Carbonic anhydrase inhibitors and methods of use thereof

Abstract

Provided herein are novel compounds, such as compounds of Formula I or Formula A: # imgabs0 # or a salt thereof wherein R1-R3, L1, R10, Ring A and Ring B have any of the values described in the specification, and compositions comprising the novel compounds herein. The compounds are typically carbonic anhydrase inhibitors and are useful in the prophylactic or therapeutic treatment of diseases or conditions mediated by carbonic anhydrase.

Description

[0001] Priority

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 430,904, filed on December 7, 2022. The entire content of the U.S. Provisional Patent Application is hereby incorporated by reference into this application.

[0003] Government Support

[0004] This invention was made with government support under AI123224 awarded by the National Institutes of Health. The government has certain rights in this invention. Background Art

[0005] Mast cell-related diseases, such as allergy / anaphylactic inflammation, mastocytosis, mast cell activation syndrome, and anaphylaxis, are becoming increasingly common. For example, allergic diseases have risen to epidemic proportions in the developed regions of the world, and it is now estimated that 30%-40% of the global population suffers from one or more allergic diseases, including atopic dermatitis, asthma, and food allergy (Pawankar et al., WAO White Book on Allergy 2011-2012: Executive Summary. World Allergy Organization (2012)). Treatment options for patients with chronic allergic inflammation are limited, and many of these treatment options have significant side effects (Bauer et al., J Allergy Clin Immunol 135, 312-323 (2015)). For example, steroids are most commonly used to treat allergy and asthma; however, steroids are known to be of limited effectiveness in treating these disease states. In addition, there are few effective treatment methods for diseases such as mastocytosis and mast cell activation syndrome (MCAS). Therefore, compounds that can effectively inhibit mast cell development and mast cell-mediated inflammation would meet an important clinical need.

[0006] Although the cellular pathways and growth factors that regulate mast cell responses have been difficult to detect, a unique mast cell progenitor has recently been identified that is defined by its expression of carbonic anhydrase (Car) 1 (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663 - 73; Inclan - Rico, J.M. et al., PLoS Pathogens, 2020. 16(5): p.e1008579; Voehringer, D., Nat Rev Immunol, 2013. 13(5): pp. 362 - 75; Dahlin, J.S. and J. Hallgren, Mol Immunol, 2015. 63(1): pp. 9 - 17). Targeting Car1 genetically or pharmacologically via CRISPR / Cas9 technology or using a Car enzyme inhibitor has been shown to be sufficient to prevent murine mast cell responses in vitro. In addition, targeting Car1 via a Car enzyme inhibitor has also been shown to be sufficient to prevent human mast cell development in culture assays (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663 - 73). Furthermore, it has been demonstrated that targeting Car1 with a Car enzyme inhibitor is sufficient to prevent murine mast cell responses and mast cell - mediated inflammation in vivo (ibid). Collectively, these data suggest that Car1 may be a therapeutic target for treating mast cell - related diseases.

[0007] There are several FDA - approved carbonic anhydrase inhibitors that are being actively used clinically. Among these inhibitors is methazolamide (MZ). MZ is capable of inhibiting mast cell development and mast cell - mediated inflammation at high doses. New carbonic anhydrase inhibitors are needed, such as those with improved potency and / or selectivity (e.g., for treating allergic inflammation and other mast cell - related disorders). SUMMARY OF THE INVENTION

[0008] In various embodiments, the present invention provides novel compounds as carbonic anhydrase inhibitors, such as carbonic anhydrase 1 inhibitors, which can be used to treat diseases or conditions mediated by carbonic anhydrase, such as mastocytosis, mast cell - mediated inflammation, allergic diseases, bacterial infections, fungal infections, and viral infections.

[0009] In one embodiment, the present invention provides a compound of formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] R 1is aryl, 5-membered heteroaryl, 6-membered heteroaryl or (C1-C3)alkyl substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any aryl, 5-membered heteroaryl and 6-membered heteroaryl are substituted by -S(=O)2NH2 and are further optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR a R b , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy;

[0013] R 2 is H, aryl, 5-membered heteroaryl, 6-membered heteroaryl or (C1-C3)alkyl optionally substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any aryl, 5-membered heteroaryl and 6-membered heteroaryl are optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR c R d , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy;

[0014] R 3 is H, fluoro, hydroxy, (C1-C6)alkyl or (C1-C6)alkoxy, wherein any (C1-C6)alkyl and (C1-C6)alkoxy are optionally substituted by one or more fluoro;

