow #6, FD&C Blue #2, D&C Green #5, D&C Orange #5, D&C Red #8, caramel, and iron oxide red);

antireflective 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), flavors (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, glycerin, propylene glycol, and sorbitol);

elutrients (examples include, but are not limited to, mineral oil and glycerin);

oils (examples include, but are not limited to, peanut oil, mineral oil, olive oil, nut 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, esters, ketones and ureas), plasticizers (examples include, but are not limited to, diethyl phthalate and glycerin);

solvents (examples include, but are not limited to, ethanol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection, and sterile water for irrigation);

hardening 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, octoxynol 9, polysorbate 80, sodium lauryl sulfate, and sorbitan monopalmitate);

suspending agents (examples include, but are not limited to, agar, bentonite, carbomers, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, kaolin, methylcellulose, tragacanth, and veegum);

- 29 040608 sweeteners (examples include, but are not limited to, aspartame, dextrose, glycerol, mannitol, propylene glycol, sodium saccharin, sorbitol and sucrose);

tablet anti-adhesives (examples include, but are not limited to, magnesium stearate and talc);

tablet binders (examples include, but are not limited to, acacia, alginic acid, sodium carboxymethylcellulose, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, uncrosslinked polyvinylpyrrolidone, and pregelatinized starch);

diluents for tablets and capsules (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, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate, and shellac);

excipients for direct compression of tablets (examples include, but are not limited to, dibasic calcium phosphate);

tablet disintegrants (examples include, but are not limited to, alginic acid, calcium carboxymethylcellulose, microcrystalline cellulose, potassium polacrilin, cross-linked polyvinylpyrrolidone, sodium alginate, sodium starch glycolate, and starch);

tablet lubricants (examples include, but are not limited to, colloidal silicon dioxide, 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 pigments (examples include, but are not limited to, titanium dioxide);

tablet polishes (examples include, but are not limited to, carnauba wax and white wax);

thickeners (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, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, sodium alginate, and tragacanth); and wetting agents (examples include, but are not limited to, heptadecaethyleneoxycetanol, lecithin, sorbitol monooleate, polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions in accordance with the present invention can be illustrated as follows:

Sterile iv solution: A 5 mg/ml solution of the objective compound of the present invention can be prepared using sterile injection water and pH adjusted if necessary. The solution is diluted for administration to 1-2 mg/ml with sterile 5% dextrose and administered as an intravenous infusion over approximately 60 minutes.

Lyophilized powder for intravenous administration: a sterile preparation can be prepared using (i) 100-1000 mg of the target compound of the present invention as a lyophilized powder, (ii) 32-327 mg/ml sodium citrate, and (iii) 300-3000 mg Dextran 40. The drug is reconstituted with sterile, injectable saline or 5% dextrose to a solution with a concentration of 10-20 mg / ml, which is further diluted with saline or 5% dextrose to 0.2-0.4 mg / ml, and injected either into / in a bolus, or in / infusion for 15-60 minutes.

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

mg/ml of the target, water-insoluble compound of the present invention;

mg/ml sodium carboxymethylcellulose;

mg/ml TWEEN 80;

mg/ml sodium chloride;

mg/ml benzyl alcohol.

Hard shell capsules: A large number of capsules are prepared by filling each standard double hard gelatin capsule with 100 mg of the powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules: Prepare a mixture of the active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil and inject using a positive displacement pump into softened gelatin to form soft gelatin capsules containing 100 mg

- 30 040608 active component. The capsules are washed and dried. The active ingredient may be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to form a water-miscible drug mixture.

Tablets: A large number of tablets are prepared according to conventional methods so that the dosage unit is 100 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. Suitable aqueous and non-aqueous coatings may be applied to increase palatability, enhance elegance and stability, or delay absorption.

Immediate release tablets/capsules: These are solid oral dosage forms produced by standard and novel processes. These units are taken orally without water for immediate release and delivery of the drug. The active ingredient is mixed in a liquid containing ingredients such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into solid tablets or caplets by freeze-drying and solid state extraction techniques. Drug compounds can be compressed with viscoelastic and thermoelastic sugars and polymers or effervescent components to form porous matrices designed for immediate release without the need to drink water.

Dose and Administration

Based on standard laboratory methods known to evaluate compounds useful in the treatment of disorders and/or diseases that are influenced by P2X4, using standard toxicity tests and standard pharmacological studies to determine treatment parameters for the conditions identified above in mammals, and by comparing these results with those of known drugs that are used to treat these conditions, the effective dosage of the compounds of the present invention for the treatment of each desired indication can be easily determined. The amount of active ingredient to be administered in the treatment of one of these conditions may vary widely according to such factors as the particular compound and dosage unit used, route of administration, period of treatment, age and sex of the patient being treated, and the nature and extent of the condition being treated. treatment.

The total amount of active ingredient to be administered will typically range from about 0.001 mg/kg to about 200 mg/kg of body weight per day. Clinically useful dosing regimens will range from dosing once to three times a day to dosing once every four weeks. In addition, drug holidays, during which the patient does not take the drug for a certain period of time, can be beneficial for the overall balance between pharmacological action and tolerability. A dosage unit may contain from about 0.5 mg to about 1500 mg of the active ingredient, and may be administered one or more times a day, or less than once a day. A preferred oral dosage unit for administering the compounds of the present invention includes, but is not limited to, the active ingredient in an amount of 0.1 mg/kg to about 10 mg/kg body weight administered from 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 the use of infusion techniques, will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosing regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosing regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily local dosing regimen will preferably be from 0.1 to 200 mg, which is applied once to four times a day. The transdermal concentration will preferably be such as is necessary to maintain a daily dose of 0.01 to 200 mg/kg. The average daily dosage regimen by inhalation will preferably be from 0.01 to 100 mg/kg of total body weight.

The clearly defined initial and ongoing dosing regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending diagnostician, the activity of the particular compound used, the age and general condition of the patient, the time of administration, route of administration, rate of elimination of the drug from the body, combinations of drugs funds, etc. The desired method of treatment and the number of doses of the compounds of the present invention or its pharmaceutically acceptable salt or ester or composition can be established by those skilled in the art using conventional methods of experimental treatment.

- 31 040608

Combination Therapy

The term combination in the present invention is used as known to those skilled in the art and can be represented as a fixed combination, a non-fixed combination, or a set of components.

The term fixed combination in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active ingredient and said second active ingredient are present together in a single dosage form or as a unit. One example of a fixed combination is a pharmaceutical composition in which said first active ingredient and said second active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a fixed combination is a pharmaceutical combination in which said first active ingredient and said second active ingredient are present in the same unit in an unmixed state.

The term non-fixed combination or set of components in the present invention is used as known to those skilled in the art and is defined as a combination in which said first active ingredient and said second active ingredient are present in more than one unit. One example of a non-fixed combination or set of components is a combination in which said first active ingredient and said second active ingredient are present separately. The components of a non-fixed combination or set of components can be entered separately, sequentially, simultaneously, in parallel, or chronologically displaced.

The compounds of the present invention may be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutical agents, where the combination does not cause unacceptable side effects. The present invention also relates to such combinations.

Such pharmaceutical agents administered in combination may be other agents having anti-proliferative, anti-nociceptive and/or anti-inflammatory effects, such as, for example, agents for the treatment of hematological tumors, solid tumors and/or their metastases, and/or agents for the treatment of various pain conditions. syndromes and/or unwanted side effects. The present invention also relates to such combinations.

Other antihyperproliferative agents suitable for use with the composition of the invention include, but are not limited to, compounds approved for use in the treatment of neoplastic diseases in Goodman and Gilman's The Pharmacological Basis of Therapeutics (ninth edition), ed. Molinoff et al., publ. McGraw-Hill, c. 1225-1287, (1996), which is incorporated herein by reference, especially (chemotherapeutic) anti-cancer agents as defined above.

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

In particular, the compounds of the present invention may be administered in combination or as concomitant preparations with hormonal contraceptives. Hormonal contraceptives can be administered by the 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.

PDAs include, but are not limited to, birth control pills or contraceptive methods that use a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic moiety in most PDAs is ethinyl estradiol. Some PDAs contain estradiol or estradiol valerate.

These PDAs contain the progestins norethinodrel, norethindrone, norethindrone acetate, ethinodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest or nomegestrol acetate.

Contraceptive pills include, for example, but not limited to, yasmin, jess, 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; belar and enrika containing ethinyl estradiol and chlormadinone acetate; claira preparation containing estradiol valerate and dienogest as active ingredients; and zoel containing estradiol and nomegestrol.

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

Anti-TB drugs include, but are not limited to, charozetta containing desogestrel; microlute containing levonorgestrel and micronor containing norethindrone.

Other progestin-only forms are intrauterine devices

- 32 040608 (VMU), such as the Mirena system containing levonorgestrel, or injectable forms, such as Depo-Provera, containing medroxyprogesterone acetate, or implants, such as Implanon, containing etonogestrel.

Other devices containing contraceptive hormones that are suitable for combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinylestradiol and etonogestrel or transdermal systems like contraceptive patches such as ortho-evra containing ethinylestradiol and norelgestromin. , or aplik (Lisvi), containing ethinylestradiol and gestodene.

A preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with COCs or POPs or other progestin-only forms, as well as in combination with vaginal rings or contraceptive patches as mentioned above.

In addition, the compounds of the present invention can be combined with therapeutic agents or active ingredients that are already approved or still under development for the treatment and/or prevention of diseases that are associated with or mediated by P2X4.

For the treatment and/or prevention of diseases of the urinary tract, the compounds of the present invention can be administered in combination or as concomitant preparations with any substance that can be used as a therapeutic agent in the following indications: painful conditions of the urinary tract, including conditions associated with obstruction of the outlet Bladder; urinary incontinence conditions such as reduced bladder capacity, increased frequency of urination, urge incontinence, stress urinary incontinence, or overreactive bladder; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms associated with overactive bladder, where these symptoms are, in particular, increased frequency of urination, nocturia, urge to urinate or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis; idiopathic bladder hypersensitivity; kidney disease such as hyperprostaglandin E syndrome, classic Bartter syndrome.

For the treatment and/or prevention of overactive bladder and symptoms associated with overactive bladder, the compounds of the present invention can be administered in combination or as concomitant drugs in addition to behavioral therapy like diet, lifestyle or bladder exercise, with anticholinergics, the likes of oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; β-3 agonists like mirabegron; neurotoxins like onabotulinumtoxin A; or antidepressants like imipramine, duloxetine.

For the treatment and/or prevention of interstitial cystitis, the compounds of the present invention can be administered in combination or as concomitant drugs 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 prevention of gynecological diseases, the compounds of the present invention can be administered in combination or as concomitant preparations with any substance that can be used as a therapeutic agent in the following indications: dysmenorrhea, including primary and secondary; dyspareunia; endometriosis; pain associated with endometriosis; symptoms associated with endometriosis, wherein said symptoms are, in particular, acute and chronic abdominal pain, dysmenorrhea, dyspareunia, dysuria or dyschezia.

For the treatment and / or prevention of dysmenorrhea, including primary and secondary; dyspareunia; endometriosis and pain associated with endometriosis, the compounds of the present invention can be administered in combination with an ovulation inhibiting treatment, in particular MDA, as mentioned above, or used in combination with contraceptive patches like Ortho-Evra or Aplik (Lisvi); or with progestogens like dienogest (Visan); or with GnRH analogous, in particular, to GnRH agonists and antagonists, such as, for example, leuprorelin, nafarelin, goserelin, cetrorelix, abarelix, ganirelix, degarelix; or with androgens: danazol.

For the treatment and/or prevention of diseases that are associated with pain or pain syndromes, the compounds of the present invention can be administered in combination or as concomitant preparations with any substance that can be used as a therapeutic agent for the following indications: pain-related 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 bone and sports injuries), neuri

- 33 040608 tu, neuralgia, poisoning, ischemic injury, interstitial cystitis, viral neuralgia, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and associated neuralgias induced by HIV and HIV treatment neuropathies.

The compounds of the present invention can be combined with other drugs and compounds that are intended for the treatment of inflammatory diseases, inflammatory pain or general pain conditions.

In addition to well-known drugs already approved and commercially available, the compounds of the present invention may be administered in combination with inhibitors of the purinergic P2X receptor family (e.g., P2X3 and P2X7), IRAK4 inhibitors, PTGES inhibitors, and prostanoid EP4 receptor antagonists. .

In particular, the compounds of the present invention can be administered in combination with drugs for the treatment of endometriosis, intended for the treatment of inflammatory diseases, inflammatory pain or general pain conditions and/or affecting endometrial proliferation and endometriosis-related symptoms, namely inhibitors of aldoketo- reductase 1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor.

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

In particular, the compounds of the present invention may be administered in combination with the following: 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, hexyl aminolevulinate, amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethion, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab, belotecan, bendamustine, belinostat, betrenbevacizumab, bicalutenamidumab bleomycin, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcium folinate, calcium levofolinate, capecitabine, capromab, carboplatin, carfilzomib, carmofur, carmustine, catumaxomab, celecoxib, celloleukin, ceritinib, cetuximab, chlormadinbucilone , cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofara bean, copanlisib, crisanthaspas, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabin, degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, dexrazoxane, dibrospidium chloride, dianhydrogalactitol, dotaclofenac, dotaclofenac, , doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, eculizumab, edrecolomab, elliptinium acetate, eltrombopag, endostatin, enocytabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, eptaplatin zeta, eptaplatin, eribulin, estramustine radio, estrameprazol, essomeprazole, essomeprazole , 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 , ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidas, glutoxim, GM- CSF, goserelin, granisetron, granulocyte colony stimulating factor, histamine dihydrochloride, gistrelin, hydroxyurea, grains I-125, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indiestron, incadronic acid, ingenol mebulate, interferon alfa, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, lanreotide, lapatinib, lasocholine, lenalidomide, lenograstim, lentinan, letrozole, leuprorelin, levamisol, levonorgrestel, levothyroxine sodium, lisuride , lobaplatin, lomustine, lonidamine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostan, mercaptopurine, mesna, methadone, methotrexate, methoxalene, methylaminolevulinate, methylprednisolone, methyltestosterone, metyrosine, mifamurtide, miltefosine, myriplatin, mitobronitol, mitobronitol, , mitotane, mitoxantrone, mogamulizumab, molgramostim, mopidamol, hydrochl Morphine oride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + pentazocine, naltrexone, nartograstim, nedaplatin, nelarabin, neridronic acid, nivolumabpentetreotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nitracrine, nivolumab, obinutuzumab, octreotide, ofatumumaxin mepesuccinate, omeprazole, ondansetron, oprelvekin, orgotein, orilotimod, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palifermin, palladium-103 grains, palonosetron, pamidronic acid, panitumumab, pantoprazole, pazopanib, pegaspargasa, peg-epoetin beta (Methoxy PEG-epoetin beta), pembrolizumab, pegfilgrastim, peginterferon alfa2b, pemetrexed, pentazocin, pentostatin, peplomycin, perflubutan, perfosfamide, pertuzumab, picibanil, pilocarpine, pyrarubicin, pixantrone, plerixafor, plicamycin, polyglusam, polyestradiol phosphate, polyvinyl pyrluronate sodium + hyaperlidone , polysaccharide-K, pomalidomide, ponatinib, sodium porfimer, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumumab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramosetron, ramucirumab, ranimustine, rasburicas, razoxan, refametinib, regorafenib, risedronic acid, etidronate

- 34 040608 rhenium-186, rituximab, romidepsin, romiplostim, romurtide, roniciclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, sipuleucel-T, sisofiran, sobuxane, sodium glycidazole, sorafenib, stanozolol, streptozocin, sunitinib, 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, thioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostan, triptorelin, trametinib, trofosfamide, thrombopoietin, tryptophan, valatinib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesin, vinflunin, vinorelbine, vismodegib, vorinostat, vorozol, yttrium-90 glass microspheres, zinos tatin, zinostatin stimalamer, zoledronic acid, zorubicin.

In addition, the compounds of the present invention can be combined with active ingredients that are well known for the treatment of cancer-related pain and chronic pain. Such combinations include, but are not limited to, stage II opioids like codeine phosphate, dextropropoxyphene, dihydrocodeine, tramadol, stage III opioids like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone, and hydromorphone; and other drugs used to treat cancer pain, like steroids such as dexamethesone and methylprednisolone; bisphosphonates like etidronate, clodronate, alendronate, risedronate and zoledronate; tricyclic antidepressants like amitriptyline, clomipramine, desipramine, imipramine and doxepin; class I antiarrhythmic drugs like mexiletine and lidocaine; anticonvulsants like carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, topiramate, alprazolam, diazepam, flurazepam, pentobarbital and phenobarbital.

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

The illustrative test experiments described herein serve to illustrate the present invention, and the invention is not limited to the examples given.

As will be clear to those skilled in the art, the invention is not limited to the specific embodiments described herein, but embraces all modifications of said embodiments that are within the spirit and scope of the invention as defined in the appended claims.

The following examples illustrate the invention in more detail, without limiting it. Further compounds in accordance with the invention, the preparation of which is not explicitly described, can be obtained in a similar way.

The compounds mentioned in the examples and their salts are preferred embodiments of the invention, as is the formula covering all subcombinations of residues of the compound of formula (I) as disclosed in the specific examples.

The term according to within the Experimental part is used in the sense that the specified methodology should be used by analogy.

Synthesis of compounds

The following schemes and general procedures illustrate the general routes for the synthesis of compounds of General formulas (I), (Ia) and (Ib) of the invention and are not intended to limit its scope. One skilled in the art will appreciate that the order of transformations exemplified in Schemes 1-5 can be modified in various ways. Thus, the order of transformations exemplified in Schemes 1-5 is not intended to be limiting. In addition, the interconversion of substituents, for example, residues R ¹ , R ² , R ^2a , R ^2b , R ^2c , R ^{3 , R 4} , R ⁵ , R ⁶ , R ^6a , R ^6b , R ^7a , ^{R 7b ,} R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ^11a or R ¹² can be carried out before and/or after the transformations given as examples. These modifications may be such as the introduction of protective groups, cleavage of protective groups, reduction or oxidation of functional groups, halogenation, metalation, substitution, or other reactions known to the person skilled in the art. These transformations include those reactions that introduce functions that allow additional interconversion of substituents. Suitable protecting groups and procedures for their introduction and cleavage are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley 1999).

All reagents used to prepare the compounds of the invention are commercially available, known in the literature, or can be prepared as described.

- 35 040608

Scheme 1: general procedures for the preparation of compounds of general formula (I) and general formula (Ia) corresponding to formula 6; R ¹ , R ^2a , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention; W corresponds to either an amino group with hydrogen and/or a protecting group PG (eg (dimethylamino)methylene, 2,4-dimethoxybenzyl); V corresponds to LG, chlorine or bromine; LG corresponds to the leaving group (eg, chlorine, fluorine, tosyl); R ² means a heteroaromatic system with a nucleophilic nitrogen (eg, pyrazole, imidazole, triazole) and experiences a nucleophilic aromatic substitution at this nitrogen atom.

Compounds of general formula 6 can be synthesized as shown in Scheme 1. A person skilled in the art is able to convert the sulfonyl chlorides 1 to the protected sulfonamides 2 and is able to select the PG protecting group which is suitable for the following steps. Examples of suitable PG protecting groups are 2,4-dimethoxybenzyl or (dimethylamino)methylene. In case V corresponds to an LG leaving group (e.g. fluoride, chloride, tosyl), compounds 2 can be converted by nucleophilic aromatic substitution reactions in a suitable solvent (e.g. acetonitrile) and in the presence of a suitable base (e.g. potassium carbonate, cesium carbonate, ...) with a heteroaromatic R ² H system containing a nucleophilic nitrogen (eg pyrazole, imidazole, triazole, ...) into compounds 3 to form a new CN bond. In case V corresponds to chlorine or bromine, compounds 3 can be prepared 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-tert-butyl(2',4',6'-triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl]-2-yl)phosphine/potassium phosphate/toluene). In the next step, the 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, catalysts based on Pd, Pt, Fe or Sn. Anilines 4 can be converted to the corresponding amides 5, for example, by reaction with acyl chlorides or by standard peptide bond formation using various known techniques, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent, for example, HATU. In the last step, the amides 5 are deprotected to give the desired sulfonamides 6. Deprotection conditions depend on the protecting group used (e.g. TFA/dichloromethane in the case of 2,4dimethoxybenzyl, or aqueous ammonia/methanol in the case of (dimethylamino)methylene).

- 36 040608

Scheme 2: general procedure for the preparation of compounds of general formula (I) and general formula (Ib) corresponding to formula 13; R ¹ , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention; W corresponds to either an amino group with hydrogen and/or a PG protecting group (eg (dimethylamino)methylene); Ar means aryl; R ² means a heteroaromatic system with a nucleophilic nitrogen (eg, pyrazole, imidazole, triazole) and experiences a nucleophilic aromatic substitution at this nitrogen atom.

Compounds of general formula 13 can be synthesized as shown in Scheme 2. One skilled in the art is able to convert the sulfonyl chlorides 7 to the protected sulfonamides 8 and is able to select the PG protecting group that is appropriate for the following steps.

An example of a suitable PG protecting group is (dimethylamino)methylene (reaction of sulfonyl chlorides 7 with ammonia, then reaction with 1,1-dimethoxy-N,N-dimethylmethanamine in DMF). Using protection and deprotection strategies, Buchwald amination of compounds 8 in the presence of suitable catalysts (see e.g. WO 2011120026A1) results in intermediates 9. Nucleophilic aromatic substitution reaction in a suitable solvent (e.g. acetonitrile) and in the presence of a suitable base ( e.g. potassium carbonate, ...) with a heteroaromatic R2H system that contains a nucleophilic nitrogen (e.g. pyrazole, imidazole, triazole, ...) leads to pyridines 10. Deprotection from 10 (under acidic conditions in the case of Y = -N =CAr ₂ ) is followed by the conversion of the resulting anilines 11 to amides 12, for example by reaction with acyl chlorides or by standard peptide bond formation using various known techniques such as the reaction of the corresponding carboxylic acids in the presence of a coupling reagent, for example HATU. In the last step, the amide 12 is deprotected to give the desired sulfonamides 13. Deprotection conditions depend on the protecting group used (eg aqueous ammonia/methanol in the case of (dimethylamino)methylene).

- 37 040608

Scheme 3: general procedures for the preparation of compounds of general formula (I) and general formula (Ia) corresponding to formula 20; R ¹ , R ^2a , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention, W corresponds to either an amino group with hydrogen and/or a PG protecting group (for example, (dimethylamino)methylene, 2,4-dimethoxybenzyl), R ² corresponds to an optionally substituted oxadiazolyl.

Compounds of general formula 20 can be synthesized as shown in Scheme 3. Starting from protected benzenethiols 14 (PG: e.g. benzyl, benzoyl), where V = COOH, substituents 1,3,4-oxadiazol2-yl- and -oxadiazol-5-yl- can be obtained from the carboxy group using methods known to the person skilled in the art (see, for example, WO 2011/028741). The conversion of protected benzenethiols 15 to benzenesulfonyl chlorides 16 can be carried out by oxidation in a protic solvent, for example, N-chlorosuccinimide in acetic acid or chlorine gas in a carbon tetrachloride/water mixture. The corresponding sulfonamides 17 can be prepared from intermediates 16 by reacting ammonia or any amine in aprotic solvents such as dichloromethane and acetonitrile. Subsequent reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran, in the presence of, for example, catalysts based on Pd, Pt, Fe or Sn, leads to aniline derivatives with the general formula 18. Subsequent acylation to the corresponding amides can be carried out, for example , by reaction with acyl chlorides, or by standard peptide bond formation using all sorts of known techniques, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent, for example, HATU. In the case of W, denoting a protected amino function, subsequent deprotection, for example, with trifluoroacetic acid (TFA), leads to compounds of general formula 20.

Alternatively, starting from intermediates 14 where V = CN, the oxidation to benzenesulfonyl chlorides 21 can be performed in the presence of a nitrile in a protic solvent, eg N-chlorosuccinimide in acetic acid or chlorine gas in carbon tetrachloride/water. The corresponding sulfonamides 22 can be prepared from intermediates 21 by reacting ammonia or any amine in aprotic solvents such as dichloromethane and acetonitrile. In a subsequent step, the nitrile group of intermediates 22 can be converted to sulfonamides 17 with a 1,2,4-oxadiazol-2-yl-substituent using methods known to the person skilled in the art (see, for example, WO 2011/028741).

- 38 040608

I 30a:V-Br ----- 27: W= NHPG/NPG _r nv-Rin^ deprotection

31.VB(OZ) _{2l_} 28:W=NH ₂

Scheme 4: general procedures for the preparation of compounds of general formula (I) and general formula (Ia) corresponding to formula 28; R ¹ , R ² , R ^2a , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention, B(OZ) ₂ corresponds to B(OH) ₂ or B(O ₂ C ₆ H ₁₂ ) or a mixture of both, and W corresponds to either an amino group with hydrogen and/or a PG protecting group (eg (dimethylamino)methylene, 2,4-dimethoxybenzyl).

Compounds of general formula 28 can be synthesized as shown in Scheme 4. Starting from the corresponding sulfonyl chlorides 23 (where V is either bromide or chloride), C-linked aryl and heteroaryl derivatives can be prepared using, for example, Suzuki cross-coupling reactions known to those skilled in the art. this field of technology. The conversion of the protected sulfonamides 24 to aryl/heteroaryl compounds of general formula 25 can be carried out by reaction with the appropriate boronic acid (or ester or mixture of both) under palladium catalyzed conditions in protic (eg, isopropanol) or aprotic solvents. The corresponding amines 26 can be obtained from intermediates 25 by reduction under hydrogenation conditions, in polar solvents such as ethanol or tetrahydrofuran, in the presence of, for example, catalysts based on Pd, Pt, Fe or Sn. Subsequent acylation to the corresponding amides 27 can be carried out, for example, by reaction with acyl chlorides or by standard peptide bond formation using various known techniques, such as the reaction of the corresponding carboxylic acid in the presence of a coupling reagent, for example, HATU. In the case of W denoting a protecting group, subsequent deprotection with, for example, trifluoroacetic acid (TFA) results in compounds of general formula 28.

Alternatively, starting from intermediates 24 where 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, leads to the formation of amines 29. The corresponding amides 30a can be prepared by reaction with acyl chlorides or by standard peptide bond formation using various known techniques. Subsequent arylation/heteroarylation using, for example, palladium-catalyzed cross-coupling reactions provides access to intermediates 27. Alternatively, bromides 30a can be converted to the corresponding boronic acids/esters intermediates 31 (B(OZ) ₂ = B(OH) ₂ or B(O ₂ C ₆ H ₁₂ )) and then subjected to transformation using, for example, palladium catalysis, known to a person skilled in the art, to obtain intermediate compounds 27, which, after deprotection, lead to the final products with the general formula 28.

- 39 040608

acylation / peptide combination

Scheme 5: general procedure for the preparation of compounds of general formula (I) and general formula (Ib) corresponding to formula 35; R ¹ , R ² , R ^2b , R ^2c , R ³ , R ⁴ are as defined in the description and claims of the present invention, W corresponds to either an amino group with hydrogen and/or a PG protecting group (for example, (dimethylamino)methylene, 2,4-dimethoxybenzyl); Ar means aryl.

Compounds of general formula 35 can be synthesized as shown in Scheme 5. Starting from intermediate 9, C-linked aryl and heteroaryl derivatives 32 can be prepared by, for example, palladium-catalyzed cross-coupling reactions, such as Suzuki reactions, known to those skilled in the art. (See, for example, US 20110281865). Deprotection, for example, under acidic conditions, leads to the formation of amines 33. Subsequent acylation to the corresponding amides can be carried out, for example, by reaction with acyl chlorides or by standard peptide bond formation using various known methods, such as the reaction of the corresponding carboxylic acid in the presence of coupling reagent, for example, HATU. In the case of W, denoting a protected amino function, subsequent deprotection (for example, with an aqueous solution of ammonia in the case of a (dimethylamino)methylene group as a protective one), leads to compounds of general formula 35.

Scheme 6: general procedure for the preparation of compounds of formula 30a; R ¹ , R ³ and R ⁴ are as defined in the description and claims of the present invention, R ^2a , R ^2b and R ^2c are hydrogen, W corresponds to either an amino group with hydrogen and/or a PG protecting group (e.g. (dimethylamino) methylene, 2,4-dimethoxybenzyl).

Compounds of general formula 30a can be synthesized as shown in Scheme 6. Starting from the corresponding aniline 36, bromination (for example, with NBS in DMF) leads to bromaniline 37. Subsequent acylation to the corresponding amides 38 can be carried out, for example, by reaction with acyl chlorides or by standard peptide bond formation using various known techniques, such as reaction of the corresponding carboxylic acid in the presence of a coupling reagent, for example, HATU. Subsequent protection of the sulfonamide moiety (e.g., 1,1-dimethoxy-N,N-dimethylmethanamine in DMF) results in protected amides 30a, which can then be further converted, e.g., using Suzuki chemistry as described in Scheme 4.

Scheme 7: general procedure for the preparation of compounds of general formula (I) and general formula (Ia) corresponding to formula 42; R ¹ , R ^2a , R ^2b , R ^2c , R ³ and R ⁴ are as defined in the description and claims of the present invention, W corresponds to either an amino group with hydrogen and/or a protective

- 40 040608 group PG (for example, (dimethylamino)methylene, 2,4-dimethoxybenzyl).

Compounds of general formula 42 can be synthesized as shown in Scheme 7. After protecting the sulfonamide moiety of bromopyrazoles 39 (for example, with a (dimethylamino)methylene group), they can be converted, for example, using Suzuki cross-coupling reactions known to a person skilled in the art, to compounds 41. In the case of W, denoting a protective group, subsequent deprotection, for example, aqueous ammonia in alcohol (for example, methanol, ethanol, propanol) leads to compounds of general formula 42.

44

Scheme 8: general procedures for the preparation of compounds of general formula (I) and general formula (Ia) corresponding to formula 44; R ¹ , R ^2a , R ^2b , R ^2c , R ³ , R ⁴ , R ⁹ and R ¹⁰ are as defined in the description and claims of the present invention.

Compounds of general formula 44 can be synthesized as shown in Scheme 8. Carboxylic acid esters 43 can be converted to the corresponding amides 44 either by direct transamidation (e.g. with a Lewis acid like bis-(trimethylaluminum)-1,4-diazabicyclo[2.2.2 ]-octane (DABAL-Me ₃ ) in THF), or by sequential hydrolysis and amidation procedures known to those skilled in the art.

In addition, exemplary 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 those skilled in the art. These can be, for example, fluorination, difluoromethylation, trifluoromethylation, cyanation, methoxylation, oxidation or alkylation reactions (for examples of oxidation see Org. Lett. 2015, 17, 6066-6069, Adv. Synth. Cat al. 2004, 346, 171184 , 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, for example by distilling off the solvent in vacuo and recrystallizing the resulting residue from a suitable solvent, or by subjecting the residue to one of the usual purification methods such as chromatography on a suitable support material. In addition, reverse phase preparative HPLC of compounds of the present invention which have sufficient basic or acidic functionality can lead to the formation of a salt such as, in the case of a compound of the present invention which is sufficiently basic, such as trifluoroacetate or formate, or, in the case of a compound of the present invention which is sufficiently acidic, for example an ammonium salt. A salt of this type can either be converted to its free base form or free acid form, respectively, by various methods known to the person skilled in the art, or directly used as such in subsequent biological assays. In addition, the drying process during isolation of the compounds of the present invention may not completely remove traces of co-solvents, especially such as formic acid or trifluoroacetic acid, resulting in solvates or inclusion complexes. One skilled in the art will determine which solvates or inclusion complexes are suitable for use in subsequent biological assays. It should be understood that the specific form (e.g., salt, free base, solvate, inclusion complex) of a compound of the present invention isolated as described herein is not necessarily the only form in which said compound can be used in a biological assay to quantify a specific biological activity.

Salts of compounds of formulas (I), (Ia) and (Ib) according to the invention can be obtained by dissolving the free compound in a suitable solvent (for example, a ketone such as acetone, methyl ethyl ketone or methyl isobutyl ketone, 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 added afterwards. An acid or base can be used to form the salt, depending on whether a mono- or polybasic acid or a mono- or polyacid base is of interest, and depending on the salt desired, in an equimolar ratio or different from it. Salts are obtained by filtration, reprecipitation, precipitation with a salt precipitator, or by evaporation of the solvent. The resulting salts can be converted to free compounds, which in turn can be converted to salts. In this way, pharmaceutically unacceptable salts, which can be obtained, for example, as process products in industrial scale production, can be converted into pharmaceutically acceptable salts using methods known to the person skilled in the art.

- 41 040608 of this field of technology. Especially preferred are the hydrochlorides and the method used in the Examples section.

Pure diastereomers and pure enantiomers of the compounds and salts according to the invention can be obtained, for example, by asymmetric synthesis, by using chiral starting compounds in the synthesis, and by separating enantiomeric and diastereomeric mixtures obtained in the synthesis.

Enantiomeric and diastereomeric mixtures can be separated into pure enantiomers and pure diastereomers using methods known to those skilled in the art. Preferably, the diastereomeric mixtures are separated by crystallization, in particular fractional crystallization, or chromatography. Enantiomeric mixtures can be separated, for example, by forming diastereomers with a chiral auxiliary agent, separating the resulting diastereomers and removing the chiral auxiliary agent. As chiral auxiliaries, for example for separating enantiomeric bases, chiral acids such as, for example, mandelic acid can be used, and for separating enantiomeric acids, chiral bases can be used, the separation being ensured by the formation of diastereomeric salts. In addition, diastereomeric derivatives such as diastereomeric esters can be obtained from mixtures of alcohol enantiomers or mixtures of acid enantiomers, respectively, using chiral acids or chiral alcohols, respectively, as chiral auxiliaries. In addition, diastereomeric complexes or diastereomeric clathrates can be used to separate enantiomeric mixtures. Alternatively, enantiomeric mixtures can be separated using chiral separating columns for chromatography. Another suitable method for isolating enantiomers is enzymatic separation.

One preferred aspect of the invention is a process for the preparation of compounds of general formula (I), (Ia) or (Ib), or N-oxides, salts, tautomers or stereoisomers of said compounds, or salts of said N-oxides, tautomers or stereoisomers, according to the examples , as well as intermediate compounds used to obtain them.

Optionally, compounds of formulas (I), (Ia) and (Ib) can be converted into their salts, or optionally salts of compounds of formulas (I), (Ia) and (Ib) can be converted into free compounds. Appropriate methods are common to a person skilled in the art.

experimental part

Abbreviations.

The following table lists the abbreviations used in this section and in the Intermediate Examples and Examples sections, as they are not explained in the main text.

Reduction Meaning ASON acetic acid (ethanoic acid) aq. water bos from/?eot-butoxycarbonyl br wide CI chemical ionization d doublet DAD diode array detector DBU 1,8-diazabicyclo(5.4.0)undec-7-ene DXM dichloromethane dd double doublet

- 42 040608

DIPEA diisopropylethylamine DMF A, A-dimethyl formamide DMSO dimethyl sulfoxide ELSD evaporative light scattering detector EtOAc ethyl acetate EtOH ethanol equiv. equivalent ESI electrospray (ES) ionization HATU hexafluorophosphate 1- [bis(dimethylamino)methylene]- 1H-1,2,3 triazolo[4,5-b]pyridinium 3-oxide HPLC high performance liquid chromatography LC-MS liquid chromatography - mass spectrometry GP multiplet MeCN acetonitrile Meon methanol MS mass spectrometry MTVE methyl ot/?et-butyl ether NMR nuclear magnetic resonance spectroscopy: chemical shifts (δ) are given in ppm. Chemical shifts were corrected by setting the DMSO signal to 2.50 ppm unless otherwise noted. PDA photodiode array PoraPak™ HPLC column available from Waters q quartet k.t. or CT room temperature Rt retention time (as measured by either HPLC or UHPLC) in minutes S singlet IV starting material SQD single quadrupole detector t triplet td triplet doublet dt doublet triplet TEA triethylamine THF tetrahydrofuran UHPLC ultra-high efficiency liquid chromatography

Other abbreviations have meanings as such common to a person skilled in the art.

The various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

Special Descriptions of Experiments

The NMR peak shapes in the following special descriptions of experiments are given as they appear in the spectra, possible higher order effects are not considered. Reactions that required microwave irradiation can be performed using a Biotage Initator® microwave oven, optionally equipped with a robotic unit. The reported reaction time in the case of using heating should be understood as a fixed reaction time after reaching the specified reaction temperature. Compounds and intermediates prepared according to the methods of the invention may require purification. Methods for purifying organic compounds are well known to the person skilled in the art, and there may be several methods for purifying the same compound. In some cases, cleaning may not be required. In some cases, compounds can be purified by crystallization. In some cases, for

- 43 040608 Contaminants can be removed using a mixing technique in a suitable solvent. In some cases, compounds can be purified by chromatography, in particular flash column chromatography, using e.g. pre-filled silica gel cartridges e.g. from Separtis, such as Isolute® Flash silica gel or Isolute® Flash NH2 silica gel, in combination with Isolera® Auto Cleaner (Biotage) and eluents such as gradients such as hexane/ethyl acetate or DCM/methanol. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters auto-purifier equipped with a diode array detector and/or an electrospray on-line ionization mass spectrometer in combination with a suitable reverse phase prepacked column and eluents such as gradients. 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 compounds of the present invention that have sufficient basic or acidic functionality, in salt form, such as in the case of a compound of the present invention that is sufficiently basic, such as trifluoroacetate or formate, or, in the case of a compound of the present invention which is sufficiently acidic, such as an ammonium salt. A salt of this type can either be converted to its free base form or free acid form, respectively, by various methods known to the person skilled in the art, or directly used as such in subsequent biological assays. It should be understood that the particular form (e.g., salt, free base, etc.) of a compound of the present invention isolated as described herein is not necessarily the only form in which said compound can be used in a biological assay to quantify a specific biological activity.

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

For a better understanding of this invention, the following examples are given. These examples are for illustrative purposes only, and should not be construed as limiting the scope of the invention in any way. All publications mentioned in this specification are incorporated by reference in their entirety.

Analytical LC-MS and UHPLC-MS conditions.

Data regarding LC-MS and UHPLC-MS given in the following specific experimental descriptions refer (unless otherwise indicated) to the following conditions.

Method A.

Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 199% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.

Method B.

Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol.% aqueous ammonia solution (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 VEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0-4.5 min 1-99% B, 4.5-5.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method D

Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol.% aqueous ammonia solution (32%), eluent B: acetonitrile; gradient: 0-4.5 min 5-95% B, 4.5-5.0 min 95% B; flow 0.8 ml/min; temperature: 50 °C; DAD scan: 210-400 nm.

Method E.

Instrument: Waters Acquity UPLCMS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.1 vol.% trifluoroacetic acid, eluent B: acetonitrile; gradient: 0-4.5 min 5-95% B, 4.5-5.0 min 95% B; flow 0.8 ml/min; temperature: 50 °C; DAD scan: 210-400 nm.

Method F (chiral HPLC).

Instrument: Agilent HPLC 1260; column: Chiralpak IB 3 µm 100x4.6 mm; eluent A: hexane + 0.1 vol.% diethylamine (99%), eluent B: ethanol; isocratic mode: 70% A + 30% B; flow 1.0 ml/min; temperature: 25°C; injected volume: 5 μl; DAD @ 254 nm.

- 44 040608

Method G

Instrument: Agilent UHPLC 1290 SingleQuad; column: Phenomenex Kinetex C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol.% trifluoroacetic acid (99%), eluent B: acetonitrile; gradient: 0-4.5 min 5-95% B, 4.5-5.0 min 95% B; flow 0.8 ml/min; temperature: 50 °C; DAD @ 254 nm.

Method N.

Instrument: Agilent: 1260, Aurora SFC-Modul; column: Luna Hilic 5 µm 100x4.6 mm; eluent A: CO ₂ , eluent B: methanol + 0.5 vol.% ammonia (32%); isocratic: 20% B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 254 nm.

Method I

Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 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°C; DAD scan: 210-400 nm.

Method J

Instrument: Waters Acquity UPLC-MS SingleQuad; column: Acquity UPLC VEN C18 1.7 µm, 50x2.1 mm; eluent A: water + 0.2 vol.% aqueous ammonia solution (32%), eluent B: methanol; gradient: 0-1.6 min 199% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60°C; DAD scan: 210-400 nm.

Method K.

Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5 µm 100x4.6 mm; eluent A: CO ₂ , eluent B: methanol + 0.2 vol.% diethylamine (99%); isocratic: 28% B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 254 nm.

Method L

Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5 µm 100x4.6 mm; eluent A: CO ₂ , eluent B: ethanol + 0.2 vol.% aqueous ammonia solution (32%); isocratic: 29% B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 220 nm.

Method M.

Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5 µm 100x4.6 mm; eluent A: CO ₂ , eluent B: methanol + 0.2 vol.% diethylamine (99%); isocratic: 28% B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 254 nm.

Method N.

Instrument: Agilent: 1260, Aurora SFC-Modul; column: Chiralpak IA 5 µm 100x4.6 mm; eluent A: CO ₂ , eluent B: methanol; isocratic: 21% B; flow 4.0 ml/min; temperature: 37.5°C; BPR: 100 bar; MWD @ 254 nm.

Method O.

Instrument: Agilent: 1260, Aurora SFC-Modul; column: YMC Cellulose SC 3 µm 100x4.6 mm; eluent A: hexane + 0.1 vol.% diethylamine (99%), eluent B: ethanol; isocratic: 10% B; flow 1.0 ml/min; temperature: 25°C; DAD @ 254 nm.

Flash column chromatography conditions

Purification by (flash) column chromatography, as indicated in the following specific experimental descriptions, refers to the use of the Biotage Isolera purification system. For technical specifications, see the Biotage product catalog at www.biotage.com.

General methods of experiments.

General methodology GP 1.1.

Sulfonamide A (for example, on a scale of 1.29 mmol) was dissolved in acetonitrile (10 ml in the case of a scale of 1.29 mmol) and cesium carbonate (1.0 eq.) and the appropriate nucleophile (1.0 eq.) were added. Stirring was continued at 110° C. until TLC showed consumption of starting material. The solvent was removed under reduced pressure, followed by the addition of water and dichloromethane. The phases were then separated, the organic phase was dried and concentrated in vacuo. The crude product was either used without further purification or purified as described in the examples.

General methodology GP1.2.

Sulfonamide A (for example, 1.29 mmol) was dissolved in acetonitrile (15 ml in the case of a scale of 1.29 mmol) and finely ground potassium carbonate (3.0 eq.) and the corresponding azole (1.5 eq.) were added. Stirring was continued at 100-110°C until TLC showed the consumption of the product

- 45 040608 new substance. The solvent was removed under reduced pressure, followed by the addition of water and dichloromethane. The phases were then separated, the organic phase was dried and concentrated in vacuo. The crude product was either used without further purification or purified as described in the examples.

General methodology GP2.1.

The crude nitro compound B (e.g., 1.29 mmol) was dissolved in dioxane (15 ml in the case of a scale of 1.29 mmol) and tin(II) chloride dihydrate (3.0 eq.) was added and the reaction mixture was stirred for 2 h at 70°C. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The filtrate was either used without further purification or purified as described in the examples.

General methodology GP2.2.

The crude nitro compound B (e.g., 1.29 mmol) was dissolved in dioxane (15 ml in the case of a scale of 1.29 mmol) and tin(II) chloride dihydrate (5.0 eq.) was added and the reaction mixture was stirred for 2 h at 70°C. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The filtrate was either used without further purification or purified as described in the examples.

General methodology GP2.3.

The crude nitro compound B (eg 1.29 mmol) was dissolved in methanol (15 ml in case of 1.29 mmol scale) and Pd/C was added (load 10%, 50 mg). The flask was evacuated three times and filled 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 product was used without further purification.

General methodology GP2.4.

The crude nitro compound B (eg 1.29 mmol) was dissolved in methanol/dioxane (15 ml in case of 1.29 mmol scale) and Pd/C was added (load 10%, 50 mg). The flask was evacuated three times and filled 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 product was used without further purification.

General methodology GP2.5.

The crude nitro compound B (eg 1.29 mmol) was dissolved in methanol/dioxane (15 ml in case of 1.29 mmol scale) and Pt/C was added (load 10%, 50 mg). The flask was evacuated three times and filled 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 product was used without further purification.

General methodology GP3.1.

Crude substituted aniline C (e.g. 1.29 mmol) was dissolved in dimethylformamide (6 ml in the case of a scale of 1.29 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), K,K-diisopropylethylamine (4.5 eq. in terms of acid) and HATU (1.5 equiv. in terms of acid). The reaction mixture was either stirred overnight at room temperature or heated at 50° C. until TLC showed consumption of the starting material. After cooling to room temperature, the reaction mixture was concentrated in vacuo. added

- 46 040608 If ethyl acetate and water, the organic phase was dried and concentrated in vacuo. The crude product was used without further purification.

General methodology GP3.2.

Crude substituted aniline C (1.29 mmol) was dissolved in dimethylformamide (10 ml in the case of a scale of 1.29 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (2.7 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was either stirred overnight at room temperature or heated at 50° C. until TLC showed consumption of the starting 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 product was used without further purification.

General methodology GP3.3.

Crude substituted aniline C (1.29 mmol) was dissolved in dimethylformamide (10 ml in the case of a scale of 1.29 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (2.7 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was either stirred overnight at room temperature or heated at 50° C. until TLC showed consumption of the starting 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 product was used without further purification.

General methodology GP3.4.

Crude substituted aniline C (1.29 mmol) was dissolved in dimethylformamide (10 ml in the case of a scale of 1.29 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (2.0 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was either stirred overnight at room temperature or heated at 50° C. until TLC showed consumption of the starting 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 product was used without further purification.

General methodology GP3.5.

Crude substituted aniline C (1.29 mmol) was dissolved in dimethylformamide (10 ml in the case of a scale of 1.29 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (4.0 eq. in terms of acid) and HATU (1.3 equiv. in terms of acid). The reaction mixture was either stirred overnight at room temperature or heated at 50° C. until TLC showed consumption of the starting 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 product was used without further purification.

General methodology GP4.1.

The crude amide D (e.g. 1.29 mmol) was dissolved in dichloromethane (5-10 ml in the case of a scale of 1.29 mmol), 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 product and the organic phase was dried and the solvent was removed under reduced pressure. The resulting residue was purified as described in the examples. Purification without extraction with water was also possible, but made HPLC purification more difficult.

General methodology GP4.2.

Crude amide D (e.g. 1.29 mmol) was dissolved in dichloromethane/trifluoroacetic acid 2/1 (6 ml in the case of 1.29 mmol scale) and the reaction mixture was stirred at room temperature until TLC indicated consumption of the starting material. The reaction mixture was concentrated in vacuo, ethyl acetate and water were added to the crude product, and the organic phase was dried and

- 47 040608 the solvent was removed under reduced pressure. The resulting residue was purified as described in the examples. Purification without extraction with water was also possible, but made HPLC purification more difficult.

General methodology GP4.3.

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

sn ₃

^C E

General methodology GP5.1.

Solutions of substituted aniline С (0.20 mmol in 0.4 ml of 1-methyl-2-pyrrolidone), the corresponding acid (0.40 mmol in 0.8 ml of 1-methyl-2-pyrrolidone), HATU (0.40 mmol in 0.8 ml of 1-methyl-2 -pyrrolidone), N-methylmorpholine (0.80 mmol in 0.267 ml of 1-methyl-2-pyrrolidone containing 2.5% 4-dimethylaminopyridine) and shaken overnight. Then, the reaction mixture was concentrated in vacuo and the residue was redissolved in a mixture of triperoxonane acid/dichloromethane 3/1 (2 ml containing 5% water). The reaction mixture was shaken again overnight followed by concentration in vacuo and purification by HPLC.

General methodology GP5.2.

Solutions of substituted aniline C (0.20 mmol in 0.8 ml of 1,2-dichloroethane) and HATU (0.40 mmol in 0.8 ml of 1,2-dichloroethane) were combined and the corresponding acid (0.40 mmol) and N,Ndiisopropylethylamine (103 mg, 0.80 mmol) were added followed by shaking overnight. Then, the reaction mixture was concentrated in vacuo and the residue redissolved in trifluoroacetic acid (1 ml containing 5% water). The reaction mixture was shaken again overnight followed by concentration in vacuo and purification by HPLC.

^F E

General methodology GP6.1.

Crude substituted aniline F (0.137 mmol) was dissolved in dimethylformamide (2 ml in the case of a scale of 0.137 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (2.7 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. Ethyl acetate and water were added, the organic phase was dried and concentrated in vacuo.

The crude product was redissolved in methanol (1 ml), treated with concentrated aqueous ammonia (70 μl) and stirred overnight. The reaction mixture was concentrated in vacuo and purified as described in the examples.

General methodology GP6.2.

Crude substituted aniline F (amount as indicated in the examples) in NMP (0.4 ml) was added to the corresponding acid (2 eq.) followed by the addition of HATU (2 eq.) in NMP (0.8 ml) and Nmethylmorpholine (4 eq.) in NMP (0.27 ml containing 2.5% 4-dimethylaminopyridine). The reaction mixture was shaken overnight. Then methanol (1 ml) and aqueous concentrated solution were added.

- 48 040608 solution of ammonia (2 ml) followed by shaking at room temperature for 4 days. Purification by HPLC provided the target compound E.

General methodology GP6.3.

Crude substituted aniline F (0.137 mmol) was dissolved in dimethylformamide (2 ml in the case of a scale of 0.137 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (2.0 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. Ethyl acetate and water were added, the organic phase was dried and concentrated in vacuo.

The crude product was redissolved in methanol (2 ml), treated with concentrated aqueous ammonia (1 ml) and stirred overnight. The reaction mixture was concentrated in vacuo and purified as described in the examples.

General methodology GP6.4.

Crude substituted aniline F (0.137 mmol) was dissolved in dimethylformamide (2 ml in the case of a scale of 0.137 mmol) followed by the addition of the appropriate acid (amount as indicated in the examples), N,N-diisopropylethylamine (1.5 eq. in terms of acid) and HATU (1.0 equiv. in terms of acid). The reaction mixture was stirred overnight at room temperature, followed by concentration in vacuo. Dichloromethane and water were added, the organic phase was dried and concentrated in vacuo.

The crude product was redissolved in methanol (2 ml), treated with concentrated aqueous ammonia (1 ml) and stirred overnight. The reaction mixture was concentrated in vacuo and purified as described in the examples.

General procedure GP7.1.

Methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxylate (amount as indicated in the examples) was dissolved in THF (2 ml in the case of a scale of 0.22 mmol ) and the vial was filled with argon. The appropriate amine (2.5 eq.) was added followed by bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (DABAL-Me ₃ , 3 eq.). The reaction mixture was stirred overnight at room temperature, quenched with 1M HCl and extracted with ethyl acetate. The organic phases were washed with brine, dried over sodium sulfate, concentrated in vacuo and purified as described in the examples.

General procedure GP8.1.

N-(4-Bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (amount as indicated in the examples) was dissolved in methanol (1.5 ml in the case of a scale of 0.33 mmol) and degassed with nitrogen. Bis(pinacolato)diboron (2.5 eq.), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'amino-1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3, 0.05 equiv.) and N,N-diisopropylethylamine (2.5 equiv.), and the reaction mixture was stirred for 1 h at 50°С. The catalyst was removed by filtration and the volume of the filtrate was reduced in vacuo.

The crude product was redissolved in n-propanol (1.5 ml in the case of a scale of 0.33 mmol) followed by degassing with nitrogen. The corresponding hetaryl bromide (2 equiv.), potassium fluoride (0.23 equiv.), bis(tri-tert-butylphosphine)palladium(0) (0.05 equiv.), and triphenylphosphine (0.05 equiv.) were added. The reaction mixture was again degassed with nitrogen and potassium phosphate (2.5 equiv.) was added, followed by irradiation for 1 h at 100°C in a microwave oven. The reaction mixture was concentrated in vacuo and extracted with water/dichloromethane. The organic phases were washed with brine, dried over sodium sulfate, concentrated in vacuo and purified as described in the examples.

General procedure GP8.2.

N-(4-Bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (amount as indicated in the examples) was dissolved in methanol (3 ml in the case of a scale of 0.59 mmol) and degassed azo

- 49 040608 vol. Bis(pinacolato)diboron (2.5 equiv.), mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2'-amino1,1'-biphenyl)]palladium(II) (cataCXium® A Pd G3, 0.05 equiv.) and N,N-diisopropylethylamine (2.5 equiv.), and the reaction mixture was stirred for 1 h at 50°С. The catalyst was removed by filtration and the volume of the filtrate was reduced in vacuo.

The crude product was redissolved in n-propanol (3 ml in the case of a scale of 0.59 mmol) followed by degassing with nitrogen. The corresponding hetaryl bromide (2 equiv.), potassium fluoride (0.23 equiv.), bis(tri-tert-butylphosphine)palladium(0) (0.05 equiv.), and triphenylphosphine (0.05 equiv.) were added. The reaction mixture was again degassed with nitrogen and potassium phosphate (2.5 equiv.) was added, followed by irradiation for 1 h at 100°C in a microwave oven.

Any precipitate that formed was removed by filtration and the filtrate was concentrated in vacuo and redissolved in methanol (2 ml on a scale of 0.59 mmol). Aqueous ammonium hydroxide solution (33%, 2 ml) was added. The reaction mixture was stirred until UPLC-MS showed complete deprotection. In most cases, stirring overnight was sufficient, however, in some cases, longer stirring and the addition of additional aqueous ammonium hydroxide solution was required. The reaction mixture was then concentrated in vacuo and purified as described in the examples.

Synthesis of intermediates

Intermediate 1.

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

To a solution of 2-chloro-5-nitrobenzenesulfonyl chloride (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 the addition of water (75 ml) and ethyl acetate (75 ml). After stirring for 10 min, the resulting precipitate was separated by filtration and dried at 40° C. overnight under vacuum to give the title compound (14.1 g, 36.5 mmol, 86% yield).

LC-MS (method A): Rt = 1.17 min; MS (ESI negative): m/z = 385 [M-H] ^- .

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

Intermediate 2.

N-(2,4-Dimethoxybenzyl)-2-fluoro-5-nitrobenzenesulfonamide

N-ethyl-N-isopropylpropan-2-amine (1.29 g, 10.0 mmol) was added to a solution of 1-(2,4-dimethoxyphenyl)methanamine (0.669 g, 4.00 mmol) in dichloromethane (40 mL) under ice-cooling. A solution of 2-fluoro-5-nitrobenzenesulfonyl chloride (0.958 g, 4.00 mmol) in dichloromethane (10 ml) was added slowly over 25 min. Stirring was continued under ice-cooling for 2 hours followed by stirring at room temperature overnight. The reaction mixture was washed with water, dried over sodium sulfate and concentrated in vacuo. Column chromatography on a Biotage Isolera system (silica gel, n-hexane/ethyl acetate gradient) gave the title compound (400 mg, 1.08 mmol, 27% yield, 70% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI negative): m/z = 369 [M-H] ^- .

Intermediate 3.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]benzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (5.69 g, 14.7 mmol) in ace

- 50 040608 tonitrile (170 ml) was added 4-(trifluoromethyl)-1H-pyrazole (3.00 g, 22.1 mmol) and powdered potassium carbonate (6.09 g, 44.1 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate. Concentration under reduced pressure gave the title compound crude (7.50 g, quant., approx. 95% pure), which was used without further purification in the next step.

LC-MS (method B): Rt = 1.31 min; MS (ESI positive): m/z = 487 [M+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.52 (s, 3H), 3.64 (s, 3H), 4.15 (d, 2H), 6.18 (d, 1H), 6.29 ( dd, 1H), 7.08 (d, 1H), 7.93 (d, 1H), 8.03-8.09 (m, 1H), 8.25 (d, 1H), 8.39 (s, 1H), 8.49 (dd, 1H), 8.94 (s, 1H).

Intermediate 4.

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

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (5.03 g, 13.0 mmol) in acetonitrile (150 mL) was added 4-chloro-1N-pyrazole (2.00 g, 19.5 mmol) and powdered carbonate potassium (5.39 g, 39.0 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The organic phase was washed with brine and dried. Concentration in vacuo gave the title compound crude (6.27 g, quant., ca. 95% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 453 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.48 (s, 3H), 3.62 (s, 3H), 4.15 (s, 2H), 6.14 (d, 1H), 6.27 ( dd, 1H), 7.08 (d, 1H), 7.84 (d, 1H), 8.05 (s, 1H), 8.09 (d, 1H), 8.21 (d, 1H), 8.45 (dd, 1H), 8.57 (s , 1H).

Intermediate 5.

N-(2,4-Dimethoxybenzyl)-2-(4-fluoro-1I-pyrazol-1-yl)-5-nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (5.00 g, 11.6 mmol) in acetonitrile (135 ml) was added 4-fluoro-1H-pyrazole (1.50 g, 17.4 mmol) and powdered carbonate potassium (4.82 g, 34.9 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate. Concentration in vacuo gave the title compound (5.54 g, quant, ca. 85% pure), which was used without further purification in the next step.

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 437 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.48 (s, 3H), 3.62 (s, 3H), 4.13 (s, 2H), 6.15 (d, 1H), 6.28 ( dd, 1H), 7.09 (d, 1H), 7.81 (d, 1H), 8.00–8.10 (m, 2H), 8.23 (d, 1H), 8.43 (dd, 1H), 8.59 (s, 1H).

Intermediate 6.

2-(4-Bromo-1H-pyrazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

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To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.75 g, 4.54 mmol) in acetonitrile (53 ml) was added 4-bromo-III-pyrazole (1.00 g, 6.80 mmol) and powdered carbonate potassium (1.88 g, 13.6 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate. Concentration in vacuo gave the title compound crude (2.38 g, quant, ca. 95% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.29 min; MS (ESI positive): m/z = 497 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm]: 3.48 (s, 3H), 3.62 (s, 3H), 4.13 (s, 2H), 6.15 (d, 1H), 6.28 (dd, 1H), 7.09 (d, 1H), 7.84 (d, 1H), 8.00–8.10 (m, 2H), 8.23 (s, 1H), 8.43 (dd, 1H), 8.65 (s, 1H).

Intermediate 7.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]benzenesulfonamide

CH ₃

II O

3-(trifluoromethyl)-1H-1,2,4-triazole (1.06 g, 7.76 mmol) and powdered potassium carbonate (2.14 g, 15.5 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate. Concentration in vacuo gave the title compound (2.33 g, 79% yield, approx. 85% purity) which was used without further purification in the next step. LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 488 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.59 (s, 3H), 3.66 (s, 3H), 4.06 (s, 2H), 6.26 (d, 1H), 6.31 ( dd, 1H), 7.02 (d, 1H), 8.02 (d, 1H), 8.36 (s, 1H), 8.40 (d, 1H), 8.55 (dd, 1H), 9.21 (s, 1H).

Intermediate 8.

2-[3-(Difluoromethyl)-1H-1,2,4-triazol-1-yl]-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide ch ₃

II O

3-(Difluoromethyl)-1H-1,2,4-triazole (254 mg, 2.13 mmol) and powdered potassium carbonate (589 mg, 4.27 mmol) and the reaction mixture were irradiated for one hour at 120°C in a microwave oven. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (504 mg, 1.07 mmol, 76% yield, 95% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 470 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.56 (s, 3H), 3.65 (s, 3H), 4.11 (s, 2H), 6.22 (d, 1H), 6.30 ( dd, 1H), 7.05 (d, 1H), 7.31 (t, 1H), 7.98 (d, 1H), 8.17-8.25 (m, 1H), 8.32 (d, 1H), 8.52 (dd, 1H), 9.12 (s, 1H).

Intermediate 9.

2-(4-Cyano-1H-pyrazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

- 52 040608

1H-pyrazole-4-carbonitrile (5.41 g, 93.1 mmol) and powdered carbonate potassium (16.1 g, 116 mmol) and the reaction mixture was stirred overnight at 100°C. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate and water. Precipitation of the pure title compound was observed and was filtered (9.09 g, 20.5 mmol, 53% yield, 97% purity), the organic phase was washed with brine and dried over sodium sulfate. Concentration in vacuo resulted in an additional portion of the crude title compound (9.11 g, ca. 60% pure).

LC-MS (method B): Rt = 1.17 min; MS (ESI negative): m/z = 442 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.53 (s, 3H), 3.64 (s, 3H), 4.08 (s, 2H), 6.20 (d, 1H), 6.29 (dd, 1H), 7.07 (d, 1H), 7.89 (d, 1H), 8.12 (br s, 1H), 8.30 (br s, 1H), 8.41-8.54 (m, 2H), 9.17 (br s, 1H).

Intermediate 10.

5-Amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide

Pd/C (load 10%, 750 mg) was added to a solution of N-(2,4-dimethoxybenzyl)-5-nitro-2-[4(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (7.50 g, 14.7 mmol) in methanol (120 ml) and stirred under hydrogen atmosphere for 4 hours at room temperature. Some ethyl acetate was added to dissolve the precipitated product, and then the solution was filtered, washed, and concentrated in vacuo to give the crude title compound (6.50 g, quant, ca. 95% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 457 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.70 (s, 3H), 3.73 (s, 3H), 3.94 (d, 2H), 6.01 (s, 2H), 6.41 -6.48 (m, 2H), 6.78 (dd, 1H), 7.09-7.14 (m, 2H), 7.18-7.27 (m, 2H), 8.12 (s, 1H), 8.56 (s, 1H).

Intermediate 11.

5-Amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide

Pt/C (load 10%, 600 mg) was added to a solution of crude 2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (6.27 g, 13.9 mmol) in ethanol (100 ml) and stirred under hydrogen atmosphere for 24 h at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title crude compound (5.99 g, quant, ca. 90% pure), which was used without further purification in the next step.

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 423 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.69 (s, 3H), 3.72 (s, 3H), 3.92 (d, 2H), 5.95 (s, 2H), 6.41 -6.47 (m, 2H), 6.76 (dd, 1H), 7.08-7.12 (m, 2H), 7.15 (d, 1H), 7.19 (t, 1H), 7.78 (d, 1H), 8.15 (d, 1H ).

Intermediate 12.

5-Amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol-1-yl)benzenesulfonamide

- 53 040608

Pt/C (load 10%, 1.76 g) was added to a solution of crude N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1Hpyrazol-1-yl)-5-nitrobenzenesulfonamide (5.50 g, 12.6 mmol) in a mixture of ethanol (125 ml) and dioxane (200 ml) and stirred under a hydrogen atmosphere for 8 hours at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title crude compound (5.07 g, quant, ca. 90% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.10 min.

MS (ESI positive): m/z = 407 [M+H]+.

1H-NMR (400 MHz, DMSO^) δ [ppm]: 3.69 (s, 3H), 3.72 (s, 3H), 3.92 (d, 2H), 5.93 (s, 2H), 6.42-6.47 ( m, 2H), 6.78 (dd, 1H), 7.08-7.19 (m, 4H), 7.74 (dd, 1H), 8.07 (dd, 1H).

Intermediate 13.

5-Amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide

Pt/C (load 10%, 1.76 g) was added to a solution of crude 2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (5.60 g, 12.8 mmol) in ethanol (140 ml) and stirred under hydrogen atmosphere for 14 h at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title crude compound (1.87 g, quant, ca. 90% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 467 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.69 (s, 3H), 3.72 (s, 3H), 3.92 (d, 2H), 5.95 (s, 2H), 6.39- 6.48 (m, 2H), 6.77 (dd, 1H), 7.08-7.23 (m, 4H), 7.79 (d, 1H), 8.15 (d, 1H).

Intermediate 14.

5-Amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]benzenesulfonamide

Pd/C (load 10%, 170 mg) was added to a solution of crude N-(2,4-dimethoxybenzyl)-5-nitro-2-[3(trifluoromethyl)-1H-1,2,4-triazol-1-yl ]benzenesulfonamide (2.33 g, 4.78 mmol) in methanol (45 ml) and stirred under hydrogen atmosphere overnight at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title crude compound (2.04 g, quant, ca. 95% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 458 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.69 (s, 3H), 3.73 (s, 3H), 3.91 (s, 2H), 6.15 (s, 2H), 6.40 -6.49 (m, 2H), 6.80 (dd, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.28 (d, 1H), 7.56 (s, 1H), 8.91 (d, 1H).

Intermediate 15.

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

- 54 040608

CH ₃

Pd/C (load 10%, 22 mg) was added to a solution of 2-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]^-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (252 mg, 0.53 mmol) in methanol (3.5 mL) and tetrahydrofuran (1.5 mL) and stirred under hydrogen atmosphere for 6 h at room temperature. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was redissolved in ethanol (5 ml), platinum/vanadium (55 mg, 1/2% on charcoal) was added and the reaction mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated in vacuo to give 213 mg of crude 5-amino-2-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-N(2,4-dimethoxybenzyl) benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (213 mg) was dissolved in dimethylformamide (5 ml) followed by the addition of (2-chlorophenyl)acetic acid (124 mg, 0.727 mmol), N,N-diisopropylethylamine (196 mg, 1.94 mmol) and HATU (276 mg, 0.727 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried using a Whatman filter, and concentrated in vacuo to give the title compound, which was purified by preparative HPLC (112 mg, 0.189 mmol, 36% yield over 2 steps, 90% purity). .

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 592 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.63 (s, 3H), 3.68 (s, 3H), 3.92 (s, 2H), 3.99 (d, 2H), 6.33-6.39 (m, 2H), 7.06 (d, 1H), 7.21 (t, 1H), 7.30-7.38 (m, 2H), 7.44-7.51 (m, 2H), 7.60 (d, 1H), 7.68 (t, 1H ), 7.95 (dd, 1H), 8.20 (d, 1H), 8.92 (s, 1H), 10.79 (s, 1H).

Intermediate 16.

N-{4-[3-(Difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide CH ₃

Pd/C (load 10%, 22 mg) was added to a solution of 2-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide ( 252 mg, 0.53 mmol) in methanol (3.5 ml) and tetrahydrofuran (1.5 ml) and stirred under hydrogen atmosphere for 6 h at room temperature. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was redissolved in ethanol (5 ml), platinum/vanadium (55 mg, 1/2% on charcoal) was added and the reaction mixture was stirred for 3 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated in vacuo to give 213 mg of crude 5-amino-2-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-N(2,4-dimethoxybenzyl) benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (213 mg) was dissolved in dimethylformamide (5 ml) followed by the addition of (2-fluorophenyl)acetic acid (112 mg, 0.727 mmol), N,N-diisopropylethylamine (196 mg, 1.94 mmol) and HATU (276 mg, 0.727 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried using a Whatman filter, and concentrated in vacuo to give the title compound, which was purified by preparative HPLC (94 mg, 0.163 mmol, 31% yield over 2 steps, 90% purity). ).

LC-MS (method B): Rt = 1.21 min, MS (ESI positive): m/z = 576 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.62 (s, 3H), 3.67 (s, 3H), 3.82 (s, 2H), 3.99 (d, 2H), 6.33-6.37 (m, 2H), 7.07 (d, 1H), 7.17-7.24 (m, 2H), 7.21 (t, 1H), 7.31-7.38 (m, 1H), 7.40-7.46 (m, 1H), 7.60 (d , 1H), 7.67 (t,

- 55 040608

1H), 7.94 (dd, 1H), 8.18 (d, 1H), 8.92 (s, 1H), 10.76 (s, 1H).

Intermediate 17.

2-Chloro-K-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide

1,1-Dimethoxy-N,K-dimethylmethanamine (3.02 g, 25.4 mmol) was added to a solution of 2-chloro-5-nitrobenzenesulfonamide (3.00 g, 12.7 mmol) in N,N-dimethylformamide (43 mL) and stirred at room temperature for 2 days. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane/water. The organic phase was washed with brine and dried. Concentration in vacuo gave the crude title compound (4.18 g, quant, ca. 90% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 0.86 min; MS (ESI positive): m/z = 292 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.94-2.96 (m, 3H), 3.20 (s, 3H), 7.91 (d, 1H), 8.31-8.33 (m, 1H ), 8.39 (dd, 1H), 8.69 (d, 1H).

Intermediate 18.

X-[(Dimethylamino)methylene]-5-nitro-2-[5-(trifluoromethyl)pyridin-3-yl]benzenesulfonamide

2-Chloro-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (1.10 g, 3.77 mmol) was dissolved in degassed n-propanol (33 mL) and treated with [5-(trifluoromethyl)pyridin-3-yl]boronic acid ( 1.08 g, 5.68 mmol), bis-(triphenylphosphine)palladium(II) dichloride (132 mg, 0.189 mmol) and triphenylphosphine (49.5 mg, 0.189 mmol). A 2M aqueous degassed potassium carbonate solution (5.65 ml) was added, the flask was sealed and stirred for 16 h at 100°C. After cooling to room temperature, water was added and the reaction mixture was extracted three times with ethyl acetate, followed by concentration in vacuo.

Partially deprotected target molecules were reprotected as described above by stirring at room temperature with 1,1-dimethoxy-X,K-dimethylmethanamine in DMF. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) to give the title compound (174 mg, 0.432 mmol, yield 11%, purity 95%).

LC-MS (method B): Rt = 1.08 min; MS (ESI positive): m/z = 403 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 2.76 (s, 3H), 2.99 (s, 3H), 7.76 (s, 1H), 7.81 (d, 1H), 8.33-8.36 (m, 1H), 8.52 (dd, 1H), 8.76 (d, 1H), 8.88 (d, 1H), 9.09 (dd, 1H).

Intermediate 19.

5-Amino-X-[(dimethylamino)methylene]-2-[5-(trifluoromethyl)pyridin-3-yl]benzenesulfonamide CH ₃

Pd/C (load 10%, 21 mg) was added to a solution of K-[(dimethylamino)methylene]-5-nitro-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (174 mg, 0.39 mmol) in a mixture methanol (10 ml) and dioxane (10 ml) and stirred under hydrogen atmosphere overnight at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title compound (140 mg, quant, 95% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 0.90 min; MS (ESI positive): m/z = 373 [M+H]+.

Intermediate 20.

2-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide

- 56 040608

2-Chloro-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (1.00 g, 3.43 mmol) was dissolved in degassed n-propanol (30 mL) and treated with 1-(difluoromethyl)-4-(4.4.5, 5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (1.25 g, 5.14 mmol), bis-(triphenylphosphine)palladium(II) dichloride (121 mg, 0.171 mmol) and triphenylphosphine (45.0 mg, 0.171 mmol). An aqueous degassed 2M potassium carbonate solution (5.14 ml) was added, the flask was sealed and stirred for 16 h at 100°C. After cooling to room temperature, water was added and the reaction mixture was extracted three times with ethyl acetate, followed by concentration in vacuo.

The residue was redissolved in a mixture of methanol (25 ml) and n-propanol (25 ml) and concentrated aqueous ammonia (50 ml) was added to completely deprotect the target molecules to facilitate purification. The reaction mixture was extracted with dichloromethane and ethyl acetate. The organic phases were dried followed by concentration in vacuo and purification by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) to give 2-[1-(difluoromethyl) -1H-pyrazol-4-yl]-5-nitrobenzenesulfonamide (383 mg).

Then, the deprotected target molecules were reprotected as described above by stirring at room temperature with 1,1-dimethoxy-N,X-dimethylmethanamine in DMF. Concentration in vacuo gave the title compound (418 mg) which was used without further purification in the next step.

LC-MS (method B): Rt = 0.98 min; MS (ESI positive): m/z = 374 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm] 2.76 (d, 3H), 3.02 (s, 3H), 7.85 (d, 1H), 7.91-7.93 (m, 2H), 7.95 (t , 1H), 8.19-8.21 (m, 1H), 8.43 (dd, 1H), 8.72 (d, 1H), 8.77 (d, 1H).

Intermediate 21.

5-Amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(dimethylamino)methylene]benzenesulfonamide

SI ₃ o Г ^%Н з °^ ^N F ϊN—(

JUJ h ₂ n^^

Pd/C (load 10%, 54 mg) was added to a solution of 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (418 mg, 1.01 mmol) in a mixture of methanol (10 ml) and dioxane (10 ml) and stirred under hydrogen atmosphere overnight at room temperature. The catalyst was filtered off, washed with ethyl acetate, and the filtrate was concentrated in vacuo to give the title crude compound (370 mg, quant, 90% pure), which was used without further purification in the next step.

LC-MS (method A): Rt = 0.74 min; MS (ESI positive): m/z = 344 [M+H]+.

Intermediate 22.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl)acetamide n ₃ s.^ch ₃

S

O=S=ON^\ ^F

Cl ⁿ

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}acetamide (2.00 g, 3.92 mmol) was dissolved in dimethylformamide (13.3 ml) and treated with dimethylformamide dimethylacetal (935 mg, 7.85 mmol) followed by stirring at room temperature over the weekend. The reaction mixture was reduced in vacuo and extracted with dichloromethane and water. The target compound has already partially precipitated. The organic phase was dried, concentrated in vacuo and further purified by stirring as a suspension in n-propanol followed by filtration. All precipitated fractions were combined to give the title compound.

- 57 040608 sufficient purity for the following steps (1.33 g, 2.59 mmol, 66% yield, 95% purity).

LC-MS (method B): Rt = 1.19 min; MS (ESI positive): m/z = 514 [M+H]+ Main E/Z isomer ¹ HNMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.77 (s, 3H), 3.01 (s, 3H), 3.91 (s, 2H), 7.30-7.36 (m, 2H), 7.43-7.52 (m, 3H), 7.58 (s, 1H), 7.97 (dd, 1H), 8.14 (s, 1H ), 8.38 (d, 1H), 8.62–8.64 (m, 1H), 10.80 (s, 1H).

Intermediate 23.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(4-fluoro-1H-pyrazol-1yl)phenyl]acetamide

2-(2-Chlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide (125 mg, 0.31 mmol) was dissolved in dimethylformamide (1 ml) and treated with dimethylformamide dimethylacetal (72.9 mg, 0.61 mmol) followed by stirring at room temperature over the weekend. The reaction mixture was reduced in vacuo and extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate and concentrated in vacuo to give the title compound in sufficient purity for the next steps (167 mg, quant.).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 464 [M+H]+.

Intermediate 24.

N-(2,4-Dimethoxybenzyl)-2-(4-methyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide

4-Methyl-1H-pyrazole (260 µl, 3.1 mmol, CAS-RN 7554-65-5) and powdered potassium carbonate (857 mg, 6.20 mmol) and the reaction mixture was irradiated for 2 h at 140° C. in a microwave oven. After additional 4-methyl-1H-pyrazole (347 µl, 4.1 mmol) was added, the mixture was again irradiated for 2 h at 140°C in a microwave oven. The reaction mixture was concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (718 mg, 64% yield, 80% purity).

LC-MS (method B): Rt = 1.30 min; MS (ESI positive): m/z = 433 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.13 (s, 3H), 3.41 (s, 3H), 3.60 (s, 3H), 4.17 (d, 2H), 6.09 ( d, 1H), 6.26 (dd, 1H), 7.09 (d, 1H), 7.77 (d, 1H), 7.81 (s, 1H), 8.11 (s, 1H), 8.17 (d, 1H), 8.28 (t , 1H), 8.40 (dd, 1H).

Intermediate 25.

N-(2,4-Dimethoxybenzyl)-2-(3-methoxy-1H-1,2,4-triazol-1-yl)-5-nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.81 mmol) in acetonitrile (19 ml) 2.71 mmol) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 1 h at 120°C in a microwave oven. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration at

- 58 040608 reduced pressure gave the title compound, which was purified by flash chromatography (293 mg, 31% yield, 85% purity). LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 450 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.30 (s, 3H), 3.51 (s, 3H), 3.62 (s, 3H), 4.12 (d, 2H), 6.16 (d, 1H), 6.27 (dd, 1H), 7.09 (d, 1H), 7.83 (t, 1H), 7.85 (d, 1H), 8.18 (d, 1H), 8.35 (s, 1H), 8.43 ( dd, 1H).

Intermediate 26.

2-(4-Cyclopropyl-1H-imidazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

5-Cyclopropyl-1H-imidazole (294 mg, 2.71 mmol, CAS-RN 89830-98-8) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 1 h at 120° C. in a microwave oven. 4-Cyclopropyl-1H-imidazole (196 mg, 1.81 mmol) was added and microwave irradiation was continued for 2 h at 140°C. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (309 mg, 22% yield, 60% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.71 (m, 2H), 0.82 (m, 2H), 1.87 (m, 1H), 3.61 (s, 3H), 3.68 (s, 3H), 4.01 (d, 2H), 6.33 (d, 1H), 6.36 (dd, 1H), 7.02 (d, 1H), 7.17 (s, 1H), 7.67 (d, 1H), 7.74 ( s, 1H), 8.41 (dd, 1H), 8.43 (d, 1H), 8.49 (t, 1H).

Intermediate 27.

N-(2,4-Dimethoxybenzyl)-2-(4-methyl-1H-imidazol-1-yl)-5-nitrobenzenesulfonamide

5-methyl-1H-imidazole (223 mg, 2.71 mmol, CAS-RN 822-36-6) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 2 h at 110° C. in a microwave oven. 4-methyl-1H-imidazole (223 mg, 2.71 mmol) was added and microwave irradiation was continued for 2 h at 110°C. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (252 mg, 29% yield, 90% purity).

LC-MS (method B): Rt = 1.03 min; MS (ESI positive): m/z = 433 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.18 (s, 3H), 3.60 (s, 3H), 3.68 (s, 3H), 4.01 (d, 2H), 6.33 (d, 1H), 6.34 (dd, 1H), 7.00 (d, 1H), 7.12 (s, 1H), 7.66 (d, 1H), 7.75 (s, 1H), 8.41 (dd, 1H), 8.43 ( d, 1H), 8.46 (t, 1H).

Intermediate 28.

2-(3-Cyclopropyl-1H-pyrazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.81 mmol) in

- 59 040608 acetonitrile (14 ml) was added 3-cyclopropyl-1H-pyrazole (240 μl, 2.71 mmol, CAS-RN 100114-57-6) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 1 h at 120°C in a microwave oven. Added 5-cyclopropyl-1H-pyrazole (240 μl, 2.71 mmol) and microwave irradiation continued for 2 h at 140°C. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (187 mg, 21% yield, 95% purity). LC-MS (method B): Rt = 1.34 min, MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm]: 0.76 (m, 2H), 1.00 (m, 2H), 2.03 (m, 1H), 3.40 (s, 3H), 3.60 (s, 3H), 4.17 (s, 2H), 6.11 (d, 1H), 6.28 (dd, 1H), 6.42 (d, 1H), 7.09 (d, 1H), 7.78 (d, 1H), 8.18 (d, 1H ), 8.21 (d, 1H), 8.37 (t, 1H), 8.39 (dd, 1H).

Intermediate 29.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-(2H-pyrazolo[3,4-b]pyridin-2-yl)benzenesulfonamide

II o

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.81 mmol) in acetonitrile (18 mL), , CAS-RN 271-73-8) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 2 h at 120° C. in a microwave oven. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (428 mg, 37% yield, 70% purity).

LC-MS (method B): Rt = 1.24 min; MS (ESI positive): m/z = 470 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.51 (s, 3H), 3.62 (s, 3H), 4.20 (d, 2H), 6.15 (d, 1H), 6.29 ( dd, 1H), 7.13 (d, 1H), 7.45 (dd, 1H), 7.98 (t, 1H), 8.14 (d, 1H), 8.24 (dd, 1H), 8.46 (dd, 1H), 8.52 (d , 1H), 8.63 (dd, 1H), 8.65 (s, 1H).

Intermediate 30.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-(2H-pirazolo[3,4-c]pyridin-2-yl)benzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.81 mmol) in acetonitrile (18 mL), , CAS-RN 271-47-6) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 2 h at 120° C. in a microwave oven. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (610 mg, 72% yield, 95% purity).

LC-MS (method B): Rt = 1.15 min, MS (ESI positive): m/z = 470 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.55 (s, 3H), 3.64 (s, 3H), 4.15 (d, 2H), 6.19 (d, 1H), 6.29 ( dd, 1H), 7.07 (d, 1H), 7.96 (dd, 1H), 7.99 (t, 1H), 8.10 (d, 1H), 8.33 (d, 1H), 8.45 (d, 1H), 8.50 (dd , 1H), 8.71 (d, 1H), 9.00 (s, 1H).

Intermediate 31.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-(2H-pyrazolo[4,3-b]pyridin-2-yl)benzenesulfonamide

- 60 040608

To a solution of 2-chloro-M-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.81 mmol) in acetonitrile (18 ml) , CAS-RN 272-52-6) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 2 h at 120° C. in a microwave oven. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (270 mg, 20% yield, 60% purity).

LC-MS (method B): Rt = 1.16 min; MS (ESI positive): m/z = 470 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm]: 3.55 (s, 3H), 3.63 (s, 3H), 4.16 (d, 2H), 6.18 (d, 1H), 6.29 (dd, 1H), 7.08 (d, 1H), 7.54 (dd, 1H), 7.99 (d, 1H), 8.00 (t, 1H), 8.01 (dd, 1H), 8.32 (d, 1H), 8.49 (dd, 1H ), 8.71 (dd, 1H), 8.80 (s, 1H).

Intermediate 32.

N-(2,4-Dimethoxybenzyl)-2-[4-(2-methoxyethyl)-1H-pyrazol-1-yl]-5-nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.41 g, 3.65 mmol) in acetonitrile (16 mL) was added 4-(2-methoxyethyl)-1H-pyrazole (260 μL, 3.1 mmol , CAS-RN 1696383-18-12) and powdered potassium carbonate (1.51 g, 10.9 mmol) and the reaction mixture was irradiated for 2 h at 140°C in a microwave oven. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by HPLC (300 mg, 15% yield, 85% purity).

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 477 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.75 (t, 2H), 3.29 (s, 3H), 3.43 (s, 3H), 3.55 (t, 2H), 3.60 (s, 3Н), 4.16 (d, 2H), 6.11 (d, 1H), 6.26 (dd, 1H), 7.09 (d, 1H), 7.78 (d, 1H), 7.85 (s, 1H), 8.17 ( s, 1H), 8.19 (d, 1H), 8.26 (t, 1H), 8.40 (dd, 1H).

Intermediate 33.

N-(2,4-Dimethoxybenzyl)-2-(3-fluoro-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide

H ₃ C ^CH 3

I o

H.N. //,0

II O

3-Fluoro-1H-pyrazole (234 mg, 2.71 mmol, CAS-RN 14521-81-4) and powdered potassium carbonate (750 mg, 5.43 mmol) and the mixture was irradiated for 2 h at 120°C in a microwave oven. 3-Fluoro-1H-pyrazole (234 mg, 2.71 mmol) was added and microwave irradiation was continued for 2 h at 120°C. The reaction mixture was filtered and concentrated in vacuo and the residue was extracted with dichloromethane and water. The aqueous phase was washed three times with dichloromethane. The combined organic phases were then washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound, which was purified by flash chromatography (567 mg, 61% yield, 85% purity).

LC-MS (method B): Rt = 1.25 min; MS (ESI positive): m/z = 437 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.52 (s, 3H), 3.63 (s, 3H), 4.14 (s, 2H), 6.19 (d, 1H), 6.28 ( dd, 1H), 6.46 (dd, 1H), 7.06 (d, 1H), 7.82 (d, 1H), 8.04 (s, 1H), 8.23 (dd, 1H), 8.26 (d, 1H), 8.44 (dd , 1H).

- 61 040608

Intermediate 34.

N-(2,2-Difluoroethyl)-1H-pyrazole-4-amine

To a solution of 1H-pyrazole-4-amine (300 mg, 95% purity, 3.43 mmol) in acetonitrile (17 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (690 μL, 5.1 mmol, CAS-RN 74427-22-8), powdered potassium carbonate (1.06 g, 7.65 mmol) and triethylamine (720 µl, 5.1 mmol). The mixture was heated at 120° C. overnight. To isolate the reaction product, the reaction mixture was filtered and the solid was washed with ethyl acetate. Concentration of the filtrate in vacuo followed by flash chromatography gave the title compound (505 mg, 90% yield, 90% purity).

LC-MS (method B): Rt = 0.43 min.

MS (ESI positive): m/z = 148 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.23 (tdd, 2H), 4.72 (t, 1H), 6.05 (tt, 1H), 7.12 (s, 2H), 12.10 ( s, 1H).

Intermediate 35.

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

N-(2,2-difluoroethyl)-1H-pyrazole-4-amine (500 mg, 3.06 mmol) and powdered potassium carbonate (634 mg, 4.59 mmol) and the reaction mixture were irradiated for 12 h at 120°C in a microwave oven. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by flash chromatography (280 mg, 31% yield, 85% purity).

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 498 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.38 (m, 2H), 3.38 (s, 3H), 3.59 (s, 3H), 4.16 (d, 2H), 5 .49 (t, 1H), 6.08 (d, 1H), 6.15 (tt, 1H), 6.25 (dd, 1H), 7.08 (d, 1H), 7.65 (s, 1H), 7.73 (d, 1H ), 7.80 (s, 1H), 8.17 (d, 1H), 8.24 (t, 1H), 8.38 (dd, 1H).

Intermediate 36.

N-(2,4-Dimethoxybenzyl)-2-[4-(2-hydroxyethyl)-1H-pyrazol-1-yl]-5-nitrobenzenesulfonamide

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (661 mg, 1.71 mmol) in acetonitrile (13 ml) mmol, CAS-RN 180207-57-2) and powdered potassium carbonate (944 mg, 6.83 mmol) and the reaction mixture was irradiated for 2 h at 140°C in a microwave oven. The 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 gave the title compound, which was purified by flash chromatography (285 mg, 34% yield, 95% purity).

LC-MS (method B): Rt = 1.08 min; MS (ESI positive): m/z = 463 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.66 (t, 2H), 3.42 (s, 3H), 3.60 (s, 3H), 3.62 (td, 2H), 4.17 (d, 2Н), 4.75 (t, 1H), 6.11 (d, 1H), 6.26 (dd, 1H), 7.09 (d, 1H), 7.78 (d, 1H), 7.85 (s, 1H), 8.15 ( s, 1H), 8.19 (d, 1H), 8.28 (t, 1H), 8.40 (dd, 1H).

Intermediate 37.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[4-(2-oxoethyl)-1H-pyrazol-1-yl]benzenesulfonamide

- 62 040608

solution

N-(2,4-dimethoxybenzyl)-2-[4-(2-hydroxyethyl)-1H-pyrazol-1-yl]-5-nitrobenzenesulfonamide (279 mg, 573 µmol, 95% purity) in dichloromethane (19 mL) was added 1,1,1tris-(acetyloxu)-1λ ⁵ ,2-benzyodoxol-3(1H)-one (486 mg, 1.15 mmol) and the mixture was stirred for 2 h at room temperature. The reaction mixture was diluted with aqueous sodium thiosulfate (10%) and saturated aqueous sodium hydrogen carbonate (1:1) and extracted with dichloromethane. The combined organic phases were washed with brine and dried using a Whatman filter. Concentration under reduced pressure gave the title compound crude, which was used without further purification (440 mg, 33% yield, 20% purity).