[0015] Ring A is phenyl, 5-membered heteroaryl or 6-membered heteroaryl, and provided that the valency permits, Ring A is optionally substituted by 1, 2, 3 or 4 groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR e R f, wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, and (C1-C6) alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl, and (C1-C6) alkoxy;

[0016] Each R a and R b is independently selected from the group consisting of H, (C1-C6) alkyl, (C3-C6) cycloalkyl, and (C3-C6) cycloalkyl(C1-C6) alkyl; or R a and R b together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, wherein aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one or more groups independently selected from halo and (C1-C6) alkyl;

[0017] Each R c and R d is independently selected from the group consisting of H, (C1-C6) alkyl, (C3-C6) cycloalkyl, and (C3-C6) cycloalkyl(C1-C6) alkyl; or R c and R d together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl being optionally substituted with one or more groups independently selected from halo and (C1-C6) alkyl; and

[0018] Each R e and R f is independently selected from the group consisting of H, (C1-C6) alkyl, (C3-C6) cycloalkyl, and (C3-C6) cycloalkyl(C1-C6) alkyl; or R e and R f together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl being optionally substituted with one or more groups independently selected from halo and (C1-C6) alkyl. In some embodiments, the compounds of formula I are characterized by having a subformula according to formula I, with structures of formula Ia, formula Ib, formula IIa, formula IIb, formula IIIa, or formula IIIb as defined herein.

[0019] In some embodiments, the present invention provides a compound of formula A or a pharmaceutically acceptable salt thereof:

[0020]

[0021] Wherein:

[0022] R 1 、R 3 and ring A are as defined herein in connection with formula I,

[0023] ring B is absent, and is an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclic group;

[0024] L 1 is absent or is an optionally substituted C 1-3 alkylene; and

[0025] R 10 is hydrogen, halogen, hydroxy, cyano, nitro, NH2, COOH, CONH2, S(O)2NH2, G 1 、OG 1 、NHG 1 、NG 1 G 1 、C(O)G 1 、C(O)OG 1 、C(O)NHG 1 、C(O)NG 1 G 1 、S(O)2G 1 、S(O)2NHG 1 or S(O)2NG 1 G 1 , wherein G 1 is independently, each time it appears, an optionally substituted (C1-C6) alkyl group, an optionally substituted (C1-C6) heteroalkyl group, an optionally substituted 3- to 7-membered carbocyclic ring, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclic group. In some embodiments, the compounds of formula A may be characterized as having sub-formulas according to formula A, such as the structures of formula A-1, formula A-1-A, formula A-2, formula A-2-A, formula A-2-B, formula A-2-C, formula A-3, formula A-E1 or formula A-E2 as defined herein.

[0026] In some embodiments, the present invention also provides a pharmaceutical composition comprising a compound of formula I or formula A, such as any sub-formula or specific compound according to formula I or formula A as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0027] Certain embodiments provide a method of inhibiting carbonic anhydrase in vitro or in vivo, which comprises contacting the carbonic anhydrase with an effective amount of a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof.

[0028] Certain embodiments provide a method of treating a carbonic anhydrase-mediated disease or condition in a mammal (e.g., a human), which comprises administering to the mammal a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof.

[0029] Certain embodiments provide a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof, for prophylactic or therapeutic treatment of a carbonic anhydrase-mediated disease or condition.

[0030] Certain embodiments provide a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof, for use in the preparation of a medicament for treating a carbonic anhydrase-mediated disease or condition.

[0031] In some embodiments, the present invention also provides a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof, for medical therapy.

[0032] In some embodiments, the present invention also provides a pharmaceutical composition comprising a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof, for treating a carbonic anhydrase-mediated disease or condition.

[0033] In some embodiments, the present invention also provides the methods and intermediates disclosed herein, which can be used to prepare a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a salt thereof.

[0034] It should be understood that the above Summary of the Invention and the following Detailed Description are both exemplary and explanatory, and do not limit the invention herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1. Mouse bone marrow cells were cultured for 7 days in medium or IL-3 (10 ng / mL). The cells were treated with the indicated doses of vehicle, MZ, or 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037), and the number of mast cells was quantified. Student's t-test (**, p < 0.01). Results represent at least 3 independent experiments.

[0036] Figure 2 . Mice were infected with Trichinella spiralis and treated with vehicle, MZ, or 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037) (intraperitoneally). On day 10 post-infection, the intestinal mast cell response was evaluated by esterase staining and histological analysis. Student's t-test. Results represent at least 4 independent experiments.

[0037] Figure 3 . Mouse bone marrow cells were cultured for 7 days in medium or IL-3 (10 ng / mL). The cells were treated with the indicated doses of MZ (126 uM), NEM-14A (14A), NEM-15A (15A), or NEM-23A (23A), and the percentage of inhibition (POI) of mast cell number was measured. Detailed Description

[0038] The present disclosure generally relates to novel carbonic anhydrase inhibitors, such as carbonic anhydrase 1 inhibitors. The present disclosure is in part based on the discovery that novel compounds of formula I or formula A as defined herein can inhibit carbonic anhydrase in vitro and / or in vivo and in some cases have efficacy similar to or better than certain FDA-approved carbonic anhydrase inhibitors such as methazolamide. The compounds herein represent a novel class of carbonic anhydrase inhibitors that can be used to treat various diseases or conditions herein, such as mastocytosis, mast cell-mediated inflammation, and various allergic diseases.

[0039] Definitions

[0040] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0041] It should be understood that all moieties and their combinations maintain proper valences.

[0042] It should also be understood that specific embodiments of variable moieties herein can be the same as or different from another specific embodiment having the same identifier.

[0043] This disclosure encompasses all combinations of aspects and / or embodiments disclosed herein. It should be understood that any and all embodiments of this disclosure can be described in combination with any one or more other embodiments to describe additional embodiments. It should also be understood that each individual element of an embodiment is intended to be combined with any and all other elements from any embodiment to describe additional embodiments.

[0044] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements, Handbook of Chemistry and Physics, 75th Edition, inside front cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry and specific functional moieties and reactivity are described in Thomas S Orrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary lists of substituents described herein.

[0045] When a numerical range is listed, every value and sub-range within that range is intended to be covered. For example, "C 1–6 " is intended to cover C1, C2, C3, C4, C5, C6, C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 .

[0046] Unless otherwise described, the following definitions are used: A halo group or halogen is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, etc. denote both straight-chain and branched-chain groups; however, a single group such as propyl only includes the straight-chain group, and branched isomers such as isopropyl are specifically mentioned.

[0047] Unless otherwise specified, the term "alkyl" by itself or as part of another substituent means a straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms (i.e., C 1-8 means one to eight carbons). Examples include (C1-C8) alkyl, (C2-C8) alkyl, (C1-C6) alkyl, (C2-C6) alkyl, and (C3-C6) alkyl. Examples of alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and higher homologues and isomers.

[0048] The term "alkoxy" refers to an alkyl group linked to the remainder of the molecule via an oxygen atom ("oxy").

[0049] The term "cycloalkyl" refers to a saturated or partially unsaturated (non-aromatic) all-carbon ring having 3 to 8 carbon atoms (i.e., a (C3-C8) carbocyclic ring). The term also includes polycondensed, saturated all-carbon ring systems (e.g., a ring system containing 2, 3, or 4 carbon rings). Accordingly, carbocyclic rings include polycyclic carbocyclic rings, such as bicyclic carbocyclic rings (e.g., having about 3 to 15 carbon atoms, about 6 to 15 carbon atoms, or 6 to 12 carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocyclic rings (e.g., tricyclic and tetracyclic carbocyclic rings having up to about 20 carbon atoms). When valence requirements permit, the rings of a multiple fused-ring system can be connected to each other via fused, spiro, and bridged bonds. For example, polycyclic carbocyclic rings can be connected to each other through a single carbon atom to form a spiro linkage (e.g., spiropentane, spiro[4,5]decane, etc.), through two adjacent carbon atoms to form a fused linkage (e.g., carbocyclic rings such as decalin, norsabinane, norcarane), or through two non-adjacent carbon atoms to form a bridged linkage (e.g., norbornane, bicyclo[2.2.2]octane, etc.). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.

[0050] As used herein, the term "aryl" refers to a single fully carbon aromatic ring or a polycondensed fully carbon ring system, wherein at least one ring is aromatic. For example, in certain embodiments, aryl has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms. Aryl includes phenyl. Aryl also includes a multiple fused carbon ring system having about 9 to 20 carbon atoms (e.g., a ring system containing 2, 3, or 4 rings), wherein at least one ring is aromatic and wherein the other rings may or may not be aromatic (i.e., cycloalkyl). When valence requirements permit, the rings of the multiple fused ring system may be connected to each other via fused, spiro, and bridging bonds. It should be understood that, as defined above, the point of attachment of the multiple fused ring system may be at any position of the ring system, including the aromatic portion or the carbocyclic portion of the ring. Non-limiting examples of aryl include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0051] Unless otherwise specified as having a different ring size, the term "heteroaryl" as used herein refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons in the ring array), in which there are ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). Ring sulfur and nitrogen atoms may optionally be oxidized and nitrogen heteroatoms may optionally be quaternized. Exemplary heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, and thiadiazolyl. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, provided that the valence allows. The bicyclic heteroaryl ring system may include one or more heteroatoms in one or both rings. In a bicyclic heteroaryl group in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, etc.), the point of attachment may be on either ring, i.e., on the ring with heteroatoms (e.g., 2-indolyl) or on the ring without heteroatoms (e.g., 5-indolyl).