LC-MS (method B): Rt = 1.11 min; MS (ESI positive): m/z = 461 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.44 (s, 3H), 3.61 (s, 3H), 3.77 (t, 2H), 4.17 (d, 2H), 6.12 ( d, 1H), 6.27 (dd, 1H), 7.09 (d, 1H), 7.80 (d, 1H), 7.90 (s, 1H), 8.20 (d, 1H), 8.23 (t, 1H), 8.26 (s , 1H), 8.42 (dd, 1H), 9.71 (t, 1H).

Intermediate 38.

2-[4-(2,2-Difluoroethyl)-1H-pyrazol-1-yl]-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

To a solution of crude N-(2,4-dimethoxybenzyl)-5-nitro-2-[4-(2-oxoethyl)-1H-pyrazol-1yl]benzenesulfonamide (440 mg, 191 µmol, 20% purity) in tetrahydrofuran (500 μl) 2methoxu-N-(2-methoxyethyl)-N-(trifluoro-λ ⁴ -sulfanyl)ethanamine (210 ml, 2.7 M in toluene, 570 μmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried using a Whatman filter and evaporated in vacuo. Purification by flash chromatography gave the title compound (56 mg, 43% yield, 70% purity).

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 483 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.16 (td, 2H), 3.44 (s, 3H), 3.61 (s, 3H), 4.16 (d, 2H), 6.12 ( d, 1H), 6.26 (tt, 1H), 6.26 (dd, 1H), 7.09 (d, 1H), 7.79 (d, 1H), 7.89 (s, 1H), 8.20 (d, 1H), 8.20 (t , 1H), 8.26 (s, 1H), 8.42 (dd, 1H).

Intermediate 39.

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

Tin(11) chloride dihydrate (530 mg, 2.35 mmol) was added to a solution of 2-[4-(2,2-difluoroethyl)-1Hpyrazol-1-yl]-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide ( 227 mg, 469 μmol) in dioxane (6 ml) followed by stirring for 6 h at 70°C. 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 phase was filtered through Celite, washed with brine, dried using sodium sulfate and concentrated in vacuo to give 245 mg of crude 5-amino-2-[4-(2,2difluoroethyl)-1H-pyrazol-1-yl]-N -(2,4-dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

- 63 040608

The crude product from the previous step (217 mg) was dissolved in DMF (6 mL) followed by the addition of (2-chlorophenyl)acetic acid (84 mg, 492 µmol), N,N-diisopropylethylamine (230 µL, 1.3 mmol) and HATU (187 mg, 492 µmol). The reaction mixture was stirred for 3.5 h at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (336 mg, 40% purity, 47% yield over 2 steps).

LC-MS (method A): Rt = 1.34 min; MS (ESI positive): m/z = 605 (M+H)+.

Intermediate 40.

2,2-Difluoro-N-( 1 H-pyrazol-4-ylmethyl)ethanamine

To a solution of 1-(1H-pyrazol-4-yl)methanamine dihydrochloride (500 mg, 2.94 mmol) in acetonitrile (30 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (590 μL, 4.4 mmol, CAS-RN 74427-22-8 ), powdered potassium carbonate (1.02 g, 7.35 mmol) and triethylamine (1.2 ml, 8.8 mmol). The mixture was heated at 100°C for 4 hours and at 70°C overnight. To isolate the reaction product, the reaction mixture was filtered and the solid was washed with dichloromethane. Concentration of the filtrate in vacuo followed by extraction of the residue with dichloromethane and evaporation of the organic phase gave the title compound (482 mg, 86% yield, 85% purity).

LC-MS (method B): Rt = 0.49 min; MS (ESI positive): m/z = 162 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.82 (td, 2H), 3.61 (s, 2H), 5.98 (tt, 1H), 7.50 (s, 2H).

Intermediate 41.

tert-Butyl (2,2-difluoroethyl)(1 H-pyrazol-4-ylmethyl)carbamate

To a solution of 2,2-difluoro-N-(1H-pyrazol-4-ylmethyl)ethanamine (370 mg, 2.30 mmol) in dichloromethane (23 ml) was added di-tert-butyl dicarbonate (551 mg, 2.53 mmol), and the mixture stirred for 90 min at room temperature. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate, and extracted with dichloromethane. The combined organic phases were concentrated under reduced pressure to give the title crude compound, which was used without further purification (302 mg, 45% yield, 90% purity).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 262 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.82 (td, 2H), 3.62 (s, 2H), 5.99 (tt, 1H), 7.74 (s, 2H), 8.12 ( s, 2H).

Intermediate 42.

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

To a solution of 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (200 mg, 517 μmol) in acetonitrile (10 ml) was added tert-butyl (2,2-difluoroethyl) ylmethyl)carbamate (300 mg, 90% purity, 1.03 mmol) and powdered potassium carbonate (286 mg, 2.07 mmol), and the mixture was irradiated for 4 h at 120°C in a microwave oven. The 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 gave the title compound, which was purified by flash chromatography (84 mg, 22% yield, 70% purity).

LC-MS (method B): Rt = 1.21 min: MS (ESI positive): m/z = 512 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.89 (td, 2H), 3.44 (s, 3H), 3.61 (s, 3H), 3.71 (s, 2H), 4.16 (d, 2H), 6.02 (tt, 1H), 6.12 (d, 1H), 6.27 (dd, 1H), 7.09 (d, 1H), 7.80 (d, 1H), 7.90 (s, 1H), 8.19 ( d, 1H), 8.21 (s, 1H), 8.26 (t, 1H), 8.41 (dd, 1H).

Intermediate 43.

tert-Butyl (2,2-difluoroethyl)[(1-{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1H-pyrazol- 64 040608

4-yl)methyl]carbamate

To a solution of 2-(4-{[(2,2-difluoroethyl)amino]methyl} -1H-pyrazol-1 -yl)-N-(2,4-dimethoxybenzyl)-5nitrobenzenesulfonamide (370 mg, 723 µmol) in dichloromethane (7 ml) was added di-tert-butyl dicarbonate (174 mg, 796 μmol) and 4-(dimethylamino)pyridine (4.4 mg, 36 μmol) and the mixture was stirred overnight at room temperature. Another portion of di-tert-butyl dicarbonate (174 mg, 796 µmol) and additional 4-(dimethylamino)pyridine (4.4 mg, 36 µmol) were added and stirring was continued for 3 h. 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 to give the title crude compound, which was used without further purification (150 mg, 17% yield, 50% purity).

LC-MS (method B): Rt = 1.42 min MS (ESI positive): m/z = 612 (M+H)+.

Intermediate 44.

tert-Butyl {[ 1 -(4- {[(2-chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1 Hpyrazol-4-yl]methyl}(2,2 -difluoroethyl)carbamate

Tin(II) chloride dihydrate (277 mg, 1.23 mmol) was added to a solution of tert-butyl (2,2difluoroethyl)[(1-{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1H-pyrazole -4yl)methyl]carbamate (150 mg, 123 μmol, 50% purity) in dioxane (3 ml) followed by stirring for 4 h at 70°C. 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 phase was filtered through celite, washed with brine, dried using sodium sulfate and concentrated in vacuo to give 74 mg of crude tert-butyl [(1-{4-amino-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl }-1H-pyrazol-4-yl)methyl](2,2-difluoroethyl)carbamate, which was used without further purification in the next step.

The crude product from the previous step (74 mg) was dissolved in DMF (2.5 ml) followed by the addition of (2-chlorophenyl)acetic acid (33 mg, 191 µmol), N,N-diisopropylethylamine (89 µl, 510 µmol) and HATU (72.6 mg, 191 µmol). The reaction mixture was stirred for 3 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (76 mg, 50% purity, 42% yield over 2 steps).

LC-MS (method A): Rt = 1.36 min; MS (ESI positive): m/z = 734 (M+H) ⁺ .

Intermediate 45.

2-(Benzylsulfanyl)-4-nitrobenzonitrile

To a solution of 2-bromo-4-nitrobenzonitrile (400 mg, 1.76 mmol) in dioxane (34 ml) was added phenylmethanethiol (197 μl, 1.67 mmol), bis-(diphenylphosphane) (51 mg, 88 µmol), tris-(dibenzylideneacetone)dipalladium(0)-chloroform adduct (91 mg, 88 µmol) and N,Ndiisopropylethylamine (614 µl, 3.5 mmol), and the mixture was stirred for 3 h at 100°C. The reaction mixture was concentrated in vacuo and taken up in water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and concentrated at

- 65 040608 under reduced pressure to give the crude title compound, which was purified by flash chromatography (457 mg, 91% yield, 95% purity).

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.58 (s, 2H), 7.28 (dd, 1H), 7.35 (dd, 2H), 7.44 (d, 2H), 8.10 ( dd, 1H), 8.12 (d, 1H), 8.30 (d, 1H).

Intermediate 46.

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

2-(Benzylsulfanyl)-4-nitrobenzonitrile (450 mg, 1.55 mmol, 95% purity) was stirred with N-chlorosuccinimide (634 mg, 4.75 mmol) in acetic acid (15 mL) at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give 390 mg of crude 2-cyano-5-nitrobenzenesulfonyl chloride, which was used without further purification in the next step.

The crude product from the previous step (390 mg) was dissolved in dichloromethane (7.7 ml) followed by the addition of 1-(2,4-dimethoxyphenyl)methanamine (291 mg, 1.74 mmol) and sodium bicarbonate (531 mg, 6.33 mmol) at 0°C . The reaction mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature. The reaction mixture was concentrated in vacuo and taken up in water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (118 mg, 12% yield, 60% purity).

LC-MS (method B): Rt = 1.05 min; MS (ESI positive): m/z = 378 (M+H)+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.56 (s, 3H), 3.62 (s, 3H), 4.11 (d, 2H), 6.11 (d, 1H), 6.26 ( dd, 1H), 7.02 (d, 1H), 8.20 (d, 1H), 8.26 (d, 1H), 8.43 (dd, 1H), 8.76 (t, 1H).

Intermediate 47.

2-[(2,4-Dimethoxybenzyl)sulfamoyl]-N'-hydroxy-4-nitrobenzenecarboximidamide

Hydroxyammonium chloride (258 mg, 3.71 mmol) was dissolved in DMSO (5 ml). Potassium tert-butoxide (416 mg, 3.71 mmol) was added in small portions at 10°C, followed by stirring for 1 h. 371 μmol) in DMSO (3 ml) and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water. The precipitate was filtered off and dried in vacuo to give the title compound (126 mg, 74% yield, 90% purity).

LC-MS (method B): Rt = 0.99 min; MS (ESI negative): m/z = 409 (M-H) ^- .

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 3.47 (s, 3H), 3.60 (s, 3H), 4.07 (d, 2H), 6.08 (d, 1H), 6.23 (s , 2H), 6.25 (dd, 1H), 7.06 (d, 1H), 7.79 (d, 1H), 7.89 (t, 1H), 8.03 (d, 1H), 8.33 (dd, 1H), 10.02 (s, 1H).

Intermediate 48.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide

2-[(2,4-Dimethoxybenzyl)sulfamoyl]-N'-hydroxy-4-nitrobenzenecarboximidamide (125 mg, 305 µmol) was stirred with trifluoroacetic anhydride (47 µl, 340 µmol) in tetrahydrofur

- 66 040608 no (2.5 ml) at reflux for 2 hours and at room temperature overnight. Another portion of trifluoroacetic anhydride (43 μl, 300 μmol) was added and the reaction mixture was heated at reflux for 90 minutes. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (87 mg, 56% yield, 95% purity).

LC-MS (method A): Rt = 1.36 min; MS (ESI negative): m/z = 487 (M-H)-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.54 (s, 3H), 3.64 (s, 3H), 4.07 (d, 2H), 6.22 (d, 1H), 6.27 (dd,

1H), 7.01 (d, 1H), 7.99 (d, 1H), 8.13 (t, 1H), 8.41 (d, 1H), 8.52 (dd, 1H).

Intermediate 49.

2-(2-Chlorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-

-yl]phenyl}acetamide

Tin(II) chloride dihydrate (196 mg, 870 µmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]benzenesulfonamide (85.0 mg, 174 µmol) in dioxane (2.2 ml) followed by stirring for 4 h at 70°C and overnight at room temperature. 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 phase was filtered through Celite, dried on a Whatman filter and concentrated in vacuo to give 74 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-[5-(trifluoromethyl)-1,2,4-oxadiazole-3 -yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (70 mg) was dissolved in DMF (3 ml) followed by the addition of (2-chlorophenyl)acetic acid (31.3 mg, 183 µmol), N,X-diisopropylethylamine (110 µl, 610 µmol) and HATU (69.7 mg, 183 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (112 mg, 40% purity, 8% yield over 2 steps).

LC-MS (method A): Rt = 1.36 min; MS (ESI negative): m/z = 609 (M-H)-.

Intermediate 50.

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

To a solution of N-(2,4-dimethoxybenzyl)-2-(4-methyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (540 mg, 80% purity, 1.00 mmol) in ethanol (12 ml) was added platinum/vanadium (130 mg, 1/2% on charcoal) and stirred under hydrogen atmosphere for three days at room temperature. The reaction mixture was filtered through celite and concentrated in vacuo to give 520 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-methyl-1H-pyrazol-1-yl)benzenesulfonamide, which was used without further purification on next stage.

The crude product from the previous step (520 mg) was dissolved in DMF (13 ml) followed by the addition of (2-chlorophenyl)acetic acid (331 mg, 1.94 mmol), DMF (900 μl, 5.2 mmol) and HATU (737 mg, 1.94 mmol ). The reaction mixture was stirred for 72 hours at room temperature. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was purified by preparative HPLC (176 mg, 60% purity, 19% yield over 2 steps).

LC-MS (method B): Rt = 1.34 min; MS (ESI positive): m/z = 555 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.09 (s, 3H), 3.59 (s, 3H), 3.66 (s, 3H), 3.79 (s, 2H), 4.01 ( d, 2H),

- 67 040608

6.33 (d, 1H), 6.34 (dd, 1H), 7.07 (d, 1H), 7.15 (m, 2H), 7.33 (m, 2H), 7.44 (d, 1H), 7.60 (s, 1H), 7.77 (t, 1H), 7.83 (s, 1H), 7.93 (dd, 1H), 8.06 (d, 1H), 10.63 (s, 1H).

Intermediate 51.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(3-methoxy-1H-1,2,4-triazol-1yl)phenyl}acetamide o I ch ₃ O \ /O ςα D' °

To a solution of N-(2,4-dimethoxybenzyl)-2-(3-methoxy-1H-1,2,4-triazol-1-yl)-5-nitrobenzenesulfonamide (290 mg, 85% purity, 0.55 mmol) in ethanol ( 6 ml) was added platinum/vanadium (71 mg, 1/2% on charcoal) and stirred under hydrogen atmosphere for two days at room temperature. The reaction mixture was filtered through celite and concentrated in vacuo to give 520 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(3-methoxy-1H-1,2,4-triazol-1yl)benzenesulfonamide, which used without further purification in the next step.

The crude product from the previous step (200 mg) was dissolved in DMF (5 ml) followed by the addition of (2-chlorophenyl)acetic acid (331 mg, 1.94 mmol), N,N-diisopropylethylamine (332 μl, 1.9 mmol) and HATU (272 mg, 0.72 mmol). The reaction mixture was stirred for 24 hours at room temperature. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter, and concentrated in vacuo to give the title compound, which was purified by preparative HPLC (17 mg, 60% purity, 3% yield over 2 steps).

LC-MS (method B): Rt = 1.16 min; MS (ESI positive): m/z = 572 [M+H]+.

Intermediate 52.

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

Tin(II) chloride dihydrate (244 mg, 1.08 mmol) was added to a solution of 2-(4-cyclopropyl-Chimidazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (99.0 mg, 216 µmol) in dioxane (5 ml) and stirred for 2 h at 70°C. 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 phase was filtered through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 140 mg of crude 5-amino-2-(4-cyclopropyl-1H-imidazol-1-yl)N-(2,4 -dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (140 mg) was dissolved in DMF (3.4 ml) followed by the addition of (2-chlorophenyl)acetic acid (83.6 mg, 490 µmol), N,N-diisopropylethylamine (230 µl, 1.3 mmol) and HATU (186 mg, 490 µmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (35 mg, 52% purity, 15% yield over 2 steps).

LC-MS (method B): Rt = 1.25 min; MS (ESI positive): m/z = 581 [M+H]+.

Intermediate 53.

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

- 68 040608

Tin(II) chloride dihydrate (784 mg, 1.08 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2(4-methyl-1H-imidazol-1-yl)-5-nitrobenzenesulfonamide (300 mg, 695 µmol ) in dioxane (16 mL) and stirred for 2.5 h at 70°С. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 243 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-methyl-1Himidazole-1- yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (243 mg) was dissolved in DMF (6.2 ml) followed by the addition of (2-chlorophenyl)acetic acid (154 mg, 904 µmol), N,N-diisopropylethylamine (420 µl, 2.4 mmol) and HATU (344 mg, 904 µmol). The reaction mixture was stirred overnight at 60°C.

Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was purified by HPLC (69 mg, 85% purity, 15% yield over 2 steps).

LC-MS (method B): Rt = 1.19 min, MS (ESI positive): m/z = 555 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.13 (s, 3H), 3.64 (s, 3H), 3.71 (s, 3H), 3.89 (d, 2H), 3.90 ( s, 2H), 6.42 (dd, 1H), 6.44 (d, 1H), 6.88 (d, 1H), 7.04 (d, 1H), 7.32 (m, 2H), 7.33 (d, 1H), 7.45 (m , 2H), 7.51 (d, 1H), 7.71 (t, 1H), 7.88 (dd, 1H), 8.26 (d, 1H), 10.73 (s, 1H).

Intermediate 54.

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

Tin(II) chloride dihydrate (437 mg, 1.94 mmol) was added to a solution of 2-(3-cyclopropyl-Spyrazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (187 mg, 387 µmol) in dioxane (9 ml) and stirred for 4.5 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 170 mg of crude 5-amino-2-(3-cyclopropyl-1H-pyrazol-1-yl)-N(2,4 -dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (170 mg) was dissolved in DMF (3.3 ml) followed by the addition of (2-chlorophenyl)acetic acid (81 mg, 475 µmol), N,N-diisopropylethylamine (220 µl, 1.3 mmol) and HATU (180 mg, 475 µmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (306 mg, 60% purity, 82% yield over 2 steps).

LC-MS (method B): Rt = 1.39 min; MS (ESI positive): m/z = 581 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 0.61 (m, 2H), 0.87 (m, 2H), 1.89 (m, 1H), 3.57 (s, 3H), 3.68 ( s, 3H), 3.90 (s, 2H), 4.00 (d, 2H), 6.24 (d, 1H), 6.36 (d, 1H), 6.37 (dd, 1H), 7.08 (d, 1H), 7.33 (m , 2H), 7.45 (d, 1H), 7.46 (m, 2H), 7.83 (t, 1H), 7.91 (d, 1H), 7.94 (dd, 1H), 8.10 (d, 1H), 10.66 (s, 1H).

Intermediate 55.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[3,4-b]pyridin-2yl)phenyl}acetamide

- 69 040608

Tin(II) chloride dihydrate (721 mg, 3.19 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-(2H-pyrazolo[3,4-b]pyridin-2-yl)benzenesulfonamide (428 mg, 70% purity, 639 µmol) in dioxane (15 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 339 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(2Hpyrazolo[3,4-b] pyridin-2-yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (339 mg) was dissolved in DMF (6.4 ml) followed by the addition of (2-chlorophenyl)acetic acid (158 mg, 925 µmol), N,N-diisopropylethylamine (430 µl, 2.5 mmol) and HATU (352 mg, 925 µmol). The reaction mixture was stirred for 5 hours at 100°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (751 mg, 45% purity, 89% yield over 2 steps).

LC-MS (method B): Rt = 1.30 min; MS (ESI positive): m/z = 592 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm] 3.68 (s, 3H), 3.69 (s, 3H), 3.93 (s, 2H), 4.03 (d, 2H), 6.37 (dd, 1H ), 6.40 (d, 1H), 7.10 (d, 1H), 7.34 (m, 3H), 7.38 (t, 1H), 7.48 (m, 2Н), 7.63 (d, 1H), 7.99 (dd, 1H) , 8.22 (d, 1H), 8.37 (dd, 1H), 8.47 (s, 1H), 8.52 (dd, 1H), 10.74 (s, 1H).

Intermediate 56.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[3,4-c]pyridin-2yl)phenyl}acetamide

Tin(II) chloride dihydrate (1.39 g, 6.17 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-(2H-pyrazolo[3,4-c]pyridin-2-yl)benzenesulfonamide (610 mg, 1.23 mmol) in dioxane (28 mL) and stirred for 4 h at 70°С. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 498 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(2H-pyrazolo[3.4c] pyridin-2-yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (498 mg) was dissolved in DMF (9.9 ml) followed by the addition of (2-chlorophenyl)acetic acid (246 mg, 1.44 mmol), N,N-diisopropylethylαmine (670 μl, 3.8 mmol) and HATU (549 mg, 1.44 mmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (1.09 g, 50% purity, 75% yield over 2 steps).

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 592 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.67 (s, 3H), 3.69 (s, 3H), 3.94 (s, 2H), 4.00 (d, 2H), 6.36 (dd , 1H), 6.38 (d, 1H), 7.08 (d, 1H), 7.35 (m, 2H), 7.40 (t, 1H), 7.48 (m, 2H), 7.68 (d, 1H), 7.87 (dd, 1H), 8.01 (dd, 1H), 8.25 (d, 1H), 8.35 (d, 1H), 8.53 (s, 1H), 8.80 (s, 1H), 10.79 (s, 1H).

Intermediate 57.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[4,3-b]pyridin-2yl)phenyl}acetamide

- 70 040608

Tin(II) chloride dihydrate (389 mg, 1.72 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-(2H-pyrazolo[4,3-b]pyridin-2-yl)benzenesulfonamide (270 mg, 60% purity, 345 µmol) in dioxane (8 ml) and stirred for 195 min at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 214 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)2-(2H-pyrazolo[4,3-b ]pyridin-2-yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (214 mg) was dissolved in DMF (3 ml) followed by the addition of (2-chlorophenyl)acetic acid (75 mg, 437 µmol), N,N-diisopropylethylamine (25 µl, 150 µmol) and HATU (166 mg, 437 µmol). The reaction mixture was stirred overnight at 80°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (405 mg, 25% purity, 50% yield over 2 steps).

LC-MS (method B): Rt = 1.25 min; MS (ESI negative): m/z = 590 [M-H]-.

Intermediate 58.

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

Tin(II) chloride dihydrate (389 mg, 1.72 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2[4-(2-methoxyethyl)-1H-pyrazol-1-yl]-5-nitrobenzenesulfonamide (928 mg, purity 80%, 1.56 mmol) in dioxane (20 mL) and stirred for 4 h at 70°С. 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 through celite, washed with brine, dried using sodium sulfate and concentrated in vacuo to give 578 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2[4-(2-methoxyethyl)-1H -pyrazol-1-yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (255 mg) was dissolved in DMF (6 ml) followed by the addition of (2-chlorophenyl)acetic acid (195 mg, 1.14 mmol), N,N-diisopropylethylamine (400 μl, 2.3 mmol) and HATU (434 mg, 1.14 mmol). The reaction mixture was stirred for 2 days at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (556 mg, 50% purity, 30% yield over 2 steps).

LC-MS (method A): Rt = 1.32 min; MS (ESI positive): m/z = 599 [M+H]+.

Intermediate 59.

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

- 71 040608

Tin(11) chloride dihydrate (1.21 g, 5.36 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2(3-fluoro-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (550 mg, purity 85 %, 1.07 mmol) in dioxane (25 mL) and stirred for 3 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 1.0 g of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(3-fluoro-1Hpyrazole-1- yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (1.0 g) was dissolved in DMF (7.6 ml) followed by the addition of (2-chlorophenyl)acetic acid (189 mg, 1.11 mmol), K,K-diisopropylethylamine (64 µl, 370 µmol) and HATU (421 mg, 1.11 mmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (847 mg, 40% purity, 57% yield over 2 steps).

LC-MS (method B): Rt = 1.34 min; MS (ESI positive): m/z = 559 [M+H]+.

Intermediate 60.

2-(2-Chlorophenyl)-N-(4-{4-[(2,2-difluoroethyl)amino]-1H-pyrazol-1-yl}-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl)acetamide

Tin(II) chloride dihydrate (318 mg, 1.41 mmol) was added to a solution of 2-{4-[(2,2difluoroethyl)amino]-1H-pyrazol-1-yl}-N-(2,4-dimethoxybenzyl)-5 -nitrobenzenesulfonamide (140 mg, 281 μmol) in dioxane (3.6 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 114 mg of crude 5-amino-2-{4-[(2,2difluoroethyl)amino]-1H-pyrazole-1- yl}-N-(2,4-dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (107 mg) was dissolved in DMF (4.5 ml) followed by the addition of (2-chlorophenyl)acetic acid (48 mg, 282 µmol), N,N-diisopropylethylamine (160 µl, 940 µmol) and HATU (107 mg, 282 µmol). The reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (196 mg, 30% purity, 34% yield over 2 steps).

LC-MS (method B): Rt = 1.27 min; MS (ESI positive): m/z = 620 [M+H]+.

Intermediate 61.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(4-methyl-1H-pyrazol-1-yl)phenyl}-2-(2fluorophenyl)acetamide

Tin(II) chloride dihydrate (1.49 g, 6.61 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2-72 040608 (4-methyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (715 mg , purity 80%, 1.32 mmol) in dioxane (17 mL) and stirred for 4.5 h at 70°С. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 440 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-methyl1H-pyrazole-1- yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (435 mg) was dissolved in DMF (8 ml) followed by the addition of (2-fluorophenyl)acetic acid (187 mg, 1.22 mmol), K,K-diisopropylethylamine (565 µl, 3.2 mmol) and HATU (462 mg, 1.22 mmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (634 mg, 65% purity, 58% yield over 2 steps).

LC-MS (method B): Rt = 1.31 min; MS (ESI positive): m/z = 539 [M+H]+.

1Н-NMR (400 MHz, DMSO-d6) δ [ppm] 2.09 (s, 3Н), 3.60 (s, 3Н), 3.67 (s, 3Н), 3.90 (s, 2H), 4.00 (d, 2H), 6.34 (dd, 1H), 6.35 (d, 1H), 7.06 (d, 1H), 7.33 (m, 2H), 7.44 (d, 1H), 7.46 (m, 2H), 7.60 (s, 1H ), 7.76 (t, 1H), 7.83 (s, 1H), 7.93 (dd, 1H), 8.08 (d, 1H), 10.65 (s, 1H).

Intermediate 62.

2-(2-Fluorophenyl)-N-{4-(4-cyclopropyl-1H-imidazol-1-yl)-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide o o

H ₃ C ^CH 3 o G

Tin(II) chloride dihydrate (650 mg, 2.88 mmol) was added to a solution of 2-(4-cyclopropyl-1nimidazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (440.0 mg, 60% purity). , 576 μmol) in dioxane (13 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 252 mg of crude 5-amino-2-(4-cyclopropyl1H-imidazol-1-yl)-N-(2,4- dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (250 mg) was dissolved in DMF (1.2 ml) followed by the addition of (2-fluorophenyl)acetic acid (27.0 mg, 175 µmol), K,K-diisopropylethylamine (81 µl, 470 µmol) and HATU (67 mg, 175 µmol). The reaction mixture was stirred overnight at 60°C and for another 2.5 h at 100°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (50 mg, 50% purity, 8% yield over 2 steps).

LC-MS (method B): Rt = 1.21 min; MS (ESI positive): m/z = 565 [M+H]+.

Intermediate 63.

K-{4-(3-Cyclopropyl-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide o o n ₃ s U ch ₃ o G

OD1 NH fa/G

Tin(II) chloride dihydrate (783 mg, 3.47 mmol) was added to a solution of 2-(3-cyclopropyl-1Hpyrazol-1-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (530 mg, 60% purity). , 694 μmol) in dioxane (16 ml) and stirred for 4 h at 70°C. 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 through celite, washed with brine, dried using a filter

- 73 040608 ra Whatman and concentrated in vacuo to obtain 315 mg of crude 5-amino-2-(3-cyclopropyl-1Hpyrazol-1-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next stages.

The crude product from the previous step (315 mg) was dissolved in DMF (5.7 ml) followed by the addition of (2-fluorophenyl)acetic acid (127 mg, 827 µmol), N,N-diisopropylethylamine (380 µl, 2.2 mmol) and HATU (314 mg, 827 µmol). The reaction mixture was stirred overnight at 60°C. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (507 mg, 50% purity, 65% yield over 2 steps).

LC-MS (method B): Rt = 1.36 min; MS (ESI positive): m/z = 565 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 0.61 (m, 2H), 0.87 (m, 2H), 1.89 (m, 1H), 3.56 (s, 3H), 3.67 (s , 3Н), 3.79 (s, 2Н), 4.00 (d, 2Н), 6.24 (d, 1H), 6.35 (d, 1H), 6.36 (dd, 1H), 7.07 (d, 1H), 7.33 (m, 2Н), 7.42 (m, 2Н), 7.44 (d, 1H), 7.84 (t, 1H), 7.91 (d, 1H), 7.95 (dd, 1H), 8.07 (d, 1H), 10.64 (s, 1H ).

Intermediate 64.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-[4-(2-methoxyethyl)-1H-pyrazol-1-yl]phenyl}-2-(2fluorophenyl)acetamide

Tin(II) chloride dihydrate (389 mg, 1.72 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2[4-(2-methoxyethyl)-1H-pyrazol-1-yl]-5-nitrobenzenesulfonamide (928 mg, purity 80%, 1.56 mmol) in dioxane (20 mL) and stirred for 4 h at 70°С. 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 through celite, washed with brine, dried using sodium sulfate and concentrated in vacuo to give 578 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2[4-(2-methoxyethyl)-III -pyrazol-1-yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (255 mg) was dissolved in DMF (6 ml) followed by the addition of (2-fluorophenyl)acetic acid (176 mg, 1.14 mmol), N,N-diisopropylethylamine (400 μl, 2.3 mmol) and HATU (434 mg, 1.14 mmol). The reaction mixture was stirred for 2 days at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (503 mg, 50% purity, 28% yield over 2 steps).

LC-MS (method A): Rt = 1.29 min; MS (ESI positive): m/z = 583 [M+H]+.

Intermediate 65.

2-(Benzylsulfanyl)-4-nitrobenzoic acid

To a solution of 2-bromo-4-nitrobenzoic acid (5.00 g, 20.3 mmol) in dioxane (500 ml) was added phenylmethanethiol (2.4 ml, 20.3 mmol), -bis-(diphenylphosphane) (588 mg, 1.02 mmol), tris-(dibenzylideneacetone)dipalladium(0)-chloroform adduct (1.05 g, 1.02 µmol) and N,Ndiisopropylethylamine (7.1 ml, 41 mmol), and the mixture was stirred for 2 h at 100°C. The reaction mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (6.2 g, 96% yield, 85% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI negative): m/z = 288 (M-H)-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.37 (s, 2H), 7.28 (dd, 1H), 7.36 (dd, 2H), 7.47 (d, 2H), 7.99 (dd, 1H), 8.08 (d, 1H), 8.20 (d, 1H).

Intermediate 66.

2-(Benzylsulfanyl)-4-nitrobenzohydrazide

- 74 040608

N,N'-dicyclohexylcarbodiimide (6.6 g, 32 mmol), 1-hydroxypyrrolidine-2,5-dione ( 3.68 g, 32 mmol) and N,N-diisopropylethylamine (5.6 ml, 32 mmol) and the mixture was stirred for 1 h at room temperature. Then hydrazine hydrate (1:1) (1.6 ml, 32 mmol) was added and stirring at room temperature was continued for 21 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (3.71 g, 36% yield, 85% purity).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 304 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.36 (s, 2H), 4.56 (s, 2H), 7.26 (dd, 1H), 7.33 (dd, 2H), 7.41 (d, 2H), 7.56 (d, 1H), 8.01 (dd, 1H), 8.14 (d, 1H), 9.78 (s, 1H).

Intermediate 67.

2-(Benzylsulfanyl)-4-nitro-N'-(trifluoroacetyl)benzohydrazide

To a suspension of 2-(benzylsulfanyl)-4-nitrobenzohydrazide (3.70 g, 85% purity, 10.4 mmol) in acetonitrile (86 mL) was added N,N-diisopropylethylamine (2.2 mL, 12 mmol) and trifluoroacetic acid anhydride (1.6 mL, 11 mmol) at -50°C. The mixture was allowed to warm to room temperature and stirred for 17 hours. The reaction mixture was poured into aqueous sodium hydroxide solution (5%). The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (4.35 g, 84% yield, 80% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI negative): m/z = 398 (M-H) ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.38 (s, 2H), 7.25 (dd, 1H), 7.33 (dd, 2H), 7.42 (d, 2H), 7.66 (d, 1H), 8.03 (dd, 1H), 8.16 (d, 1H).

Intermediate 68.

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-(trifluoromethyl)-1,3,4-oxadiazole

I O

A solution of 2-(benzylsulfanyl)-4-nitro-N'-(trifluoroacetyl)benzohydrazide (4.34 g, 80% purity, 8.69 mmol) and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1 -ide 2,2-dioxide (8.29 g, 34.8 mmol) in tetrahydrofuran (150 mL) was irradiated for 30 min at 150°C in a microwave oven. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (3.28 g, 94% yield, 95% purity).

LC-MS (method A): Rt = 1.43 min; MS (ESI positive): m/z = 382 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.55 (s, 2H), 7.29 (dd, 1H), 7.35 (dd, 2H), 7.47 (d, 2H), 8.16 ( dd, 1H), 8.22 (d, 1H), 8.38 (d, 1H).

- 75 040608

Intermediate 69.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]benzenesulfonamide

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-(trifluoromethyl)-1,3,4-oxadiazole (3.60 g, 95% purity, 8.97 mmol) was stirred with N-chlorosuccinimide (3.59 g, 26.9 mmol) in acetic acid (80 ml) at room temperature for 6 h. The reaction mixture was concentrated in vacuo to give 9.14 g of crude 5-nitro-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl] benzenesulfonyl chloride, which was used without further purification in the next step.

The crude product from the previous step (3.21 g) was dissolved in dichloromethane (42 ml) followed by the addition of sodium hydrogen carbonate (1.51 g, 17.9 mmol) and the slow addition of 1-(2,4dimethoxyphenyl)methanamine (1.31 ml, 9 mmol) at room temperature. The reaction mixture was stirred for 17 hours at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (582 mg, 13% yield, 95% purity).

LC-MS (method A): Rt = 1.31 min; MS (ESI negative): m/z = 487 (M-H)-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.56 (s, 3H), 3.65 (s, 3H), 4.06 (d, 2H), 6.22 (d, 1H), 6.26 (dd, 1H), 6.97 (d, 1H), 8.14 (d, 1H), 8.43 (d, 1H), 8.51 (t, 1H), 8.55 (dd, 1H).

Intermediate 70.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,3,4-oxadiazol2-yl]phenyl}acetamide

Tin(II) chloride dihydrate (1.02 g, 4.51 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]benzenesulfonamide (464 mg, 95% purity, 903 µmol) in dioxane (12 ml) followed by stirring for 7 h at 70° C. and overnight at room temperature. 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 through Celite, dried on a Whatman filter and concentrated in vacuo to give 485 mg of crude 5-aminoN-(2,4-dimethoxybenzyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2 -yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (207 mg) was dissolved in DMF (9 ml) followed by the addition of (2-chlorophenyl)acetic acid (154 mg, 902 µmol), N,N-diisopropylethylamine (310 µl, 1.8 mmol) and HATU (343 mg, 902 µmol). The reaction mixture was stirred for 5 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (369 mg, 40% purity, 10% yield over 2 steps).

LC-MS (method A): Rt = 0.81 min; MS (ESI negative): m/z = 609 (M-H)-.

Intermediate 71.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}-2-(2fluorophenyl)acetamide

- 76 040608

Tin(II) chloride dihydrate (1.02 g, 4.51 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]benzenesulfonamide (464 mg, 95% purity, 903 µmol) in dioxane (12 ml) followed by stirring for 7 h at 70° C. and overnight at room temperature. 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 through Celite, dried on a Whatman filter and concentrated in vacuo to give 485 mg of crude 5-aminoN-(2,4-dimethoxybenzyl)-2-[5-(trifluoromethyl)-1,3,4-oxadiazol-2 -yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (207 mg) was dissolved in DMF (9 mL) followed by the addition of (2-fluorophenyl)acetic acid (139 mg, 902 µmol), N,N-diisopropylethylamine (310 µL, 1.8 mmol) and HATU (343 mg, 902 µmol). The reaction mixture was stirred for 5 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (403 mg, 40% purity, 16% yield over 2 steps).

LC-MS (method A): Rt = 0.77 min; MS (ESI negative): m/z = 593 (M-H)-.

Intermediate 72.

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

O'CHz o=s=o L .sn ₃ νά* II O

2-Bromo-5-nitrobenzenesulfonyl chloride (5.00 g, 16.6 mmol) was dissolved in dichloromethane (48 ml) and sodium bicarbonate (2.80 g, 33.3 mmol) was added followed by the slow addition of 1-(2,4dimethoxyphenyl)methanamine (2.7 ml, 18 mmol ). The reaction mixture was stirred for 30 min at room temperature. Dichloromethane and water were added. The phases were separated and the organic phase was washed with brine. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was crystallized from diethyl ether (5.57 g, 78% yield).

LC-MS (method B): Rt = 1.16 min; MS (ESI negative): m/z = 429 [M-H]-.

Intermediate 73.

5-Amino-2-bromo-N-(2,4-dimethoxybenzyl)benzenesulfonamide

Ammonium chloride (3.52 g, 65.7 mmol) and iron powder (3.67 g, 65.7 mmol) were suspended in water (150 ml). Then a solution of 2-bromo-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (5.67 g, 13.1 mmol) in THF/methanol (1/1; 150 ml) was added and the reaction mixture was heated at 80°C for 2 hours After that, the mixture was filtered through celite, the solvent was removed under reduced pressure. The crude product was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (5.10 g, 96% purity, 97% yield).

LC-MS (method A): Rt = 1.05 min; MS (ESI negative): m/z = 399 [M-H]-.

Intermediate 74.

N-{4-Bromo-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2-chlorophenyl)acetamide

- 77 040608

5-Amino-2-bromo-N-(2,4-dimethoxybenzyl)benzenesulfonamide (5.00 g, 12.5 mmol) was dissolved in DMF (100 mL) and (2-chlorophenyl)acetic acid (2.55 g, 15.0 mmol) was added followed by addition of Ν,N-diisopropylethylamine (11 ml, 62 mmol) and HATU (6.16 g, 16.2 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give the title compound (5.70 g, 94% purity, 83% yield).

LC-MS (method A): Rt = 1.29 min; MS (ESI negative): m/z = 551 [M-H]-.

Intermediate 75.

2-Bromo-5-nitrobenzenesulfonamide

2-Bromo-5-nitrobenzenesulfonyl chloride (20.0 g, 66.6 mmol) was dissolved in 1,4-dioxane (100 ml) and cooled to 0°C. An aqueous ammonia solution (400 mL, 0.50 M, 200 mmol) was added slowly and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and dichloromethane was added. The organic phase was washed three times with water. The suspension was filtered (solid - product) and the organic phase was washed with brine. The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude product was recrystallized from diethyl ether to give 16.4 g of the final product (purity 93%, yield 88%).

LC-MS (method B): Rt = 0.45 min; MS (ESI positive): m/z = 281 [M+H]+.

Intermediate 76.

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide

2-Bromo-5-nitrobenzenesulfonamide (16.4 g, 58.3 mmol) was dissolved in DMF (200 ml) at room temperature and 1,1-dimethoxy-N-Nimethylmethanamine (15 ml, 120 mmol) was added. Stirring was continued until completion of the reaction. The solvent was removed under reduced pressure and the crude product was partitioned between dichloromethane and brine. The organic phase was dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (19.2 g, 78% purity, 98% yield).

LC-MS (method A): Rt = 0.92 min; MS (ESI positive): m/z = 336 [M+H]+.

Intermediate 77.

-Amuho-2-6pom-N -[(dimethylamino)methylidene]benzenesulfonamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (12.7 g, 37.8 mmol) was dissolved in methanol (170 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 1.61 g, 8.26 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring continued

- 78 040608 at room temperature until the reaction is complete. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (5.5 g, 76% purity, 59% yield).

LC-MS (method A): Rt = 0.75 min; MS (ESI positive): m/z = 306 [M+H]+.

Intermediate 78.

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide n ₃ %. SN ₃

S o=s=o rad Cl ⁿ

5-Amino-2-bromo-N-[(dimethylamino)methylidene]benzenesulfonamide (4.85 g, 15.8 mmol) was dissolved in DMF (100 mL) and (2-chlorophenyl)acetic acid (3.24 g, 19.0 mmol) was added followed by N,N-diisopropylethylamine (13 ml, 79 mmol) and HATU (9.64 g, 25.3 mmol). The reaction mixture was stirred for 3 hours at 50°C. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was suspended in dichloromethane and filtered, the solvent was removed and the crude product was used without further purification in the next step (15.7 g).

LC-MS (method B): Rt = 1.08 min; MS (ESI positive): m/z = 458 [M+H]+.

This intermediate can also be used as the HCl salt.

Intermediate 79.

N-(4-Bromo-3-{(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-fluorophenyl)acetamide n ₃ % _x SN ₃

S o=s=o raD'

5-Amino-2-bromo-N-[(dimethylamino)methylidene]benzenesulfonamide (1.00 g, 3.27 mmol) was dissolved in DMF (21 mL) and (2-fluorophenyl)acetic acid (604 mg, 3.92 mmol) was added followed by N,N-diisopropylethylamine (2.7 ml, 16 mmol) and HATU (1.99 g, 5.23 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was suspended in tert-butyl methyl ether/hexane (1/1), filtered and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (1.17 g, 85% purity, 81% yield).

LC-MS (method B): Rt = 1.05 min; MS (ESI positive): m/z = 442 [M+H]+.

Intermediate 80.

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chloro-4-fluorophenyl)acetamide

Н ₃ %хСН ₃ % o=s=o 'idL” Cl ⁿ

5-Amino-2-bromo-N-[(dimethylamino)methylidene]benzenesulfonαmide (1.00 g, 3.27 mmol) was dissolved in DMF (21 mL) and (2-chloro-4-fluorophenyl)acetic acid (739 mg, 3.92 mmol) was added ) followed by the addition of N,N-diisopropylethylamine (2.7 ml, 16 mmol) and HATU (1.99 g, 5.23 mmol). The reaction mixture was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure and water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was triturated in dichloromethane and diethyl ether and filtered. The solid was used in the next step without further purification (1.10 g, 82% purity, 71% yield).

LC-MS (method A): Rt = 1.12 min; MS (ESI negative): m/z = 474 [M-H]-.

- 79 040608

Intermediate 81.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-( 1H-pyrazol-4yl)phenyl]acetamide

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(tetrahydro-2H-pyran-2-yl)1H-pyrazol-4-yl]phenyl)acetamide (1.30 g, 2.45 mmol) was dissolved in dichloromethane (20 ml) and trifluoroacetic acid (4.7 ml, 61 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was co-distilled with toluene and used without further purification in the next step.

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 446 [M+H]+.

Intermediate 82.

4-Amino-X-(2,4-dimethoxybenzyl)biphenyl-2-sulfonamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (300 mg, 776 µmol) and phenylboronic acid (113 mg, 931 µmol) were dissolved in DMF (10 ml) and [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) (1:1) (CAS 95464-05-4) (127 mg, 155 µmol) and aqueous potassium carbonate solution (1.2 ml, 1.0 M, 1.2 mmol). The reaction mixture was heated at 120° C. for 1 hour in a microwave oven. After that, water and ethyl acetate were added and the phases were separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 260 mg of final product (99% purity, 78% yield).

LCMS (method A): Rt = 1.33 min; MS (ESI positive): m/z = 429 [M+H]+.

N-(2,4-dimethoxybenzyl)-4-nitrobiphenyl-2-sulfonamide (260 mg, 607 μmol) was dissolved in THF (15 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 6.46 mg, 60.7 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature until completion of the reaction. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (270 mg).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 399 [M+H]+.

Intermediate 83.

5-Amino-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide

2-Bromo-5-nitrobenzenesulfonamide (800 mg, 2.85 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (1.18 g, 5.69 mmol) was dissolved in n-propanol (38 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (100 mg, 142 μmol), triphenylphosphine (37.3 mg, 142 μmol) and aq. . potassium carbonate solution (4.3 ml, 2.0 M, 8.5 mmol). The reaction mixture was purged with argon for 5 min and then heated at 120° C. for 1 h in a microwave oven (4 bar/40 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with methanol and used without further purification in the next step.

2-(1-Methyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (800 mg, 2.83 mmol) was dissolved in THF (78 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 308 mg, 2.89 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature until completion of the reaction. The reaction mixture was filtered through celite and a solution

- 80 040608 the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step (1.6 g).

LC-MS (method B): Rt = 0.50 min; MS (ESI positive): m/z = 253 [M+H]+.

Intermediate 84.

5-Amino-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide

2-Chloro-5-nitrobenzenesulfonamide (674 mg, 2.85 mmol) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g, 4.27 mmol) was dissolved in n-propanol (34 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (100 mg, 142 μmol) and triphenylphosphine (37.3 mg, 142 μmol) were added. The reaction mixture was purged with argon for 5 min and aq. potassium carbonate solution (5.7 ml, 1.0 M, 5.7 mmol). The reaction mixture was heated at 100° C. for 3 hours. After that, the mixture was filtered through celite and the solvent was removed under reduced pressure. Ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(1-Cyclopropyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (1.17 g, 3.79 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1.0 ml, 7.6 mmol) were dissolved in DMF (25 ml) and the reaction mixture was stirred at room temperature until completion of the reaction. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(1-Cyclopropyl-1H-pyrazol-4-yl)-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (1.84 g, 5.06 mmol) was dissolved in THF (30 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 53.9 g, 506 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature until completion of the reaction. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (1.3 g, purity 53%, yield over 3 steps 75%).

LC-MS (method A): Rt = 0.70 min; MS (ESI positive): m/z = 334 [M+H]+.

Intermediate 85.

5-Amino-2-(1-tert-butyl-1H-pyrazol-4-yl)benzenesulfonamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (200 mg, 686 µmol) and 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (206 mg, 823 µmol) was dissolved in npropanol (9.2 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (24.1 mg, 34.3 µmol), triphenylphosphine was added (8.99 mg, 34.3 µmol) and aq. potassium carbonate solution (860 μl, 2.0 M, 1.7 mmol). The reaction mixture was purged with argon for 5 min and heated at 80° C. for 16 h. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

2-(1-tert-Butyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (250 mg, 771 μmol) was dissolved in methanol (50 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 83.6 mg, 786 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature until completion of the reaction. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (230 mg).

LC-MS (method A): Rt = 0.80 min; MS (ESI positive): m/z = 295 [M+H]+.

Intermediate 86.

5-Amino-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide

2-(1-Methyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (800 mg, 2.83 mmol) was dissolved in meta

- 81 040608 zero (100 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 308 mg, 2.89 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued until completion of the reaction. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step (1.59 g).

LC-MS (method B): Rt = 0.50 min; MS (ESI positive): m/z = 253 [M+H]+.

Intermediate 87.

5-Amino-N-[(dimethylamino)methylidene]-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]benzenesulfonamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (2.0 g, 6.86 mmol) and 1(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (3.81 g, 13.7 mmol) was dissolved in n-propanol (92 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03) was added -2) (241 mg, 342 µmol), triphenylphosphine (90 mg, 340 µmol) and aq. potassium carbonate solution (8.6 ml, 2.0 M, 17 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80° C. for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

5-Nitro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-n-nirazol-4-yl]benzenesulfonamide (3.00 g, 8.51 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine ( 2.3 ml, 17 mmol) was dissolved in DMF (29 ml) and stirred for 24 h at room temperature. The solvent was removed under reduced pressure and dichloromethane and brine were added. The phases were separated and the organic phase was washed with water. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

N-[(Dimethylamino)methylidene]-5-nitro-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl]benzenesulfonamide (3.50 g, 8.59 mmol) was dissolved in methanol (860 ml ) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 932 mg, 8.76 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature. After 1 hour, the flask was evacuated three times and filled with hydrogen. Stirring was continued for 3 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (3.4 g).

LC-MS (method A): Rt = 0.88 min; MS (ESI positive): m/z = 378 [M+H]+.

Intermediate 88.

5-Amino-2-(1-cyclopentyl-1H-π-pyrazol-4-yl)benzenesulfonamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (550 mg, 1.89 mmol) and 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-III-pyrazole (989 mg, 3.77 mmol) was dissolved in n-propanol (25 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (66.4 mg, 94.3 µmol), triphenylphosphine was added (24.7 mg, 94.3 µmol) and aq. potassium carbonate solution (2.4 ml, 2.0 M, 4.7 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80° C. for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

2-(1-Cyclonentyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (640 mg, 1.90 mmol) was dissolved in methanol (50 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 206 mg, 1.94 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (590 mg).

LC-MS (method A): Rt = 0.87 min; MS (ESI positive): m/z = 307 [M+H]+.

Intermediate 89.

5-Amino-2-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]benzenesulfonamide

- 82 040608

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (550 mg, 1.89 mmol) and 1-(2methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-III-pyrazole (951 mg, 3.77 mmol) was dissolved in n-propanol (25 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (66.4 mg, 94.3 µmol), triphenylphosphine (24.7 mg, 94.3 µmol) and aq. potassium carbonate solution (2.4 ml, 2.0 M, 4.7 mmol). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step.

2-[1-(2-Methoxyethyl)-1H-pyrazol-4-yl]-5-nitrobenzenesulfonamide (620 mg, 1.90 mmol) was dissolved in methanol (50 ml) and the flask was purged with nitrogen. Thereafter, palladium on charcoal (load 10%, 206 mg, 1.94 mmol) was added and the flask was evacuated and refilled with hydrogen (1 bar). The reaction mixture was stirred at room temperature until completion of the reaction. The mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (580 mg).

LC-MS (method A): Rt = 0.59 min; MS (ESI positive): m/z = 297 [M+H]+.

Intermediate 90.

5-Amino-2-(1,3-dimethyl-1H-pyrazol-5-yl)benzenesulfonamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (400 mg, 1.19 mmol) and (1,3dimethyl-1H-pyrazol-5-yl)boronic acid (333 mg, 2.38 mmol) were dissolved in n- propanol (110 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (41.9 mg, 59.5 µmol), triphenylphosphine (21.6 mg, 59.5 µmol) and aq. potassium carbonate solution (1.8 ml, 2.0 M, 3.6 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 120° C. for 1 h in a microwave oven (4 bar/40 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with methanol and used without further purification in the next step.

2-(1,3-Dimethyl-1H-pyrazol-5-yl)-5-nitrobenzenesulfonamide (450 mg, 1.52 mmol) was dissolved in methanol (33 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 165 mg, 1.55 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step (435 mg).

LC-MS (method B): Rt = 0.56 min; MS (ESI positive): m/z = 267 [M+H]+.

Intermediate 91.

5-Amino-2-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (550 mg, 1.89 mmol) and 1-methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-3-(trifluoromethyl)-1H-pyrazole (1.04 g, 3.77 mmol) was dissolved in n-propanol (25 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-032) (66.4 mg, 94.3 µmol), triphenylphosphine (24.7 mg, 94.3 µmol) and aq. potassium carbonate solution (2.4 ml, 2.0 M, 4.7 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80° C. for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

2-[1-Methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-5-nitrobenzenesulfonamide (660 mg, 1.88 mmol) was dissolved in methanol (190 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 375 mg, 1.92 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 18 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without additional

- 83 040608 thorough purification in the next stage (600 mg).

LC-MS (method A): Rt = 0.86 min; MS (ESI positive): m/z = 321 [M+H]+.

Intermediate 92.

5-Amino-N-[(dimethylamino)methylidene]-2-[5-(trifluoromethyl)pyridin-3-yl]benzenesulfonamide

5-Amino-2-bromo-N-[(dimethylamino)methylidene]benzenesulfonamide (300 mg, 980 µmol) and [5(trifluoromethyl)pyridin-3-yl]boronic acid (374 mg, 1.96 mmol) were dissolved in DMF (27 ml) and triphenylphosphine (12.8 mg, 49.0 µmol) and potassium fluoride (14.2 mg, 245 µmol) were added. The solution was purged with argon for 5 min and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-032) (34.5 mg, 49.0 µmol) was added followed by addition of aq. potassium phosphate solution (730 µl, 2.0 M, 1.5 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (365 mg).

LC-MS (method B): Rt = 0.91 min; MS (ESI positive): m/z = 373 [M+H]+.

Intermediate 93.

-Amino-2-(1,3-dimethyl-1 H-pyrazol-4-yl)benzenesulfonamide nh ₂ pH ₃ O=S=O

J. JL/ ¹ JL J CH ₃

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (550 mg, 1.89 mmol) and 1,3dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazole (837 mg, 3.77 mmol) was dissolved in n-propanol (25 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (66.4 mg, 94.3 µmol) was added , triphenylphosphine (24.7 mg, 94.3 µmol) and aq. potassium carbonate solution (2.4 ml, 2.0 M, 4.7 mmol). The reaction mixture was heated at 80° C. for 16 hours. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step.

2-(1,3-Dimethyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (560 mg, 1.89 mmol) was dissolved in methanol (50 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 205 mg, 1.93 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 16 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (500 mg).

LC-MS (method A): Rt = 0.63 min; MS (ESI positive): m/z = 267 [M+H]+.

Intermediate 94.

-Amino-2-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl] benzenesulfonamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (800 mg, 2.3 mmol) and 1(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)-1H-pyrazole (700 mg, 2.87 mmol) was dissolved in n-propanol (15 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (84 mg, 119 µmol) was added ) and triphenylphosphine (31 mg, 119 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (3.6 ml, 2.0 M, 7.2 mmol). The reaction mixture was heated at 100° C. for 16 hours. Water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (2.16 g, 5.79 mmol) was dissolved in tetrahydrofuran (50 ml) and platinum on charcoal was added (load 5%, 307 mg, 1.57 mmol). The flask was evacuated three times and filled with hydrogen (1 bar). The reaction mixture was stirred for 4 hours at room temperature. According to UHPLC-MS, the reaction was not yet complete, so the same amount of platinum on charcoal was added and the reaction

- 84 040608 the mixture was stirred in the atmosphere for an additional 16 hours. After that, the mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

5-Amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(dimethylamino)methylidene]benzenesulfonamide (670 mg, 1.95 mmol) was dissolved in methanol (25 ml) and treated with 25% aqueous ammonia solution (25 ml) at room temperature until the reaction is complete. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, dichloromethane/ethyl acetate gradient) followed by HPLC purification ((Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water+0.1% formic acid) to give 53 mg of final product (purity 99%, yield over 3 steps 9%) The reactions were repeated and the crude product was used for the next steps using this intermediate.

LC-MS (method B): Rt = 0.58 min; MS (ESI positive): m/z = 289 [M+H]+.

Intermediate 95.

tert-Butyl 4-[4-(4-amino-2-sulfamoylphenyl)-III-pyrazol-1-yl]piperidine-1-carboxylate

2-Chloro-X-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (250 mg, 857 µmol) and tert-butium 4-[4-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolane-2 -yl)-1 H-pyrazol-1 -yl]piperidine-1-carboxylate (485 mg, 1.29 mmol) was dissolved in n-propanol (12 mL) and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03) was added -2) (30.2 mg, 42.9 µmol), triphenylphosphine (11.2 mg, 42.9 µmol) and aq. potassium carbonate solution (1.1 ml, 2.0 M, 2.1 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80° C. for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

tert-Butyl 4-[4-(4-nitro-2-sulfamoylphenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (400 mg, 886 μmol) was dissolved in tetrahydrofuran (89 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 96.1 mg, 904 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (380 mg).

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 422 [M+H]+.

Intermediate 96.

1-(Oxetan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1I-pyrazole (500 mg, 2.58 mmol) was dissolved in DMF (20.0 ml) and 2-(bromomethyl) was added oxetane (778 mg, 5.15 mmol) and cesium carbonate (1.68 g, 5.15 mmol). The reaction mixture was heated for 1 h at 100° C. in a microwave oven (0 bar/18 W). The suspension was filtered and the solvent was removed under reduced pressure. The reagent was used without further purification in the next step (770 mg).

LC-MS (method B): Rt = 0.83 min; MS (ESI positive): m/z = 266 [M+H]+.

Intermediate 97.

5-Bromo-2-chloro-N-[(dimethylamino)methylidene]pyridine-3-sulfonamide

5-Bromo-2-chloropyridine-3-sulfonamide (3.86 g, 14.2 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (3.8 ml, 28 mmol) were dissolved in DMF (40 ml) and stirred for 2 h at room temperature. The solvent was removed under reduced pressure and dichloromethane and brine were added. The phases were separated and the organic phase was washed with water. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (5.12 g).

LC-MS (method B): Rt = 0.89 min; MS (ESI positive): m/z = 326 [M+H]+.

- 85 040608

Intermediate 98.

2-Chloro-N-[(dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]pyridine-3-sulfonamide

5-Bromo-2-chloro-N-[(dimethylamino)methylidene]pyridine-3-sulfonamide (5.00 g, 15.3 mmol), 1,1diphenylmethanimine (3.9 ml, 23 mmol), XantPhos (886 mg, 1.53 mmol) and acetate palladium(II) (172 mg, 765 µmol) was dissolved in dioxane (150 ml). The solution was purged with argon for 5 min and cesium carbonate (15.0 g, 45.9 mmol) was added. The reaction mixture was heated at 100° C. for 1 hour. After that, the solvent was removed under reduced pressure, and water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate.

The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. Half of the crude product was used without further purification and 3 g was purified by ammonia-coated silica gel chromatography (Biotage, hexane/ethyl acetate) to give 1.00 g of final product (78% purity, 15% yield based on total starting material).

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 427 [M+H]+.

Intermediate 99.

2-[1-(Difluoromethyl)-1H-n-pyrazol-4-yl]-N-[(dimethylamino)methylidene]-5[(diphenylmethylidene)amino]pyridine-3-sulfonamide

2-Chloro-N-[(dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]π-pyridine-3-sulfonamide (1.50 g, 3.51 mmol, crude) and 1-(difluoromethyl)-4-(4.4.5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.71 g, 7.03 mmol) was dissolved in n-propanol (30 ml)/DMF (15 ml) and bis(triphenylphosphine) dichloride was added )palladium(II) (CAS 13965-03-2) (371 mg, 527 µmol), triphenylphosphine (225 mg, 0.85 mmol), potassium fluoride (408 mg, 7.03 mmol) and aq. potassium phosphate solution (1.8 ml, 2.0 M, 3.5 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 100° C. for 1 h in a microwave oven (1 bar/30 W). The solvent was removed under reduced pressure and water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by ammonia-coated silica gel chromatography (Biotage, hexane/ethyl acetate) (1.54 g, 65% purity, 86% yield).

LC-MS (method B): Rt = 1.26 min; MS (ESI positive): m/z = 509 [M+H]+.

Intermediate 100.

-Amino-2-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl] -N-[(dimethylamino)methylidene] pyridine-3 sulfonamide

2-[1-(Difluoromethyl)-1H-n-pyrazol-4-yl]-N-[(dimethylamino)methylidene]-5[(diphenylmethylidene)amino]pyridine-3-sulfonamide (1.54 g, 3.03 mmol) was dissolved in dioxane ( 15 ml) and aq. HCl (2.0 ml, 3.0 M, 6.1 mmol). The reaction mixture was stirred for 1 hour at room temperature. The solvent was removed under reduced pressure and the crude product was used

- 86 040608 without further purification in the next step (2.45 g).

LC-MS (method B): Rt = 0.66 min; MS (ESI positive): m/z = 345 [M+H]+.

Intermediate 101.

N-[(Dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]-2-(1-methyl-1H-pyrazole-4-

DMF was dried over molecular sieves and purged with argon. Then 2-χλορ-Ν[(dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]pyridine-3-sulfonamide (350 mg, 820 µmol), 1-methyl-4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-1H-pyrazole (341 mg, 1.64 mmol) and potassium fluoride (143 mg, 2.46 mmol) were dissolved in dry and degassed DMF (15 ml) and the solution was again purged with argon in for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (251 mg, 492 µmol). The reaction mixture was heated for 18 hours at 100°C. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (450 mg).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 473 [M+H]+.

Intermediate 102.

5-Amino-N-[(dimethylamino)methylidene]-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3-sulfonamide

N-[(Dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]-2-(1-methyl-1H-pyrazol-4yl)pyridine-3-sulfonamide (430 mg, 910 µmol) was dissolved in dioxane (16.0 ml) and an aqueous solution of HCl (610 μl, 3.0 M, 1.8 mmol) was added and the reaction mixture was stirred for 1 h at room temperature. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (500 mg).

LC-MS (method B): Rt = 0.52 min; MS (ESI positive): m/z = 309 [M+H]+.

Intermediate 103.

N-[(Dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]-5'-(trifluoromethyl)-2,3'-bipyridine-3sulfonamide

2-Chloro-N-[(dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]pyridine-3-sulfonamide (150 mg, 351 µmol) and [5-(trifluoromethyl)pyridin-3-yl]boronic acid (80.5 mg, 422 µmol) was dissolved in n-propanol (10 mL) and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (12.4 mg, 17.6 µmol), triphenylphosphine (4.61 mg, 17.6 µmol) was added and water, potassium carbonate solution (1.1 ml, 1.0 M, 1.1 mmol). The reaction mixture was heated at 100° C. for 1 hour. The solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was dissolved in DMF (10 ml) and 1,1 dimethoxy-N,N-dimethylmethanamine (140 μl, 1.1 mmol) was added. The reaction mixture was stirred at room

- 87 040608 nay temperature for 2 hours the Solvent was removed under reduced pressure and the crude product was used without further purification in the next stage (260 mg).

LC-MS (method B): Rt = 1.33 min; MS (ESI positive): m/z = 538 [M+H]+.

Intermediate 104.

5-Amino-N-[(dimethylamino)methylidene]-5'-(trifluoromethyl)-2,3'-bipyridine-3-sulfonamide

N-[(Dimethylamino)methylidene]-5-[(diphenylmethylidene)amino]-5'-(trifluoromethyl)-2,3'-bipyridine-3 sulfonamide (230 mg, 428 µmol) was dissolved in dioxane (20 ml) and added aq. HCl solution (290 μl, 3.0 M, 860 μmol) and stirring was continued at room temperature for 2 h. After that, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (250 mg).

LC-MS (method B): Rt = 0.81 min; MS (ESI positive): m/z = 374 [M+H]+.

Intermediate 105.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol), 4.4.4'.4'.5.5 ,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (346 mg, 1.4 mmol) and CataXCium A Pre Cat (20.0 mg, 27.2 µmol) were dissolved in methanol (10 ml) and N,N-diisopropylethylamine (237 μl, 1.4 mmol) was added under argon. The reaction mixture was stirred for 2 hours at 50°C. The solution as such was used in the next step.

The reaction was performed exclusively on this scale several times.

LC-MS (method B): Rt = 1.23 min; MS (ESI positive): m/z = 506 [M+H]+.

Intermediate 106.

5-Amino-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide

2-Bromo-4-nitrobenzoic acid (1.50 g, 6.10 mmol) was dissolved in DMF (50 mL) and cyclopropanecarbohydrazide (671 mg, 6.71 mmol), HATU (2.78 g, 7.32 mmol) and N,N-diisopropylethylαmin (5.3 mL) were added. , 30 mmol). The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (7.9 g).

2-Bromo-N'-(cyclopropylcarbonyl)-4-nitrobenzohydrazide (7.87 g, 24.0 mmol) was dissolved in DMF (100 ml) and N,N-diisopropylethylamine (8.4 ml, 48 mmol) and 4-methylbenzenesulfonyl chloride (4.57 g, 24.0 mmol). The reaction mixture was stirred at room temperature for 2 hours. The same amount of reagent was added and stirring continued for 2 hours. After that, the solvent was removed under reduced pressure and the crude product was dissolved in ethyl acetate. After washing with water, the aqueous phase was extracted three times with ethyl acetate and the combined organic layers were dried on a Whatman filter. The crude product was purified on silica gel (Biotage, hexane/ethyl acetate) to give 1.35 g of final product (85% purity, 18% yield over 2 steps).

LC-MS (method B): Rt = 1.16 min; MS (ESI positive): m/z = 310 [M+H]+.

2-(2-Bromo-4-nitrophenyl)-5-cyclopropyl-1,3,4-oxadiazole (1.00 g, 3.22 mmol) was dissolved in 1,4dioxane (75 ml) and XantPhos (93.3 mg, 161 µmol) was added, dipalladium-tris complex

- 88 040608 (dibenzylideneacetone) chloroform (CAS 52522-40-4) (167 mg, 161 µmol) and N,N-diisopropylethylamine (1.1 ml, 6.4 mmol). The reaction mixture was heated to 100°C and a solution of phenylmethanethiol (360 μl, 3.1 mmol) in 1,4-dioxane (1 ml) was added. Stirring was continued for 1 hour at 100°C. Thereafter, the solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (1.42 g).

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-cyclopropyl-1,3,4-oxadiazole (1.42 g, 4.02 mmol) was dissolved in acetic acid (40 ml) and N-chlorosuccinimide (1.61 g, 12.1 mmol), and the reaction mixture was stirred for 3 h at room temperature. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (1.96 g).

2-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-5-nitrobenzenesulfonyl chloride (1.96 g, 5.94 mmol) was added to a solution of ammonia in 1,4-dioxane (0.5 M, 300 ml) and stirring was continued for 16 hours at room temperature. The solvent was removed under reduced pressure and the crude product was redissolved in 1,4-dioxane (100 ml) and treated with concentrated ammonia until the reaction was complete. The solvent was removed under reduced pressure. The crude product was suspended in 1,4dioxane and the suspension was filtered. The filtrate was concentrated and HPLC purification (three times, Chromatorex C-18 10 µm, 125×30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) gave a pure product weighing 3.6 g (194%, 43% purity). .

LC-MS (method A): Rt = 0.88 min; MS (ESI positive): m/z = 311 [M+H] ⁺ .

2-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-5-nitrobenzenesulfonamide (3.60 g, 11.6 mmol) was dissolved in DMF (40 ml) and 1,1-dimethoxy-N,N-dimethylmethanamine was added (3.1 ml, 23 mmol). The reaction mixture was stirred at room temperature until completion of the reaction. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The pure compound was obtained after silica gel chromatography (Biotage, hexane/ethyl acetate) (0.4 g, 99% purity, 9% yield).

LC-MS (method B): Rt = 0.91 min; MS (ESI positive): m/z = 366 [M+H] ⁺ 2-(5-Cyclopropyl-1,3,4oxadiazol-2-yl)-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (400 mg, 1.09 mmol) was dissolved in THF (200 mL) and platinum on charcoal was added (load 5%, 214 mg, 109 μmol). The flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued for 4 hours at room temperature. LC-MS indicated that the reaction was not complete. The mixture was filtered through Celite and the solvent was removed under reduced pressure. The crude product was dissolved in ethanol (200 ml) and palladium on charcoal was added (load 10%, 214 mg, 109 µmol). The flask was evacuated and then filled with hydrogen (1 bar) and the reaction mixture was stirred for 3 h. After this, more catalyst (214 mg, 109 μmol) was added and stirring was continued for another 3 h. The mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (260 mg, 85% purity, 70% yield).

LC-MS (method A): Rt = 0.71 min; MS (ESI positive): m/z = 336 [M+H] ⁺ .

Intermediate 107.

2-[4-(Difluoromethyl)-1H-pyrazol-1-yl]-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide

H3C^CH3

2-Chloro-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (2.02 g, 6.94 mmol) and 1-(1Hpyrazol-4-yl)ethanone (1.00 g, 10.4 mmol) were dissolved in acetonitrile, powdered potassium carbonate ( 2.88 g, 20.8 mmol) and the reaction mixture was stirred at 100°C overnight. The reaction mixture was then concentrated in vacuo and extracted with dichloromethane/water. The organic phase was washed again with brine, followed by drying over sodium sulfate and concentration in vacuo.

Since the protecting groups were partially lost, the product was redissolved in DMF (6.6 ml) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.882 g, 7.4 mmol) was added. The reaction mixture was stirred overnight, concentrated in vacuo and extracted with dichloromethane/water. The organic phase was washed again with brine, followed by drying over sodium sulfate and concentration in vacuo to provide 1.3 g of crude N-[(dimethylamino)methylene]-2-(3-formyl-1Hpyrazol-1-yl)-5-nitrobenzenesulfonamide.

Bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®; 3.09 ml 2.7M solution in toluene, 8.34

- 89 040608 mmol) was added to the crude product from the previous stage (1.03 g, 2.94 mmol) and the reaction mixture was stirred for 5 h at 80°C. Ethyl acetate and 2M aqueous potassium carbonate were added for extraction. The organic phase was dried over sodium sulfate and concentrated in vacuo. Purification by (flash) column chromatography on a Biotage system gave the title compound (600 mg, 1.61 mmol, 24% yield over 3 steps, 90% purity).

LC-MS (method A): Rt = 0.96 min; MS (ESI positive): m/z = 374 [M+H]+.

Intermediate 108.

5-Amino-2-(4-cyano-1H-pyrazol-1-yl)-N-[(dimethylamino)methylene]pyridine-3-sulfonamide

2-Chloro-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]pyridine-3-sulfonamide (480 mg, 1.12 mmol) was dissolved in DMSO (14 mL). 1H-pyrazole-4-carbonitrile (209 mg, 2.25 mmol), potassium iodide (187 mg, 1.12 mmol) and potassium phosphate (358 mg, 1.69 mmol) were added and the reaction mixture was stirred overnight at 100°C. Thereafter, the reaction mixture was concentrated in vacuo, extracted with dichloromethane/water, and the organic phase was washed with brine and dried over sodium sulfate, followed by concentration in vacuo.

Due to partial deprotection, the material was redissolved in DMF (2 ml) and stirred overnight with 1,1-dimethoxy-N,N-dimethylmethanamine (0.4 ml). Thereafter, the reaction mixture was concentrated in vacuo, extracted with dichloromethane/water, and the organic phase was washed with brine and dried over sodium sulfate, followed by concentration in vacuo.

LC-MS (method A): Rt = 1.22 min, MS (ESI positive): m/z = 484 [M+H]+.

The compound from the previous step was dissolved in dioxane (2.5 ml) and a 2M solution of HCl in dioxane (1.18 ml, 2.36 mmol) was added, followed by stirring overnight. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate/water. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (110 mg) which was used without further purification in the next steps.

LC-MS (method A): Rt = 0.58 min, MS (ESI positive): m/z = 320 [M+H]+.

Intermediate 109.

5-Amino-2-(4-chloro-1H-pyrazol-1-yl)-N-[(dimethylamino)methylene]pyridine-3-sulfonamide h ₃ c. _{n.ch 3}

S

O=S=O N=\ r Η

Η ₂ Ν^^

2-Chloro-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]-pyridine-3-sulfonamide (1.00 g, 2.34 mmol) was dissolved in DMSO (18 ml). 4-Chloro-1H-pyrazole (480 mg, 4.69 mmol), potassium iodide (389 mg, 2.34 mmol) and potassium phosphate (746 mg, 3.51 mmol) were added and the reaction mixture was stirred overnight at 100°C. Thereafter, the reaction mixture was concentrated in vacuo, extracted with dichloromethane/water, and the organic phase was washed with brine and dried over sodium sulfate, followed by concentration in vacuo.

Due to partial deprotection, the material was redissolved in DMF (2 ml) and stirred overnight with 1,1-dimethoxy-N,N-dimethylmethanamine (0.5 ml). Stirring overnight resulted in a precipitate which was removed by filtration (229 mg, pure 2-(4-chloro-Spyrazol-1-yl)-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]pyridine -3-sulfonamide). The filtrate was concentrated in vacuo, extracted with dichloromethane/water and the organic phase was washed with brine and dried over sodium sulfate followed by concentration in vacuo to give crude 2-(4-chloro-1H-pyrazol-1-yl)-N-[(dimethylamino )methylene]-5[(diphenylmethylene)amino]pyridine-3-sulfonamide (549 mg).

LC-MS (method A): Rt = 1.31 min, MS (ESI positive): m/z = 493 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm] 2.80 (s, 3H), 3.09 (s, 3H), 7.27-7.33 (m, 2H), 7.38-7.44 (m, 3H), 7.49-7.56 (m, 2H), 7.58-7.64 (m, 1H), 7.67 (s, 1H), 7.69-7.76 (m, 2H), 7.79-7.83 (m, 2H), 8.17 (d, 1H), 8.32(d, 1H).

The pure substance (229 mg) from the previous step was dissolved in dioxane (2.0 ml) and a 2M solution of HCl in dioxane (1.00 ml, 2.00 mmol) was added, followed by stirring overnight. reaction

- 90 040608 This mixture was concentrated in vacuo and extracted with ethyl acetate/water. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (200 mg) which was used without further purification in the following steps.

LC-MS (method A): Rt = 0.71 min, MS (ESI positive): m/z = 329 [M+H]+.

Intermediate 110.

5-Amino-2-(4-bromo-1H-pyrazol-1-yl)-N-[(dimethylamino)methylene]pyridine-3-sulfonamide

2-Chloro-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]pyridine-3-sulfonamide (1.00 g, 2.34 mmol) was dissolved in DMSO (18 mL). 4-Bromo-1H-pyrazole (689 mg, 4.69 mmol), potassium iodide (389 mg, 2.34 mmol) and potassium phosphate (746 mg, 3.51 mmol) were added and the reaction mixture was stirred overnight at 100°C. Thereafter, the reaction mixture was concentrated in vacuo, extracted with dichloromethane/water, and the organic phase was washed with brine and dried over sodium sulfate, followed by concentration in vacuo.

Due to partial deprotection, the material was redissolved in DMF (2 ml) and stirred overnight with 1,1-dimethoxy-N,N-dimethylmethanamine (0.5 ml). Stirring overnight resulted in a precipitate which was removed by filtration (213 mg, pure 2-(4-bromo-Spyrazol-1-yl)-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]pyridine -3-sulfonamide). The filtrate was concentrated in vacuo, extracted with dichloromethane/water and the organic phase was washed with brine and dried over sodium sulfate followed by concentration in vacuo to give crude 2-(4-bromo-1H-pyrazol-1-yl)-N-[(dimethylamuno )methylene]-5[(diphenylmethylene)amino]pyridine-3-sulfonamide (758 mg).

LC-MS (method A): Rt = 1.32 min, MS (ESI positive): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm] 2.79 (s, 3H), 3.09 (s, 3H), 7.27-7.33 (m, 2H), 7.38-7.45 (m, 3H), 7.49-7.56 (m, 2H), 7.58-7.67 (m, 2H), 7.73 (d, 2H), 7.79-7.83 (m, 2H), 8.16 (d, 1H), 8.31 (d, 1H).

The pure material (213 mg) from the previous step was dissolved in dioxane (2.0 ml) and a 2M solution of HCl in dioxane (1.00 ml, 2.00 mmol) was added, followed by stirring overnight. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate/water. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (168 mg) which was used without further purification in the following steps.

LC-MS (method A): Rt = 0.73 min, MS (ESI positive): m/z = 373/375 [M+H]+.

Intermediate 111.

5-Amino-N-[(dimethylamino)methylene]-2-(4-fluoro-1H-pyrazol-1-yl)pyridine-3-sulfonamide

2-Chloro-N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]pyridine-3-sulfonamide (1.00 g, 2.34 mmol) was dissolved in DMSO (18 mL). 4-Fluoro-1H-pyrazole (403 mg, 4.69 mmol), potassium iodide (389 mg, 2.34 mmol) and potassium phosphate (746 mg, 3.51 mmol) were added and the reaction mixture was stirred overnight at 100°C. Thereafter, the reaction mixture was concentrated in vacuo, extracted with dichloromethane/water, and the organic phase was washed with brine and dried over sodium sulfate, followed by concentration in vacuo.

Due to partial deprotection, the material was redissolved in dimethylformamide (2 ml) and stirred overnight with 1,1-dimethoxy-N,N-dimethylmethanamine (0.5 ml). The reaction mixture was concentrated in vacuo, extracted with dichloromethane/water and the organic phase was washed with brine and dried over sodium sulfate followed by concentration in vacuo to give crude N-[(dimethylamino)methylene]-5-[(diphenylmethylene)amino]-2- (4-fluoro-1 H-pyrazol-1 yl) pyridine-3-sulfonamide (723 mg).

LC-MS (method A): Rt = 1.25 min, MS (ESI positive): m/z = 477 [M+H]+.

The crude product (723 mg) from the previous step was dissolved in dioxane (4.0 ml) and a 2M solution of HCl in dioxane (3.00 ml, 6.00 mmol) was added, followed by stirring overnight. reaction

- 91 040608 the mixture was concentrated in vacuo and extracted with ethyl acetate/water. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the crude title compound (455 mg) which was used without further purification in the following steps.

LC-MS (method A): Rt = 0.62 min, MS (ESI positive): m/z = 313 [M+H]+.

Intermediate 112.

5-Amino-N-[(dimethylamino)methylidene]-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine-3sulfonamide

The reaction was carried out three times on a 1 g scale. 2-Chloro-N-[(dimethylamino)methylidene]-5[(diphenylmethylidene)amino]pyridine-3-sulfonamide (3.00 g, 7.03 mmol) and 4-(trifluoromethyl)-1H-pyrazole (1.43 g, 10.5 mmol) were dissolved in DMSO (110 ml, 1.6 mol) and potassium iodide (583 mg, 3.51 mmol) and potassium phosphate (2.24 g, 10.5 mmol) were added. The reaction mixture was heated for 5 hours in a microwave oven at 100°C. Thereafter, the solid was filtered off and ethyl acetate and water were added to the filtrate. The organic phase was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give 15.7 g of the final product (424% yield).

LC-MS (method A): Rt = 1.40 min; MS (ESI positive): m/z = 472 [M+H]+.

5-[(Diphenylmethylidene)amino]-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine-3-sulfonamide (3.50 g, 7.42 mmol) was dissolved in 1,4-dioxane (100 ml) and HCl (4.9 ml, 3.0 M, 15 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the crude product was partitioned between ethyl acetate and water. After that, the organic phase was dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was dissolved in acetonitrile and water and lyophilized overnight.

LC-MS (method B): Rt = 0.56 min; MS (ESI positive): m/z = 307 [M+H]+.

Intermediate 113.

Methyl 1 - (4- {[(2-chlorophenyl) acetyl] amino} -2-sulfamoylphenyl) -1H-pyrazole-4-carboxylate nh ₂ o \u003d s \u003d on ^\ o οι ⁿ

According to general methods GP1.2, GP2.3, GP3.3 and ΘΡ4.1,2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (2.04 g, 5.29 mmol), methyl 1H-pyrazole-4 -carboxylate (1.00 g, 7.93 mmol) and (2-chlorophenyl)acetic acid (10.5 g, 6.16 mmol) were converted without purification of intermediates to the title compound and purified in the final step by crystallization from hexane/ethyl acetate (2/ 1) (1.10 g, 2.45 mmol, yield over 4 steps 46%, purity 90%).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 449 [M+H]+.

Intermediate 114.

N-(4-Bromo-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide nh ₂ o=s=o ricU Cl ⁿ

3-Aminobenzenesulfonamide (70.0 g, 406 mmol) was dissolved in dimethylformamide (540 ml) and cooled to 0°C. A solution of N-bromosuccinimide (76.0 g, 427 mmol) in dimethylformamide (300 mL) was added over 1.5 h. The reaction mixture was allowed to warm to room temperature over 1 h and stirring at room temperature was continued for 2 h. The reaction mixture was concentrated in vacuo , extracted with ethyl acetate (500 ml) and washed several times with water (250 ml) and brine (300 ml). The aqueous phases were re-extracted twice with ethyl acetate and all organic phases were combined, dried over sodium sulfate and concentrated in vacuo to give 141 g of crude 5-amino-2-bromobenzenesulfonamide.

LC-MS (method A): Rt = 0.56 min; MS (ESI positive): m/z = 251/253 [M+H]+.

- 92 040608 ¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 5.71 (s, 2H), 6.60 (dd, 1H), 7.25-7.24 (br s, 2H), 7.27 (d , 1H), 7.34 (d, 1H).

A portion of the crude 5-amino-2-bromobenzenesulfonamide from the previous step (54.3 g) and (2chlorophenyl)acetic acid (38.8 g, 0.23 mmol) were suspended in dimethylformamide (1000 ml) and cooled to 0°C. K,K-diisopropylethylamine (83.9 g, 0.65 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 90.5 g, 0.24 mmol), while maintaining the temperature below 10°C. The reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate (1250 ml), washed with 1M sodium hydroxide solution (500 ml) and twice with water (500 ml). The organic phase was dried over sodium sulfate and concentrated in vacuo. This crude product (66 g) was suspended in dichloromethane (350 ml) and agitated in an ultrasonic bath, resulting in a white precipitate of the title compound, which was filtered off and dried in an oven (25.0 g, 61.9 mmol, yield over 2 steps 40 %, purity 96%).

LCMS (method A): Rt = 1.00 min; MS (ESI positive): m/z = 403/405 [M+H]+.

1I-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.86 (s, 2H), 7.28-7.35 (m, 2H), 7.40-7.48 (m, 2H), 7.57 (s, 2H) , 7.70-7.78 (m, 2H), 8.34-8.38 (m, 1H), 10.65 (s, 1H).

Intermediate 115.

N-(4-Bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide

N-(4-Bromo-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide (25.0 g, 61.9 mmol) was dissolved in dimethylformamide (320 ml) and 1,1-dimethoxy-N,X-dimethylmethanamine (14.6 g , 119 mmol). The reaction mixture was stirred at room temperature for 3 hours followed by concentration in vacuo and extraction with ethyl acetate (80 ml). Under these conditions, the title compound went into solution and recrystallized under ice-cooling. This precipitate was filtered off and washed with a small amount of ethyl acetate to give the pure title compound (25.8 g, 56.2 mmol, 97% purity, 91% yield).

LC-MS (method B): Rt = 1.09 min; MS (ESI positive): m/z = 458/460 [M+H]+.

^-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.93 (s, 3H), 3.19 (s, 3H), 3.86 (s, 2H), 7.28-7.35 (m, 2H), 7.407 .48 (m, 2H), 7.68 (d, 1H), 7.74 (dd, 1H), 8.27 (s, 1H), 8.37 (d, 1H), 10.63 (s, 1H).

Intermediate 116 and Intermediate 117.

Tris-(dibenzylideneacetone)dipalladium(0) (409 mg, 0.45 mmol) and 2-di-tert-butylphosphino-3,4,5,6tetramethyl-2',4',6'-triisopropyl-1,1'-biphenyl (tetramethyl di-tBuXPhos, 215 mg, 0.45 mmol) was dissolved in toluene (12 ml) and the flask was evacuated three times and filled with argon. The mixture was heated to 120°C (resulting in a brownish color) and 2-bromo-N-[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (3.00 g, 8.92 mmol) and 4-(trifluoromethyl)-1H-1,2,3 were added -triazole (2.08 g, 15.2 mmol) followed by the addition of potassium phosphate (3.79 g, 17.9 mmol) and stirring at 20° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. In order to re-protect the title compound, the crude product was redissolved in dimethylformamide (9 ml) and 1,1-dimethoxy-X,H-dimethylmethanamine (1.5 ml) was added. The reaction mixture was stirred at room temperature overnight and extracted with dichloromethane/water. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Chromatography on a Biotage Isolera system allowed purification and separation of the two title compounds.

Intermediate 116.

N-[(Dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]benzenesulfonamide

- 93 040608

193 mg, 0.492 mmol, 6% yield, 90% purity.

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 393 [M+H]+.

1Н-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.87 (s, 3H), 3.14 (s, 3H), 7.92 (s, 1H), 8.07 (d, 1H), 8.62 ( dd, 1H), 8.79 (d, 1H), 8.87 (s, 1H).

Intermediate 117.

N-[(Dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]benzenesulfonamide

180 mg, 0.459 mmol, 5% yield, 90% purity.

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 393 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH) δ [ppm]: 2.80 (d, 3H), 3.08 (s, 3H), 7.88 (s, 1H), 8.11 (d, 1H), 8.65 (dd, 1H), 8.77 (d, 1H), 9.35 (d, 1H).

Intermediate 118.

2-(4-Cyano-1H-pyrazol-1-yl)-5-nitrobenzene sulfonamide

2-Chloro-5-nitrobenzenesulfonamide (250 mg, 1.06 mmol) was dissolved in acetonitrile (10 mL) followed by the addition of 1H-pyrazole-4-carbonitrile (148 mg, 1.59 mmol) and finely ground potassium carbonate (438 mg, 3.17 mmol). The reaction mixture was stirred overnight at 100°C. After cooling to room temperature, dichloromethane and water were added and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) gave the title compound (128 mg, 0.436 mmol, 41% yield, 70% purity).

LC-MS (method A): Rt = 0.78 min; MS (ESI positive): m/z = 294 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 7.94 (br d, 2H), 7.98 (d, 1H), 8.42 (d, 1H), 8.61 (dd, 1H), 8.83 ( d, 1H), 9.04 (d, 1H).

Intermediate 119.

5-Amino-2-(4-cyano-1H-pyrazol-1-yl)benzenesulfonamide

2-(4-Cyano-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (128 mg, 0.44 mmol) was dissolved in methanol (17 ml) and dioxane (3 ml). The flask was evacuated and purged with nitrogen followed by the addition of palladium on charcoal (13 mg, 10% load). The flask was again evacuated and immediately purged with hydrogen, followed by stirring under a hydrogen atmosphere for 5 hours at room temperature. The hydrogen was removed, the catalyst was filtered off and the filtrate was concentrated in vacuo. The product was redissolved in dichloromethane and concentrated again in vacuo to give the title compound (81 mg, 0.308 mmol, 70% yield, 79% purity).

LC-MS (method B): Rt = 0.46 min; MS (ESI positive): m/z = 264 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 6.06 (s, 2H), 6.77 (dd, 1H), 7.17-7.23 (m, 4H), 8.23 (d, 1H), 8.71(d, 1H).

Intermediate 120.

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

- 94 040608

Ethyl 1H-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 the reaction mixture was heated for 19 h at 90°C. The 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 gave the title compound, which was used without further purification (7.8 g, 98% yield, 80% purity). LC-MS (method A): Rt = 1.27 min; MS (ESI positive): m/z = 491 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 6.28 (dd, 1H), 7.07 (d, 1H), 7.91 (d, 1H), 8.05 (br s, 1H), 8.24 (d, 1H), 8.29 (s, 1H), 8.46 (dd, 1H), 8.84 (s, 1H).

Intermediate 121.

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

Lithium hydroxide solution (1.55 g, 64.6 mmol) in water (11.6 ml) and the reaction mixture was stirred for 18 h at room temperature. The solvent was evaporated and the crude product was suspended in water (15 ml) and acidified to pH 5 using aq. HCl solution (55 ml, 1.0 M). The slurry was stirred for 30 min and filtered. The precipitate was dried at 50°C in a vacuum (5.7 g, 91% yield, 95% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 463 [M+H] ⁺ .

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

Intermediate 122.

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

H ₃ C'°

CH ₃ ii-CH ₃

II O

To a solution of 1-{2-[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1H-pyrazole-4-carboxylic acid (5.7 g, 11.7 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 at 50°C for 75 min. Then 2-(trimethylsilyl)ethanol (8.39 mL, 58.5 mmol) was added and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried using a Whatman filter and evaporated in vacuo. Purification by flash chromatography gave the title compound (6.5 g, 86% yield, 89% purity).

LC-MS (method A): Rt = 1.46 min; MS (ESI positive): m/z = 578 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.07 (s, 9H), 1.03 (m, 2H), 3.46 (s, 3H), 3.63 (s, 3H), 4.18 (d, 2Н), 4.21 (m, 2H), 6.14 (d, 1H), 6.29 (dd, 1H), 7.10 (d, 1Н), 7.81 (d, 1H), 7.88 (s, 1H), 8.17 ( t, 1H), 8.20 (d,

- 95 040608

1H), 8.21 (s, 1H), 8.40 (dd, 1H), 9.74 (s, 1H).

Intermediate 123.

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

Tin(II) chloride dihydrate (11.1 g, 50.3 mmol) was added to a solution of 2-(trimethylsilyl)ethyl (1-{2[(2,4-dimethoxybenzyl)sulfamoyl]-4-nitrophenyl}-1H-pyrazol-4-yl )carbamate (6.5 g, 89% purity, 10.1 mmol) in dioxane (129 mL) followed by stirring for 4 h at 70°C and overnight at room temperature. The reaction mixture was concentrated in vacuo. Water was added to the residue, and the mixture was neutralized with an aqueous 5% sodium hydroxide solution, and then extracted three times with ethyl acetate. The combined organic phases were filtered through Celite, dried on a Whatman filter and concentrated in vacuo to give 5.5 g of crude 2-(trimethylsilyl)ethyl (1-{4-amino-2-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}-1H-pyrazole -4-yl)carbamate, which was used without further purification in the next step.

The crude product 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), K,X-diisopropylethylamine (5.6 ml, 32.1 mmol) and HATU (6.11 d, 16.1 mmol). The reaction mixture was stirred for 17 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter, and concentrated in vacuo to give the title compound, which was used without further purification (10.55 g, 50% purity, 75% yield over 2 steps).

LC-MS (method B): Rt = 1.49 min; MS (ESI positive): m/z = 700 [M+H]+.

Intermediate 124.

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

To a solution of 2-(trimethylsilyl)ethyl [1-(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4dimethoxybenzyl)sulfamoyl]phenyl)-1H-pyrazol-4-yl]carbamate (10.55 g, 7.53 mmol) in tetrahydrofuran (4 ml) was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (15.1 ml, 15.1 mmol) and the mixture was heated for 2.5 h at 50°C. An additional 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (3.77 ml, 3.77 mmol) was added and heating to 50° C. was continued for 3 hours. The 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 gave the title compound, which was purified by flash chromatography (2.9 g, 55% yield, 80% purity).

LC-MS (method B): Rt = 1.18 min; MS (ESI positive): m/z = 556 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 6.31 (d, 1H), 7.02 (d, 1H), 7.24 (s, 1H), 7.28 (s, 1H), 7.30 (m, 2H), 7.36 ( d, 1H), 7.42 (m, 2H), 7.77 (t, 1H), 7.87 (dd, 1H), 8.02 (d, 1H), 10.57 (s, 1H).

Intermediate 125.

N-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1H-pyrazol-4yl]-2,2-difluoroacetamide

- 96 040608

Na{4-(4-Amino-III-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide (200 mg, 360 µmol) was dissolved in DMF ( 6.9 ml), and difluoroacetic acid (45.4 µl, 719 µmol), N,N-diisopropylethylamine (251 µl, 1.44 mmol) and HATU (274 mg, 719 µmol) were added. The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the crude title compound (251 mg) which was used without further purification.

LC-MS (method B): Rt = 1.24 min; MS (ESI positive): m/z = 634 [M+H]+.

Intermediate 126.

N-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1H-pyrazol-4yl]-3,3,3-trifluoropropanamide

N-{4-(4-amino-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide mixture (200 mg, 288 µmol, 80 purity %), N,N-diisopropylethylamine (150 µl, 863 µmol), and 3,3,3-trifluoropropanoyl chloride (35.6 µl, 345 µmol) in THF (400 µl) were vigorously stirred at room temperature for 7 days. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the crude title compound (285 mg) which was used without further purification.

LC-MS (method B): Rt = 1.27 min; MS (ESI positive): m/z = 666 [M+H]+.

Intermediate 127.

(±)-N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1Hpyrazol-4-yl]-3,3, 3-trifluoro-2-methylpropanamide

N-{4-(4-amino-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide mixture (216 mg, 350 µmol, 90 purity %), N,N-diisopropylethylamine (305 μl, 1.75 mmol) and (±)-3,3,3-trifluoro-2-methylpropanoyl chloride (112 mg, 700 μmol) were combined at 0°C and stirred at room temperature for night. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with dichloromethane. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the crude title compound (327 mg) which was used without further purification.

LC-MS (method A): Rt = 1.31 min; MS (ESI positive): m/z = 680 [M+H]+.

Intermediate 128.

2-(2-Chlorophenyl)-N-(3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-{4-(2,5-dimethylpyrrolidin-1-yl)-1Hpyrazol-1-yl}phenyl)acetamide (mixture of stereoisomers)

- 97 040608

To a solution of ^{4-(4-amino-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide (400 mg, 575 µmol, purity 80 %) in acetonitrile (10 ml), 2.5 dibromohexane (107 μl, 691 μmol, CAS-RN 24774-58-1) and powdered potassium carbonate (191 mg, 1.38 mmol) were added, and the mixture was stirred for 6 days at 90° WITH. The 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 gave the crude title compound (531 mg) as a mixture of stereoisomers which was used without further purification.

LC-MS (method A): Rt = 1.29 min and 1.36 min; MS (ESI positive): m/z = 638 [M+H]+ each.

Intermediate 129.

N-(4-{4-[(2,2-Difluoroethyl)amino]-1H-pyrazol-1-yl}-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)2-(2-fluorophenyl)acetamide

Tin(II) chloride dihydrate (621 mg, 2.75 mmol) was added to a solution of 2-{4-[(2,2difluoroethyl)amino]-1H-pyrazol-1-yl}-N-(2,4-dimethoxybenzyl)-5 -nitrobenzenesulfonamide (274 mg, 551 μmol) in dioxane (7.1 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 114 mg of crude 5-amino-2-{4-[(2,2difluoroethyl)amino]-1 H-pyrazole-1 - yl}-N-(2,4-dimethoxybenzyl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (230 mg) was dissolved in DMF (10 mL) followed by the addition of (2-fluorophenyl)acetic acid (114 mg, 738 µmol), N,N-diisopropylethylamine (343 µL, 1.97 mmol) and HATU (281 mg, 738 µmol). The reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (426 mg, 60% purity, 77% yield over 2 steps).

LC-MS (method B): Rt = 1.25 min; MS (ESI positive): m/z = 604 [M+H] ⁺ .

Intermediate 130.

N-(2,2,2-Trifluoroethyl)-1H-pyrazole-4-αmin

To a solution of 1H-pyrazol-4-amine (300 mg, 95% purity, 3.43 mmol) in acetonitrile (17 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (741 μL, 5.1 mmol, CAS-RN 6226-25-1 ), powdered potassium carbonate (1.06 g, 7.65 mmol) and triethylamine (720 µl, 5.1 mmol). The mixture was heated at 90° C. for 4 hours and stirred at room temperature overnight. The reaction mixture was filtered to isolate the reaction product and the solid was washed with ethyl acetate. Concentration of the filtrate in vacuo followed by flash chromatography gave the title compound (435 mg, 73% yield, 95% purity).

LC-MS (method A): Rt = 0.61 min; MS (ESI positive): m/z = 166 (M+H) ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.62 (qd, 2H), 5.06 (t, 1H), 7.13 (s, 2H), 12.12 (s, 1H).

Intermediate 131.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-{4-[(2,2,2-trifluoroethyl)amino]-1H-pyrazol-1yl}benzenesulfonamide

- 98 040608

N-(2,2,2-trifluoroethyl)-1H-pyrazole-4 -amine (430 mg, 1.82 mmol) and powdered potassium carbonate (377 mg, 2.73 mmol) and the reaction mixture were irradiated for 12 h at 120°C in a microwave oven. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by flash chromatography (345 mg, 55% yield, 75% purity).

LC-MS (method B): Rt = 1.28 min; MS (ESI positive): m/z = 516 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.38 (s, 3H), 3.59 (s, 3H), 3.81 (qd, 2H), 4.16 (d, 2H), 5 .80 (t, 1H), 6.08 (d, 1H), 6.25 (dd, 1H), 7.08 (d, 1H), 7.67 (s, 1H), 7.70 (d, 1H), 7.83 (s, 1H), 8.16 (d, 1H), 8.22 (t, 1H), 8.38 (dd, 1H).

Intermediate 132.

2-(2-Chlorophenyl)-N-(3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-{4-[(2,2,2-trifluoroethyl)amino]-1Hpyrazol-1 -yl}phenyl) acetamide

Tin(II) chloride dihydrate (558 mg, 2.47 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-{4-[(2,2,2-trifluoroethyl)amino]-III-pyrazole- 1-yl}benzenesulfonamide (340 mg, 495 µmol, 75% purity) in dioxane (6.3 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 320 mg of crude 5-amino-N-(2,4dimethoxybenzyl)-2-{4-[(2,2,2- trifluoroethyl)amino]-1H-pyrazol-1-yl}benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (315 mg) was dissolved in DMF (8.2 ml) followed by the addition of (2-chlorophenyl)acetic acid (116 mg, 681 µmol), N,N-diisopropylethylamine (316 µl, 1.82 mmol) and HATU (259 mg, 681 µmol). The reaction mixture was stirred overnight at room temperature. Water was added and the mixture was extracted three times with ethyl acetate.

All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (528 mg, 55% purity, 92% yield over 2 steps).

LC-MS (method B): Rt = 1.33 min; MS (ESI positive): m/z = 638 [M+H]+.

Intermediate 133.

N-(2,4-Dimethoxybenzyl)-2-(4-isopropyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide

4-isopropyl-1H-pyrazole hydrochloride (568 mg, 3.88 mmol, CAS- RN 1390654-61-1) and powdered potassium carbonate (1.43 g, 10.3 mmol). The mixture was irradiated overnight at 120°C and another night at 130°C in a microwave oven. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by flash chromatography (646 mg, 49% yield, 90% purity).

LC-MS (method B): Rt = 1.37 min; MS (ESI positive): m/z = 461 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (d, 6H), 2.89 (sept, 1H), 3.42 (s, 3H), 3.60 (s, 3H), 4.16 (d,

- 99 040608

2H), 6.11 (d, 1H), 6.26 (dd, 1H), 7.09 (d, 1H), 7.81 (d, 1H), 7.89 (s, 1H), 8.16 (s, 1H), 8.20 (d, 1H ), 8.28 (t, 1H), 8.40 (dd, 1H).

Intermediate 134.

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

Tin(II) chloride dihydrate (1.42 g, 6.29 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2(4-isopropyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (644 mg, 1.26 mmol , purity 90%) in dioxane (16 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 443 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4isopropyl-1H-pyrazole-1- yl)benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (220 mg) was dissolved in DMF (5 mL) followed by the addition of (2-chlorophenyl)acetic acid (124 mg, 728 µmol), N,N-diisopropylethylamine (338 µL, 1.94 mmol) and HATU (277 mg, 728 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (410 mg, 65% purity, 73% yield over 2 steps).

LC-MS (method A): Rt = 1.43 min; MS (ESI positive): m/z = 583 [M+H]+.

Intermediate 135.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(4-isopropyl-1H-pyrazol-1-yl)phenyl}-2-(2fluorophenyl)acetamide

Crude 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-isopropyl-1H-pyrazol-1-yl)benzenesulfonamide (220 mg) was dissolved in DMF (5 ml) followed by the addition of (2-fluorophenyl )acetic acid (112 mg, 728 µmol), N,N-diisopropylethylamine (338 µL, 1.94 mmol), and HATU (277 mg, 728 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter, and concentrated in vacuo to give the title compound, which was used without further purification (407 mg, 65% purity, 74% yield over 2 steps).

LC-MS (method A): Rt = 1.40 min; MS (ESI positive): m/z = 567 [M+H]+.

Intermediate 136.

2-[(Dimethylamino)methylene]-4,4,4-trifluoro-N,N-dimethylbutan-1-iminium hexafluorophosphate

Phosphoryl chloride (3.28 ml, 35.2 mmol) was added dropwise to a solution of 4,4,4-trifluorobutanoic acid (5.0 g, 35.2 mmol, CAS-RN 406-93-9) in DMF (17.5 mL) at 50°C. After stirring for 2 hours at 70°C, the solution was cooled to room temperature. This reaction mixture and 5 N. NaOH (12.7 mL, 63.3 mmol) was simultaneously added over 30 min to a mixture of 55% hexafluorophosphoric acid

- 100 040608 slots (6.1 ml, 38.0 mol) and 5 n. NaOH (14.1 ml) in water (46 ml), keeping the temperature <10°C. The mixture was stirred for 1 hour at 0° C. and filtered. The yellow solid was washed with water then dried in vacuo at <40° C. to give the title compound (545 mg, 4% yield, 95% purity).

LC-MS (method A): Rt = 0.56 min; MS (ESI positive): m/z = 209 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.30 (s, 12H), 3.62 (q, 2H), 7.72 (s, 2H).

Intermediate 137.

4-(2,2,2-Trifluoroethyl)-1H-pyrazole ^HN JL J^ ^F

Hydrazine monohydrate (82 mg, 1.69 mmol) was added dropwise to a stirred solution of 2-[(dimethylamino)methylene]-4,4,4-trifluoro-N,N-dimethylbutan-1-iminium hexafluorophosphate (543 mg, 1.53 mmol) in methanol (7.5 ml). The resulting solution was heated at reflux for 90 minutes and cooled to room temperature. Concentrated hydrochloric acid (378 µl) was added and reflux continued for 2 hours The solvent was evaporated in vacuo and the residue taken up in water and the pH adjusted to 10 with 2M NaOH (3 ml). on a Whatman filter and concentrated in vacuo to give the title compound (226 mg, 88% yield, 90% purity), which was used without further purification.

LC-MS (method B): Rt = 0.71 min; MS (ESI positive): m/z = 151 [M+H]+.

1H-NMR (400 MHz, DMSO^) δ [ppm]: 3.48 (q, 2H), 7.44 (s, 1H), 7.72 (s, 1H), 12.85 (s, 1H).

Intermediate 138.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide

4-(2,2,2-trifluoroethyl)-1H-pyrazole (270 mg, 1.62 mmol, 90% purity) and powdered potassium carbonate (447 mg, 3.24 mmol). The mixture was irradiated for 195 min at 120° C. in a microwave oven. The 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 gave the title compound, which was purified by flash chromatography (185 mg, 29% yield, 85% purity). LC-MS (method B): Rt = 1.33 min; MS (ESI positive): m/z = 501 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.46 (s, 3H), 3.61 (s, 3H), 3.65 (q, 1H), 4.16 (d, 2H), 6.14 (d, 1H), 6.27 (dd, 1H), 7.09 (d, 1H), 7.81 (d, 1H), 7.94 (s, 1H), 8.16 (t, 1H), 8.21 (d, 1H), 8.34 ( s, 1H), 8.42 (dd, 1H).

Intermediate 139.

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

Tin(II) chloride dihydrate (344 mg, 1.53 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl ]benzenesulfonamide (180 mg, 306 μmol, 85% purity) in dioxane (3.9 ml) and stirred for 4 h at 70°C. 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 through Celite, washed with brine, dried using a Whatman filter and concentrated in vacuo to give 196 mg of crude 5-amino-N-(2,4-dimethoxybenzyl)2-[4-(2,2,2- trifluoroethyl)-1H-pyrazol-1-yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (145 mg) was dissolved in DMF (6 ml) followed by the addition

- 101 040608 (2-chlorophenyl)acetic acid (63 mg, 371 µmol), N,N-diisopropylethylamine (215 µl, 1.24 mmol) and HATU (141 mg, 371 µmol). The reaction mixture was stirred at room temperature for 2 days. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (220 mg, 85% purity, 98% yield over 2 steps).

LC-MS (method A): Rt = 1.37 min; MS (ESI positive): m/z = 623 [M+H]+.

Intermediate 140.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-[4-(2,2,2-trifluoroethyl)-1H-n-nirazol-1-yl]phenyl}-2-(2fluorophenyl)acetamide

Crude 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1yl]benzenesulfonamide (89 mg) was dissolved in DMF (4 ml), followed by adding (2fluorophenyl)acetic acid (117 mg, 760 µmol), N,N-diisopropylethylamine (165 µl, 950 µmol) and HATU (217 mg, 570 µmol). The reaction mixture was stirred for 3 days at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (136 mg, 85% purity, 98% yield over 2 steps).

LC-MS (method A): Rt = 1.36 min; MS (ESI positive): m/z = 607 [M+H]+.

Intermediate 141.

2-(5-Cyclopropyl-1,2,4-oxadiazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide o o

H ₃ C γγ CH ₃

I o

ΗΝ //.O _p Ν^θ Ϊ A^-<1 - ΓΪΙ ^Ν (E II O

2-[(2,4-Dimethoxybenzyl)sulfamoyl]-N'-hydroxy-4-nitrobenzenecarboximidamide (84 mg, 205 µmol) was stirred with cyclopropanecarboxylic acid anhydride (51 µl, 450 µmol) in toluene (4.2 ml) under reflux at during the night. Another portion of cyclopropanecarboxylic acid anhydride (27 μl, 225 μmol) was added and the reaction mixture was heated under reflux for 3 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic phase was washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (60 mg, 48% yield, 75% purity).

LC-MS (method B): Rt = 1.32 min; MS (ESI negative): m/z = 459 (M-H) ^- .

¹ H-NMR (400 MHz, DMSOL) δ [ppm]: 1.19 (m, 2H), 1.38 (m, 2H), 2.53 (m, 1H), 3.42 (s, 3H), 3.60 (s, 3H), 4.16 (d, 2H), 6.07 (d, 1H), 6.25 (dd, 1H), 7.06 (d, 1H), 7.75 (t, 1H), 7.98 (d, 1H), 8.18 (d, 1H ), 8.43 (dd, 1H).

Intermediate 142.

2-(2-Chlorophenyl)-N-{4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide

Tin(II) chloride dihydrate (252 mg, 1.12 mmol) was added to a solution of 2-(5-cyclopropyl-1,2,4

- 102 040608 oxadiazol-3-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (103 mg, 224 µmol) in dioxane (2.9 ml) followed by stirring for 4 h at 70°C and for nights at room temperature. The reaction mixture was concentrated in vacuo. Ethyl acetate was added to the residue, and the mixture was extracted with brine. The organic phase was filtered through Celite, dried on a Whatman filter and concentrated in vacuo to give 118 mg of crude 5-amino-2-(5-cyclopropyl-1,2,4-oxadiazol3-yl)-N-(2,4-dimethoxybenzyl) benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (118 mg) was dissolved in DMF (4.4 ml) followed by the addition of (2-chlorophenyl)acetic acid (76.4 mg, 448 µmol), N,N-diisopropylethylamine (156 µl, 896 µmol) and HATU (170 mg, 448 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with ethyl acetate. The organic phase was then washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (135 mg, 95% purity, 98% yield over 2 steps).

LC-MS (method A): Rt = 1.35 min; MS (ESI positive): m/z = 583 [M+H]+.

Intermediate 143.

5-[2-(Benzylsulfanyl)-4-nitrophenyl]-3-(trifluoromethyl)-1,2,4-oxadiazole

I o

To a suspension of 2-(benzylsulfanyl)-4-nitrobenzoic acid (715 mg, 2.35 mmol, 95% purity) in toluene (7.4 mL) was added thionyl chloride (343 μL, 4.70 mmol). The mixture was heated at 70°C for 210 min. The solvent was removed under reduced pressure, the residue was co-distilled with toluene and then dissolved in THF (10 ml). 2,2,2-Trifluoro-N-hydroxyethanimidamide (341 mg, 2.53 mmol, CASRN 4314-35-6) and N,N-diisopropylethylamine (1.20 mL, 6.90 mmol) were added and the mixture was stirred at room temperature overnight and under reflux for 2 hours. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (640 mg, 69% yield, 95% purity).

LC-MS (method B): Rt = 1.51 min; MS (ESI positive): m/z = 382 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.57 (s, 2H), 7.29 (dd, 1H), 7.35 (dd, 2H), 7.47 (d, 2H), 8.16 (dd, 1H), 8.38 (d, 1H), 8.38 (d, 1H).

Intermediate 144.

N-(2,4-Dimethoxybenzyl)-5-nitro-2-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]benzenesulfonαmide

II o

5-[2-(Benzylsulfanyl)-4-nitrophenyl]-3-(trifluoromethyl)-1,2,4-oxadiazole (636 mg, 1.58 mmol, 95% purity) was stirred with N-chlorosuccinimide (952 mg, 7.13 mmol) in acetic acid (15 ml) at room temperature for 5 h. The reaction mixture was concentrated in vacuo to give 565 mg of crude 5-nitro-2-[3-(trifluoromethyl)-1,2,4-oxadiazol-3-yl] benzenesulfonyl chloride, which was used without further purification in the next step.

The crude product from the previous step (565 mg) was dissolved in dichloromethane (8 ml) followed by the addition of sodium bicarbonate (531 mg, 6.32 mmol), and the slow addition of 1-(2,4dimethoxyphenyl)methanamine (291 μl, 1.74 mmol) at room temperature . The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (153 mg, 16% yield, 80% purity).

LC-MS (method A): Rt = 1.36 min; MS (ESI negative): m/z = 487 (M-H)-.

- 103 040608

1H-NMR (400 MHz, DMSOCH) δ [ppm]: 3.57 (s, 3H), 3.65 (s, 3H), 4.06 (d, 2H), 6.24 (d, 1H), 6.26 (dd, 1H ), 6.97 (d, 1H), 8.18 (d, 1H), 8.44 (d, 1H), 8.55 (dd, 1H), 8.56 (t, 1H).

Intermediate 145.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[3-(trifluoromethyl)-1,2,4-oxadiazole-

-yl]phenyl}acetamide

Tin(II) chloride dihydrate (425 mg, 1.88 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-5nitro-2-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]benzenesulfonamide (230 mg, 80% purity, 377 µmol) in dioxane (4.8 ml) followed by stirring for 5 h at 70°C and overnight at room temperature. 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 through Celite, dried on a Whatman filter and concentrated in vacuo to give 217 mg of crude 5-aminoN-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)-1,2,4-oxadiazole-5 -yl]benzenesulfonamide, which was used without further purification in the next step.

The crude product from the previous step (216 mg) was dissolved in DMF (8 ml) followed by the addition of (2-chlorophenyl)acetic acid (129 mg, 754 µmol), N,N-diisopropylethylamine (263 µl, 1.51 mmol) and HATU (287 mg, 754 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (355 mg, 65% purity, 98% yield over 2 steps).

LC-MS (method B): Rt = 1.43 min; MS (ESI negative): m/z = 609 (M-H)-.

Intermediate 146.

2-(Benzylsulfanyl)-N'-(difluoroacetyl)-4-nitrobenzohydrazide

N,N-diisopropylethylamine (1.73 ml, 9.92 mmol) and difluoroacetic acid anhydride (1.13 ml, 9.10 mmol) at -50°C. The mixture was allowed to warm to room temperature and stirred for 5 h. The reaction mixture was poured into aqueous sodium hydroxide solution (5%). The mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was used without purification (3.57 g, 91% yield, 80% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI negative): m/z = 380 (M-H)-.

1H-NMR (400 MHz, DMSO-de) δ [ppm]: 4.32 (s, 2H), 5.97 (t, 1H), 7.25 (dd, 1H), 7.32 (dd, 2H), 7.43 (d , 2H), 7.69 (d, 1H), 7.96 (dd, 1H), 8.11 (d, 1H).

Intermediate 147.

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole

A solution of 2-(benzylsulfanyl)-N'-(difluoroacetyl)-4-nitrobenzohydrazide (3.57 g, 80% purity, 7.49 mmol) and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1- 2,2-dioxide ide (7.38 g, 31.0 mmol) in tetrahydrofuran (90 mL) was irradiated for 30 min at 150°С in a microwave oven. To the reaction mixture

- 104 040608 si water was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (2.18 g, 76% yield, 95% purity).

LCMS (method A): Rt = 1.33 min; MS (ESI positive): m/z = 364 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.54 (s, 2H), 7.29 (dd, 1H), 7.35 (dd, 2H), 7.47 (d, 2H), 7.59 (t, 1H), 8.15 (dd, 1H), 8.20 (d, 1H), 8.36 (d, 1H).

Intermediate 148.

2-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide

II O

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-(difluoromethyl)-1,3,4-oxadiazole (1.23 g, 95% purity, 2.93 mmol) was stirred with N-chlorosuccinimide (1.76 g, 13.2 mmol) in acetic acid (29 ml) at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give 3 g of crude 2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-nitrobenzenesulfonyl chloride , which was used without further purification in the next step.

The crude product from the previous step (3 g) was dissolved in dichloromethane (13.5 ml) followed by the addition of sodium hydrogen carbonate (983 mg, 17.7 mmol), and the slow addition of 1-(2,4dimethoxyphenyl)methanamine (484 μl, 3.22 mmol) at 0° WITH. The reaction mixture was stirred for 3 hours at 0° C. and for 22 hours at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (242 mg, 16% yield, 90% purity).

LC-MS (method B): Rt = 1.21 min; MS (ESI positive): m/z = 488 (M+H+NH ₃ )+

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.53 (s, 3H), 3.64 (s, 3H), 4.09 (d, 2H), 6.19 (d, 1H), 6.26 (dd , 1H), 6.99 (d, 1H), 7.64 (t, 1H), 8.14 (d, 1H), 8.33 (t, 1H), 8.39 (d, 1H), 8.52 (dd, 1H).

Intermediate 149.

2-(2-Chlorophenyl)-N-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide

Tin(11) chloride dihydrate (1.12 g, 4.95 mmol) was added to a solution of 2-[5-(difluoromethyl)-1,3,4oxadiazol-2-yl]-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide ( 466 mg, 990 µmol) in dioxane (12.7 mL) followed by stirring for 4.5 h at 70°С. 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 through Celite, dried on a Whatman filter and concentrated in vacuo to give 489 mg of crude 5-amino-2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(2 ,4dimethoxybenzyl)benzenesulfonamide, which was used without further purification.

The crude product from the previous step (218 mg) was dissolved in DMF (5.1 mL) followed by the addition of (2-chlorophenyl)acetic acid (127 mg, 742 µmol), Ν,N-diisopropylethylamine (345 µL, 1.98 mmol) and HATU (282 mg, 742 µmol). The reaction mixture was stirred for 23 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (499 mg, 60% purity, 23% yield over 2 steps).

LC-MS (method B): Rt = 0.83 min; MS (ESI positive): m/z = 593 (M+H)+.

Intermediate 150.

N-{4-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide

- 105 040608

Raw •

5-Amino-2-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-N-(2,4-dimethoxybenzyl)benzene sulfonamide (218 mg) was dissolved in DMF (5 ml) followed by by adding (2-fluorophenyl)acetic acid (92 mg, 594 µmol), Ν,N-diisopropylethylamine (207 µl, 1.19 mmol) and HATU (226 mg, 594 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (466 mg, 37% purity, 60% yield over 2 steps).

LC-MS (method B): Rt = 0.80 min; MS (ESI positive): m/z = 577 [M+H]+.

Intermediate 151.

5-[2-(Benzylsulfanyl)-4-nitrophenyl]-3-methyl-1,2,4-oxadiazole

Thionyl chloride (3.42 ml, 46.8 mmol) was added to a suspension of 2-(benzylsulfanyl)-4-nitrobenzoic acid (1.94 g, 6.69 mmol) in toluene (20 mL). The mixture was heated at 70°C for 150 min. The solvent was removed under reduced pressure, the residue was co-distilled with toluene and then dissolved in THF (77 ml). This solution was added dropwise over 30 min to a solution of acetohydrazide (991 mg, 13.4 mmol) and N,N-diisopropylethylamine (1.28 ml, 7.36 mmol) in THF (11 ml) and the mixture was stirred at room temperature and under reflux under within 75 min. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give 2.44 g of crude N'-acetyl-2-(benzylsulfanyl)-4-nitrobenzohydrazide.

A solution of crude hydrazide (2.43 g) and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2dioxide (7.55 g, 31.7 mmol) in tetrahydrofuran (75 ml) was irradiated for 30 min at 150°C in the microwave. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (2.08 g, 86% yield, 90% purity).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 328 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.61 (s, 3H), 4.50 (s, 2H), 7.28 (dd, 1H), 7.35 (dd, 2H), 7.47 ( d, 2H), 8.11 (d, 1H), 8.13 (dd, 1H), 8.32 (d, 1H).

Intermediate 152.

N-(2,4-Dimethoxybenzyl)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-5-nitrobenzenesulfonamide

2-[2-(Benzylsulfanyl)-4-nitrophenyl]-5-methyl-1,3,4-oxadiazole (1.81 g, 5.51 mmol) was stirred with N-chlorosuccinimide (3.32 g, 24.8 mmol) in acetic acid (55 ml ) at room temperature for 210 min. The reaction mixture was concentrated in vacuo to give 7.34 g of crude 2-(5-methyl1,3,4-oxadiazol-2-yl)-5-nitrobenzenesulfonyl chloride, which was used without further purification in the next step.

The crude product from the previous step (7.34 g) was dissolved in dichloromethane (61 ml) followed by the addition of sodium hydrogen carbonate (1.85 g, 22.1 mmol), and the slow addition of 1-(2.4

- 106 040608 dimethoxyphenyl)methanamine (911 µl, 6.07 mmol) at 0°C. The reaction mixture was stirred for 18 hours at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (462 mg, 17% yield, 90% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 435 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.65 (s, 3H), 3.44 (s, 3H), 3.61 (s, 3H), 4.14 (d, 2H), 6.11 (d, 1H), 6.24 (dd, 1H), 7.01 (d, 1H), 8.08 (d, 1H), 8.16 (t, 1H), 8.28 (d, 1H), 8.48 (dd, 1H).

Intermediate 153.

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2yl)phenyl}acetamide

Tin(II) chloride dihydrate (1.07 g, 4.75 mmol) was added to a solution of N-(2,4-dimethoxybenzyl)-2(5-methyl-1,3,4-oxadiazol-2-yl)-5-nitrobenzenesulfonamide (459 mg, 951 µmol, 90% purity) in dioxane (12.1 ml) followed by stirring for 4 h at 70°С. 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 through Celite, dried on a Whatman filter and concentrated in vacuo to give 459 mg of crude 5-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2,4dimethoxybenzyl )benzenesulfonamide, which was used without further purification.

The crude product from the previous step (127 mg) was dissolved in DMF (3.2 ml) followed by the addition of (2-chlorophenyl)acetic acid (80.1 mg, 470 µmol), Ν,N-diisopropylethylamine (218 µl, 1.25 mmol) and HATU (179 mg, 470 µmol). The reaction mixture was stirred for 17 hours at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (260 mg, 60% purity, 88% yield over 2 steps).

LC-MS (method B): Rt = 1.23 min; MS (ESI positive): m/z = 557 (M+H)+.

Intermediate 154.

K-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl}-2-(2fluorophenyl)acetamide

Crude 5-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide (229 mg) was dissolved in DMF (5 ml) followed by the addition of ( 2-fluorophenyl)acetic acid (147 mg, 951 µmol), Ν,N-diisopropylethylamine (331 µL, 1.90 mmol) and HATU (362 mg, 951 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (427 mg, 60% purity, 88% yield over 2 steps).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 541 [M+H]+.

Intermediate 155.

K-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl}-2-(4methylphenyl)acetamide

- 107 040608

Crude 5-amino-2-(5-methyl-1,3,4-oxadiazol-2-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide (229 mg) was dissolved in DMF (5 ml) followed by ( 4-methylphenyl)acetic acid (143 mg, 952 µmol), N,N-diisopropylethylamine (332 µl, 1.90 mmol) and HATU (362 mg, 952 µmol). The reaction mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added and the mixture was extracted three times with ethyl acetate. All organic phases were then combined, washed with brine, dried on a Whatman filter and concentrated in vacuo to give the title compound, which was used without further purification (351 mg, 72% purity, 88% yield over 2 steps).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 537 [M+H]+.

Intermediate 156.

tert-Butyl 3-(4-{[(2-chlorophenyl)acetyl]amino}-2-{[(dimethylamino)methylene]sulfamoyl}phenyl)-

H-pyrrole-1-carboxylate

CH ₃

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (500 mg, 1.09 mmol), tert-butyl 3-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrol-1-carboxylate (479 mg, 1.64 mmol) and potassium fluoride (139 mg, 2.4 mmol) were dissolved in dry and degassed DMF (11 ml) and the solution was again purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (28 mg, 54 µmol). The reaction mixture was heated for 3 h at 100°C. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (470 mg, 75% yield, 95% purity).

LC-MS (method A): Rt = 1.30 min; MS (ESI positive): m/z = 545 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.57 (s, 9H), 2.74 (s, 3H), 2.92 (s, 3H), 3.87 (s, 2H), 6.41 (dd , 1H), 7.26 (dd, 1H), 7.31 (d, 1H), 7.32 (m, 2Н), 7.37 (dd, 1H), 7.45 (m, 2H), 7.58 (s, 1H), 7.84 (dd, 1H), 8.29 (d, 1H), 10.57 (s, 1H).

Intermediate 157.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(1H-pyrrol-3-yl)phenyl]acetamide

tert-Butyl 3-(4-{[(2-chlorophenyl)acetyl]amino}-2-{[(dimethylamino)methylene]sulfamoyl}phenyl)1H-pyrrole-1-carboxylate (350 mg, 610 µmol, 95% purity ) was dissolved in dichloromethane (6 mL) and treated with trifluoroacetic acid (1.18 mL, 15.3 mmol) followed by stirring at room temperature for 5 h. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (60 mg, yield 18%, purity 80%).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 445 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.66 (s, 3H), 2.84 (s, 3H), 3.86 (s, 2H), 6.16 (dd, 1H), 6.76 (dd, 1H), 6.88 (dd, 1H), 7.22 (d, 1H), 7.25 (s, 1H), 7.32 (m, 2H), 7.44 (m, 2H), 7.79 (dd, 1H), 8.25 ( d, 1H), 10.49 (s,

- 108 040608

1H), 10.91 (s, 1H).

Intermediate 158.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(1-methyl-1H-pyrrol-3yl)phenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200mg, 436µmol), 1-methyl-3-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (181 mg, 872 µmol, CAS-RN 953040-54-5) and potassium fluoride (76 mg, 1.3 mmol) were dissolved in dry and degassed DMF (4.4 ml) and the solution was again purged with argon for 5 min, followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (11 mg, 22 µmol, CAS-RN 53199-31-8). The reaction mixture was heated for 4 hours at 100°C. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give the crude title compound, which was purified by flash chromatography (107 mg, 51% yield, 95% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 459 (M+H) ⁺ .

'h-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.67 (s, 3H), 2.89 (s, 3H), 3.67 (s, 3H), 3.86 (s, 2H), 6.09 ( dd, 1H), 6.70 (dd, 1H), 6.84 (dd, 1H), 7.20 (d, 1H), 7.32 (m, 2H), 7.40 (s, 1H), 7.44 (m, 2H), 7.79 (dd , 1H), 8.25 (d, 1h), 10.49 (s, 1H).

Intermediate 159.

2-(2-Chlorophenyl)-N-[4-(5-cyano-1-methyl-1 H-pyrrol-2-yl)-3-{[(dimethylamino)methylene]sulfamoyl}phenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol), (5-cyano-1-methyl-1H-pyrrole- 2-yl)boronic acid (163 mg, 1.09 mmol, CAS-RN 860617-71-6) and potassium fluoride (95 mg, 1.64 mmol) were dissolved in dry and degassed DMF (5.5 ml) and the solution was again purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (14 mg, 27 µmol, CAS-RN 53199-31-8). The reaction mixture was heated for 3 h at 100°C. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and it was extracted with ethyl acetate. The product precipitated from both phases was filtered off and dried under reduced pressure to give the title compound in sufficient purity (100 mg, 35% yield, 94% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 484 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.82 (s, 3H), 2.98 (s, 3H), 3.35 (s, 3H), 3.90 (s, 2H), 6.12 (d , 1H), 7.01 (d, 1H), 7.24 (s, 1H), 7.33 (m, 2H), 7.34 (d, 1H), 7.45 (m, 2H), 7.93 (dd, 1H), 8.37 (d, 1H), 10.73(s, 1H).

Synthesis of examples

Example 1

2-(2-Chlorophenyl)-N-[4-(2-oxopyridin-1(2H)-yl)-3-sulfamoylphenyl]acetamide nh ₂

According to general procedures GP1.1, GP2.2, GP3.1 and GP4.1, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), pyridin-2-ol ( 123 mg, 1.29 mmol) and (2-chlorophenyl)acetic acid (240 mg, 1.41 mmol) were converted without purification of intermediates

- 109 040608 in the title compound and purified in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (9.3 mg, 0.0222 mmol, 1% yield over 4 steps, 98% purity). The O-linked regioisomer was also isolated.

LC-MS (method B): Rt = 0.74 min; MS (ESI positive): m/z = 418 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.89 (s, 2H), 6.32 (td, 1H), 6.47 (d, 1H), 7.18 (s, 2H), 7.28- 7.34 (m, 2H), 7.37 (d, 1H), 7.42-7.47 (m, 2H), 7.48-7.56 (m, 2H), 7.92 (dd, 1H), 8.34 (d, 1H), 10.74 (s, 1H).

Example 2

N-[4-(4-Chlορ-2-οksοpyridin-1(2H)-yl)-3-sulfamοylphenyl]-2-(2-hlορphenyl)-acetamide nh ₂

Cl ^H

According to the general procedures GP1.1, GP2.1, GP3.1 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.50 g, 3.88 mmol), 4-chloropyridine-2- ol (502 mg, 3.88 mmol) and (2-chlorophenyl)acetic acid (634 mg, 3.72 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.2% aqueous ammonia (32%))) followed by a second preparative HPLC (Phenomenex Kinetex C18 5 µm 100x30 mm, acetonitrile/water + 0.1% trifluoroacetic acid) (7.3 mg, 0.0161 mmol, yield over 4 steps 1%, purity 97%). The O-linked regioisomer was also isolated.

LC-MS (method C): Rt = 1.91 min; MS (ESI positive): m/z = 452 [M+H] ⁺ .

'H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 6.43 (dd, 1H), 6.63 (d, 1H), 7.26-7.36 (m, 4H) , 7.40 (d, 1H), 7.43-7.48 (m, 2H), 7.58 (d, 1H), 7.91 (dd, 1H), 8.36 (d, 1H), 10.76 (s, 1H).

Example 3

2-(2-Chlορphenyl)-N-[4-(3,5-dichlορ-2-οksοpyridin-1(2H)-yl)-3-sulfamοylphenyl]-acetamide

According to general procedures GP1.1, GP2.1, GP3.1 and GP4.1, 2-chloro-Na-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (3.00 g, 7.76 mmol), 3,5-dichloropyridine- 2-ol (1.27 g, 7.76 mmol) and (2-chlorophenyl)acetic acid (879 mg, 5.16 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Phenomenex Kinetex C18 5 µm 100x30 mm, acetonitrile/water + 0.1% trifluoroacetic acid) followed by crystallization from methanol (13 mg, 0.0267 mmol, 1% yield over 4 steps, 99% purity).

LC-MS (method C): Rt = 2.14 min; MS (ESI positive): m/z = 486 [M+H] ⁺ .

'H-NMR (500 MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.38 (s, 2H), 7.43-7.49 (m, 3H ), 7.83 (d, 1H), 7.90 (dd, 1H), 8.04 (d, 1H), 8.36 (d, 1H), 10.77 (s, 1H).

Example 4

N-[4-(3-Chlορ-2-οksοpyρidin-1(2H)-yl)-3-sulfamοylphenyl]-2-(2-hlορphenyl)-acetamide nh ₂

OjuS”?

According to the general procedures GP1.1, GP2.1, GP3.1 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.50 g, 3.88 mmol), 3-chloropyridine-2- ol (502 mg, 3.88 mmol) and (2-chlorophenyl)acetic acid (646 mg, 3.78 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (YMC Triart C18 5 µm 100x30 mm , acetonitrile/water + 0.1% formic acid) followed by crystallization from methanol (21.8 mg, 0.0482 mmol, 1% yield over 4 steps, 98% purity). The O-linked regioisomer was also isolated.

LC-MS (method C): Rt = 1.83 min; MS (ESI positive): m/z = 452 [M+H] ⁺ .

'H-NMR (500 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 6.33 (t, 1H), 7.25-7.36 (m, 4H), 7.41-7.47 (m, 3H ),

- 110 040608

7.53 (dd, 1H), 7.83 (dd, 1H), 7.92 (dd, 1H), 8.37 (d, 1H), 10.77 (s, 1H).

Examples 5 and 6.

According to general procedures GP1.2, GP2.3, GP3.2 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-methyl-1H- 1,2,4-triazole (161 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (202 mg, 1.18 mmol) were converted without purification of intermediates into 2-(2-chlorophenyl)-N-[4-(3 -methyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide and 2-(2-chlorophenyl)-N-[4-(5-methyl-1H-1,2,4- triazol-1-yl)-3-sulfamoylphenyl]acetamide. The two regioisomers were purified and finally separated by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile /water + 0.1% formic acid).

Example 5

2-(2-Chlorophenyl)-N-[4-(3-methyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-acetamide nh ₂

O=S=O r= ^N .

puTr* ~ mg, 0.0912 mmol, yield over 4 steps 7%, purity 98%.

LC-MS (method A): Rt = 0.89 min; LC-MS (method F): Rt = 3.37 min; MS (ESI positive): m/z = 406 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.36 (s, 3H), 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.42-7.52 (m, 4Н), 7.56 (d, 1H), 7.96 (dd, 1H), 8.39 (d, 1H), 8.66 (s, 1H), 10.83 (s, 1H).

Example 6

2-(2-Chlorophenyl)-N-[4-(5-methyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-acetamide nh ₂

O=S=O Na=\ qaAX ci ^H mg, 0.0197 mmol, yield after 4 steps 2%, purity 97%.

LC-MS (method A): Rt = 0.89 min; LC-MS (method F): Rt = 1.68 min; MS (ESI positive): m/z = 452 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.22 (s, 3H), 3.93 (s, 2H), 7.25 (s, 2H), 7.31-7.38 (m, 2H) , 7.437.50 (m, 2H), 7.57 (d, 1H), 7.98 (dd, 1H), 8.03 (s, 1H), 8.41 (d, 1H), 10.87 (s, 1H).

Example 7

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide

According to general procedures GP1.2, GP2.3, GP3.2 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-(trufluoromethyl)- 1H-1,2,4-triazole (266 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (175 mg, 1.02 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (35 mg, 0.0761 mmol, 6% yield over 4 steps, 98% purity).

LC-MS (method B): Rt = 0.79 min; MS (ESI positive): m/z = 460 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d6) δ [ppm]: 3.93 (s, 2H), 7.30-7.36 (m, 2H), 7.43-7.46 (m, 2H), 7.54 (s, 2H ), 7.66 (d, 1H), 7.96 (dd, 1H), 8.45 (d, 1H), 9.03 (s, 1H), 10.87 (s, 1H).

Example 8

2-(2-Chlorophenyl)-N- {4-[5 -methyl-3 -(trifluoromethyl)- 1H-1,2,4-triazol-1 -yl] -3 sulfamoylphenyl}acetamide

- 111 040608

According to general procedures GP1.2, GP2.3, GP3.2 and GP4.2, 2-chloro-Ni(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-methyl-5-( trifluoromethyl)-1H-1,2,4triazole (293 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (203 mg, 1.19 mmol) were converted without purification of intermediates to the title compound and purified at the final step using preparative HPLC (YMC Triart C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (49.4 mg, 0.104 mmol, 8% yield over 4 steps, 98% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 474 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.29 (s, 3H), 3.93 (s, 2H), 7.30-7.37 (m, 2H), 7.44-7.50 (m, 2H), 7.61 (s, 2H), 7.65 (d, 1H), 7.95 (dd, 1H), 8.46 (d, 1H), 10.91 (s, 1H).

Example 9

2-(2-Chloρphenyl)-N-[4-(1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

According to general procedures GP1.2, GP2.3, GP3.2 and GP4.2, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 1H-imidazole (132 mg , 1.94 mmol) and (2-chlorophenyl)acetic acid (203 mg, 1.19 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (6 mg, 0.0154 mmol, 1% yield over 4 steps, 99% purity).

LC-MS (method B): Rt = 0.68 min; MS (ESI positive): m/z = 391 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.91 (s, 2H), 7.02 (t, 1H), 7.30-7.37 (m, 3H), 7.40 (d, 1H) , 7.437.49 (m, 2H), 7.52 (s, 2H), 7.75 (t, 1H), 7.89 (dd, 1H), 8.40 (d, 1H), 10.78 (s, 1H).

Example 10

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}acetamide

According to general procedures GP1.2, GP2.3, GP3.2 and GP4.2, 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-(trifluoromethyl)- 1H-imidazole (264 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (199 mg, 1.17 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (11 mg, 0.0240 mmol, yield for 4 stages 2%, purity 99%).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 459 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.49 (m, 2H), 7.51 (d, 1H ), 7.72 (s, 2H), 7.90 (dd, 1H), 7.95 (s, 1H), 7.97-7.99 (m, 1H), 8.42 (d, 1H), 10.83 (s, 1H).

Example 11.

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

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-(trifluoromethyl)- 1H-pyrazole (264

- 112 040608 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (243 mg, 1.42 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XB ridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (6.7 mg, 0.0146 mmol, yield over 4 steps 1%, purity 98%).

LC-MS (method B): Rt = 1.05 min; MS (ESI positive): m/z = 459 [M+H]+.

1Н-NMR (400 MHz, DMSO-d6) δ [ppm] 3.92 (s, 2H), 6.98 (d, 1H), 7.29-7.36 (m, 2H), 7.40-7.52 (m, 4H), 7.61 (d, 1H), 7.98 (dd, 1H), 8.26-8.30 (m, 1H), 8.42 (d, 1H), 10.85 (s, 1H).

Example 12.

2-(2-Chlorophenyl)-X-{4-[3-(difluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂

O=S=O F αχά '

^ClH

According to general procedures GP1.2, GP2.3, GP3.3 and GP4.1, X-(2,4-dimethoxybenzyl)-2fluoro-5-nitrobenzenesulfonamide (250 mg, 0.68 mmol), 3-(difluoromethyl)- 1H-pyrazole (120 mg, 1.01 mmol) and (2-chlorophenyl)acetic acid (102 mg, 0.60 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Chromatorex C- 18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (4 mg, 0.00907 mmol, 1% yield over 4 steps, 80% purity).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 441 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.92 (s, 2H), 6.75-6.78 (m, 1H), 7.18 (t, 1H), 7.31-7.36 (m, 2H), 7.38 (m, 2H), 7.43-7.49 (m, 2H), 7.58 (d, 1H), 7.98 (dd, 1H), 8.20 (d, 1H), 8.40 (d, 1H), 10.82 (s, 1H) .

Example 13

2-(2-Chlorophenyl)-X- {4-[5-cyclopropyl-3 -(difluoromethyl)-1 H-pyrazol-1 -yl]-3 sulfamoylphenyl}acetamide

According to general procedures GP1.2, GP2.3, GP3.3 and GP4.2, X-(2,4-dimethoxybenzyl)-2fluoro-5-nitrobenzenesulfonamide (350 mg, 0.95 mmol), 5-cyclopropyl-3- (difluoromethyl)-1H-pyrazole (224 mg, 1.42 mmol) and (2-chlorophenyl)acetic acid (202 mg, 1.18 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (12.7 mg, 0.0264 mmol , yield over 4 stages 3%, purity 90%).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 481 [M+H]+.

1Н-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 0.70-0.75 (m, 2Н), 0.76-0.84 (m, 2Н), 1.52-1.60 (m, 1Н), 3.92 (s, 2Н), 6.37 (s, 1Н), 7.06 (t, 1Н), 7.12 (s, 2Н), 7.31-7.37 (m, 2Н), 7.43-7.50 (m, 2Н), 7.63 (d, 1Н), 8.00 (dd, 1H), 8.41 (d, 1H), 10.84 (s, 1H).

Example 14

2-(2-Chlorophenyl)-X-{4-[4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-methyl-3- (trifluoromethyl)-1Hpyrazole (291 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (255 mg, 1.50 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonite

- 113 040608 reel/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Chromatorex C-18 10 µm, 125^30 mm, acetonitrile/water + 0.1% formic acid) (43 mg, 0.0909 mmol , yield over 4 steps 7%, purity 97%).

LC-MS (method B): Rt = 1.18 min; MS (ESI positive): m/z = 473 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.19 (s, 3H), 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.41 (s, 2H), 7.43

7.49 (m, 2H), 7.58 (d, 1H), 7.98 (dd, 1H), 8.10 (s, 1H), 8.40 (d, 1H), 10.83 (s, 1H).

Example 15

2-(2-Chlorophenyl)-N-{4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-methyl-3- (trifluoromethyl)-1Hpyrazole (291 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (268 mg, 1.57 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (36.5 mg, 0.0772 mmol, 6% yield over 4 steps, 98% purity). LC-MS (method B): Rt = 1.13 min; MS (ESI positive): m/z = 473 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.12 (s, 3H), 3.92 (s, 2H), 6.73 (s, 1H), 7.24 (s, 2H), 7.31- 7.36 (m, 2H), 7.44-7.49 (m, 2H), 7.57 (d, 1H), 7.97 (dd, 1H), 8.42 (d, 1H), 10.88 (s, 1H).

Example 16

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1H-1,2,4-triazol-1 -yl)phenyl]acetamide nh ₂ o=s=o ^== N ςαΛ'' il ^H

According to general procedures GP1.2, GP2.3, GP3.4 and GP4.2, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 1H-1,2, 4-triazole (134 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (303 mg, 1.77 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (27 mg, 0.0689 mmol, 5% yield over 4 steps, 97% purity).

LC-MS (method B): Rt = 0.68 min; MS (ESI positive): m/z = 392 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.50 (m, 4H), 7.59 (d, 1H) , 7.98 (dd, 1H), 8.23 (s, 1H), 8.42 (d, 1H), 8.82 (s, 1H), 10.85 (s, 1H).

Example 17.

2-(2-Chlorophenyl)-N-{4-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂

O=S=O __, ^F

2-(2-Chlorophenyl)-N-{4-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide (112 mg, 0.189 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (129 mg, 1.14 mmol) followed by stirring at room temperature overnight and for one hour at 55°C. The reaction mixture was concentrated in vacuo and extracted with dichloromethane and sodium bicarbonate solution. The aqueous phase was re-extracted twice with dichloromethane and twice with 1-butanol. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated in vacuo. Purification by HPLC gave the title compound (5 mg, 0.0113 mmol, 6% yield, 95% purity).

LC-MS (method B): Rt = 0.79 min; MS (ESI positive): m/z = 442 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.93 (s, 2H), 7.21 (t, 1H), 7.30-7.37 (m, 2H), 7.43-7.49 (m, 2H) , 7.55 (s, 2Н), 7.64 (d, 1H), 7.97 (dd, 1H), 8.44 (d, 1H), 8.95 (s, 1H), 10.90 (s, 1H).

Example 18.

N-{4-[3-(Difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide

- 114 040608

N-{4-[3-(Difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide (94 mg, 0.163 mmol) was dissolved in dichloromethane (5 ml) and treated with trifluoroacetic acid (112 mg, 0.979 mmol) followed by stirring at room temperature overnight and for one hour at 55°C. The reaction mixture was concentrated in vacuo and extracted with dichloromethane and sodium bicarbonate solution. The aqueous phase was re-extracted twice with dichloromethane and twice with 1-butanol. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated in vacuo. Purification by HPLC gave the title compound (2 mg, 0.00470 mmol, 3% yield, 98% purity).

LC-MS (method B): Rt = 0.70 min; MS (ESI positive): m/z = 426 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.82 (s, 2H), 7.07-7.37 (m, 4H), 7.39-7.44 (m, 1H), 7.55 (s, 2H ), 7.64 (d, 1H), 7.96 (dd, 1H), 8.43 (d, 1H), 8.95 (s, 1H), 10.86 (s, 1H).

Example 19.

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

O=S=O Nc=AF ci ^H

5-Amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (22.3 g, 48.9 mmol) was dissolved in DMF (460 ml) followed by the addition of ( 2-chlorophenyl)acetic acid (12.5 g, 73.3 mmol), N,N-diisopropylethylamine (25.3 g, 195 mmol) and HATU (27.9 g, 73.3 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with sodium bicarbonate solution, brine and ammonium chloride solution, dried over sodium sulfate and concentrated again in vacuo. The protected product had already partially precipitated during the ammonium chloride wash and was removed before drying with sodium sulfate.

Both portions of the product, the residue and the precipitate, were dissolved in dichloromethane (150 ml) and treated with trifluoroacetic acid (75 ml) followed by stirring overnight at room temperature.

Again, the product had already partially precipitated and was removed. The remaining solution was concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with bicarbonate solution and brine, dried over sodium sulfate and finally concentrated in vacuo. During treatment with water, the product partially precipitated again. The combined residual fractions plus the fraction from the organic phase concentration were combined and purified by crystallization from refluxing ethyl acetate to give the title compound (12.3 g, 26.8 mmol, 55% yield over 2 steps, 98% purity).

LC-MS (method B): Rt = 1.06 min; MS (ESI positive): m/z = 459 [M+H]+.

D-NMR (400 MHz, DMSO-d6) δ [ppm] 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.42-7.48 (m, 4H), 7.60 (d, 1H), 7.98 (dd, 1H), 8.18 (s, 1H), 8.39 (d, 1H), 8.74 (s, 1H), 10.83 (s, 1H).

Example 20.

2-(2-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide nh ₂

O=S=O Nc=A F qaZ/^

5-Amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (350 mg, 0.767 mmol) was dissolved in DMF (15 ml) followed by the addition of ( 2-fluorophenyl)acetic acid (130 mg, 0.843 mmol), N,N-diisopropylethylamine (496 mg, 3.83 mmol) and HATU (466 mg, 1.23 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated again in vacuo.

The residue was dissolved in dichloromethane (10 ml) and treated with trifluoroacetic acid (4.37 g, 38.3 mmol) followed by stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10

- 115 040608 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (60.5 mg, 0.137 mmol, 18% yield over 2 steps, 98% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 443 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.82 (s, 2H), 7.17-7.23 (m, 2H), 7.31-7.49 (m, 4H), 7.60 (d, 1H) , 7.98 (dd, 1H), 8.18 (s, 1H), 8.39 (d, 1H), 8.74 (s, 1H), 10.82 (s, 1H).

Example 21.

2-[2-(Difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 yl]phenyl} acetamide

5-Amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (350 mg, 0.767 mmol) was dissolved in DMF (15 mL) followed by the addition of [ 2(difluoromethyl)phenyl]acetic acid (157 mg, 0.843 mmol), N,N-diisopropylethylamine (496 mg, 3.83 mmol) and HATU (466 mg, 1.23 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated again in vacuo.

The residue was dissolved in dichloromethane (10 ml) and treated with trifluoroacetic acid (4.37 g, 38.3 mmol) followed by stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (65 mg, 0.137 mmol, 18% yield over 2 steps , purity 95%).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 475 [M+H] ⁺ .

'I-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.95 (s, 2H), 7.24 (t, 1H), 7.41-7.48 (m, 4H), 7.51-7.56 (m, 1H ), 7.58-7.63 (m, 2H), 7.97 (dd, 1H), 8.18 (s, 1H), 8.38 (d, 1H), 8.74 (s, 1H), 10.81 (s, 1H).

Example 22.

N-{3-Sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[2(trifluoromethyl)phenyl]acetamide

5-Amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (350 mg, 0.767 mmol) was dissolved in DMF (15 mL) followed by the addition of [ 2(trifluoromethyl)phenyl]acetic acid (172 mg, 0.843 mmol), N,N-diisopropylethylamine (496 mg, 3.83 mmol) and HATU (466 mg, 1.23 mmol). The reaction mixture was stirred overnight at room temperature. It was then concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with brine, dried over sodium sulfate and concentrated again in vacuo.

The residue was dissolved in dichloromethane (10 ml) and treated with trifluoroacetic acid (4.37 g, 38.3 mmol) followed by stirring overnight at room temperature. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (48 mg, 0.0975 mmol, 13% yield over 2 steps , purity 95%).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 493 [M+H] ⁺ .

'I-NMR (400 MHz, DMSO-ds) δ [ppm] 4.01 (s, 2H), 7.43 (s, 2H), 7.49-7.63 (m, 3H), 7.65-7.76 (m, 2H) , 7.96 (dd, 1H), 8.18 (s, 1H), 8.38 (d, 1H), 8.74 (s, 1H), 10.82 (s, 1H).

Example 23.

N-[4-(3-tert-Butyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

In accordance with the general methods GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloro-N-(2,4

- 116 040608 dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-tert-butyl-1H-1,2,4-triazole (242 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (296 mg , 1.74 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (96 mg, 0.214 mmol, yield over 4 stages 17%, purity 97%).

LC-MS (method B): Rt = 0.92 min; MS (ESI positive): m/z = 448 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.34 (s, 9H), 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.50 (m, 4Н), 7.63 (d, 1H), 7.99 (dd, 1H), 8.40 (d, 1H), 8.71 (s, 1H), 10.83 (s, 1H).

Example 24.

2-(2-Chlorophenyl)-N-[4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ O=S=O

^ClH

According to general procedures GP1.2, GP2.1, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-chloro-1H- 1,2,4-triazole (201 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (203 mg, 1.19 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (9 mg, 0.0211 mmol, 2% yield over 4 steps, 97% purity).

LC-MS (method B): Rt = 0.70 min; MS (ESI positive): m/z = 426 [M+H] ⁺ .

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 3.92 (s, 2H), 7.31-7.35 (m, 2H), 7.43-7.49 (m, 2H), 7.60 (s, 2Н), 7.62 (d, 1H), 7.95 (dd, 1H), 8.42 (d, 1H), 8.81 (s, 1H), 10.87 (s, 1H).

Example 25.

2-(2-Chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.1, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chloro-1H- pyrazole (199 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (313 mg, 1.83 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.2% aqueous ammonia (32%)) (55 mg, 0.129 mmol, 10% yield over 4 steps, 99% purity).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 425 [M+H] ⁺ .

1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.31-7.37 (m, 2H), 7.41 (s, 2H), 7.44-7.49 (m, 2H) , 7.55 (d, 1H), 7.87 (s, 1H), 7.97 (dd, 1H), 8.35 (d, 1H), 8.38 (d, 1H), 10.81 (s, 1H).

Example 26.

2-(2-Chlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-ul)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.1, GP3.4 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-fluoro-1H- pyrazole (167 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (151 mg, 1.89 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.2% aqueous ammonia (32%)) (43 mg, 0.105 mmol, 8% yield over 4 steps, 97% purity).

LC-MS (method B): Rt = 0.88 min; MS (ESI positive): m/z = 409 [M+H] ⁺ .

¹ H-NMR (500 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.30-7.37 (m, 2H), 7.39 (s, 2H), 7.43-7.50 (m, 2H ), 7.53 (d, 1H), 7.84 (d, 1H), 7.97 (dd, 1H), 8.26 (d, 1H), 8.37 (d, 1H), 10.79 (s, 1H).

Example 27.

2-(2-Chlorophenyl)-N-[4-(4-isopropoxy-1H-pyrazol-1-yl)-3-sulfamoulfenyl]acetamide

- 117 040608

According to general procedures GP1.2, GP2.2, GP3.5 and GP4.1, 2-chloro-Ni(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (400 mg, 1.03 mmol), 4-isopropoxy-1H-pyrazole (196 mg, 1.55 mmol) and (2-chlorophenyl)acetic acid (264 mg, 1.55 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (16 mg, 0.0356 mmol, 3% yield over 4 steps, 95% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 449 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 (d, 6H), 3.89 (s, 2H), 4.25-4.32 (m, 1H), 7.29-7.36 (m, 2H) , 7.38-7.48 (m, 4H), 7.52 (d, 1H), 7.56 (d, 1H), 7.86 (d, 1H), 7.96 (dd, 1H), 8.33 (d, 1H), 10.74 (s, 1H ).

Example 28.

N-[4-(4-Bροm-1H-pyρazοl-1-yl)-3-sulfamοylphenyl]-2-(2-chlorophenyl)acetamide nh ₂

O=S=O 14=, OLD ⁰ ' Cl ^H

According to the general procedures GP1.2, GP2.2, GP3.5 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (400 mg, 1.03 mmol), 4-bromo-1H- pyrazole (228 mg, 1.55 mmol) and (2-chlorophenyl)acetic acid (264 mg, 1.55 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.1% formic acid) (27 mg, 0.0575 mmol, 6% yield over 4 steps, 95% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 469/471 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.41 (s, 2H), 7.42-7.48 (m, 2H ), 7.54 (d, 1H), 7.87 (d, 1H), 7.96 (dd, 1H), 8.34 (d, 1H), 8.37 (d, 1H), 10.80 (s, 1H).

Example 29.

2-(2-Chlορphenyl)-N-[4-(3-isobutyl-1H-1,2,4-triazοl-1-yl)-3-sulfamοylphenyl]acetamide

According to the general methods GP1.2, GP2.2, GP3.3 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-isobutyl-1H- pyrazole (243 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (27 mg, 0.0603 mmol, 5% yield over 4 steps, 98% purity).

LC-MS (method B): Rt = 0.93 min; MS (ESI positive): m/z = 448 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.93 (d, 6H), 1.99-2.11 (m, 1H), 2.57 (d, 2H), 3.91 (s, 2H), 7.277.37 (m, 2H), 7.37-7.49 (m, 4H), 7.58 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H), 8.68 (s, 1H), 10.82 (s, 1H).

Example 30.

2-(2-Chlορphenyl)-N-{4-[4-(methylsulfanyl)-1H-pyρazοl-1-yl]-3-sulfamοylphenyl}acetamide nh ₂

According to the general procedures GP1.2, GP2.2, GP3.5 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (400 mg, 1.03 mmol), 4-(methylsulfanyl)- 1H-pyrazole (177 mg, 1.55 mmol) and (2-chlorophenyl)acetic acid (264 mg, 1.55 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% mu

- 118 040608 ravic acid) (31 mg, 0.0709 mmol, yield over 4 steps 7%, purity 95%).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 437 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.40 (s, 3H), 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.39-7.49 (m, 4Н), 7.54 (d, 1H), 7.81 (d, 1H), 7.97 (dd, 1H), 8.17 (d, 1H), 8.36 (d, 1H), 10.78 (s, 1H).

Example 31.

2-(2-Chlorophenyl)-N-[4-(4-methoxy-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

NH ₂ o=s=on=\ I ⁿ z cwy' ·

^ClH

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-methoxy-1H- pyrazole (190 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (304 mg, 1.78 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.2% aqueous ammonia (32%)) (83 mg, 0.0197 mmol, 15% yield over 4 steps, 98% purity).

LC-MS (method B): Rt = 0.90 min; MS (ESI positive): m/z = 421 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.75 (s, 3H), 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.40-7.48 (m, 4H), 7.51 (d, 1H), 7.59 (d, 1H), 7.89 (d, 1H), 7.97 (dd, 1H), 8.34 (d, 1H), 10.74 (s, 1H).

Example 32.

N-[4-( 1 H-Benzimidazol-1 -yl)-3-sulfamoylphenyl] -2-(2-chlorophenyl)acetamide nh ₂

O=S=O old

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), N-benzimidazole (229 mg , 1.94 mmol) and (2-chlorophenyl)acetic acid (322 mg, 1.89 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (83 mg, 0.0197 mmol, 15% yield over 4 steps, 98% purity).

LC-MS (method B): Rt = 0.83 min; MS (ESI positive): m/z = 441 [M+H]+.

L-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.94 (s, 2H), 7.07-7.12 (m, 1H), 7.20-7.28 (m, 2H), 7.30-7.37 (m, 2H), 7.44-7.52 (m, 3H), 7.58 (s, 2H), 7.69-7.74 (m, 1H), 7.95 (dd, 1H), 8.22 (s, 1H), 8.50 (d, 1H), 10.85 (s, 1H).

Example 33.

Ν-[4-(4-Xλορ-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

According to general procedures GP1.2, GP2.1, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chloro-1H- imidazole (199 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (255 mg, 1.50 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (23 mg, 0.0541 mmol, yield over 4 steps 4 %, purity 96%).

LC-MS (method B): Rt = 0.75 min, MS (ESI positive): m/z = 425 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.40-7.48 (m, 4H), 7.65 (s, 2H), 7.72 (d, 1H), 7.87 (dd, 1H), 8.39 (d, 1H), 10.80 (s, 1H).

Example 34.

2-(2-Chlorophenyl)-N-{4-[3-(dimethylamino)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide

- 119 040608 nh ₂

O \u003d S \u003d O f \u003d ^N \ I ^N s

Cl ^H

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloroD-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), N,N-dimethyl-1H- 1,2,4-triazol-3amine (217 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (310 mg, 1.82 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (45 mg, 0.103 mmol, yield over 4 stages 8%, purity 99%).

LC-MS (method B): Rt = 0.80 min; MS (ESI positive): m/z = 435 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.93 (s, 6H), 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.49 (m, 2Н), 7.56 (d, 1H), 7.59 (s, 2Н), 7.96 (dd, 1H), 8.37 (d, 1H), 8.45 (s, 1H), 10.79 (s, 1H).

Example 35.

2-(2-Chloρphenyl)-N-[4-(3-ethyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

0=3=0 |=Ν CH ₃ ci ^H

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloroρ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-ethyl-1H- 1,2,4-triazole (188 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (286 mg, 1.67 mmol) were converted without purification of intermediates to the title compound and finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (20 mg, 0.0476 mmol , yield over 4 steps 4%, purity 97%).

LC-MS (method B): Rt = 0.75 min; MS (ESI positive): m/z = 420 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.25 (t, 3H), 2.73 (q, 2H), 3.91 (s, 2H), 7.29-7.36 (m, 2H) , 7.427.50 (m, 4H), 7.58 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H), 8.68 (s, 1H), 10.82 (s, 1H).

Example 36 and Example 37.

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-cyclopropane-1H- 1,2,4-triazole (212 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (310 mg, 1.82 mmol) were converted without purification of intermediates into (2-chlorophenyl)-N-[4-(3-cyclonρopyl -1H-1,2,4-triazol-1-yl)-3sulfamoylphenyl]acetamide and 2-(2-chlorophenyl)-N-[4-(5-cyclonρopyl-1H-1,2,4-triazol-1- yl)-3sulfamoylphenyl]acetamide. The two regioisomers were purified and finally separated by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (YMC Triart C18 5 µm 100x30 mm, acetonitrile /water + 0.1% formic acid).

Example 36.

(2-Chlorophenyl)-N-[4-(3-cyclonρopyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O p= ^N .__ OLD'

Cl ⁿ

83.4 mg, 0.124 mmol, yield over 4 steps 10%, purity 98%.

LC-MS (method E): Rt = 1.86 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.83-0.88 (m, 2H), 0.94-1.01 (m, 2H), 2.06-2.13 (m, 1H), 3.91 (s , 2H), 7.29-7.36 (m, 2H), 7.41-7.53 (m, 4H), 7.57 (d, 1H), 7.95 (dd, 1H), 8.39 (d, 1H), 8.61 (s, 1H), 10.82(s, 1H).

Example 37.

2-(2-Chlorophenyl)-N-[4-(5-cyclopronyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide

- 120 040608 nh ₂

O=S=O №=\ ραΛϊ Cl ^H

12.6 mg, 0.0292 mmol, yield over 4 steps 2%, purity 98%.

LC-MS (method E): Rt = 1.82 min; MS (ESI positive): m/z = 432 [M+H]+.

'H-NMR (400 MHz, DMSO-dj) δ [ppm]: 0.92 (s, 4H), 1.63-1.71 (m, 1H), 3.92 (s, 2H), 7.22 (s, 2H), 7.307.37 (m, 2H), 7.43-7.49 (m, 2H), 7.61 (d, 1H), 7.98 (s, 1H), 8.00 (dd, 1H), 8.42 (d, 1H), 10.86 (s, 1H).

Example 38.

2-(2-Chlorophenyl)-N-{4-[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂

O=S=O I O-CH,

Cl ^H

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-(methoxymethyl)- 1H-1,2,4-triazole (219 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (306 mg, 1.80 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14.5 mg, 0.0333 mmol, 3% yield over 4 steps, 98% purity).

LC-MS (method B): Rt = 0.67 min; MS (ESI positive): m/z = 436 [M+H]+.

1I-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.31 (s, 3H), 3.92 (s, 2H), 4.50 (s, 2H), 7.29-7.37 (m, 2H), 7.437 .49 (m, 4H), 7.60 (d, 1H), 7.97 (dd, 1H), 8.41 (d, 1H), 8.78 (s, 1H), 10.84 (s, 1H).

Example 39.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

Method 1: Pd/C (load 10%, 350 mg) was added to a solution of 2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (9.09 g, 20.5 mmol ) in a mixture of methanol (120 ml) and tetrahydrofuran (250 ml) and stirred at room temperature for 3 h in a stream of hydrogen. The catalyst was removed by filtration, followed by washing with tetrahydrofuran and concentration of the filtrate in vacuo. The reaction mixture was extracted with ethyl acetate/water. Sodium carbonate solution was added and the mixture was stirred overnight. The resulting precipitate was removed by filtration and discarded. The organic phase was separated, dried over sodium sulfate and concentrated in vacuo to give crude 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (6.37 g), which was used without further purification in the next step.

LC-MS (method B): Rt = 1.06 min; MS (ESI positive): m/z = 414 [M+H]+.

1I-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.69 (s, 3H), 3.72 (s, 3H), 3.92 (br d, 2H), 6.04 (s, 2H), 6.40- 6.48 (m, 2H), 6.78 (dd, 1H), 7.08-7.14 (m, 2H), 7.19 (d, 1H), 7.27 (br t, 1H), 8.25 (s, 1H), 8.70 (s, 1H ).

The crude product from the previous step (6.37 g) was dissolved in DMF (87 ml) followed by the addition of (2-chlorophenyl)acetic acid (3.94 g, 23.1 mmol), Ν,Ν-diisopropylethylamine (5.97 g, 46.2 mmol) and HATU (8.78 d, 23.1 mmol). The reaction mixture was stirred over the weekend at room temperature. It was then concentrated in vacuo and extracted with ethyl acetate and water. The organic phase was washed with ammonium chloride, sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated again in vacuo to give crude 2-(2chlorophenyl)-N-{4-(4-cyano-1H-pyrazol-1-yl) -3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}acetamide (9.77 g), which was used without further purification in the next step.

LC-MS (method B): Rt = 1.27 min; MS (ESI positive): m/z = 566 [M+H]+ The crude product from the previous step (9.77 g) was dissolved in a mixture of dichloromethane (30 ml) and trifluoroacetic acid (15 ml) and stirred at room temperature overnight . The reaction mixture was concentrated in vacuo, taken up in dichloromethane and concentrated again in vacuo to remove residual trifluoroacetic acid. The reaction mixture was then stirred in dichloromethane/water over the weekend. The resulting precipitate was removed by filtration and provided specified in

- 121 040608 title pure compound (5.40 g, 13.0 mmol, yield over 3 steps 63%, purity 97%). The purity could be further improved by recrystallization from ethyl acetate/hexanes.

LC-MS (method B): Rt = 0.84 min, MS (ESI positive): m/z = 416 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.91 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.49 (m, 4H), 7.58 (d, 1H), 7.97 (dd, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 8.86 (d, 1H), 10.84 (br s, 1H).

Method 2: 5-amino-2-(4-cyano-III-pyrazol-1-yl)benzenesulfonamide (81 mg, 0.31 mmol) was dissolved in dimethylformamide (1 ml) followed by the addition of N,X-diisopropylethylamine (119 mg, 0.92 mmol), (2-chlorophenyl)acetic acid (63 mg, 0.37 mmol) and HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3- oxide, 140 mg, 0.37 mmol). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo, ethyl acetate and water were added and the organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo. Purification by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) gave the title compound (33 mg, 0.0794 mmol, 26% yield, 50 purity %).

Example 40.

N-[4-(4-tert-Butyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide n ₃ with CH ₃ ^NH 2 U ^CH 3 o=s=od ci ⁿ

Following the general procedures of GP1.2 (but using 4.5 equivalents of 4-tert-butyl-1H-imidazole and 9 equivalents of base, 2 d, 100°C), GP2.4, GP3.4 and GP4.2, 2 -chloro-X-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-tert-butyl-1H-imidazole (723 mg, 5.82 mmol) and (2chlorophenyl)acetic acid (333 mg, 1.95 mmol ) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (YMC Trairt C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (25 mg, 0.0559 mmol, 4% yield over 4 steps, 97% purity).

LC-MS (method B): Rt = 0.91 min; MS (ESI positive): m/z = 447 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.24 (s, 9H), 3.90 (s, 2H), 6.99 (d, 1H), 7.28-7.36 (m, 2H), 7.367.49 (m, 5H), 7.63 (d, 1H), 7.87 (dd, 1H), 8.38 (d, 1H), 10.75 (s, 1H).

Example 41.

2-(2-Chlorophenyl)-N-[4-(3-cyano-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ O=S=O /= N

According to general procedures GP1.2, GP2.2, GP3.5 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (400mg, 1.03mmol), 1H-1.2, 4-triazole-3-carbonitrile (145 mg, 1.55 mmol) and (2-chlorophenyl)acetic acid (264 mg, 1.55 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (YMC Trairt C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (3.8 mg, 0.00912 mmol, yield over 4 steps 1%, purity 95%).

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 417 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.93 (s, 2H), 7.28-7.38 (m, 2H), 7.41-7.51 (m, 2H), 7.60-7.69 ( m, 3H), 7.92-8.02 (m, 1H), 8.43 (s, 1H), 9.12 (s, 1H), 10.90 (s, 1H).

Example 42.

K-[4-(4-Bromo-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide nh ₂ o=s=or= ^N ₄ dA

According to general procedures GP1.2, GP2.2, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-bromo-1H- imidazole (285 mg, 1.94

- 122 040608 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified at the final stage using preparative HPLC (Waters XBridge C18 5 μm 100x30 mm, acetonitrile/ water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (20 mg, 0.0426 mmol, 3% yield over 4 steps, 98% purity).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 469/471 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.29-7.35 (m, 2H), 7.41-7.48 (m, 4H), 7.65 (s, 2H ), 7.73 (d, 1H), 7.89 (dd, 1H), 8.40 (d, 1H), 10.80 (s, 1H).

Example 43 and Example 44.

According to general procedures GP1.2, GP2.2, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3H-imidazo[4, 5-b]pyridine (231 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates into 2-(2-chlorophenyl)-X-[4-(3Н-imidazo [4,5-b]pyridin-3-yl)-3-sulfamoylphenyl]acetamide and 2-(2-chlorophenyl)-N-[4-(1H-imidazo[4,5-b]pyridin-1-yl) -3-sulfamoylphenyl]acetamide. The two regioisomers were purified and finally separated by preparative HPLC (YMC Triart C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid).

Example 43.

2-(2-Chlorophenyl)-N-[4-(3H-imidazo[4,5-b]pyridin-3-yl)-3-sulfamoylphenyl]acetamide

NH ₂ o=s=o mg, 0.00226 mmol, yield after 4 steps 1%, purity 98%.

LC-MS (method G): Rt = 1.52 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (600 MHz, DMSO-di) δ [ppm]: 3.93 (s, 2H), 7.26 (dd, 1H), 7.31-7.37 (m, 2H), 7.44-7.49 (m, 2H ), 7.53-7.56 (m, 2H), 7.61 (s, 2H), 7.96 (dd, 1H), 8.46 (dd, 1H), 8.47 (d, 1H), 8.49 (d, 1H), 10.87 (s, 1H).

Example 44.

2-(2-Chlorophenyl)-X-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ °=S=° ςv/τό mg, 0.0113 mmol , yield over 4 stages 1%, purity 95%.

LC-MS (method G): Rt = 1.61 min; MS (ESI positive): m/z = 442 (M+H)+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.31-7.37 (m, 3H), 7.45-7.49 (m, 2H), 7.52-7.57 (m , 3H), 7.95 (dd, 1H), 8.16 (dd, 1H), 8.29 (dd, 1H), 8.46 (s, 1H), 8.48 (d, 1H), 10.84 (s, 1H).

Example 45 and Example 46.

According to general procedures GP1.2, GP2.2, GP3.5 and GP4.1, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3H-imidazo[4, 5-c]pyridine (231 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates into 2-(2-chlorophenyl)-N-[4-(1Н-imidazo [4,5-c]pyridin-1-yl)-3-sulfamoylphenyl]acetamide and 2-(2-chlorophenyl)-X-[4-(3H-imidazo[4,5-c]pyridin-3-yl) -3-sulfamoylphenyl]acetamide. The two regioisomers were purified and finally separated by preparative HPLC (Phenomenex Kinetex C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Luna Hilic 5 µm 250x30 mm, CO ₂ /methanol + 0.5% ammonia (32%)).

Example 45.

2-(2-Chlorophenyl)-X-[4-(1H-imidazo[4,5-c]pyridin-1-yl)-3-sulfamoylphenyl]acetamide

mg, 0.0113 mmol, yield over 4 steps 1%, purity 95%.

LC-MS (method H): Rt = 2.75 min, MS (ESI positive): m/z = 442 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.28 (d, 1H), 7.31-7.38 (m, 2H), 7.43-7.50 (m, 2H ), 7.58 (d, 1H), 7.61-7.68 (m, 2H), 7.97 (dd, 1H), 8.37-8.43 (m, 1H), 8.47-8.54 (m, 2H), 9.15 (s, 1H), 10.90(s, 1H).

- 123 040608

Example 46.

2-(2-Chlorophenyl)-N-[4-(3H-imidazo[4,5-c]pyridin-3-yl)-3-sulfamoylphenyl]acetamide

mg, 0.0113 mmol, yield after 4 steps 1%, purity 85%.

LC-MS (method H): Rt = 3.34 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.27-7.39 (m, 2H), 7.42-7.50 (m, 2H), 7.67 (d, 1H), 7.73-7.82 (m, 3H), 7.94 (dd, 1H), 7.98-8.03 (m, 1H), 8.42-8.48 (m, 2H), 8.95 (s, 1H), 10.91 (s, 1H) .

Example 47.

2-(2-Chlorophenyl)-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ ch ₃ o=s=o

Cl ^H

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 2,4-dimethyl- 1H-imidazole (207 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (262 mg, 1.53 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Waters YMC Triart C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (1 mg, 0.00239 mmol, yield 4 stages 1%, purity 95%).

LC-MS (method A): Rt = 0.76 min; MS (ESI positive): m/z = 419 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.97 (s, 3H), 2.07 (s, 3H), 3.90 (s, 2H), 6.74 (s, 1H), 7.26- 7.38 (m, 5H), 7.41-7.49 (m, 2H), 7.87 (dd, 1H), 8.37 (d, 1H), 10.77 (s, 1H).

Example 48.

2-(2-Fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (450 mg, 1.17 mmol), 4-fluoro-1H- pyrazole (150 mg, 1.75 mmol) and (2-fluorophenyl)acetic acid (284 mg, 1.85 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.1% formic acid) (38 mg, 0.0969 mmol, 8% yield over 4 steps, 93% purity).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 393 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.80 (s, 2H), 7.15-7.22 (m, 2H), 7.29-7.44 (m, 4H), 7.52 (d, 1H ), 7.83 (dd, 1H), 7.96 (dd, 1H), 8.26 (dd, 1H), 8.36 (d, 1H), 10.76 (s, 1H).

Example 49.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethyl)phenyl]acetamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chloro-1H- pyrazole (199 mg, 1.94 mmol) and [2-(difluoromethyl)phenyl]acetic acid (330 mg, 1.77 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (29 mg, 0.0659 mmol, 5% yield over 4 steps, 90% purity).

- 124 040608

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 441 [M+H]+.

¹ H-NMR (400 MHz, DMSO^) δ [ppm]: 3.94 (s, 2H), 7.23 (t, 1H), 7.38-7.46 (m, 4H), 7.49-7.62 (m, 3H) , 7.86 (d, 1H), 7.95 (dd, 1H), 8.34 (d, 1H), 8.35 (d, 1H), 10.77 (s, 1H).

Example 50.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chloro-1H- pyrazole (199 mg, 1.94 mmol) and (2-fluorophenyl)acetic acid (273 mg, 1.77 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm , acetonitrile/water + 0.1% formic acid) (25 mg, 0.0659 mmol, 5% yield over 4 steps, 90% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 409 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.80 (s, 2H), 7.16-7.23 (m, 2H), 7.30-7.44 (m, 4H), 7.54 (d, 1H ), 7.86 (d, 1H), 7.96 (dd, 1H), 8.34 (d, 1H), 8.36 (d, 1H), 10.78 (s, 1H).

Example 51.

2-[2-(Difluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (450 mg, 1.17 mmol), 4-fluoro-1H- pyrazole (150 mg, 1.75 mmol) and [2-(difluoromethyl)phenyl]acetic acid (343 mg, 1.85 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (24 mg, 0.566 mmol, 5% yield over 4 steps, 90% purity).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 425 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.23 (t, 1H), 7.38 (s, 2H), 7.42-7.46 (m, 2H) , 7.507.55 (m, 2H), 7.58-7.63 (m, 1H), 7.83 (dd, 1H), 7.95 (dd, 1H), 8.26 (dd, 1H), 8.35 (d, 1H), 10.76 (s , 1H).

Example 52.

X-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

According to general procedures GP1.2, GP2.4, GP3.4 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 2.59 mmol), 1H-pyrazole-4- carbonitrile (361 mg, 3.88 mmol) and (2-fluorophenyl)acetic acid (226 mg, 1.47 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) followed by another preparative HPLC (YMC Triart C-18 5 µm, 100x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (44 mg, 0.110 mmol, 4% yield, 98% purity.

LC-MS (method B): Rt = 0.73 min; MS (ESI positive): m/z = 400 [M+H]+.

1I-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.81 (s, 2H), 7.16-7.23 (m, 2H), 7.30-7.50 (m, 4H), 7.58 (d, 1H ), 7.96 (dd, 1H), 8.31 (d, 1H), 8.39 (d, 1H), 8.86 (d, 1H), 10.82 (s, 1H).

Example 53.

2-(2-Methoxyphenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide

- 125 040608 nh ₂ O=S=O __ F °'CH ₃

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-methoxyphenyl)acetic acid (0.40 mmol) was converted to the title compound (3.4 mg, 0.00747 mmol, 4% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 456 [M+H]+.

Example 54.

2-(2-Fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide nh ₂

O=S=O __F ^,F

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (12.7 mg, 0.0286 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 444 [M+H]+.

Example 55.

2-(3-Fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide nh ₂

O=S=O ^F '

Η

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (3-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (11.6 mg, 0.0262 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 444 [M+H]+.

Example 56.

2-(2-Chloro-4-fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide nh ₂

O=S=O __ F ^F pji^ ^,F Cl ⁿ

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro-4-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (13.8 mg, 0.0289 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 478 [M+H]+.

Example 57.

2-[2-(Difluoromethoxy)phenyl]-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

_NH2

O=S=O __ F ςα/Γ' ^,P °^ ^{F n}

F

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy)phenyl]acetic acid (0.40 mmol) was converted to the title compound (3.4 mg, 0.00692 mmol, 3% yield, 100% purity).

- 126 040608

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 492 [M+H]+.

Example 58.

2-(2-Chloro-5-fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro-5-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (5.2 mg, 0.0109 mmol, 5% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 478 [M+H]+.

Example 59.

2-(3-Chloropyridin-4-yl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (3-chloropyridin-4-yl)acetic acid (0.40 mmol) was converted to the title compound (8.0 mg, 0.0174 mmol, 9% yield, 82% purity).

LC-MS (method A): Rt = 0.92 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 60.

2-[4-(Difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and [4-(difluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (11.4 mg, 0.0240 mmol, 12% yield, 100% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 476 [M+H]+.

Example 61.

2-(2-Chlorophenyl)-2,2-difluoro-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chlorophenyl)(difluoro)acetic acid (0.40 mmol) was converted to the title compound (16.2 mg, 0.0327 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 496 (M+H)+.

Example 62.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)-2,2-difluoroacetamide

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chlorophenyl)(difluoro) acetic acid (0.40

- 127040608 mmol) was converted into the title compound (5.8 mg, 0.0115 mmol, 6% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 505 [M+H]+.

Example 63.

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

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (9.6 mg, 0.0212 mmol, 11% yield, 100% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 453 [M+H]+.

Example 64.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (23.4 mg, 0.0465 mmol, 23% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 503 [M+H]+.

Example 65.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide nh ₂ o=s=o N=\ Η

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (12.3 mg, 0.0271 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 453 [M+H]+.

Example 66.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide nh ₂ O=S=ON=A sn ₃ ⁿ

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (25.9 mg, 0.0576 mmol, 29% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 449 [M+H]+.

Example 67.

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

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloropyridin-3-yl )acetic acid (0.40 mmol) was converted to the title compound (13.4 mg, 0.0285 mmol, 14% yield, 79% purity).

- 128 040608

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 68.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloro-4-fluorophenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (3.0 mg, 0.00615 mmol, 3% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 487 [M+H]+.

Example 69.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide nh ₂ O=S=O

Br

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (21.5 mg, 0.0429 mmol, 21% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 501 [M+H]+.

Example 70.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide

NH ₂ o \u003d s \u003d o Br

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (16.8 mg, 0.0324 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 519 [M+H]+.

Example 71.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloro-4,5-difluorophenyl)acetamide nh ₂

Brci

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4.5 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (4.6 mg, 0.00910 mmol, 5% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 505 [M+H]+.

Example 72.

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

- 129 040608

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-chloropyridin-4-yl )acetic acid (0.40 mmol) was converted to the title compound (5.9 mg, 0.0125 mmol, 6% yield, 92% purity).

LC-MS (method A): Rt = 0.96 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 73.

N-[4-(4-Bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide nh ₂

According to the general procedure GP5.1, 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [4-(difluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (15.7 mg, 0.0323 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 485 [M+H]+.

Example 74.

2-(2-Bromophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-bromophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (28.8 mg, 0.0613 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 469 [M+H]+.

Example 75.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methoxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-methoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (2.7 mg, 0.0642 mmol, 3% yield, 100% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 421 [M+H]+.

Example 76.

2-(4-Chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-chlorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (5.8 mg, 0.0136 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 425 [M+H]+.

Example 77.

2-(2-Chloro-6-fluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (33.9 mg, 0.0765 mmol, 38% yield, purity

- 130 040608

100%).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 78.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-nitrophenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-nitrophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (8.3 mg, 0.0190 mmol, 10% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 436 [M+H]+.

Example 79.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide nh ₂ o=s=o N^\

Cl

ci

Cl

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,4-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (4.2 mg, 0.00914 mmol, 5% yield, 100% purity).

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 459 [M+H]+.