[0052] As used herein, unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means a stable straight-chain or branched alkyl group, e.g., having 2 to 14 carbons in the chain, such as 2 to 10 carbons, in which one or more carbons have been replaced by heteroatoms selected from S, O, P, and N, and in which the nitrogen, phosphine, and sulfur atoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. One or more of the heteroatoms S, O, P, and N may be placed at any internal position of the heteroalkyl or at the position where the alkyl is attached to the remainder of the molecule. When a heteroalkyl is said to be substituted, the substituent may replace one or more hydrogen atoms attached to the carbon atoms and / or heteroatoms of the heteroalkyl. In some embodiments, heteroalkyl is C 1-4Heteroalkyl, which refers to heteroalkyl having 1 to 4 carbon atoms as defined herein. C 1-4 Examples of heteroalkyl include, but are not limited to, C4 heteroalkyl such as -CH2-CH2-N(CH3)-CH3, C3 heteroalkyl such as -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, C2 heteroalkyl such as -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3 and C1 heteroalkyl such as -CH2-OH, -CH2-NH2, -O-CH3. Preferably, the C 1-4 heteroalkyl (or C 1-4 heteroalkylene) contains 1 or 2 heteroatoms, such as one oxygen, one nitrogen, two oxygens, two nitrogens or one oxygen and one nitrogen. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent group derived from heteroalkyl, for example, but not limited to, -CH2-CH2-O-CH2-CH2- and –O-CH2-CH2-NH-CH2-. For heteroalkylene groups, the heteroatom can also occupy either or both chain termini (e.g., alkyleneoxy, alkylenedioxy, alkylamino, alkylenediamino, etc.). Additionally, for alkylene and heteroalkylene linking groups, the orientation of the linking group is not implied by the direction in which the formula of the linking group is written. In the recitation of "heteroalkyl", together with the recitation of a specific heteroalkyl group such as alkoxy or -NR'R ” etc., it should be understood that the terms heteroalkyl and alkoxy or -NR'R” are neither redundant nor mutually exclusive. Instead, the recitation of specific heteroalkyls is for increased clarity. Thus, the term "heteroalkyl" should not be construed herein as excluding specific heteroalkyls, such as alkoxy or -NR'R ” etc.

[0053] Unless specified to have a different ring size, "heterocyclic group" or "heterocycle", as used alone or as part of another group, refers to a group of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10 membered heterocyclic group"). In a heterocyclic group containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, provided that the valence allows. The heterocyclic group can be monocyclic ("monocyclic heterocyclic group") or a fused, bridged, or spiro ring system such as a bicyclic ring system ("bicyclic heterocyclic group"), and can be saturated or can be partially unsaturated. The bicyclic heterocyclic ring system can include one or more heteroatoms in one or two rings.

[0054] As used herein, unless otherwise specified or the context dictates otherwise, a "ring structure", "cyclic structure", or simply "ring" having a specified number of ring members, such as a "3- to 10-membered ring structure", "3- to 12-membered ring structure", or "5- or 6-membered ring", is understood to encompass any ring structure having the specified number of ring members (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.), which ring structure can be (1) monocyclic or polycyclic (so long as chemically feasible), such as monocyclic or bicyclic (including fused, spiro, and bridged bicyclic, as well as those ring systems in which two monocycles are connected by a single bond or double bond); (2) aromatic, partially unsaturated, or fully saturated; and in the case of a polycyclic structure, each ring can independently be aromatic, partially unsaturated, or fully saturated; and (3) contain no heteroatoms or contain 1 to 4 heteroatoms; in the case of a polycyclic structure, each ring can independently be without ring heteroatoms or have 1 to 4 ring heteroatoms (e.g., O, N, S, etc.). When a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom can be optionally oxidized. One or more of the ring carbon atoms in the ring structure can be present as C(=O). A fully saturated ring is one in which neither the ring carbon nor nitrogen (if present) atoms form a double or triple bond with any other atom. The ring structure can optionally be substituted with one or more of the substituents described herein. Substituents of the ring structure herein can also have a cyclic structure, and in some cases, two substituents of the ring structure can be said to be connected to form a cyclic structure.