Example 80.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-dichlorophenyl)acetamide

NH ₂ o=s=o

Cl ci

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,6-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (43.4 mg, 0.0944 mmol, 47% yield, 100% purity).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 459 [M+H]+.

Example 81.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,4-difluorophenyl)acetamide nh ₂

O=S=O N^\

Cl n

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3,4-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (7.1 mg, 0.0166 mmol, 8% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 427 [M+H]+.

Example 82.

2-(3-Chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O Nc=A

Cl

Cl n

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-chlorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (11.4 mg, 0.0268 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min, MS (ESI positive): m/z = 425 [M+H]+.

Example 83.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,5-difluorophenyl)acetamide

- 131 040608

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3,5-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (6.3 mg, 0.0148 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 427 [M+H]+.

Example 84.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-fluorophenyl)acetamide nh ₂ o=s=o N^=\

Η

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (8.2 mg, 0.0201 mmol, 10% yield, 100% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 409 [M+H]+.

Example 85.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (12.5 mg, 0.0307 mmol, 15% yield, 100% purity).

LCMS (method A): Rt = 1.00 min; MS (ESI positive): m/z = 407 [M+H]+.

Example 86.

K-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide νη ₂ O=S=O Ντ=Λ

Η

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (5.5 mg, 0.0135 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 407 [M+H]+.

Example 87.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,3-difluorophenyl)acetamide nh ₂

O=S=O №=\

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,3-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (18.4 mg, 0.0431 mmol, 22% yield, 100% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 427 [M+H]+.

Example 88.

2-(2-Chloro-4-fluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O

- 132 040608

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (14.5 mg, 0.0327 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 89.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloropyridin-3-yl)acetamide nh ₂ o=s=o

Cl

Cl

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloropyridin-3-yl )acetic acid (0.40 mmol) was converted to the title compound (21.3 mg, 0.0500 mmol, 25% yield, 81% purity).

LC-MS (method A): Rt = 0.96 min, MS (ESI positive): m/z = 426 [M+H]+.

Example 90.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-chloro-3-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-chloro-3-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (30.4 mg, 0.0616 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 1.24 min; MS (ESI positive): m/z = 493 [M+H]+.

Example 91.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide

NH ₂ O=S=O Cl

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (20.7 mg, 0.0453 mmol, 23% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 457 [M+H]+.

Example 92.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide

NH ₂ o=s=o Νΐ=\

Cl

According to the general procedure GP5.1, 5-amino-2-(4-chloro-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (14.1 mg, 0.0297 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 475 [M+H]+.

Example 93.

2-(2-Chloro-4,5-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

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According to the general procedure GP5.1, 5-amino-2-(4-chloro-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4.5 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (9.8 mg, 0.0212 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 94.

2-(2-Chloro-4-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (16.4 mg, 0.0360 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 455 [M+H]+.

Example 95.

2-(2-Chloro-6-fluoro-3-methylphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluoro -3-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (18.3 mg, 0.0400 mmol, 20% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 457 [M+H]+.

Example 96.

2-(2-Chloro-3,6-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-3,6 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (20.1 mg, 0.0436 mmol, 22% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 97.

2-(2-Chloro-5-methylphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

_NH2

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-methylphenyl )acetic acid (0.40 mmol) was converted to the title compound (29.6 mg, 0.0674 mmol, 34% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 439 [M+H]+.

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Example 98.

2-(2-Chloro-5-fluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (17.2 mg, 0.0388 mmol, 19% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 99.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,5-dichlorophenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,5-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (26.1 mg, 0.0568 mmol, 28% yield, 100% purity).

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 459 [M+H]+.

Example 100.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-isopropylphenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-isopropylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (24.2 mg, 0.0559 mmol, 28% yield, 100% purity).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 433 [M+H]+.

Example 101.

2-(2-Chloro-5-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (8.0 mg, 0.0176 mmol, 9% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 455 [M+H]+.

Example 102.

2-(2-Chloro-4,6-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4,6 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (25.8 mg, 0.0559 mmol, 28% yield, 92% purity).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 103.

- 135 040608

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-chloro-6-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-chloro-6-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (26.7 mg, 0.0541 mmol, 27% yield, 100% purity).

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 493 [M+H]+.

Example 104.

2-(5-Bromo-4-fluoro-2-methylphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (5-bromo-4-fluoro -2-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (11.2 mg, 0.0223 mmol, 11% yield, 83% purity).

LC-MS (method A): Rt = 1.24 min; MS (ESI positive): m/z = 501 [M+H]+.

Example 105.

2-(2-Chloro-6-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

CH, O=S=O N=\•Cl

CI

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (23.6 mg, 0.0518 mmol, 26% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 455 [M+H]+.

Example 106.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-difluorophenyl)propanamide nh ₂

O=S=O N=\

Cl

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and 2-(2,6-difluorophenyl ) propanoic acid (0.40 mmol) was converted to the title compound (21.1 mg, 0.0479 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 441 [M+H]+.

Example 107.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [4-(difluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (20.0 mg, 0.0454 mmol, 23% yield, 100% purity).

- 136 040608

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 441 [M+H]+.

Example 108.

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

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (4-chlorophenyl) acetic acid (0.40 mmol) was converted to the title compound (18.5 mg, 0.0403 mmol, 23% yield, 100% purity).

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 459 [M+H]+.

Example 109.

2-(2-Chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2,2-difluoroacetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chlorophenyl)(difluoro) acetic acid (0.40 mmol) was converted to the title compound (3.4 mg, 0.00737 mmol, 4% yield, 81% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 110.

2-(2-Nitrophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)N-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-nitrophenyl) acetic acid (0.40 mmol) was converted to the title compound (14.0 mg, 0.0298 mmol, 15% yield, 91% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 111.

2-(2,4-Dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl] phenyl} acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)N-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2,4- dichlorophenyl)acetic acid (0.40 mmol) was converted to the title compound (16.4 mg, 0.0332 mmol, 17% yield, 100% purity).

LC-MS (method A): Rt = 1.28 min; MS (ESI positive): m/z = 493 [M+H]+.

Example 112.

2-(2-Methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)N-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-methoxyphenyl) acetic acid (0.40 mmol) was converted to the title compound (13.8 mg, 0.0304 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 455 [M+H]+.

Example 113.

2-(2-Chloro-6-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 137 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 6-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (10.0 mg, 0.0210 mmol, 10% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 477 [M+H]+.

Example 114.

2-(3-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (3-fluorophenyl) acetic acid (0.40 mmol) was converted to the title compound (13.5 mg, 0.0305 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 115.

2-(3,5-Difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide nh ₂

FO=S=ON=A ^F

Η

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (3,5- difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (16.4 mg, 0.0356 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 116.

2-(2,6-Dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl] phenyl} acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2,6- dichlorophenyl)acetic acid (0.40 mmol) was converted to the title compound (15.8 mg, 0.0320 mmol, 16% yield, 100% purity).

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 493 [M+H]+.

Example 117.

2-(2-Bromophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 -yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-bromophenyl) acetic acid (0.40 mmol) was converted to the title compound (7.4 mg, 0.0147 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 503 [M+H]+.

Example 118.

2-(3,4-Difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 138 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (3,4- difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (13.3 mg, 0.0289 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 119.

2-(4-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (4-fluorophenyl) acetic acid (0.40 mmol) was converted to the title compound (20.9 mg, 0.0472 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 120.

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

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (3-chlorophenyl) acetic acid (0.40 mmol) was converted to the title compound (12.6 mg, 0.0275 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 459 [M+H]+.

Example 121.

2-(4-Methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (4-methoxyphenyl) acetic acid (0.40 mmol) was converted to the title compound (14.3 mg, 0.0315 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 455 [M+H]+.

Example 122.

2-(2,3-Difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2,3- difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (8.0 mg, 0.0174 mmol, 92% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 461 [M+H]+.

Example 123.

2-(2-Methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 139 040608

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-methylphenyl) acetic acid (0.40 mmol) was converted to the title compound (21.4 mg, 0.0488 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 439 [M+H]+.

Example 124.

2-(3-Methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (3-methylphenyl) acetic acid (0.40 mmol) was converted to the title compound (15.8 mg, 0.0360 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 439 [M+H]+.

Example 125.

2-[2-(Difluoromethoxy)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy )phenyl]acetic acid (0.40 mmol) was converted to the title compound (5.3 mg, 0.0108 mmol, 5% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 491 [M+H]+.

Example 126.

2-(2-Chloropyridin-3-yl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloropyridine- 3-yl)acetic acid (0.40 mmol) was converted to the title compound (12.7 mg, 0.0276 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 460 [M+H]+.

Example 127.

2-(2-Chloro-4-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 4-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (9.1 mg, 0.0191 mmol, 10% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 477 [M+H]+.

Example 128.

- 140 040608

2-(2-Chloro-5-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 5-Methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (13.7 mg, 0.0290 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 473 [M+H]+.

Example 129.

N-{3-Sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[2(trifluoromethoxy)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and [2-(trifluoromethoxy )phenyl]acetic acid (0.40 mmol) was converted to the title compound (9.5 mg, 0.0189 mmol, 9% yield, 100% purity).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 509 [M+H]+.

Example 130.

2-(2-Chloro-4,5-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 4,5-Difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (17.1 mg, 0.0346 mmol, 17% yield, 100% purity).

LC-MS (method A): Rt = 1.24 min; MS (ESI positive): m/z = 495 [M+H]+.

Example 131.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1I-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and [2-chloro- 3-(trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (15.3 mg, 0.0290 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.28 min; MS (ESI positive): m/z = 527 [M+H]+.

Example 132.

2-(2-Chloro-6-fluoro-3-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

- 141 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 6-Fluoro-3-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (10.9 mg, 0.0222 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.25 min; MS (ESI positive): m/z = 491 [M+H]+.

Example 133.

2-(2-Chloro-3,6-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide nh ₂

O=S=O Nt=^\ ^F ci ⁿ

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 3,6-Difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (16.4 mg, 0.0331 mmol, 17% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 495 [M+H]+.

Example 134.

2-[2-Chloro-6-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and [2-chloro- 6-(trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (11.2 mg, 0.0213 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 527 [M+H]+.

Example 135.

2-(2-Chloro-4-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide nh ₂

O=S= ^O _7f

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 4-Methoxyphenyl)acetic acid (0.40 mmol) was converted to the title compound (17.9 mg, 0.0366 mmol, 18% yield, purity

100%).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 489 [M+H]+.

Example 136.

2-(2,5-Dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2,5- dichlorophenyl)acetic acid (0.40 mmol) was converted to the title compound (10.3 mg, 0.0209 mmol, 10% yield, 100% purity).

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 493 [M+H]+.

Example 137.

2-(2-Isopropylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 142 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-isopropylphenyl) acetic acid (0.40 mmol) was converted to the title compound (19.8 mg, 0.0424 mmol, 21% yield, 100% purity).

LC-MS (method A): Rt = 1.30 min; MS (ESI positive): m/z = 467 [M+H]+.

Example 138.

2-(2-Chloro-5-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 5-Methoxyphenyl)acetic acid (0.40 mmol) was converted to the title compound (6.7 mg, 0.0137 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 489 [M+H]+.

Example 139.

2-(2-Chloro-5-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 5-fluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (12.6 mg, 0.0264 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 477 [M+H]+.

Example 140.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-N-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (11.8 mg, 0.0267 mmol, 13% yield, 92% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 141.

2-(5-Bromo-4-fluoro-2-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]nyl}acetamide phenyl-

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (5-bromo- 4-Fluoro-2-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (19.5 mg, 0.0364 mmol, 18% yield, 100% purity).

- 143 040608

LC-MS (method A): Rt = 1.29 min; MS (ESI positive): m/z = 535 [M+H]+.

Example 142.

2-(2-Chloro-6-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 6-Methoxyphenyl)acetic acid (0.40 mmol) was converted to the title compound (23.8 mg, 0.0487 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 489 [M+H]+.

Example 143.

2-(2-Chloro-4,6-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide nh ₂

O=S=O F

Cl ⁿ

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1H-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloro- 4,6-Difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (7.7 mg, 0.0156 mmol, 8% yield, 91% purity).

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 495 [M+H]+.

Example 144.

2-(3-Fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (3-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (12.9 mg, 0.0328 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 393 [M+H]+.

Example 145.

2-(3,4-Difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O N=\ /alD

Η

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (3,4-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (16.0 mg, 0.0390 mmol, 19% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 411 [M+H]+.

Example 146.

2-(3,5-Difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (3,5-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (11.4 mg, 0.0278 mmol, 14% yield, 81% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 411 [M+H]+.

- 144 040608

Example 147.

N-[4-(4-Fluoro-III-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (8.8 mg, 0.0225 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 391 [M+H]+.

Example 148.

2-(3-Chlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (3-chlorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (15.2 mg, 0.0372 mmol, 19% yield, 86% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 409 [M+H]+.

Example 149.

2-(4-Fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (4-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (20.3 mg, 0.0517 mmol, 26% yield, 92% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 393 [M+H]+.

Example 150.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (4-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (13.9 mg, 0.0356 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 0.85 min; MS (ESI positive): m/z = 391 [M+H]+.

Example 151.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (3-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (6.1 mg, 0.0157 mmol, 8% yield, 100% purity).

LC-MS (method A): Rt = 1.09 min, MS (ESI positive): m/z = 389 [M+H]+.

Example 152.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide

- 145 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (4-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (11.4 mg, 0.0293 mmol, 15% yield, 91% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 389 [M+H]+.

Example 153.

K-[4-(4-Fluoro-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (4-methoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (21.8 mg, 0.0539 mmol, 27% yield, 100% purity).

LC-MS (method A): Rt = 1.01 min, MS (ESI positive): m/z = 405 [M+H]+.

Example 154.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide nh ₂ o=s=o oDD sn ₃ ⁿ

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (18.9 mg, 0.0487 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min, MS (ESI positive): m/z = 389 [M+H]+.

Example 155.

2-(2,3-Difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

NH ₂ O=S=ON^=\ dD

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2,3-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (10.4 mg, 0.0253 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 411 [M+H]+.

Example 156.

2-(2-Ethoxyphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-ethoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (20.2 mg, 0.0483 mmol, 24% yield, 92% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 419 [M+H]+.

Example 157.

2-[2-(Difluoromethoxy)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 146 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (14.9 mg, 0.0338 mmol, 17% yield, 88% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 441 [M+H] ⁺ .

Example 158.

2-(2-Chloropyridin-3-yl)-X-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloropyridin-3-yl )acetic acid (0.40 mmol) was converted to the title compound (7.1 mg, 0.0173 mmol, 9% yield, 100% purity).

LC-MS (method A): Rt = 0.88 min; MS (ESI positive): m/z = 410 [M+H] ⁺ .

Example 159.

2-(2-Chloro-6-fluoro-3-methylphenyl)-I-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluoro -3-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (17.7 mg, 0.0401 mmol, 20% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 441 [M+H] ⁺ .

Example 160.

X-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (16.4 mg, 0.0358 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 459 [M+H] ⁺ .

Example 161.

2-(2-Chloro-4,5-difluorophenyl)-X-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]

According to the general procedure GP5.1, 5-amino-X-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloro-4.5 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (6.4 mg, 0.0144 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 445 [M+H] ⁺ .

Example 162.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-X-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 147040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and [2-chloro-3-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (13.6 mg, 0.0285 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 477 [M+H]+.

Example 163.

2-(2,5-Dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2,5-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (13.8 mg, 0.0311 mmol, 16% yield, 92% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 164.

2-(2-Chloro-3,6-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloro-3,6 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (19.1 mg, 0.0429 mmol, 22% yield, 90% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 445 [M+H]+.

Example 165.

2-(2-Chloro-5-methylphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-methylphenyl )acetic acid (0.40 mmol) was converted to the title compound (20.6 mg, 0.0487 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 423 [M+H]+.

Example 166.

2-(5-Bromo-4-fluoro-2-methylphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (5-bromo-4-fluoro -2-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (13.7 mg, 0.0282 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 485 [M+H]+.

Example 167.

N-[4-(4-Fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-isopropylphenyl)acetamide

- 148 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-N-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-isopropylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (21.3 mg, 0.0511 mmol, 26% yield, 100% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 417 [M+H]+.

Example 168.

2-(2-Chloro-5-fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (16.7 mg, 0.0391 mmol, 20% yield, 84% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 427 [M+H]+.

Example 169.

2-[2-Chloro-6-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and [2-chloro-6-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (10.8 mg, 0.0226 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min, MS (ESI positive): m/z = 477 [M+H]+.

Example 170.

X-[4-(4-Chloro-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-methoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (12.2 mg, 0.0290 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 421 [M+H]+.

Example 171.

2-(2,6-Difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]propanamide nh ₂ o=s=o N=\

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2,6-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (12.2 mg, 0.0287 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 425 [M+H]+.

Example 172.

X-[4-(4-Chloro-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide

- 149 040608

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (8.8 mg, 0.0217 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min, MS (ESI positive): m/z = 405 [M+H]+.

Example 173.

N-[4-(4-Chloro-1H-nirazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide nh ₂ o=s=o N=\ c?^

CH ₃ ^H

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (13.7 mg, 0.0338 mmol, 17% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 405 [M+H]+.

Example 174.

N-[4-(4-Chloro-1H-nirazol-1-yl)-3-sulfamoulfenyl]-2-(3-methylphenyl)acetamide nh ₂ o=s=o N^=\

Η

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (27.3 mg, 0.0674 mmol, 34% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 405 [M+H]+.

Example 175.

Ν-[4-(4-Χλορ-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]-2-(2-ethoxyphenyl)acetamide

ΝΗ ₂ o=s=o №=\ ό ⁿ sn ₃

According to the general procedure GP5.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-ethoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (28.3 mg, 0.0651 mmol, 33% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 435 [M+H]+.

Example 176.

2-(2-Ethoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[4-(trifluoromethyl)1I-pyrazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-ethoxyphenyl) acetic acid (0.40 mmol) was converted to the title compound (4.9 mg, 0.0105 mmol, 5% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 469 [M+H]+.

Example 177.

2-(2-Bromophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 150 040608

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2-bromophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (17.9 mg, 0.0395 mmol, 20% yield, 91% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 453 [M+H]+.

Example 178.

2-(2,4-Dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2,4-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (8.3 mg, 0.0187 mmol, 9% yield, 100% purity).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 179.

2-(2,6-Dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-(4-fluoro-1H-pyrazol1-yl)benzenesulfonamide (0.20 mmol) and (2,6-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (20.0 mg, 0.0451 mmol, 23% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 443 [M+H]+.

Example 180.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-nitrophenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-nitrophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (19.0 mg, 0.0446 mmol, 22% yield, 100% purity).

LC-MS (method A): Rt = 0.95 min; MS (ESI positive): m/z = 427 [M+H]+.

Example 181.

2-(4-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and 4-chlorophenyl)acetic acid (0.40 mmol) was converted to the title compound (17.8 mg, 0.0428 mmol, 21% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 416 [M+H]+.

Example 182.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methoxyphenyl)acetamide

- 151 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-methoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (24.1 mg, 0.0586 mmol, 29% yield, 100% purity).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 412 [M+H]+.

Example 183.

2-(2-Chloro-6-fluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o N=\

-=Nci

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (37.3 mg, 0.0860 mmol, 43% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 434 [M+H]+.

Example 184.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide nh ₂

O=S=O N=N=N

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (28.1 mg, 0.0625 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 185.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (24.7 mg, 0.0618 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 400 [M+H]+.

Example 186.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,4-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (25.9 mg, 0.0575 mmol, 29% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 187.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-dichlorophenyl)acetamide

- 152 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,6-dichlorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (27.8 mg, 0.0617 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 188.

2-(2-Bromophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O Ντ=\

-=Ν

Br

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-bromophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (32.0 mg, 0.0695 mmol, 35% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 460 [M+H]+.

Example 189.

N-[4-(4-Cyano-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl] -2-(3,4-difluorophenyl)acetamide nh ₂

O=S=O Nc=A

=N

H

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3,4-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (4.0 mg, 0.00958 mmol, 5% yield, 86% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 418 [M+H]+.

Example 190.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,5-difluorophenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3,5-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (6.2 mg, 0.0149 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 418 [M+H]+.

Example 191.

2-(3-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O N=\

Cl

-=N n

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-chlorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (28.6 mg, 0.0688 mmol, 34% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 416 [M+H]+.

Example 192.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-fluorophenyl)acetamide

- 153 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-fluorophenyl)acetic acid ( 0.40 mmol) was converted to the title compound (8:7 mg, 0.0218 mmol, 11% yield, 100% purity).

LCMS (method A): Rt = 0:99 min; MS (ESI positive): m/z = 400 [M+H]+.

Example 193.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide NH ₂

O=S=O N^\

-=N

He

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (18:5 mg, 0.0466 mmol, 23% yield, 100% purity).

LCMS (method A): Rt = 0:88 min; MS (ESI positive): m/z = 398 [M+H]+.

Example 194.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-hydroxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (14.4 mg, 0.0362 mmol, 18% yield, 100% purity).

LCMS (Method A): Rt = 0:79 min; MS (ESI positive): m/z = 398 [M+H]+.

Example 195.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (27.2 mg, 0.0688 mmol, 34% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 396 [M+H]+.

Example 196.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (4-methoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (25.9 mg, 0.0629 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 0.96 min; MS (ESI positive): m/z = 412 [M+H]+.

Example 197.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide

- 154 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (14.9 mg, 0.0377 mmol, 19% yield, 100% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 396 [M+H]+.

Example 198.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-methylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (22.0 mg, 0.0556 mmol, 28% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 396 [M+H]+.

Example 199.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-ethoxyphenyl)acetamide nh ₂ o=s=o N=\ eN

sn ₃

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-ethoxyphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (27.6 mg, 0.0649 mmol, 32% yield, 100% purity).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 426 [M+H]+.

Example 200.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,3-difluorophenyl)acetamide nh ₂ o=s=o N=\=N

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,3-difluorophenyl)acetic the acid (0.40 mmol) was converted to the title compound (28.0 mg, 0.0671 mmol, 34% yield, 100% purity).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 418 [M+H]+.

Example 201.

2-(2-Chloropyridin-3-yl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O Nc=\

=N

Cl

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloropyridin-3-yl )acetic acid (0.40 mmol) was converted to the title compound (20.7 mg, 0.0497 mmol, 25% yield, 92% purity).

LC-MS (method A): Rt = 0.83 min; MS (ESI positive): m/z = 417 [M+H]+.

Example 202.

2-(2-Chloro-4-fluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 155 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (23.4 mg, 0.0539 mmol, 27% yield, 100% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 434 [M+H]+.

Example 203.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(difluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (28.4 mg, 0.0635 mmol, 32% yield, 100% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 448 [M+H]+.

Example 204.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide nh ₂ o=s=o N=\

-=N

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-(trifluoromethoxy)phenyl] acetic acid (0.40 mmol) was converted to the title compound (25.1 mg, 0.0539 mmol, 27% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 466 [M+H]+.

Example 205.

2-(2-Chloro-4,5-difluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

=N ci

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4.5 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (16.5 mg, 0.0365 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 452 [M+H]+.

Example 206.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-chloro-3-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (14.4 mg, 0.0298 mmol, 15% yield, purity

- 156 040608

100%).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 484 [M+H]+.

Example 207.

2-(2-Chloro-6-fluoro-3-methylphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluoro -3-methylphenyl)acetic acid (0.40 mmol) was converted to the title compound (28.1 mg, 0.0627 mmol, 31% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 448 [M+H]+.

Example 208.

2-(2-Chloro-3,6-difluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-3,6 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (6.5 mg, 0.0144 mmol, 7% yield, 100% purity).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 452 [M+H]+.

Example 209.

2-(2-Chloro-5-methylphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-methylphenyl )acetic acid (0.40 mmol) was converted to the title compound (19.4 mg, 0.0451 mmol, 23% yield, 100% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 430 [M+H]+.

Example 210.

2-(2-Chloro-4-methoxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O №=\ _

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (14.9 mg, 0.0334 mmol, 17% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 446 [M+H]+.

Example 211.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,5-dichlorophenyl)acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2,5-dichlorophenyl)acetic acid (0.40 mmol)

- 157 040608 was converted to the title compound (17.1 mg, 0.0380 mmol, 19% yield, 100% purity). LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 212.

2-(5-Chloro-2-methoxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (5-chloro-2-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (26.8 mg, 0.0601 mmol, 30% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 446 [M+H]+.

Example 213.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfαmoylphenyl]-2-[2-(propan-2-yl)phenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-isopropylphenyl)acetic acid ( 0.40 mmol) was converted to the title compound (33.3 mg, 0.0786 mmol, 39% yield, 100% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 424 [M+H]+.

Example 214.

2-(2-Chloro-5-fluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-5-fluorophenyl )acetic acid (0.40 mmol) was converted to the title compound (23.0 mg, 0.0530 mmol, 27% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min, MS (ESI positive): m/z = 434 [M+H]+.

Example 215.

2-[2-Chloro-6-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [2-chloro-6-( trifluoromethyl)phenyl]acetic acid (0.40 mmol) was converted to the title compound (25.0 mg, 0.0517 mmol, 26% yield, purity

100%).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 484 [M+H]+.

Example 216.

2-(2-Chloro-6-methoxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 158 040608

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-6-methoxyphenyl )acetic acid (0.40 mmol) was converted to the title compound (7.8 mg, 0.0175 mmol, 9% yield, 100% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 446 [M+H]+.

Example 217.

2-(2-Chloro-4,6-difluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfαmoylphenyl]acetαamide nh ₂ o=s=o N=^\ = N

ci

According to the general procedure GP5.2, 5-amino-2-(4-cyano-III-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chloro-4,6 -difluorophenyl)acetic acid (0.40 mmol) was converted to the title compound (18.0 mg, 0.0398 mmol, 20% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 452 [M+H]+.

Example 218.

2-(3-Chloropyridin-4-yl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (3-chloropyridin-4-yl )acetic acid (0.40 mmol) was converted to the title compound (31.2 mg, 0.0748 mmol, 37% yield, 100% purity).

LC-MS (method A): Rt = 0.81 min; MS (ESI positive): m/z = 417 [M+H]+.

Example 219.

N-[4-(4-Cyano-1H-pyrazol-1-yl)-3-sulfαmoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide

According to general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and [4-(difluoromethyl)phenyl] acetic acid (0.40 mmol) was converted to the title compound (21.8 mg, 0.0505 mmol, 25% yield, 100% purity).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 432 [M+H]+.

Example 220.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2,2-difluoroacetamide nh ₂

O=S=O N^\

-=N

According to general procedure GP5.2, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N-(2,4dimethoxybenzyl)benzenesulfonamide (0.20 mmol) and (2-chlorophenyl)(difluoro) acetic acid (0.40 mmol) was converted to the title compound (10.9 mg, 0.0241 mmol, 12% yield, 100% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 452 [M+H]+.

Example 221.

2-(2-Fluorophenyl)-X-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

- 159 040608

According to the general procedure GP6, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (47.0 mg, 0.126 mmol) and (2-fluorophenyl)acetic acid ( 29.2 mg, 0.189 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14 mg, 0.0309 mmol, yield Stage 2 25%, purity 97%).

LC-MS (method B): Rt = 0.97 min; MS (ESI positive): m/z = 454 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.80 (s, 2H), 7.15-7.23 (m, 2H), 7.30-7.52 (m, 5H), 7.87 (dd, 1H), 8.12-8.15 (m, 1H), 8.40 (d, 1H), 8.81 (d, 1H), 8.96 (d, 1H), 10.71 (s, 1H).

Example 222.

X-{3-Sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-2-[2-(trifluoromethoxy)phenyl]acetamide

F

According to general procedure GP6, 5-amino-X-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (47.0 mg, 0.126 mmol) and [2-(trifluoromethoxy)phenyl] acetic acid (41.7 mg, 0.189 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (14 mg, 0.0270 mmol, yield over stage 2 21%, purity 98%).

LC-MS (method B): Rt = 1.11 min; MS (ESI positive): m/z = 520 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.85 (s, 2H), 7.34-7.49 (m, 6H), 7.51 (dd, 1H), 7.88 (dd, 1H), 8.12-8.15 (m, 1H), 8.37 (d, 1H), 8.82 (d, 1H), 8.96 (d, 1H), 10.72 (s, 1H).

Example 223.

N-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-methylphenyl)acetamide nh ₂

O=S=O r^N F

CH ₃ ^H

According to the general procedure GP6, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (2-methylphenyl) acetic acid (30.8 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (13 mg, 0.0309 mmol , yield over stage 2 23%, purity 97%). LC-MS (method c): Rt = 0.93 min; MS (ESI positive): m/z = 421 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.72 (s, 2H), 7.12-7.20 (m, 3H), 7.22-7.28 (m, 1H), 7.39 (s, 2H ), 7.47 (d, 1H), 7.84 (t, 1H), 7.86 (dd, 1H), 8.01 (s, 1H), 8.34 (d, 1H), 8.42 (s, 1H), 10.57 (s, 1H) .

Example 224.

X-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-[2(trifluoromethyl)phenyl]acetamide

According to the general procedure GP6, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-X[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and [2-(trifluoromethyl )phenyl]acetic acid (42.0 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14 mg , 0.0295 mmol, yield after 2 steps 22%, purity 97%).

LC-MS (method B): Rt = 1.00 min; MS (ESI positive): m/z = 475 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.97 (s, 2H), 7.40 (s, 2H), 7.45-7.57 (m, 3H), 7.63-7.74 (m, 2H ), 7.83 (dd, 1H), 7.84 (t, 1H), 8.01 (s, 1H), 8.34 (d, 1H), 8.42 (s, 1H), 10.62 (s, 1H).

Example 225.

2-[2-(Difluoromethyl)phenyl]-N- {4-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

- 160 040608

According to the general procedure GP6, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and [2-(difluoromethyl )phenyl]acetic acid (38.2 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14 mg , 0.0307 mmol, yield after 2 steps 22%, purity 99%).

LC-MS (method B): Rt = 0.94 min; MS (ESI positive): m/z = 457 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-de) δ [ppm]: 3.92 (s, 2H), 7.24 (t, 1H), 7.30-7.56 (m, 6H), 7.60 (d, 1H), 7.84 (dd, 1H), 7.84 (t, 1H), 8.01 (s, 1H), 8.34 (d, 1H), 8.42 (s, 1H), 10.62 (s, 1H).

Example 226.

N-{4-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-methoxyphenyl)acetamide

According to the general procedure GP6.1, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (2- methoxyphenyl)acetic acid (34.1 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (15 mg, 0.0344 mmol, 25% yield, 98% purity.

LC-MS (method B): Rt = 0.89 min; MS (ESI positive): m/z = 437 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.67 (s, 2H), 3.77 (s, 3H), 6.91 (td, 1H), 6.98 (dd, 1H), 7.20 -7.29 (m, 2H), 7.39 (s, 2H), 7.46 (d, 1H), 7.84 (t, 1H), 7.84 (dd, 1H), 8.01 (s, 1H), 8.36 (d, 1H), 8.42 (s, 1H), 10.47 (s, 1H).

Example 227.

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

According to the general procedure GP6.1, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (4- fluorophenyl)acetic acid (31.6 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14 mg, 0.0330 mmol, 24% yield, 98% purity. LC-MS (method c): Rt = 0.89 min; MS (ESI positive): m/z = 425 [M+H] ⁺ .

1H-NMR (400 MHz, DMSOCH) δ [ppm]: 3.68 (s, 2H), 7.12-7.20 (m, 2H), 7.32-7.44 (m, 4H), 7.46 (d, 1H), 7.83 (t, 1H), 7.84 (dd, 1H), 8.00 (s, 1H), 8.33 (d, 1H), 8.42 (s, 1H), 10.57 (s, 1H).

Example 228.

2-(2-Chloro-5-fluorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP6.1, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (2- chloro-5-fluorophenyl)acetic acid (38.7 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (13 mg, 0.0283 mmol, 21% yield over step 2, 99% purity).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 459 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.20 (td, 1H), 7.37 (dd, 1H), 7.41 (s, 2H), 7.46 - 7.53

- 161 040608 (m, 2H), 7.83 (dd, 1H), 7.84 (t, 1H), 8.01 (s, 1H), 8.35 (d, 1H), 8.42 (d, 1H), 10.66 (s, 1H) .

Example 229.

2-(2,3-Dichlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP6.1, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (2, 3-dichlorophenyl)acetic acid (42.1 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (14 mg, 0.0295 mmol, yield after stage 2 22%, purity 98%).

LC-MS (method B): Rt = 1.02 min; MS (ESI positive): m/z = 475 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.97 (s, 2H), 7.33-7.45 (m, 4H), 7.48 (d, 1H), 7.58 (dd, 1H) , 7.83 (dd, 1H), 7.84 (t, 1H), 8.01 (s, 1H), 8.35 (d, 1H), 8.42 (d, 1H), 10.67 (s, 1H).

Example 230.

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

According to the general procedure GP6.1, 5-amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N[(dimethylamino)methylene]benzenesulfonamide (47.0 mg, 0.137 mmol) and (3- chloropyridin-4-yl)-acetic acid (35.2 mg, 0.205 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (11 mg, 0.0249 mmol, 18% yield over step 2, 98% purity).

LC-MS (method B): Rt = 0.72 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.96 (s, 2H), 7.42 (s, 2H), 7.47-7.53 (m, 2H), 7.83 (dd, 1H) , 7.84 (t, 1H), 8.01 (s, 1H), 8.34 (d, 1H), 8.43 (d, 1H), 8.50 (d, 1H), 8.62 (s, 1H), 10.73 (s, 1H).

Example 231.

2-(2-Chlorophenyl)-N-[4-(3-cyclobutyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.2, GP3.3 and GP4.1, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (350 mg, 0.904 mmol), 3-cyclobutyl-1H- 1,2,4-triazole (167 mg, 1.36 mmol) and (2-chlorophenyl)acetic acid (231 mg, 1.36 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (YMC Triart 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (8.8 mg, 0.0197 mmol, yield over 4 steps 2%, purity 97%).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 446 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.85-1.97 (m, 1H), 1.98-2.08 (m, 1H), 2.22-2.32 (m, 4H), 3.63 (quin , 1H), 3.91 (s, 2H), 7.29-7.36 (m, 2H), 7.38-7.50 (m, 4H), 7.59 (d, 1H), 7.96 (dd, 1H), 8.39 (d, 1H), 8.70 (s, 1H), 10.82 (s, 1H).

Example 232.

N-[4-(4-Acetyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetαmide

According to general procedures GP1.2, GP2.2, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (350 mg, 0.904 mmol), 1-(1H-pyrazole -4-yl)ethanone (149 mg,

- 162 040608

1.36 mmol) and (2-chlorophenyl)acetic acid (231 mg, 1.36 mmol) were converted without purification of the intermediates to the title compound and finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (YMC Triart 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (5.4 mg, 0.0125 mmol, 4 steps yield 1%, purity 97%) .

LC-MS (method A): Rt = 0.94 min; MS (ESI positive): m/z = 433 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.44 (s, 3H), 3.91 (s, 2H), 7.29-7.37 (m, 2H), 7.38-7.49 (m, 4H) , 7.60 (d, 1H), 7.99 (dd, 1H), 8.17 (d, 1H), 8.39 (d, 1H), 8.75 (d, 1H), 10.82 (s, 1H).

Example 233.

2-(2-Chlorophenyl)-X-[4-(3-isopropyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.2, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (350 mg, 0.904 mmol), 3-isopropyl-1H- 1,2,4-triazole (51 mg, 1.36 mmol) and (2-chlorophenyl)acetic acid (231 mg, 1.36 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (YMC Triart 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (16 mg, 0.0369 mmol, yield over stage 4 4%, purity 96%).

LC-MS (method A): Rt = 1.00 min, MS (ESI positive): m/z = 434 [M+H]+.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: 1.28 (d, 6H), 3.05 (sept., 1H), 3.91 (s, 2H), 7.29-7.37 (m, 2H), 7.40-7.52 (m, 4H), 7.60 (d, 1H), 7.97 (dd, 1H), 8.39 (d, 1H), 8.69 (s, 1H), 10.82 (s, 1H).

Example 234.

N-[4-(4-Chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide

According to general procedures GP3.3 and GP4.1, 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-X-(2,4dimethoxybenzyl)benzenesulfonamide (500 mg, 1.18 mmol) and [ 2-(trifluoromethyl)phenyl]acetic acid (362 mg, 1.77 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (70 mg, 0.153 mmol, 13% yield over step 2, 95% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.99 (s, 2H), 7.40 (s, 2H), 7.48-7.58 (m, 3H), 7.67 (t, 1H), 7.73 (d, 1H), 7.86 (s, 1H), 7.94 (dd, 1H), 8.32-8.38 (m, 2H), 10.78 (s, 1H).

Example 235.

Ethyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxylate

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 0.645 mmol), ethyl 1H-pyrazole-4 -carboxylate (544 mg, 3.88 mmol) and (2-chlorophenyl)acetic acid (661 mg, 3.88 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (YMC Triart 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (22 mg, 0.0475 mmol, yield over 4 steps 7%, purity 98%).

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 463 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 3.91 (s, 2H), 4.26 (q, 2H), 7.30-7.36 (m, 2H), 7.40

- 163 040608

7.49 (m, 4H), 7.59 (d, 1H), 7.96 (dd, 1H), 8.12 (d, 1H), 8.38 (d, 1H), 8.62 (d, 1H), 10.82 (s, 1H).

Example 236.

Ethyl 1 - (4- {[(2-fluorophenyl) acetyl] amino} -2-sulfamoylphenyl) -1 H-pyrazole-4-carboxylate nh ₂ o \u003d s \u003d on ^ \ P ° ^ ^snz

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 0.645 mmol), ethyl 1H-pyrazole-4 -carboxylate (544 mg, 3.88 mmol) and (2-fluorophenyl)acetic acid (596 mg, 3.88 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (YMC Triart 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (28 mg, 0.0627 mmol, yield over 4 steps 10%, purity 95%).

LC-MS (method B): Rt = 0.92 min; MS (ESI positive): m/z = 447 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.29 (t, 3H), 3.81 (s, 2H), 4.26 (q, 2H), 7.16 - 7.22 (m, 2H), 7.307.37 (m, 1H), 7.41 (m, 3H), 7.58 (d, 1H), 7.96 (dd, 1H), 8.12 (d, 1H), 8.37 (d, 1H), 8.62 (d, 1H) , 10.79(s, 1H).

Example 237.

2-(2-Fluorophenyl)-N-{4-[4-(2-hydroxypropαn-2-yl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂

O=S=ON^\ θ ^Η 3

A solution of 1.4M methylmagnesium bromide in toluene/tetrahydrofuran (4.8 mL, 6.72 mmol) was added slowly under nitrogen at 0°C to a solution of ethyl 1-(4-{[(2-fluorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H -pyrazole-4-carboxylate (250 mg, 0.600 mmol) in tetrahydrofuran (10 ml). Stirring at 0° C. was continued for 2 hours followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo.

Purification by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) followed by another preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) gave the title compound (25 mg, 0.0578 mmol, 10% yield, 95% purity).

LC-MS (method B): Rt = 0.79 min; MS (ESI positive): m/z = 433 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.45 (s, 6H), 3.79 (s, 2H), 4.98 (s, 1H), 7.15-7.23 (m, 2H) , 7.307.37 (m, 1H), 7.41 (td, 1H), 7.50 (d, 1H), 7.48 (s, 2H), 7.71 (d, 1H), 7.94 (d, 1H), 7.97 (dd, 1H ), 8.33 (d, 1H), 10.73 (s, 1H).

Example 238.

2-(2-Chlorophenyl)-N-{4-[4-(2-hydroxypropαn-2-yl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide

A solution of 1.4 M methylmagnesium bromide in toluene/tetrahydrofuran (2.8 ml, 3.89 mmol) was slowly added under nitrogen at 0°С to a solution of ethyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H -pyrazole-4-carboxylate (150 mg, 0.324 mmol) in tetrahydrofuran (10 ml). Stirring at 0° C. was continued for 2 hours followed by stirring at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo.

Purification by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) gave the title compound (30 mg, 0.0668 mmol, 21% yield, 97% purity).

LC-MS (method B): Rt = 0.85 min; MS (ESI positive): m/z = 449 [M+H] ⁺ .

- 164 040608

1P-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.45 (s, 6H), 3.89 (s, 2H), 4.98 (s, 1H), 7.29-7.36 (m, 2H), 7.417.54 (m, 5H), 7.72 (d, 1H), 7.94 (d, 1H), 7.98 (dd, 1H), 8.34 (d, 1H), 10.75 (s, 1H).

Example 239.

2-(2-Chloropyridin-3-yl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide

According to general procedure GP5.1, 5-amino-N-(2,4-dimethoxybenzyl)-2-[3-(trifluoromethyl)1H-1,2,4-triazol-1-yl]benzenesulfonamide (0.20 mmol) and (2-chloropyridin-3-yl)acetic acid (0.40 mmol) was converted to the title compound (4.0 mg, 0.00868 mmol, 4% yield, 98% purity).

LC-MS (method B): Rt = 0.63 min; MS (ESI positive): m/z = 461 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.97 (s, 2H), 7.45 (dd, 1H), 7.63-7.70 (m, 3H), 7.91 (dd, 1H) , 7.95 (dd, 1H), 8.35 (dd, 1H), 8.44 (d, 1H), 9.04–9.06 (m, 1H), 10.95 (s, 1H).

Example 240.

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

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl)acetamide (200 mg, 0.39 mmol) was dissolved in tetrahydrofuran (5 mL) and treated portionwise with sodium hydride (14.4 mg, 0.39 mmol, 65% purity). After stirring at room temperature for 10 minutes, a 2M solution of iodomethane in methyl t-butyl ether was added and stirring was continued overnight. The reaction mixture was extracted with water and ethyl acetate, and the organic phase was washed with ammonium chloride solution and brine, followed by drying over sodium sulfate. Concentration in vacuo gave 2-(2-chlorophenyl)-N-(3{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)-Nmethylacetamide, which redissolved in methanol (1 ml). An aqueous ammonia solution (1 ml, 33%) was added and stirring was continued overnight. Added a second batch of aqueous ammonia (1 ml, 33%) and stirring was continued over the weekend. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) to give the title compound (28 mg, 0.0592 mmol, yield 15%, purity 99%).

LC-MS (method B): Rt = 1.00 min; MS (ESI positive): m/z = 473 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: NMe overlaps with water signal, 3.55-3.90 (m, 2H), 7.257.31 (m, 2H), 7.31-7.36 (m , 1H), 7.39-7.44 (m, 1H), 7.55-7.64 (m, 2H), 7.71-7.78 (m, 1H), 7.80-7.84 (m, 1H), 8.06 (d, 1H), 8.21 (s , 1H), 8.77 (s, 1H).

Example 241 and Example 242.

Tris-(dibenzylideneacetone)dipalladium(0) (81.7 mg, 0.079 mmol) and di-tert-butyl(2',4',6'triisopropyl-3,4,5,6-tetramethyl-[1,1'-biphenyl ]-2-yl)phosphine (42.9 mg, 0.089 mmol) was dissolved in toluene (1.2 ml), the flask was evacuated three times and refilled with argon and then heated under reflux (resulting in a brown color). In a separate flask, 2-6pom-N[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (600 mg, 1.79 mmol) and 4-(trifluoromethyl)-2P-1,2,3triazole (294 mg, 2.15 mmol) were dissolved in toluene ( 1.2 ml), the flask was evacuated three times and refilled with argon and then added to the hot catalyst solution. Potassium phosphate (758 mg, 3.58 mmol) was added and the reaction mixture was stirred overnight at reflux. The reaction mixture was diluted with ethyl acetate and washed twice with brine, followed by drying over sodium sulfate. Concentration in vacuo gave a crude mixture of the two regioisomers, which was used in the next step without further purification.

The intermediate from the previous step was redissolved in methanol (9 ml), palladium on charcoal (90 mg, load 10%) was added and the reaction mixture was stirred for 5 hours under a hydrogen atmosphere. The catalyst was removed by filtration followed by concentration in vacuo.

The crude intermediate was redissolved in DMF (10 ml). (2chlorophenyl)acetic acid (383 mg, 2.25 mmol), HATU (855 mg, 2.25 mmol) and N,N-diisopropylethylamine (775 mg, 5.99 mmol) were added and the reaction mixture was stirred overnight. reaction

- 165 040608 This mixture was concentrated in vacuo and extracted with dichloromethane and water. The organic phase was washed with brine and dried over sodium sulfate, followed by filtration and concentration in vacuo.

The intermediate from the previous step was redissolved in methanol (5 ml) and an aqueous ammonia solution (2.5 ml, 33%) was added, followed by stirring overnight. A second batch of aqueous ammonia solution (2 ml, 33%) was added and the reaction mixture was again stirred overnight. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give two regioisomers, 2-(2-chlorophenyl)-N-{3-sulfamoyl -4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide (17 mg, 0.0370 mmol, 2% yield, 85% purity) and 2-(2-chlorophenyl) -N-{3-sulfamoyl-4-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide (11 mg, 0.0239 mmol, 1% yield, 90% purity), which could be separated under the HPLC conditions.

Example 241.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide nh ₂

O=S=O N^\ F

Cl ⁿ

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 460 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.93 (s, 2H), 7.30-7.48 (m, 6H), 7.75 (d, 1H), 8.00 (dd, 1H), 8.46 (d, 1H), 8.69 (s, 1H), 10.91 (s, 1H).

Example 242.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide nh ₂ o=s=o nN f

Cl ^H

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 460 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.30-7.36 (m, 2H), 7.43-7.48 (m, 2H), 7.65 (s, 2H), 7.67 (d, 1H), 7.98 (dd, 1H), 8.46 (d, 1H), 9.16 (d, 1H), 10.92 (s, 1H).

Example 243.

2-(2-Chloro-5-cyanophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide (50 mg, 0.11 mmol) was dissolved in trifluoroacetic acid (0.25 ml) and treated portionwise with Niodosuccinimide (111 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 5 min, then at 65°C for 3.5 h. Ethyl acetate (100 ml) was added and the reaction mixture was washed with 10% aqueous sodium thiosulfate followed by neutralization (to pH8) with aqueous sodium bicarbonate and more one stage washing with water. The organic phase was then dried over sodium sulfate and concentrated in vacuo.

The product was redissolved in DMSO (0.5 ml) in a high-pressure tube, copper(1) cyanide (14.6 mg, 0.16 mmol) and N,N-dimethylethylenediamine (14.4 mg, 0.16 mmol) were added, and the sealed high-pressure tube was heated at 140°С for 2 h. The reaction mixture was purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia solution (32%)), followed by a second preparative HPLC (Chiralpak IA 5 µm 250x30 mm , ethanol/hexane + 0.1 vol% diethylamine) and a third preparative HPLC (Chiralpak IE 5 µm 250x30 mm, ethanol/hexane + 0.1 vol% diethylamine) to give the title compound (5 mg, 0.0103 mmol, 9% yield, purity 98%).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 484 [M+H]+.

1H-NMR (400 MHz, chloroform-d) δ [ppm]: 3.84 (s, 2H), 7.31 (d, 1H), 7.46-7.49 (m, 2H), 7.61-7.64 (m, 1H) , 7.85 (s, 1H), 7.96-7.98 (m, 1H), 8.01 (d, 1H), 8.14 (dd, 1H).

Example 244.

2-(2-Chlorophenyl)-N-{3-cyano-5-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 166 040608

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl)acetamide (51.4 mg, 0.10 mmol), N -cyano-4-methyl-N-phenylbenzenesulfonamide (54.5 mg, 0.20 mmol), tris-(acetonitrile)pentadienylrhodium(111) hexafluoroantimonate (8.3 mg, 0.01 mmol) and silver carbonate (11.0 mg, 0.04 mmol) were introduced into a tube of high pressure, and it was filled with argon followed by the addition of dioxane (0.5 ml). The tube was sealed and the reaction mixture was stirred at 130° C. overnight. Water was added and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, concentrated in vacuo and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) to give 2-(2-chlorophenyl)-N- (3-cyano-5-{[(dimethylamino)methylene]sulfamoyl}-4[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)acetamide.

This intermediate was redissolved in methanol (2 ml) and aqueous ammonia (1 ml, 25%) was added followed by stirring at 50° C. overnight, concentrated in vacuo and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (6.3 mg, 0.0130 mmol, 13% yield, 95% purity).

LC-MS (method B): Rt = 0.81 min; MS (ESI positive): m/z = 484 [M+H]+.

¹ H-NMR (400 MHz, chloroform-d) δ [ppm]: 3.92 (s, 2H), 5.81 (s, 2H), 7.31-7.36 (m, 2H), 7.38-7.42 (m, 1H ), 7.45-7.50 (m, 1H), 8.00 (s, 1H), 8.02 (s, 1H), 8.09 (s, 1H), 8.12 (d, 1H), 8.66 (d, 1H).

Example 245.

2-(5-Bromo-2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide (100 mg, 0.22 mmol) was dissolved in trifluoroacetic acid, N- bromosuccinimide (48.4 mg, 0.27 mmol) and the reaction mixture was stirred at 60° C. overnight. A second batch of N-bromosuccinimide (19.4 mg, 0.11 mmol) was added and the reaction mixture was again stirred at 60° C. overnight. Water (1 ml) and saturated sodium bicarbonate solution (1 ml) were added and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated in vacuo. Purification by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) followed by another preparative HPLC (Chiralpak ID 5 µm 250x30 mm, ethanol/hexane + 0.1% trifluoroacetic acid) and another washing step with 1M HCl gave 2-(5-bromo-2-chlorophenyl)-N-{3-sulfamoyl-4-[4(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide (8.3 mg, 0.0154 mmol, 7% yield, 98% purity.

LC-MS (method B): Rt = 1.19 min; MS (ESI positive): m/z = 537/539 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.93 (s, 2H), 7.35-7.47 (m, 3H), 7.53 (dd, 1H), 7.60 (d, 1H), 7.71 (d, 1H), 7.95 (dd, 1H), 8.17 (s, 1H), 8.38 (d, 1H), 8.74 (s, 1H), 10.86 (s, 1H).

Example 246.

Ν-[4-(3-Xλορ-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

According to general procedures GP1.2, GP2.5, GP3.3 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (161 mg, 1.03 mmol), 3-chloro-1H- 1,2,4-triazole (201 mg, 1.56 mmol) and (2-fluorophenyl)acetic acid (273 mg, 1.77 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by a second preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) and a third preparative HPLC (YMC Triart C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (13 mg, 0.0317 mmol, yield

- 167 040608 for 4 stages 3%, purity 98%).

LC-MS (method B): Rt = 0.66 min; MS (ESI positive): m/z = 410 [M+H]+.

1H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm]: 3.82 (s, 2H), 7.15-7.23 (m, 2H), 7.30-7.44 (m, 2H), 7.54-7.66 (m , 3H), 7.94 (dd, 1H), 8.41 (d, 1H), 8.81 (s, 1H), 10.85 (s, 1H).

Example 247.

2-(2-Chlorophenyl)-N-[3-cyano-4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-X-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(4-fluoro-1H-pyrazol-1yl)phenyl]acetamide (51.4 mg, 0.11 mmol), K-cyano -4-methyl-X-phenylbenzenesulfonamide (58.7 mg, 0.22 mmol), tris-(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate (8.3 mg, 0.01 mmol) and silver carbonate (11.9 mg, 0.04 mmol) were introduced into a high-pressure tube, and it was filled with argon followed by the addition of dioxane (0.5 ml). The tube was sealed and the reaction mixture was stirred at 130° C. overnight. Water was added and the reaction mixture was extracted twice with dichloromethane. The organic phases were combined, concentrated in vacuo and purified by preparative HPLC to give 2-(2-chlorophenyl)-X-[3-cyano-5-{[(dimethylamino)methylene]sulfamoyl}-4-(4-fluoro-1H -pyrazol-1-yl)phenyl]acetamide.

This intermediate was redissolved in methanol (2 ml), and an aqueous ammonia solution (2 ml) was added, followed by stirring at 50° C. overnight. Water was added and the reaction mixture was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried and concentrated in vacuo. Purification by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) gave the title compound (4.9 mg, 0.0113 mmol, 10% yield, 95% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 434 [M+H]+.

1H-NMR (400 MHz, methanol^) δ [ppm]: 3.94 (s, 2H), 7.27-7.33 (m, 2H), 7.38-7.44 (m, 2H), 7.78 (dd, 1H), 8.05 (dd, 1H), 8.41 (d, 1H), 8.56 (d, 1H).

Example 248.

2-(2-Chlorophenyl)-X-[4-(4-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ CH3 O=S=O

^ClH

2-(2-Chlorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-methyl-1H-pyrazol-1yl)phenyl}acetamide (170 mg, 306 µmol) was dissolved in dichloromethane (8 ml) and treated with trifluoroacetic acid (142 μl, 1.84 mmol) followed by stirring at room temperature for 3 h. Additional trifluoroacetic acid (71 μl, 0.92 mmol) was added and stirring continued overnight at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (26 mg, 21% yield, 99% purity).

LC-MS (method B): Rt = 1.02 min; MS (ESI positive): m/z = 405 [M+H]+.

1Н-NMR (400 MHz, DMSO-d6) δ [ppm] 2.10 (s, 3Н), 3.90 (s, 2Н), 7.33 (m, 2Н), 7.45 (m, 2Н), 7.48 (s, 2Н), 7.49 (d, 1Н), 7.60 (s, 1Н), 7.87 (s, 1Н), 7.96 (dd, 1Н), 8.34 (d, 1Н), 10.75 (s, 1Н).

Example 249.

2-(2-Chlorophenyl)-N-[4-(3-methoxy-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(3-methoxy-1H-1,2,4-triazol-1yl)phenyl}acetamide (17 mg, 18 µmol, 60% purity was dissolved in dichloromethane (0.8 ml) and treated with trifluoroacetic acid (13.7 µl, 178 µmol) followed by stirring at room temperature for 6 h. Additional trifluoroacetic acid (13.7 µl, 178

- 168040608 µmol) and stirring was continued overnight at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (4.3 mg, 47% yield, 82% purity).

LC-MS (method B): Rt = 0.73 min; MS (ESI positive): m/z = 422 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.26 (s, 3H), 3.90 (s, 2H), 7.25 (s, 2H), 7.32 (m, 2H), 7.45 ( m, 2H), 7.49 (d, 1H), 7.95 (dd, 1H), 8.19 (s, 1H), 8.34 (d, 1H), 10.77 (s, 1H).

Example 250.

2-(2-Chlorophenyl)-N-[4-(4-cyclopropyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{4-(4-cyclopropyl-1H-imidazol-1-yl)-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide (35.0 mg, 60.2 µmol) was dissolved in dichloromethane (1.6 ml) and treated with trifluoroacetic acid (231 μl, 3.0 mmol) followed by stirring at room temperature for 48 h. Additional trifluoroacetic acid (13.7 μl, 178 μmol) was added and stirring continued overnight at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (13.4 mg, 51% yield, 99% purity).

LC-MS (method D): Rt = 0.84 min; MS (ESI positive): m/z = 431 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 0.68 (m, 2H), 0.78 (m, 2H), 1.82 (m, 1H), 3.90 (s, 2H), 7.06 (d , 1H), 7.32 (m, 2H), 7.37 (d, 1H), 7.45 (m, 2H), 7.47 (d, 1H), 7.50 (s, 2H), 7.86 (dd, 1H), 8.38 (d, 1H), 10.75 (s, 1H).

Example 251.

2-(2-Chlorophenyl)-N-[4-(4-methyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-methyl-1H-imidazol-1yl)phenyl}acetamide (69.5 mg, 125 µmol) was dissolved in dichloromethane (4.0 ml) and treated with trifluoroacetic acid (480 μl, 6.3 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (12 mg, 22% yield, 95% purity).

LC-MS (method B): Rt = 0.74 min; MS (ESI positive): m/z = 405 [M+H]+.

1Н-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.14 (s, 3Н), 3.90 (s, 2Н), 7.01 (d, 1H), 7.32 (m, 2Н), 7.36 (d , 1H), 7.45 (m, 2Н), 7.47 (s, 2Н), 7.60 (d, 1H), 7.86 (dd, 1H), 8.37 (d, 1H), 10.76 (s, 1H).

Example 252.

2-(2-Chlorophenyl)-X-[4-(3-cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-K-{4-(3-cyclopropyl-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}acetamide (306 mg, 527 µmol) was dissolved in dichloromethane (6.8 ml) and treated with trifluoroacetic acid (410 μl, 5.3 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (12 mg, 5% yield, 90% purity). LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 431 [M+H]+.

'H-NMR (400 MHz, DMSO-d6) δ [ppm] 0.69 (m, 2H), 0.93 (m, 2H), 1.98 (m), 3.89 (s, 2H), 6.23 (d, 1H), 7.32 (m, 2H), 7.45 (m, 2H), 7.49 (d, 1H), 7.54 (s, 2H), 7.96 (dd, 1H), 7.94 (d, 1H), 8.33 (d, 1H ), 10.74 (s, 1H).

Example 253.

2-(2-Chlorophenyl)-N-[4-(2H-pyrazolo[3,4-b]pyridin-2-yl)-3-sulfamoylphenyl]acetamide

- 169 040608

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[3,4-b]pyridin-2yl)phenyl}acetamide (751 mg, 863 µmol , purity 68%) was dissolved in dichloromethane (11 mL) and treated with trifluoroacetic acid (2.0 mL, 26 mmol) followed by stirring at room temperature for 48 h. Additional trifluoroacetic acid (2.66 mL, 34.5 mmol) was added and stirring was continued for for 1 h at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (41 mg, 11% yield, 98% purity).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.93 (s, 2H), 7.31 (s, 2H), 7.34 (m, 1H), 7.35 (m, 2H), 7.47 ( m, 2Н), 7.67 (d, 1H), 8.02 (dd, 1H), 8.38 (dd, 1H), 8.45 (s, 1H), 8.45 (d, 1H), 8.56 (dd, 1H), 10.83 (s , 1H).

Example 254.

2-(2-Chlorophenyl)-N-[4-(2H-pyrazolo[3,4-c]pyridin-2-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[3,4-c]pyridin-2yl)phenyl}acetamide (1.09 g, 1.84 mmol ) was dissolved in dichloromethane (24 ml) and treated with trifluoroacetic acid (1.4 ml, 18 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (210 mg, 26% yield, 99% purity).

LC-MS (method A): Rt = 0.78 min; MS (ESI positive): m/z = 442 [M+H]+.

D-NMR (400 MHz, DMSO-d6) δ [ppm] 3.94 (s, 2H), 7.33 (s, 2H), 7.34 (m, 2H), 7.47 (m, 2H), 7.71 (d, 1H), 7.87 (d, 1H), 8.04 (dd, 1H), 8.34 (d, 1H), 8.49 (d, 1H), 8.50 (s, 1H), 8.80 (s, 1H), 10.88 (s, 1H ).

Example 255.

2-(2-Chlorophenyl)-N-[4-(2H-pyrazolo[4,3-b]pyridin-2-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(2H-pyrazolo[4,3-b]pyridin-2yl)phenyl}acetamide (405mg, 171µmol , purity 25%) was dissolved in dichloromethane (2.2 ml) and treated with trifluoroacetic acid (790 μl, 10 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (20 mg, 25% yield, 95% purity).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.93 (s, 2H), 7.32 (s, 2H), 7.34 (m, 2H), 7.44 (dd, 1H), 7.46 (m , 2H), 7.63 (d, 1H), 7.82 (ddd, 1H), 8.03 (dd, 1H), 8.46 (d, 1H), 8.58 (d, 1H), 8.63 (dd, 1H), 10.86 (s, 1H).

Example 256.

2-(2-Chlorophenyl)-K- {4-[4-(2-methoxyethyl)-1 H-pyrazol-1 -yl]-3-sulfamoylphenyl}acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[4-(2-methoxyethyl)-1H-pyrazol-1yl]phenyl}acetamide (551 mg, 570 µmol , purity 62%) was dissolved in dichloromethane (7.3 ml) and treated with trifluoroacetic acid (2.2 ml, 28 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (203 mg, 74% yield, 94% purity).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 449 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.72 (t, 2H), 3.28 (s, 3H), 3.52 (t, 2H), 3.89 (s, 2H), 7.33 ( m, 2H),

- 170 040608

7.45 (m, 2H), 7.47 (s, 2H), 7.50 (d, 1H), 7.65 (s, 1H), 7.92 (s, 1H), 7.97 (dd, 1H), 8.34 (d, 1H), 10.75 (s, 1H). Example 257.

2-(2-Chlorophenyl)-N-[4-(3-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(3-fluoro-1H-pyrazol-1yl)phenyl}acetamide (840 mg, 601 µmol, 40% purity ) was dissolved in dichloromethane (7.7 ml) and treated with trifluoroacetic acid (2.3 ml, 30 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (36 mg, 14% yield, 95% purity).

LC-MS (method B): Rt = 0.93 min; MS (ESI positive): m/z = 409 [M+H]+.

'H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.90 (s, 2H), 6.26 (dd, 1H), 7.33 (m, 2H), 7.39 (s, 2H), 7.45 ( m, 2H), 7.53 (d, 1H), 7.95 (dd, 1H), 7.98 (dd, 1H), 8.36 (d, 1H), 10.79 (s, 1H).

Example 258.

2-(2-Chlorophenyl)-N-(4-{4-[(2,2-difluoroethyl)amino]-1H-pyrazol-1-yl}-3-sulfamoylphenyl)acetamide

2-(2-Chlorophenyl)-N-(4-{4-[(2,2-difluoroethyl)amino]-1H-pyrazol-1-yl}-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl)acetamide ( 190 mg, 184 µmol, 60% purity was dissolved in dichloromethane (2.4 ml) and treated with trifluoroacetic acid (710 µl, 9.2 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (13 mg, 14% yield, 90% purity).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 470 [M+H] ⁺ .

D-NMR (400 MHz, DMSO-de) δ [ppm] 3.34 (m, 2H), 3.89 (s, 2H), 5.18 (t, 1H), 6.12 (tt, 1H), 7.32 (m, 2H), 7.41 (d, 1H), 7.45 (m, 2H), 7.48 (s, 2H), 7.49 (d, 1H), 7.56 (d, 1H), 7.95 (dd, 1H), 8.32 (d, 1H ), 10.71(s, 1H).

Example 259.

2-(2-Chlorophenyl)-N-{4-[4-(2,2-difluoroethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide

2-(2-Chlorophenyl)-N-{4-[4-(2,2-difluoroethyl)-1H-pyrazol-1-yl]-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide (336 mg, 222 µmol, 40% purity was dissolved in dichloromethane (4.3 ml) and treated with trifluoroacetic acid (860 µl, 11 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (66 mg, 62% yield, 95% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 455 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-de) δ [ppm] 3.12 (td, 2H), 6.22 (tt, 1H), 7.33 (m, 2H), 7.45 (m, 2H), 7.45 (s , 2Н), 7.50 (d, 1H), 7.70 (s, 1H), 7.97 (dd, 1H), 8.02 (s, 1Н), 8.35 (d, 1H), 10.77 (s, 1H).

Example 260.

2-(2-Chlorophenyl)-N-[4-(4-{[(2,2-difluoroethyl)amino]methyl}-1H-pyrazol-1-yl)-3sulfamoylphenyl]acetamide

tert-Butyl {[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1Hpyrazol-4-yl]methyl} (2,2- difluoroethyl)carbamate (75.0 mg, 102 μmol) was dissolved in dichloromethane (3.0 μl) and treated with trifluoroacetic acid (390 μl, 5.1 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified with

- 171 040608

HPLC to give the title compound (9 mg, 16% yield, 90% purity).

LC-MS (method A): Rt = 0.79 min; MS (ESI positive): m/z = 484 [M+H]+.

¹ H-NMR (400 MHz, DMSOL) δ [ppm] 2.87 (td, 2H), 3.68 (s, 2H), 3.90 (s, 2H), 6.01 (tt, 1H), 7.33 (m, 2H ), 7.45 (m, 2H), 7.46 (s, 2H), 7.51 (d, 1H), 7.71 (s, 1H), 7.97 (s, 1H), 7.97 (dd, 1H), 8.34 (d, 1H) , 10.76(s, 1H).

Example 261.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenyl}acetamide nd?o _n r ² t oluU '

Cl ^H

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,2,4-oxadiazol3-yl]phenyl}acetamide (112 mg, 156 μmol, 85% purity was dissolved in dichloromethane (3.0 ml) and treated with trifluoroacetic acid (600 μl, 7.8 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (8 mg, 10% yield, 90% purity).

LC-MS (method A): Rt = 1.19 min; MS (ESI positive): m/z = 461 [M+H]+.

¹ I-NMR (400 MHz, DMSOCH) δ [ppm] 3.93 (s, 2H), 7.33 (m, 2H), 7.44 (m, 2H), 7.46 (m, 2H), 7.75 (d, 1H ), 8.00 (dd, 1H), 8.45 (d, 1H), 10.90 (s, 1H).

Example 262.

2-(2-Fluorophenyl)-N-[4-(4-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o N=\ I l λ—mon.

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(4-methyl-1H-pyrazol-1-yl)phenyl}-2-(2fluorophenyl)acetamide (599 mg, 65% purity, 1.003 mmol ) was dissolved in dichloromethane (29 ml) and treated with trifluoroacetic acid (514 μl, 6.67 mmol) followed by stirring at room temperature overnight. Additional trifluoroacetic acid (257 μl, 334 μmol) was added and stirring was continued for 2 hours at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (85 mg, 96% purity).

LC-MS (method D): Rt = 1.02 min; MS (ESI positive): m/z = 389 [M+H]+.

¹ I-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.09 (s, 3H), 3.79 (s, 2H), 7.18 (m, 1H), 7.19 (m, 1H), 7.33 ( m, 1H), 7.41 (ddd, 1H), 7.48 (s, 2Н), 7.49 (d, 1H), 7.60 (s, 1H), 7.87 (s, 1H), 7.96 (dd, 1H), 8.33 (d , 1H), 10.73 (s, 1H).

Example 263.

N-[4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

N-{4-(4-Cyclopropyl-1H-imidazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide (50.0 mg, 44.3 µmol, 50% purity ) was dissolved in dichloromethane (280 μl) and treated with trifluoroacetic acid (170 μl, 2.2 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (2.3 mg, 11% yield, 90% purity).

LC-MS (method B): Rt = 0.74 min; MS (ESI positive): m/z = 415 [M+H]+.

¹ H-NMR (400 MHz, DMSO-dg) δ [ppm] 0.68 (m, 2H), 0.78 (m, 2H), 1.82 (m, 1H), 3.79 (s, 2H), 7.06 (d , 1H), 7.18 (m, 1H), 7.19 (m, 1H), 7.33 (m, 1H), 7.39 (m, 1H), 7.37 (d, 1H), 7.50 (s, 2Н), 7.57 (d, 1H), 7.85 (dd, 1H), 8.37 (d, 1H), 10.73 (s, 1H).

Example 264.

N-[4-(3-Cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

- 172 040608

N-{4-(3-Cyclopropyl-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamidoacetamide (507mg, 494µmol, 55% purity ) was dissolved in dichloromethane (3.2 ml) and treated with trifluoroacetic acid (230 μl, 3.0 mmol) followed by stirring at room temperature overnight. Additional trifluoroacetic acid (799 μl, 10.4 mmol) was added and stirring was continued for 4 hours at room temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (115 mg, 53% yield, 95% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 415 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 0.69 (m, 2H), 0.93 (m, 2H), 1.98 (m, 1H), 3.79 (s, 2H), 6.24 (d , 1H), 7.18 (m, 1H), 7.19 (m, 1H), 7.33 (m, 1H), 7.40 (m, 1H), 7.49 (d, 1H), 7.53 (s, 2H), 7.95 (dd, 1H), 7.94 (d, 1H), 8.23 (d, 1H), 10.72 (s, 1H).

Example 265.

2-(2-Fluorophenyl)-N-{4-[4-(2-methoxyethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-[4-(2-methoxyethyl)-1H-pyrazol-1-yl]phenyl}-2-(2fluorophenyl)acetamide (500mg, 566µmol , purity 66%) was dissolved in dichloromethane (7.3 ml) and treated with trifluoroacetic acid (2.2 ml, 28 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (197 mg, 72% yield, 90% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 433 [M+H]+.

1Н-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.72 (t, 2H), 3.28 (s, 3H), 3.52 (t, 2H), 3.79 (s, 2H), 7.18 (m , 1H), 7.19 (m, 1H), 7.33 (m, 1H), 7.40 (ddd, 1H), 7.47 (s, 2H), 7.50 (d, 1H), 7.65 (s, 1H), 7.92 (s, 1H), 7.96 (dd, 1H), 8.34 (d, 1H), 10.73 (s, 1H).

Example 266.

2-(2-Chlorophenyl)-N-(2-sulfamoylbiphenyl-4-yl)acetamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (300 mg, 776 µmol) and phenylboronic acid (113 mg, 931 µmol) were dissolved in DMF (10 ml) followed by the addition of bis-(triphenylphosphine) dichloride palladium(II) (CAS 13965-03-2) (127 mg, 155 µmol) and aq. potassium carbonate solution (1.2 ml, 1.0 M, 1.2 mmol). The reaction mixture was heated for 1 hour at 120° C. in a microwave oven. Ethyl acetate was then added and washed with water. The combined organic phases were dried on a Whatman filter, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate 1/1) to give N-(2,4dimethoxybenzyl)-4-nitrobiphenyl-2-sulfonamide by weight 260 mg (99% purity, 78% yield).

LCMS (method A): Rt = 1.33 min; MS (ESI negative): m/z = 427 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.62 (s, 3H), 3.68 (s, 3H), 3.91 (s, 2H), 6.28-6.37 (m, 2H ), 6.96 (d, 1H), 7.33-7.41 (m, 2H), 7.41-7.47 (m, 3H), 7.54 (d, 1H), 7.96 (s, 1H), 8.33 (dd, 1H), 8.50 ( d, 1H).

N-(2,4-dimethoxybenzyl)-4-nitrobiphenyl-2-sulfonamide (260 mg, 607 µmol) was dissolved in THF (15 ml) and palladium on charcoal was added (load 10%, 6.46 mg, 60.7 µmol). The flask was evacuated and filled with hydrogen (1 bar) and stirring was continued at room temperature until the reaction was complete. The mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

4-Amino-N-(2,4-dimethoxybenzyl)biphenyl-2-sulfonamide (90.0 mg, 226 µmol) was dissolved in DMF (4.0 ml) and (2-chlorophenyl)acetic acid (46.2 mg, 271 µmol) was added, followed by addition of N,N-diisopropylethylamine (190 µl, 1.1 mmol) and HATU (129 mg, 339 µmol). The reaction mixture was heated at 50° C. for 16 hours. After that, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

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2-(2-Chlorophenyl)-N-{2-[(2,4-dimethoxybenzyl)sulfamoyl]biphenyl-4-yl}acetamide (490 mg, 889 µmol) was dissolved in dichloromethane (2 ml) and treated with triflate acid (2.0 ml, 26 mmol). The reaction mixture was stirred at room temperature until completion of the reaction. The solvent was evaporated and the crude product was dissolved in ethyl acetate and an aqueous NaOH/NaCl solution (30 g/5 g in 90 g water) was added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter, the solvent was removed under reduced pressure, and the crude product was purified by HPLC chromatography (Waters XBrigde C18 5 μm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (43 mg, purity 97%, yield over stage 3 12%).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 401 [M+H] ⁺ .

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.89 (s, 2H), 7.04 (s, 2H), 7.24 (d, 1H), 7.30-7.35 (m, 2H) , 7.357.40 (m, 5H), 7.42-7.48 (m, 2H), 7.82 (dd, 1H), 8.34 (d, 1H), 10.60 (s, 1H).

Example 267.

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

O=S=O

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200mg, 436µmol), 1-(cyclopropylmethyl)-4-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (216 mg, 872 µmol), bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) ( 15.3 mg, 21.8 µmol), potassium fluoride (50.7 mg, 872 µmol) and triphenylphosphine (5.72 mg, 21.8 µmol) were dissolved in n-propanol (3.6 ml). After that, potassium fluoride (50.7 mg, 872 µmol) and an aqueous solution of potassium carbonate (540 µL, 2.0 M, 1.1 mmol) were added and the solution was purged with argon for 5 min. The reaction mixture was heated for 3 h at 80°C. The crude product was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(4-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (240 mg, 480 µmol) was dissolved in methanol (4.9 ml) and 32% aq. sodium hydroxide solution (210 µl, 7.2 mmol). The reaction mixture was heated at 80°C until completion of the reaction and the solvent was removed under reduced pressure. The crude product was partitioned between dichloromethane and water, the organic phases were combined and dried on a Whatman filter, and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the final compound (9.20 mg, 95% purity, 4% yield over 2 steps)

LC-MS (method B): Rt = 1.00 min; MS (ESI positive): m/z = 445 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.30-0.43 (m, 2H), 0.50-0.59 (m, 2H), 1.21-1.34 (m, 1H), 3.88 ( s, 2H), 3.99 (d, 2H), 7.16 (s, 2H), 7.29-7.39 (m, 2H), 7.41-7.50 (m, 3H), 7.70 (d, 1H), 7.78-7.86 (m, 1H), 8.018.09 (m, 1H), 8.28-8.35 (m, 1H), 10.57 (s, 1H).

Example 268.

2-(2-Chlorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

5-Amino-2-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]benzenesulfonamide (190 mg, 641 µmol) was dissolved in DMF (4.5 ml) and HATU (390 mg, 1.03 mmol), N ,N-diisopropylethylamine (560 µl, 3.2 mmol) and (2-chlorophenyl)acetic acid (131 mg, 769 µmol). The reaction mixture was stirred for 18 hours at 50°C. After that, water and dichloromethane were added, the phases were separated and the combined organic phases were dried on a Whatman filter. The solvents were removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (70.0 mg, 95% purity, 23% yield).

LC-MS (method B): Rt = 0.92 min; MS (ESI positive): m/z = 449 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.24 (s, 3H), 3.70 (t, 2H), 3.87 (s, 2H), 4.28 (t, 2H), 7.08 (s, 2H), 7.27-7.37 (m, 2H), 7.40-7.50 (m, 3H), 7.70 (m, 1H), 7.81 (dd, 1H), 8.00 (m, 1H), 8.32 (d, 1H), 10.56(s, 1H).

Example 269.

2-(2-Chlorophenyl)-N-{4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

- 174 040608

tert-Butyl 4-[4-(4-amino-2-sulfamoylphenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (190 mg, 451 µmol) was dissolved in DMF (3.2 ml) and (2- chlorophenyl)acetic acid (92.3 mg, 541 µmol) followed by the addition of N,N-diisopropylethylamine (390 µl, 2.3 mmol) and HATU (274 mg, 721 µmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

tert-Butyl 4-[4-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-1yl]piperidine-1-carboxylate (260 mg, 453 µmol) was dissolved in dichloromethane (2.7 ml) and trifluoroacetic acid (1.7 ml, 23 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was co-distilled twice with toluene. The pure title compound was obtained after HPLC purification (first: Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%); then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acids) (2.6 mg, purity 96%, yield over 3 steps 2%).

LC-MS (method B): Rt = 0.87 min; MS (ESI negative): m/z = 472 [M-H]-.

1H-NMR (400 MHz, DMSOD): δ [ppm]=1.87-2.03 (m, 2H), 2.04-2.13 (m, 2H), 2.73-2.86 (m, 2H), 3.153.23 (m , 2H), 3.88 (s, 2H), 4.25-4.38 (m, 1H), 7.21 (s, 2H), 7.25-7.38 (m, 2H), 7.41-7.50 (m, 3H), 7.74 (s, 1H ), 7.82 (dd, 1H), 8.07 (s, 1H), 8.29–8.36 (m, 2H), 10.61 (s, 1H).

Example 270.

2-(2-Fluorophenyl)-N-{4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

tert-Butyl 4-[4-(4-amino-2-sulfamoylphenyl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (190 mg, 451 µmol) was dissolved in DMF (3.7 ml) and (2- fluorophenyl)acetic acid (83.4 mg, 541 µmol) followed by N,N-diisopropylethylamine (390 µl, 2.3 mmol) and HATU (274 mg, 721 µmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were then added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

tert-Butyl 4-[4-(4-{[(2-fluorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-1yl]piperidine-1-carboxylate (250 mg, 448 µmol) was dissolved in dichloromethane (2.6 ml) and trifluoroacetic acid (1.7 ml, 22 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was co-distilled twice with toluene. The pure title compound was obtained after HPLC purification (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (13.6 mg, 90% purity, 12% yield over 3 steps).

LC-MS (method B): Rt = 0.81 min; MS (ESI negative): m/z = 456 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.74-1.96 (m, 2H), 1.96-2.09 (m, 2H), 2.63-2.75 (m, 2H), 3.063 .17 (m, 2H), 3.77 (s, 2H), 4.17-4.32 (m, 1H), 7.13-7.23 (m, 4H), 7.26-7.48 (m, 3H), 7.72 (s, 1H), 7.81 (dd, 1H), 8.05 (s, 1H), 8.31 (d, 1H), 10.55 (s, 1H), 10.51-10.61 (m, 1H).

Example 271.

N-{4-[1-(Azetidin-3-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-chlorophenyl)acetamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (170 mg, 583 µmol) and tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (305 mg, 874 μmol) was dissolved in n-propanol (7.8 ml) and bis dichloride was added

- 175 040608 (triphenylphosphine)palladium(II) (CAS 13965-03-2) (20.5 mg, 29.1 µmol), triphenylphosphine (7.64 mg, 29.1 µmol) and aq. potassium carbonate solution (730 µl, 2.0 M, 1.5 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80° C. for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

tert-Butyl 3-[4-(4-nitro-2-sulfamoylphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (250 mg, 590 µmol) was dissolved in THF (59 ml)/methanol (50 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 64.1 mg, 602 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

tert-Butyl 3-[4-(4-amino-2-sulfamoylphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (230 mg, 585 µmol) was dissolved in DMF (4.1 ml) and (2- chlorophenyl)acetic acid (120 mg, 701 µmol) followed by the addition of N,K-diisopropylethylamine (510 µl, 2.9 mmol) and HATU (356 mg, 935 µmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were then added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

tert-Butyl 3-[4-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-1-yl]azetidine1-carboxylate (150 mg, 275 µmol) was dissolved in dichloromethane (1.6 ml) and trifluoroacetic acid (1.1 ml, 14 mmol) was added and stirring was continued at room temperature until the reaction was complete. Dichloromethane and water were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was co-distilled with toluene and the pure product was obtained after purification by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (4.90 mg, 90% purity, 4% yield over 3 steps).

LC-MS (method I): Rt = 1.05 min; MS (ESI negative): m/z = 444 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.87 (s, 2H), 3.94-4.04 (m, 2H), 4.07-4.18 (m, 2H), 5.23-5.35 (m, 1H), 7.09-7.28 (m, 2H), 7.29-7.35 (m, 2H), 7.41-7.48 (m, 3H), 7.76-7.88 (m, 2H), 8.12 (s, 1H), 8.28 -8.38 (m, 2H), 10.61 (s, 1H).

Example 272.

2-(3-Chlorophenyl)-X-(2-sulfamoylbiphenyl-4-yl)acetamide

4-Amino-N-(2,4-dimethoxybenzyl)biphenyl-2-sulfonamide (75.0 mg, 188 µmol) was dissolved in DMF (1.5 ml) and (3-chlorophenyl)acetic acid (38.5 mg, 226 µmol) was added, followed by addition of X,X-diisopropylethylamine (160 μl, 940 μmol) and HATU (107 mg, 282 μmol). The reaction mixture was stirred at 60° C. for 2 hours. The solvent was removed under reduced pressure and the crude product was used without further purification.

2-(3-Chlorophenyl)-X-{2-[(2,4-dimethoxybenzyl)sulfamoyl]biphenyl-4-yl}acetamide (340 mg, 617 µmol) was dissolved in dichloromethane (1.9 ml) and trifluoroacetic acid (1.9 ml, 24 mmol) and stirring was continued at room temperature until the reaction was completed. The solvent was removed under reduced pressure and the crude product was dissolved in ethyl acetate and washed with aqueous sodium hydroxide/sodium chloride (30 g/5 g in 90 g water). The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (41.7 mg, 98% purity, 17% yield over 2 steps).

LC-MS (method A): Rt = 1.16 min; MS (ESI negative): m/z = 399 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.73 (s, 2H), 7.07 (s, 2H), 7.24 (d, 1H), 7.29-7.40 (m, 8H) , 7.43 (s, 1H), 7.80-7.86 (m, 1H), 8.31 (d, 1H), 10.57 (s, 1H).

Example 273.

2-(2-Chlorophenyl)-H-[4-(3-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

- 176 040608 nh ₂

2-Chloro-X-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-methyl-Spyrazole (159 mg, 1.94 mmol) and potassium carbonate (536 mg, 3.88 mmol) were dissolved in acetonitrile (15 ml) and the reaction mixture was stirred at 100° C. overnight. The solvent was removed under reduced pressure and water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

N-2,4-Dimethoxybenzyl)-2-(3-methyl-1H-pyrazol-1-yl)-5-nitrobenzenesulfonamide (500 mg, 1.16 mmol) was dissolved in ethyl acetate/ethanol (1/1, 40 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 123 mg, 116 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 18 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

5-Amino-N-(2,4-dimethoxybenzyl)-2-(3-methyl-1H-pyrazol-1-yl)benzenesulfonamide (410 mg, 1.02 mmol) was dissolved in DMF (30 ml) and (2-chlorophenyl )acetic acid (209 mg, 1.22 mmol) followed by X,N-diisopropylethylamine (890 µl, 5.1 mmol) and HATU (799 mg, 2.04 mmol). The reaction mixture was stirred at 50° C. for 3 hours. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 80 mg of final product (14% yield over 3 steps).

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(3-methyl-1H-pyrazol-1yl)phenyl}acetamide (80.0 mg, 144 µmol) was dissolved in dichloromethane (2.0 ml) and trifluoroacetic acid (1.5 ml, 19 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the pure title compound was obtained after purification by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (9.00 mg, 95% purity, 15% yield). %).

LC-MS (method B): Rt = 0.98 min; MS (ESI negative): m/z = 403 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.27 (s, 3H), 3.90 (s, 2H), 6.31 (d, 1H), 7.27-7.37 (m, 2H) , 7.437.50 (m, 2H), 7.52 (s, 2H), 7.86-8.08 (m, 2H), 8.35 (d, 1H), 10.75 (s, 1H).

Example 274.

2-(2-Chlorophenyl)-X-[4-(6-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide

2-Bromo-X-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (632 mg, 1.88 mmol) and 2-chloro-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (450 mg, 1.88 mmol) was dissolved in n-propanol (35 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (66.1 mg, 93.9 µmol) and triphenylphosphine (24.6 mg, 93.9 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (5.6 ml, 1.0 M, 5.6 mmol). The reaction mixture was heated at 100° C. for 3 hours. After that, the mixture was filtered through celite, the solvent was removed and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(6-Chloropyridin-3-yl)-X-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (660 mg, 1.79 mmol) was dissolved in THF (50 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 698 mg, 179 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 2 hours. Platinum on charcoal (698 mg, 179 μmol) was added again and stirring was continued for 2 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

5-Amino-2-(6-chloropyridin-3-yl)-X-[(dimethylamino)methylidene]benzenesulfonamide (630 mg, 1.86 mmol) was dissolved in DMF (25 ml) and (2-chlorophenyl)acetic acid (381 mg, 2.23 mmol) followed by the addition of X,X-diisopropylethylamine (1.6 ml, 9.3 mmol) and HATU (1.41 g, 3.72 mmol).

- 177 040608

The reaction mixture was stirred at 50° C. for 16 hours. Water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, 2% ethanol in dichloromethane gradient) to give 100 mg of final product (yield over 3 steps 11%).

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 489 [M-H] ^- .

2-(2-Chlorophenyl)-N-[4-(6-chloropyridin-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (100 mg, 204 µmol) was dissolved in methanol (30 ml ) and treated with 25% aqueous ammonia (30 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (4.90 mg, 95% purity , yield 5%).

LC-MS (method B): Rt = 1.01 min; MS (ESI negative): m/z = 434 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.90 (s, 2H), 7.26-7.36 (m, 3H), 7.39 (s, 2H), 7.43-7.50 (m , 2H), 7.53 (d, 1H), 7.84 (δ, 2H), 8.36 (dd, 2H), 10.70 (s, 1H).

Example 275.

2-(2-Chlorophenyl)-N-[4-(3,5-dimethyl-1,2-oxazol-4-yl)-3-sulfamoylphenyl]acetamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (400 mg, 1.19 mmol) and (3,5dimethyl-1,2-oxazol-4-yl)boronic acid (335 mg, 2.38 mmol) were dissolved in n-propanol (110 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (41.9 mg, 59.5 µmol), triphenylphosphine (21.6 mg, 59.5 µmol) and aq. potassium carbonate solution (1.8 ml, 2.0 M, 3.6 mmol). The reaction mixture was stirred at 120° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with methanol and used without further purification in the next step.

2-(3,5-Dimethyl-1,2-oxazol-4-yl)-5-nitrobenzenesulfonamide (450 mg, 1.51 mmol) was dissolved in methanol (69 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 164 mg, 1.54 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step.

5-Amino-2-(3,5-dimethyl-1,2-oxazol-4-yl)benzenesulfonamide (200 mg, 748 µmol) was dissolved in DMF (5.3 ml) and (2-chlorophenyl)acetic acid (153 mg) was added , 898 µmol) followed by the addition of N,N-diisopropylethylαmine (620 µl, 3.7 mmol) and HATU (455 mg, 1.20 mmol). The reaction mixture was stirred at 50° C. for 4 h, then water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. HPLC purification gave pure product (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) (28.4 mg, 95% purity, 9% yield over 3 steps).

LC-MS (method J): Rt = 0.99 min; MS (ESI negative): m/z = 418 [M-H]-.

¹ H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=1.94 (s, 3H), 2.12 (s, 3H), 3.89 (s, 2H), 7.22 (d, 1H), 7.29-7.38 (m, 4H), 7.42-7.48 (m, 2H), 7.85 (dd, 1H), 8.34 (d, 1H), 10.67 (s, 1H).

Example 276.

2-(2-Chlorophenyl)-N-(4-{1-[(3-methyloxetan-3-yl)methyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (225mg, 490µmol) and 1-[(3-methyloxetαn-3-yl)methyl ]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolαn-2-yl)-1Hpyrazole (273 mg, 981 µmol) was dissolved in n-propanol (9.0 ml) and bis( triphenylphosphine)palladium(II) (CAS 13965-03-2) (17.3 mg, 24.5 µmol), triphenylphosphine (6.43 mg, 24.5 µmol) and potassium fluoride (6.55 mg, 113 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (610 µl, 2.0 M, 1.2 mmol). The reaction mixture was heated at 100°C for

- 178 040608 for 1 hour in the microwave. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{1-[(3-methyloxetan-3yl)methyl]-1H-pyrazol-4-yl}phenyl)acetamide (270 mg, 509 μmol) was dissolved in methanol (5.2 ml) and treated with 32% aqueous sodium hydroxide solution (300 μl) at 50°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (20.8 mg, 95% purity, 8% yield over 2 steps).

LC-MS (method A): Rt = 0.99 min; MS (ESI negative): m/z = 473 [M-H]-.