[0055] As used herein, the term "alkoxycarbonyl" refers to the group (alkyl)-O-C(=O), where the term alkyl has the meaning defined herein.

[0056] As used herein, the term "alkanoyloxy" refers to the group (alkyl)-C(=O)-O-, where the term alkyl has the meaning defined herein.

[0057] As used herein, the term "alkanoyl" refers to the group (alkyl)-C(=O)-, where the term alkyl has the meaning defined herein.

[0058] As used herein, the term "heteroatom" is intended to include oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

[0059] As is commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyclylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent groups of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups, respectively.

[0060] An "optionally substituted" group, such as an optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted carbocyclic group, optionally substituted heterocyclic group, optionally substituted aryl, optionally substituted heteroaryl group or optionally substituted ring structure, means the corresponding group that is unsubstituted or substituted. Generally speaking, the term "substituted", whether or not preceded by the term "optionally", means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced by a permitted substituent, such as a substituent that produces a stable compound (e.g., a compound that does not spontaneously transform, such as by rearrangement, cyclization, elimination or other reactions) after substitution. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position is substituted in any given structure, the substituents at each position can be the same or different. Usually, when substituted, the optionally substituted groups herein can be substituted by 1-5 substituents. Depending on the circumstances, the substituents can be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents or sulfur atom substituents.

[0061] In a broad aspect, the permitted substituents herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, the permitted substituents can be one or more and the same or different. For the purpose of disclosure, a heteroatom (such as nitrogen) can have a hydrogen substituent and / or any permitted substituent of the organic compounds described herein that satisfies the valence of the heteroatom. The substituents can include any of the substituents described herein, such as halogen, hydroxy, carbonyl (such as carboxy, alkoxycarbonyl, formyl or acyl), thiocarbonyl (such as thioester, thioacetate or thiocarboxylate), alkoxy, cycloalkoxy, phosphoryl, phosphate, phosphonate, phosphite, amino, amido, amidine, imino, cyano, nitro, azido, mercapto, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclic group, aralkyl, aryl or heteroaryl, each of which can be substituted where appropriate.

[0062] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkynylene-heteroaryl, —OH, hydroxyalkyl, haloalkyl, —O-alkyl, —O-haloalkyl, -alkylene-O-alkyl, —O-aryl, —O-alkylene-aryl, acyl, —C(O)-aryl, halo, —NO2, —CN, —SF5, —C(O)OH, —C(O)O-alkyl, —C(O)O-aryl, —C(O)O—alkylene-aryl, —S(O)-alkyl, —S(O)2-alkyl, —S(O)-aryl, —S(O)2-aryl, —S(O)-heteroaryl, —S(O)2-heteroaryl, —S-alkyl, —S-aryl, —S-heteroaryl, —S-alkylene-aryl, —S-alkylene-heteroaryl, —S(O)2-alkylene-aryl, —S(O)2-alkylene-heteroaryl, cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH2, —C(═NH)—NH2, —C(═NH)—NH(alkyl), —N(Y1)(Y2), -alkylene-N(Y1)(Y2), —C(O)N(Y1)(Y2) and —S(O)2N(Y1)(Y2), where Y1 and Y2 may be the same or different and are independently selected from hydrogen, alkyl, aryl, cycloalkyl and -alkylene-aryl.

[0063] Some examples of suitable substituents include, but are not limited to, (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10)cycloalkyl group, halogen (F, Cl, Br or I), halo (C1-C8) alkyl group (such as but not limited to -CF3), -O-(C1-C8) alkyl group, -OH, -S-(C1-C8) alkyl group, -SH, -NH(C1-C8) alkyl group, -N((C1-C8) alkyl)2 group, -NH2, -C(O)NH2, -C(O)NH(C1-C8) alkyl group, -C(O)N((C1-C8) alkyl)2, -NHC(O)H, -NHC(O)(C1-C8) alkyl group, -NHC(O)(C3-C8) cycloalkyl group, -N((C1-C8) alkyl)C(O)H, -N((C1-C8) alkyl)C(O)(C1-C8) alkyl group, -NHC(O)NH2, -NHC(O)NH(C1-C8) alkyl group, -N((C1-C8) alkyl)C(O)NH2 group, -NHC(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)N((C1-C8) alkyl)2 group, -N((C1-C8) alkyl)C(O)NH((C1-C8) alkyl), -C(O)H, -C(O)(C1-C8) alkyl group, -CN, -NO2, -S(O)(C1-C8) alkyl group, -S(O)2(C1-C8) alkyl group, -S(O)2N((C1-C8) alkyl)2 group, -S(O)2NH(C1-C8) alkyl group, -S(O)2NH(C3-C8) cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1-C8) alkyl group, -N((C1-C8) alkyl)S(O)2(C1-C8) alkyl group, -(C1-C8) alkyl-O-(C1-C8) alkyl group, -O-(C1-C8) alkyl-O-(C1-C8) alkyl group, -C(O)OH, -C(O)O(C1-C8) alkyl group, NHOH, NHO(C1-C8) alkyl group, -O-halo (C1-C8) alkyl group (such as but not limited to -OCF3), -S(O)2-halo (C1-C8) alkyl group (such as but not limited to -S(O)2CF3), -S-halo (C1-C8) alkyl group (such as but not limited to -SCF3), -(C1-C6) heterocycle (such as but not limited to pyrrolidine, tetrahydrofuran, pyran or morpholine), -(C1-C6) heteroaryl (such as but not limited to tetrazole, imidazole, furan, pyrazine or pyrazole), -phenyl, -NHC(O)O-(C1-C6) alkyl group, -N((C1-C6) alkyl)C(O)O-(C1-C6) alkyl group, -C(═NH)-(C1-C6) alkyl group, -C(═NOH)-(C1-C6) alkyl group or -C(═N-O-(C1-C6) alkyl)-(C1-C6) alkyl group.

[0064] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogen, –CN, –NO2, –N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, mercapto, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3–10 carbocyclic group, C 6–10 aryl, 3- to 10-membered heterocyclic group, 5- to 10-membered heteroaryl, etc. For example, exemplary carbon atom substituents may include F, Cl, -CN, –SO2H, –SO3H, –OH, –OC 1–6 alkyl, –NH2, –N(C 1–6 alkyl)2, –NH(C 1–6 alkyl), –SH, –SC 1–6 alkyl, –C(=O)(C 1–6 alkyl), –CO2H, –CO2(C 1–6 alkyl), –OC(=O)(C 1–6 alkyl), –OCO2(C 1–6 alkyl), –C(=O)NH2, –C(=O)N(C 1–6 alkyl)2, –OC(=O)NH(C 1–6 alkyl), –NHC(=O)(C 1–6 alkyl), –N(C 1–6 alkyl)C(=O)(C 1–6 alkyl), –NHCO2(C 1–6 alkyl), –NHC(=O)N(C 1–6 alkyl)2, –NHC(=O)NH(C 1–6 alkyl), –NHC(=O)NH2, –NHSO2(C 1–6 alkyl), –SO2N(C 1–6 alkyl)2, –SO2NH(C 1–6 alkyl), –SO2NH2, –SO2C 1–6 alkyl, –SO2OC 1–6 alkyl, –OSO2C 1–6 alkyl, –SOC 1–6 alkyl, C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclic group, C 6–10 aryl, 3– to 10-membered heterocyclic group, 5– to 10-membered heteroaryl; or two geminal substituents may be linked to form =O.

[0065] In some embodiments, unless otherwise specified or contrary to the context, any optionally substituted group herein can be unsubstituted or substituted with 1 - 5 substituents, provided that the valence allows. When substituted: (i) each substituent is independently selected from halo, hydroxy, cyano, nitro, (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, (C1 - C6)alkanoyloxy, and NR e R f , where any (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, and (C1 - C6)alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3 - C6)cycloalkyl, and (C1 - C6)alkoxy, where each R e and R f is independently selected from the group consisting of H, (C1 - C6)alkyl, (C3 - C6)cycloalkyl, and (C3 - C6)cycloalkyl(C1 - C6)alkyl; or R e and R f together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, and the aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one or more groups independently selected from halo and (C1 - C6)alkyl; or (ii) two substituents are joined to form a 3 - to 10 - membered ring and the remaining substituents are as defined in (i).