¹ H-NMR (400 MHz, DMSOCH): δ [ppm]=1.17 (s, 3H), 3.88 (s, 2H), 4.25 (d, 2H), 4.36 (s, 2H), 4.61 (d , 2H), 7.13 (s, 2H), 7.26-7.39 (m, 2H), 7.39-7.50 (m, 3H), 7.69-7.71 (m, 1H), 7.82 (dd, 1H), 8.03 (s, 1H ), 8.33 (d, 1H), 10.58 (s, 1H).

Example 277.

2-(2-Chloro-4-fluorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chloro-4-fluorophenyl)acetamide (250mg, 524µmol) and 1-(2-methoxyethyl)-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (264 mg, 1.05 mmol) was dissolved in n-propanol (9.6 ml) and bis(triphenylphosphine) dichloride was added )palladium(II) (CAS 13965-03-2) (18.5 mg, 26.2 µmol) and triphenylphosphine (6.88 mg, 26.2 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (660 µl, 2.0 M, 1.3 mmol). The reaction mixture was heated at 120°C for 1 h (5 bar/25 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (37.8 mg, purity 95%, yield 15%).

LC-MS (method B): Rt = 0.93 min; MS (ESI negative): m/z = 465 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.25 (s, 3H), 3.71 (t, 2H), 3.87 (s, 2H), 4.28 (t, 2H), 7.09 (s, 2H), 7.23 (td, 1H), 7.43-7.52 (m, 3H), 7.71 (s, 1H), 7.81 (dd, 1H), 8.01 (s, 1H), 8.32 (d, 1H) , 10.57(s, 1H).

Example 278.

2-(2-Chloro-4-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chloro-4-fluorophenyl)acetamide (250 mg, 524 µmol) and 1-cyclopropyl-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (246 mg, 1.05 mmol) was dissolved in n-propanol (9.6 ml) and bis(triphenylphosphine)palladium(P) dichloride was added ) (CAS 13965-03-2) (18.5 mg, 26.2 µmol) and triphenylphosphine (6.88 mg, 26.2 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (660 µl, 2.0 M, 1.3 mmol). The reaction mixture was heated at 120°C for 1 h in a microwave oven (2 bar/25 W). Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was dissolved in methanol (5 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80° C. until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (38.2 mg, 95% purity, 15% yield over 2 steps) .

LC-MS (method B): Rt = 0.98 min; MS (ESI negative): m/z = 447 [M-H]-.

¹ H-NMR (400 MHz, DMSO-06): δ [ppm]=0.94-1.01 (m, 2H), 1.05-1.11 (m, 2H), 3.74 (tt, 1H), 3.87 (s, 2H), 7.17-7.25 (m, 3H), 7.41-7.52 (m, 3H), 7.67 (s, 1H), 7.80 (dd, 1H), 8.04 (s, 1H), 8.31 (d, 1H), 10.57 (s, 1H).

Example 279.

- 179 040608

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{1-[2-(trifluoromethoxy)ethyl]-1H-pyrazol-4yl}phenyl)acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-1-[2-(trifluoromethoxy)ethyl]-III-pyrazole (334 mg, 1.09 mmol) was dissolved in n-propanol (10 ml) and bis(triphenylphosphine) dichloride was added palladium(II) (CAS 13965-03-2) (19.2 mg, 27.2 µmol) and triphenylphosphine (7.15 mg, 27.2 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (680 µl, 2.0 M, 1.4 mmol). The reaction mixture was heated at 80° C. for 18 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{1-[2-(trifluoromethoxy)ethyl]1H-pyrazol-4-yl}phenyl)acetamide (250 mg , 448 µmol) was dissolved in methanol (4.6 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (1.60 mg, 95% purity, 2 steps yield 1%) .

LC-MS (method B): Rt = 1.06 min; MS (ESI negative): m/z = 501 [M-H]-.

'll-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 4.48 (s, 4H), 7.14 (s, 2H), 7.28-7.37 (m, 2H) , 7.417.49 (m, 3H), 7.76 (s, 1H), 7.82 (dd, 1H), 8.07 (s, 1H), 8.33 (d, 1H), 10.59 (s, 1H).

Example 280.

2-(2-Chlorophenyl)-N-[4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (225 mg, 490 µmol) and (1-cyclobutyl-1H-pyrazol-4-yl) boronic acid (163 mg, 981 µmol) was dissolved in npropanol (9.0 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (17.3 mg, 24.5 µmol), triphenylphosphine (6.43 mg, 24.5 µmol) and potassium fluoride (6.55 mg, 113 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (610 µl, 2.0 M, 1.2 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-[4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (250 mg, 500 µmol) was dissolved in methanol (5.1 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (71.8 mg, 95% purity, 31% yield over 2 steps).

LCMS (method A): Rt = 1.10 min; MS (ESI negative): m/z = 443 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.74-1.84 (m, 2H), 2.35-2.44 (m, 2H), 3.88 (s, 2H), 4.85 (quin , 1H), 7.22 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.48 (m, 3H), 7.74 (s, 1H), 7.81 (dd, 1H), 8.05 (s, 1H), 8.32 (d, 1H), 10.58 (s, 1H).

Example 281.

2-(2-Chlorophenyl)-N-(4-{1-[2-(pyrrolidin-1-yl)ethyl]-1 H-pyrazol-4-yl}-3 sulfamoylphenyl)acetamide

- 180 040608

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (90.0 mg, 196 µmol) and 1-[2-(pyrrolidin-1-yl)ethyl ]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (114 mg, 392 µmol) was dissolved in n-propanol (3.6 ml) and added bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (6.90 mg, 9.81 µmol), triphenylphosphine (2.57 mg, 9.81 µmol) and potassium fluoride (2.62 mg, 45.1 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (250 µl, 2.0 M, 490 µmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{1-[2-(pyrrolidin-1-yl)ethyl]1H-pyrazol-4-yl}phenyl) acetamide (110 mg, 203 μmol) was dissolved in methanol (2.1 ml) and treated with 32% aqueous sodium hydroxide solution (80 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (4.00 mg, 95% purity, 4% yield).

LC-MS (method A): Rt = 0.81 min; MS (ESI negative): m/z = 486 [M-H] ^- .

¹ H-NMR (400 MHz, DMSOCH): δ [ppm]=1.69 (s, 4H), 2.79 (t, 2H), 3.88 (s, 2H), 4.25 (t, 2H), 6.94 (s , 2H), 7.28-7.37 (m, 2H), 7.41-7.50 (m, 3H), 7.66 (s, 1H), 7.84 (dd, 1H), 8.05 (s, 1H), 8.32 (d, 1H), 10.58(s, 1H).

Example 282.

2-(2-Chlorophenyl)-N-[4-(5-cyanopyridin-3-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 545 µmol) and 5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) pyridine-3-carbonitrile (125 mg, mg,

545 µmol) was dissolved in n-propanol (10 mL), and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (19.2 mg, 27.2 µmol) and triphenylphosphine (7.15 mg, 27.2 µmol) were added. The solution was purged with argon for 5 min and aq. potassium carbonate solution (1.6 ml, 1.0 M, 1.6 mmol). The reaction mixture was heated at 100° C. for 1 hour. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(2-Chlorophenyl)-N-[4-(5-cyanopyridin-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (270 mg, 560 µmol) was dissolved in methanol (25 ml ) and treated with 25% aqueous ammonia (25 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by two HPLC runs (first Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Chromatorex C18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the final product (10.4 mg, 98% purity, 4% yield over step 2).

LC-MS (method B): Rt = 0.90 min; MS (ESI negative): m/z = 425 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.91 (s, 2H), 7.30-7.39 (m, 3H), 7.41-7.53 (m, 4H), 7.89 (dd, 1H), 8.27 (t, 1H), 8.39 (d, 1H), 8.79 (d, 1H), 9.02 (d, 1H), 10.74 (s, 1H).

Example 283.

2-(2-Chlorophenyl)-N-(4-{1-[oxetan-2-ylmethyl]-1H-pyrazol-4-yl}-3-sulfamoylphenyl)acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and 1-[oxetan-2-ylmethyl]-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (288

- 181 040608 mg, 1.09 mmol) was dissolved in n-propanol (10 ml) and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (19.2 mg, 27.2 µmol), triphenylphosphine (7.15 mg, 27.2 µmol) and potassium fluoride (7.28 mg, 125 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (680 µl, 2.0 M, 1.4 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the final product (16.7 mg, purity 95%, yield over stage 2 6%).

LC-MS (method B): Rt = 0.88 min; MS (ESI negative): m/z = 459 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.34-2.46 (m, 1H), 2.60-2.70 (m, 1H), 3.88 (s, 2H), 4.29-4.51 (m, 4H), 4.98-5.05 (m, 1H), 7.14 (s, 2H), 7.28-7.38 (m, 2H), 7.41-7.50 (m, 3H), 7.73 (d, 1H), 7.82 (dd , 1H), 8.05 (s, 1H), 8.33 (d, 1H), 10.58 (s, 1H).

Example 284.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]phenyl}acetamide

K-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (210 mg, 458 µmol) and 5-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyrimidine (251 mg, 824 µmol) was dissolved in n-propanol (6.2 ml) and bis(triphenylphosphine)palladium( P) (CAS 13965-03-2) (16.1 mg, 22.9 µmol), triphenylphosphine (6.00 mg, 22.9 µmol), potassium fluoride (53.2 mg, 915 µmol) and aq. potassium carbonate solution (690 µl, 2.0 M, 1.4 mmol). The solution was purged with argon for 5 minutes and the reaction mixture was heated at 80° C. for 1 hour. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-K-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]phenyl)acetamide (250 mg, 450 µmol) was dissolved in methanol (4.6 ml) and treated with 25% aqueous ammonia solution (4.6 ml) at room temperature for 18 h. After that, 32% aqueous sodium hydroxide solution (50 µl) was added and stirring was continued until the reaction was completed. The solvent was removed under reduced pressure and the crude product was purified by HPLC (two times, Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (2.50 mg, purity 95%, yield over 2 stages 1%).

LC-MS (method B): Rt = 1.05 min; MS (ESI negative): m/z = 499 [M-H]-.

¹ I-NMR (400 MHz, DMSO-d6): δ [ppm]=3.91 (s, 2H), 5.09 (q, 2H), 7.30-7.48 (m, 7H), 7.89 (dd, 1H) , 8.39 (d, 1H), 8.61 (s, 2H), 10.71 (s, 1H).

Example 285.

2-(2-Chlorophenyl)-N-[4-(2-methoxypyrimidin-5-yl)-3-sulfamoylphenyl]acetamide

The title compound was isolated as a byproduct of the deprotection of 2(2-chlorophenyl)-X-{3-sulfamoyl-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]phenyl}acetamide (56.8 mg, 95% purity, 28% yield).

LC-MS (method B): Rt = 0.85 min; MS (ESI negative): m/z = 431 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.90 (s, 2H), 3.97 (s, 3H), 7.28-7.41 (m, 5H), 7.41-7.51 (m , 2H), 7.87 (dd, 1H), 8.38 (d, 1H), 8.53 (s, 2H), 10.70 (s, 1H).

Example 286.

2-(2-Chlorophenyl)-N-(4-{1-[2-(propan-2-yloxy)ethyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide

- 182 040608

N-(4-6pOM-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2chlorophenyl)acetamide hydrochloride (1:1) (200 mg, 404 µmol), 1-[2-(propane- 2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H-pyrazole (226 mg, 808 µmol) and potassium fluoride (51.6 mg, 888 µmol ) was dissolved in dry and degassed DMF (8.0 ml) and the solution was again purged with argon for 5 min, followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (10.3 mg, 20.2 µmol ). The reaction mixture was heated for 18 hours at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{1-[2-(propan-2-yloxy)ethyl]1H-pyrazol-4-yl}phenyl) acetamide (230 mg, 432 μmol) was dissolved in methanol (4.4 ml) and treated with 32% aqueous sodium hydroxide solution (170 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%), then acetonitrile/water + 0.1% formic acid) to give the title compound (11.8 mg , purity 95%, yield over 2 stages 5%).

LC-MS (method A): Rt = 1.11 min; MS (ESI negative): m/z = 475 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.05 (d, 6H), 3.54 (spt, 1H), 3.73 (t, 2H), 3.88 (s, 2H), 4.24 (t, 2H), 7.07 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.48 (m, 3H), 7.70 (d, 1H), 7.82 (dd, 1H), 8.03 (s, 1H), 8.33 (d, 1H), 10.57 (s, 1H).

Example 287.

2-(2-Chlorophenyl)-N-{4-[1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide

X-(4-bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (250mg, 505µmol), 2-methyl-4-[ 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hpyrazol-1-yl]butan-2-ol (283 mg, 1.01 mmol) and potassium fluoride (64.5 mg , 1.11 mmol) was dissolved in dry and degassed DMF (14 ml) and the solution was again purged with argon for 5 min, followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (12.9 mg , 25.2 µmol). The reaction mixture was heated for 18 hours at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(3-hydroxy-3-methylbutyl)1H-pyrazol-4-yl]phenyl)acetamide (250 mg, 470 μmol) was dissolved in methanol (4.8 ml) and treated with 32% aqueous sodium hydroxide solution (180 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (31.3 mg, 95% purity, 2-step yield 14 %).

LC-MS (method B): Rt = 0.92 min; MS (ESI negative): m/z = 475 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.15 (s, 6H), 1.88-1.99 (m, 2H), 3.88 (s, 2H), 4.16-4.23 (m , 2H), 4.48 (s, 1H), 7.15 (s, 2H), 7.29-7.37 (m, 2H), 7.41-7.49 (m, 3H), 7.66-7.70 (m, 1H), 7.81 (dd, 1H ), 8.01 (s, 1H), 8.31 (d, 1H), 10.57 (s, 1H).

Example 288.

2-(2-Chlorophenyl)-N-{4-[5-(2-hydroxypropan-2-yl)-1-methyl-1 H-pyrazol-3-yl]-3 sulfamoylphenyl}acetamide

- 183 040608

N-(4-bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (500 mg, 1.01 mmol) and methyl 1-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-pyrazole-5-carboxylate (537 mg, 2.02 mmol) was dissolved in n-propanol (19 ml) and bis dichloride was added -(triphenylphosphine)palladium(II) (CAS 13965-03-2) (35.5 mg, 50.5 µmol), triphenylphosphine (13.2 mg, 50.5 µmol) and potassium fluoride (13.5 mg, 232 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (1.3 ml, 2.0 M, 2.5 mmol). The reaction mixture was heated at 100° C. for 1 hour. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) (260 mg, 47% yield).

LC-MS (method B): Rt = 1.10 min; MS (ESI negative): m/z = 516 [M-H]-.

Propyl 3-(4-{[(2-chlorophenyl)acetyl]amino}-2-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-1 methyl-1H-pyrazole-5-carboxylate (250 mg, 458 µmol) was dissolved in dry THF (8.3 ml) and methylmagnesium bromide in THF (14 ml, 1.0 M, 14 mmol) was added. The reaction mixture was stirred for 18 hours at 22° C., then saturated aqueous ammonium chloride and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[5-(2-hydroxypropan-2-yl)-1methyl-1H-pyrazol-3-yl]phenyl) acetamide (250 mg, 483 μmol) was dissolved in methanol (5.0 ml) and treated with 32% aqueous sodium hydroxide solution (0.6 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the final product (10.1 mg, 95% purity, 4% yield over 2 steps) .

LC-MS (method B): Rt = 1.02 min; MS (ESI negative): m/z = 461 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.55 (s, 6H), 3.88 (s, 2H), 4.02 (s, 3H), 5.45 (s, 1H), 6.45 (s, 1H), 7.28-7.38 (m, 2H), 7.41-7.49 (m, 2H), 7.49-7.78 (m, 3H), 7.93 (dd, 1H), 8.28 (d, 1H), 10.64 ( s, 1H).

Example 289.

2-(2-Chlorophenyl)-N-{4-[5-(difluoromethoxy)pyridin-3-yl]-3-sulfamoylphenyl}acetamide

F nh ₂

O=S=O

N-(4-6pom-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2chlorophenyl)acetamide hydrochloride (1:1) (250 mg, 505 µmol) and [5-(difluoromethoxy)pyridine- Potassium 3-yl](trifluoro)borate (380 mg, 1.51 mmol) was dissolved in n-propanol (9.3 mL) and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (17.8 mg, 25.2 μmol) was added ), triphenylphosphine (6.62 mg, 25.2 µmol) and potassium fluoride (7.33 mg, 126 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (760 µl, 2.0 M, 1.5 mmol). The reaction mixture was heated at 100° C. for 2 hours in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(4-[5-(difluoromethoxy)pyridin-3-yl]-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (250 mg, 478 µmol) was dissolved in methanol (4.9 ml) and treated with 32% aqueous sodium hydroxide solution (0.6 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (39.1 mg, 95% purity, 17% yield over 2 steps).

- 184 040608

LC-MS (method A): Rt = 1.09 min; MS (ESI negative): m/z = 466 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.91 (s, 2H), 7.15-7.54 (m, 8H), 7.65 (t, 1H), 7.88 (dd, 1H) , 8.39-8.49 (m, 3H), 10.71 (s, 1H).

Example 290.

N-[4-(2-Chloro-5-methoxypyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (250 mg, 505 µmol), (2-chloro-5- methoxypyridin-3-yl)boronic acid (189 mg, 1.01 mmol) and potassium fluoride (64.5 mg, 1.11 mmol) were dissolved in dry and degassed DMF (14 ml) and the solution was again purged with argon for 5 min followed by the addition of CataXCium A Pre Cat (18.4 mg, 25.2 µmol). The reaction mixture was heated for 18 hours at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

N-[4-(2-Chloro-5-methoxypyridin-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (350mg, 25% purity, 168µmol) was dissolved in methanol (1.7 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (25.5 mg, 90% purity, 29% yield over 2 steps).

LC-MS (method A): Rt = 1.08 min; MS (ESI negative): m/z = 464 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.84 (s, 3H), 3.90 (s, 2H), 7.27 (d, 1H), 7.31-7.38 (m, 5H) , 7.437.50 (m, 2H), 7.85 (dd, 1H), 8.12 (d, 1H), 8.35 (d, 1H), 10.70 (s, 1H).

Example 291.

2-(2-Chlorophenyl)-X- {4-[1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl] -3-sulfamoylphenyl} acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (250 mg, 505 µmol), 2-[4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanol (240 mg, 1.01 mmol) and potassium fluoride (65.0 mg, 1.1 mmol) were dissolved in dry and degassed DMF (6.6 ml) and the solution was again purged with argon for 5 min, followed by the addition of bis(tri-tertbutylphosphine)palladium(0) (CAS 53199-31-8) (12.9 mg, 25.2 µmol). The reaction mixture was heated for 4 hours at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(2-hydroxyethyl)-1Hpyrazol-4-yl]phenyl)acetamide (250mg, 510µmol) was dissolved in methanol (5.2 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80°C until the reaction was completed. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (28.1 mg, 90% purity, 11% yield over 2 steps). The second fraction was further crystallized from diethyl ether (47.1 mg, 95% purity, 20% yield over 2 steps).

LC-MS (method A): Rt = 0.89 min; MS (ESI negative): m/z = 433 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.75 (q, 2H), 3.88 (s, 2H), 4.16 (t, 2H), 4.94 (t, 1H), 7.04 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.48 (m, 3H), 7.71 (s, 1H), 7.83 (dd, 1H), 8.01 (s, 1H), 8.32 (d, 1H), 10.57 (s, 1H).

Example 292.

N-[4-(5-tert-Butyl-1H-pyrazol-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

- 185 040608

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (250 mg, 505 µmol), (3-(tert-butyl )-1H-pyrazol-5-yl)potassium trifluoroborate (232 mg, 1.01 mmol) and potassium fluoride (65.0 mg, 1.1 mmol) were dissolved in dry and degassed DMF (14 mL) and the solution was again purged with argon for 5 min followed by by adding bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (12.9 mg, 25.2 µmol). The reaction mixture was heated for 18 hours at 100°C. The mixture was then filtered through silica gel and washed with ethyl acetate. After removing the solvent, the reaction was repeated. After filtration through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

N-[4-(5-tert-Butyl-1H-pyrazol-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (270 mg, 30% purity, 161 µmol) was dissolved in methanol (1.7 ml) and treated with 32% aqueous sodium hydroxide solution (63 µl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (10.1 mg, 90% purity, 2-step yield 12 %).

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 445 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.33 (s, 9H), 3.88 (s, 2H), 6.38 (s, 1H), 7.30-7.36 (m, 2H ), 7.427.49 (m, 2H), 7.64 (d, 1H), 7.86-7.97 (m, 3H), 8.30 (d, 1H), 10.64 (s, 1H), 12.89 (s, 1H).

Example 293.

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

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200 mg, 436 µmol) and 1-benzyl-4-(4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (248 mg, 872 μmol) was dissolved in n-propanol (8.0 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (15.3 mg, 21.8 µmol) and triphenylphosphine (5.72 mg, 21.8 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (540 μl, 2.0 M, 1.1 mmol). The reaction mixture was heated at 80° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was used without further purification in the next step.

N-[4-(1-Benzyl-1 H-pyrazol-4-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (250 mg, 466 µmol) was dissolved in methanol (4.8 ml) and treated with 32% aqueous sodium hydroxide solution (0.6 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) to give the title compound (5.50 mg, 80% purity, 2-step yield 2%) .

LC-MS (method J): Rt = 1.29 min; MS (ESI negative): m/z = 479 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 5.36 (s, 2H), 7.22-7.37 (m, 8H), 7.42-7.46 (m, 3H), 7.73 (s, 1H), 7.81 (dd, 1H), 8.12 (s, 1H), 8.33 (d, 1H), 8.45 (s, 1H), 10.60 (s, 1H).

Example 294.

2-(2-Chlorophenyl)-N-[4-(6-methylpyridazin-4-yl)-3-sulfamoylphenyl]acetamide

- 186 040608

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (400 mg, 1.19 mmol) and 3-methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridazine (524 mg, 2.38 mmol) was dissolved in npropanol (110 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (41.9 mg, 59.5 µmol), triphenylphosphine (21.6 mg, 59.5 µmol) and aq. potassium carbonate solution (1.8 ml, 2.0 M, 3.6 mmol). The reaction mixture was heated at 120°C for 1 h in a microwave oven (4 bar/40 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

2-(6-Methylpyridazin-4-yl)-5-nitrobenzenesulfonamide (400 mg, 1.36 mmol) was dissolved in THF (140 ml)/methanol (50 ml) and the flask was filled with nitrogen. Palladium on charcoal (148 mg, 1.39 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

5-Amino-2-(6-methylpyridazin-4-yl)benzenesulfonamide (200 mg, 757 µmol) was dissolved in DMF (5.3 ml) and (2-chlorophenyl)acetic acid (155 mg, 908 µmol) was added followed by the addition of N ,N-diisopropylethylamine (630 µl, 3.8 mmol) and HATU (460 mg, 1.21 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were then added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified twice by HPLC (first Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid, then Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the indicated in the title compound (2.20 mg, 95% purity, 1% yield over 3 steps).

LC-MS (method B): Rt = 0.78 min; MS (ESI negative): m/z = 415 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.66 (s, 3H), 3.91 (s, 2H), 7.30-7.37 (m, 3H), 7.43-7.55 (m , 5H), 7.89 (dd, 1H), 8.40 (d, 1H), 9.05 (d, 1H), 10.75 (s, 1H).

Example 295.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[6-(trifluoromethyl)pyridin-2-yl]phenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (150 mg, 327 µmol), 4.4.4'.4'.5.5 ,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane (208 mg, 817 µmol) and CataXCium A Pre Cat (11.9 mg, 16.3 µmol) were dissolved in dry methanol (20.0 ml) under argon followed by the addition of N,N-diisopropylethylamine (140 μl, 820 μmol). The reaction mixture was heated for 2 h at 50°C. After cooling to room temperature, potassium fluoride (38.0 mg, 654 µmol) and 2-bromo-6-(trifluoromethyl)pyridine (148 mg, 654 µmol) were added. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (8.35 mg, 16.3 µmol) was added. The reaction mixture was heated at 80° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-X-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[6-(trifluoromethyl)pyridin-2yl]phenyl)acetamide (56.0 mg, 107 µmol) was dissolved in methanol (25 ml) and treated with 32% aqueous sodium hydroxide solution (1.6 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (5.50 mg, 95% purity, 2 step yield 10 %).

LC-MS (method B): Rt = 1.16 min; MS (ESI negative): m/z = 468 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.92 (s, 2H), 7.07 (br s, 2H), 7.30-7.37 (m, 2H), 7.43-7.50 (m , 2H), 7.57 (d, 1H), 7.92-8.04 (m, 3H), 8.18-8.24 (m, 1H), 8.37 (d, 1H), 10.76 (s, 1H).

Example 296.

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

- 187 040608

N4-Brom-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-fluorophenyl)acetamide (250 mg, 565 µmol) and 1-(difluoromethyl)-4-(4.4.5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (276 mg, 1.13 mmol) was dissolved in n-propanol (10 mL) and bis-(triphenylphosphine)palladium(11) dichloride (CAS 13965-03-2) (19.9 mg, 28.3 µmol), triphenylphosphine (7.41 mg, 28.3 µmol) and potassium fluoride (7.55 mg, 130 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (710 µl, 2.0 M, 1.4 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

N-(4-[1-(Difluoromethyl)-1 H-pyrazol-4-yl]-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2fluorophenyl)acetamide (280 mg, 584 µmol) was dissolved in methanol (2.4 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (21.8 mg, 96% purity, 8% yield over 2 steps).

LCMS (method A): Rt = 1.00 min; MS (ESI positive): m/z = 425 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ): δ [ppm]=3.77 (s, 2H), 7.14-7.20 (m, 2H), 7.30-7.34 (m, 1H), 7.37-7.42 ( m, 3H), 7.46 (d, 1H), 7.66-7.96 (m, 2H), 8.00 (s, 1H), 8.34 (d, 1H), 8.41 (s, 1H), 10.61 (s, 1H).

Example 297.

2-(2-Chlorophenyl)-N-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-sulfamoylpyridin-3-yl}acetamide

5-Amino-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(dimethylamino)methylidene]pyridine-3sulfonamide (750 mg, 2.18 mmol) was dissolved in DMF (43 mL) and ( 2-chlorophenyl)acetic acid (372 mg, 2.18 mmol) followed by the addition of Ν,N-diisopropylethylamine (1.9 ml, 11 mmol) and HATU (994 mg, 2.61 mmol). The reaction mixture was stirred at 50° C. for 1 hour. The solvent was removed under reduced pressure and water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give 160 mg of the final product (yield over 4 steps 15%).

LC-MS (method B): Rt = 1.00 min; MS (ESI negative): m/z = 495 [M-H]-.

2-(2-Chlorophenyl)-N-(6-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-5-{[(dimethylamino)methylidene]sulfamoyl}pyridin-3-yl)acetamide (160 mg, 322 μmol) was dissolved in methanol (10 ml) and treated with 25% aqueous ammonia solution (10 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (two times, Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (18.9 mg, purity 92%, yield 13%).

LC-MS (method B): Rt = 0.71 min; MS (ESI negative): m/z = 440 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.94 (s, 2H), 7.30-7.38 (m, 2H), 7.43-7.52 (m, 2H), 7.71-8.08 ( m, 3H), 8.29 (s, 1H), 8.70 (s, 1H), 8.78 (d, 1H), 8.93 (d, 1H), 10.88 (s, 1H).

Example 298.

N-[4-(6-Chloro-5-methylpyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-bromo-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (300 mg, 606 µmol),

- 188 040608 (6-chloro-5-methylpyridin-3-yl)boronic acid (208 mg, 1.21 mmol) and potassium fluoride (77.4 mg, 1.33 mmol) were dissolved in dry and degassed DMF (9.3 ml) and the solution was again purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (15.5 mg, 30.3 µmol). The reaction mixture was heated for 1 h at 100°C. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was again subjected to the reaction conditions. The mixture was then filtered through celite, the solvent was removed under reduced pressure and used without further purification in the next step.

N-[4-(6-Chloro-5-methyl-pyridin-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (250 mg, 495 µmol) was dissolved in methanol ( 2.0 ml) and treated with 25% aqueous ammonia solution (10 ml) at room temperature for 18 hours. After that, 32% aqueous sodium hydroxide solution (0.2 ml) was added and the reaction mixture was heated at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) and by silica gel chromatography (Biotage, 35% ethyl acetate in hexane), and indicated in title pure compound was obtained after recrystallization from a mixture of dichloromethane/diethyl ether (6.30 mg, purity 90%, yield over 2 steps 3%). LC-MS (method B): Rt = 1.05 min; MS (ESI negative): m/z = 448 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.36 (s, 3H), 3.90 (s, 2H), 7.29-7.39 (m, 5H), 7.42-7.50 (m , 2H), 7.76 (d, 1H), 7.86 (dd, 1H), 8.19 (d, 1H), 8.38 (d, 1H), 10.70 (s, 1H).

Example 299.

2-(2-Chlorophenyl)-N-{4-[2-(cyclopropylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide hydrochloride (1:1) (250 mg, 505 µmol), N-cyclopropyl-5-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrimidin-2-amine (264 mg, 1.01 mmol) and potassium fluoride (64.5 mg, 1.11 mmol) were dissolved in dry and degassed DMF (7.7 ml) and the solution was again purged with argon for 5 min, followed by the addition of bis-(tri-tertbutylphosphine)palladium(0) (CAS 53199-31-8) (12.9 mg, 25.2 µmol) and the solution was again purged with argon. The reaction mixture was heated for 2 h at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(4-[2-(cyclopropylamino)pyrimidin-5-yl]-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (250 mg, 487 µmol) was dissolved in methanol ( 2.0 ml) and treated with 25% aqueous ammonia solution (10 ml) at room temperature for 4 hours. After that, 32% aqueous sodium hydroxide solution (0.2 ml) was added and stirring was continued until the reaction was completed. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (34.0 mg, 95% purity, yield over 2 steps 14 %).

LC-MS (method B): Rt = 0.91 min; MS (ESI negative): m/z = 456 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=0.48-0.53 (m, 2H), 0.65-0.71 (m, 2H), 2.73 (tq, 1H), 3.89 (s, 2H), 7.28-7.39 (m, 5H), 7.43-7.49 (m, 3H), 7.84 (dd, 1H), 8.26 (s, 2H), 8.36 (d, 1H), 10.65 (s, 1H).

Example 300.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[1-(tetrahydrofuran-3-yl)-1H-πyrazol-4-yl]phenyl}acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250mg, 545µmol), 1(tetrahydrofuran-3-yl)-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (288 mg, 1.09 mmol) and potassium fluoride (69.6 mg, 1.20 mmol) were dissolved in dry and degassed DMF (7.7 ml) and races

- 189 040608 the solution was again purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(O) (CAS 53199-31-8) (13.9 mg, 27.2 µmol). The reaction mixture was again purged with argon for 1 min and heated for 18 h at 100°C. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was again subjected to the reaction conditions. After filtration and removal of the solvent, the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(tetrahydrofuran-3-yl)-1Hpyrazol-4-yl]phenyl)acetamide (300 mg, pure 20%, 116 µmol) was dissolved in methanol (0.5 ml) and treated with 32% aqueous sodium hydroxide solution (45 µl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) and the pure title compound was obtained after crystallization from dichloromethane/diethyl ether (4.70 mg, purity 95%, yield over stage 2 8%).

LC-MS (method A): Rt = 0.98 min; MS (ESI negative): m/z = 459 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.36-2.42 (m, 1H), 3.76-3.91 (m, 4H), 3.92-4.04 (m, 3H), 4.995 .11 (m, 1H), 7.18 (s, 2H), 7.30-7.34 (m, 2H), 7.43-7.48 (m, 3H), 7.74 (s, 1H), 7.82 (dd, 1H), 8.06 (d , 1H), 8.32 (d, 1H), 10.58 (s, 1H).

Example 301.

2-(2-Chlorophenyl)-N-{4-[2-(methylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and N-methyl-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (256 mg, 1.1 mmol) was dissolved in n-propanol (8.1 ml) and bis-(triphenylphosphine)palladium(II) dichloride was added ( CAS 13965-03-2) (19.2 mg, 27.2 µmol), triphenylphosphine (5.4 µl, 27 µmol), potassium fluoride (7.91 mg, 136 µmol) and aqueous potassium phosphate (540 µl, 2.0 M, 1.1 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 100° C. for 1 h in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(methylamino)pyrimidin-5yl]phenyl)acetamide (300 mg, 616 µmol) was dissolved in methanol (2.5 ml) and treated with 32% aqueous sodium hydroxide solution (240 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, ethyl acetate), the solid was triturated in diethyl ether/ethyl acetate and the filtrate was then subjected to HPLC purification (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution ( 32%)) to give the title compound (36.0 mg, 95% purity, 13% yield over step 2).

LC-MS (method B): Rt = 0.84 min; MS (ESI negative): m/z = 430 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.84 (d, 3H), 3.89 (s, 2H), 7.18 (q, 1H), 7.26-7.38 (m, 5H ), 7.437.49 (m, 2H), 7.83 (dd, 1H), 8.24 (s, 2H), 8.35 (d, 1H), 10.64 (s, 1H).

Example 302.

2-(2-Chlorophenyl)-N-[6-(1-methyl-1H-pyrazol-4-yl)-5-sulfamoylpyridin-3-yl]acetamide

5-Amino-N-[(dimethylamino)methylidene]-2-(1-methyl-1H-pyrazol-4-yl)pyridine-3-sulfonamide (500 mg, 1.62 mmol) was dissolved in DMF (15 ml) and ( 2-chlorophenyl)acetic acid (277 mg, 1.62 mmol) followed by the addition of N,N-diisopropylethylamine (1.4 ml, 8.1 mmol) and HATU (925 mg, 2.43 mmol). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and water and ethyl acetate were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography.

- 190 040608 (Biotage, 2% ethanol gradient in dichloromethane) to give 120.0 mg of final product (yield over 3 steps 16%).

LC-MS (method B): Rt = 0.93 min; MS (ESI negative): m/z = 459 [M-H] ^- .

2-(2-Chlorophenyl)-N-[5-{[(dimethylamino)methylidene]sulfamoyl}-6-(1-methyl-1H-pyrazol-4yl)pyridin-3-yl]acetamide (120mg, 260µmol ) was dissolved in methanol (20 ml) and treated with 25% aqueous ammonia solution (20 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (2.60 mg, 97% pure , yield 2%).

LC-MS (method B): Rt = 0.65 min; MS (ESI negative): m/z = 404 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.81-3.98 (m, 5H), 7.26-7.37 (m, 2H), 7.42-7.51 (m, 2H), 7.65 ( s, 2H), 7.99 (d, 1H), 8.26 (s, 1H), 8.71 (d, 1H), 8.88 (d, 1H), 10.77 (s, 1H).

Example 303.

2-(2-Chlorophenyl)-N-{4-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

DMF was dried over molecular sieves and purged with argon. Then N-(4-6pom-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250mg, 545µmol), 1-(2,2difluoroethyl)-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (281 mg, 1.09 mmol) and potassium fluoride (69.6 mg, 1.20 mmol) were dissolved in dry and degassed DMF (8.3 ml ) and the solution was again purged with argon for 5 min, followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (13.9 mg, 27.2 µmol). The reaction mixture was heated for 1 h at 100°C. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was dissolved in dry DMF (8.0 ml). 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-pyrazole (281 mg, 1.09 mmol), bis-( triphenylphosphine)palladium(II) (CAS 13965-03-2) (19.2 mg, 27.2 µmol) and an aqueous solution of potassium phosphate (540 µL, 2.0 M, 1.1 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 100 mg of the final product (36% yield).

LC-MS (method B): Rt = 1.07 min; MS (ESI negative): m/z = 508 [M-H] ^- .

2-(2-Chlorophenyl)-N-(4-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (100 mg, 196 μmol) was dissolved in methanol (0.8 ml) and treated with 32% aqueous sodium hydroxide solution (280 μl) at room temperature overnight. A 32% aqueous sodium hydroxide solution (280 μl) was added and the reaction mixture was heated at 50° C. until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (9.20 mg, 95% purity, 10% yield).

LC-MS (method A): Rt = 1.02 min; MS (ESI negative): m/z = 453 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 4.65 (td, 2H), 6.19-6.59 (m, 1H), 7.19 (s, 2H) , 7.297.36 (m, 2H), 7.42-7.48 (m, 3H), 7.78 (s, 1H), 7.83 (dd, 1H), 8.08 (s, 1H), 8.33 (d, 1H), 10.59 (s , 1H).

Example 304.

N-{3-Sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-2-[2-(trifluoromethyl)phenyl]acetamide

5-Amino-N-[(dimethylamino)methylidene]-2-[5-(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (185 mg, 497 µmol) was dissolved in DMF (3.5 ml) and [2-(trifluoromethyl) was added phenyl]acetic acid (122 mg, 596 µmol) followed by the addition of N,N-diisopropylethylamine (410 µl, 2.5 mmol) and HATU (302 mg, 795 µmol). The reaction mixture was stirred at 50°C for 2 hours.

- 191 040608 water and dichloromethane. The phases were separated and the aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 200 mg of final product (41% purity, 72% yield over 2 steps).

LC-MS (method B): Rt = 1.21 min; MS (ESI negative): m/z = 557 [M-H]-.

N-(3-{[(Dimethylamino)methylidene]sulfamoyl}-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl)-2-[2(trifluoromethyl)phenyl]acetamide (200 mg, 358 µmol) was dissolved in methanol (1.5 ml) and treated with 25% aqueous ammonia solution (0.5 ml) at room temperature overnight. Then 32% aqueous sodium hydroxide solution (0.2 ml) was added and stirring was continued at 50°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, 40% ethyl acetate in hexanes) and then by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the indicated in the title compound (10.0 mg, 95% purity, 5% yield).

LC-MS (method A): Rt = 1.18 min; MS (ESI negative): m/z = 502 [M-H]-.

1H-NMR (500 MHz, DMSO-d6): shift [ppm]=4.00 (s, 2H), 7.28-7.45 (m, 2H), 7.48-7.59 (m, 2H), 7.657.70 (m , 1H), 7.73 (d, 1H), 7.87 (dd, 1H), 8.08-8.23 (m, 1H), 8.31 (s, 1H), 8.38 (d, 1H), 8.82 (d, 1H), 8.95 ( d, 1H), 10.70 (s, 1H).

Example 305.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-5'-(trifluoromethyl)-2,3'-bipyridin-5-yl]acetamide

5-Amino-N-[(dimethylamino)methylidene]-5'-(trifluoromethyl)-2,3'-bipyridine-3-sulfonamide (250 mg, 670 µmol) was dissolved in DMF (10 ml) and (2-chlorophenyl )acetic acid (126 mg, 737 µmol) followed by the addition of N,N-diisopropylethylamine (580 µl, 3.3 mmol) and HATU (306 mg, 804 µmol). The reaction mixture was stirred at 50° C. for 3 hours. The same amount of acid was then added and stirring was continued for 2 hours. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) to give 160 mg of the final product (yield over 3 steps 45%). LC-MS (method B): Rt = 1.13 min; MS (ESI negative): m/z = 524 [M-H]-.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-5'-(trifluoromethyl)-2,3'bipyridin-5-yl]acetamide (160 mg, 304 µmol) was dissolved in methanol (20 ml) and treated with 25% aqueous ammonia solution (20 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (11.6 mg, 99% pure). , yield 8%).

LC-MS (method B): Rt = 0.81 min; MS (ESI negative): m/z = 469 [M-H]-.

1H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.96 (s, 2H), 7.29-7.40 (m, 2H), 7.43-7.52 (m, 2H), 7.77 (s, 2H ), 8.28-8.35 (m, 1H), 8.86 (d, 1H), 8.99 (d, 1H), 9.02 (dd, 2Н), 10.99 (s, 1H).

Example 306.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (250 mg, 494 µmol), 5-bromo-2-(trifluoromethyl)pyrimidine (224 mg, 988 µmol) and potassium fluoride (57.4 mg, 988 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (12.6 mg, 24.7 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 hour. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

- 192 040608

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(trifluoromethyl)pyrimidin5-yl]phenyl)acetamide (300 mg, 570 µmol) was dissolved in methanol (2.3 ml) and treated with aqueous ammonia solution (810 μl, 7.0 M, 5.7 mmol) at room temperature. Thereafter, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was completed. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex

C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (19.1 mg, 95% purity, 7% yield over 3 steps).

LC-MS (method B): Rt = 0.98 min; MS (ESI negative): m/z = 469 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.92 (s, 2H), 7.24-7.40 (m, 3H), 7.41-7.55 (m, 4H), 7.93 (dd , 1H), 8.42 (d, 1H), 9.03 (s, 2H), 10.77 (s, 1H).

Example 307.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethoxy)pyridin-3-yl]phenyl}acetαmide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 197 µmol), 3-bromo-5-(trifluoromethoxy)pyridine (95.7 mg, 395 µmol) and potassium fluoride (23.0 mg, 395 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (5.05 mg, 9.88 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 h. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 81.3 mg of final product (yield 76%).

LC-MS (method B): Rt = 1.21 min; MS (ESI negative): m/z = 539 [M-H]-.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[5-(trifluoromethoxy)pyridin-3yl]phenyl)acetamide (190 mg, 351 µmol) was dissolved in methanol (1.4 ml) and treated with aqueous ammonia solution (500 µl, 7.0 M, 3.5 mmol) at room temperature. After 18 hours, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-

10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (27.3 mg, 95% purity, 15% yield over 3 steps).

LC-MS (method B): Rt = 1.11 min; MS (ESI negative): m/z = 484 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.91 (s, 2H), 7.29-41 (m, 3H), 7.43-7.53 (m, 4H), 7.80-7.97 (m, 2H), 8.40 (d, 1H), 8.58 (d, 1H), 8.67 (d, 1H), 10.73 (s, 1H).

Example 308.

2-(2-Chlorophenyl)-N-[4-(2-cyclopropylpyrimidin-5-yl)-3-sulfαmoylphenyl]acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-2-cyclopropylpyrimidine (78.7 mg, 395 µmol) and potassium fluoride (23.0 mg, 395 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (5.05 mg, 9.88 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 h. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 50.0 mg of final product (yield 51%).

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 496 [M-H]-.

2-(2-Chlorophenyl)-N-[4-(2-cyclopropylpyrimidin-5-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (50.0 mg, 100 µmol) was dissolved in methanol (0.4 ml ) and treated with aqueous ammonia solution (140 μl, 7.0 M, 3.5 mmol) at room temperature. After 18 hours, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was complete. Ras

- 193 040608 the solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex

C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (6.30 mg, 95% purity, 13% yield).

LC-MS (method B): Rt = 0.95 min; MS (ESI negative): m/z = 441 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.93-1.17 (m, 4H), 2.11-2.28 (m, 1H), 3.90 (s, 2H), 7.19-7.40 (m, 3H), 7.42-7.59 (m, 4H), 7.87 (dd, 1H), 8.39 (d, 1H), 8.57 (s, 2H), 10.70 (s, 1H).

Example 309.

2-(2-Chlorophenyl)-N-[4-(2-ethoxypyrimidin-5-yl)-3-sulfamoylphenyl]acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-2-ethoxypyrimidine (80.3 mg, 395 µmol) and potassium fluoride (23.0 mg, 395 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (5.05 mg, 9.88 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 h. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 50.0 mg of final product (50% yield).

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 500 [M-H]-.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(2-ethoxypyrimidin-5yl)phenyl]acetamide (50.0 mg, 99.6 µmol) was dissolved in methanol (0.4 ml) and treated with aqueous ammonia solution (140 μl, 7.0 M, 3.5 mmol) at room temperature. After 18 hours, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (1.00 mg, 95% purity , yield 2%).

LC-MS (method B): Rt = 0.96 min; MS (ESI negative): m/z = 445 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.37 (t, 3H), 3.90 (s, 2H), 4.40 (q, 2H), 7.09-7.63 (m, 7H ), 7.87 (dd, 1H), 8.36 (s, 1H), 8.53 (s, 2H), 10.68 (s, 1H).

Example 310.

2-(2-Chlorophenyl)-K-{4-[2-(propan-2-ylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-N-(propan-2-yl)pyrimidin-2-amine (85.4 mg, 395 µmol) and potassium fluoride (23.0 mg, 395 µmol) were added ) in an argon atmosphere. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (5.05 mg, 9.88 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 h. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 50.0 mg of final product (yield 49%).

LC-MS (method B): Rt = 1.17 min; MS (ESI negative): m/z = 513 [M-H]-.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(propan-2ylamino)pyrimidin-5-yl]phenyl)acetamide (50.0 mg, 97.1 µmol) was dissolved in methanol (0.4 ml) and treated with aqueous ammonia solution (140 μl, 7.0 M, 3.5 mmol) at room temperature. After 18 hours, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (2.70 mg, 95% pure , yield 6%).

LC-MS (method B): Rt = 1.03 min; MS (ESI negative): m/z = 458 [M-H]-.

- 194 040608

1H-NMR (400 MHz, DMSOD): δ [ppm]=1.18 (d, 6H), 3.89 (s, 2H), 4.07 (spt, 1H), 7.10 (d, 1H), 7.29 (d, 1H), 7.31-7.39 (m, 4H), 7.42-7.50 (m, 2H), 7.83 (dd, 1H), 8.23 (s, 2H), 8.35 (d, 1H), 10.63 (s, 1H).

Example 311.

2-(2-Chlorophenyl)-N-{4-[2-(propan-2-yloxy)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-2-(propan-2-yloxy)pyrimidine (94.6 mg, 436 µmol) and potassium fluoride (25.3 mg, 436 µmol) were added in an argon atmosphere . The solution was purged with argon for 5 min, and palladium tri-tert-butylphosphane (1:2) (5.57 mg, 10.9 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 hour. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

LC-MS (method B): R _t = 1.16 min; MS (ESI positive): m/z = 516 [M+H]+.

2-(2-Chlorophenyl)-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(propan-2-yloxy)pyrimidin5-yl]phenyl)acetamide (150 mg, 291 µmol) was dissolved in methanol (1.1 ml) and treated with 32% aqueous sodium hydroxide solution (140 µl) at 50°C for 4 hours. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/ water + 0.2% aqueous ammonia (32%)) to give the title compound (23.7 mg, 95% purity, 17% yield over 2 steps).

LC-MS (method B): Rt = 1.02 min; MS (ESI negative): m/z = 459 [M-H] ⁺ .

1I-NMR (400 MHz, DMSO-d6): δ [ppm]=1.35 (d, 6H), 3.89 (s, 2H), 5.24 (quin, 1H), 6.99-7.67 (m, 7H), 7.85-8.04 (m, 1H), 8.36 (d, 1H), 8.51 (s, 2H), 10.68 (s, 1H).

Example 312.

2-(2-Chlorophenyl)-N-{4-[2-(ethylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-N-ethylpyrimidin-2-amine (88.1 mg, 436 µmol) and potassium fluoride (25.3 mg, 436 µmol) were added under argon atmosphere. The solution was purged with argon for 5 min, and bis(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (5.57 mg, 10.9 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 hour. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

LC-MS (method B): R _t = 1.05 min; MS (ESI positive): m/z = 501 [M+H]+.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(ethylamino)pyrimidin-5yl]phenyl)acetamide (150 mg, 299 µmol) was dissolved in methanol (1.2 ml) and treated with 32% aqueous sodium hydroxide solution (140 μl) at 50°C until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) to give 25.1 mg of the final product (purity 95%, yield 2 stages 18%).

LC-MS (method B): R _t = 0.95 min; MS (ESI positive): m/z = 446 [M+H]+.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.15 (t, 3H), 3.89 (s, 2H), 7.14-7.41 (m, 6H), 7.42-7.56 (m, 2H ), 7.83 (dd, 1H), 8.23 (s, 2H), 8.35 (d, 1H), 10.64 (s, 1H).

Example 313.

2-(2-Chlorophenyl)-N-[4-(2-methylpyrimidin-5-yl)-3-sulfamoylphenyl]acetamide

- 195 040608

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 5-bromo-2-methylpyrimidine (75.4 mg, 436 µmol) and potassium fluoride (25.3 mg, 436 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (5.57 mg, 10.9 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 1 hour. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

LC-MS (method B): R _t = 0.98 min; MS (ESI positive): m/z = 472 [M+H]+.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(2-methylpyrimidin-5yl)phenyl]acetamide (150 mg, 318 µmol) was dissolved in methanol (1.3 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl) at 80°C until the reaction is complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (10.0 mg, 93% purity, 7% yield over 2 steps).

LC-MS (method A): R _t = 1.12 min; MS (ESI positive): m/z = 417 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=2.67 (s, 3H), 3.91 (s, 2H), 7.28-7.38 (m, 3H), 7.41-7.58 (m , 4H), 7.88 (dd, 1H), 8.40 (d, 1H), 8.63 (s, 2H), 10.71 (s, 1H).

Example 314.

2-(2-Chlorophenyl)-N-{4-[2-(propylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (150 mg, 297 µmol), 5-bromo-N-propylpyrimidin-2-amine (141 mg, 654 µmol) and potassium fluoride (38.0 mg, 654 µmol) were added under argon atmosphere. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (8.35 mg, 16.3 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 2 h. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 90.0 mg of final product (yield 53%).

LC-MS (method B): R _t = 1.12 min; MS (ESI positive): m/z = 515 [M+H+].

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(propylamino)pyrimidin-5yl]phenyl)acetamide (90.0 mg, 175 µmol) was dissolved in methanol (1.8 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (30.3 mg, 95% pure). , yield 36%).

LC-MS (method B): Rt = 1.01 min; MS (ESI positive): m/z = 460 [M+H+].

¹ H-NMR (400 MHz, DMSOD): δ [ppm]=0.91 (t, 3H), 1.56 (sxt, 2H), 3.23-3.29 (m, 2H), 3.89 (s, 2H), 7.21 -7.37 (m, 6H), 7.42-7.52 (m, 2H), 7.83 (dd, 1H), 8.23 (s, 2H), 8.35 (d, 1H), 10.64 (s, 1H).

Example 315.

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{2-[(2,2,2-trifluoroethyl)amino]pyrimidin-5yl}phenyl)acetamide

- 196 040608

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (150 mg, 297 µmol), 5-bromo-N-(2,2,2-trifluoroethyl)pyrimidin-2-amine (167 mg, 654 µmol) and potassium fluoride (38.0 mg, 654 µmol) in an argon atmosphere. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (8.35 mg, 16.3 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 150 mg of final product (purity 80%, yield 66%).

LC-MS (method B): Rt = 1.14 min; MS (ESI positive): m/z = 555 [M+H+].

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{2-[(2,2,2trifluoroethyl)amino]pyrimidin-5-yl}phenyl)acetamide (150 mg , purity 80%, 216 µmol) was dissolved in methanol (2.2 ml) and treated with 32% aqueous sodium hydroxide solution (200 µl) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (41.3 mg, 95% pure). , yield 36%).

LC-MS (method B): Rt = 0.99 min; MS (ESI positive): m/z = 500 [M+H+] ¹ H-NMR (400 MHz, DMSOd6): δ [ppm]=3.90 (s, 2H), 4.12-4.25 (m, 2H), 7.29-7.35 (m, 3H), 7.39 (s, 2H), 7.43-7.49 (m, 2H), 7.81-7.92 (m, 2H), 8.32 (s, 2H), 8.36 (d, 1H) , 10.66(s, 1H).

Example 316.

2-(2-Chlorophenyl)-N-{4-[2-(cyclobutyloxy)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (150 mg, 297 µmol), 5-bromo-2-(cyclobutyloxy)pyrimidine (150 mg, 654 µmol) and potassium fluoride (38.0 mg, 654 µmol) were added under argon. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (8.35 mg, 16.3 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 2 hours. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 110 mg of final product (yield 64%).

LC-MS (method B): R _t = 1.20 min; MS (ESI positive): m/z = 528 [M+H+].

2-(2-Chlorophenyl)-N-(4-[2-(cyclobutyloxy)pyrimidin-5-yl]-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (110 mg, 208 µmol) was dissolved in methanol ( 2.3 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (10.6 mg, 95% purity , 10% yield.

LC-MS (method B): Rt = 1.07 min; MS (ESI positive): m/z = 473 [M+H+] ¹ H-NMR (400 MHz, DMSOd ₆ ): δ [ppm]=1.59-1.71 (m, 1H), 1.81 (q , 1H), 2.06-2.24 (m, 2H), 2.39-2.47 (m, 2H), 3.89 (s, 2H), 5.08-5.26 (m, 1H), 7.26-7.40 (m, 5H), 7.42-7.52 (m, 2H), 7.86 (dd, 1H), 8.37 (d, 1H), 8.50 (s, 2H), 10.69 (s, 1H).

Example 317.

N-[4-(2-Chloro-4-methylpyrimidin-5-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

- 197 040608

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-X-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (400 mg, 792 µmol), 5-bromo-2-chloro-4-methylpyrimidine (362 mg, 1.74 mmol) and potassium fluoride (101 mg, 1.74 mmol) were added under argon atmosphere. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (22.3 mg, 43.6 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80°C for 2 hours. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to obtain 124 mg of the final product (yield 28%).

LC-MS (method B): Rt = 1.12 min; MS (ESI negative): m/z = 504 [M-H ⁺ ].

N-[4-(2-Chloro-4-methylpyrimidin-5-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (124 mg, 245 µmol) was dissolved in methanol ( 2.5 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (2.60 mg, 95% purity, 2% yield).

LC-MS (method A): R _t = 1.04 min; MS (ESI positive): m/z = 451 [M+H ⁺ ] ¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.20 (s, 3H), 3.91 (s, 2H), 7.27-7.39 (m, 3H), 7.41-7.56 (m, 4H), 7.89 (dd, 1H), 8.31-8.45 (m, 2H), 10.73 (s, 1H).

Example 318.

2-(2-Chlorophenyl)-X-{3-sulfamoyl-4-[4-(trifluoromethyl)pyridin-2-yl]phenyl}acetamide

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-X-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (300 mg, 594 µmol), 2-bromo-4-(trifluoromethyl)pyridine (296 mg, 1.31 mmol) and potassium fluoride (76.0 mg, 1.31 mmol) were added under argon. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (16.7 mg, 32.7 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80°C for 3 hours. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to obtain 150 mg of the final product (yield 44%).

LC-MS (method B): Rt = 1.17 min; MS (ESI positive): m/z = 525 [M+H] ⁺ .

2-(2-Chlorophenyl)-X-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[4-(trifluoromethyl)pyridin-2yl]phenyl)acetamide (50.0 mg, 95.2 µmol) was dissolved in methanol (1.2 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl) at 80°C until the reaction was completed. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (9.90 mg, 95% pure , yield 21%).

LC-MS (method B): Rt = 1.17 min; MS (ESI positive): m/z = 470 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.91 (s, 2H), 6.90-7.22 (s, 1H), 7.25-7.42 (m, 3H), 7.44-7.53 (m, 2Н), 7.61 (d, 1H), 7.78 (d, 1H), 7.97 (dd, 1H), 8.10 (s, 1Н), 8.35 (s, 1H), 8.93 (d, 1H), 10.73 ( s, 1H).

Example 319.

2-(2-Chlorophenyl)-X-[4-(5-chloropyridin-2-yl)-3-sulfamoylphenyl]acetamide

To a solution containing an ester of boronic acid, intermediate compound 2-(2

- 198 040608 chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)phenyl]acetamide (300 mg , 594 µmol), 2-bromo-5-chloropyridine (252 mg, 1.31 mmol) and potassium fluoride (76.0 mg, 1.31 mmol) were added under argon. The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (16.7 mg, 32.7 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 3 hours. After that, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 100 mg of final product (31% yield).

LC-MS (method B): R _t = 1.11 min; MS (ESI negative): m/z = 489 [M-H] ⁺ .

2-(2-Chlorophenyl)-N-[4-(5-chloropyridin-2-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (68.8 mg, 140 µmol) was dissolved in methanol (0.6 ml ) and treated with 32% aqueous sodium hydroxide solution (200 μl) at room temperature for 1 h, followed by stirring at 80°C until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (7.20 mg, 93% purity, 11% yield).

LC-MS (method B): R _t = 1.13 min; MS (ESI negative): m/z = 434 [M-H] ⁺ .

1H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.91 (s, 2H), 7.26-7.38 (m, 2H), 7.39-7.51 (m, 4H), 7.56 (d, 1H ), 7.65 (d, 1H), 7.98 (dd, 1H), 8.03–8.15 (m, 1H), 8.36 (d, 1H), 8.73 (d, 1H), 10.74 (s, 1H).

Example 320.

2-(2-Chlorophenyl)-N-[4-(1,2-dimethyl-1H-imidazol-4-yl)-3-sulfamoylphenyl]acetamide nh ₂ pS

I* ¹

To a solution containing an ester of boronic acid intermediate 2-(2chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan2-yl)phenyl]acetamide (100 mg, 198 µmol), 4-bromo-1,2-dimethyl-1H-imidazole (76.3 mg, 436 µmol) and potassium fluoride (25.3 mg, 436 µmol) were added under argon. The solution was purged with argon for 5 min, and bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (7.67 mg, 10.9 µmol) was added. The solution was again purged with argon and the reaction mixture was heated at 80° C. for 2 h. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate) to give 11.6 mg of final product (11% yield).

LC-MS (method A): Rt = 0.8 min; MS (ESI negative): m/z = 472 [M-H] ⁺ .

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(1,2-dimethyl-1H-imidazol-4yl)phenyl]acetamide (11.6 mg, 24.5 µmol) was dissolved in ammonia in methanol (1.2 ml, 7M, 10 eq.) and stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure and the crude product was purified by HPLC chromatography (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (1.80 mg, purity 95%, yield 17%).

LC-MS (method B): R _t = 0.99 min; MS (ESI positive): m/z = 419 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.34 (s, 3H), 3.61 (s, 3H), 3.87 (s, 2H), 7.27-7.36 (m, 2H) , 7.38 (s, 1H), 7.40-7.55 (m, 3H), 7.87 (dd, 1H), 8.23 (d, 1H), 8.31 (s, 2H), 10.57 (s, 1H).

Example 321.

N-{6-[1 -(Difluoromethyl)-1 H-pyrazol-4-yl]-5-sulfamoylpyridin-3-yl} -2-(2-fluorophenyl)acetamide

-Amino-2-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl] -N-[(dimethylamino)methylidene] pyridine-3 sulfonamide (400 mg, 1.16 mmol) was dissolved in DMF (10 ml) and added (2-fluorophenyl)acetic acid (179 mg, 1.16 mmol) followed by the addition of N,N-diisopropylethylamine (1.0 ml, 5.8 mmol) and HATU (530 mg, 1.39 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chroma

- 199 040608 torex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give 30.0 mg of the final product (5% yield).

LC-MS (method B): Rt = 0.99 min; MS (ESI positive): m/z = 481 [M+H] ⁺ .

N-(6-[1-(Difluoromethyl)-1H-pyrazol-4-yl]-5-{[(dimethylamino)methylidene]sulfamoyl}pyridin-3yl)-2-(2-fluorophenyl)acetamide (30.0 mg, 62.4 µmol) was dissolved in ammonia in methanol (10 ml, 7 M) and stirred at room temperature. Thereafter, the solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (10.1 mg, purity 99%, 38% yield.

LC-MS (method B): R _t = 0.66 min; MS (ESI positive): m/z = 426 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.83 (s, 2H), 7.15-7.24 (m, 2H), 7.31-7.38 (m, 1H), 7.42 (td, 1H), 7.71-8.07 (m, 3H), 8.29 (s, 1H), 8.70 (s, 1H), 8.78 (d, 1H), 8.93 (d, 1H), 10.86 (s, 1H).

Example 322.

2-(2-Chlorophenyl)-N-{4-[5-(pyrrolidin-1-yl)pyridin-3-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250mg, 545µmol) and [5-(pyrrolidin-1-yl)pyridin-3 -yl]boronic acid (209 mg, 1.09 mmol) was dissolved in n-propanol (8.1 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (19.2 mg, 27.2 μmol), triphenylphosphine was added (7.16 mg, 27 µmol) and potassium fluoride (7.91 mg, 136 µmol). The solution was purged with argon for 5 min, and aqueous potassium phosphate (540 μL, 2.0 M, 1.1 mmol) was added. The reaction mixture was heated at 100° C. for 3 hours in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

LC-MS (method B): R _t = 1.16 min; MS (ESI positive): m/z = 526 [M+H]+.

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[5-(pyrrolidin-1-yl)pyridin3-yl]phenyl)acetamide (190 mg, 361 µmol) was dissolved in methanol (1.5 ml) and treated with 32% aqueous sodium hydroxide solution (200 μl, 3.6 mmol) for 1 h at room temperature, followed by stirring at 80°C until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (79.1 mg, 95% purity , yield beyond stage 2 44%).

LC-MS (method B): Rt= 1.08 min; MS (ESI positive): m/z = 417 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.87-2.06 (m, 4H), 3.22-3.30 (m, 4H), 3.90 (s, 2H), 6.86-6.97 ( m, 1H), 7.20 (s, 2H), 7.27-7.40 (m, 3H), 7.43-7.52 (m, 2H), 7.80 (d, 1H), 7.83 (dd, 1H), 7.90 (d, 1H) , 8.37 (d, 1H), 10.65 (s, 1H).

Example 323.

2-(2-Chlorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-hydroxyethanamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (1.45 g, 3.16 mmol), 1-cyclopropyl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (740mg, 3.16mmol), Bis(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (111mg, 158 µmol) and triphenylphosphine (41.5 mg, 158 µmol) were dissolved in n-propanol (40 ml) and the solution was purged with argon for 5 min. After that, an aqueous solution of potassium carbonate (9.5 ml, 1.0 M, 9.5 mmol) was added and the reaction mixture was stirred for 1 h at 80°C. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed three times with ethyl acetate. The combined organic layers were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage Isolera, hexane/ethyl acetate gradient) to give 310 mg of final product (20% yield).

This intermediate amide (310 mg, 638 μmol) was dissolved in methanol (30 ml) and treated with 25% aqueous ammonia (30 ml). The reaction mixture was stirred at room temperature

- 200 040608 over 16 hours. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (43.3 mg, purity 99%, yield 15%).

LC-MS (method B): Rt = 0.88 min; MS (ESI positive): m/z = 447 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.98 (dd, 2H), 1.04-1.14 (m, 2H), 3.67-3.80 (m, 1H), 5.51 (d , 1H), 6.69 (d, 1H), 7.18 (s, 2H), 7.30-7.49 (m, 4H), 7.58 (s, 1H), 7.68 (d, 1H), 7.87 (d, 1H), 8.05 ( s, 1H), 8.51 (d, 1H), 10.42 (s, 1H).

Example 324.

2-(2-Chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2hydroxyethanamide

This compound was isolated as a by-product formed during the Suzuki reaction (observed when potassium carbonate was used as the base).

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (1.10 g, 2.40 mmol), 1-(difluoromethyl)-4-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (585 mg, 2.40 mmol), bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (84.4 mg, 120 µmol) and triphenylphosphine (31.4 mg, 120 µmol) were dissolved in n-propanol (40 ml) and the solution was purged with argon for 5 min. After that, an aqueous solution of potassium carbonate (7.2 ml, 1.0 M, 7.2 mmol) was added and the reaction mixture was stirred for 1 h at 100°C. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed three times with ethyl acetate. The combined organic layers were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage Isolera, hexane/ethyl acetate gradient) to give 460 mg of the final product (39% yield).

This intermediate amide (460 mg, 928 μmol) was dissolved in methanol (40 ml) and treated with 25% aqueous ammonia (40 ml). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound ( 4.7 mg, 95% purity, 1% yield.

LC-MS (method B): Rt = 0.86 min; MS (ESI positive): m/z = 457 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=5.52 (d, 1H), 6.72 (d, 1H), 7.30-7.44 (m, 4H), 7.44-7.53 (m , 2H), 7.60 (dd, 1H), 7.67–8.06 (m, 3H), 8.44 (s, 1H), 8.56 (d, 1H), 10.50 (s, 1H).

Example 325.

2-(2-Chlorophenyl)-N-[4-(5-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 2.59 mmol) and (5-chloropyridin-3-yl)boronic acid (814 mg, 5.17 mmol) were dissolved in DMF (10 ml) followed by adding bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (273 mg, 388 µmol) and aq. potassium carbonate solution (6.2 ml, 1.0 M, 6.2 mmol). The reaction mixture was heated for 1 hour at 120° C. in a microwave oven. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, hexane/ethyl acetate 1/1) to give 700 mg of the final product (58% yield).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 396 [M+H]+.

Iron (421 mg, 7.54 mmol) and ammonium acetate (404 mg, 7.54 mmol) were suspended in water (20 ml). 2-(5-Chloropyridin-3-yl)-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (700 mg, 1.51 mmol) was dissolved in THF/methanol (10 ml/10 ml) and added to the aqueous suspension . The reaction mixture was heated for 2 hours at 80° C. and filtered through celite after completion of the reaction. The solvent was removed under reduced pressure and the crude product was dissolved in ethyl acetate and water. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

5-Amino-2-(5-chloropyridin-3-yl)-N-(2,4-dimethoxybenzyl)benzenesulfonamide (690 mg, 1.59 mmol)

- 201 040608 was dissolved in dichloromethane (9.4 ml) and the solution was cooled to 0°C. (2-Chlorophenyl)acetyl chloride (110 μl, 800 μmol) and triethylamine (1.3 ml, 9.5 mmol) were added and stirring was continued for 4 h at 0°C. (2-Chlorophenyl)acetyl chloride (110 μl, 800 μmol) was added and stirring was continued at room temperature for 18 h. Water was then added and the phases were separated. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (Biotage, 10% ethyl acetate in hexanes gradient) to give 179 mg of final product (19% yield).

LC-MS (method B): Rt = 1.32 min; MS (ESI positive): m/z = 586 [M+H]+.

2-(2-Chlorophenyl)-N-{4-(5-chloropyridin-3-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}acetamide (179 mg, 305 µmol) was dissolved in dichloromethane (3.9 ml) and trifluoroacetic acid (3.9 ml, 50 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was taken up in ethyl acetate and washed with water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC chromatography (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (12.0 mg, 95% purity, 9% yield). .

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 436 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.90 (s, 2H), 7.27-7.38 (m, 3H), 7.41 (s, 2H), 7.43-7.48 (m , 2H), 7.82-7.94 (m, 2H), 8.38 (d, 1H), 8.48 (d, 1H), 8.61 (d, 1H), 10.70 (s, 1H).

Example 326.

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

F

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (1.50 g, 3.27 mmol), 1-(difluoromethyl)-4-(4.4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (958 mg, 3.92 mmol) and potassium fluoride (418 mg, 7.19 mmol) were dissolved in DMF (36 mL). The mixture was purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (83.5 mg, 163 µmol). The reaction mixture was heated for 1 h at 100°C, filtered through a glass fiber filter and the procedure was repeated. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (2.78 g).

2-(2-Chlorophenyl)-N-(4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide (2.78 g, 5.61 mmol) was dissolved in methanol (90 ml) and treated with 25% aqueous ammonia solution (90 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, 8% ethanol in dichloromethane) and then by HPLC (Chromatorex C18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%) ) to give the title compound (1.09 g, 99% pure, 34% yield over Step 2).

LC-MS (method B): Rt = 0.94 min; MS (ESI positive): m/z = 441 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.89 (s, 2H), 7.31-7.35 (m, 2H), 7.41 (s, 2H), 7.43-7.50 (m , 3Н), 7.69–8.00 (m, 2H), 8.02 (m, 1H), 8.36 (d, 1H), 8.43 (m, 1H), 10.65 (s, 1H).

Example 327.

2-(2-Chlorophenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (400 mg, 1.19 mmol) and (5fluoropyridin-3-yl)boronic acid (335 mg, 2.38 mmol) were dissolved in n-propanol (110 ml, 1.5 mol) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (41.9 mg, 59.5 µmol), triphenylphosphine (21.6 mg, 59.5 µmol) and aq. potassium carbonate solution (1.8 ml, 2.0 M, 3.6 mmol). The reaction mixture was heated at 120°C for 1 h (4 bar/40 W). The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and

- 202 040608 was used without further purification in the next step.

2-(5-Fluoropyridin-3-yl)-5-nitrobenzenesulfonamide (400 mg, 1.35 mmol) was dissolved in methanol (37 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 71.4 mg, 366 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature until completion of the reaction. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (400 mg).

5-Amino-2-(5-fluoropyridin-3-yl)benzenesulfonamide (200 mg, 748 µmol) was dissolved in DMF (5.3 ml) and (2-chlorophenyl)acetic acid (153 mg, 898 µmol) was added followed by N ,N-diisopropylethylamine (620 µl, 3.7 mmol) and HATU (455 mg, 1.20 mmol). The reaction mixture was stirred for 18 hours at 50°C. After that, dichloromethane and water were added and the phases were separated. The aqueous phase was washed with dichloromethane and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the indicated in the title compound (4.70 mg, 95% purity, 1% yield over 3 steps).

LC-MS (method B): Rt = 0.93 min; MS (ESI positive): m/z = 420 [M+H]+.

¹ I-NMR (400 MHz, DMSO-d6): δ [ppm]=3.90 (s, 2H), 7.31-7.37 (m, 3H), 7.40 (s, 2H), 7.42-7.48 (m, 2H), 7.68-7.75 (m, 1H), 7.87 (dd, 1H), 8.34-8.44 (m, 2H), 8.57 (d, 1H), 10.71 (s, 1H).

Example 328.

2-(2-Chlorophenyl)-K-{4-[ 1 -(2-methylpropyl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

X-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200 mg, 436 µmol) and 1-(2-methylpropyl)-4-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (220 µl, 870 µmol) was dissolved in n-propanol (5.9 ml) and bis(triphenylphosphine)palladium(P) dichloride was added ) (CAS 13965-03-2) (15.3 mg, 21.8 µmol), triphenylphosphine (5.72 mg, 21.8 µmol) and aq. potassium carbonate solution (540 μl, 2.0 M, 1.1 mmol). The reaction mixture was purged with argon for 5 minutes and then heated at 80° C. for 3 hours. The mixture was then filtered through celite and the solvent was removed under reduced pressure.

The crude product was dissolved in methanol (51 ml) and treated with 32% aqueous sodium hydroxide solution (100 ml) at 40° C. to complete the reaction. The reaction mixture was neutralized by adding 2N. HCl. The solvent was removed under reduced pressure and dichloromethane and water were added. The phases were separated and the aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (10.9 mg, 98% purity, 3 steps yield 5 %).

LC-MS (method B): Rt = 1.09 min; MS (ESI negative): m/z = 445 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.86 (d, 6H), 2.01-2.22 (m, 1H), 3.87 (s, 2H), 3.92 (d, 2H ), 7.16 (s, 2H), 7.27-7.38 (m, 2H), 7.38-7.51 (m, 3H), 7.64-7.73 (m, 1H), 7.78-7.83 (m, 1H), 7.95-8.00 (m , 1H), 8.31 (d, 1H), 10.57 (s, 1H).

Example 329.

2-(2-Chlorophenyl)-N-[4-(1-cyclopentyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

X-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200 mg, 436 µmol) and 1-cyclopentyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (229 mg, 872 µmol) was dissolved in n-propanol (5.9 ml) and bis-(triphenylphosphine)palladium(11) dichloride (CAS 13965-03-2) (15.3 mg, 21.8 µmol), triphenylphosphine (5.72 mg, 21.8 µmol) and aq. potassium carbonate solution (540 µl, 2M, 1.1 mmol). The reaction mixture was purged with argon for 5 min and then stirred for 2 h at 80°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (250 mg).

2-(2-Chlorophenyl)-N-[4-(1-cyclopentyl-1H-pyrazol-4-yl)-3- 203 040608 {[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (250 mg, 486 µmol) was dissolved in methanol (5.0 ml) and treated with 32% aqueous sodium hydroxide solution (300 μl) at 65°C until the reaction was complete. Dichloromethane and water were added and the phases were separated. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Chromatorex C-18 10 µm , 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (7.80 mg, 98% purity, 3% yield).

LC-MS (method B): Rt = 1.12 min; MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (400 MHz, DMSOCH): δ [ppm]=1.56-1.71 (m, 2H), 1.74-1.89 (m, 2H), 1.90-2.03 (m, 2H), 2.032.17 ( m, 2H), 3.87 (s, 2H), 4.63-4.77 (m, 1H), 7.17 (s, 2H), 7.27-7.36 (m, 2H), 7.39-7.50 (m, 3H), 7.70 (s, 1H), 7.77-7.85 (m, 1H), 8.03 (s, 1H), 8.31 (d, 1H), 10.56 (s, 1H).

Example 330.

2-(2-Chlorophenyl)-N-[2'-fluoro-3'-(propan-2-yloxy)-2-sulfamoylbiphenyl-4-yl]acetamide

X-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and [2-fluoro-3-(propan-2-yloxy )phenyl]boronic acid (108 mg, 545 µmol) was dissolved in n-propanol (10 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (19.2 mg, 27.2 µmol) and triphenylphosphine were added (7.15 mg, 27.2 µmol). The reaction mixture was purged with argon for 5 min and aq. potassium carbonate solution (1.6 ml, 1.0 M, 1.6 mmol). The reaction mixture was heated at 100° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was used without further purification in the next step (630 mg).

2-(2-Chlorophenyl)-N-[2-{[(dimethylamino)methylidene]sulfamoyl}-2'-fluoro-3'-(propan-2yloxy)biphenyl-4-yl]acetamide (630 mg, 1.18 mmol) was dissolved in methanol (25 ml) and treated with 33% aqueous ammonia solution (25 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the final product (37.6 mg, 95% purity, yield for 2 stages 6%).

LC-MS (method B): Rt = 1.24 min; MS (ESI positive): m/z = 477 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.24-1.34 (m, 6H), 3.89 (s, 2H), 4.54-4.66 (m, 1H), 6.77-6.90 ( m, 1H), 7.00-7.11 (m, 1H), 7.17 (m, 3H), 7.22-7.39 (m, 3H), 7.43-7.52 (m, 2H), 7.81 (dd, 1H), 8.34 (d, 1H), 10.65 (s, 1H).

Example 331.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

X-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (500 mg, 1.09 mmol) and [5-(trifluoromethyl)pyridin-3-yl]boronic acid (520 mg, 2.72 mmol) was dissolved in npropanol (15 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (38.4 mg, 54.5 µmol), triphenylphosphine (14.3 mg, 54.5 µmol) was added ), potassium fluoride (23.1 mg, 270 µmol) and aq. potassium carbonate solution (1.4 ml, 2.0 M, 2.7 mmol). The reaction mixture was heated at 100°C for 1 h in a microwave oven (1 bar/15 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step.

2-(2-Chlorophenyl)-X-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[5-(trifluoromethyl)pyridin-3yl]phenyl)acetamide (1.50 g, 2.86 mmol) was dissolved in methanol (29 ml) and treated with 32% aqueous sodium hydroxide solution (1.6 ml) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, 40% ethyl acetate in hexanes) and then by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% mu- 204 040608 ravic acid) to give the indicated in title compound (562 mg, 95% purity, 40% yield over step 2).

LC-MS (method A): Rt = 1.13 min; MS (ESI negative): m/z = 468 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.91 (s, 2H), 7.28-7.37 (m, 2H), 7.39 (d, 1H), 7.42-7.51 (m , 4H),

7.88 (dd, 1H), 8.10-8.16 (m, 1H), 8.40 (d, 1H), 8.81 (d, 1H), 8.96 (d, 1H), 10.73 (s, 1H).

Example 332.

N-[4-(6-Chloro-5-methoxypyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

Hydrochloride

N-(4-bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2 chlorophenyl)acetamide (1:1) (250 mg, 50% purity, 252 µmol) and 2-chloro-3 -methoxy-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)pyridine (81.6 mg, 303 µmol) was dissolved in DMF (7 ml) and potassium fluoride (32.3 mg, 555 µmol). The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (6.45 mg, 12.6 µmol) was added. The solution was again purged with argon for 1 min and then heated at 100° C. for 18 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was co-distilled with THF and used without further purification in the next step (270 mg ).

LC-MS (method B): Rt = 1.12 min; MS (ESI positive): m/z = 521 [M+H]+.

Na[4-(6-Chloro-5-methoxypyridin-3-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2chlorophenyl)acetamide (270 mg, 259 µmol) was dissolved in methanol (2.7 ml) and treated with 32% aqueous sodium hydroxide solution (100 μl, 850 μmol) at 80°C until the reaction is complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (24.2 mg, 95% purity, 2-step yield 19 %).

LC-MS (method B): Rt = 1.02 min; MS (ESI positive): m/z = 466 [M+H]+.

'H-NMR (400 MHz, DMSO-d6): shift [ppm]=3.86-3.91 (m, 5H), 7.28-7.39 (m, 5H), 7.41-7.47 (m, 2H), 7.54 ( d, 1H), 7.86 (dd, 1H), 7.91 (d, 1H), 8.37 (d, 1H), 10.68 (s, 1H).

Example 333.

2-(2-Chloro-6-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

5-Amino-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide (200 mg, 600 µmol) was dissolved in DMF (10 ml) and (2-chloro- 6-fluorophenyl)acetic acid (136 mg, 720 µmol) followed by the addition of Ν,N-diisopropylethylamine (520 µL, 3.0 mmol) and HATU (456 mg, 1.20 mmol). The reaction mixture was heated at 50° C. for 16 hours. After that, the solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (750 mg). 2-(2-Chloro-6-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (302mg, 600µmol ) was dissolved in methanol (5.0 ml) and treated with 25% aqueous ammonia solution (10 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (21.5 mg, 94% purity, yield for 5 stages 8%).

LC-MS (method A): Rt = 1.03 min; MS (ESI negative): m/z = 447 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d6): δ[ppm]=0.91-1.00 (m, 2H), 1.04-1.12 (m, 2H), 3.66-3.79 (m, 1H), 3.92 (d , 2H), 7.13-7.33 (m, 3H), 7.33-7.46 (m, 3H), 7.63-7.71 (m, 1H), 7.74-7.81 (m, 1H), 8.00-8.08 (m, 1H), 8.31 (d, 1H), 10.66 (s, 1H).

Example 334.

2-(2-Chloro-3-fluorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

- 205 040608

5-Amino-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide (200 mg, 793 µmol) was dissolved in DMF (6.6 ml) and (2-chloro-3-fluorophenyl)acetic acid (179 mg) was added , 951 µmol) followed by the addition of X,K-diisopropylethylamine (690 µl, 4.0 mmol) and HATU (482 mg, 1.27 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were then added. The phases were separated and the aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (111 mg, 95% purity, 4 steps yield 32%) .

LC-MS (method B): Rt = 0.90 min; MS (ESI negative): m/z = 421 [M-H]-.

1H-NMR (400 MHz, DMSO-4 ₆ ): δ [ppm]=3.86 (s, 3H), 3.93 (s, 2H), 7.17 (s, 2H), 7.27-7.45 (m, 4H) , 7.647.68 (m, 1H), 7.77-7.83 (m, 1H), 7.94-7.98 (m, 1H), 8.31 (d, 1H), 10.60 (s, 1H).

Example 335.

X-[4-(1-tert-Butyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide nh ₂

O=S=O CH ₃ ci ^H

5-Amino-2-(1-tert-butyl-1H-pyrazol-4-yl)benzenesulfonamide (125 mg, 425 µmol) was dissolved in DMF (3.0 ml) and (2-chlorophenyl)acetic acid (86.9 mg, 510 µmol) followed by the addition of X,X-diisopropylethylamine (370 µl, 2.1 mmol) and HATU (258 mg, 679 µmol). The reaction mixture was stirred for 18 hours at 50°C. Water and dichloromethane were added and the phases were separated. The aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters

XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%), then Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) to give the title compound (5.60 mg, pure 80%, yield over 4 stages 2%).

LC-MS (method B): Rt = 1.07 min; MS (ESI negative): m/z = 445 [M-H]-.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.54 (s, 9H), 3.87 (s, 2H), 7.15 (s, 2H), 7.30-7.39 (m, 2H), 7.397.52 (m, 3H), 7.74 (d, 1H), 7.78-7.86 (m, 1H), 8.10 (d, 1H), 8.31 (d, 1H), 10.56 (s, 1H).

Example 336.

2-(2-Chlorophenyl)-X-{4-[2-(propan-2-yloxy)pyridin-3-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200 mg, 436 µmol) and [2-(propan-2-yloxy)pyridine-3 -yl]boronic acid (78.9 mg, 436 µmol) was dissolved in n-propanol (10 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (15.3 mg, 21.8 µmol) and triphenylphosphine were added (5.72 mg, 21.8 µmol). The mixture was purged with nitrogen for 5 min and aq. potassium carbonate solution (1.3 ml, 1.0 M, 1.3 mmol). The reaction mixture was heated at 100° C. for 1 hour. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was used without further purification in the next step (590 mg).

2-(2-Chlorophenyl)-X-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[2-(propan-2-yloxy)pyridin3-yl]phenyl)acetamide (590 mg, 1.15 mmol) was dissolved in methanol (51 ml) and treated with 25% aqueous ammonia solution (51 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (19.5 mg, 96% purity, yield for 2 stages 4%).

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 458 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.15 (d, 6H), 3.89 (s, 2H), 5.15-5.28 (m, 1H), 6.86-6.99 (m, 1H), 7.12 (s, 2H), 7.19 (d, 1H), 7.29-7.38 (m, 2H), 7.45-7.57 (m, 3H), 7.75-7.85 (m, 1H), 8.07-8.14 (m, 1H), 8.30 (d, 1H), 10.61 (s, 1H).

- 206 040608

Example 337.

2-(2-Chloro-3-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

5-Amino-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide (200 mg, 600 µmol) was dissolved in DMF (10 ml) and (2-chloro- 3-fluorophenyl)acetic acid (136 mg, 720 µmol) followed by the addition of Ν,N-diisopropylethylamine (520 µL, 3.0 mmol) and HATU (456 mg, 1.20 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Ethyl acetate and water were then added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (810 mg).

2-(2-Chloro-3-fluorophenyl)-K-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (302mg, 600µmol ) was dissolved in methanol (5 ml) and treated with 25% aqueous ammonia solution (5 ml) at room temperature for 16 h, then the same amount of ammonia solution was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (19.7 mg, 98% purity, 7% yield over 2 steps).

LC-MS (method B): Rt = 1.06 min; MS (ESI negative): m/z = 502 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.90-1.00 (m, 2H), 1.03-1.14 (m, 2H), 3.68-3.81 (m, 1H), 3.93 ( s, 2Н), 7.20 (s, 2Н), 7.28-7.49 (m, 4Н), 7.67 (s, 1Н), 7.74-7.83 (m, 1Н), 8.03 (s, 1Н), 8.30 (d, 1Н) , 10.61 (s, 1H).

Example 338.

2-(2-Fluorophenyl)-N-[4-(pyridin-3-yl)-3-sulfamoylphenyl]acetamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 2.59 mmol) and pyridin-3ylboronic acid (477 mg, 3.88 mmol) were dissolved in DMF (8.0 ml) followed by the addition of aq. potassium carbonate solution (4.1 ml, 1.0 M, 4.1 mmol). The reaction mixture was purged with argon for 5 min and then bis-(triphenylphosphine)palladium(11) dichloride (CAS 13965-03-2) (273 mg, 388 µmol) was added. The reaction mixture was heated for 1 hour at 120° C. in a microwave oven. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give 390 mg of final product (35% yield).

K-2,4-Dimethoxybenzyl)-5-nitro-2-(pyridin-3-yl)benzenesulfonamide (390 mg, 908 μmol) was dissolved in THF (20 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 966 mg, 908 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 2 hours. After that, the same amount of palladium on charcoal was added and stirring was continued until the reaction was complete. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (490 mg).

5-Amino-N-(2,4-dimethoxybenzyl)-2-(pyridin-3-yl)benzenesulfonamide (245 mg, 613 µmol) was dissolved in DMF (5.0 ml) and (2-fluorophenyl)acetic acid (113 mg , 736 µmol) followed by the addition of Ν,N-diisopropylethylamine (530 µl, 3.1 mmol) and NATO (303 mg, 797 µmol). The reaction mixture was stirred at 50° C. for 16 hours. Ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (490 mg).

K-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(pyridin-3-yl)phenyl}-2-(2-fluorophenyl)acetamide (328 mg, 613 µmol) was dissolved in dichloromethane (2.0 ml) and trifluoroacetic acid (2.0 ml, 26

- 207 040608 mmol), and stirring was continued at room temperature until the reaction was completed. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution. Dichloromethane was added and the phases were separated. The aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (49.2 mg, 97% purity, 21% yield over 4 steps).

LC-MS (method A): Rt = 0.75 min; MS (ESI negative): m/z = 384 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.79 (s, 2H), 7.15-7.22 (m, 2H), 7.28-7.37 (m, 4H), 7.38-7.44 (m, 2H), 7.73-7.80 (m, 1H), 7.82-7.87 (m, 1H), 8.37 (d, 1H), 8.49-8.58 (m, 2H), 10.65 (s, 1H).

Example 339.

2-(2-Chloro-6-fluorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O ι?Χώ~......

5-Amino-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide (200 mg, 793 µmol) was dissolved in DMF (6.6 ml) and (2-chloro-6-fluorophenyl)acetic acid (179 mg) was added , 951 µmol) followed by the addition of N,N-diisopropylethylamine (690 µl, 4.0 mmol) and HATU (482 mg, 1.27 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added and the phases were separated. The aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (67.6 mg, 95% purity, 2 steps yield 19%) .

LC-MS (method B): Rt = 0.89 min; MS (ESI negative): m/z = 421 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.86 (s, 3H), 3.92 (d, 2H), 7.18 (s, 2H), 7.22-7.29 (m, 1H ), 7.337.45 (m, 3Н), 7.62-7.69 (m, 1H), 7.75-7.79 (m, 1Н), 7.94-7.98 (m, 1H), 8.31 (d, 1H), 10.65 (s, 1H ).

Example 340.

2-(2-Chlorophenyl)-N-[3'-fluoro-5'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]acetamide

2-Chloro-5-nitrobenzenesulfonamide (330 mg, 1.39 mmol) and [3-fluoro-5-(2-hydroxypropan-2yl)phenyl]boronic acid (552 mg, 2.79 mmol) were dissolved in n-propanol (130 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (49.1 mg, 69.7 µmol), triphenylphosphine (18.3 mg, 69.7 µmol) and aq. potassium carbonate solution (2.1 ml, 2.0 M, 4.2 mmol). The reaction mixture was purged with argon for 5 min and then heated at 120° C. for 2 h in a microwave oven (4 bar/40 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was co-distilled with THF and used without further purification in the next step (550 mg).

3'-Fluoro-5'-(2-hydroxypropan-2-yl)-4-nitrobiphenyl-2-sulfonamide (330 mg, 931 μmol) was dissolved in THF (93 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 185 mg, 950 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 1 hour. After that, the flask was evacuated three times and purged with hydrogen, and stirring was continued until the reaction was complete. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (350 mg).

4-Amino-3'-fluoro-5'-(2-hydroxypropan-2-yl)biphenyl-2-sulfonamide (175 mg, 539 µmol) was dissolved in DMF (3.8 ml) and (2-chlorophenyl)acetic acid (2-chlorophenyl)acetic acid ( 110 mg, 647 µmol) followed by the addition of N,N-diisopropylethylamine (470 µl, 2.7 mmol) and HATU (328 mg, 863 µmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were then added. The phases were separated and the aqueous phase was washed with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (two times Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) to give the title compound (10.0 mg, 98% purity, 3 step yield 4 %).