[0066] Provided that the valence allows, the nitrogen atom can be substituted or unsubstituted and includes primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, acyl groups, esters, sulfones, sulfoxides, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclic group, 3 - to 14 - membered heterocyclic group, C 6–14An aryl and a 5- to 14-membered heteroaryl, or two substituent groups attached to a nitrogen atom are linked to form a 3- to 14-membered heterocyclic group or a 5- to 14-membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl, and heteroaryl may be further substituted as defined herein. In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups are well known in the art and include those nitrogen protecting groups described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary nitrogen protecting groups include, but are not limited to, those protecting groups that form carbamates, such as the benzyloxycarbonyl (Cbz) group, the p-methoxybenzylcarbonyl (Moz or MeOZ) group, the tert-butoxycarbonyl (BOC) group, Troc, the 9-fluorenylmethoxycarbonyl (Fmoc) group, etc., those protecting groups that form amides, such as acetyl, benzoyl, etc., those protecting groups that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc., those protecting groups that form sulfonamides, such as tosyl, nitrobenzenesulfonyl (Nosyl), etc., and other protecting groups such as p-methoxyphenyl.

[0067] Exemplary oxygen atom substituents include, but are not limited to, acyl groups, esters, sulfonates, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclic group, 3- to 14-membered heterocyclic group, C 6–14Aryl and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group, aryl and heteroaryl may be further substituted as defined herein. In certain embodiments, the oxygen substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxy protecting group). Oxygen protecting groups are well known in the art and include those described in detail in Protective Groups in Organic Synthesis, T.W. Greene and P.G.M. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is incorporated herein by reference. Exemplary oxygen protecting groups include, but are not limited to, those that form alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl, such as 4-methoxybenzyl, methoxymethyl (MOM), benzyloxymethyl (BOM), 2-methoxyethoxymethyl (MEM), etc., those that form silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), etc., those that form acetals or ketals, such as tetrahydropyranyl (THP), those that form esters such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, etc., those that form carbonates or sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts), etc.

[0068] Unless stated to the contrary explicitly, combinations of substituents and / or variables are permissible only if such combinations are chemically allowed and result in a stable compound. A "stable" compound is one that can be prepared and isolated and whose structure and properties remain substantially unchanged or can be caused to remain substantially unchanged for a period of time sufficient to permit the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0069] As used herein, the term "protecting group" refers to a substituent that is commonly used to block or protect a particular functional group on a compound. For example, an "amino protecting group" is a substituent that is attached to an amino group to block or protect the amino functionality in a compound. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, a "hydroxy protecting group" refers to a hydroxy substituent that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy protecting group" refers to a carboxy substituent that blocks or protects the carboxy functionality. Common carboxy protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrosulfonyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl, and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W.G. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, Wiley-Interscience, New York, 2006.

[0070] As used herein, a wavy line that intersects a bond in a chemical structure indicates the point of attachment of the bond at which the wavy bond intersects in the chemical structure to the remainder of the molecule.

[0071] The terms "treat / treatment / treating", when referring to a disease or disorder, include inhibiting, eliminating, and / or alleviating one or more symptoms of the disease or disorder. The terms "treat / treatment / treating" also refer to therapeutic treatment and / or prophylactic or preventive measures, where the aim is to prevent or slow down (mitigate) an undesired physiological change or condition, such as the development or spread of a bacterial, fungal, viral infection, mastocytosis, mast cell-mediated inflammation or allergic disease. By way of example, beneficial or desired clinical outcomes include, but are not limited to, alleviation of detectable or non-detectable symptoms, diminishment of the extent of a disease or disorder, stabilization (i.e., non-worsening) of the state of a disease or disorder, delay or slowing of disease progression, improvement or alleviation of the disease state or disorder, and remission (partial or total). "Treat / treatment / treating" may also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those who already have the disease or disorder as well as those who are predisposed to having the disease or disorder or are to prevent the disease or disorder. In one embodiment, "treat / treatment / treating" does not include "preventing / prevention".

[0072] The term "therapeutically effective amount" or "effective amount" is an amount sufficient to achieve a beneficial or desired result such as a clinical outcome. The effective amount may be administered in one or more administrations. The effective amount is generally sufficient to alleviate, improve, stabilize, reverse, slow or delay the progression of a disease state.

[0073] The term "mammal" refers to any mammalian species such as a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, livestock, etc. Thus, in certain embodiments, the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit or livestock. In certain embodiments, the mammal is a patient (e.g., a human patient). In certain embodiments, the mammal is a pet such as a dog, cat, hamster, guinea pig or rabbit. In certain embodiments, the mammal is a livestock mammal (e.g., cow, sheep, horse, pig, chicken, etc.).

[0074] As used herein, the term "food" refers to a substance that can be consumed, e.g., to provide nutritional or therapeutic support to an organism. The term may include, but is not limited to, proteins, carbohydrates, fats, therapeutic agents such as pharmaceuticals, etc.