LC-MS (method J): Rt = 1.28 min; MS (ESI negative): m/z = 475 [M-H]-.

- 208 040608

1H-NMR (400 MHz, DMSO^ ₆ ): δ [ppm]=1.43 (s, 6H), 3.89 (s, 2H), 5.15 (s, 1H), 6.99-7.08 (m, 1H), 7.127.22 (s, 2H), 7.22-7.40 (m, 5H), 7.42-7.50 (m, 2H), 7.76-7.90 (m, 1H), 8.35 (d, 1H), 10.65 (s, 1H).

Example 341.

2-(2-Chlorophenyl)-N-[4-(5-methoxypyridin-3-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and 3-methoxy-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (192 mg, 817 µmol) was dissolved in n-propanol (10 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 1396503-2) was added ) (19.2 mg, 27.2 µmol) and triphenylphosphine (7.15 mg, 27.2 µmol), and the solution was purged with argon for 5 min. After that, aq. potassium carbonate solution (1.6 ml, 1.0 M, 1.6 mmol) and the reaction mixture was stirred for 2 h at 100°C. The mixture was filtered through celite, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, 5% ethanol in dichloromethane) to give 60 mg of the final product (yield 23%).

LC-MS (method B): Rt = 1.05 min; MS (ESI negative): m/z = 485 [M-H]-.

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(5-methoxypyridin-3yl)phenyl]acetamide (60.0 mg, 123 µmol) was dissolved in methanol (10 ml) and treated with 25% aqueous ammonia solution (10 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (4.2 mg, 90% purity, yield for 2 stages 8%).

LC-MS (method B): Rt = 0.92 min; MS (ESI negative): m/z = 430 [M-H]-.

1H-NMR (400 MHz, CD ₃ OD): δ [ppm]=3.91 (s, 3H), 3.94 (s, 2H), 7.31 (d, 3H), 7.38-7.49 (m, 2H), 7.527.60 (m, 1H), 7.82-7.92 (m, 1H), 8.12-8.35 (m, 2H), 8.41-8.53 (m, 1H).

Example 342.

2-(2-Chlorophenyl)-N-[3'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200mg, 436µmol) and [3-(2-hydroxypropan-2-yl)phenyl ]boronic acid (157 mg, 872 µmol) was dissolved in n-propanol (12 mL) and bis(triphenylphosphine)palladium(11) dichloride (CAS 13965-03-2) (15.3 mg, 21.8 µmol), triphenylphosphine (7.90 mg, 21.8 µmol) and potassium fluoride (50.7 mg, 872 µmol). The solution was purged for 5 min with argon and aq. potassium carbonate solution (650 µl, 2.0 M, 1.3 mmol). The reaction mixture was heated at 80° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (250 mg).

2-(2-Chlorophenyl)-N-[2-{[(dimethylamino)methylidene]sulfamoyl}-3'-(2-hydroxypropan-2yl)biphenyl-4-yl]acetamide (250 mg, 486 µmol) was dissolved in methanol (1.8 ml) and treated with 32% aqueous sodium hydroxide solution (140 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC ((Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) to give the title compound (7.70 mg, 95% purity, 3% yield over step 2).

LC-MS (method B): Rt = 1.02 min; MS (ESI negative): m/z = 457 [M-H]-.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.43 (s, 6H), 3.89 (s, 2H), 5.01 (s, 1H), 6.94 (s, 2H), 7.18- 7.40 (m, 5H), 7.42-7.52 (m, 4H), 7.82 (dd, 1H), 8.34 (d, 1H), 10.62 (s, 1H).

Example 343.

2-(2-Fluorophenyl)-X- {4-[1 -(propan-2-yl)-1 H-pyrazol-4-yl] -3-sulfamoylphenyl} acetamide

- 209 040608

N-4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-fluorophenyl)acetamide (250mg, 565µmol) and 1-(propan-2-yl)-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (267 mg, 1.13 mmol) was dissolved in n-propanol (10 ml) and bis-(triphenylphosphine)palladium dichloride was added (P) (CAS 13965-03-2) (19.9 mg, 28.3 µmol), triphenylphosphine (7.41 mg, 28.3 µmol) and potassium fluoride (7.55 mg, 130 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (710 µl, 2.0 M, 1.4 mmol). The reaction mixture was heated at 120°C for 1 h in a microwave oven (4 bar/25 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (270 mg).

N-(3-{[(Dimethylamino)methylidene]sulfamoyl}-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]phenyl)-2-(2fluorophenyl)acetamide (250mg, 530 µmol) was dissolved in methanol (15 ml) and treated with 32% aqueous sodium hydroxide solution (470 µl) at 80° C. until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (47.5 mg, 95% purity, 20% yield over 2 steps).

LCMS (method A): Rt = 1.00 min; MS (ESI negative): m/z = 415 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.44 (d, 6H), 3.76 (s, 2H), 4.43-4.56 (m, 1H), 7.09-7.24 (m , 4H), 7.27-7.51 (m, 3H), 7.67-7.74 (m, 1H), 7.77-7.85 (m, 1H), 8.02-8.05 (m, 1H), 8.30 (d, 1H), 10.55 (s , 1H).

Example 344.

N-[4-(1-Cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide nh ₂ p O=S=O

5-Amino-2-(1-cyclopropyl-1H-pyrazol-4-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide (200 mg, 600 µmol) was dissolved in DMF (10 ml) and (2-fluorophenyl) was added acetic acid (111 mg, 720 µmol) followed by the addition of N,N-diisopropylethylamine (520 µl, 3.0 mmol) and HATU (456 mg, 1.20 mmol). The reaction mixture was stirred at 50° C. for 16 h, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

N-[4-(1-Cyclopropyl-1H-pyrazol-4-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2-(2fluorophenyl)acetamide (282 mg, 600 µmol) was dissolved in methanol ( 5 ml) and treated with 25% aqueous ammonia solution (5 + 5 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (27.2 mg, 98% purity, yield for 2 stages 11%).

LC-MS (method B): Rt = 0.91 min; MS (ESI negative): m/z = 413 [M-H]-.

¹ H-NMR (400 MHz, DMSOCH): δ [ppm]=0.91-1.01 (m, 2H), 1.04-1.13 (m, 2H), 3.67-3.82 (m, 3H), 7.137.26 ( m, 4H), 7.28-7.37 (m, 1H), 7.37-7.47 (m, 2H), 7.67 (d, 1H), 7.80 (dd, 1H), 7.98-8.07 (m, 1H), 8.30 (d, 1H), 10.55 (s, 1H).

Example 345.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl]phenyl}acetamide

5-Amino-N-[(dimethylamino)methylidene]-2-[1 -(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl]benzenesulfonamide (3.40 g, 9.01 mmol) was dissolved in DMF (63 ml) and added (2

- 210 040608 chlorophenyl)acetic acid (1.84 g, 10.8 mmol) followed by the addition of N,Ndiisopropylethylamine (7.8 ml, 45 mmol) and HATU (5.48 g, 14.4 mmol). The reaction mixture was stirred at 50° C. for 18 hours. The solvent was removed under reduced pressure and dichloromethane and water were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by ammonia-coated silica gel chromatography (10% ethyl acetate gradient in hexanes) to give 2.1 g of the final product (50% purity, 43% yield).

LC-MS (method A): Rt = 1.12 min; MS (ESI negative): m/z = 528 [M-H] ^- .

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(tetrahydro-2H-pyran-2-yl)1H-pyrazol-4-yl]phenyl)acetamide (350 mg, 660 μmol) was dissolved in methanol (15 ml) and treated with 32% aqueous sodium hydroxide solution (190 μl) at 80°C until the reaction was complete. Added aq. HCl solution (100 μl, 6.0 M), adjusting the pH to 7. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (31 mg, 80% purity, 8% yield over 3 steps) . LC-MS (method B): Rt = 1.02 min; MS (ESI negative): m/z = 473 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.45-1.61 (m, 2H), 1.61-1.74 (m, 1H), 1.88-2.01 (m, 2H), 2.022 .17 (m, 1H), 3.60-3.71 (m, 1H), 3.81-3.98 (m, 3H), 5.42 (dd, 1H), 7.24 (s, 2H), 7.30-7.36 (m, 2H), 7.42 -7.48 (m, 3H), 7.77 (s, 1H), 7.81 (dd, 1H), 8.14 (s, 1H), 8.32 (d, 1H), 10.59 (s, 1H).

Example 346.

N-[4-(1-tert-Butyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

5-Amino-2-(1-tert-butyl-1H-nirazol-4-yl)benzenesulfonamide (125 mg, 425 µmol) was dissolved in DMF (3.5 ml) and (2-fluorophenyl)acetic acid (78.5 mg, 510 µmol) followed by the addition of N,N-diisopropylethylamine (370 µl, 2.1 mmol) and HATU (258 mg, 679 µmol). The reaction mixture was stirred at 50° C. for 18 h and water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) to give the indicated in the title compound (12.8 mg, 96% purity, 7% yield over step 2).

LC-MS (method B): Rt = 1.03 min; MS (ESI negative): m/z = 429 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.54 (s, 9H), 3.77 (s, 2H), 7.11-7.22 (m, 4H), 7.29-7.37 (m, 1H), 7.37-7.43 (m, 1H), 7.46 (d, 1H), 7.74 (s, 1H), 7.78-7.85 (m, 1H), 8.10 (s, 1H), 8.31 (d, 1H), 10.55 (s, 1H).

Example 347.

N-[3'-Fluoro-5'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]-2-(2-fluorophenyl)acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-fluorophenyl)acetamide (500 mg, 1.13 mmol) and [3-(ethoxycarbonyl)-5-fluorophenyl]boronic acid (479 mg, 2.26 mmol) was dissolved in n-propanol (21 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (39.8 mg, 56.5 µmol), triphenylphosphine (14.8 mg, 56.5 µmol) was added and potassium fluoride (15.1 mg, 260 µmol). The solution was purged with argon and aq. potassium carbonate solution (1.4 ml, 2.0 M, 2.8 mmol). The reaction mixture was heated at 100° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give 220 mg of the final product (yield 37%). LC-MS (method B): Rt = 1.28 min; MS (ESI negative): m/z = 528 [M-H]-.

Ethyl 2'-{[(dimethylamino)methylidene]sulfamoyl}-5-fluoro-4'-{[(2-fluorophenyl)acetyl]amino}biphenyl-3-carboxylate (220 mg, 415 µmol) was dissolved in dry THF (7.6 ml), a solution of methylmagnesium bromide in THF (12 ml, 1.0 M, 12 mmol) was added and stirring was continued for 18 h at room temperature. Ethyl acetate was then added followed by saturated aqueous

- 211 040608 ammonium chloride solution. The precipitate was filtered off, the phases were separated and the organic phase was concentrated under reduced pressure. The crude product was used without further purification in the next step (430 mg).

N[2-{[(Dimethylamino)methylidene]sulfamoyl}-3'-fluoro-5'-(2-hydroxypropan-2-yl)biphenyl-4-yl]2-(2-fluorophenyl)acetamide (250mg, 485 µmol) was dissolved in methanol (1.8 ml) and treated with 32% aqueous sodium hydroxide solution (430 µl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (50.2 mg, 95% purity, 2-step yield 21 %).

LC-MS (method B): Rt = 1.01 min; MS (ESI negative): m/z = 459 [M-H]-.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm]=1.43 (s, 6H), 3.79 (s, 2H), 5.15 (s, 1H), 6.98-7.10 (m, 1H) , 7.157.37 (m, 8H), 7.38-7.45 (m, 1H), 7.76-7.86 (m, 1H), 8.35 (d, 1H), 10.63 (s, 1H).

Example 348.

N-[4-(1-Cyclopentyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

5-Amino-2-(1-cyclonentyl-1H-pyrazol-4-yl)benzenesulfonamide (290 mg, 947 µmol) was dissolved in DMF (7.8 ml) and (2-fluorophenyl)acetic acid (175 mg, 1.14 mmol) was added followed by the addition of Ν,N-diisopropylethylamine (820 µl, 4.7 mmol) and HATU (576 mg, 1.51 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was dissolved in methanol (2 ml) and treated with 32% aqueous sodium hydroxide solution (210 μl) at 80° C. for 2 h. aq. HCl. Thereafter, the solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) to give the title compound (37.1 mg, 95% purity, 8% yield over 3 steps) .

LC-MS (method J): Rt = 1.26 min; MS (ESI negative): m/z = 441 [M-H]-.

Ή-NMR (400 MHz, DMSOCH): δ [ppm]=1.57-1.73 (m, 2H), 1.73-1.89 (m, 2H), 1.89-2.03 (m, 2H), 2.032.15 (m , 2H), 3.76 (s, 2H), 4.63-4.79 (m, 1H), 7.13-7.25 (m, 4H), 7.28-7.49 (m, 3H), 7.71 (d, 1H), 7.76-7.85 (m , 1H), 8.03 (d, 1H), 8.30 (d, 1H), 10.55 (s, 1H).

Example 349.

2-(2-Chlorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (500 mg, 1.09 mmol), 1-cyclopropyl-4-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-n-pyrazole (510 mg, 2.18 mmol) and potassium fluoride (139 mg, 2.4 mmol) were dissolved in dry and degassed DMF (30 ml) and the solution again purged with argon for 5 min followed by the addition of bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-31-8) (28 mg, 54 µmol). The reaction mixture was heated for 2 h at 100°C. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step.

2-(2-Chlorophenyl)-N-[4-(1-cyclopropyl-1H-πyrazol-4-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (560 mg, 1.15 mmol) was dissolved in methanol (54 ml) and treated with 32% aqueous sodium hydroxide solution (560 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure and purified by silica gel chromatography (Biotage, ethyl acetate/hexane) and then by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title in the title compound (192 mg, 95% purity, 37% yield over step 2).

LC-MS (method B): Rt = 0.96 min; MS (ESI negative): m/z = 429 [M-H]-.

- 212 040608 ¹ H-NMR (400 MHz, DMSOD): δ [ppm]=0.94-1.01 (m, 2H), 1.05-1.10 (m, 2H), 3.67-3.80 (m, 1H), 3.88 (s, 2H), 7.19 (s, 2H), 7.30-7.35 (m, 2H), 7.40-7.48 (m, 3H), 7.67 (d, 1H), 7.81 (dd, 1H), 8.04 (s, 1H ), 8.31 (d, 1H), 10.57 (s, 1H).

Example 350.

2-(2-Chloro-6-fluorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

5-Amino-2-[1-(2-methoxyethyl)-III-pyrazol-4-yl]benzenesulfonamide (190 mg, 641 μmol) was dissolved in DMF (5.3 ml) and (2-chloro-6-fluorophenyl)acetic acid (145 mg, 769 µmol) followed by the addition of Ν,N-diisopropylethylamine (560 µl, 3.2 mmol) and HATU (390 mg, 1.03 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) to give the indicated in the title compound (53.8 mg, 99% purity, 18% yield over 3 steps).

LC-MS (method I): Rt = 1.17 min; MS (ESI negative): m/z = 465 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.24 (s, 3H), 3.70 (t, 2H), 3.92 (d, 2H), 4.28 (t, 2H), 7.10 (s, 2H), 7.22-7.32 (m, 1H), 7.32-7.50 (m, 3H), 7.69-7.72 (m, 1H), 7.78 (dd, 1H), 8.00-8.02 (m, 1H), 8.32 (d, 1H), 10.66 (s, 1H).

Example 351.

2-(2-Chlorophenyl)-N-[4-(1,3-dimethyl-1H-pyrazol-5-yl)-3-sulfamoylphenyl]acetamide

5-Amino-2-(1,3-dimethyl-1H-pyrazol-5-yl)benzenesulfonamide (200 mg, 751 µmol) was dissolved in DMF (5.3 ml) and (2-chlorophenyl)acetic acid (154 mg, 901 µmol) followed by the addition of Ν,N-diisopropylethylamine (620 µl, 3.8 mmol) and HATU (457 mg, 1.20 mmol). The reaction mixture was stirred at 50° C. for 5 hours. Water and dichloromethane were added and the phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel coated with ammonia (Biotage, hexane/ethyl acetate) and then subjected to HPLC purification (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the indicated in title compound (12.6 mg, 95% purity, 4% yield over step 3).

LC-MS (method B): Rt = 0.87 min; MS (ESI negative): m/z = 417 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=2.16 (s, 3H), 3.41 (s, 3H), 3.89 (s, 2H), 6.07 (s, 1H), 7.08 (s, 2H), 7.26-7.39 (m, 3H), 7.41-7.51 (m, 2H), 7.86 (dd, 1H), 8.36 (d, 1H), 10.72 (s, 1H).

Example 352.

2-(2-Chlorophenyl)-N-(4'-chloro-2-sulfamoylbiphenyl-4-yl)acetamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (400 mg, 1.03 mmol) and (4-chlorophenyl)boronic acid (243 mg, 1.55 mmol) were dissolved in DMF (50 ml) followed by the addition of bis-dichloride (triphenylphosphine)palladium(11) (CAS 13965-03-2) (109 mg, 155 µmol) and aq. potassium carbonate solution (2.5 ml, 1.0 M, 2.5 mmol). The reaction mixture was heated for 1 h at 120° C. in a microwave oven (2 bar, 50 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give 467 mg of final product (82% purity, 97% yield).

LC-MS (method B): Rt = 1.39 min; MS (ESI negative): m/z = 461 [M-H]-.

4'-Chloro-N-(2,4-dimethoxybenzyl)-4-nitrobiphenyl-2-sulfonamide (467 mg, 1.01 mmol) was dissolved in dioxane (4.8 ml) and tin(II) chloride dihydrate (1.14 g, 5.04 mmol) was added ). The reaction mixture

- 213 040608 was stirred for 2 hours at 70°C. The mixture was then filtered through silica gel, the solvent was removed under reduced pressure and the crude product was suspended in dichloromethane and filtered again. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (230 mg).

4-Amino-4'-chloro-N-(2,4-dimethoxybenzyl)biphenyl-2-sulfonamide (110 mg, 254 µmol) was dissolved in DMF (1.8 ml) and (2-chlorophenyl)acetic acid (52.0 mg, 305 µmol) followed by the addition of K,X-diisopropylethylamine (210 µl, 1.3 mmol) and HATU (155 mg, 407 µmol). The reaction mixture was stirred at 50° C. for 4 hours and water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (150 mg).

K-{4'-Chloro-2-[(2,4-dimethoxybenzyl)sulfamoyl]biphenyl-4-yl}-2-(2-chlorophenyl)acetamide (150 mg, 256 µmol) was dissolved in dichloromethane (1.5 ml) and trifluoroacetic acid (990 μl, 13 mmol) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was co-distilled with toluene. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (29.8 mg, 95% purity, 25% yield over 3 steps) .

LC-MS (method B): Rt = 1.20 min; MS (ESI negative): m/z = 432 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.89 (s, 2H), 7.17-7.27 (m, 3H), 7.30-7.39 (m, 4H), 7.40-7.48 (m, 4H), 7.82 (dd, 1H), 8.35 (d, 1H), 10.63 (s, 1H).

Example 353.

2-(2-Chlorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-sulfamoylphenyl}acetamide

5-Amino-2-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]benzenesulfonamide (300 mg, 937 µmol) was dissolved in DMF (6.6 ml) and (2-chlorophenyl)acetic acid ( 192 mg, 1.12 mmol) followed by the addition of X,K-diisopropylethylamine (820 μl, 4.7 mmol) and HATU (570 mg, 1.50 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%), then acetonitrile/water + 0.1% formic acid) to give the title compound (28.2 mg, pure 99%, yield over 3 stages 6%).

LC-MS (method A): Rt = 1.14 min; MS (ESI negative): m/z = 471 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.59 (s, 3H), 3.91 (s, 2H), 6.72 (s, 1H), 7.31-7.35 (m, 2H ), 7.387.48 (m, 5H), 7.85-7.93 (m, 1H), 8.40 (d, 1H), 10.79 (s, 1H).

Example 354.

2-(2-Chlorophenyl)-X-[4-(pyridin-3-yl)-3-sulfamoylphenyl]acetamide

K-{4-bromo-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2-chlorophenyl)acetamide (250 mg, 451 µmol) and pyridin-3-ylboronic acid (83.2 mg, 677 µmol ) was dissolved in DMF (10 ml) followed by the addition of aq. potassium carbonate solution (1.1 ml, 1.0 M, 1.1 mmol). The solution was purged with argon for 5 min, and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (47.7 mg, 67.7 µmol) was added. The reaction mixture was heated for 30 min at 120° C. in a microwave oven. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (740 mg).

2-(2-Chlorophenyl)-K-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(pyridin-3-yl)phenyl}acetamide (347 mg, 628 µmol) was dissolved in dichloromethane (5.0 ml) and trifluoroacetic acid (5.0 ml, 65 mmol) was added. Stirring was continued at room temperature until completion of the reaction. Solvent

- 214 040608 was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (49.6 mg, 95% purity, 2-step yield 19 %).

LC-MS (method B): Rt = 0.85 min; MS (ESI negative): m/z = 400 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.90 (s, 2H), 7.27-7.36 (m, 5H), 7.38-7.42 (m, 1H), 7.44-7.46 (m, 2H), 7.73-7.81 (m, 1H), 7.81-7.89 (m, 1H), 8.38 (d, 1H), 8.49-8.59 (m, 2H), 10.66 (s, 1H).

Example 355.

2-(2-Chlorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (200mg, 436µmol) and [1-methyl-3-(trifluoromethyl)-1H- pyrazol-4-yl]boronic acid (169 mg, 872 µmol) was dissolved in n-propanol (8.0 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (15.3 mg, 21.8 µmol) was added ) and triphenylphosphine (5.72 mg, 21.8 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (540 µl, 2.0 M, 1.1 mmol). The reaction mixture was heated at 80° C. for 2 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (250 mg).

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-methyl-3-(trifluoromethyl)-1Hpyrazol-4-yl]phenyl)acetamide (250mg, 474 µmol) was dissolved in methanol (4.9 ml) and treated with 32% aqueous sodium hydroxide solution (130 µl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (3.60 mg, 98% purity, 2-step yield 2%) .

LC-MS (method B): Rt = 1.20 min; MS (ESI negative): m/z = 471 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 3.93 (s, 3H), 7.14-7.29 (m, 3H), 7.29-7.39 (m, 2H), 7.41-7.53 (m, 2H), 7.80 (dd, 1H), 7.84-7.89 (m, 1H), 8.32 (d, 1H), 10.65 (s, 1H).

Example 356.

2-(2-Chlorophenyl)-N-(3'-chloro-2-sulfamoylbiphenyl-4-yl)acetamide

2-Chloro-N-(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide (400 mg, 1.03 mmol) and (3chlorophenyl)boronic acid (243 mg, 1.55 mmol) were dissolved in DMF (20 ml) followed by the addition of bis-dichloride (triphenylphosphine)palladium(II) (CAS 13965-03-2) (109 mg, 155 µmol) and aq. potassium carbonate solution (2.5 ml, 1.0 M, 2.5 mmol). The reaction mixture was heated for 1 h at 120° C. in a microwave oven (2 bar, 50 W). Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography (Biotage, ethyl acetate/hexane) to give 702 mg of product.

LC-MS (method A): Rt = 1.39 min; MS (ESI negative): m/z = 461 [M-H]-.

3'-Chloro-N-(2,4-dimethoxybenzyl)-4-nitrobiphenyl-2-sulfonamide (470 mg, 1.02 mmol) was dissolved in dioxane (4.9 ml) and tin(II) chloride dihydrate (1.15 g, 5.08 mmol) was added ). The reaction mixture was stirred for 2 hours at 70°C. The mixture was then filtered through silica gel, the solvent was removed under reduced pressure and the crude product was suspended in dichloromethane and filtered again. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (652 mg).

4-Amino-3'-chloro-X-(2,4-dimethoxybenzyl)biphenyl-2-sulfonamide (200 mg, 60% purity, 277 µmol) was dissolved in DMF (2.0 ml) and (2-chlorophenyl)acetic acid was added (56.7 mg, 333 µmol) followed by the addition of N,N-diisopropylethylamine (230 µl, 1.4 mmol) and HATU (169 mg, 443 µmol). The reaction mixture was stirred at 50° C. for 4 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried

- 215 040608 on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (170 mg).

N-{3'-Chloro-2-[(2,4-dimethoxybenzyl)sulfamoyl]buphenyl-4-yl}-2-(2-chlorophenyl)acetamide (170 mg, 290 µmol) was dissolved in dichloromethane (1.5 ml) and trifluoroacetic acid (1.1 ml) was added and stirring was continued at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was co-distilled with toluene. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (22.6 mg, 95% purity, 4 steps yield 17%) .

LC-MS (method B): Rt = 1.15 min; MS (ESI negative): m/z = 433 [M-H]-.

1H-NMR (400 MHz, DMSO-06): δ[ppm]=3.90 (s, 2H), 7.22-7.29 (m, 3H), 7.31-7.35 (m, 3H), 7.38-7.42 (m , 3Н), 7.43-7.48 (m, 2H), 7.82 (dd, 1H), 8.35 (d, 1H), 10.65 (s, 1H).

Example 357.

2-(2-Chlorophenyl)-N-(4-{1-[(2,2-dichlorocyclopropyl)methyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(1H-pyrazol-4yl)phenyl]acetamide (200 mg, 448 µmol) was dissolved in DMF (3 ml) and cesium carbonate (292 mg, 897 µmol), potassium iodide (74.5 mg, 448 µmol) and 2-(bromomethyl)-1,1-dichlorocyclopropane (101 mg, 493 µmol) were added. The reaction mixture was stirred for 18 hours at 100°C. Added the same amount of reagents and stirring was continued for 24 h at 100°C. Then water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(2-Chlorophenyl)-N-(4-{1-[(2,2-dichlorocyclonpropyl)methyl]-1H-pyrazol-4-yl}-3{[(dimethylamino)methylidene]sulfamoyl}phenyl)acetamide ( 302 mg, 531 µmol) was dissolved in methanol (4.4 ml) and treated with 25% aqueous ammonia solution (4.4 ml) at room temperature. After 16 hours, 32% aqueous sodium hydroxide solution (200 μl) was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (6.80 mg, 95% purity, 3 steps yield 2%) .

LC-MS (method B): Rt = 1.11 min; MS (ESI negative): m/z = 511 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.57-1.71 (m, 1H), 1.81-1.90 (m, 1H), 2.26-2.35 (m, 1H), 3.87 (s, 2H), 4.33 (m, 2H), 7.14 (s, 2H), 7.27-7.40 (m, 2H), 7.40-7.53 (m, 3H), 7.76 (s, 1H), 7.80-7.86 (m , 1H), 8.11 (s, 1H), 8.30–8.39 (m, 1H), 10.59 (s, 1H).

Example 358.

2-(2-Chlorophenyl)-N-[4-(1,3-dimethyl-1H-n-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

5-Amino-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzenesulfonamide (250 mg, 939 µmol) was dissolved in DMF (6.6 ml) and (2-chlorophenyl)acetic acid (192 mg, 1.13 mmol) followed by the addition of N,N-diisopropylethylamine (820 µl, 4.7 mmol) and HATU (571 mg, 1.50 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 ml) and 32% aqueous sodium hydroxide solution (210 μl) was added. The reaction mixture was stirred at 80° C. for 2 hours. After that, the reaction mixture was neutralized with 6 N. HCl and water and dichloromethane were added. The phases were separated, the organic phase was dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Chromatorex C-18 10 µm, 125x30 mm, aceto

- 216 040608 nitrile/water + 0.2% aqueous ammonia (32%)) to give the final compound (19.6 mg, 90% purity, 4% yield over 3 steps).

LC-MS (method B): Rt = 0.94 min; MS (ESI negative): m/z = 417 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.99 (s, 3H), 3.77 (s, 3H), 3.87 (s, 2H), 6.91 (s, 2H), 7.23(d,

1H), 7.27-7.38 (m, 2H), 7.38-7.52 (m, 2H), 7.59 (s, 1H), 7.77-7.88 (m, 1H), 8.30 (d, 1H), 10.58 (s, 1H) .

Example 359.

2-(2-Chlorophenyl)-N-{4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

2-Chloro-5-nitrobenzenesulfonamide (500 mg, 2.11 mmol) and 1-(propan-2-yl)-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H -pyrazole (998 mg, 4.23 mmol) was dissolved in n-propanol (28 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (74.4 mg, 106 µmol), triphenylphosphine (27.7 mg , 106 µmol) and aq. potassium carbonate solution (3.2 ml, 2.0 M, 6.3 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated for 1 h at 120° C. in a microwave oven (4 bar/40 W). The mixture was then filtered through Celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with methanol and used without further purification in the next step (700 mg).

5-Nitro-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzenesulfonamide (700 mg, 2.26 mmol) was dissolved in THF (230 ml) and methanol (50 ml) and the flask was filled with nitrogen . Palladium on charcoal (load 10%, 245 mg, 2.30 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 16 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (600 mg).

5-Amino-2-[1-(propan-2-yl)-1H-pyrazol-4-yl]benzenesulfonamide (300 mg, 1.07 mmol) was dissolved in DMF (7.5 ml) and (2-chlorophenyl)acetic acid was added ( 219 mg, 1.28 mmol) followed by addition of Ν,Ν-diisopropylethylamine (880 μl, 5.4 mmol) and HATU (651 mg, 1.71 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) to give the title compound (66.6 mg, 95% purity, 14% yield over 3 steps).

LC-MS (method I): Rt = 1.27 min; MS (ESI negative): m/z = 431 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.45 (d, 6H), 3.88 (s, 2H), 4.45-4.58 (m, 1H), 7.16 (s, 2H ), 7.277.40 (m, 2H), 7.41-7.49 (m, 3H), 7.72 (s, 1H), 7.78-7.89 (m, 1H), 8.04 (s, 1H), 8.32 (d, 1H), 10.57(s, 1H).

Example 360.

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

K-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (900 mg, 1.96 mmol) and 1-methyl-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-πirazole (490 mg, 2.35 mmol) was dissolved in DMF (25 mL) followed by the addition of potassium fluoride (251 mg, 4.32 mmol). The solution was purged with argon for 5 min, and bis-(tri-tert-butylphosphine)palladium(0) (CAS 53199-318) (50.1 mg, 98.1 µmol) was added. The reaction mixture was heated for 1 h at 100°C. The mixture was filtered through a glass fiber filter and the solvent was removed under reduced pressure. The crude product was once more subjected to the reaction procedure described above. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (2.39 g).

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(1-methyl-1H-pyrazol-4yl)phenyl]acetamide (2.39 g, 5.20 mmol) was dissolved in methanol (80 ml) and treated with 25% aqueous ammonia solution (80 ml) at room temperature. UHPLC indicated that the reaction was not complete, so 25% aqueous ammonia (80 ml) was added again and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified with

- 217 040608 silica gel chromatography (Biotage, 10% ethanol in dichloromethane) followed by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (327 mg , purity 98%, yield 2 stages 15%).

LC-MS (method B): Rt = 0.86 min; MS (ESI negative): m/z = 403 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.78-3.96 (m, 5H), 7.17 (s, 2H), 7.28-7.37 (m, 2H), 7.38-7.52 (m, 3H), 7.66 (d, 1H), 7.82 (dd, 1H), 7.96 (s, 1H), 8.32 (d, 1H), 10.57 (s, 1H).

Example 361.

2-(2-Chlorophenyl)-N-{4-[1-(2-hydroxy-3,3-dimethylbutyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide n ₃ s ch ₃ nh ₂ h ₃ s ~v

O=S=O ^OH ci ^H

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-( 1H-pyrazol-4yl)phenyl]acetamide (250 mg, 561 µmol) was dissolved in DMF (10 ml) and 2-tert-butyloxirane (1.68 g, 16.8 mmol) and cesium carbonate (365 mg, 1.12 mmol) were added. The reaction mixture was heated at 130°C for 30 min in a microwave oven. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (306 mg).

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-{1-[2-hydroxy-3,3dimethylbutyl]-1H-pyrazol-4-yl}phenyl)acetamide ( 306 mg, 560 μmol) was dissolved in methanol (5.8 ml) and treated with 32% aqueous sodium hydroxide solution (480 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (8.80 mg, 95% purity, 3% yield over 2 steps) .

LC-MS (method B): Rt = 1.28 min; MS (ESI negative): m/z = 489 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=0.93 (s, 9H), 3.37-3.51 (m, 1H), 3.85-3.93 (m, 3H), 4.26 (dd , 1H), 4.91 (d, 1H), 6.99 (s, 2H), 7.29-7.36 (m, 2H), 7.41-7.49 (m, 3H), 7.70 (s, 1H), 7.84 (dd, 1H), 8.02 (s, 1H), 8.31 (d, 1H), 10.58 (s, 1H).

Example 362.

2-(2-Fluorophenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-fluorophenyl)acetamide (750 mg, 1.70 mmol) and (5-fluoropyridin-3-yl)boronic acid (478 mg, 3.39 mmol) was dissolved in n-propanol (15 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (59.7 mg, 84.8 μmol) and triphenylphosphine (22.2 mg, 84.8 μmol) were added . The solution was purged with argon for 5 min and aq. potassium carbonate solution (2.1 ml, 2.0 M, 4.2 mmol). The reaction mixture was heated at 100° C. for 1 hour. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (970 mg).

N-[3-{[(Dimethylamino)methylidene]sulfamoyl}-4-(5-fluoropyridin-3-yl)phenyl]-2-(2fluorophenyl)acetamide (970 mg, 2.12 mmol) was dissolved in methanol (50 ml) and treated with 25% aqueous ammonia (50 ml) at room temperature for 4 hours. UHPLC indicated that the reaction was not complete, so 25% aqueous ammonia (50 ml) was added again. Stirring was continued at room temperature until completion of the reaction. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (126 mg, 99% pure , output for 2 stages 15%).

LC-MS (method B): Rt = 0.83 min; MS (ESI negative): m/z = 402 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.80 (s, 2H), 7.14-7.24 (m, 2H), 7.30-7.47 (m, 5H), 7.68-7.75 ( m, 1H), 7.87 (dd, 1H), 8.33-8.44 (m, 2H), 8.57 (d, 1H), 10.69 (s, 1H).

- 218 040608

Example 363.

2-(2-Chlorophenyl)-N-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (170 mg, 583 µmol) and 5-methyl1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-pyrazole (248 mg, 874 µmol) was dissolved in n-propanol (7.8 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (20.5 mg, 29.1 µmol), triphenylphosphine (7.64 mg, 29.1 µmol) and aq. potassium carbonate solution (730 µl, 2.0 M, 1.5 mmol). The reaction mixture was heated at 80° C. for 16 hours. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step (210 mg).

The protecting group was partially removed under the reaction conditions. The mixture was subjected to the following steps.

2-(5-Methyl-1-phenyl-1H-pyrazol-4-yl)-5-nitrobenzenesulfonamide (210 mg, 586 μmol) was dissolved in methanol (30 ml) and THF (59 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 63.6 mg, 598 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 16 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (190 mg).

5-Amino-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)benzenesulfonamide (190 mg, 579 µmol) was dissolved in DMF (4.1 ml) and (2-chlorophenyl)acetic acid (118 mg) was added , 694 µmol) followed by the addition of N,N-diisopropylethylamine (500 µl, 2.9 mmol) and HATU (352 mg, 926 µmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was dissolved in methanol (5 ml) and treated with 32% aqueous sodium hydroxide solution (130 μl) at 45° C. until completely deprotected. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the indicated in the title compound (10.0 mg, 95% purity, 3% yield over 3 steps).

LC-MS (method A): Rt = 1.35 min; MS (ESI negative): m/z = 479 [M-H]-.

¹ I-NMR (400 MHz, DMSO-d6): δ [ppm]=2.16 (s, 3H), 3.89 (s, 2H), 7.05 (s, 2H), 7.27-7.37 (m, 3H) , 7.407.49 (m, 3H), 7.51-7.62 (m, 4H), 7.65 (s, 1H), 7.84-7.93 (m, 1H), 8.35 (d, 1H), 10.63 (s, 1H).

Example 364.

4'-{[(2-Chlorophenyl)acetyl]amino}-N-[2-(dimethylamino)ethyl]-2'-sulfamoylbiphenyl-3carboxamide

CH ₃

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300mg, 654µmol) and N-[2-(dimethylamino)ethyl]-3- (4,4,5,5-Tetramethyl-1,3,2-dioxαborolan-2-yl)benzamide (229 mg, 719 µmol) was dissolved in n-propanol (13 mL) and bis(triphenylphosphine)palladium(P) dichloride was added ) (CAS 13965-03-2) (23.0 mg, 32.7 µmol) and triphenylphosphine (8.58 mg, 32.7 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (2.0 ml, 1.0 M, 2.0 mmol). The reaction mixture was heated at 100° C. for 2 hours. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and the crude product was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (350 mg).

4'-{[(2-Chlorophenyl)acetyl]amino}-N-[2-(dimethylamino)ethyl]-2'{[(dimethylamino)methylidene]sulfamoyl}biphenyl-3-carboxamide (350 mg, 614 µmol) was dissolved in methanol (40 ml) and treated with 25% aqueous ammonia solution (40 ml) at room temperature until

- 219 040608 completion of the reaction. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (19.5 mg, 96% purity , yield over stage 2 6%).

LC-MS (method B): Rt = 0.95 min; MS (ESI negative): m/z = 513 [M-H] ^- .

¹ H-NMR (600 MHz, DMSO-d ₆ ): δ [ppm]=2.20 (s, 6H), 2.44 (t, 2H), 3.34-3.40 (m, 2H), 3.90 (s, 2H ), 7.17 (s, 2H), 7.28 (d, 1H), 7.30-7.36 (m, 2H), 7.42-7.49 (m, 3H), 7.51-7.58 (m, 1H), 7.76-7.86 (m, 3H ), 8.16 (s, 1H), 8.31–8.44 (m, 2H), 10.63 (s, 1H).

Example 365.

2-(2-Chlorophenyl)-N-[4-(pyrazolo[1,5-a]pyrimidin-3-yl)-3-sulfamoylphenyl]acetamide nh ₂

2-Bromo-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (229 mg, 680 µmol) and 3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[ 1,5-a]pyrimidine (250 mg, 1.02 mmol) was dissolved in n-propanol (9.1 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (23.9 mg, 34.0 µmol) was added , triphenylphosphine (8.92 mg, 34.0 µmol) and aq. potassium carbonate solution (850 μl, 2.0 M, 1.7 mmol). The solution was purged with argon for 5 minutes and the reaction mixture was heated at 80° C. for 4 hours. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was partitioned between dichloromethane and water. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used in the next step without further purification (260 mg).

N-[(Dimethylamino)methylidene]-5-nitro-2-(pyrazolo[1,5-a]n-yrimidin-3-yl)benzenesulfonamide (260 mg, 694 µmol) was dissolved in methanol (30 ml) and THF (70 ml ) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 75.4 mg, 708 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 16 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

5-Amino-N-[(dimethylamino)methylidene]-2-(pyrazolo[1,5-a]pyrimidin-3-yl)benzenesulfonamide (330 mg, 958 µmol) was dissolved in DMF (6.7 ml) and (2- chlorophenyl)acetic acid (196 mg, 1.15 mmol) followed by the addition of N,N-diisopropylethylamine (830 µl, 4.8 mmol) and HATU (583 mg, 1.53 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (480 mg).

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(πyrazolo[1,5-a]pyrimidin-3yl)phenyl]acetamide (450 mg, 905 µmol) was dissolved in methanol (10 ml) and treated with 32% aqueous sodium hydroxide solution (100 μl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (9.60 mg, 95% purity, 4 steps yield 2%) .

LC-MS (method B): Rt = 0.90 min; MS (ESI negative): m/z = 440 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.90 (s, 2H), 7.05-7.13 (m, 1H), 7.23 (s, 2H), 7.29-7.38 (m, 2H), 7.43-7.50 (m, 2H), 7.57 (d, 1H), 7.83-7.91 (m, 1H), 8.40 (d, 1H), 8.44 (s, 1H), 8.51-8.61 (m, 1H) , 9.11-9.21 (m, 1H), 10.64 (s, 1H).

Example 366.

2-(2-Chlorophenyl)-N-{4-[5-(n-irrolidin-1-ylcarbonyl)pyridin-3-yl]-3-sulfamoylphenyl}acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (250 mg, 545 µmol) and pyrrolidin-1-yl-[5-(4.4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl]methanone (165 mg, 545 µmol) was dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(P) dichloride was added ) (CAS 13965-03-2) (19.2 mg, 27.2 µmol) and triphenylphosphine (7.15 mg, 27.2

- 220 040608 µmol). The solution was purged with argon for 5 min and aq. potassium carbonate solution (1.6 ml, 1.0 M, 1.6 mmol). The reaction mixture was heated at 100° C. for 1 hour. Thereafter, the mixture was filtered through celite, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was washed with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification (280 mg).

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[5-(pyrrolidin-1ylcarbonyl)pyridin-3-yl]phenyl)acetamide (280 mg, 505 µmol) was dissolved in methanol (25 ml) and treated with 25% aqueous ammonia solution (25 ml) at room temperature until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (67.3 mg, 97% purity , yield over stage 2 26%).

LC-MS (method B): Rt = 0.89 min; MS (ESI negative): m/z = 497 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.73-1.99 (m, 4H), 3.43-3.52 (m, 4H), 3.91 (s, 2H), 7.29-7.37 ( m, 3H), 7.38-7.43 (m, 2H), 7.43-7.49 (m, 2H), 7.82-7.89 (m, 2H), 8.40 (d, 1H), 8.58 (d, 1H), 8.68 (d, 1H), 10.71(s, 1H).

Example 367.

2-(2-Chlorophenyl)-N-[4-(1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl]phenyl}acetamide (197 mg, 414 µmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (950 μl, 12 mmol) was added and stirring was continued at room temperature until the reaction was complete. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (30.9 mg, 95% purity, 18% yield).

LC-MS (method A): Rt = 0.89 min; MS (ESI negative): m/z = 389 [M-H]-.

1I-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 7.15 (s, 2H), 7.29-7.37 (m, 2H), 7.42-7.48 (m, 3H ), 7.70-7.91 (m, 2H), 7.91-8.11 (m, 1H), 8.33 (d, 1H), 10.57 (s, 1H), 12.92 (s, 1H).

Example 368.

2-(2-Fluorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-sulfamoylphenyl}acetamide

2-Chloro-N-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (550 mg, 1.89 mmol) and 1-methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-3-(trifluoromethyl)-1H-pyrazole (1.04 g, 3.77 mmol) was dissolved in n-propanol (25 ml) and bis-(triphenylphosphine)palladium(11) dichloride (CAS 13965-032) (66.4 mg, 94.3 µmol), triphenylphosphine (24.7 mg, 94.3 µmol) and aq. potassium carbonate solution (2.4 ml, 2.0 M, 4.7 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 80°C for 16 h. The mixture was then filtered through celite, the solvent was removed under reduced pressure and the crude product was co-distilled with THF and used without further purification in the next step (660 mg ).

2-[1-Methyl-3-(trifluoromethyl)-1N-pyrazol-5-yl]-5-nitrobenzenesulfonamide (660 mg, 1.88 mmol) was dissolved in methanol (30 ml) and THF (30 ml) and the flask was filled with nitrogen. Platinum on charcoal (load 5%, 375 mg, 1.92 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (600 mg). Under the reaction conditions, a partial deprotection was observed, respectively, the mixture was transferred to the next stages.

5-Amino-2-[1-methyl-3-(trifluoromethyl)-1N-pyrazol-5-yl]benzenesulfonamide (300 mg, 937 µmol) was dissolved in DMF (7.8 ml) and (2-fluorophenyl)acetic acid ( 173 mg, 1.12 mmol) followed by addition of Ν,Ν-diisopropylethylamine (820 μl, 4.7 mmol) and IATi (570 mg, 1.50 mmol).

- 221 040608

The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure.

The crude product was dissolved in methanol (20 ml) and treated with 32% aqueous sodium hydroxide solution (1.6 ml) at 80° C. for 2 hours. The reaction mixture was neutralized and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the indicated in the title compound (10.2 mg, 95% purity, 2% yield over 3 steps).

LCMS (method A): Rt = 1.10 min; MS (ESI negative): m/z = 455 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.58 (s, 3H), 3.80 (s, 2H), 6.72 (s, 1H), 7.14-7.25 (m, 2H ), 7.297.48 (m, 5H), 7.84-7.93 (m, 1H), 8.40 (d, 1H), 10.77 (s, 1H).

Example 369.

2-(2-Fluorophenyl)-N- {4-[1 -(2-methoxyethyl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

5-Amino-2-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]benzenesulfonamide (190 mg, 641 µmol) was dissolved in DMF (5.3 ml) and (2-fluorophenyl)acetic acid (119 mg) was added , 769 µmol) followed by addition of Ν,N-diisopropylethylamine (560 µl, 3.2 mmol) and HATU (390 mg, 1.03 mmol). The reaction mixture was stirred at 50° C. for 16 h, then water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (66.4 mg, 95% purity, 23% yield).

LC-MS (method B): Rt = 0.96 min; MS (ESI negative): m/z = 529 [M-H]-.

1H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.24 (s, 3H), 3.70 (t, 2H), 3.77 (s, 2H), 4.28 (t, 2H), 7.09 ( s, 2H), 7.14-7.25 (m, 2H), 7.29-7.48 (m, 3H), 7.70 (s, 1H), 7.81 (dd, 1H), 8.01 (s, 1H), 8.31 (d, 1H) , 10.55(s, 1H).

Example 370.

2-(2-Chlorophenyl)-N-{4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(1H-pyrazol-4yl)phenyl]acetamide (180 mg, 404 µmol) was dissolved in DMF (4 ml), 2,2-dimethyloxirane (1.3 ml, 14 mmol) and cesium carbonate (263 mg, 807 μmol) were added and the reaction mixture was heated for 30 min at 130° C. in a microwave oven (2 bar/35 W). The mixture was then filtered, the solvent was removed under reduced pressure and the crude product was used without further purification in the next step (250 mg).

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylidene]sulfamoyl}-4-[1-(2-hydroxy-2-methylpropyl)1H-pyrazol-4-yl]phenyl)acetamide (250 mg, 483 µmol) was dissolved in methanol (5.0 ml) and treated with 32% aqueous sodium hydroxide solution (270 µl) at 80°C until the reaction was complete. The solvent was removed under reduced pressure, the crude product was dissolved in dichloromethane and washed with water. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%), then Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution ( 32%)) to give the title compound (2.60 mg, 95% purity, 1% yield over 2 steps).

LC-MS (method B): Rt = 0.88 min; MS (ESI negative): m/z = 461 [M-H]-.

1H-NMR (400 MHz, DMSO-d6): δ[ppm]=1.09 (s, 6H), 3.88 (s, 2H), 4.04 (s, 2H), 4.77 (s, 1H), 7.04 ( s, 2Н), 7.29-7.37 (m, 2Н), 7.41-7.50 (m, 3Н), 7.67 (s, 1Н), 7.83 (dd, 1Н), 8.02 (s, 1Н), 8.32 (d, 1Н) , 10.57 (s, 1H).

Example 371.

2-(5-Chloro-2-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide

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5-Amino-2-(1-cyclopropyl-III-pyrazol-4-yl)-M-[(dimethylamino)methylidene]benzenesulfonamide (200 mg, 600 µmol) was dissolved in DMF (10 ml) and (5-chloro- 2-fluorophenyl)acetic acid (136 mg, 720 µmol) followed by X,X-diisopropylethylamine (520 µl, 3.0 mmol) and HATU (456 mg, 1.20 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and ethyl acetate were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used in the next step without further purification.

2-(5-Chloro-2-fluorophenyl)-X-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (302mg, 600 µmol) was dissolved in methanol (5.0 ml) and treated with 25% aqueous ammonia solution (5.0 ml) at room temperature. After 16 hours, the same amount of ammonia was added and stirring was continued until the reaction was complete. The solvent was removed under reduced pressure and the crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (27.6 mg, 96% purity, yield for 2 stages 10%).

LC-MS (method B): Rt = 0.99 min; MS (ESI negative): m/z = 447 [M-H]-.

¹ H-NMR (600 MHz, CD3OD): δ [ppm]=1.03-1.08 (m, 2H), 1.13-1.19 (m, 2H), 3.66-3.73 (m, 1H), 7.12 (t, 1H), 7.29-7.36 (m, 1H), 7.37-7.45 (m, 2H), 7.69 (s, 1H), 7.80 (dd, 1H), 7.97 (s, 1H), 8.37 (d, 1H).

Example 372.

2-(2-Chlorophenyl)-X-[4-(6-methylpyridin-3-yl)-3-sulfamoylphenyl]acetamide

2-Bromo-X-[(dimethylamino)methylidene]-5-nitrobenzenesulfonamide (200 mg, 595 µmol) and 2-methyl5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )pyridine (261 mg, 1.19 mmol) was dissolved in n-propanol (55 mL) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (20.9 mg, 29.7 µmol), triphenylphosphine (10.8 mg , 29.7 µmol) and aq. potassium carbonate solution (890 μl, 2.0 M, 1.8 mmol). The solution was purged with argon for 5 minutes and heated at 120° C. for 1 hour in a microwave oven. The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with THF and used without further purification in the next step. Under the reaction conditions, deprotection was observed, respectively, the free sulfonamide was transferred to the next steps.

2-(6-Methylpyridin-3-yl)-5-nitrobenzenesulfonamide (450 mg, 1.53 mmol) was dissolved in methanol (70 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 167 mg, 1.56 mmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was co-distilled with THF and used without further purification in the next step (400 mg).

5-Amino-2-(6-methylpyridin-3-yl)benzenesulfonamide (200 mg, 760 µmol) was dissolved in DMF (5.3 ml) and (2-chlorophenyl)acetic acid (155 mg, 911 µmol) was added followed by X ,K-diisopropylethylamine (630 μl, 3.8 mmol) and HATU (462 mg, 1.22 mmol). The reaction mixture was stirred at 50° C. for 16 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (33.3 mg, 95% purity, 10% yield over 3 steps) .

LC-MS (method B): Rt = 0.94 min; MS (ESI negative): m/z = 414 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=1.11 (s, 3H), 3.89 (s, 2H), 7.20-7.39 (m, 6H), 7.42-7.52 (m, 2H), 7.62-7.70 (m, 1H), 7.78-7.89 (m, 1H), 8.31-8.44 (m, 2H), 10.66 (s, 1H).

Example 373.

2-(2-Chlorophenyl)-N-{4-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide

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2-Bromo-5-nitrobenzenesulfonamide (100 mg, 356 µmol) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1H -pyrazole (107 mg, 427 µmol) was dissolved in n-propanol (4.8 ml) and bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (12.5 mg, 17.8 µmol), triphenylphosphine (4.67 mg , 17.8 µmol) and aq. potassium carbonate solution (530 µl, 2.0 M, 1.1 mmol). The solution was purged with argon for 5 min and the reaction mixture was heated at 120° C. for 1 h in a microwave oven (4 bar/40 W). The mixture was then filtered through celite, the solvent was removed under reduced pressure, and the crude product was co-distilled with methanol and used without further purification in the next step (120 mg).

5-Nitro-2-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]benzenesulfonamide (120 mg, 370 μmol) was dissolved in THF (37 ml) and the flask was filled with nitrogen. Palladium on charcoal (load 10%, 40.2 mg, 377 µmol) was added and the flask was evacuated and then filled with hydrogen (1 bar). Stirring was continued at room temperature for 4 hours. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (110 mg).

5-Amino-2-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]benzenesulfonamide (110 mg, 374 µmol) was dissolved in DMF (2.6 ml) and (2-chlorophenyl)acetic acid was added ( 76.5 mg, 448 µmol) followed by the addition of Ν,N-diisopropylethylamine (330 µl, 1.9 mmol) and HATU (227 mg, 598 µmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) to give the title compound (38.6 mg, 95% purity, 3 steps yield 22%) .

LC-MS (method J): Rt = 1.09 min; MS (ESI negative): m/z = 445 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm]=3.88 (s, 2H), 4.86-5.00 (m, 4H), 5.54-5.68 (m, 1H), 7.19 (s, 2H), 7.29-7.37 (m, 2H), 7.40-7.51 (m, 3H), 7.78-7.86 (m, 2H), 8.11 (s, 1H), 8.27-8.35 (m, 1H), 10.58 (s, 1H).

Example 374.

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

5-Amino-2-(1-methyl-1H-pyrazol-4-yl)benzenesulfonamide (200 mg, 793 µmol) was dissolved in DMF (6.6 ml) and (2-fluorophenyl)acetic acid (147 mg, 951 µmol) was added followed by the addition of Ν,N-diisopropylethylamine (350 µl, 4.0 mmol) and HATU (482 mg, 1.27 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Water and dichloromethane were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified by HPLC (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (75.6 mg, 95% purity, 23% yield).

LC-MS (method A): Rt = 0.90 min; MS (ESI negative): m/z = 387 [M-H]-.

'll-NMR (400 MHz, DMSO-d6): δ [ppm]=3.76 (s, 2H), 3.86 (s, 3H), 7.12-7.27 (m, 4H), 7.30-7.44 (m, 3H), 7.66 (d, 1H), 7.77-7.86 (m, 1H), 7.95 (s, 1H), 8.30 (d, 1H), 10.55 (s, 1H).

Example 375.

N-[4-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

A mixture of (dimethylamino)methylene-protected/unprotected starting material was used.

5-Amino-2-(1,3-dimethyl-1H-pyrazol-4-yl)benzenesulfonamide (250 mg, 939 µmol) was dissolved in DMF (7.8 ml) and (2-fluorophenyl)acetic acid (174 mg, 1.13 mmol) followed by the addition of Ν,Ν-diisopropylethylamine (820 µl, 4.7 mmol) and HATU (571 mg, 1.50 mmol). The reaction mixture was stirred at 50° C. for 18 hours. Dichloromethane and water were added. The phases were separated and the water

- 224 040608 the phase was extracted with dichloromethane. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The residue was redissolved in methanol (10 ml) and treated with 32% aqueous sodium hydroxide solution (0.2 ml) at 80°C for 2 h. The reaction mixture was neutralized and water and dichloromethane were added. The phases were separated and the combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was purified with (Waters XBrigde C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give the title compound (28.0 mg, 90% purity, 7% yield).

LC-MS (method B): Rt = 0.94 min; MS (ESI negative): m/z = 456 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.99 (s, 3H), 3.77 (s, 5H), 6.91 (s, 2H), 7.14-7.25 (m, 3H ), 7.297.46 (m, 2H), 7.59 (s, 1H), 7.77-7.85 (m, 1H), 8.29 (d, 1H), 10.56 (s, 1H).

Example 376.

N-[4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide nh ₂ χ o=s=o OD Od#'

5-Amino-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide (100 mg, 298 µmol) was dissolved in DMF (5.0 ml) and ( 2-fluorophenyl)acetic acid (55.2 mg, 358 µmol) followed by the addition of N,N-diisopropylethylamine (260 µl, 1.5 mmol) and HATU (227 mg, 596 µmol). The reaction mixture was stirred at room temperature for 2 hours. After that, the solvent was removed under reduced pressure and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (290 mg).

LCMS (method A): Rt = 1.00 min; MS (ESI positive): m/z = 472 [M+H] ⁺ .

N-[4-(5-Cyclopropyl-1,3,4-oxadiazol-2-yl)-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl]-2(2-fluorophenyl)acetamide (290mg, 615µmol ) was dissolved in methanol (50 ml) and treated with concentrated ammonia solution (10 ml) at room temperature for 2 h. The solvent was removed under reduced pressure and after HPLC purification (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2 % aqueous ammonia (32%)) gave the pure title compound (56.8 mg, 98% purity, 22% yield over 2 steps).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 417 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=1.07-1.22 (m, 4H), 2.34 (tt, 1H), 3.82 (s, 2H), 7.15-7.24 (m , 2H), 7.30-7.38 (m, 1H), 7.41 (td, 1H), 7.62 (s, 2H), 7.88 (d, 1H), 7.99 (dd, 1H), 8.43 (d, 1H), 10.88 ( s, 1H).

Example 377.

2-(2-Chlorophenyl)-N-[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide

5-Amino-2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-N-[(dimethylamino)methylidene]benzenesulfonamide (100 mg, 298 µmol) was dissolved in DMF (5.0 ml) and ( 2-chlorophenyl)acetic acid (61.0 mg, 358 µmol) followed by the addition of N,N-diisopropylethylamine (260 µl, 1.5 mmol) and HATU (227 mg, 596 µmol). The reaction mixture was stirred at room temperature for 2 h. After that, 0.5 equiv. all reagents and stirring was continued for 16 h at room temperature. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried on a Whatman filter and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step (340 mg).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 488 [M+H] ⁺ .

2-(2-Chlorophenyl)-N-[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3{[(dimethylamino)methylidene]sulfamoyl}phenyl]acetamide (340mg, 697µmol ) was dissolved in methanol (10 ml) and treated with concentrated ammonia solution (10 ml) at room temperature for 2 h. water + 0.1% formic acid) (56.6 mg, 93% purity, 17% yield over stage 2).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 433 [M+H] ⁺ .

- 225 040608

1P-NMR (400 MHz, DMSO-d6): δ [ppm]=1.06-1.22 (m, 4H), 2.28-2.39 (m, 1H), 3.93 (s, 2H), 7.29-7.38 (m , 2H), 7.42-7.50 (m, 2H), 7.62 (s, 2H), 7.88 (d, 1H), 7.99 (dd, 1H), 8.44 (d, 1H), 10.90 (s, 1H).

Example 378.

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

According to general methods GP2.3 and GP6.1, 2-[4-(difluoromethyl)-1P-pyrazol-1-yl]-K[(dimethylamino)methylene]-5-nitrobenzene sulfonamide (250 mg, 0.670 mmol) and (2-fluorophenyl)acetic acid (154 mg, 1.00 mmol) were converted without purification of intermediates to the title compound and finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acids).

LC-MS (method A): Rt = 1.02 min, MS (ESI positive): m/z = 425 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.80 (s, 2H), 7.11 (t, 1H), 7.15-7.23 (m, 2H), 7.30-7.47 (m, 4H ), 7.56 (d, 1H), 7.97 (dd, 1H), 7.99 (d, 1H), 8.37 (d, 1H), 8.41–8.44 (m, 1H), 10.79 (s, 1H).

Example 379.

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

According to general procedures GP2.3 and GP6.1, 2-[4-(difluoromethyl)-1H-pyrazol-1-yl]-N[(dimethylamino)methylene]-5-nitrobenzenesulfonamide (250 mg, 0.670 mmol) and (2-chlorophenyl)acetic acid (154 mg, 1.00 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid ).

LC-MS (method A): Rt = 1.05 min, MS (ESI positive): m/z = 441 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.12 (t, 1H), 7.29-7.37 (m, 2H), 7.39-7.49 (m, 4H ), 7.56 (d, 1H), 7.97 (dd, 1H), 7.99 (s, 1H), 8.38 (d, 1H), 8.41-8.44 (m, 1H), 10.81 (s, 1H).

Example 380.

2-(2-Chlorophenyl)-N-{5-sulfamoyl-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}acetamide

5-Amino-N-[(dimethylamino)methylidene]-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine-3sulfonamide (250 mg, 690 µmol) and (2-chlorophenyl)acetic acid (177 mg, 1.03 mmol) was dissolved in DMF (10 mL) and Ν,N-diisopropylethylamine (600 µL, 3.4 mmol) and 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4 were added successively ,6-trioxatrifosfinan (310 µl, 1.0 mmol). The reaction mixture was stirred at room temperature overnight. Thereafter, the solvent was removed under reduced pressure, and ethyl acetate and water were added. The phases were separated and the organic phase was dried on a Whatman filter. The solvent was removed under reduced pressure and the crude product was used without further purification in the next step (400 mg).

2-(2-Chlorophenyl)-N-(5-{[(dimethylamino)methylidene]sulfamoyl}-6-[4-(trifluoromethyl)-1H-pyrazol1-yl]pyridin-3-yl)acetamide (400mg, 777 µmol) was dissolved in methanol (37 ml) and treated with 40% aqueous sodium hydroxide solution (24 µl, 1.9 mmol) for 1 h at 50°C. Thereafter, the solvent was removed under reduced pressure and the crude product was purified by HPLC chromatography (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) to give 3.8 mg of the title compound (purity 95%, yield over stage 2 1%).

LC-MS (method B): Rt = 0.93 min; MS (ESI positive): m/z = 460 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm]=3.95 (s, 2H), 7.29-7.39 (m, 2H), 7.43-7.52 (m, 2H), 7.61 (s, 2H), 8.24 (s, 1H), 8.86 (d, 1H), 8.91 (d, 1H), 8.97 (d, 1H), 11.06 (s, 1H).

Example 381.

2-(2-Fluorophenyl)-N-{5-sulfamoyl-6-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridin-3-yl}αcetamide

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The title compound was prepared analogously to Example 380 in the 2nd step starting from 5-amino-N-[(dimethylamino)methylidene]-2-[4-(trifluoromethyl)-1H-pyrazol-1-yl]pyridine-3-sulfonamide (250 mg, 690 µmol), after final HPLC purification (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (12.8 mg, 90% purity, 4% yield).

LC-MS (method B): Rt = 0.90 min; MS (ESI positive): m/z = 444 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6): δ[ppm]=3.85 (s, 2H), 7.13-7.26 (m, 2H), 7.29-7.47 (m, 2H), 7.61 (s, 2H), 8.23 (s, 1H), 8.86 (d, 1H), 8.91 (d, 1H), 8.97 (s, 1H), 11.04 (s, 1H).

Example 382.

N-[6-(4-Cyano-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]-2-(2-fluorophenyl)acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (200 mg) and (2- fluorophenyl)acetic acid (145 mg, 0.94 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) (13 mg, 0.0325 mmol, yield over 5 steps 2%, purity 99%).

LC-MS (method A): Rt = 0.96 min, MS (ESI positive): m/z = 401 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.85 (s, 2H), 7.16-7.23 (m, 2H), 7.30-7.38 (m, 1H), 7.42 (td, 1H ), 7.63 (s, 2Н), 8.35 (d, 1H), 8.87 (d, 1H), 8.89 (d, 1H), 9.10 (d, 1H), 11.06 (s, 1H).

Example 383.

2-(2-Chlorophenyl)-N-[6-(4-cyano-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-cyano-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (55 mg) and (2- chlorophenyl)acetic acid (41 mg, 0.26 mmol) was converted without purification of intermediates to the title compound. The title compound precipitated during the reaction and was isolated by filtration, no further purification required (20.5 mg, 0.0492 mmol, 9% yield over 5 steps, 97% purity).

LC-MS (method A): Rt = 1.01 min, MS (ESI positive): m/z = 417 [M+H]+.

'H-NMR (400 MHz, DMSOL) δ [ppm]: 3.95 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.50 (m, 2H), 7.63 (s, 2H), 8.36 (d, 1H), 8.87 (d, 1H), 8.90 (d, 1H), 9.10 (d, 1H), 11.08 (s, 1H).

Example 384.

2-(2-Fluorophenyl)-N-[6-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]acetamide

According to the general procedure GP6.1, crude 5-amino-N-[(dimethylamino)methylene]-2-(4-fluoro1H-pyrazol-1-yl)pyridine-3-sulfonamide (150 mg) and (2-fluorophenyl )acetic acid (111 mg, 0.72 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (24 mg , 0.061 mmol, yield after 5 steps 8%, purity 97%).

LC-MS (method A): Rt = 0.98 min, MS (ESI positive): m/z = 394 [M+H] ⁺ .

'H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.94 (s, 2H), 7.30-7.37 (m, 2H), 7.44-7.49 (m, 2H), 7.60 (s, 2H ), 7.93 (dd, 1H), 8.50 (dd, 1H), 8.83 (d, 1H), 8.88 (d, 1H), 10.99 (s, 1H).

Example 385.

2-(2-Chlorophenyl)-N-[6-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]acetamide

- 227 040608

According to the general procedure GP6.1, crude 5-amino-X-[(dimethylamino)methylene]-2-(4-fluoro1H-pyrazol-1-yl)pyridine-3-sulfonamide (150 mg) and (2-chlorophenyl )acetic acid (123 mg, 0.72 mmol) was converted without purification of intermediates to the title compound and was finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (25 mg , 0.061 mmol, yield after 5 steps 8%, purity 98%).

LC-MS (method A): Rt = 1.03 min, MS (ESI positive): m/z = 410 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.84 (s, 2H), 7.16-7.23 (m, 2H), 7.31-7.38 (m, 1H), 7.42 (td, 1H), 7.60 (s, 2H), 7.93 (dd, 1H), 8.50 (dd, 1H), 8.83 (d, 1H), 8.88 (d, 1H), 10.97 (s, 1H).

Example 386.

N-[6-(4-Bromo-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]-2-(2-fluorophenyl)acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (84 mg) and (2- fluorophenyl)acetic acid (50.5 mg, 0.33 mmol) was converted without purification of intermediates to the title compound. The target product precipitated during the reaction and was isolated by filtration, no further purification was required (14 mg, 0.0308 mmol, yield over 5 steps 12%, purity 97%).

LC-MS (method A): Rt = 1.10 min, MS (ESI positive): m/z = 454/456 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.84 (s, 2H), 7.16-7.23 (m, 2H), 7.31-7.38 (m, 1H), 7.42 (td, 1H), 7.59-7.65 (m, 2H), 7.94 (d, 1H), 8.58 (d, 1H), 8.83 (d, 1H), 8.88 (d, 1H), 10.99 (s, 1H).

Example 387.

2-(2-Chlorophenyl)-N-[6-(4-chloro-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (100 mg) and (2- chlorophenyl)acetic acid (77.8 mg, 0.46 mmol) was converted without purification of intermediates to the title compound. The title compound precipitated during the reaction and was isolated by filtration, no further purification required (38 mg, 0.0891 mmol, 27% yield over 5 steps, 99% purity).

LC-MS (method A): Rt = 1.13 min, MS (ESI positive): m/z = 426 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.94 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.49 (m, 2H), 7.60 (s, 2H ), 7.94 (d, 1H), 8.58 (d, 1H), 8.84 (d, 1H), 8.89 (d, 1H), 11.01 (s, 1H).

Example 388.

N-[6-(4-Chloro-1H-nirazol-1-yl)-5-sulfamoylniridin-3-yl]-2-(2-fluorophenyl)acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-chloro-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (100 mg) and (2- fluorophenyl)acetic acid (70 mg, 0.46 mmol) was converted without purification of intermediates to the title compound. The title compound precipitated during the reaction and was isolated by filtration, no further purification required (8 mg, 0.0195 mmol, 6% yield over 5 steps, 99% purity).

LC-MS (method A): Rt = 1.08 min, MS (ESI positive): m/z = 410 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.84 (s, 2H), 7.16-7.24 (m, 2H), 7.31-7.38 (m, 1H), 7.42 (td, 1H ), 7.60 (s, 2Н), 7.94 (d, 1H), 8.58 (d, 1H), 8.83 (d, 1H), 8.88 (d, 1H), 10.99 (s, 1H).

- 228 040608

Example 389.

X-[6-(4-Bromo-1H-pyrazol-1-yl)-5-sulfamoylpyridin-3-yl]-2-(2-chlorophenyl)acetamide

According to the general procedure GP6.1, crude 5-amino-2-(4-bromo-1H-pyrazol-1-yl)-N[(dimethylamino)methylene]pyridine-3-sulfonamide (84 mg) and (2- chlorophenyl)acetic acid (55.9 mg, 0.33 mmol) was converted without purification of intermediates to the title compound. The title compound precipitated during the reaction and was isolated by filtration, no further purification required (20 mg, 0.0425 mmol, 17% yield over 5 steps, 98% purity).

LC-MS (method A): Rt = 1.14 min, MS (ESI positive): m/z = 470/472 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.31-7.36 (m, 2H), 7.43-7.49 (m, 2H), 7.60 (s, 2H ), 7.94 (d, 1H), 8.57 (d, 1H), 8.83 (d, 1H), 8.87 (d, 1H), 11.02 (s, 1H).

Example 390.

2-(2-Fluorophenyl)-X-{3-sulfamoyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}acetamide

2-(2-Fluorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,3,4-oxadiazol2-yl]phenyl}acetamide (268 mg, 451 μmol) was dissolved in dichloromethane (7.3 ml) and treated with trifluoroacetic acid (1.7 ml, 23 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (25 mg, 12% yield, 99% purity).

LC-MS (method A): Rt = 0.93 min.

MS (ESI positive): m/z = 445 (M+H)+.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ [ppm] 3.85 (s, 2H), 7.19 (m, 2H), 7.34 (m, 1H), 7.41 (m, 1H), 7.91 ( dd, 1H), 8.06 (d, 1H), 8.29 (d, 1H), 11.00 (s, 1H).

Example 391.

2-(2-Chlorophenyl)-X-{3-sulfamoyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}acetamide

2-(2-Chlorophenyl)-X-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[5-(trifluoromethyl)-1,3,4-oxadiazol2-yl]phenyl}acetamide (276 mg, 451 μmol) was dissolved in dichloromethane (7.3 ml) and treated with trifluoroacetic acid (1.7 ml, 23 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (23 mg, 11% yield, 95% purity).

LC-MS (method A): Rt = 0.97 min MS (ESI positive): m/z = 461 (M+H) ⁺ .

1Н-NMR (400 MHz, DMSO-d6) δ [ppm] 3.95 (s, 2Н), 7.33 (m, 2Н), 7.46 (m, 2Н), 7.90 (dd, 1H), 8.06 (d, 1H), 8.28 (d, 1H), 11.01 (s, 1H).

Example 392.

2-(2-Chlorophenyl)-X- {4-[3 - (pyridin-3 -yl)- 1H-1,2,4-triazol-1 -yl] -3-sulfamoylphenyl} acetamide

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-(1H-1 ,2,4-triazol-3-yl)pyridine (283 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (197 mg, 1.15 mmol) were converted without purification of intermediates to the title compound and purified in the final step with preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm,

- 229 040608 methanol/water + 0.1% trifluoroacetic acid) (10 mg, 0.0213 mmol, 2% yield over 4 steps, 96% purity).

LC-MS (method A): Rt = 0.90 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.31-7.39 (m, 2H), 7.44-7.50 (m, 2H), 7.55 (s, 2Н), 7.61 (dd, 1H), 7.69 (d, 1H), 8.00 (dd, 1H), 8.46 (d, 1H), 8.48 (dt, 1H), 8.71 (dd, 1H), 8.93 (s, 1H ), 9.28 (d, 1H), 10.88 (s, 1H).

Example 393.

2-(2-Fluorophenyl)-X-[4-(1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=on=\

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.3, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (250 mg, 0.65 mmol), lH-pyrazole (66 mg , 0.97 mmol) and (2fluorophenyl)acetic acid (120 mg, 0.78 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1 % formic acid) (ll mg, 0.294 mmol, yield over 4 steps 5%, purity 95%).

LC-MS (method A): Rt = 0.91 min; MS (ESI positive): m/z = 375 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.80 (s, 2H), 6.51 (t, 1H), 7.15-7.23 (m, 2H), 7.30-7.37 (m, 1H), 7.41 (td, 1H), 7.46 (s, 2Н), 7.53 (d, 1H), 7.78 (dd, 1H), 7.97 (dd, 1H), 8.10 (dd, 1H), 8.36 (d, 1H ), 10.75 (s, 1H).

Example 394.

X-[4-(4-tert-Butyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

According to general procedures GPl.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-tert-butyl- 1H-pyrazole (241 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (28 mg, 0.0626 mmol, 3% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 447 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 (s, 9H), 3.89 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.48 (m, 2H) , 7.50 (s, 2H), 5.52 (d, 1H), 7.72 (d, 1H), 7.94 (d, 1H), 7.97 (dd, 1H), 8.33 (d, 1H), 10.74 (s, 1H).

Example 395 and Example 396.

According to general procedures GPl.2, GP2.1, GP3.3 and GP4.1, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 2H-indazole (229 mg , 1.94 mmol) and (2-chlorophenyl)acetic acid (321 mg, 1.88 mmol) were converted without purification of intermediates to the two title compounds and purified and separated in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)).

Example 395.

2-(2-Chlorophenyl)-X-[4-( l H-indazol-1 -yl)-3-sulfamoylphenyl]acetamide

mg, 0.132 mmol, yield over 4 steps 10%, purity 99%.

LC-MS (method B): Rt = 1.33 min; MS (ESI positive): m/z = 441 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.93 (s, 2H), 7.26 (ddd, 1H), 7.29-7.40 (m, 5H), 7.41-7.49 (m, 3H ), 7.64 (d, 1H), 7.89 (dt, 1H), 8.05 (dd, 1H), 8.40 (d, 1Н), 8.46 (d, 1H), 10.84 (s, 1H).

Example 396.

2-(2-Chlorophenyl)-X-[4-(2H-indazol-2-yl)-3-sulfamoylphenyl]acetamide

- 230 040608

mg, 0.0318 mmol, yield over 4 steps 2%, purity 99%.

LC-MS (method B): Rt = 1.27 min; MS (ESI positive): m/z = 441 [M+H]+.

Ή-NMR (400 MHz, DMSOCH) δ [ppm]: 3.93 (s, 2H), 7.14 (ddd, 1H), 7.30-7.39 (m, 3H), 7.44-7.50 (m, 2H), 7.64 (br s, 2H), 7.70 (d, 1H), 7.74 (dd, 1H), 7.78-7.82 (m, 1H), 8.04 (dd, 1H), 8.44 (d, 1H), 8.71 (d, 1H) , 10.86(s, 1H).

Example 397 and Example 398.

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 2H-indazole (229 mg , 1.94 mmol) and (2-fluorophenyl)acetic acid (290 mg, 1.88 mmol) were converted without purification of intermediates to the two title compounds and purified and separated at the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)).

Example 397.

2-(2-Fluorophenyl)-N-[4-(2H-indazol-2-yl)-3-sulfamoylphenyl]acetamide

mg, 0.0353 mmol, yield over 4 steps 3%, purity 99%.

LC-MS (method B): Rt = 1.21 min; MS (ESI positive): m/z = 425 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.83 (s, 2H), 7.11-7.24 (m, 3H), 7.31-7.38 (m, 2H), 7.43 (td, 1H ), 7.63 (br s, 2H), 7.70 (d, 1H), 7.74 (dd, 1H), 7.78-7.82 (m, 1H), 8.03 (dd, 1H), 8.43 (d, 1H), 8.72 (d , 1H), 10.85 (s, 1H).

Example 398.

2-(2-Fluorophenyl)-N-[4-(1H-indazol-1-yl)-3-sulfamoylphenyl]acetamide

mg, 0.0165 mmol, yield over 4 steps 13%, purity 99%.

LC-MS (method B): Rt = 1.27 min; MS (ESI positive): m/z = 425 [M+H]+.

Ή-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.83 (s, 2H), 7.17-7.23 (m, 2H), 7.26 (t, 1H), 7.29-7.39 (m, 4H) , 7.41-7.47 (m, 2H), 7.64 (d, 1H), 7.89 (d, 1H), 8.05 (dd, 1H), 8.40 (s, 1H), 8.46 (d, 1H), 10.84 (s, 1H ).

Example 399.

1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-N,N-dimethyl-1H-pyrazole-4-carboxamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), N,N-dimethyl- 1H-pyrazole-4carboxamide (270 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (35 mg, 0.0758 mmol, 6% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 0.91 min; MS (ESI positive): m/z = 462 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.97 (br s, 3H), 3.18 (br s, 3H), 3.91 (s, 2H), 7.30-7.37 (m, 2H ), 7.38-7.48 (m, 4H), 7.60 (d, 1H), 7.97 (dd, 1H), 8.00 (d, 1H), 8.38 (d, 1H), 8.42 (d, 1H), 10.80 (s, 1H).

Example 400.

N-[1 -(4- {[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1 H-pyrazole-4- 231 040608 yl]cyclopropanecarboxamide

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-^(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), N-(1H-pyρazοl- 4yl)cyclopropanecarboxamide (293 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (44 mg, 0.0928 mmol, 7% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 474 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.76-0.82 (m, 4H), 1.72 (quin, 1H), 3.90 (s, 2H), 7.29-7.36 (m, 2H ), 7.39-7.48 (m, 4H), 7.52 (d, 1H), 7.77 (d, 1H), 7.95 (dd, 1H), 8.14 (s, 1H), 8.35 (d, 1H), 10.40 (s, 1H), 10.75 (s, 1H).

Example 401.

2-(2-chlorophenyl)-N-{4-[4-(pyrazin-2-yl)-1H-pyrazοl-1-yl]-3-sulfamοylphenyl}acetamide nh ₂ oX

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-^(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 2-(1H-pyρazοl- 4-yl)pyrazine (283 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (41 mg, 0.0874 mmol, 7% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 469 [M+H]+.

1I-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.43-7.50 (m, 4H), 7.65 (d, 1H) , 8.01 (dd, 1H), 8.40 (d, 1H), 8.43 (d, 1H), 8.49 (d, 1H), 8.62 (dd, 1H), 8.81 (d, 1H), 9.11 (d, 1H), 10.82(s, 1H).

Example 402.

2-(2-Chloορphenyl)-N-{4-[4-(pyρidin-2-yl)-1H-pyρazοl-1-yl]-3-sulfamοylphenyl}acetamide nh ₂

O=S=O N—λ

^ClH

According to the general methods GP1.2, GP2.1, GP3.3 and GP4.1, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 2-(1N-pyrazole -4-yl)pyridine (281 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC ( Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (54 mg, 0.115 mmol, 9% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 0.91 min; MS (ESI positive): m/z = 468 [M+H]+.

1I-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.24 (ddd, 1H), 7.30-7.37 (m, 2H), 7.42-7.51 (m, 4H) , 7.64 (d, 1H), 7.76-7.85 (m, 2H), 8.00 (dd, 1H), 8.34 (d, 1H), 8.39 (d, 1H), 8.57 (ddd, 1H), 8.67 (d, 1H ), 10.80 (s, 1H).

Example 403.

2-(2-Chlορphenyl)-N- {4-[4-(pyridin-3-yl)-1 H-pyrazol-1 -yl] -3-sulfamoylphenyl}acetamide nh ₂

O=S=O N^\ λ-n

X°

Cl ^H

In accordance with the general methods GP1.2, GP2.1, GP3.3 and GP4.1, 2-chlορ-N-(2,4

- 232 040608 dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3-(1H-pyrazol-4-yl)pyridine (281 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol ) was converted without purification of intermediates to the title compound and purified twice in the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (20 mg, 0.0427 mmol, yield over 4 stage 3%, purity 97%).

LC-MS (method A): Rt = 0.92 min; MS (ESI positive): m/z = 468 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.40-7.52 (m, 5H), 7.63 (d, 1H), 8.01 (dd, 1H), 8.09 (dt, 1H), 8.35 (s, 1H), 8.39 (d, 1H), 8.45 (dd, 1H), 8.70 (s, 1H), 8.97 (d, 1H ), 10.81 (s, 1H).

Example 404.

2-(2-Chlorophenyl)-N-{4-[4-(pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂ o=s=on—

Cl ^H

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (250 mg, 0.65 mmol), 4-(1H-pyrazole -4-yl)pyrimidine (142 mg, 0.97 mmol) and (2-chlorophenyl)acetic acid (162 mg, 0.95 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (6.1 mg, 0.0130 mmol, 2% yield over 4 steps , purity 95%).

LC-MS (method I): Rt = 1.21 min; MS (ESI positive): m/z = 469 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.92 (s, 2H), 7.28-7.39 (m, 2H), 7.43-7.52 (m, 4H), 7.64 (d, 1H ), 7.87 (dd, 1H), 8.00 (dd, 1H), 8.40 (d, 1H), 8.46 (s, 1H), 8.77 (d, 1H), 8.87 (s, 1H), 9.12 (d, 1H) , 10.83(s, 1H).

Example 405.

2-(2-Fluorophenyl)-N-{4-[4-(pyrimidin-4-yl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide nh ₂

O=S=O N=\ N- yx* "

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.2, 2-χλορ-Ν-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (250 mg, 0.65 mmol), 4-(1H-pyrazole -4-yl)pyrimidine (142 mg, 0.97 mmol) and (2-fluorophenyl)acetic acid (146 mg, 0.95 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (7.3 mg, 0.0161 mmol, 2% yield over 4 steps , purity 95%).

LC-MS (method I): Rt = 1.16 min; MS (ESI positive): m/z = 453 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.81 (s, 2H), 6.50-8.00 (very broad baseline peak, 2H), 7.15-7.24 (m, 2H), 7.29-7.37 (m, 1H), 7.42 (td, 1H), 7.64 (d, 1H), 7.87 (dd, 1H), 8.00 (dd, 1H), 8.40 (d, 1H), 8.46 (s, 1H) , 8.77 (d, 1H), 8.87 (s, 1H), 9.12 (d, 1H), 10.85 (s, 1H).

Example 406 and 407.

According to general procedures GP2.4 and GP6.3, a regioisomeric mixture of N[(dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl] benzenesulfonamide and N[(dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1 -yl]benzenesulfonamide (159 mg, 0.404 mmol) and (4-methoxyphenyl )acetic acid (99.8 mg, 0.60 mmol) was converted without purification of intermediates to the title compounds, which were purified and separated by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia solution ( 32%)).

Example 406.

2-(4-Methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide ue ₂

O=S=O N=\

Η mg, 0.0373 mmol, yield after 3 steps 9%, purity 97%.

- 233 040608

LC-MS (method B): Rt = 0.99 min; MS (ESI negative): m/z = 454 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.64 (s, 2H), 3.73 (s, 3H), 6.90 (d, 2H), 7.27 (d, 2H), 7.39 (br s, 2Н), 7.73 (d, 1H), 8.01 (dd, 1H), 8.42 (d, 1H), 8.69 (s, 1H), 10.78 (s, 1H).

Example 407.

2-(4-Methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide

mg, 0.105 mmol, yield over 3 steps 26%, purity 97%.

LC-MS (method B): Rt = 0.81 min; MS (ESI negative): m/z = 454 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.65 (s, 2H), 3.73 (s, 3H), 6.91 (d, 2H), 7.27 (d, 2H), 7.33 (br s, 2H), 7.65 (d, 1H), 7.99 (dd, 1H), 8.43 (d, 1H), 9.16 (d, 1H), 10.79 (s, 1H).

Example 408 and 409.

According to general procedures GP2.4 and GP6.3, a regioisomeric mixture of N[(dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl] benzenesulfonamide and N[(dimethylamino)methylene]-5-nitro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1 -yl]benzenesulfonamide (159 mg, 0.404 mmol) and (4-methylphenyl )acetic acid (90.1 mg, 0.60 mmol) was converted without purification of intermediates to the title compounds, which were purified and separated by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia solution ( 32%)).

Example 408.

2-(4-Methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide

12.4 mg, 0.0282 mmol, 7% yield over 3 steps, 98% purity, after further purification by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) LC-MS (method A) : Rt = 1.19 min; MS (ESI negative): m/z = 438 [M-H] ^- .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.28 (s, 3H), 3.67 (s, 2H), 7.15 (d, 2H), 7.24 (d, 2H), 7.44 (s, 2Н), 7.73 (d, 1H), 8.01 (dd 1H), 8.42 (d, 1H), 8.69 (s, 1H), 10.80 (s, 1H).

Example 409.

2-(4-Methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide

22.3 mg, 0.0507 mmol, yield over 3 steps 13%, purity 98%.

LC-MS (method B): Rt = 0.98 min; MS (ESI negative): m/z = 438 [M-H] ^- .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.28 (s, 3H), 3.67 (s, 2H), 7.15 (d, 2H), 7.24 (d, 2H), 7.62 ( br s, 2H), 7.65 (d, 1H), 7.99 (dd, 1H), 8.43 (d, 1H), 9.16 (d, 1H), 10.80 (s, 1H).

Example 410.

2-[4-(Difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-2H-1,2,3-triazol-2-yl]benzenesulfonamide ( 48 mg, 0.123 mmol) and [4(difluoromethyl)phenyl]acetic acid (36.5 mg, 0.20 mmol) were converted without purification of intermediates to the title compound, which precipitated from the reaction mixture after the last step (15 mg, 0.0316 mmol, yield for 3 stages 26%, purity 95%).

LC-MS (method A): Rt = 1.16 min; MS (ESI negative): m/z = 474 [M-H] ^- .

'H-NMR (400 MHz, DMSO-06) δ [ppm]: 3.81 (s, 2H), 7.02 (t, 1H), 7.45 (s, 2H), 7.49 (d, 2H), 7.55 ( d, 2H),

- 234 040608

7.74 (d, 1H), 8.01 (dd, 1H), 8.43 (d, 1H), 8.69 (d, 1H), 10.88 (s, 1H).

Example 411.

2-[4-(Difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide ( 45 mg, 0.115 mmol) and [4(difluoromethyl)phenyl]acetic acid (40 mg, 0.22 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (16 mg, 0.0337 mmol, 29% yield over 3 steps, 98% purity).

LC-MS (method B): Rt = 0.88 min; MS (ESI positive): m/z = 476 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.82 (s, 2H), 7.03 (t, 1H), 7.37-7.60 (m, 6H), 7.67 (d, 1H) , 7.99 (dd, 1H), 8.43 (d, 1H), 9.16 (d, 1H), 10.89 (s, 1H).

Example 412.

2-(2-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-2H-1,2,3-triazol-2-yl]benzenesulfonamide ( 48 mg, 0.123 mmol) and (2fluorophenyl)acetic acid (30.2 mg, 0.20 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile /water + 0.1% formic acid) (3 mg, 0.00677 mmol, yield over 3 steps 6%, purity 97%).

LC-MS (method A): Rt = 1.13 min; MS (ESI negative): m/z = 442 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.83 (s, 2H), 7.15-7.23 (m, 2H), 7.30-7.51 (m, 4H), 7.75 (d, 1H), 8.00 (dd, 1H), 8.45 (d, 1H), 8.70 (d, 1H), 10.90 (s, 1H).

Example 413.

2-(2-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide ( 45 mg, 0.115 mmol) and (2fluorophenyl)acetic acid (33.2 mg, 0.22 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile /water + 0.1% aqueous ammonia (32%)) (21 mg, 0.0474 mmol, 41% yield over 3 steps, 98% purity).

LC-MS (method B): Rt = 0.82 min; MS (ESI positive): m/z = 444 [M+H] ⁺ .

'h-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.83 (s, 2H), 7.15-7.23 (m, 2H), 7.31-7.38 (m, 1H), 7.42 (td, 1H ), 7.57 (br s, 2H), 7.67 (d, 1H), 7.97 (dd, 1H), 8.46 (d, 1H), 9.17 (d, 1H), 10.90 (s, 1H).

Example 414.

2-[2-Chloro-4-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4- 235 040608 (trifluoromethyl)-2H-1,2,3-triazol-2-yl ]benzenesulfonamide (48 mg, 0.123 mmol) and [2-chloro-4(trifluoromethyl)phenyl]acetic acid (46.7 mg, 0.20 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC ( Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) (5 mg, 0.00947 mmol, 5% yield over 3 steps, 97% purity).

LC-MS (method A): Rt = 1.29 min; MS (ESI negative): m/z = 526 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 4.06 (s, 2H), 7.46 (br s, 2H), 7.68-7.78 (m, 3H), 7.89 (s, 1H ), 7.99 (dd, 1H), 8.44 (d, 1H), 8.70 (s, 1H), 10.99 (s, 1H).

Example 415.

2-[2-Chloro-4-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide ( 45 mg, 0.115 mmol) and [2-chloro-4(trifluoromethyl)phenyl]acetic acid (51.4 mg, 0.22 mmol) were converted without purification of intermediates to the title compound and purified in the final step using preparative HPLC (Chromatorex C- 18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) (17 mg, 0.0322 mmol, 28% yield over 3 steps, 97% purity).

LC-MS (method B): Rt = 1.04 min; MS (ESI positive): m/z = 528 [M+H]+.

¹ H-NMR (400 MHz, DMSOD) δ [ppm]: 4.06 (s, 2H), 7.57 (br s, 2H), 7.65-7.77 (m, 3H), 7.90 (s, 1H), 7.97 (dd, 1H), 8.45 (d, 1H), 9.17 (s, 1H), 10.99 (s, 1H).

Example 416.

2-(2,4-Dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-2H-1,2,3-triazol-2-yl]benzenesulfonamide ( 48 mg, 0.123 mmol) and (2,4dichlorophenyl)acetic acid (40.2 mg, 0.20 mmol) were converted without purification of intermediates to the title compound, which precipitated after the last step from the reaction mixture (26 mg, 0.0526 mmol, yield over 3 stage 43%, purity 97%).

LC-MS (method A): Rt = 1.26 min; MS (ESI negative): m/z = 492 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.94 (s, 2H), 7.41-7.52 (m, 4H), 7.64 (d, 1H), 7.75 (d, 1H) , 7.99 (dd, 1H), 8.44 (d, 1H), 8.70 (s, 1H), 10.92 (s, 1H).

Example 417.

2-(2,4-Dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]phenyl}acetamide

According to general procedures GP2.4 and GP6.4, N-[(dimethylamino)methylene]-5-nitro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]benzenesulfonamide ( 45 mg, 0.115 mmol) and (2,4-dichlorophenyl)acetic acid (44.1 mg, 0.22 mmol) were converted without purification of intermediates to the title compound and finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm , acetonitrile/water + 0.1% aqueous ammonia (32%)) (17 mg, 0.0344 mmol, 30% yield over 3 steps, 97% purity).

LC-MS (method B): Rt = 0.98 min; MS (ESI positive): m/z = 494 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.94 (s, 2H), 7.44 (dd, 1H), 7.50 (dd, 1H), 7.53-7.71 (m, 4H), 7.97 (dd, 1H), 8.45 (d, 1H), 9.17 (d, 1H), 10.93 (s, 1H).

- 236 040608

Example 418.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,3-thiazol-5-yl)phenyl]acetamide

According to the general procedure GP8.1, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (150 mg, 0.33 mmol) and 5-bromo- 1,3-thiazole (97.3 mg, 0.59 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (5.9 mg, 0.0145 mmol, 4% yield, 90% purity).

LC-MS (method I): Rt = 1.22 min; MS (ESI positive): m/z = 408 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.38 (s, 2H), 7.42-7.49 (m, 3H ), 7.85 (dd, 1H), 7.94 (s, 1H), 8.40 (d, 1H), 9.13 (s, 1H), 10.72 (s, 1H).

Example 419.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-3-yl)phenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 3-bromo- 1,2-thiazole (195 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia (32%)) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia solution (32%)) (2.9 mg, 0.00711 mmol, 1% yield, 95% purity).

LC-MS (method J): Rt = 1.19 min; MS (ESI positive): m/z = 408 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.40-7.50 (m, 4H), 7.60-7.67 ( m, 2H), 7.96 (dd, 1H), 8.36 (d, 1H), 9.15 (d, 1H), 10.74 (s, 1H).

Example 420.

2-(2-Chlorophenyl)-X-[4-(2-methyl-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- 2-methyl-1,3-thiazole (211 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (19 mg, 0.0450 mmol, yield 7%, purity 97%).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 422 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.73 (s, 3H), 3.89 (s, 2H), 7.30-7.35 (m, 2H), 7.42-7.48 (m, 2H) , 7.59-7.63 (m, 3H), 7.71 (s, 1H), 7.93 (dd, 1H), 8.32 (d, 1H), 10.69 (s, 1H).

Example 421.

2-(2-Chlorophenyl)-N-[4-(2-methoxy-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- 2-methoxy-1,3-thiazole (230 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (25 mg, 0.057

- 237040608 mmol, yield 9%, purity 97%).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 438 [M+H]+.

1H-NMR (500 MHz, DMSO-d ₆ ) δ [ppm]: 3.89 (s, 2H), 4.05 (s, 3H), 7.25 (s, 1H), 7.30-7.35 (m, 2H), 7.427.47 (m, 2H), 7.49 (s, 2H), 7.61 (d, 1H), 7.92 (dd, 1H), 8.31 (d, 1H), 10.69 (s, 1H).

Example 422.

2-(2-Chlorophenyl)-X-[4-(2-methoxy-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 2-methoxy-1,3-thiazole (230 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water+0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (23 mg, 0.0525 mmol, 8% yield, 98% purity).

LC-MS (method B): Rt = 0.97 min; MS (ESI positive): m/z = 438 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.89 (s, 2H), 4.04 (s, 3H), 7.22 (s, 1H), 7.29-7.35 (m, 2H), 7.37 (s, 2H), 7.41-7.47 (m, 3H), 7.83 (dd, 1H), 8.36 (d, 1H), 10.69 (s, 1H).

Example 423.

2-(2-Chlorophenyl)-X-[4-(2-methyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide

According to general procedure GP8.2, N-(4-bromo-3{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300mg, 0.65mmol) and 5-bromo2-methyl -1,3-thiazole (211 mg, 1.19 mmol) was converted to the title compound and purified twice by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (20 mg, 0.0474 mmol, yield 7%, purity 97%).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 422 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.67 (s, 3H), 3.89 (s, 2H), 7.28-7.38 (m, 4H), 7.39-7.48 (m, 3H ), 7.65 (s, 1H), 7.83 (dd, 1H), 8.37 (d, 1H), 10.70 (s, 1H).

Example 424.

2-(2-Chlorophenyl)-X-[4-(3-methyl-1,2-thiazol-5-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 3-methyl-1,2-thiazole (211 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.2% aqueous ammonia (32%)) (32 mg, 0.0758 mmol, 12% yield, 97% purity).

LC-MS (method J): Rt = 1.22 min; MS (ESI positive): m/z = 422 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.45 (s, 3H), 3.90 (s, 2H), 7.28-7.36 (m, 3H), 7.39-7.50 (m, 5H ), 7.87 (dd, 1H), 8.40 (d, 1H), 10.75 (s, 1H).

Example 425.

2-(2-Chlorophenyl)-X-[4-(4-methyl-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide nh ₂

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]

- 238 040608 sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo-4-methyl-1,3-thiazole (211 mg, 1.19 mmol) were converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (35 mg, 0.0830 mmol, 13% yield, 98% purity).

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 422 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.43 (d, 3H), 3.90 (s, 2H), 7.28-7.37 (m, 2H), 7.41-7.49 (m, 3H ), 7.72-7.78 (m, 3H), 7.99 (dd, 1H), 8.38 (d, 1H), 10.81 (s, 1H).

Example 426.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-4-yl)phenyl]acetamide nh ₂

O=S=O qJ?

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- 1,2-thiazole (195 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (9 mg, 0.0221 mmol, 3% yield, 95% purity).

LC-MS (method B): Rt = 0.86 min; MS (ESI positive): m/z = 408 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.30-7.35 (m, 2H), 7.37 (s, 2H), 7.40 (d, 1H) , 7.427.48 (m, 2Н), 7.85 (dd, 1H), 8.38 (d, 1H), 8.63 (s, 1H), 9.04 (s, 1H), 10.68 (s, 1H).

Example 427.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,3-thiazol-2-yl)phenyl]acetamide nh ₂ o=s=o qa/C ci ^H

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo- 1,3-thiazole (195 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (6 mg, 0.0147 mmol, 2% yield, 95% purity).

LC-MS (method B): Rt = 1.01 min; MS (ESI positive): m/z = 408 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.91 (s, 2H), 7.29-7.37 (m, 2H), 7.42-7.49 (m, 2H), 7.73 (s, 2H), 7.77 (d, 1H), 7.91 (d, 1H), 7.98-8.03 (m, 2H), 8.40 (d, 1H), 10.82 (s, 1H).

Example 428.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo- 1,3-thiazole-4-carbonitrile (224 mg, 1.19 mmol) was converted to the title compound and purified twice by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (5 mg, 0.0116 mmol, 2% yield, 95% purity.

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 433 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.92 (s, 2H), 7.30-7.36 (m, 2H), 7.43-7.53 (m, 4H), 7.75 (d, 1H ), 7.98 (dd, 1H), 8.42 (d, 1H), 9.01 (s, 1H), 10.87 (s, 1H).

Example 429.

2-(2-Chlorophenyl)-N-{4-[2-(difluoromethyl)-1,3-thiazol-5-yl]-3-sulfamoylphenyl}acetamide

- 239 040608

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 2-(difluoromethyl)-1,3-thiazole (254 mg, 1.19 mmol) was converted to the title compound and purified twice by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid). acids) (11 mg, 0.0240 mmol, 4% yield, 85% purity). LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 458 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 7.30-7.35 (m, 2H), 7.38 (tr, 1H), 7.42-7.48 (m, 2H), 7.49-7.55 (m, 3H), 7.88 (dd, 1H), 8.00 (s, 1H), 8.42 (d, 1H), 10.77 (s, 1H).

Example 430.

2-(2-Chlorophenyl)-N-[4-(2-cyclopropyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 2-cyclopropyl-1,3-thiazole (242 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (26 mg, 0.0580 mmol, yield 9%, purity 95%). LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 448 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.97-1.02 (m, 2H), 1.09-1.15 (m, 2H), 2.39 (tt, 1H), 3.89 (s, 2H), 7.30-7.34 (m, 2H), 7.37 (s, 2H), 7.40-7.47 (m, 3H), 7.60 (s, 1H), 7.82 (dd, 1H), 8.37 (d, 1H), 10.69 (s, 1H).

Example 431.

2-(2-Chlorophenyl)-N-[4-(2-cyclopropyl-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- 2-cyclopropyl-1,3-thiazole (242 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (12 mg, 0.0268 mmol, 4% yield, 95% purity. LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 448 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.95-0.99 (m, 2H), 1.16-1.21 (m, 2H), 1H overlaps with solvent signal, 3.89 (s, 2H ), 7.29-7.36 (m, 2H), 7.42-7.49 (m, 2H), 7.54-7.64 (m, 4H), 7.93 (dd, 1H), 8.30 (d, 1H), 10.69 (s, 1H).

Example 432.

2-(2-Chlorophenyl)-N-[4-(4-methyl-1,3-oxazol-2-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, X-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo hydrochloride -2-methyl-1,3oxazole (235 mg, 1.19 mmol) was converted to the title compound and purified twice by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) ( 1 mg, 0.00246 mmol, 1% yield, 80% purity. LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 406 [M+H]+.

L-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.18 (d, 3H), 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.41-7.49 (m, 2H) ,

- 240 040608

7.87 (s, 2H), 7.91 (d, 1H), 7.96-8.03 (m, 2H), 8.39 (d, 1H), 10.83 (s, 1H).

Example 433.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- 2-(trifluoromethyl)-1,3thiazole (275 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) with followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (9 mg, 0.0189 mmol, 3% yield, 85% purity).

LC-MS (method B): Rt = 1.14 min; MS (ESI negative): m/z = 474 [M-H]-.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.91 (s, 2H), 7.28-7.38 (m, 4H), 7.42-7.49 (m, 2H), 7.67 (d, 1H), 7.95 (dd, 1H), 8.35 (s, 1H), 8.39 (d, 1H), 10.76 (s, 1H).

Example 434.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo- 4-(trifluoromethyl)-1,3thiazole (275 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) with followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (5 mg, 0.0105 mmol, 2% yield, 97% purity).

LC-MS (method A): Rt = 1.18 min; MS (ESI positive): m/z = 476 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.92 (s, 2H), 7.28-7.37 (m, 2H), 7.41-7.51 (m, 4H), 7.80 (d, 1H), 8.00 (dd, 1H), 8.43 (d, 1H), 8.69 (d, 1H), 10.87 (s, 1H).

Example 435.

2-(2-Chlorophenyl)-N-{4-[2-(2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-(5 -bromo-1,3-thiazol-2-yl)propan2-ol (263 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (25 mg, 0.0537 mmol, 8% yield, 99% purity).

LC-MS (method A): Rt = 0.95 min; MS (ESI positive): m/z = 466 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.54 (s, 6H), 3.89 (s, 2H), 5.99 (s, 1H), 7.28-7.40 (m, 4H) , 7.417.48 (m, 3H), 7.70 (s, 1H), 7.83 (dd, 1H), 8.38 (d, 1H), 10.70 (s, 1H).

Example 436.

2-(2-Chlorophenyl)-N-{4-[2-(2-hydroxypropan-2-yl)-1,3-thiazol-4-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-(4 -bromo-1,3-thiazol-2-yl)propan2-ol (263 mg, 1.19 mmol) was converted to the title compound and purified with prep

- 241 040608 Rative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (42 mg, 0.0901 mmol, 14% yield, 97% purity). LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 466 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO^) δ [ppm]: 1.53 (s, 6H), 3.89 (s, 2H), 6.15 (s, 1H), 7.29-7.36 (m, 2H), 7.417 .48 (m, 2H), 7.59-7.66 (m, 3H), 7.74 (s, 1H), 7.95 (dd, 1H), 8.31 (d, 1H), 10.69 (s, 1H).

Example 437.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,3-thiazol-4-yl)phenyl]acetamide nh ₂

O=S=O N==\

Od/D

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (600 mg, 1.31 mmol) and 4-bromo- 1,3-thiazole (389 mg, 2.37 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC ( Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (3 mg, 0.00735 mmol, 1% yield, 97% purity).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 408 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.89 (s, 2H), 7.29-7.36 (m, 2H), 7.41-7.49 (m, 2H), 7.54-7.65 (m , 3H), 7.92-7.97 (m, 2H), 8.34 (d, 1H), 9.25 (d, 1H), 10.70 (s, 1H).

Example 438.

2-(2-Chlorophenyl)-N-[4-(5-cyclopropyl-1,2-oxazol-3-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 3-bromo- 5-cyclopropyl-1,2-oxazole (223 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (12 mg, 0.0427 mmol, yield 7%, purity 97%). LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.79-0.85 (m, 2H), 1.00-1.07 (m, 2H), 2.00-2.07 (m, 1H), 3.90 (s, 2H), 6.60 (s, 1H), 7.28-7.36 (m, 2H), 7.40-7.50 (m, 4H), 7.67 (d, 1H), 7.92 (dd, 1H), 8.40 (d, 1H), 10.80 (s, 1H).

Example 439.

2-(2-Chlorophenyl)-N-[4-(2-cyclopropyl-1,3-oxazol-5-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 2-cyclopropyl-1,3-oxazole (223 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water+0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, methanol/water + 0.1% formic acid) (12 mg, 0.0427 mmol, 7% yield, 97% purity).

LC-MS (method I): Rt = 1.31 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 0.98-1.10 (m, 4H), 2.13-2.21 (m, 1H), 3.89 (s, 2H), 7.28-7.36 (m , 2H), 7.39-7.48 (m, 5H), 7.68 (d, 1H), 7.89 (dd, 1H), 8.37 (d, 1H), 10.71 (s, 1H).

Example 440.

2-(2-Chlorophenyl)-N-(4-{4-[(3,3-difluoroazetidin-1-yl)carbonyl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide

- 242 040608

According to the general procedure GP7.1, methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and 3,3-difluoroazetidine (51.8 mg, 0.56 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (31 mg, 0.0608 mmol, 28% yield, 97 purity %).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 510 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.91 (s, 2H), 4.35-4.56 (m, 2H), 4.74-5.00 (m, 2H), 7.30-7.37 ( m, 2H), 7.38-7.49 (m, 4H), 7.59 (d, 1H), 7.98 (dd, 1H), 8.07 (s, 1H), 8.39 (d, 1H), 8.50 (s, 1H), 10.82 (s, 1H).

Example 441.

N-{4-[4-(Azetidin-1-ylcarbonyl)-1 H-pyrazol-1-yl]-3-sulfamoylphenyl}-2-(2chlorophenyl)acetamide nh ₂ o=s=on=\ o f/g Ji ⁿ

According to the general procedure GP7.1, methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H-n-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and azetidine (31.8 mg, 0.56 mmol) was converted to the title compound and purified by preparative HPLC (Waters

XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (17 mg, 0.0359 mmol, 16% yield, 98% purity).

LC-MS (method A): Rt = 0.90 min; MS (ESI positive): m/z = 474 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.24-2.32 (m, 2H), 3.91 (s, 2H), 4.00 (br t, 2H), 4.39 (br. t, 2H ), 7.30-7.36 (m, 2H), 7.40-7.48 (m, 4H), 7.58 (d, 1H), 7.97 (dd, 1H), 8.01 (d, 1H), 8.38 (d, 1H), 8.41 ( d, 1H), 10.80 (s, 1H).

Example 442.

2-(2-Chlorophenyl)-N-{4-[4-(pyrrolidin-1-ylcarbonyl)-1H-pyrazol-1-yl]-3sulfamoylphenyl}acetamide nh ₂

O=S=O Pffo

According to the general procedure GP7.1, methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and pyrrolidine (39.6 mg, 0.56 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (21 mg, 0.0430 mmol, 20% yield, 98% purity).

LC-MS (method A): Rt = 0.95 min; MS (ESI positive): m/z = 488 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.79-1.88 (m, 2H), 1.89-1.97 (m, 2H), 3.46 (t, 2H), 3.68 (t, 2H ), 3.91 (s, 2H), 7.29-7.37 (m, 2H), 7.40-7.49 (m, 4H), 7.60 (d, 1H), 7.97 (dd, 1H), 8.06 (d, 1H), 8.38 ( d, 1H), 8.46 (d, 1H), 10.80 (s, 1H).

Example 443.

2-(2-Chlorophenyl)-N-(4-{4-[(3,3-difluoropyrrolidin-1-yl)carbonyl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide nh ₂

O=S=O P

Cl

According to general procedure GP7.1, methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and 3,3-difluoropyrrolidine (59.7 mg, 0.56 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (31 mg,

- 243 040608

0.0592 mmol, 27% yield, 95% purity.

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 524 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.70 (br t, 1H), 3.88 (br t, 1H), 3.91 (s, 2H), 3.97 (br t, 1H ), 4.19 (br t, 1H), 7.29-7.36 (m, 2H), 7.40-7.49 (m, 4H), 7.62 (br t, 1H), 7.98 (dd, 1H), 8.10 (s, 1H), 8.38 (d, 1H), 8.53 (br d, 1H), 10.81 (s, 1H), 2H, possibly overlapping with water signal.

Example 444.

2-(4-Chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (4-chlorophenyl)acetic acid were converted to the title compound (12.9 mg, 0.0275 mmol , yield 14%, purity 100%).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 445.

2-(2-Chloro-6-fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2-chloro-6-fluorophenyl)acetic acid were converted to the title compound (18.0 mg, 0.0369 mmol, yield 18%, purity 100%).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 488 [M+H]+.

Example 446.

N-{3-Sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-2-[4-(trifluoromethyl)phenyl]acetamide nh ₂ o=s=o

methodology

In accordance with the general

GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and [4-(trifluoromethyl)phenyl]acetic acid were converted to the title compound (10.6 mg , 0.0211 mmol, 11% yield, 100% purity.

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 504 [M+H]+.

Example 447.

2-(3-Fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (3-fluorophenyl)acetic acid were converted to the title compound (20.7 mg, 0.0457 mmol , yield 23%, purity 100%).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 454 [M+H]+.

Example 448.

2-(2,4-Dichlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2,4-dichlorophenyl)acetic acid were converted to the title compound (15.0 mg, 0.0297 mmol, 15% yield, 100% purity.

- 244 040608

LC-MS (method A): Rt = 1.22 min; MS (ESI positive): m/z = 504 [M+H]+.

Example 449.

2-(2-Bromophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2-bromophenyl)acetic acid were converted to the title compound (12.9 mg, 0.0251 mmol , yield 13%, purity 100%).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 514 [M+H]+.

Example 450.

2-(2,4-Difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2,4-difluorophenyl)acetic acid were converted to the title compound (13.9 mg, 0.0295 mmol, 15% yield, 100% purity.

LCMS (method A): Rt = 1.10 min; MS (ESI positive): m/z = 472 [M+H]+.

Example 451.

2-(3,4-Difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

GP6.2 method,

In accordance with the general

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (3,4-difluorophenyl)acetic acid were converted to the title compound (20.3 mg, 0.0431 mmol, 22% yield, 100% purity.

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 472 [M+H]+.

Example 452.

2-(3,5-Difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (3,4-difluorophenyl)acetic acid were converted to the title compound (20.3 mg, 0.0431 mmol, 22% yield, 100% purity.

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 472 [M+H]+.

Example 453.

2-(3-Chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide nh ₂ o=s=o

CI

n

In accordance with the general methodology of GP6.2,

-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (3-chlorophenyl)acetic acid were converted to the title compound (7.0 mg, 0.0149 mmol , yield 7%, purity 78%).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 454.

2-(4-Methylphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

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According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (4-methylphenyl)acetic acid were converted into the title compound (13.2 mg, 0.0294 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 455.

2-(4-Methoxyphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (4-methoxyphenyl)acetic acid were converted to the title compound (17.9 mg, 0.0385 mmol, 19% yield, 100% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 466 [M+H]+.

Example 456.

2-(2-Fluoro-4-methylphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

According to general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2-fluoro-4-methylphenyl) acetic acid was converted to the title compound (21.6 mg, 0.0462 mmol, 23% yield, 100% purity).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 468 [M+H]+.

Example 457.

2-(2-Fluoro-4-methoxyphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

According to general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and (2-fluoro-4-methoxyphenyl) acetic acid was converted to the title compound (23.5 mg, 0.0486 mmol, 24% yield, 100% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 484 [M+H]+.

Example 458.

2-[4-(Difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide

According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-[5(trifluoromethyl)pyridin-3-yl]benzenesulfonamide (0.20 mmol) and [4-(difluoromethyl)phenyl]acetic the acid was converted to the title compound (17.1 mg, 0.0352 mmol, 18% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 486 [M+H]+.

Example 459.

2-(4-Chlorophenyl)-N-[4-(6-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide

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In accordance with the general

method GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (4-chlorophenyl)acetic acid were converted to the title compound (14.0 mg, 0.0321 mmol, 15% yield, 81% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 436 [M+H]+.

Example 460.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

In accordance with the general methodology

GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2-fluorophenyl)acetic acid were converted to the title compound (15.0 mg, 0.0357 mmol, 17% yield, 91% purity).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 420 [M+H]+.

Example 461.

2-(2-Chloro-6-fluorophenyl)-X-[4-(6-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide

In accordance with the general methodology

GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2-chloro-6-fluorophenyl)acetic acid were converted to the title compound (10.3 mg, 0.0223 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 454 [M+H]+.

Example 462.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-[4-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and [4-(trifluoromethyl)phenyl]acetic acid were converted to the title compound (12.6 mg, 0.0268 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.16 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 463.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and [2-(trifluoromethyl)phenyl]acetic acid were converted to the title compound (20.0 mg, 0.0426 mmol, 20% yield, 76% purity).

LC-MS (method A): Rt = 1.12 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 464.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide

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According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (3-fluorophenyl)acetic acid were converted to the title compound (13.1 mg, 0.0312 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 420 [M+H]+.

Example 465.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2,4-dichlorophenyl)acetic acid were converted to the indicated title compound (13.0 mg, 0.0276 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 470 [M+H]+.

Example 466.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(2,4-difluorophenyl)acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2,4-difluorophenyl)acetic acid were converted to the indicated title compound (13.0 mg, 0.0297 mmol, 14% yield, 82% purity).

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 438 [M+H]+.

Example 467.

2-(2-Bromophenyl)-X-[4-(6-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide

In accordance with the general methodology

GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2-bromophenyl)acetic acid were converted to the title compound (18.8 mg, 0.0391 mmol, 19% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 480 [M+H]+.

Example 468.

K-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(3,4-difluorophenyl)acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (3,4-difluorophenyl)acetic acid were converted to the indicated title compound (13.9 mg, 0.0317 mmol, 15% yield, 100% purity).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 438 [M+H]+.

Example 469.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide

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In accordance with

by general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (4-methylphenyl)acetic acid were converted to the title compound (9.4 mg, 0.0226 mmol, 11% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 416 [M+H]+.

Example 470.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide ' ^H2 .N^CI o=s=o S o _____ JL n ₃ s' o n

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (4-methoxyphenyl)acetic acid were converted to the title compound (18.8 mg, 0.0435 mmol, 21% yield, 92% purity).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 432 [M+H]+.

Example 471.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluoro-4-methylphenyl)acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2-fluoro-4-methylphenyl)acetic acid were converted to the title compound (21.2 mg, 0.0489 mmol, 23% yield, 85% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 434 [M+H]+.

Example 472.

K-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluoro-4-methoxyphenyl)acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and (2-fluoro-4-methoxyphenyl)acetic acid were converted into the title compound (15.3 mg, 0.0340 mmol, 16% yield, 100% purity).

LC-MS (method A): Rt = 1.04 min; MS (ESI positive): m/z = 450 [M+H]+.

Example 473.

X-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide

According to the general procedure GP6.2, 5-amino-2-(6-chloropyridin-3-yl)-X[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and [4-(difluoromethyl)phenyl]acetic acid were converted to the title compound (12.6 mg, 0.0279 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.06 min; MS (ESI positive): m/z = 452 [M+H]+.

Example 474.

K-[4-(6-Chloropyridin-3-yl)-3-sulfamoylphenyl]-2-[2-chloro-4-(trifluoromethyl)phenyl]acetamide

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In accordance with the general

GP6.2 method,

5-amino-2-(6-chloropyridin-3-yl)-N

[(dimethylamino)methylene]benzenesulfonamide (0.21 mmol) and [2-chloro-4-(trifluoromethyl)phenyl]acetic acid were converted to the title compound (13.7 mg, 0.0272 mmol, 13% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 504 [M+H]+.

Example 475.

2-(2,4-Dichlorophenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-(5-fluoropyridin3-yl)benzenesulfonamide (0.25 mmol) and (2,4-dichlorophenyl)acetic acid were converted to the indicated in title compound (16.0 mg, 0.0352 mmol, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 454 [M+H]+.

Example 476.

2-(2-Fluoro-4-methylphenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-(5-fluoropyridin3-yl)benzenesulfonamide (0.25 mmol) and (2-fluoro-4-methylphenyl)acetic acid were converted to the title compound (42.2 mg, 0.101 mmol, 40% yield, 73% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 418 [M+H]+.

Example 477.

2-[4-(Difluoromethyl)phenyl]-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP6.2, 5-amino-N-[(dimethylamino)methylene]-2-(5-fluoropyridin3-yl)benzenesulfonamide (0.25 mmol) and [4-(difluoromethyl)phenyl]acetic acid were converted to the indicated title compound (27.5 mg, 0.0632 mmol, 25% yield, 78% purity).

LCMS (method A): Rt = 1.00 min; MS (ESI positive): m/z = 436 [M+H]+.

Example 478.

2-(2-Chlorophenyl)-N-[4-(4-cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general methods GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-Ni(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-cyclopropyl-1H-pyrazole (210 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (330 mg, 1.94 mmol) were converted without purification of intermediates to the title compound and purified twice as a final step using preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (1 mg, 0.00232 mmol, 2% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 1.27 min; MS (ESI positive): m/z = 431 [M+H]+.

1I-NMR (400 MHz, DMSO-06) δ [ppm]: 0.55-0.61 (m, 2H), 0.84-0.90 (m, 2H), 1.73-1.81 (m, 1H), 3.89 (s, 2H), 7.29-7.37 (m, 2H), 7.42-7.51 (m, 5H), 7.58 (s, 1H), 7.88 (s, 1H), 7.96 (dd, 1H), 8.33 (d, 1H), 10.74 (s, 1H).

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Example 479 and Example 480.

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4,6-difluoro- 2H-benzotriazole (300 mg, 1.94 mmol) and (2-fluorophenyl)acetic acid (267 mg, 1.74 mmol) were converted without purification of intermediates to the title compounds, which were purified and finally separated by preparative HPLC (Chromatorex C -18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Phenomenex Kinetex C18 EVO 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)).

Example 479.

N-(4-(4,6-Difluoro-2H-benzotriazol-2-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

F

NH ₂ \=\

O=S=O Νΐ/ E– ^F OdD' mg, 0.0238 mmol, yield after 4 steps 2%, purity 95%.

LC-MS (method J): Rt = 1.32 min; MS (ESI positive): m/z = 460 [M-H]-.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.84 (s, 2H), 7.16-7.24 (m, 2H), 7.31-7.38 (m, 1H), 7.43 (td, 1H) , 7.52-7.61 (m, 3H), 7.81 (dd, 1H), 7.87 (d, 1H), 8.05 (dd, 1H), 8.50 (d, 1H), 10.93 (s, 1H).

Example 480.

N-(4-(4,6-Difluoro-1H-benzotriazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide

NH ₂ o \u003d s \u003d o nN _f OdD ^

6.1 mg, 0.0132 mmol, yield over 4 steps 1%, purity 95%.

LC-MS (method J): Rt = 1.22 min; MS (ESI positive): m/z = 460 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.85 (s, 2H), 7.15-7.24 (m, 3H), 7.31-7.39 (m, 1H), 7.40-7.48 (m , 2H), 7.50 (s, 2H), 7.66 (d, 1H), 8.02 (dd, 1H), 8.52 (d, 1H), 10.93 (s, 1H).

Example 481 and Example 482.

According to general procedures GP1.2, GP2.1, GP3.3 and GP4.1, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4,6-difluoro- 2H-benzotriazole (300 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (296 mg, 1.74 mmol) were converted without purification of intermediates to the title compounds, which were purified and separated at the final step by preparative HPLC (Chromatorex C -18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Phenomenex Kinetex C18 EVO 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)).

Example 481.

2-(2-Chlorophenyl)-N-[4-(4,6-difluoro-1H-benzotriazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o _f pddbD ci ^HF

10.6 mg, 0.0222 mmol, yield over 4 steps 2%, purity 95%.

LC-MS (method J): Rt = 1.28 min; MS (ESI positive): m/z = 476 [M-H]-.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.95 (s, 2H), 7.19 (dd, 1H), 7.30-7.38 (m, 2H), 7.41-7.54 (m, 5H) , 7.66 (d, 1Н), 8.02 (dd, 1Н), 8.53 (d, 1Н), 10.95 (s, 1Н).

Example 482.

2-(2-Chlorophenyl)-N-[4-(4,6-difluoro-2H-benzotriazol-2-yl)-3-sulfamoylphenyl]acetamide

F

NH ₂ \=\

O=S=O NcX E— ^F

ODD'

13.1 mg, 0.0274 mmol, yield over 4 steps 2%, purity 95%.

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LC-MS (method J): Rt = 1.36 min; MS (ESI positive): m/z = 476 [M-H]-.

'H-NMR (600 MHz, DMSO-d6) δ [ppm]: 3.95 (s, 2H), 7.31-7.37 (m, 2H), 7.45-7.49 (m, 2H), 7.52-7.60 (m , 3H), 7.82 (dd, 1H), 7.88 (d, 1H), 8.06 (dd, 1H), 8.51 (d, 1H), 10.97 (s, 1H).

Example 483.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl}acetamide

According to general procedure GP8.2, sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65

N-(4-bromo-3-{[(dimethylamino)methylene]mmol) and 5-bromo-2-(trifluoromethyl)-1,3thiazole (275 mg, 1.19 mmol) were converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (11 mg, 0.0462 mmol, 7% yield, 97% purity). LCMS (method a): Rt = 1.16 min; MS (ESI positive): m/z = 476 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.91 (s, 2H), 7.29-7.36 (m, 2H), 7.41-7.48 (m, 2H), 7.53-7.58 (m, 3H), 7.90 (dd, 1H), 8.13 (d, 1H), 8.42 (d, 1H), 10.80 (s, 1H).

Example 484, Example 485, Example 486, Example 487 and Example 488.

To a mixture of 2-(2-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide (200 mg, 0.48 mmol), sodium trifluoromethanesulfinate (600 mg, 3.85 mmol ) and copper(II) triflate (35 mg; 0.10 mmol), acetonitrile (2 mL) was added under argon. tert-Butyl hydroperoxide (70 wt% in water, 0.53 mL, 3.85 mmol) was added dropwise to the resulting mixture with vigorous stirring using a syringe pump over 30 min. After stirring for an additional 15 hours, the reaction mixture was filtered. The resulting filtrate was concentrated in vacuo to approx. 1 ml and purified by HPLC to give and separate the title compounds.

Example 484.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-5-sulfamoyl-2-(trifluoromethyl)phenyl]acetamide

0.9 mg, yield 1%, purity 85%.

LC-MS (method M): Rt = 2.63 min; MS (ESI positive): m/z = 484 [M+H]+.

'H-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.99 (s, 2H), 6.33 (s, 2H), 7.35 (m, 2H), 7.45 (m, 1H), 7.48 (m , 1H), 7.87 (s, 1H), 8.14 (d, 1H), 8.22 (bs, 1H), 8.45 (d, 1H), 8.76 (s, 1H).

Example 485.

2-[2-Chloro-5-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

6.5 mg, 2% yield, 85% purity.

LC-MS (method M): Rt = 2.64 min; MS (ESI positive): m/z = 484 [M+H]+.

¹ H-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.99 (s, 2H), 6.33 (s, 2H), 7.35 (m, 2H), 7.45 (m, 1H), 7.48 (m , 1H), 7.87 (s, 1H), 8.14 (d, 1H), 8.22 (s, 1H), 8.45 (d, 1H), 8.76 (s, 1H).

Example 486.

2-[2-Chloro-5-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

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5.0 mg, 2% yield, 90% purity.

LC-MS (method M): Rt = 2.93 min; MS (ESI positive): m/z = 552 [M+H]+.

1H-NMR (600 MHz, CD3CN) δ [ppm] 4.07 (s, 2H), 6.34 (s, 2H), 7.66 (m, 2H), 7.78 (m, 1H), 7.89 (s, 1H) , 8.15 (d, 1H), 8.39 (s, 1H), 8.46 (d, 1H), 8.67 (s, 1H).

Example 487.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoyl-2-(trifluoromethyl)phenyl]acetamide

0.7 mg, yield 1%, purity 90%.

LC-MS (method M): Rt = 2.33 min; MS (ESI positive): m/z = 484 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 3.94 (s, 2H), 6.08 (s, 2H), 7.34 (m, 2H), 7.43 (m, 1H), 7.47 (m, 1H ), 7.73 (d, 1H), 8.02 (d, 1H), 8.13 (d, 1H), 8.37 (s, 1H), 8.47 (d, 1H).

Example 488.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

5.3 mg, 2% yield, 90% purity.

LC-MS (method M): Rt = 2.89 min; MS (ESI positive): m/z = 552 [M+H]+.

1Н-NMR (600 MHz, CD ₃ CN) δ [ppm] 4.13 (s, 2H), 6.37 (s, 2H), 7.54 (t, 1H), 7.74 (d, 1H), 7.81 (d, 1H), 7.92 (s, 1H), 8.18 (s, 1H), 8.40 (s, 1H), 8.49 (s, 1H), 8.71 (s, 1H).

Example 489, Example 490 and Example 491.

To a mixture of 2-(2-chlorophenyl)-N-(4-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)acetamide (150 mg, 0.30 mmol), sodium trifluoromethanesulfinate (378 mg, 2.42 mmol), and copper(II) triflate (22 mg; 0.06 mmol), acetonitrile (1.5 mL) was added under argon. tert-Butyl hydroperoxide (70 wt% in H ₂ O, 0.33 mL, 2.42 mmol) was added dropwise to the resulting mixture with vigorous stirring using a syringe pump over 30 min. After stirring for an additional 15 hours, the reaction mixture was filtered. The resulting filtrate was concentrated in vacuo to approx. 1 ml and purified by HPLC to give the following intermediates: 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3{[(dimethylamino)methylene] sulfamoyl}-2-(trifluoromethyl)phenyl}acetamide (5.4 mg, 3.0% yield, 95% purity), 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-(4-[1-(difluoromethyl) -1H-pyrazol-4-yl]-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)acetamide (6.1 mg, 3.2% yield, 90% purity), 2-(2-chlorophenyl)-N-{4- [1(difluoromethyl)-1H-pyrazol-4-yl]-5-{[(dimethylamino)methylene]sulfamoyl}-2-(trifluoromethyl)phenyl}acetamide (5.0 mg, 2.8% yield, 95% purity) and 2 -(2-chlorophenyl)-N-(4-[1-(difluoromethyl)-5-(trifluoromethyl)1H-pyrazol-4-yl]-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)acetamide (2.3 mg , yield 1.2%, purity 90%).

These intermediates were separately redissolved in methanol (0.5 ml) and an aqueous ammonia solution (0.5 ml) was added, followed by stirring at room temperature in

- 253 040608 within 2 days. Water was added and the resulting mixture was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried and concentrated in vacuo to give the title compounds.

Example 489.

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

4.3 mg, 3% yield, 95% purity.

LC-MS (method M): Rt = 2.64 min; MS (ESI positive): m/z = 509 [M+H]+.

1H-NMR (600 MHz, CD3CN) δ [ppm] 3.92 (s, 2H), 5.57 (s, 2H), 7.33 (m, 2H), 7.42 (t, 1H), 7.43 (m, 1H) , 7.46 (m, 1H), 7.60 (d, 1H), 7.82 (d, 1H), 7.92 (s, 1H), 8.20 (s, 1H), 8.25 (s, 1H).

Example 490.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide

5.0 mg, yield 3%, purity 90%.

LC-MS (method M): Rt = 2.82 min; MS (ESI positive): m/z = 509 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 3.99 (s, 2H), 5.50 (bs, 2H), 7.40 (t, 1H), 7.42 (d, 1H), 7.49 (dd, 1H ), 7.68 (dd, 1H), 7.75 (dd, 1H), 7.79 (dd, 1H), 7.89 (s, 1H), 8.22 (d, 1H), 8.38 (d, 1H), 8.88 (s, 1H) .

Example 491.

2-(2-Chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-sulfamoyl-2(trifluoromethyl)phenyl}acetamide

4.6 mg, 3% yield, 90% purity.

LC-MS (method M): Rt = 2.92 min; MS (ESI positive): m/z = 509 [M+H]+.

1Н-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.95 (s, 2H), 5.65 (s, 2H), 7.35 (m, 2H), 7.41 (t, 1H), 7.45 (m, 1H), 7.48 (m, 1H), 7.76 (s, 1H), 7.94 (s, 1H), 8.12 (s, 1H), 8.28 (s, 1H), 8.62 (s, 1H).

Example 492.

2-(2-Chlorophenyl)-N- {4-[1 -(difluoromethyl)-5 -(trifluoromethyl)-1 H-pyrazol-4-yl] -3 sulfamoylphenyl}acetamide

2.4 mg, 1% yield, 80% purity.

LC-MS (method M): Rt = 2.87 min; MS (ESI positive): m/z = 509 [M+H]+.

1H-NMR (600 MHz, CD3CN) δ [ppm] 3.92 (s, 2H), 5.50 (bs, 2H), 7.35 (m, 3H), 7.45 (m, 1H), 7.47 (m,

- 254 040608

1H), 7.59 (t, 1H), 7.81 (dd, 1H), 7.82 (s, 1H), 8.43 (d, 1H), 8.90 (s, 1H).

Example 493 and Example 494.

In a high pressure tube to a mixture of 2-(2-chlorophenyl)-N-(4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3{[(dimethylamino)methylene]sulfamoyl}phenyl)acetamide (200 mg, 0.40 mmol) and bis-(tetrafluoroborate) 1-chloromethyl-4-fluoro-1,4-diazonium-bicyclo[2.2.2]octane (286 mg, 0.81 mmol) under argon were added acetonitrile (2 ml). The resulting mixture was stirred vigorously at 80° C. for 15 h, then concentrated in vacuo and purified by HPLC to give the following intermediates: 2-(2-chlorophenyl)-N-(4-[1-(difluoromethyl)- 1H-pyrazol-4-yl]-3-{[(dimethylamino)methylene]sulfamoyl}-2-fluorophenyl)acetamide (18.5 mg, 8.5% yield, 95% purity) and 2-(2-chlorophenyl)-N-( 4-[1(difluoromethyl)-1H-pyrazol-4-yl]-5-{[(dimethylamino)methylene]sulfamoyl}-2-fluorophenyl)acetamide (4.9 mg, 2.0% yield, 85% purity).

These intermediates were individually redissolved in methanol (0.5 ml), and an aqueous ammonia solution (0.5 ml) was added, followed by stirring at room temperature for 2 days. Water was added and the resulting mixture was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried and concentrated in vacuo to give the title compounds.

Example 493.

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

0.%% NF rlZh' ⁴

16.1 mg, 8% yield, 95% purity.

LC-MS (method M): Rt = 2.41 min; MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.95 (s, 2H), 5.95 (bs, 2H), 7.16 (dd, 1H), 7.33 (m, 2H), 7.38 (t , 1H), 7.42 (m, 1H), 7.46 (m, 1H), 7.76 (s, 1H), 8.04 (s, 1H), 8.25 (t, 1H), 8.47 (s, 1H).

Example 494.

2-(2-Chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-5-sulfamoylphenyl}acetamide

4.1 mg, 2% yield, 85% purity.

LC-MS (method M): Rt = 2.56 min; MS (ESI positive): m/z = 459 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 3.95 (s, 2H), 5.62 (bs, 2H), 7.32 (m, 3H), 7.41 (t, 1H), 7.42 (m, 1H ), 7.46 (m, 1H), 7.91 (s, 1H), 8.26 (s, 1H), 8.53 (s, 1H), 8.90 (d, 1H).

Example 495.

2-(2-Chlorophenyl)-N-{4-[2-(dimethylamino)-1,3-thiazol-4-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-bromo- N,N-dimethyl-1,3-thiazol-2amine (123 mg, 0.59 mmol) was converted to the title compound and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid). acids) (30 mg, 0.0665 mmol, 10% yield, 97% purity). LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 452 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.06 (s, 6H), 3.88 (s, 2H), 6.91 (s, 1H), 7.29-7.35 (m, 2H) , 7.427.48 (m, 2H), 7.56 (d, 1H), 7.83 (s, 2H), 7.90 (dd, 1H), 8.27 (d, 1H), 10.65 (s, 1H).

Example 496.

2-(2-Chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-5-yl)phenyl]acetamide

- 255 040608

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 1,2-thiazole (195 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters Phenomenex Kinetex EVO C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (6.5 mg, 0.0159 mmol, 2% yield, 97% purity).

LC-MS (method I): Rt = 1.25 min; MS (ESI positive): m/z = 408 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.29-7.35 (m, 2H), 7.41-7.52 (m, 5H), 7.56 (d, 1H) , 7.88 (dd, 1H), 8.42 (d, 1H), 8.54 (d, 1H), 10.76 (s, 1H).

Example 497.

—(4— {[(2-Chlorophenyl)acetyl]amino} -2-sulfamoylphenyl)-N-cyclopropyl-N-methyl-1 H-pyrazole-4carboxamide nh ₂

O=S=O P OdD^

Cl ^H

According to the general procedure GP7.1, methyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2sulfamoylphenyl)-1H-pyrazole-4-carboxylate (100 mg, 0.22 mmol) and N-methylcyclopropanamine (39.6 mg, 0.56 mmol) in THF (0.25 ml only) was converted to the title compound and purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC ( Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (2.4 mg, 0.00492 mmol, 2% yield, 97% purity).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 488 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.58-0.64 (m, 2H), 0.80-0.87 (m, 2H), 2.97 (s, 3H), 3.03-3.11 (m , 1H), 3.91 (s, 2H), 7.29-7.37 (m, 2H), 7.37-7.49 (m, 4H), 7.58 (d, 1H), 7.98 (dd, 1H), 8.07 (s, 1H), 8.38 (d, 1H), 8.50 (s, 1H), 10.81 (s, 1H).

Example 498.

2-(2-Chlorophenyl)-2-hydroxy-N- {3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-pyrazol-1 yl] phenyl} ethanamide nh ₂ o=s=o ₇ ^f

D ' ^υι but

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide (160 mg, 0.35 mmol) was dissolved in ethylene glycol (1.2 mL) in a roll-sealed microwave vial (5 mL) and copper(II) trifluoroacetate hydrate (151 mg, 0.52 mmol) was added, the vessel was sealed with a rubber cap, and the flask was heated at 150°C for 12 h. Dichloromethane (30 mL) was added ) and water (20 ml), the layers were separated, the aqueous layer was extracted with dichloromethane (2x30 ml), the organic layers were combined, dried over sodium sulfate and the solvent was removed under reduced pressure. The crude reaction mixture was purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by a second preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% ammonia solution (32 %)) to give the title compound (1.5 mg, 0.003 mmol, 1% yield, 98% purity).

LC-MS (method B): Rt = 0.98 min; MS (ESI positive): m/z = 474 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSOD) δ ppm 5.53 (d, 1H) 6.77 (br s, 1H) 7.29-7.49 (m, 5H) 7.55-7.66 (m, 2H) 8.07 (dd, 1H) 8.18 (s, 1H) 8.61 (d, 1H) 8.73 ( s, 1H) 10.72 (s, 1H).

Example 499.

2-(2-Chlorophenyl)-N-{3-chloro-5-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide

- 256 040608

2-(2-Chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl)acetamide (135 mg, 0.26 mmol) was dissolved in dichloroethane (1 ml) in a roll-sealed microwave vial (5 ml) and copper(II) trifluoroacetate hydrate (91 mg, 0.32 mmol) was added, the vial was sealed with a rubber cap, and the flask was heated at 130°C for 24 h. Methanol was added (3 ml) and aqueous ammonia solution (25%, 1 ml) and the flask was heated at 50°C for 36 h. Dichloromethane (30 ml) and water (20 ml) were added, the layers were separated and the aqueous layer was extracted with dichloromethane (2x30 ml), the organic layers were combined, dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting mixture was purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the title compound (5 mg, 0.01 mmol, 4% yield over 2 steps, 81% purity ).

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 493 [M+H]+.

1H-NMR (400 MHz, DMSO-06) δ [ppm]: 3.94 (s, 2H), 7.26-7.33 (m, 2H), 7.37-7.45 (m, 2H), 8.06 (d, 1H), 8.25(d, 1H), 8.29(d, 1H), 8.35(s, 1H).

Example 500.

2-(2-Chlorophenyl)-N-(4-(4-cyano-3-hydroxy-1H-pyrαzol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3 {[(dimethylamino)methylene]sulfamoyl}phenyl]acetamide (200 mg, 0.425 mmol) was placed in a microwave sealable vial (5 ml), the vial was capped and filled with argon for 5 min. A solution of 0,5-cyclooctadiene)(methoxy)iridium(I) dimer (14 mg, 0.021 mmol), 4,4'-ditert-butyl-2,2'-dipyridyl (11.4 mg, 0.042 mmol) and bis-(pinacolato)diboron (129.4 mg, 0.51 mmol) in THF (0.42 mL), which was previously stirred under argon for 1 h at 80°С. The vessel was then heated at 80°C for 24 h, after which the solvent was removed under reduced pressure. Potassium hydroxide (72 mg, 1.27 mmol), water (2 ml) and dimethylformamide (2 ml) were added and hydrogen peroxide (30% solution in water, 0.13 ml, 1.27 mmol) was added dropwise. The mixture was stirred for 1 h at RT, after which aqueous ammonia (4 ml) was added and the mixture was stirred at RT overnight. Added an additional volume of aqueous ammonia (6 ml) and the mixture was stirred for another 48 h at RT. Dichloromethane (30 ml) and water (20 ml) were added, the layers were separated and the aqueous layer was extracted with dichloromethane (2x30 ml) and ethyl acetate (30 ml), the organic layers were combined, dried over sodium sulfate and the solvent was removed under reduced pressure. The solid was first purified by flash chromatography (MeOH:DCM 2:98 to 20:80) followed by purification by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give the indicated in the title compound (5.5 mg, 0.01 mmol, 3% yield over step 3, 95% purity).

LC-MS (method A): Rt = 1.84 min; MS (ESI positive): m/z = 431 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.90 (s, 2H), 7.28-7.36 (m, 2H), 7.41-7.48 (m, 2H), 7.50 (br s, 2H). 7.55 (d, 1H), 7.95 (dd, 1H), 8.34 (d, 1H), 8.54 (s, 1H), 10.79 (s, 1H), 11.35-12.45 (br s, 1H).

Example 501.

2-(2-Chlorophenyl)-N-[4-(1H-pyrazolo[4,3-c]pyridin-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.3, 2-χλορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 1H-pyrazolo[4, 3-c]pyridine (231 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (352 mg, 2.07 mmol) were converted to the title compound without purification of intermediates to the title compound and finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge

- 257 040608

C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (4.4 mg, 0.0100 mmol, 1% yield over 4 steps, 99% purity).

LC-MS (method A): Rt = 0.72 min; MS (ESI positive): m/z = 442 [M+H]+.

¹ H-NMR (400 MHz, DMSOL) δ [ppm]: 3.93 (s, 2H), 7.26-7.38 (m, 5H), 7.44-7.49 (m, 2H), 7.63 (d, 1H), 8.03 (dd, 1H), 8.40 (d, 1H), 8.47 (d, 1H), 8.58 (d, 1H), 9.21 (d, 1H), 10.87 (s, 1H).

Example 502.

2-(2-Chlorophenyl)-N-[4-(4,5-dimethyl-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo- 4,5-dimethyl-1,3-thiazole (114 mg, 0.59 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32 %)) (2.5 mg, 0.00573 mmol, 1% yield, 99% purity).

LC-MS (method B): Rt = 1.19 min; MS (ESI positive): m/z = 436 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.32 (s, 3H), 2.41 (s, 3H), 3.90 (s, 2H), 7.28-7.36 (m, 2H), 7.417.49 (m, 2H), 7.68 (d, 1H), 7.75 (s, 2H), 7.97 (dd, 1H), 8.36 (d, 1H), 10.79 (s, 1H).

Example 503.

2-(2-Chlorophenyl)-N-[4-(2,4-dimethyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide nh ₂ ch ₃ o=s=o rlDC

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 2,4-dimethyl-1,3-thiazole (114 mg, 0.59 mmol) was converted to the title compound and purified by preparative

HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Laomatic XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (2.4 mg , 0.00551 mmol, 1% yield, 99% purity.

LC-MS (method B): Rt = 0.94 min; MS (ESI positive): m/z = 436 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.03 (s, 3H), 2.60 (s, 3H), 3.89 (s, 2H), 7.25 (s, 2H), 7.28 -7.37 (m, 3H), 7.41-7.48 (m, 2H), 7.83 (dd, 1H), 8.35 (d, 1H), 10.69 (s, 1H).

Example 504.

2-(2-Chlorophenyl)-^[4-(4-methyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o rlDC

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 5-bromo- 4-methyl-1,3-thiazole (106 mg, 0.59 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Laomatic XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (3.7 mg, 0.00877 mmol, 1% yield, 97% purity).

LC-MS (method B): Rt = 0.90 min; MS (ESI positive): m/z = 422 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.13 (s, 3H), 3.90 (s, 2H), 7.25-7.37 (m, 5H), 7.42-7.48 (m, 2H) , 7.84 (dd, 1H), 8.37 (d, 1H), 9.01 (s, 1H), 10.71 (s, 1H).

Example 505.

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

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N-{4-(4-Amino-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide (403mg, 435µmol, 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 (ESI positive): m/z = 406 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.88 (s, 2H), 4.14 (s, 2H), 7.30 (d, 1H), 7.32 (m, 2H), 7.35 ( d, 1H), 7.44 (m, 2H), 7.45 (d, 1H), 7.48 (s, 2H), 7.94 (dd, 1H), 8.32 (d, 1H), 10.70 (s, 1H).

Example 506.

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

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1H-pyrazol-4yl]-2,2-difluoroacetamide (231 mg, 182 µmol, 50% purity) was dissolved in dichloromethane (3.6 ml) and treated with trifluoroacetic acid (0.7 ml, 9.1 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (8.6 mg, 10% yield, 99% purity).

LC-MS (method A): Rt = 0.98 min; MS (ESI positive): m/z = 484 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.90 (s, 2H), 6.44 (t, 1H), 7.33 (m, 2H), 7.41 (s, 2H), 7.45 ( m, 2Н), 7.55 (d, 1H), 7.91 (s, 1H), 7.96 (dd, 1H), 8.27 (s, 1H), 8.37 (d, 1H), 10.79 (s, 1H), 11.13 (s , 1H).

Example 507.

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

N-[1 -(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-1 H-pyrazol-4yl]-3,3,3-trifluoropropanamide (285 mg, 214 µmol, 50% purity) was dissolved in dichloromethane (2.8 ml) and treated with trifluoroacetic acid (0.8 ml, 10.7 mmol) followed by stirring at room temperature for 195 min. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (14.9 mg, 13% yield, 95% purity).

LC-MS (method A): Rt = 1.03 min; MS (ESI positive): m/z = 516 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.44 (q, 2H), 3.90 (s, 2H), 7.33 (m, 2H), 7.42 (s, 2H), 7.45 ( m, 2Н), 7.55 (d, 1H), 7.83 (d, 1H), 7.96 (dd, 1H), 8.21 (d, 1H), 8.36 (d, 1H), 10.59 (s, 1H), 10.77 (s , 1H).

Example 508 (racemic compound), Example 509 (enantiomer A) and Example 510 (enantiomer B).

Example 508.

N-[1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-3,3,3-trifluoro-2methylpropanamide

(±)-H1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)-Spyrazol-4-yl]-3,3,3-trifluoro -2-methylpropanamide (298 mg, 350 µmol, 80% purity) was dissolved in dichloromethane (7 ml) and treated with trifluoroacetic acid (1.3 ml, 17.5 mmol) followed by

- 259 040608 by stirring at room temperature for 4 hours. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (55 mg, 30% yield, 100% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 530 (M+H)+.

^-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.35 (d, 3H), 3.47 (m, 1H), 3.90 (s, 2H), 7.33 (m, 2H), 7.42 (s , 2H), 7.45 (m, 2H), 7.55 (d, 1H), 7.84 (d, 1H), 7.95 (dd, 1H), 8.22 (d, 1H), 8.36 (d, 1H), 10.63 (s, 1H), 10.77 (s, 1H).

mg of racemic compound was separated into enantiomers by chiral phase HPLC (instrument: Sepiatec: Prep SFC100; column: Chiralpak IA 5 µm 250x30 mm; eluent A: CO ₂ , eluent B: methanol; isocratic mode: 21% B; flow 100.0 ml /min; temperature: 40° C.; BPR: 150 bar; MWD @ 254 nm) to give the following two isomers.

Example 509.

N-[1 - (4- {[(2-Chlorophenyl) acetyl] amino} -2-sulfamoylphenyl) -1 H-pyrazol-4-yl] -3,3,3-trifluoro-2-methylpropanamide (enantiomer A), mg , purity 96%.

LC (method N): Rt = 2.56 min.

Example 510.

N-[1 - (4- {[(2-Chlorophenyl) acetyl] amino} -2-sulfamoylphenyl) -1 H-pyrazol-4-yl] -3,3,3-trifluoro-2-methylpropanamide (enantiomer B), mg , purity 99%.

LC (method N): Rt = 3.62 min.

Example 511 (cis racemic compound), Example 512 (trans enantiomer A) and Example 513 (trans enantiomer B).

Example 511.

2-(2-Chlorophenyl)-N-(4-{4-[(cis)-2,5-dimethylpyrrolidin-1-yl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide

2-(2-Chlorophenyl)-N-(3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-{4-(2,5-dimethylpyrrolidin-1-yl)-1Hpyrazol-1-yl}phenyl)acetamide (mixture of stereoisomers) (531 mg, 575 µmol, 80% purity) was dissolved in dichloromethane (7.4 ml) and treated with trifluoroacetic acid (2.2 ml, 28.8 mmol) followed by stirring at room temperature for 5 h. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (23.5 mg, 8% yield, 97% purity) as the meso isomer.

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 488 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.57 (m, 2H), 1.98 (m, 2H), 1.19 (d, 6H), 3.30 (m, 2H), 3.89 ( s, 2H), 7.33 (m, 2H), 7.45 (m, 2H), 7.46 (d, 1H), 7.52 (m, 2H), 7.54 (d, 1H), 7.54 (d, 1H), 7.95 (dd , 1H), 8.33 (d, 1H), 10.72 (s, 1H).

The racemic trans isomer 2-(2-chlorophenyl)-N-(4-{4-[(trans)-2,5dimethylpyrrolidin-1-yl]-1H-pyrazol-1-yl}-3- sulfamoylphenyl)acetamide (85.6 mg, 21%, 70% pure).

LC-MS (method A): Rt = 1.02 min; MS (ESI positive): m/z = 488 (M+H)+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.52 (m, 2H), 2.15 (m, 2H), 1.01 (d, 6H), 3.64 (m, 2H), 3.89 ( s, 2H), 7.33 (m, 2H), 7.40 (d, 1H), 7.44 (d, 1H), 7.45 (m, 2H), 7.49 (m, 2H), 7.53 (d, 1H), 7.95 (dd , 1H), 8.33 (d, 1H), 10.72 (s, 1H).

mg of racemic compound was separated into enantiomers by chiral phase HPLC (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; column: YMC Cellulose SC 5 µm 250x30 mm; eluent A: hexane + 0.1 vol. diethylamine (99%), eluent B: ethanol; gradient: 2050% B over 20 min; flow 40.0 ml/min; UV @ 254 nm) to give the following two isomers.

Example 512.

2-(2-Chlorophenyl)-N-(4-{4-[(trans)-2,5-dimethylpyrrolidin-1-yl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide (enantiomer A).

22.3 mg, 100% pure.

LC (method O): Rt = 4.35 min.

Example 513.

2-(2-Chlorophenyl)-N-(4-{4-[(trans)-2,5-dimethylpyrrolidin-1-yl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide (enantiomer B).

mg, 99% purity.

LC (method O): Rt = 5.32 min.

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Example 514.

N-(4-{4-[(2,2-Difluoroethyl)amino]-1H-pyrazol-1-yl}-3-sulfamoylphenyl)-2-(2-fluorophenyl)acetamide

N-(4-{4-[(2,2-Difluoroethyl)amino]-1H-pyrazol-1-yl}-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl)2-(2-fluorophenyl)acetamide (420 mg, 417 µmol, 60% purity) was dissolved in dichloromethane (5.4 ml) and treated with trifluoroacetic acid (1.6 ml, 20.9 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (13.8 mg, 7% yield, 95% purity).

LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 454 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.33 (m, 2H), 3.78 (s, 2H), 5.18 (t, 1H), 6.12 (tt, 1H), 7.19 ( m, 2H), 7.33 (m, 1H), 7.40 (m, 1H), 7.41 (d, 1H), 7.47 (s, 2H), 7.49 (d, 1H), 7.56 (d, 1H), 7.95 (dd , 1H), 8.32 (d, 1H), 10.74 (s, 1H).

Example 515.

2-(2-Chlorophenyl)-N-(3-sulfamoyl-4-{4-[(2,2,2-trifluoroethyl)amino]-1H-pyrazol-1yl}phenyl)acetamide

2-(2-Chlorophenyl)-N-(3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-{4-[(2,2,2-trifluoroethyl)amino]-1Hpyrazol-1-yl}phenyl) acetamide (528 mg, 455 µmol, 55% purity) was dissolved in dichloromethane (5.9 ml) and treated with trifluoroacetic acid (1.8 ml, 22.8 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (30 mg, 13% yield, 99% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 488 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.74 (dq, 2H), 3.89 (s, 2H), 5.51 (t, 1H), 7.32 (m, 2H), 7.43 ( d, 1H), 7.46 (s, 2H), 7.46 (d, 1H), 7.46 (m, 2H), 7.58 (d, 1H), 7.95 (dd, 1H), 8.32 (d, 1H), 10.72 (s , 1H).

Example 516.

2-(2-Chlorophenyl)-N-[4-(4-isopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(4-isopropyl-1H-pyrazol-1yl)phenyl}acetamide (410 mg, 457 µmol, 65% purity ) was dissolved in dichloromethane (5.9 ml) and treated with trifluoroacetic acid (1.8 ml, 22.9 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (44 mg, 22% yield, 100% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 433 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.22 (d, 6H), 2.86 (sept, 1H), 3.89 (s, 2H), 7.33 (m, 2H), 7.45 ( m, 2H), 7.50 (s, 2H), 7.51 (d, 1H), 7.68 (s, 1H), 7.91 (s, 1H), 7.97 (dd, 1H), 8.33 (d, 1H), 10.74 (s , 1H).

Example 517.

2-(2-Fluorophenyl)-N-[4-(4-isopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(4-isopropyl-1H-pyrazol-1-yl)phenyl}-2-(2fluorophenyl)acetamide (407 mg, 467 µmol, 65% purity ) was dissolved in dichloromethane (6.0 ml) and treated with trifluoroacetic acid 1.8 ml, 23.3 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (70 mg, 34% yield, 95% purity).

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LC-MS (method A): Rt = 1.17 min; MS (ESI positive): m/z = 417 [M+H]+.

¹ H-NMR (400 MHz, DMSOL) δ [ppm] 1.22 (d, 6H), 2.86 (sept, 1H), 3.79 (s, 2H), 7.18 (m, 1H), 7.20 (m, 1H ), 7.38 (m, 1H), 7.41 (m, 1H), 7.50 (s, 2H), 7.51 (d, 1H), 7.68 (s, 1H), 7.91 (s, 1H), 7.97 (dd, 1H) , 8.33 (d, 1H), 10.72 (s, 1H).

Example 518.

2-(2-Chlorophenyl)-N-{3-sulfamoyl-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]phenyl}acetamide

2-(2-Chlorophenyl)-N-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1yl]phenyl}acetamide (219 mg, 300 µmol, 85% purity) was dissolved in dichloromethane (6.0 ml) and treated with trifluoroacetic acid (1.2 ml, 15.0 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (56 mg, 39% yield, 100% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 473 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.60 (q, 2H), 3.90 (s, 2H), 7.33 (m, 2H), 7.43 (s, 2H), 7.45 ( m, 2H), 7.52 (d, 1H), 7.75 (s, 1H), 7.97 (dd, 1H), 8.10 (s, 1H), 8.36 (d, 1H), 10.78 (s, 1H).

Example 519.

2-(2-Fluorophenyl)-N-{3-sulfamoyl-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]phenyl}acetamide

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]phenyl}-2-(2fluorophenyl)acetamide (136 mg, 190 µmol, 85% purity) was dissolved in dichloromethane (3.8 ml) and treated with trifluoroacetic acid (0.7 ml, 9.50 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (22 mg, 24% yield, 95% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 457 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 3.60 (q, 2H), 3.80 (s, 2H), 7.19 (m, 2H), 7.33 (m, 1H), 7.41 (m , 1H), 7.43 (s, 2H), 7.52 (d, 1H), 7.75 (s, 1H), 7.97 (dd, 1H), 8.10 (s, 1H), 8.36 (d, 1H), 10.76 (s, 1H).

Example 520.

2-(2-Chlorophenyl)-N-[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-sulfamoylphenyl]acetamide nh ₂

O=S=O Ν-θ

ci

2-(2-Chlorophenyl)-K-{4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide (135mg, 220µmol , purity 95%) was dissolved in dichloromethane (4.4 ml) and treated with trifluoroacetic acid (847 μl, 11.0 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (13 mg, 14% yield, 100% purity).

LC-MS (method A): Rt = 1.11 min; MS (ESI positive): m/z = 433 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.18 (m, 2H), 1.32 (m, 2H), 2.46 (m, 1H), 3.91 (s, 2H), 7.33 ( m, 2H), 7.35 (s, 2H), 7.46 (m, 2H), 7.75 (d, 1H), 7.98 (dd, 1H), 8.40 (d, 1H), 10.85 (s, 1H).

Example 521.

2-(2-Chlorophenyl)-X-{3-sulfamoyl-4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl}acetamide nh ₂ o=s=o ON

Cl

2-(2-Chlorophenyl)-K-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-[3-(trifluoromethyl)-1,2,4-oxadiazol5-yl]phenyl}acetamide (355 mg, 380 µmol, 65% purity was dissolved in dichloromethane (4.9 ml) and treated with trifluoroacetic acid (1.46 ml, 19.0 mmol) followed by stirring at room temperature.

- 262 040608 night temperature. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (13 mg, 7% yield, 90% purity).

LC-MS (method A): Rt = 1.20 min; MS (ESI positive): m/z = 461 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.94 (s, 2H), 7.33 (m, 2H), 7.46 (m, 2H), 7.72 (s, 2H), 7.95 ( d, 1H), 8.00 (dd, 1H), 8.50 (d, 1H), 11.01 (s, 1H).

Example 522.

2-(2-Chlorophenyl)-X-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-sulfamoylphenyl}acetamide nh ₂ o=s=of

Cl

2-(2-Chlorophenyl)-K-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-[(2,4dimethoxybenzyl)sulfamoyl]phenyl}acetamide (498 mg, 495 µmol, 60% purity was dissolved in dichloromethane (6.4 ml) and treated with trifluoroacetic acid (1.91 ml, 24.8 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (15 mg, 6% yield, 90% purity).

LC-MS (method A): Rt = 1.08 min; MS (ESI positive): m/z = 443 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 3.93 (s, 2H), 7.33 (m, 2H), 7.46 (m, 2H), 7.55 (t, 1H), 7.64 ( s, 2H), 7.89 (d, 1H), 8.00 (dd, 1H), 8.47 (d, 1H), 10.95 (s, 1H).

Example 523.

N-{4-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide nh ₂ o=s=o nn _f

K-{4-[5-(Difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2fluorophenyl)acetamide (466 mg, 297 µmol, 37% purity was dissolved in dichloromethane (3.8 ml) and treated with trifluoroacetic acid (1.14 ml, 14.9 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (30 mg, 21% yield, 90% purity).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 427 [M+H]+.

1H-NMR (400 MHz, DMSOCH) δ [ppm] 3.83 (s, 2H), 7.19 (m, 1H), 7.20 (m, 1H), 7.34 (m, 1H), 7.41 (m, 1H) , 7.55 (t, 1H), 7.64 (s, 2H), 7.88 (d, 1H), 8.00 (dd, 1Н), 8.46 (d, 1H), 10.93 (s, 1H).

Example 524.

2-(2-Chlorophenyl)-K-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o nn ^x Xch ₃ o

ci

2-(2-Chlorophenyl)-K-{3-[(2,4-dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2yl)phenyl}acetamide (260mg, 313µmol , purity 60%) was dissolved in dichloromethane (6.4 ml) and treated with trifluoroacetic acid (1.21 ml, 15.7 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (51 mg, 39% yield, 96% purity).

LC-MS (method A): Rt = 0.96 min; MS (ESI positive): m/z = 407 [M+H]+.

1Н-NMR (400 MHz, DMSO-d6) δ [ppm] 2.59 (s, 3H), 3.92 (s, 2H), 7.33 (m, 2H), 7.45 (m, 2H), 7.62 (s, 2H), 7.85 (d, 1H), 8.01 (dd, 1H), 8.43 (d, 1H), 10.91 (s, 1H).

Example 525.

2-(2-Fluorophenyl)-X-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o nn o ^VcH3

K-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl}-2-(2

- 263 040608 fluorophenyl)acetamide (427 mg, 476 µmol, 60% purity) was dissolved in dichloromethane (6.1 ml) and treated with trifluoroacetic acid (1.83 ml, 23.8 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by flash chromatography to give the title compound (105 mg, 51% yield, 95% purity).

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 391 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 2.59 (s, 3H), 3.82 (s, 2H), 7.18 (m, 1H), 7.19 (m, 1H), 7.34 ( m, 1H), 7.41 (m, 1H), 7.61 (s, 2H), 7.85 (d, 1H), 8.01 (dd, 1H), 8.43 (d, 1H), 10.89 (s, 1H).

Example 526.

N-[4-(5-Methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide

N-{3-[(2,4-Dimethoxybenzyl)sulfamoyl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl}-2-(4methylphenyl)acetamide (351mg, 476µmol , purity 72%) was dissolved in dichloromethane (6.1 ml) and treated with trifluoroacetic acid (1.83 ml, 23.8 mmol) followed by stirring at room temperature overnight. The mixture was concentrated in vacuo and purified by HPLC to give the title compound (21 mg, 11% yield, 95% purity).

LC-MS (method B): Rt = 0.85 min; MS (ESI positive): m/z = 387 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm] 2.28 (s, 3H), 2.58 (s, 3H), 3.65 (s, 2H), 7.14 (d, 2H), 7.23 (d , 2Н), 7.60 (s, 2Н), 7.84 (d, 1H), 8.02 (dd, 1H), 8.40 (d, 1H), 10.78 (s, 1H).

Example 527.

2-(2-Chlorophenyl)-N-[4-(1H-pyrrol-3-yl)-3-sulfamoylphenyl]acetamide

tert-Butyl 3-(4-{[(2-chlorophenyl)acetyl]amino}-2-{[(dimethylamino)methylene]sulfamoyl}phenyl)1H-pyrrole-1-carboxylate (50 mg, 92 µmol) was dissolved in methanol (2 ml) and treated with 30% aqueous ammonia solution (2 ml) at room temperature for 3 days. The solvent was removed under reduced pressure and the crude product was purified by HPLC to give 22 mg of final product (94% purity, 58% yield).

LC-MS (method A): Rt = 0.97 min; MS (ESI positive): m/z = 390 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.86 (s, 2H), 6.36 (ddd, 1H), 6.56 (s, 2H), 6.83 (ddd, 1H), 7.13 ( ddd, 1H), 7.32 (m, 2H), 7.40 (d, 1H), 7.44 (m, 2H), 7.79 (dd, 1H), 8.27 (d, 1H), 10.50 (s, 1H), 11.04 (s , 1H).

Example 528.

2-(2-Chlorophenyl)-N-{4-[5-(difluoroacetyl)-1H-pyrrol-3-yl]-3-sulfamoylphenyl}acetamide

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(1H-pyrrol-3-yl)phenyl]acetamide (67 mg, 136 µmol, 90% purity) was dissolved in dichloromethane (6 ml) and treated with difluoroacetyl chloride (93 mg, 813 mmol) and N,N-diisopropylethylamine (242 μl, 1.35 mmol) followed by stirring at room temperature overnight. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and it was extracted with dichloromethane. The combined organic phases were washed with brine, dried on a Whatman filter and concentrated under reduced pressure to give crude 2-(2-chlorophenyl)-N-(4-[1-(difluoroacetyl)-1H-pyrrol-3-yl]-3{ [(dimethylamino)methylene]sulfamoyl}phenyl)acetamide (57 mg), which was used without further purification.

The crude acylation product (57 mg) was dissolved in methanol (1 ml) and THF (1 ml) and treated with 25% aqueous ammonia (2 ml) at 50° C. for 3 h. The solvent was removed under reduced pressure and the crude product was purified with by HPLC to give 7 mg (95% purity, 13% yield) of the title compound.

LC-MS (method B): Rt = 0.95 min; MS (ESI positive): m/z = 468 (M+H)+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.88 (s, 2H), 6.85 (t, 1H), 7.22 (s, 2H), 7.32 (m, 2H), 7.43 (d ,

- 264 040608

1H), 7.43 (s, 1H), 7.45 (m, 2Н), 7.64 (s, 1H), 7.83 (dd, 1H), 8.32 (d, 1H), 10.60 (s, 1H), 12.53 (s, 1H ).

Example 529.

2-(2-Chlorophenyl)-N-[4-(1-methyl-1H-pyrrol-3-yl)-3-sulfamoylphenyl]acetamide

2-(2-Chlorophenyl)-N-[3-{[(dimethylamino)methylene]sulfamoyl}-4-(1-methyl-1H-pyrrol-3yl)phenyl]acetamide (105 mg, 229 µmol) was dissolved in methanol (0.8 ml) and treated with 30% aqueous ammonia solution (4.5 ml) at room temperature for 2 days. The solvent was removed under reduced pressure and the crude product was purified by HPLC to give 30 mg of final product (95% purity, 31% yield).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 404 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.65 (s, 3H), 3.86 (s, 2H), 6.31 (dd, 1H), 6.70 (s, 2H), 6.76 ( dd, 1H), 7.08 (dd, 1H), 7.32 (m, 2H), 7.38 (d, 1H), 7.44 (m, 2Н), 7.78 (dd, 1H), 8.26 (d, 1H), 10.50 (s , 1H).

Example 530.

2-(2-Chlorophenyl)-N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-sulfamoylphenyl]acetamide nh ₂

2-(2-Chlorophenyl)-N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3{[(dimethylamino)methylene]sulfamoyl}phenyl]acetamide (93mg, 192µmol ) was dissolved in methanol (0.8 ml) and THF (0.9 ml) and treated with 30% aqueous ammonia solution (2 ml) at 50°C overnight. The solvent was removed under reduced pressure and the crude product was purified by HPLC to give 43 mg of the final product (99% purity, 51% yield).

LC-MS (method A): Rt = 1.07 min; MS (ESI positive): m/z = 429 [M+H]+.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.37 (s, 3H), 3.90 (s, 2H), 6.21 (d, 1H), 7.16 (s, 2H), 6.97 ( d, 1H), 7.33 (m, 2H), 7.35 (d, 1H), 7.45 (m, 2H), 7.87 (dd, 1H), 8.37 (d, 1H), 10.74 (s, 1H).

Example 531, Example 532, Example 533 and Example 534.

To a mixture of 2-(2-chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-4-[4-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl)acetamide (200 mg, 0.39 mmol) , sodium trifluoromethanesulfinate (486 mg, 3.11 mmol), and copper(II) triflate (28 mg, 0.08 mmol), acetonitrile (4 mL) was added under argon. tert-Butyl hydroperoxide (70 wt% in H ₂ O, 0.42 ml, 3.11 mmol) was added dropwise to the resulting mixture with vigorous stirring using a syringe pump over 30 min. After stirring for an additional 15 h, additional amounts of sodium trifluoromethanesulfinate (486 mg, 3.11 mmol) and tert-butyl hydroperoxide (70 wt% in H ₂ O, 0.42 ml, 3.11 mmol) were added. The reaction mixture was stirred for 12 hours and then filtered. The resulting filtrate was concentrated in vacuo to approx. 1 ml and purified by HPLC to give the following intermediates:

2-(2-chlorophenyl)-N-(3-{[(dimethylamino)methylene]sulfamoyl}-2-(trifluoromethyl)-4-[4(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)acetamide (3.1 mg, yield 1.1%, purity 80%),

2-(2-chlorophenyl)-N-(5-{[(dimethylamino)methylene]sulfamoyl}-2-(trifluoromethyl)-4-[4(trifluoromethyl)-1H-pyrazol-1-yl]phenyl)acetamide (5.5 mg, yield 1.8%, purity 75%),

2-[2-chloro-3-(trifluoromethyl)phenyl]-N-(5-{[(dimethylamino)methylene]sulfamoyl}-2-(trifluoromethyl)4-[4-(trifluoromethyl)-1H-nirazole-1- yl]phenyl)acetamide (5.0 mg, yield 1.5%, purity 75%),

2-[2-chloro-5-(trifluoromethyl)phenyl]-X-(5-{[(dimethylamino)methylene]sulfamoyl}-2-(trifluoromethyl)4-[4-(trifluoromethyl)-1H-pyrazole-1- yl]phenyl)acetamide (3.9 mg, 1.3% yield, 85% purity).

The appropriate intermediates were redissolved in methanol (0.5 ml), and an aqueous ammonia solution (0.5 ml) was added, followed by stirring at room temperature for 2 days. Water was added and the resulting mixture was extracted three times with dichloromethane. The combined organic layers were washed with brine, dried, concentrated in vacuo and the isolated residues further purified by HPLC to give the title compounds.

Example 531.

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

- 265 040608

2.8 mg, yield 1.1%, purity 80%.

LC-MS (method K): Rt = 2.93 min; MS (ESI positive): m/z = 527 [M+H]+.

¹ H-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.94 (s, 2H), 6.10 (s, 2H), 7.34 (m, 2H), 7.43 (m, 1H), 7.47 (m , 1H), 7.75 (d, 1H), 8.01 (d, 1H), 8.06 (s, 1H), 8.35 (s, 1H), 8.38 (s, 1H).

Example 532.

2-(2-Chlorophenyl)-N-{5-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide

0.6 mg, yield 0.2%, purity 75%.

LC-MS (method K): Rt = 3.22 min; MS (ESI positive): m/z = 527 [M+H]+.

¹ H-NMR (600 MHz, CD ₃ CN) δ [ppm] 3.99 (s, 2H), 6.39 (s, 2H), 7.36 (m, 2H), 7.46 (m, 1H), 7.48 (m , 1H), 7.90 (s, 1H), 8.07 (s, 1H), 8.20 (s, 1H), 8.35 (s, 1H), 8.78 (s, 1H).

Example 533.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-{5-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl}acetamide

1.5 mg, yield 0.6%, purity 95%.

LC-MS (method K): Rt = 3.42 min; MS (ESI positive): m/z = 595 [M+H]+.

1H-NMR (600 MHz, CD3CN) δ [ppm] 4.10 (s, 2H), 6.40 (s, 2H), 7.52 (t, 1H), 7.71 (d, 1H), 7.78 (d, 1H) , 7.92 (s, 1H), 8.08 (s, 1H), 8.34 (s, 1H), 8.36 (s, 1H), 8.68 (s, 1H).

Example 534.

2-[2-Chloro-5-(trifluoromethyl)phenyl]-N-{5-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1Hpyrazol-1 -yl]phenyl}acetamide

1.4 mg, 0.6% yield, 99% purity.

LC-MS (method K): Rt = 3.45 min; MS (ESI positive): m/z = 595 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 4.07 (s, 2H), 6.41 (s, 2H), 7.65 (m, 2H), 7.78 (d, 1H), 7.92 (s, 1H ), 8.08 (s, 1H), 8.37 (s, 1H), 8.38 (s, 1H), 8.66 (s, 1H).

Example 535, Example 536, Example 537 and Example 538.

To a mixture of 2-(2-chlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide (200 mg, 0.49 mmol), sodium trifluoromethanesulfinate (611 mg, 3.91 mmol ) and copper(II) triflate (35 mg; 0.10 mmol), acetonitrile (6 mL) was added under argon. tert-Butyl hydroperoxide (70 wt% in H ₂ O, 0.54 mL, 3.91 mmol) was added dropwise to the resulting mixture with vigorous stirring using a syringe pump over 30 min. After stirring for an additional 15 h, additional amounts of sodium trifluoromethanesulfinate (611 mg, 3.91 mmol) and tert-butyl hydroperoxide (70 wt.% in H ₂ O, 0.54 ml, 3.91 mmol) were added. The reaction mixture was stirred for 12 hours and then filtered. The resulting filtrate was concentrated in vacuo to approx.

- 266 040608 ml and purified using HPLC to obtain separated specified in the title compounds.

Example 535.

2-[2-Chloro-6-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

3.0 mg, yield 0.8%, purity 70%.

LC-MS (method K): Rt = 3.10 min; MS (ESI positive): m/z = 545 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 4.22 (s, 2H), 6.45 (s, 2H), 7.51 (t, 1H), 7.75 (m, 3H), 7.83 (s, 1H ), 7.94 (d, 1H), 8.35 (s, 1H), 8.55 (s, 1H).

Example 536.

2-[2-Chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

5.4 mg, yield 1.8%, purity 90%.

LC-MS (method K): Rt = 3.14 min; MS (ESI positive): m/z = 545 [M+H]+.

¹ H-NMR (600 MHz, CD ₃ CN) δ [ppm] 4.08 (s, 2H), 6.46 (s, 2H), 7.51 (t, 1H), 7.71 (d, 1H), 7.74 (d , 1H), 7.78 (d, 1H), 7.82 (s, 1H), 7.94 (d, 1H), 8.31 (s, 1H), 8.63 (s, 1H).

Example 537.

2-[2-Chloro-5-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

6.5 mg, yield 1.7%, purity 70%.

LC-MS (method K): Rt = 3.19 min; MS (ESI positive): m/z = 545 [M+H]+.

¹ H-NMR (600 MHz, CD3CN) δ [ppm] 4.06 (s, 2H), 6.46 (s, 2H), 7.65 (m, 2H), 7.74 (d, 1H), 7.78 (d, 1H ), 7.82 (s, 1H), 7.95 (d, 1H), 8.33 (s, 1H), 8.61 (s, 1H).

Example 538.

2-[2-Chloro-4-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide

3.2 mg, yield 0.9%, purity 75%.

LC-MS (method K): Rt = 3.23 min; MS (ESI positive): m/z = 545 [M+H]+.

D-NMR (600 MHz, CD3CN) δ [ppm] 4.06 (s, 2H), 6.46 (s, 2H), 7.64 (m, 2H), 7.74 (d, 1H), 7.81 (s, 1H) , 7.83 (s, 1H), 7.95 (d, 1H), 8.33 (s, 1H), 8.61 (s, 1H).

Example 539.

N-[4-(3-tert-Butyl-4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

- 267 040608

According to general methods GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-Ni(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 2.59 mmol), 3-tert-butyl-1H -pyrazole-4carbonitrile (579 mg, 3.88 mmol) and (2-chlorophenyl)acetic acid (661 mg, 3.88 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) (303 mg, 0.642 mmol, 25% yield over 4 steps, 98% purity).

LCMS (method A): Rt = 1.23 min; MS (ESI positive): m/z = 472 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 1.39 (s, 9H), 3.91 (s, 2H), 7.30-7.36 (m, 2H), 7.39-7.48 (m, 4H), 7.61 (d, 1H), 7.98 (dd, 1H), 8.38 (d, 1H), 8.84 (s, 1H), 10.84 (s, 1H).

Example 540.

N-[4-(3-Bροm-4-cyanoο-1H-pyρazοl-1-yl)-3-sulfamοylphenyl]-2-(2-chlorophenyl)acetamide

According to the general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (1.00 g, 2.59 mmol), 3-6ροm-1H- pyrazοl-4-carbοnitρyl (667 mg, 3.88 mmol) and (2-chlorophenyl)acetic acid (480 mg, 2.81 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Chromatorex C- 18 10 µm, 125x30 mm, acetonitrile/water + 0.1% formic acid) (92 mg, 0.186 mmol, 7% yield over 4 steps, 97% purity).

LC-MS (method A): Rt = 1.15 min; MS (ESI positive): m/z = 494/496 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.92 (s, 2H), 7.30-7.36 (m, 2H), 7.42-7.48 (m, 2H), 7.55 (s, 2H), 7.60 (d, 1H), 7.94 (dd, 1H), 8.40 (d, 1H), 8.56 (s, 1H), 10.87 (s, 1H).

Example 541.

2-(2-Chlορphenyl)-N-{4-[4-chlορ-3-(triftορmethyl)-1H-pyρazοl-1-yl]-3-sulfamοylphenyl}acetamide

According to general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chlορ-3- (triftορmethyl)-1Hpyrazole (331 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (293 mg, 1.72 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (90 mg, 0.182 mmol, 14% yield over 4 steps, 90% purity).

LC-MS (method A): Rt = 1.26 min; MS (ESI positive): m/z = 493 [M+H]+.

1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 3.92 (s, 2H), 7.30-7.37 (m, 2H), 7.42-7.49 (m, 2H), 7.53 (s, 2H) , 7.62 (d, 1H), 7.95 (dd, 1H), 8.41 (d, 1H), 8.55 (d, 1H), 10.86 (s, 1H).

Example 542.

2-(2-Chlορphenyl)-N-[4-(3,4-dimethyl-1 H-pyrazol-1 -yl)-3-sulfamoylphenyl]acetamide

According to the general methods GP1.2, GP2.2, GP3.2 and GP4.2, 2-chlορ-N-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 3,4-dimethyl- 1H-pyrazole (186 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (216 mg, 1.27 mmol) were converted without purification of intermediates to the title compound and finally purified with

- 268 040608 preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (27 mg, 0.0645 mmol, 5% yield over 4 steps, 90% purity).

LC-MS (method A): Rt = 1.13 min; MS (ESI positive): m/z = 419 [M+H]+.

¹ H-NMR (400 MHz, DMSOL) δ [ppm]: 2.01 (d, 3H), 2.17 (s, 3H), 3.89 (s, 2H), 7.29-7.36 (m, 2H), 7.41

7.49 (m, 3H), 7.56 (s, 2H), 7.78 (s, 1H), 7.94 (dd, 1H), 8.32 (d, 1H), 10.72 (s, 1H).

Example 543.

N-[4-(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide

According to general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 4-chloro-3, 5-dimethyl-1H-pyrazole (253 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (291 mg, 1.71 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (52 mg, 0.115 mmol, 9% yield over 4 steps, 98% purity).

LC-MS (method A): Rt = 1.21 min; MS (ESI positive): m/z = 453 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.02 (s, 3H), 2.19 (s, 3H), 3.91 (s, 2H), 7.15 (s, 2H), 7.30- 7.37 (m, 2H), 7.42-7.52 (m, 3H), 7.96 (dd, 1H), 8.37 (d, 1H), 10.82 (s, 1H).

Example 544.

2-(2-Chlorophenyl)-N-[4-(1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ o=s=o Nc=\ φχά Cl ^H

According to general procedures GP1.2, GP2.4, GP3.2 and GP4.3, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 1H-pyrazole (132 mg , 1.94 mmol) and (2-chlorophenyl)acetic acid (339 mg, 1.99 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by two additional preparative HPLCs (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (25 mg, 0.640 mmol, 4 steps yield 5%, purity 97%).

LC-MS (method A): Rt = 1.01 min; MS (ESI positive): m/z = 391 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.90 (s, 2H), 6.51 (dd, 1H), 7.29-7.36 (m, 2H), 7.40-7.50 (m, 4Н), 7.53 (d, 1H), 7.78 (d, 1H), 7.98 (dd, 1H), 8.09 (dd, 1H), 8.36 (d, 1H), 10.77 (s, 1H).

Example 545.

2-(2-Chlorophenyl)-N-[4-(3-cyano-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-methyl-1H- pyrazole-3-carbonitrile (208 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (292 mg, 1.71 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters YMC C18 5 µm 100x50 mm, acetonitrile/water + 0.2% aqueous ammonia solution (32%)) (110 mg, 0.256 mmol, yield for 4 stages 20%, purity 90%).

LC-MS (method B): Rt = 0.94 min; MS (ESI negative): m/z = 428 [M-H]-.

1H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.09 (s, 3H), 3.93 (s, 2H), 6.92 (s, 1H), 7.31-7.36 (m, 2H), 7.39 (br s, 2H), 7.44-7.49 (m, 2H), 7.52 (d, 1H), 7.96 (dd, 1H), 8.42 (d, 1H), 10.89 (s, 1H).

- 269 040608

Example 546.

2-(2-Chlorophenyl)-N-[4-(3-hydroxy-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

According to general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-methyl-1H- pyrazol-3-ol (190 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (229 mg, 1.34 mmol) were converted without purification of intermediates to the title compound and were finally purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.2% aqueous ammonia (32%)) (16.1 mg, 0.0383 mmol, yield for 4 stages 3%, purity 98%). LC-MS (method B): Rt = 0.61 min; MS (ESI positive): m/z = 421 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d6) δ [ppm]: 2.01 (s, 3H), 3.89 (s, 2H), 5.55 (s, 1H), 7.30-7.36 (m, 4H), 7.437.48 (m, 3H), 7.95 (dd, 1H), 8.32 (d, 1H), 10.00 (s, 1H), 10.76 (s, 1H).

Example 547 and Example 548.

According to general procedures GP1.2, GP2.2, GP3.2 and GP4.2, 2-chloro-X-(2,4dimethoxybenzyl)-5-nitrobenzenesulfonamide (500 mg, 1.29 mmol), 5-methyl-1H- pyrazole-4-carbonitrile (208 mg, 1.94 mmol) and (2-chlorophenyl)acetic acid (291 mg, 1.71 mmol) were converted without purification of intermediates to the title compounds and purified and separated at the final step by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Sepiatec Prep SFC100; Chiralpak IA 5 µm 250x30 mm; eluent A: CO ₂ , eluent B: ethanol + 0.2 vol% aqueous solution ammonia (32%)).

Example 547.

2-(2-Chlorophenyl)-N-[4-(4-cyano-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

mg, 0.105 mmol, yield over 4 steps 8%, purity 98%.

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 430 [M+H]+.

LC-MS (method L): Rt = 1.69 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.20 (s, 3H), 3.91 (s, 2H), 7.21-7.37 (m, 4H), 7.41-7.49 (m, 2H), 7.54 (d, 1H), 7.94 (dd, 1H), 8.15 (s, 1H), 8.41 (d, 1H), 10.88 (s, 1H).

Example 548.

2-(2-Chlorophenyl)-N-[4-(4-cyano-3-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide nh ₂ CH ₃ o=s=o nA =N

ci mg, 0.221 mmol, yield over 4 steps 16%, purity 98%.

LC-MS (method A): Rt = 1.05 min; MS (ESI positive): m/z = 430 [M+H]+.

LC-MS (method L): Rt = 2.81 min.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 2.37 (s, 3H), 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.37-7.50 (m, 4H), 7.55 (d, 1H), 7.93 (dd, 1H), 8.38 (d, 1H), 8.72 (s, 1H), 10.83 (s, 1H).

Example 549.

2-(2-Chlorophenyl)-N-{4-[4-(morpholin-4-yl)-1,3-thiazol-2-yl]-3-sulfamoylphenyl}acetamide

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 4-(2 -bromo-1,3-thiazol-4-yl) morpholine (148 mg,

- 270 040608

0.59 mmol) was converted to the title compound and purified by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (16 mg, 0.0325 mmol, 5% yield, 97% purity).

LC-MS (method A): Rt = 1.09 min; MS (ESI positive): m/z = 493 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.34-3.40 (m, 4H), 3.71-3.77 (m, 4H), 3.88 (s, 2H), 7.05 (s, 1H), 7.29-7.36 (m, 2H), 7.41-7.48 (m, 2H), 7.57 (d, 1H), 7.62 (s, 2H), 7.90 (dd, 1H), 8.28 (d, 1H), 10.66 (s, 1H).

Example 550.

2-(2-Chlorophenyl)-N-{4-[5-(morpholin-4-yl)-1,3-thiazol-2-yl]-3-sulfamoylphenyl}acetamide nh ₂ o=s=o

According to the general procedure GP8.2, N-(4-6pom-3{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300mg, 0.65mmol) and 4-(2bromo- 1,3-thiazol-5-yl)-morpholine (148 mg, 0.59 mmol) was converted to the title compound and purified twice by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (23 mg, 0.0467 mmol, 8% yield, 97% purity). LC-MS (method A): Rt = 0.99 min; MS (ESI positive): m/z = 493 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.37-3.42 (m, 4H), 3.69-3.76 (m, 4H), 3.88 (s, 2H), 7.27-7.35 ( m, 5H), 7.38-7.47 (m, 3H), 7.81 (dd, 1H), 8.34 (d, 1H), 10.65 (s, 1H).

Example 551.

2-(2-Chlorophenyl)-N-[4-(5-methyl-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide nh ₂ ch ₃ o=s=os% 94-5%

According to the general procedure GP8.2, N-(4-bromo-3-{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (300 mg, 0.65 mmol) and 2-bromo- 5-methyl-1,3-thiazole (211 mg, 1.19 mmol) was converted to the title compound and purified by preparative HPLC (Waters

XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) followed by another preparative HPLC (Waters Phenomenex Kinetex EVO C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) (2.1 mg, 0.00498 mmol, yield 1 %, purity 98%).

LC-MS (method A): Rt = 1.14 min; MS (ESI positive): m/z = 422 [M+H]+.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: methyl signal overlaps with solvent signal, 3.90 (s, 2H), 7.29-7.36 (m, 2H), 7.42-7.48 (m, 2H), 7.65-7.74 (m, 4H), 7.98 (dd, 1H), 8.38 (d, 1H), 10.80 (s, 1H).

Example 552.

2-(2-Chlorophenyl)-X-[4-(pyridin-4-yl)-3-sulfamoylphenyl]acetamide

N-(4-Bromo-3-{[(dimethylamino)methylidene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide (500 mg, 1.09 mmol), pyridin-4-ylboronic acid (268 mg, 2.18 mmol) , bis-(triphenylphosphine)palladium(II) dichloride (CAS 13965-03-2) (38.4 mg, 54.5 µmol) and triphenylphosphine (14.3 mg, 54.5 µmol) were dissolved in n-propanol (10 ml). After purging with argon for 5 min, an aqueous solution of potassium carbonate (2.7 ml, 1.0 M, 2.7 mmol) was added and the solution was again purged with argon for 5 min. The reaction mixture was heated for 1 h at 100°C. Added the same amount of reagents and the reaction mixture was heated for 1 h at 100°C. Thereafter, the crude product was filtered through celite and the solvent was removed under reduced pressure. The crude product was used without further purification in the next step.

Crude 2-(2-chlorophenyl)-N-[3-{[(dimethylamino)methylidene]sulfamoyl}-4-(pyridin-4yl)phenyl]acetamide from the previous step (530 mg, 1.16 mmol) was dissolved in methanol (50 ml ) and an aqueous ammonia solution (50 ml) was added. The reaction mixture was stirred at room temperature until the reaction was complete, and the solvent was removed under reduced pressure. The crude product was purified from

- 271 040608 by HPLC (Chromatorex C-18 10 µm, 125x30 mm, acetonitrile/water + 0.1% aqueous ammonia solution (32%)). Traces of triphenylphosphine oxide were removed after a second HPLC run to give the title compound (79.3 mg, 90% purity, 15% yield over 2 steps).

LC-MS (method A): Rt = 0.80 min; MS (ESI positive): m/z = 402 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO^) δ [ppm]: 3.91 (s, 2H), 7.26-7.37 (m, 4H), 7.37-7.41 (m, 3H), 7.44-7.49 (m, 2H ), 7.86 (dd, 1H), 8.38 (d, 1H), 8.55–8.61 (m, 2H), 10.70 (s, 1H).

Example 553.

1-(4-{[(2-Chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxamide

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3{[(dimethylamino)methylene]sulfamoyl}phenyl]acetamide (200 mg, 0.425 mmol) was placed in a sealed a microwave vial (5 ml) was sealed, the vial was capped and filled with argon for 5 min. A solution of 0,5-cyclooctadiene)(methoxy)iridium(I) dimer (14 mg, 0.021 mmol), 4,4'-di-tert-butyl-2,2'-dipyridyl (11.4 mg, 0.042 mmol), and bis-(pinacolato)diboron (129.4 mg, 0.51 mmol) in THF (0.42 mL), which was previously stirred under argon for 1 h at 80°С. The vessel was then heated at 80°C for 24 h, after which the solvent was removed under reduced pressure. Potassium hydroxide (72 mg, 1.27 mmol), water (2 ml) and dimethylformamide (2 ml) were added and hydrogen peroxide (30% solution in water, 0.13 ml, 1.27 mmol) was added dropwise. The mixture was stirred for 1 h at room temperature after which aqueous ammonia (4 ml) was added and the mixture was stirred at room temperature overnight. Added an additional volume of aqueous ammonia (6 ml) and the mixture was stirred for another 48 h at room temperature. Dichloromethane (30 ml) and water (20 ml) were added, the layers were separated and the aqueous layer was extracted with dichloromethane (2x30 ml) and ethyl acetate (30 ml), the organic layers were combined, dried over sodium sulfate and the solvent was removed under reduced pressure. The solid was first purified by flash chromatography (MeOH:DCM, 2/98 to 20/80) followed by purification by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid) to give white solid (9.7 mg, 0.01 mmol, 5% yield over Step 3, 92% purity).

LC-MS (method A): Rt = 0.84 min; MS (ESI positive): m/z = 434 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d6) δ ppm 3.91 (s, 2H) 7.19 (br s, 1H) 7.27-7.37 (m, 2H) 7.38-7.51 (m, 4 H) 7.57 (d, 1 H) 7.70 (br s, 1H) 7.97 (dd, 1H) 8.10 (s, 1H) 8.37 (d, 1H) 8.44 (s, 1H) 10.81 (s, 1H).

Example 554, Example 555, Example 556 and Example 557.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide (500 mg, 1.2 mmol) was dissolved in acetonitrile (4 mL) and ferrocene ( 224 mg, 1.2 mmol) along with trifluoroacetic acid (308 µl, 2.4 mmol). The mixture was stirred at room temperature and hydrogen peroxide (30% aqueous, 491 µl, 4.81 mmol) was added over 15 min using a syringe pump. The mixture was stirred for 1 hour at room temperature, after which an aqueous solution of sodium thiosulfate (saturated solution, 2 ml) was added and the mixture was stirred for another 5 minutes. Then brine (50 ml) was added and the aqueous layer was extracted with dichloromethane (3x70 ml), the organic layers were combined, a peroxide test was performed on the organic layer (negative), the organic phase was passed through a water repellent filter and the solvent was removed under reduced pressure. The resulting solid was purified by flash chromatography (MeOH/DCM, 2/98 to 20/80 to 100/0) followed by preparative HPLC (Waters XBridge C18 5 µm 100x30 mm, acetonitrile/water + 0.1% formic acid ) to give the four separated title compounds as white solids.

Example 554.

2-(2-Chloro-3-hydroxyphenyl)-X-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

19.2 mg, 0.04 mmol, 4% yield, 95% purity.

LC-MS (method A): Rt = 0.82 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.85 (s, 2H) 6.85 (dd, 1H) 6.90 (dd, 1H) 7.05-7.14 (m, 1 H) 7.44 ( br s, 2Н) 7.58 (d, 1H) 7.97 (dd, 1H) 8.31 (s, 1H) 8.39 (d, 1Н) 8.86 (s, 1Н) 10.13 (br s, 1H) 10.80 (s, 1H).

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Example 555.

2-(2-Chloro-4-hydroxyphenyl)-Ni[4-(4-cyano-III-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

mg, 0.04 mmol, yield 4%, purity 95%.

LC-MS (method A): Rt = 0.84 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.76 (s, 2H) 6.72 (dd, 1H) 6.83 (d, 1H) 7.22 (d, 1H) 7.44 (br s , 2Н) 7.57 (d, 1H) 7.96 (dd, 1H) 8.31 (s, 1H) 8.39 (d, 1Н) 8.86 (s, 1Н) 9.84 (br s, 1H) 10.75 (s, 1H).

Example 556.

2-(2-Chloro-5-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide

17.4 mg, 0.04 mmol, 4% yield, 95% purity.

LC-MS (method A): Rt = 0.87 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.79 (s, 2H), 6.70 (dd, 1H), 6.84 (d, 1H), 7.21 (d, 1H), 7.45 (br s, 2Н), 7.58 (d, 1H), 7.98 (dd, 1H), 8.29-8.32 (m, 1H), 8.40 (d, 1H), 8.86 (s, 1H), 9.67 (s, 1H) , 10.81(s, 1H).

Example 557.

2-(2-Chloro-6-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrαzol-1-yl)-3-sulfamoylphenyl]acetamide

19.4 mg, 0.04 mmol, 4% yield, 95% purity.

LC-MS (method A): Rt = 0.93 min; MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm]: 3.86 (s, 2H), 6.81 (d, 1H), 6.90 (dd, 1H), 7.07-7.14 (m, 1H) , 7.44 (s, 2Н), 7.56 (d, 1H), 7.94 (dd, 1H), 8.30 (s, 1H), 8.41 (d, 1Н), 8.85 (s, 1H), 10.02 (s, 1H), 10.74(s, 1H).

Example 558.

2-(2-Chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-hydroxyacetamide

A 100 ml Erlenmeyer flask containing sterile cell growth medium (20 ml) was inoculated with DMSO with a cryo-culture (0.2 ml) of Streptomyces antibioticus (NRRL 3238). Cell growth medium consisting of D-(+)-glucose monohydrate (10 g/l), yeast extract (1 g/l), meat extract (1 g/l) and tryptose (2 g/l) was adjusted to pH 7.2 with sodium hydroxide solution (16% in water) and sterilized at 121°C for 20 min. After inoculation, the growth flask was agitated on an orbital shaker (165 rpm) at 27°C for 72 h. preculture (5 ml). Then, the flask was shaken on an orbital shaker (165 rpm) at 27°C for 72 hours.

A 10 L fermentor was filled with the same cell growth medium (8.3 L) and adjusted to pH 7.2. Silicone oil (0.5 ml) and Synperonic (0.5 ml) were added and the mixture was sterilized at 121°C for 40 min. A 2 L Erlenmeyer flask culture was added to the fermenter under sterile conditions. The fermenter was operated under gauge pressure (0.7 bar), aerated with air (3 L min– ¹ ) and agitated (300 rpm) at 27°C. After 8 hours, example 39 (250 mg, 0.601 mmol) dissolved in DMF (20 ml) was added and fermentation was continued for 123.5 hours.

The culture liquid was extracted with methyl isobutyl ketone (20 L) for 19.5 h, and again with methyl isobutyl ketone (10 L) for 14.3 h. The two organic phases were combined and concentrated to dryness under reduced pressure. The residue was treated with methanol/water. This solution was extracted three times with n-hexane (50 ml). The methanol/water layer was concentrated to dryness. The crude product was absorbed on the Isolute and chromatographed first on the Biotage Isolera, then on the preparation

- 273 040608 active HPLC (Waters XBridge C18 5 µ, 100x30 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 0.00-0.50 min 10% B (40 >70 ml/min), 0.51-5.50 min 21-41% B (70 ml/min, room temperature) to give the title compound.

25.3 mg, 0.0586 mmol, 10% yield, 99% purity.

Optical rotation: [a] _D ²⁰ = -15° +/-0.2° (c=1, DMSO).

MS (ESI positive): m/z = 432 [M+H] ⁺ .

¹ H-NMR (400 MHz, DMSOD) δ [ppm]: 5.53 (d, 1H), 6.79 (d, 1H), 7.34-7.40 (m, 2H), 7.43 (br s, 2H), 7.47 (dd, 1H), 7.57-7.62 (m, 2H), 8.08 (dd, 1H), 8.31 (s, 1H), 8.62 (d, 1H), 8.87 (s, 1H), 10.74 (s, 1H).

Biological analyzes

The following analyzes can be used to illustrate the industrial applicability of the compounds in accordance with the present invention.

Examples were tested in selected biological assays one or more times. When testing has been performed more than once, data are reported either as mean (average) values or as median values, where the mean, also referred to as the arithmetic mean, means the sum of the values obtained divided by the number of values obtained, and the median value means the median number of a group of received values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the median value. If the number of values in the data set is even, the median is the average of the two median values.

If a meaningful calculation of means or medians is not possible due to the presence of measured values outside the detection range of the given assay (indicated by < or > in the tables below), all individual measured values are reported.

The examples were synthesized one or more times. When synthesis was run more than once, data from biological assays are mean values or median values calculated using datasets obtained from testing one or more batches of synthesis.

In vitro studies

FLIPR analysis using P2X4 human HEK cells.

HEK293 cells stably expressing human P2X4 were plated in poly-D-lysine coated 384-well plates at a seeding density of 30,000 cells/well and incubated overnight. P2X4 function was assessed by measuring changes in intracellular calcium using the calcium chelating dye Fluo8-AM (Molecular Devices) on a fluorescence imaging plate reader spectrophotometer (FLEX/FLIPR station; Molecular Devices). On the day of analysis, medium was removed and cells were incubated for 30 min at 37°C and 5% CO ₂ in 30 μl of dye buffer (Hanks' balanced salt solution, 10 mM HEPES, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 2 mM probenecid , 5 mM D-glucose monohydrate, 5 μM Fluo8-AM, pH=7.4). Compounds diluted in probenecid buffer (Hanks' balanced salt solution, 10 mM HEPES, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 2 mM probenecid, 5 mM D-glucose monohydrate, pH 7.4) were added in a volume of 10 μl and left to incubate in for 30 min at room temperature. The final concentration of DMSO in the analyzed sample was 0.5%. The agonist, Bz-ATP (Tocris), was added in a volume of 10 μl at a concentration representing the EC ₈₀ value. The EC ₈₀ Bz-ATP value was determined each day of analysis prior to compound profiling. Fluorescence was measured over a 120 second interval at 2 second intervals. The excitation and emission wavelengths used for fluorescence monitoring 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 basal fluorescence and the data was normalized to the control agonist. Compounds were tested in triplicate per plate and averages were plotted in Excel XLFit to determine IC ₅₀ values, percent maximum inhibition, and Hill coefficients.

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Example Number P2X4 human HEK cells (FLIPR analysis) cf. 1C ₅₀ [nM] P2X4 human HEK cells (FLIPR analysis) cf. efficiency [%] 2 19384 50 3 942 76 4 259 83 5 249 91 6 1069 84 7 3081 73 8 2555 79 9 7 83 10 7 81 AND >25000 31 12 >25000 34 13 514 100 14 >25000 26 15 379 99 16 262 89 17 288 89 18 4700 66 19 47 71 20 140 67 21 170 67 22 224 76 23 1176 89 24 45 92 25 26 93 26 27 85 27 70 74 28 31 90 29 FROM 75 thirty 222 87 31 112 81 32 139 93 33 31 79 34 448 79 35 224 90 36 667 81 37 848 81 38 329 87 39 32 96 40 1236 90 41 357 70 42 24 71 43 210 87 44 378 97 45 75 74

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46 916 87 47 472 66 48 297 82 49 135 94 50 149 88 51 134 94 52 154 82 53 169 52 54 557 75 55 1403 74 56 121 70 57 141 71 58 73 54 59 4650 73 60 917 80 61 400 79 62 249 94 63 130 87 64 104 83 65 355 62 66 86 90 67 1510 98 68 128 75 69 210 80 70 118 85 71 132 80 72 576 96 73 168 52 74 49 84 75 213 87 76 >25000 34 77 71 82 78 517 97 79 2035 78 80 79 96 81 >25000 40 82 >25000 36 83 >25000 36 84 >25000 29 85 42 92 86 353 97 87 342 82 88 80 87 89 2315 83

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90 774 85 91 169 94 92 143 92 93 74 73 94 413 72 95 54 87 96 233 83 97 201 103 98 124 77 99 499 87 100 319 86 101 202 83 102 99 80 103 174 103 104 2231 95 105 108 101 106 4633 92 107 >25000 44 108 >25000 35 109 655 86 110 267 51 111 373 58 112 263 62 FROM 133 86 114 367 69 115 802 57 116 155 75 117 102 66 118 347 53 119 270 55 120 >25000 31 121 292 70 122 266 88 123 109 79 124 166 62 125 292 86 126 1906 92 127 209 85 128 107 91 129 157 89 130 284 71 131 155 58 132 80 62 133 107 82

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134 147 89 135 73 90 136 211 84 137 1168 89 138 238 100 139 107 100 140 77 92 141 638 96 142 116 78 143 247 84 144 292 62 145 >25000 49 146 364 66 147 80 100 148 132 63 149 211 56 150 433 80 151 81 83 152 105 79 153 182 74 154 thirty 84 155 108 86 156 243 94 157 153 90 158 2598 89 159 12 82 160 58 89 161 >25000 43 162 19 92 163 93 89 164 27 83 165 42 93 166 1519 78 167 64 94 168 70 75 169 85 86 170 126 70 171 2238 90 172 48 58 173 28 80 174 45 79 175 226 88 176 268 71 177 35 83

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178 40 70 179 35 89 180 319 77 181 179 59 182 161 89 183 39 96 184 67 96 185 248 71 186 40 78 187 33 84 188 31 89 189 199 60 190 540 58 191 180 76 192 575 69 193 427 84 194 325 84 195 86 68 196 164 75 197 86 87 198 136 94 199 299 85 200 131 90 201 4326 83 202 48 90 203 99 86 204 72 86 205 73 89 206 29 98 207 12 98 208 33 91 209 37 91 210 116 76 211 75 94 212 149 86 213 47 93 214 36 86 215 38 95 216 96 101 217 51 84 218 957 92 219 250 65 220 276 108 221 40 63

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222 92 83 223 26 87 224 28 94 225 70 91 226 111 104 227 404 95 228 37 92 229 16 94 230 351 90 231 51 81 232 81 89 233 93 80 234 93 96 235 >25000 35 236 36 54 237 1885 72 238 682 76 239 2592 81 240 3438 93 241 48 92 242 37 86 243 496 87 244 141 73 245 474 88 246 252 100 247 69 64 248 84 74 249 8463 72 250 193 82 251 21 96 252 808 88 253 257 85 254 41 102 255 25 81 256 130 83 257 51 81 258 thirty 97 259 50 91 260 398 100 261 111 81 262 235 92 263 337 96 264 4067 76 265 352 84

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266 7 94 267 2 98 268 5 103 269 1043 81 270 >25000 51 271 1146 82 272 507 90 273 35 60 274 19 97 275 507 82 276 195 96 277 186 90 278 93 102 279 61 96 280 60 101 281 481 76 282 56 80 283 60 94 284 54 94 285 246 97 286 6 87 287 31 78 288 275 68 289 6 89 290 36 81 291 100 95 292 58 87 293 76 75 294 174 75 295 >25000 9 296 136 87 297 32 87 298 108 104 299 203 88 300 27 100 301 10 74 302 56 97 303 97 91 304 73 65 305 21 49 306 278 80 307 115 62 308 64 91 309 317 93

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310 86 59 311 285 104 312 37 69 313 713 82 314 27 83 315 34 81 316 362 86 317 1206 68 318 >25000 43 319 7277 73 320 >25000 51 321 87 84 322 186 81 323 2584 81 324 3050 59 325 9 94 326 17 95 327 AND 94 328 12 94 329 13 100 330 14 101 331 25 66 332 326 89 333 15 101 334 18 98 335 20 98 336 28 109 337 thirty 96 338 32 91 339 33 92 340 34 89 341 41 86 342 41 101 343 42 101 344 44 102 345 46 93 346 46 105 347 85 89 348 47 96 349 37 99 350 49 87 351 51 88 352 54 91 353 57 87

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354 60 92 355 62 76 356 63 96 357 71 87 358 74 88 359 77 84 360 132 93 361 97 83 362 102 78 363 108 110 364 715 77 365 FROM 89 366 128 97 367 131 83 368 133 100 369 141 110 370 143 76 371 152 99 372 166 83 373 167 89 374 386 82 375 660 79 376 9 98 377 27 80 378 89 84 379 29 87 380 299 69 381 1241 77 382 315 87 383 45 93 384 524 81 385 47 72 386 76 64 387 34 73 388 196 68 389 22 77 390 1698 91 391 186 98 392 9659 64

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393 134:16400; >25000; >25000 49 394 740 86 395 73 86 396 9580; >25000; >25000; >25000; >25000 44 397 >25000 43 398 207 57 399 84 92 400 87 88 401 23 82 402 41 85 403 16 88 404 175 73 405 5665 65 406 6839 64 407 429 86 408 2645 74 409 445 85 410 5450 69 411 84 90 412 1595 68 413 74 89 414 >25000 20 415 200 69 416 8300; 17800; >25000; >25000 51 417 51 68 418 15 91 419 274 89 420 69 75 421 680 86 422 46 90 423 53 86 424 29 88 425 50 74 426 24 86 427 72 65 428 27 57 429 108 91 430 86 87 431 2880 83 432 597 92 433 >25000 28 434 17800; >25000 50 435 588 77 436 12527 56

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437 39 53 438 18 75 439 4 94 440 112 96 441 185 91 442 181 89 443 122 84 444 635 77 445 60 71 446 621 76 447 1022 68 448 472 63 449 135 73 450 148 72 451 244 86 452 76 65 453 74 77 454 1442 58 455 5 74 456 18 59 457 558 70 458 1075 85 459 1340 88 460 646 84 461 137 93 462 929 89 463 18 99 464 648 92 465 26 92 466 363 91 467 9 93 468 278 97 469 453 90 470 483 93 471 269 92 472 197 97 473 530 93 474 323 93 475 64 88 476 58 89 477 259 91 478 47 82 479 145 79 480 125 105 481 50 103

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482 2341 73 483 71 86 484 401 63 485 128 100 486 7343 71 487 >25000 45 488 2330 78 489 2055 83 490 91 95 491 9092 67 492 531 92 493 228 90 494 205 94 495 128 75 496 22 87 497 54 97 498 18200; >25000 50 499 347 69 500 >25000 40 501 3 92 502 13785 49 503 47 102 504 33 98 505 131 93 506 391 91 507 180 86 508 172 63 509 326 71 510 439 73 511 343 60 512 4253 76 513 893 94 514 106 102 515 45 101 516 96 68 517 187 74 518 36 80 519 105 82 520 43 76 521 6900; 17200; >25000; >25000; >25000; >25000 52 522 71 87 523 149 89 524 322 87 525 5170 72

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526 331 51 527 125 86 528 42 95 529 72 92 530 33 112 531 2317 84 532 11500; 12900; 17000 60 533 >25000 26 534 >25000 17 535 3839 91 536 12400; 16800 67 537 3618 95 538 3908 83 539 127 103 540 1 79 541 >25000 50 542 20 97 543 267 98 544 1 85 545 19 100 546 97 75 547 60 94 548 5 94 549 8 85 550 1 87 552 1 88 553 5 82 554 383 83 555 22 94 556 65 94 557 AND 89 558 1377 75

FLIPR methods for h/m/rP2X4 1321N1 astrocytoma cells.

1321N1 astrocytoma cells stably expressing human P2X4 or rat P2X4 or mouse P2X4 were seeded in a Collagen I TC-treated microplate at a seeding density of 10,000 cells/well and incubated overnight. P2X4 function was assessed by measuring changes in intracellular calcium using calcium chelating dye F1uo8-AM (Molecular Devices) on a fluorescence imaging plate reader spectrophotometer (FLEX/FLIPR station; Molecular Devices). On the day of analysis, the medium was removed and cells were incubated for 30 min at 37°C and 5% CO ₂ in 30 μl of dye buffer (Hanks' balanced salt solution, 10 mM HEPES, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 2 mM probenecid, 5 mM D-glucose monohydrate, 5 µM Fluo8-AM, pH 7.4). Compounds diluted in probenecid buffer (Hanks' balanced salt solution, 10 mM HEPES, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 2 mM probenecid, 5 mM D-glucose monohydrate, pH 7.4) were added in a volume of 10 μl and left to incubate in for 30 min at room temperature. The final concentration of DMSO in the analyzed sample was 0.25%. The agonist, Mg-ATP (Sigma), was added in a volume of 10 μl at a concentration representing the EC ₈₀ value. The EC ₈₀ value was determined to be 0.5 μM for human and mouse P2X4 and 5 μM for rat P2X4. Fluorescence was measured over a 120 second interval at 2 second intervals. The excitation and emission wavelengths used for fluorescence monitoring were 470-495 nm and 515-575 nm, respectively. The data were analyzed based on the peak increase in relative fluorescence units (RFU) compared to basal fluorescence and the data were normalized to the control agonist. Compounds were tested in triplicate per plate and averages were plotted in Excel XLFit to determine IC ₅₀ values, percent maximum inhibition, and Hill coefficients.

Example number P2X4 1321N1 human astrocytoma cells (FLIPR assay) cf. 1C ₅₀ [nM] P2X4 1321N1 human astrocytoma cells (FLIPR assay) cf. efficiency G%1 19 57 nM 60% 39 64 nM 83% 326 46 nM 80% Example number P2X4 1321N1 mouse astrocytoma cells (FLIPR assay) cf. 1C ₅₀ |nM] P2X4 1321N1 mouse astrocytoma cells (FLIPR assay) cf. efficiency G%1 19 43 nM 69% 39 37 nM 87% 326 26 nM 87%

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Example number P2X4 1321N1 rat astrocytoma cells (FLIPR assay) cf. 1C ₅₀ |nM] P2X4 1321N1 rat astrocytoma cells (FLIPR assay) cf. efficiency G%1 19 71 nM 57% 39 308 nM 87% 326 325 nM 99%

Electrophysiological analysis using P2X4 human HEK cells.

Electrophysiological analysis a.

HEK293 cells stably expressing human P2X4 were plated in T75 cell culture flasks at a density of 7*10 ⁶ cells and incubated overnight. P2X4 function was analyzed using an automated patch-clamp PatchLiner platform (Nanion) in single-electrode mode. The composition of the extracellular buffer was as follows (in mM): NaCl 145, KCl 4, HEPES 10, CaCl ₂ 1, MgCl ₂ 0.5, D-glucose monohydrate 10, pH 7.4. The intracellular buffer contained (in mM): CsF 135, EGTA 1, HEPES 10, NaCl 10, pH 7.2. On the day of analysis, cells were harvested using Accumax (Sigma) and resuspended in extracellular buffer. The ligand agonist, adenosine 5'-triphosphate (ATP, 5 μM), was added in a volume of 5 μl, washed off immediately with extracellular buffer (40 μl). The cell voltage was fixed at -80 mV, and the ligand was added every 5 min for 20 min. During this period, the response to the agonist was stable and the compounds were measured at one concentration per well. Compounds diluted in extracellular buffer (final concentration of DMSO in the analyzed sample 0.3%) were added in a volume of 40 µl and left to incubate for 8 min at room temperature. The data was analyzed based on the reduction in the peak amplitude of the current and normalized to the control agonist. Mean values were plotted in Excel XLFit to determine IC ₅₀ values, percent maximum inhibition, and Hill coefficients.

Example number P2X4 human HEK cells (PatchLiner system, electrophysiology) cf. 1C ₅₀ |nM] 19 111 39 138 326 57 380 320

Electrophysiological analysis B.

Cell culture conditions: HEK-293 mito-Photina pcDNA3(neo-)/pPURO N/pcDNA3_P2RX4, clone 2a/4 (HEK-293 mito-Photina/hP2RX4) cells were cultured in EMEM, Minimum Essential Eagle's Medium with Earl's Balanced Salt Solution ( BioWhittaker cat. BE12-125F) supplemented with 5 ml 200 mM ultraglutamine1 (BioWhittaker cat. BE17-605E/U1), 5 ml 100X penicillin/streptomycin (BioWhittaker cat. DE17-602E; final concentration 1%), 4 ml 50 mg/ ml G418 (Sigma cat. G8168-100 ml; final concentration 400 µg/ml), 10 µl 10 mg/ml puromycin (InvivoGen cat. antpr-1; final concentration 0.2 µg/ml) and 50 ml fetal bovine serum ( Sigma Cat F7524, 10% final concentration.

Experimental protocol: HEK-293 cell lines were seeded 72 or 96 hours before the experiment at a concentration of 5 or 2.5 million cells, respectively, per T225 flask. Shortly before experiments, cells were washed twice with Ca ²⁺ /Mg ²⁺ free D-PBS (Euroclone cat. ECB4004L) and detached from the flask with trypsin-EDTA (Sigma, cat. T4174 diluted 1/10). The cells were then resuspended in the suspension solution: 25 ml of EX-CELL ACF CHO medium (Sigma, cat. C5467); 0.625 ml HEPES (BioWhittaker, cat. BE17-737E); 0.25 ml 100x penicillin/streptomycin (BioWhittaker, cat. DE17602E), 0.1 ml soybean trypsin inhibitor 10 mg/ml (Sigma, cat. T6522), and placed on a QPatch 16X.

Preparation and storage of compounds: stock solutions of compounds were used (10 mM; 100% DMSO; stored at -20°C). Fresh stock solutions (1 or 3 mM, 100% DMSO) were prepared shortly before the experiments (0.1% final DMSO concentration).

A DMSO solution was obtained from SIGMA (Cat.# D-5879) and stored at room temperature.

Patch-clamp analysis with QPatch16X (FIG. 1): Standard whole-cell voltage clamp experiments were performed at room temperature using multi-electrode technology.

In the case of experiments with voltage clamping at hP2X4, data were collected at a frequency of 2 kHz. After placing the seal and channel in the whole cell configuration, the cells were maintained at -90 mV and the hP2X4 current was induced by the agonist in the absence (vehicle period, ie 0.1% DMSO) or in the presence of the compound of interest at increasing concentrations; see application protocol in FIG. 1.

Output: maximum incoming current induced by the agonist (ATP 5 μM).

The intracellular solution contained (mM) 135 CsF, 10 NaCl, I EGTA, 10 HEPES (pH 7.2 with

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CsOH), while the extracellular solution contained (mM) 145 NaCl, 4 KCl, 0.5 MgCl2, 1 CaCl2, 10 HEPES, 10 glucose (pH 7.4 with NaOH).

Sophion software was used for data collection and analysis was performed offline using Excel and GraphPad Prism software.

If possible, i.e. when the % inhibition value for the highest concentration tested was greater than 50%, the dose-response curve data was fitted using the following equation:

Y=100/(1 + ^10A ((LogIC ₅₀ -X)*HillSlope))

[X means log concentration; Y means normalized response (from 100 to 0%, decreasing as X increases); LogIC ₅₀ - same log units as X; HillSlope means dimensionless slope or Hill slope].

Example number P2X4 human HEK cells (QPatch, electrophysiology) cf. 1C ₅ o [nM] Number of exp. 19 278 4 20 195 4 25 222 5 26 222 5 321 227 4 Example number P2X4 human HEK cells (QPatch, electrophysiology) cf. 1C ₅₀ [nM] Number of exp. 326 51 6 331 155 5 349 117 3 360 205 3 380 157 4 381 2583 3

Ex vivo studies

Analysis using P2X4 human monocytes.

The principle of the assay is to measure calcium influx through endogenous P2X4 channels into primary human monocytes after activation with 2',3'-O-(4-benzoylbenzoyl)-ATP (BzATP). Changes in intracellular calcium concentration were measured with a FliprTM device (Molecular Devices) using a calcium sensitive dye (Fluo-8). In primary monocytes, P2X4 is located on the lysosomal membrane, so exocytosis must be triggered to expose P2X4 to the cell membrane.

Human peripheral blood mononuclear cells (PBMC) from anticoagulated blood (blood cells, BC) were isolated by density gradient centrifugation. Whole blood was diluted 1:3 with PBS. 30 ml samples were carefully layered on top of 15 ml Biocoll (BIOCHROM) in 50 ml centrifuge tubes (Falcon). The tubes were centrifuged at 914xg for 25 min at RT without applying a brake. The PBMC layer was removed with a 10 ml pipette and transferred to ice-cold PBS tubes to a total volume of 50 ml. Cells were washed twice by centrifugation sedimentation 300xg at 4°C for 10 min and for 5 min respectively. PBMCs were resuspended in 10 ml medium (X-vivo, Biozym Scientific) and counted in a Neubauer chamber.

Monocytes were isolated by negative selection using Monocyte isolation kit II from Miltenyi (#130-091-153) according to the instructions. Isolation had to be done quickly, and cells and solutions had to be kept on ice at all times. PBMCs in batches of 10exp8 cells were pelleted by centrifugation (300xg, 10 min) and resuspended with 300 µl of MACS buffer in a 50 ml Falcon tube. FcR blocking reagent (100 µl) and Biotin-Ab (100 µl) were added and the mixture was stirred and incubated on ice for 10 min. MACS buffer (300 µl) and antibiotic microbeads (100 µl) were added and mixed and incubated on ice for 15 min. Cells were washed by centrifugation pelleting (300xg for 10 min) and resuspended in 500 µl of MACS buffer. For each batch, one separation column was placed in a MACS separator and washed with 3 ml of MACS buffer. The cell suspension was added to the column, followed by the addition of 3x3 ml of MACS wash buffer, and the eluent containing monocytes was collected. Cells were pelleted by centrifugation (300xg for 10 min), resuspended in X-vivo medium and counted. Monocytes were seeded in fibronectin-coated microplates (384-well, black, flat-bottom; Corning #3848) at a density of 30,000 cells/well in 50 μl, and cultured overnight (37° C., 5% CO ₂ ).

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The test substances were dissolved in 100% DMSO at a base concentration of 10 mm and stored at -20°C in aliquots. Serial dilutions (2x) were made in DMSO and diluted 500x with assay buffer to give an antagonist plate. To perform the Flipr measurement, 10 μl of the mixture was transferred per well (4x dilution) and final upper concentrations of 5 μM and 0.05% DMSO were obtained in the assay mixture. The BzATP agonist was stored at a concentration of 10 mM in aliquots and diluted to an intermediate concentration of 15 μM to obtain an agonist plate. To perform a Flipr measurement, 10 μl of the mixture was transferred per well (5x dilution), resulting in a final concentration of 3 μM in the assay mixture.

For the experiment, the cell plate medium was discarded manually and 70 μl/well loading buffer was added and the mixture was incubated for 1 h (37° C., 5% CO ₂ ). Loading buffer contained HBSS (no calcium/magnesium), 10 mM HEPES pH 7.4, 5 μM Fluo-8 (AM) (Tebu-bio) and 50 mM methylamine (Sigma) to trigger exocytosis. The loading buffer was manually discarded and 30 μl/well of low calcium assay buffer (5 mM KCl, 145 mM NaCl, 0.5 mM CaCl ₂ , 13 mM glucose, 10 mM HEPES pH 7.4) was added.

The antagonist plate was transferred (10 μl/well) and after 15 min at RT, the agonist plate (10 μl/well) was transferred.

The addition of the agonist was recorded for 240 seconds after the 10 second baseline. The background correction was used in the analysis and the maximum of the curve was found. Data were normalized to 0% inhibition (signal at 3 μM BzATP) and 100% inhibition (no BzATP stimulation) and fitted to a four parameter sigmoidal inhibition curve using a Prism GraphPad to obtain IC ₅₀ values.

Example number P2X4 human monocytes (FLIPR analysis) 1C ₅ o (efficiency) for various donors 19 59 nM (57%), 21 nM (74%), 76 nM (48%), 59 nM (46%), 45 nM (93%) 24 141 nM (79%), 34 nM (77%), 91 nM (88%) 25 27 nM (87%), 5 nM (82%), 127 nM (70%), 87 nM (70%), 118 nM (70%), 59 nM (53%), 63 nM (68%), 39 nM (111%) 26 290 nM (71%), 182 nM (88%) 28 78 nM (64%), 164 nM (90%) 39 105 nM (88%), 32 nM (81%), 71 nM (78%) 170 303 nM (60%), 183 nM (69%), 110 nM (54%) 321 158 nM (49%), 94 nM (49%), 157 nM (60%), 537 nM (60%), 173 nM (34%), 331 nM (46%), 39 nM (95%) 326 407nM (86%), 167nM (89%), 149nM (82%), 45nM (91%), 49nM (70%) 380 263nM (70%), 251nM (70%), 434nM (70%), 93nM (43%), 50nM (32%), 207nM (107%) 387 122 nM (35%), 104 nM (51%)

Analysis of human whole blood for P2X4.

In this ex vivo assay, the blood of healthy female volunteers was first sensitized with lipopolysaccharide (LPS) and then stimulated with ATP to trigger the release of interleukin 1 beta (IL-1p). This system tested the effectiveness of P2X4 antagonists in relation to the production of IL-1p in whole blood. Cells were first treated with 100 ng/ml LPS for 2 hours and then stimulated with 3 mM ATP and treated in triplicate with compounds of Examples 19, 28, 39, 321, 326 and 380 at various concentrations. After 1 hour incubation, the supernatant was removed and after centrifugation analyzed for IL-1P in the supernatant using standard ELISA kits. The analysis was performed with blood from three different donors (see FIGS. 2a and 2b).

In FIG. 2a and 2b, as a non-limiting illustrative example of compounds according to the invention, the effect of compounds according to examples 19, 28, 39, 321, 326 and 380 on the formation of IL-1p in human whole blood after ATP stimulation following cell priming with lipopolysaccharide during 2 h and the specified treatment. Data showing the absolute amount of IL-13 in pg/ml in blood supernatant from three donors is presented on the y-axis, and data on control treatments and treatments with different concentrations of the compounds of examples are presented on the x-axis. For each bar, the average of three technical repetitions and SD are shown. The data show inhibition of IL-1P release by several, but not all, of the Example compounds tested.

- 290 040608

In vivo studies

CFA Model of Inflammation in Mice Recording Pain Behavior Female C57BL/6 wild-type (Taconic) mice received an intraplantar injection of complete Freund's adjuvant (CFA) (30 μl, 1 mg/ml, Sigma) into the left hindpaw under isoflurane anesthesia. Animals were administered orally example 326 (0.3, 1, and 3 mg/kg, n=10/group) on day 2 after CFA injection. Spontaneous pain-related behavior of free-moving animals was assessed using an automated dynamic weight-bearing device (DWB, Bioseb, France) one hour after compound treatment according to published and validated protocols (Robinson et al., 2012; Tetreault et al., 2011; Gruen et al. 2014). For behavioral testing, animals were placed inside a Plexiglas chamber in which the applied floor pressure was measured. Animals were allowed to move freely in the apparatus for 5 min and then pain behavior was recorded during the next 5 min testing period. Relative weight distribution was calculated by determining the ratio of the weight applied by the previously unexperimented paw (contralateral) to the weight applied by the CFA intraplantar injection paw (ipsilateral).

In FIG. 3, as a non-limiting illustrative example of compounds of the invention, shows the ratio of weight distribution in percent (y-axis) of mice that were orally treated with Example 326 or vehicle 1 hour before weight distribution was measured. Each symbol represents a relative weight distribution for a single mouse. Statistical analysis was performed by one-way ANOVA followed by Dunnett's multiple comparison test against vehicle controls using GraphPad PRISM software, *p<0.05, **p<0.01. Example 326 significantly reduces pain behavior.

Rat model of CFA-induced mechanical hyperalgesia.

Male Sprague Dawley rats were used. Mechanical hyperalgesia was induced by injecting 25 μl of complete Freund's adjuvant (CFA) into the plantar surface of the left hind paw. Mechanical hyperalgesia was measured using a Pressure Application Measurement (Ugo Basile, Gemonno, Italy). Briefly, a linearly increasing pressure was applied to an area of approximately 50 mm of the plantar side of the hind paw until a behavioral response (paw withdrawal) occurred or until a pressure of 1000 gram-force was reached. The pressure at which the behavioral response occurred was recorded as paw withdrawal threshold (PWT). Both CFA-injected and contralateral PWT values were determined for each rat, in each treatment group, and for each time point of the studies. Rats received 3 oral doses of test compound at approximately 12 hour intervals starting 1 hour prior to CFA injection. Mechanical hyperalgesia testing was performed 2 hours before the CFA injection and 2 hours after the last dosing (FIGS. 4a and 4b).

In FIG. 4a and 4b, as non-limiting illustrative examples of compounds according to the invention, show the paw withdrawal threshold in grams (y-axis) of the ipsilateral paw of all test animals before CFA administration and 26 hours after CFA and vehicle administration or treatment with Example 39 (FIG. 4a). ) or Example 326 (FIG. 4b). Statistical analysis was performed by one-way ANOVA followed by Dunnett's multiple comparison test versus vehicle controls using GraphPad PRISM software, *p<0.05, **p<0.01, ***p<0.001. Examples 39 and 326 significantly increased the value of PWT compared to animals that received the carrier.

Claims (24)

CLAIM 1. Compound of formula (I) different in that X is CR ^2a or N; R ¹ is a group selected from: - 291 040608 where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is phenyl, wherein said phenyl group is optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ substituents, which are, independently of one another, identical or different, or substituted by two adjacent substituents R ¹¹ which together represent a methylenedioxy group to form a 5-membered ring; or 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, or [5,6]annelated bicyclic heteroaryl, wherein the heteroaryl contains at least one oxygen, nitrogen, or sulfur heteroatom, and wherein said heteroaryl groups are optionally substituted with one three times with R ¹¹ substituents that are independently the same or different, or substituted once with R ^11a and optionally once or twice with R ¹¹ that are independently the same or different; R ^2a represents hydrogen, cyano, nitro, halogen, C ₁ -C ₂ -αkyl or C ₁ -C ₂ haloalkyl; R ^2b is hydrogen, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2c represents hydrogen, halogen, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -haloalkyl, where at least one of R ^2a , R ^2b and R ^2c represents hydrogen; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen, fluorine, methyl or OH; R ⁵ represents hydrogen or C ₁ -C ₃ -alkyl; R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, C1- _C4 haloalkoxy or F3CS-; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C1-C ₄ -alkoxy, C1-C ₄ -haloalkoxy, HO-(C ₂ -C ₄ -alkoxy) -, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH -, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-; R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C1-C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O )-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-; or R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-; R ^7a and R ^7b are the same or different and are, independently of one another, hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl; R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl; R ⁹ and R ¹⁰ are the same or different and are, independently of one another, hydrogen, C1- _C4 alkyl, _C3 - _C6 cycloalkyl, C1- _C4 haloalkyl, or ( _CH3 ) _2N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times independently with halo or C ₁ -C ₄ alkyl; R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C1- C4-alkyl)-S- or (C1-C4-alkyl)-SO2-; R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino, - 292 040608 where * denotes the point of attachment of the specified group to the rest of the molecule; R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C1- _C4 alkyl, _C2 - _C4 alkenyl, _C1 - _C4 haloalkyl, _C1 - _C4 hydroxyalkyl, C1 -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, (C 1-C 4 alkoxy) - (C ₂ -C ₄ -alkyl) -, (C ₁ -C ₄ -haloalkoxy) - (C ₂ -C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1 -C4-alkyl)-SO2-; n is 0, 1, 2 or 3; or its N-oxide, pharmaceutically acceptable salt or stereoisomer. 2. Compound according to claim 1 of formula (Ia) characterized in that: R ¹ is a group selected from: where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is phenyl, wherein said phenyl is optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one to two times with R ¹¹ substituents, which are independently apart from each other, identical or different, or substituted by two adjacent substituents R ¹¹ which together represent a methylenedioxy group to form a 5-membered ring; R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ alkyl or C 1 -C ₂ haloalkyl; R ^2b is hydrogen or halogen; R ^2c is hydrogen or halogen; where at least one of R ^2a , R ^2b and R ^2c is hydrogen; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen, fluorine, methyl or OH; R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, _C1 - _C4 haloalkyl, C1- _C4 alkoxy, _C1 - _C4 haloalkoxy, or F3CS-; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -; - 293 040608 R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1 -C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -; or R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-; R ^7a and R ^7b are the same or different and are, independently of one another, hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl; R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl; R ⁹ and R ¹⁰ are the same or different and are, independently of one another, hydrogen, C1- _C4 alkyl, _C3 - _C6 cycloalkyl, C1- _C4 haloalkyl, or ( _CH3 ) _2N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times independently with halogen or C 1 -C ₄ alkyl; R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C ₁ -C ₄ -alkyl)-S- or (C ₁ -C ₄ -alkyl)-SO ₂ -; R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino, where * denotes the point of attachment of the specified group to the rest of the molecule; R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C1- _C4 alkyl, _C2 - _C4 alkenyl, _C1 - _C4 haloalkyl, _C1 - _C4 hydroxyalkyl, C1 -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, (C 1-C 4 alkoxy) - (C ₂ -C ₄ -alkyl) -, (C ₁ -C ₄ -haloalkoxy) - (C ₂ -C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1 -C4-alkyl)-SO2-; n is 0, 1, 2 or 3; or its N-oxide, pharmaceutically acceptable salt or stereoisomer. 3. Compound according to claim 1 of formula (Ib) different in that R ¹ is a group selected from: where * denotes the point of attachment of the specified group to the rest of the molecule; R ² is phenyl, - 294 040608 wherein said phenyl is optionally substituted one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with R ^11a and optionally one or two times with R ¹¹ substituents that are independently , identical or different, or substituted by two adjacent substituents R ¹¹ which together represent a methylenedioxy group to form a 5-membered ring; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen, fluorine, methyl or OH; R ⁶ is halo, cyano, nitro, OH, C ₁ -C ₄ alkyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, or F3CS-; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, HO-(C2-C4- alkoxy)-, (C1-C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -; R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-haloalkyl, C1-C4-haloalkoxy, HO-(C2-C4-alkoxy) -, (C1 -C4-alkoxy)-(C2-C4-alkoxy)-, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C ₄ -alkyl)-SO ₂ -; or R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-; R ^7a and R ^7b are the same or different and are, independently of one another, hydrogen, hydroxy, halogen, C1- _C4 alkyl or C1- _C4 haloalkyl; R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C 1 -C ₄ - haloalkyl; R ⁹ and R ¹⁰ are the same or different and are, independently of each other, hydrogen, C 1 -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl or (CH ₃ ) ₂ N- C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C ₁ -C ₆ -alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times, independently of one another, with halo or C1 -C ₄ alkyl; R ¹¹ are, independently of one another, halogen, hydroxy, nitro, cyano, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C6 hydroxyalkyl, C1-C4 alkoxy, C1- C4-haloalkoxy, (C1-C4alkoxy)-(C1-C4-alkyl)-, (C1-C4-haloalkoxy)-(C1-C4-alkyl)-, R ⁹ R ¹⁰ N-(C1-C ₄ -alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)-, (C ₁ -C ₄ -alkyl)-S- or (C ₁ -C ₄ -alkyl)-SO ₂ -; R ^11a is a group selected from C ₃ -C ₆ -cycloalkyl, morpholino, where * denotes the point of attachment of the specified group to the rest of the molecule; R ¹² are, independently of one another, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ alkyl, C ₂ -C ₄ alkenyl, C 1 -C ₄ haloalkyl, C 1 -C ₄ hydroxyalkyl, C 1 - C ₄ alkoxy, C 1 -C ₄ haloalkoxy, (C 1 -C ₄ alkoxy) - (C 2 -C 4 alkyl) -, (C 1 -C 4 haloalkoxy) - (C 2 -C 4 alkyl) -, R ⁹ R ¹⁰ N-, R ⁸ -C(O)-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)- SO2-; n is 0, 1, 2 or 3; or its N-oxide, pharmaceutically acceptable salt or stereoisomer. 4. A compound according to any one of claims 1 to 3, characterized in that R ¹ is - 295 040608 where * denotes the point of attachment of the specified group to the rest of the molecule; R ⁶ is halo, cyano, nitro, OH, C1- _C4 alkyl, C1- _C4 haloalkyl, C1- _C4 alkoxy, or _C1 - _C4 haloalkoxy; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -alkoxy, C1-C ₄ -haloalkoxy, BUT -(C2-C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C2-C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-; R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O) -, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (CpCd-alkyl) ^-. 5. A compound according to any one of claims 1 to 4, characterized in that R ¹ is where * denotes the point of attachment of the specified group to the rest of the molecule; R ⁶ is halogen, cyano, nitro, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C 1 -C ₄ alkoxy or C 1 -C ₄ haloalkoxy; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -alkoxy, C1-C ₄ -haloalkoxy, BUT -(C ₂ -C ₄ -alkoxy) -, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH- , R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-; R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C1-C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C1-C ₄ -haloalkyl, C1-C ₄ -haloalkoxy, HO- (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O) -, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-αkyl)-SO2-. 6. A compound according to any one of claims 1 to 5, characterized in that R ¹ is a group selected from: where * denotes the point of attachment of the specified group to the rest of the molecule; R ^7a and R ^7b are the same or different and are, independently of each other, hydrogen, hydroxy, fluorine, chlorine, C1- _C4 alkyl, difluoromethyl or trifluoromethyl. 7. A compound according to any one of claims 1 to 6, characterized in that R ² is a group selected from: where * denotes the point of attachment of the specified group to the rest of the molecule and these groups are optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different. 8. A compound according to any one of claims 1 to 7, characterized in that R ² is a group selected from: - 296 040608 n where * denotes the point of attachment of the specified group to the rest of the molecule and these groups are optionally substituted once or twice by R ¹¹ substituents, which are independently the same or different, or substituted once by R ^11a and optionally once by R ¹¹ , being, independently of each other, the same or different. 9. A compound according to any one of claims 1 to 8, characterized in that R ³ is hydrogen; And R ⁴ is hydrogen, methyl or OH. 10. A compound according to any one of claims 1 to 9, characterized in that R ⁸ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₄ haloalkyl. 11. A compound according to any one of claims 1 to 10, characterized in that R ⁹ are, independently of each other, C 1 -C ₄ -alkyl or C ₃ -C ₆ -cycloalkyl; R ¹⁰ are, independently of one another, hydrogen or C1- _C4 alkyl. 12. The compound according to any one of claims 1-11, selected from the following list: 2-(2-chlorophenyl)-N-[4-(2-oxopyridin-1(2H)-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-2-oxopyridin-1(2H)-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3,5-dichloro-2-oxopyridin-1(2H)-yl)-3-sulfamoylphenyl]acetamide; N-[4-(3-chloro-2-oxopyridin-1(2H)-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3-methyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(5-methyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-methyl-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-( 1 H-imidazol-1 -yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[3-(difluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-cyclopropyl-3-(difluoromethyl)-1H-pyrazol-1-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[4-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1H-1,2,4-triazol-1-yl)phenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[3-(difluoromethyl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide; N-{4-[3-(difluoromethyl)-1 H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-[2-(difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[2(trifluoromethyl)phenyl]acetamide; N-[4-(3-t-butyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-isopropoxy-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3-isobutyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[4-(methylsulfanyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-methoxy-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(1H-benzimidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; N-[4-(4-chloro-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[3-(dimethylamino)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(3-ethyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; (2-chlorophenyl)-N-[4-(3-cyclopropyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(5-cyclopropyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[3-(methoxymethyl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-t-butyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; - 297 040608 2-(2-chlorophenyl)-N-[4-(3-cyano-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-6poM-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3H-imidazo[4,5-b]pyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(1H-imidazo[4,5-b]pyridin-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(1H-imidazo[4,5-c]pyridin-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3H-imidazo[4,5-c]pyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2,4-dimethyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethyl)phenyl]acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-[2-(difluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-methoxyphenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1 H-1,2,4-triazol-1-yl]phenyl}acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide; 2-(3-fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl]phenyl}acetamide; 2-(2-chloro-4-fluorophenyl)-N-{3-sulfαmoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triαzol-1yl]phenyl}acetamide; 2-[2-(difluoromethoxy)phenyl]-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide; 2-(2-chloro-5-fluorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide; 2-(3-chloropyridin-4-yl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide; 2-[4-(difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1 H-1,2,4-triazol-1 yl]phenyl}acetamide; 2-(2-chlorophenyl)-2,2-difluoro-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1H-1,2,4-triazol-1yl]phenyl}acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)-2,2-difluoroacetamide; Ν-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; N-[4-(4-bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide; Ν-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloropyridin-3-yl)acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloro-4-fluorophenyl)acetamide; N-[4-(4-bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide; N-[4-(4-bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloro-4,5-difluorophenyl)acetamide; N-[4-(4-6ρομ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-chloropyridin-4-yl)acetamide; N-[4-(4-bromo-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide; 2-(2-bromophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methoxyphenyl)acetamide; 2-(4-chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-nitrophenyl)acetamide; Ν-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-dichlorophenyl)acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,4-difluorophenyl)acetamide; 2-(3-chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,5-difluorophenyl)acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-fluorophenyl)acetamide; Ν-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide; Ν-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,3-difluorophenyl)acetamide; 2-(2-chloro-4-fluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chloropyridin-3-yl)acetamide; N-[4-(4-χλορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-chloro-3-(trifluoromethyl)phenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide; 2-(2-chloro-4,5-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluoro-3-methylphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-3,6-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; - 298 040608 2-(2-chloro-5-methylphenyl)^-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-5-fluorophenyl)-N[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; Ν-[4-(4-χΛορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,5-dichlorophenyl)acetamide; Ν-[4-(4-χΛορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-isopropylphenyl)acetamide; 2-(2-chloro-5-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4,6-difluorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-chloro-6-(trifluoromethyl)phenyl]acetamide; 2-(5-bromo-4-fluoro-2-methylphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-methoxyphenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-χΛορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-difluorophenyl)propanamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide; 2-(4-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2,2-difluoroacetamide; 2-(2-nitrophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2,4-dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-methoxyphenyl)^-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chloro-6-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(3-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(3,5-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2,6-dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-bromophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(3,4-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(4-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(3-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(4-methoxyphenyl)^-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2,3-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(3-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-[2-(difluoromethoxy)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1 yl]phenyl}acetamide; 2-(2-chloropyridin-3-yl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chloro-4-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chloro-5-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-2-[2(trifluoromethoxy)phenyl]acetamide; 2-(2-chloro-4,5-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-6-fluoro-3-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-3,6-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-[2-chloro-6-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-4-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2,5-dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-isopropylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chloro-5-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-5-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide; 2-(5-bromo-4-fluoro-2-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-6-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chloro-4,6-difluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(3-fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(3,4-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(3,5-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; - 299 040608 Ν-[4-(4-φτορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide; 2-(3-chlorophenyl)-M-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(4-fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; Ν-[4-(4-φτορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide; N-[4-(4-φτορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide; N-[4-(4-φτορ-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide; N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide; N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide; 2-(2,3-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-ethoxyphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-(difluoromethoxy)phenyl]-M-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloropyridin-3-yl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluoro-3-methylphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide; 2-(2-chloro-4,5-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2,5-dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-3,6-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-5-methylphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(5-bromo-4-fluoro-2-methylphenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-isopropylphenyl)acetamide; 2-(2-chloro-5-fluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-chloro-6-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide; 2-(2,6-difluorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]propanamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-ethoxyphenyl)acetamide; 2-(2-ethoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-bromophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2,4-dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2,6-dichlorophenyl)-N-[4-(4-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-nitrophenyl)acetamide; 2-(4-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methoxyphenyl)acetamide; 2-(2-chloro-6-fluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,6-dichlorophenyl)acetamide; 2-(2-bromophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,4-difluorophenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3,5-difluorophenyl)acetamide; 2-(3-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-fluorophenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-hydroxyphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-hydroxyphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-methylphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(3-methylphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-ethoxyphenyl)acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,3-difluorophenyl)acetamide; 2-(2-chloropyridin-3-yl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4-fluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(difluoromethoxy)phenyl]acetamide; N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethoxy)phenyl]acetamide; 2-(2-chloro-4,5-difluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluoro-3-methylphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-3,6-difluorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; - 300 040608 2-(2-chloro-5-methylphenyl)-N-[4-(4-cyano-1H-nurazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4-methoxyphenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; Na[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2,5-dichlorophenyl)acetamide; 2-(5-chloro-2-methoxyphenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; Na[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(propan-2-yl)phenyl]acetamide; 2-(2-chloro-5-fluorophenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-chloro-6-(trifluoromethyl)phenyl]-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-methoxyphenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4,6-difluorophenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(3-chloropyridin-4-yl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; Na[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide; 2-(2-chlorophenyl)-M-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2,2-difluoroacetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; N-{3-sulfamoyl-4-[5-(trifluoromethyl)nurudin-3-yl]phenyl}-2-[2(trifluoromethoxy)phenyl]acetamide; N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-methylphenyl)acetamide; N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-[2(trifluoromethyl)phenyl]acetamide; 2-[2-(difluoromethyl)phenyl]-N-{4-[1-(difluoromethyl)-1 H-pyrazol-4-yl]-3 sulfamoylphenyl}acetamide; N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-methoxyphenyl)acetamide; N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(4-fluorophenyl)acetamide; 2-(2-chloro-5-fluorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2,3-dichlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(3-chloropyridin-4-yl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(3-cyclobutyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-acetyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(3-isopropyl-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide; ethyl 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxylate; ethyl 1-(4-{[(2-fluorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxylate; 2-(2-fluorophenyl)-N-{4-[4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chloronurudin-3-yl)-N-{3-sulfαmoyl-4-[3-(trifluoromethyl)-1H-1,2,4-truαzol-1yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-methyl-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfαmoyl-4-[4-(trifluoromethyl)-2H-1,2,3-truαzol-2-yl]phenyl}αcetαmud; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide; 2-(2-chloro-5-cyanophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-cyano-5-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(5-bromo-2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; N-[4-(3-chloro-1H-1,2,4-triazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[3-cyano-4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3-methoxyu-1H-1,2,4-truαzol-1-yl)-3-sulfαmoylphenyl]αcetamide; 2-(2-chlorophenyl)-N-[4-(4-cyclopropyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-methyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3-cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2H-pyrazolo[3,4-b]pyridin-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2H-pyrazolo[3,4-c]pyridin-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2H-pyrazolo[4,3-b]pyridin-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[4-(2-methoxyethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(3-fluoro-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-{4-[(2,2-difluoroethyl)amino]-1H-pyrazol-1-yl}-3-sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[4-(2,2-difluoroethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-{[(2,2-difluoroethyl)amino]methyl}-1H-pyrazol-1-yl)-3sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfαmoyl-4-[5-(trifluoromethyl)-1,2,4-oxαduαzol-3-yl]phenyl}αcetαmud; 2-(2-fluorophenyl)-N-[4-(4-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-cyclopropyl-1H-imidazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; - 301 040608 N-[4-(3-cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-fluorophenyl)-N-{4-[4-(2-methoxyethyl)-III-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-(2-sulfamoylbiphenyl-4-yl)acetamide; 2-(2-chlorophenyl)-N-{4-[1-(cyclopropylmethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[ 1 -(piperidin-4-yl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-{4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; N-{4-[1-(azetidin-3-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-chlorophenyl)acetamide; 2-(3-chlorophenyl)-N-(2-sulfamoylbiphenyl-4-yl)acetamide; 2-(2-chlorophenyl)-N-[4-(3-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(6-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3,5-dimethyl-1,2-oxαzol-4-yl)-3-sulfαmoylphenyl]αcetαmid; 2-(2-chlorophenyl)-N-(4-{1-[(3-methyloxetan-3-yl)methyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide; 2-(2-chloro-4-fluorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chloro-4-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-{1-[2-(trifluoromethoxy)ethyl]-1H-pyrazol-4yl}phenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1-cyclobutyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-{1-[2-(pyrrolidin-1-yl)ethyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(5-cyanopyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-{1-[oxetan-2-ylmethyl]-1H-pyrazol-4-yl}-3-sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(2-methoxypyrimidin-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-{1-[2-(propan-2-yloxy)ethyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[1-(3-hydroxy-3-methylbutyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-(2-hydroxypropan-2-yl)-1-methyl-1H-pyrazol-3-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-(difluoromethoxy)pyridin-3-yl]-3-sulfamoylphenyl}acetamide; N-[4-(2-chloro-5-methoxypyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; N-[4-(5-t-butyl-1H-pyrazol-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; N-[4-(1-benzyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(6-methylpyridazin-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[6-(trifluoromethyl)pyridin-2-yl]phenyl}acetamide; N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-sulfamoylpyridin-3-yl}acetamide; N-[4-(6-chloro-5-methylpyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[2-(cyclopropylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(methylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[6-(1-methyl-1H-pyrazol-4-yl)-5-sulfamoylpyridin-3-yl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2,2-difluoroethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}-2-[2-(trifluoromethyl)phenyl]acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-5'-(trifluoromethyl)-2,3'-bipyridin-5-yl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)pyrimidin-5-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethoxy)pyridin-3-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(2-cyclopropylpyrimidin-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2-ethoxypyrimidin-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[2-(propan-2-ylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(propan-2-yloxy)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(ethylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(2-methylpyrimidin-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[2-(propylamino)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-{2-[(2,2,2-trifluoroethyl)amino]pyrimidin-5yl}phenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[2-(cyclobutyloxy)pyrimidin-5-yl]-3-sulfamoylphenyl}acetamide; N-[4-(2-chloro-4-methylpyrimidin-5-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)pyridin-2-yl]phenyl}acetamide; - 302 040608 2-(2-chlorophenyl)-N-[4-(5-chloropyridin-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(1,2-dimethyl-1H-imidazol-4-yl)-3-sulfamoylphenyl]acetamide; N-{6-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-sulfamoylpyridin-3-yl}-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[5-(pyrrolidin-1-yl)pyridin-3-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-M-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-hydroxyethanamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}-2hydroxyethanamide; 2-(2-chlorophenyl)-N-[4-(5-chloropyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[ 1 -(difluoromethyl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2-methylpropyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(1-cyclopentyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[2'-fluoro-3'-(propan-2-yloxy)-2-sulfamoylbiphenyl-4-yl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; N-[4-(6-chloro-5-methoxypyridin-3-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chloro-6-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-3-fluorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; N-[4-(1-t-butyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[2-(propan-2-yloxy)pyridin-3-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chloro-3-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-[4-(pyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[3'-fluoro-5'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]acetamide; 2-(2-chlorophenyl)-N-[4-(5-methoxypyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[3'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]acetamide; 2-(2-fluorophenyl)-N-{4-[1-(propan-2-yl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4yl]phenyl}acetamide; N-[4-(1-t-butyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; N-[3'-fluoro-5'-(2-hydroxypropan-2-yl)-2-sulfamoylbiphenyl-4-yl]-2-(2-fluorophenyl)acetamide; N-[4-(1-cyclopentyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-fluorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(1,3-dimethyl-1H-pyrazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4'-chloro-2-sulfamoylbiphenyl-4-yl)acetamide; 2-(2-chlorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(pyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-(3'-chloro-2-sulfamoylbiphenyl-4-yl)acetamide; 2-(2-chlorophenyl)-N-(4-{1-[(2,2-dichlorocyclopropyl)methyl]-1H-pyrazol-4-yl}-3sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[ 1 -(propan-2-yl)-1 H-pyrazol-4-yl]-3-sulfamoylphenyl} acetamide; 2-(2-chlorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2-hydroxy-3,3-dimethylbutyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-[4-(5-fluoropyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(5-methyl-1-phenyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 4'-{[(2-chlorophenyl)acetyl]amino}-N-[2-(dimethylamino)ethyl]-2'-sulfamoylbiphenyl-3carboxamide; 2-(2-chlorophenyl)-N-[4-(p-yrazolo[1,5-a]-pyrimidin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[5-(π-pyrrolidin-1-ylcarbonyl)-π-pyridin-3-yl]-3-sulfamoyl-phenyl}-acetamide; 2-(2-chlorophenyl)-N-[4-(1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-{4-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-{4-[1-(2-methoxyethyl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide; 2-(5-chloro-2-fluorophenyl)-N-[4-(1-cyclopropyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(6-methylpyridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-(oxetan-3-yl)-1H-pyrazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-[4-(1-methyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]acetamide; - 303 040608 N-[4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; N-[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide; N-{4-[4-(difluoromethyl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[4-(difluoromethyl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{5-sulfamoyl-6-[4-(trifluoromethyl)-1H-iirazol-1-yl]iiridin-3-yl}acetamide; 2-(2-fluorophenyl)-N-{5-sulfamoyl-6-[4-(trifluoromethyl)-1H-iirazol-1-yl]iiridin-3-yl}acetamide; N-[6-(4-cyano-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[6-(4-cyano-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-acetamide; 2-(2-fluorophenyl)-N-[6-(4-fluoro-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-acetamide; 2-(2-chlorophenyl)-N-[6-(4-fluoro-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-acetamide; N-[6-(4-bromo-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[6-(4-chloro-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-acetamide; N-[6-(4-chloro-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-2-(2-fluorophenyl)acetamide; N-[6-(4-bromo-1H-iirazol-1-yl)-5-sulfamoyl-yridin-3-yl]-2-(2-chlorophenyl)acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[3-(iiridin-3-yl)-1H-1,2,4-triazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-[4-(1H-iirazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-t-butyl-1H-iirazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1H-indazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2H-indazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-[4-(2H-indazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-[4-(1 H-indazol-1-yl)-3-sulfamoylphenyl]acetamide; 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-N,N-dimethyl-1H-iirazole-4-carboxamide; N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-iirazol-4yl]cycloiroyancarboxamide; 2-(2-chlorophenyl)-N-{4-[4-(iirazin-2-yl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[4-(iiridin-2-yl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[4-(iiridin-3-yl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[4-(iirimidin-4-yl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-fluorophenyl)-N-{4-[4-(iirimidin-4-yl)-1H-iirazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(4-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide; 2-(4-methoxyphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide; 2-(4-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide; 2-(4-methylphenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1 H-1,2,3-triazol-1-yl]phenyl}acetamide; 2-[4-(difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide; 2-[4-(difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]phenyl}acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2-yl]phenyl}acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}acetamide; 2-[2-chloro-4-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide; 2-[2-chloro-4-(trifluoromethyl)phenyl]-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1yl]phenyl}acetamide; 2-(2,4-dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-2H-1,2,3-triazol-2yl]phenyl}acetamide; 2-(2,4-dichlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-1,2,3-triazol-1 yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,3-thiazol-5-yl)phenyl]acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-3-yl)phenyl]acetamide; 2-(2-chlorophenyl)-N-(4-(2-methyl-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2-methoxy-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2-methoxy-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(2-methyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3-methyl-1,2-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-methyl-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-4-yl)phenyl]acetamide; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,3-thiazol-2-yl)phenyl]acetamide; 2-(2-chlorophenyl)-N-(4-(4-cyano-1,3-thiazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[2-(difluoromethyl)-1,3-thiazol-5-yl]-3-sulfamoylphenyl}acetamide; - 304 040608 2-(2-chlorophenyl)-I-[4-(2-cycloiroyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-I-[4-(2-cycloiroyl-1,3-thiazol-4-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-I-[4-(4-methyl-1,3-oxazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)-1,3-thiazol-4-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1,3-thiazol-2-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(2-hydroxyiroan-2-yl)-1,3-thiazol-5-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(2-hydroxyiroan-2-yl)-1,3-thiazol-4-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-I-[3-sulfamoyl-4-(1,3-thiazol-4-yl)phenyl]acetamide; 2-(2-chlorophenyl)-I-[4-(5-cycloiroyl-1,2-oxazol-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-I-[4-(2-cycloiroyl-1,3-oxazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-{4-[(3,3-difluoroazetidin-1-yl)carbonyl]-1H-iirazol-1-yl}-3sulfamoylphenyl)acetamide; N-{4-[4-(azetidin-1-ylcarbonyl)-III-iirazol-1-yl]-3-sulfamoylphenyl}-2-(2chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[4-(pyrrolidin-1-ylcarbonyl)-1H-pyrazol-1-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-(4-{4-[(3,3-difluoroirrolidin-1-yl)carbonyl]-1H-iirazol-1-yl}-3sulfamoylphenyl)acetamide; 2-(4-chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(2-chloro-6-fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; K-{3-sulfamoyl-4-[5-(trifluoromethyl)iiridin-3-yl]phenyl}-2-[4-(trifluoromethyl)phenyl]acetamide; 2-(3-fluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(2,4-dichlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(2-bromophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(2,4-difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(3,4-difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(3,5-difluorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(3-chlorophenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(4-methylphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(4-methoxyphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)iiridin-3-yl]phenyl}acetamide; 2-(2-fluoro-4-methylphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-(2-fluoro-4-methoxyphenyl)-N-{3-sulfamoyl-4-[5-(trifluoromethyl)pyridin-3-yl]phenyl}acetamide; 2-[4-(difluoromethyl)phenyl]-N-{3-sulfamoyl-4-[5-(trifluoromethyl)iiridin-3-yl]phenyl}acetamide; 2-(4-chlorophenyl)-N-[4-(6-chloro-iridin-3-yl)-3-sulfamoylphenyl]acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chloro-6-fluorophenyl)-N-[4-(6-chloro-iridin-3-yl)-3-sulfamoylphenyl]acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-[4-(trifluoromethyl)phenyl]acetamide; N-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-[2-(trifluoromethyl)phenyl]acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(3-fluorophenyl)acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(2,4-dichlorophenyl)acetamide; N-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(2,4-difluorophenyl)acetamide; 2-(2-bromophenyl)-N-[4-(6-chloro-iridin-3-yl)-3-sulfamoylphenyl]acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(3,4-difluorophenyl)acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide; K-[4-(6-chloroiridin-3-yl)-3-sulfamoylphenyl]-2-(4-methoxyphenyl)acetamide; K-[4-(6-chloro-iridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluoro-4-methylphenyl)acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-(2-fluoro-4-methoxyphenyl)acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-[4-(difluoromethyl)phenyl]acetamide; K-[4-(6-chloro-iiridin-3-yl)-3-sulfamoylphenyl]-2-[2-chloro-4-(trifluoromethyl)phenyl]acetamide; 2-(2,4-dichlorophenyl)-N-[4-(5-fluoroiridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluoro-4-methylphenyl)-N-[4-(5-fluoroiridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-[4-(difluoromethyl)phenyl]-N-[4-(5-fluoroiridin-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-(4-cyclopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; K-[4-(4,6-difluoro-2H-benzotriazol-2-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; K-[4-(4,6-difluoro-1H-benzotriazol-1-yl)-3-sulfamoylphenyl]-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-(4-(4,6-difluoro-1H-benzotriazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-(4-(4,6-difluoro-2H-benzotriazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[2-(trifluoromethyl)-1,3-thiazol-5-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-III-iirazol-1-yl)-5-sulfamoyl-2-(trifluoromethyl)phenyl]acetamide; 2-[2-chloro-5-(trifluoromethyl)phenyl]-N-[4-(4-cyano-III-iirazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-[2-chloro-5-(trifluoromethyl)phenyl]-M-[4-(4-cyano-III-iirazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; - 305 040608 2-(2-chlorophenyl)-M-[4-(4-cyano-III-pyrazol-1-yl)-3-sulfamoyl-2-(trifluoromethyl)phenyl]acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-cyano-1H-n-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-n-pyrazol-4-yl]-3-sulfamoyl-2(trifluoromethyl)phenyl}acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-5-sulfamoyl-2(trifluoromethyl)phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl]-3sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[1-(difluoromethyl)-1H-pyrazol-4-yl]-2-fluoro-5-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[2-(dimethylαmino)-1,3-tuαzol-4-yl]-3-sulfαmoylphenyl}αcetαmud; 2-(2-chlorophenyl)-N-[3-sulfamoyl-4-(1,2-thiazol-5-yl)phenyl]acetamide; 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-N-cyclopropyl-N-methyl-1H-pyrazole-4carboxamide; 2-(2-chlorophenyl)-2-hydroxy-N-{3-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}ethanamide; 2-(2-chlorophenyl)-N-{3-chloro-5-sulfamoyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-3-hydroxy-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(1H-pyrazolo[4,3-c]pyridin-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4,5-dimethyl-1,3-tuαzol-2-yl)-3-sulfαmoylphenyl]αcetamide; 2-(2-chlorophenyl)-N-[4-(2,4-dimethyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-methyl-1,3-thiazol-5-yl)-3-sulfamoylphenyl]acetamide; N-{4-(4-amino-1H-pyrazol-1-yl)-3-[(2,4-dimethoxybenzyl)sulfamoyl]phenyl}-2-(2chlorophenyl)acetamide; N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-2,2difluoroacetamide; N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-3,3,3trifluoropropanamide; N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-3,3,3-trifluoro-2methylpropanamide (racemic); N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-3,3,3-trifluoro-2methylpropanamide (enantiomer A); N-[1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazol-4-yl]-3,3,3-trifluoro-2methylpropanamide (enantiomer B); 2-(2-chlorophenyl)-N-(4-{4-[(cis)-2,5-dimethylpyrrolidin-1-yl]-1H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide; 2-(2-chlorophenyl)-N-(4-{4-[(trans)-2,5-dimethylpyrrolidin-1-yl]-1 H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide (enantiomer A); 2-(2-chlorophenyl)-N-(4-{4-[(trans)-2,5-dimethylpyrrolidin-1-yl]-1 H-pyrazol-1-yl}-3sulfamoylphenyl)acetamide (enantiomer B); N-(4-{4-[(2,2-difluoroethyl)amino]-1H-pyrazol-1-yl}-3-sulfamoylphenyl)-2-(2fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-{4-[(2,2,2-trifluoroethyl)amino]-1H-pyrazol-1yl}phenyl)acetamide; 2-(2-chlorophenyl)-N-(4-(4-isopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-N-[4-(4-isopropyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-fluorophenyl)-N-{3-sulfamoyl-4-[4-(2,2,2-trifluoroethyl)-1H-pyrazol-1-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(5-cyclopronul-1,2,4-oxαduazol-3-ul)-3-sulfαmoylphenyl]αcetamud; 2-(2-chlorophenyl)-N-{3-sulfamoyl-4-[3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-sulfamoylphenyl}acetamide; N-{4-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-3-sulfamoylphenyl}-2-(2-fluorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide; 2-(2-fluorophenyl)-M-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]acetamide; N-[4-(5-methyl-1,3,4-oxadiazol-2-yl)-3-sulfamoylphenyl]-2-(4-methylphenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1H-pyrrol-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-{4-[5-(difluoroacetyl)-1H-pyrrol-3-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-(4-(1-methyl-1H-pyrrol-3-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-sulfamoylphenyl]acetamide; - 306 040608 2-(2-chlorophenyl)-N-{3-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1H-pyrazol-1yl]phenyl}acetamide; 2-(2-chlorophenyl)-N-{5-sulfαmoyl-2-(Ίpifluoromethyl)-4-[4-(Ίpifluoromethyl)-1H-nyrαzol-1yl]phenyl}acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-{5-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl}acetamide; 2-[2-chloro-5-(trifluoromethyl)phenyl]-N-{5-sulfamoyl-2-(trifluoromethyl)-4-[4-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl}acetamide; 2-[2-chloro-6-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; 2-[2-chloro-3-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; 2-[2-chloro-5-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; 2-[2-chloro-4-(trifluoromethyl)phenyl]-N-[4-(4-fluoro-1H-pyrazol-1-yl)-5-sulfamoyl-2(trifluoromethyl)phenyl]acetamide; N-[4-(3-t-butyl-4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; N-[4-(3-bromo-4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-{4-[4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-[4-(3,4-dimethyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; N-[4-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-(2-chlorophenyl)acetamide; 2-(2-chlorophenyl)-N-[4-(1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3-cyano-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(3-hydroxy-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-5-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-3-methyl-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-K-{4-[4-(morpholin-4-yl)-1,3-thiazol-2-yl]-3-sulfamoylphenyl}acetamide; 2-(2-chlorophenyl)-N-{4-[5-(morpholin-4-yl)-1,3-thiαzol-2-yl]-3-sulfαmoylphenyl}αcetαmid; 2-(2-chlorophenyl)-N-[4-(5-methyl-1,3-thiαzol-2-yl)-3-sulfαmoylphenyl]αcetαmid; 2-(2-chlorophenyl)-N-[4-(pyridin-4-yl)-3-sulfamoylphenyl]acetamide; 1-(4-{[(2-chlorophenyl)acetyl]amino}-2-sulfamoylphenyl)-1H-pyrazole-4-carboxamide; 2-(2-chloro-3-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-4-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-5-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chloro-6-hydroxyphenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]acetamide; 2-(2-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3-sulfamoylphenyl]-2-hydroxyacetamide. 13. The compound according to claim 1, which is 2-(2-chlorophenyl)-N-[4-(4-cyano-1H-pyrazol-1-yl)-3sulfamoylphenyl]acetamide. 14. The use of a compound of general formula I, a stereoisomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the prevention or treatment of a urogenital, gastrointestinal, proliferative, pain-related or inflammation-related disease, condition or disorder. 15. The use of a compound of general formula I, a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 for the preparation of a medicament for the prevention or treatment of a genitourinary, gastrointestinal, proliferative, pain-associated or inflammation-associated disease, condition or disorder . 16. The use of claim 15 wherein the inflammation-related disease, condition or disorder is a fibrotic disease, including pulmonary fibrosis, cardiac fibrosis, renal fibrosis. 17. The use of compounds of General formula I according to claim 15, where the specified disease, condition or disorder is selected from the group including associated with endometriosis dysmenorrhea, dyspareunia, dysuria or dyschezia; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis; idiopathic bladder hypersensitivity; irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), functional bowel disorders, arthritis, osteoarthritis and rheumatoid arthritis, fatty liver disease, NASH (non-alcoholic steatohepatitis), inflammatory pain, low back pain, surgical pain, visceral pain, toothache, premenstrual pain, pain associated with endometriosis, pain associated with fibrotic diseases, central pain, pain caused by burning mouth syndrome, pain caused by burns, pain caused by migraine, cluster headache, hyperalgesia, allodynia, pain, pain caused by traumatic nerve injury, pain caused by post-traumatic injury, pain caused by bone and sports injuries, pain caused by trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy, chronic low back pain, phantom pain in amputated limbs, pelvic pain syndrome, chronic - 307 040608 pelvic pain, neuroma pain, complex regional pain syndrome, pain associated with gastrointestinal bloating, chronic arthritis pain and associated neuralgia, and pain associated with malignancy, pain associated with chemotherapy, induced by HIV and HIV-treated neuropathy, itching; impaired wound healing; and skeletal disease like joint degeneration, ankylosing spondylitis. 18. A pharmaceutical composition as a P2X4 antagonist or negative allosteric modulator, comprising at least one compound according to any one of claims 1 to 13 together with at least one pharmaceutically acceptable adjuvant. 19. Intermediate compound of formula 3 a, 3b where R ² represents phenyl, where the specified phenyl group is optionally substituted one to three times with substituents R ¹¹ that are independently the same or different, or substituted once with R ^11a and optionally once or twice by R ¹¹ substituents independently of one another, the same or different, or substituted by two adjacent R ¹¹ substituents which together represent a methylenedioxy group to form a 5-membered ring; or 5-membered monocyclic heteroaryl; or 6-membered monocyclic heteroaryl; or [5,6]annelated bicyclic heteroaryl, wherein the heteroaryl contains at least one oxygen, nitrogen, or sulfur heteroatom, and wherein said 5-membered monocyclic heteroaryl or 6-membered monocyclic heteroaryl, or [5,6] -annelated bicyclic heteroaryl groups are optionally substituted one to three times with R ¹¹ substituents, which are independently the same or different, or substituted once with R ^11a and optionally one or two times with R ¹¹ substituents, which are independently of each other, the same or different; where R ¹¹ and R ^11a have the meanings according to the definition given in paragraph 1; R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ -αkyl or C 1 -C ₂ -haloalkyl; R ^2b is hydrogen, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2c represents hydrogen, halogen, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -haloalkyl, where at least one of R ^2a , R ^2b and R ^2c represents hydrogen. 20. Intermediate according to claim 19, which is 2-(4-cyano-1H-pyrazol-1-yl)-N(2,4-dimethoxybenzyl)-5-nitrobenzenesulfonamide. 21. Intermediate compound of formula 4a, 4b wherein R ² is phenyl, wherein said phenyl group is optionally substituted one to three times with R ¹¹ substituents independently of one another, the same or different, or substituted once with R ^11a and optionally one two times R ¹¹ substituents independently of one another, the same or different, or substituted by two adjacent R ¹¹ substituents which together represent a methylenedioxy group to form a 5-membered ring; or 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, or [5,6]annelated bicyclic heteroaryl, in which the heteroaryl contains at least one heteroatom representing oxygen, nitrogen or sulfur, and where the specified 5-membered monocyclic heteroaryl, or 6-membered monocyclic heteroaryl, or [5,6]-annelated bicyclic heteroaryl groups are optionally substituted - 308 040608 one to three times with R ¹¹ substituents that are independently the same or different, or substituted once with R ^11a and optionally one or two times with R ¹¹ substituents that are independently the same or different ; where R ¹¹ and R ^11a have the meanings according to the definition given in paragraph 1; R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2b is hydrogen, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2c represents hydrogen, halogen, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -haloalkyl, where at least one of R ^2a , R ^2b and R ^2c represents hydrogen. 22. An intermediate compound of the following formula: o Of W od ° ^r Vy ^vr: Η 12b where R ¹ is a group selected from: where * denotes the point of attachment of the specified group to the rest of the molecule, where R ⁶ is halo, cyano, nitro, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ haloalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ haloalkoxy, or F3CS-; R ^6a and R ^6b are, independently of each other, respectively, R ^6a - hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -haloalkoxy, HO-(C ₂ -C ₄ -alkoxy) -, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O )-NH-, R ⁸ -C(O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C1-C4-alkyl)-SO2-; R ^6b - hydrogen, halogen, hydroxy, nitro, cyano, C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₁ -C ₄ -haloalkyl, C ₁ -C ₄ -haloalkoxy, HO - (C ₂ -C ₄ -alkoxy)-, (C ₁ -C ₄ -alkoxy) - (C ₂ -C ₄ -alkoxy) -, R ⁹ R ¹⁰ N-, R ⁸ -C (O) -NH-, R ⁸ C (O)-, R ⁸ -OC(O)-, R ⁹ R ¹⁰ NC(O)- or (C^-alkyl) ^-; or R ^6a and R ^6b adjacent to each other together represent a group selected from -O-CH2-CH2-, -O-CH2-O- or -O-CH2-CH2-O-; R ^7a and R ^7b are the same or different and are, independently of each other, hydrogen, hydroxy, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ haloalkyl; R ⁸ is, regardless of the presence in each respective case, C ₁ -C ₆ -alkyl, C ₁ -C ₄ -alkoxy-C ₁ -C ₄ -alkyl, C ₃ -C ₆ -cycloalkyl or C ₁ -C ₄ -haloalkyl; R ⁹ and R ¹⁰ are the same or different and are independently hydrogen, C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ haloalkyl or (CH ₃ ) ₂ N -C ₁ -C ₄ -alkyl, or together with the nitrogen atom to which they are attached, form a 4-6-membered nitrogen-containing heterocyclic ring, and the specified ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a represents a C ₁ -C ₆ -alkyl or C ₁ -C ₆ haloalkyl group, and is optionally substituted one to three times, independently of each other, with halogen or C ₁ -C ₄ -alkyl; R ^2a is hydrogen, cyano, nitro, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2b is hydrogen, halogen, C ₁ -C ₂ alkyl or C ₁ -C ₂ haloalkyl; R ^2c represents hydrogen, halogen, C ₁ -C ₂ -alkyl or C ₁ -C ₂ -haloalkyl, where at least one of R ^2a , R ^2b and R ^2c represents hydrogen; R ³ represents hydrogen or fluorine; R ⁴ represents hydrogen, fluorine, methyl or OH; W is an amino group which is optionally substituted with a (dimethylamino)methylene or 2,4-dimethoxybenzyl group; V represents chlorine or bromine. 23. An intermediate compound according to claim 22, which is N-(4-6pom-3{[(dimethylamino)methylene]sulfamoyl}phenyl)-2-(2-chlorophenyl)acetamide. 24. A compound that is 2-(4-cyano-1 H-pyrazol-1 -yl)-5-nitrobenzenesulfonamide, 5-amino-2-(4-cyano-1H-pyrazol-1-yl)benzenesulfonamide.