[0075] As used herein, the singular forms "a", "an" and "the" include plural referents unless expressly stated otherwise or clearly apparent from the context that this is not intended.

[0076] As used herein, the term "and / or" in a phrase such as "A and / or B" means including: both A and B; A or B; A alone; and B alone. Similarly, the term "and / or" in a phrase such as "A, B and / or C" means covering each of the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A alone; B alone; and C alone.

[0077] The headings and subheadings are used only for convenience and / or formal compliance, do not limit the subject technology, and are not mentioned in connection with the interpretation of the description of the subject technology. In various embodiments, the features described under one heading or one subheading of the subject disclosure may be combined with the features described under other headings or subheadings. Additionally, not all features under a single heading or a single subheading in an embodiment are necessarily used together.

[0078] The compounds disclosed herein may also exist as tautomers in certain cases. Although only one delocalized resonance structure is depicted, all such forms are contemplated within the scope of the present invention.

[0079] Those skilled in the art will understand that the present invention also includes any compound claimed, which may be enriched with one or more isotopes on any or all atoms at an isotope ratio higher than the naturally occurring one, such as but not limited to deuterium ( 2 H or D). As a non-limiting example, the -CH3 group may be replaced with -CD3.

[0080] The pharmaceutical compositions of the present invention may contain one or more excipients. When used in combination with the pharmaceutical compositions of the present invention, the term "excipient" generally refers to an additional ingredient that is combined with a compound of Formula I or Formula A, such as any sub-formula or specific compound of Formula I or Formula A as defined herein, or a pharmaceutically acceptable salt thereof to provide the corresponding composition. For example, when used in combination with the pharmaceutical compositions of the present invention, the term "excipient" includes but is not limited to: carriers, binders, disintegrants, lubricants, sweeteners, flavoring agents, coatings, preservatives, and dyes.

[0081] The stereochemical definitions and conventions used herein generally follow those of S.P. Parker, Editor, McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Compounds of the present invention may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present invention (including but not limited to diastereomers, enantiomers, and atropisomers) and mixtures thereof (such as racemic mixtures) are part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to its chiral center. The prefixes d and l or (+) and (-) are used to specify the sign of rotation of the compound for plane-polarized light, (-) or l meaning that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is commonly referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which can occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that are not optically active.

[0082] Those skilled in the art will understand that compounds of the present invention having chiral centers may exist in optically active and racemic forms and be separated in optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically active, polymorphic, or stereoisomeric form of the compounds of the present invention or mixtures thereof, which have the useful properties described herein, and it is well known in the art how to prepare optically active forms (e.g., by resolution of the racemic form using recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).

[0083] When the bonds in the chemical formulas of the compounds herein are drawn in a non-stereochemical manner (e.g., flat), the atoms to which the bonds are attached include all stereochemical possibilities. Unless otherwise indicated, when the bonds in the chemical formulas of the compounds herein are drawn in a defined stereochemical manner (e.g., bold, bold wedge, dash or dash wedge), it should be understood that the atoms attached to the stereochemical bond are enriched in the absolute stereoisomers shown. In one embodiment, the compound can be at least 51% of the depicted absolute stereoisomer. In another embodiment, the compound can be at least 60% of the absolute stereoisomer shown. In another embodiment, the compound can be at least 80% of the absolute stereoisomer shown. In another embodiment, the compound can be at least 90% of the absolute stereoisomer shown. In another embodiment, the compound can be at least 95% of the absolute stereoisomer shown. In another embodiment, the compound can be at least 99% of the absolute stereoisomer shown.

[0084] The specific values listed below for groups, substituents, and ranges are for illustration only; they do not exclude other defined values for the groups and substituents or other values within the defined ranges. It should be understood that two or more values can be combined. It should also be understood that the values (or subsets thereof) listed below herein can be excluded.

[0085] Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl or hexyl; (C3-C6)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, 3-pentyloxy or hexyloxy; (C1-C6)alkanoyl can be acetyl, propionyl or butyryl; (C1-C6)alkoxycarbonyl can be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl or hexyloxycarbonyl; (C1-C6)alkanoyloxy can be formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentyryloxy or hexyryloxy; and aryl can be phenyl, indenyl or naphthyl.

[0086] Formula I

[0087] Some embodiments of the present disclosure relate to compounds of Formula I as defined herein or pharmaceutically acceptable salts thereof.

[0088] In one specific embodiment, the compound of Formula I is a compound of Formula Ia:

[0089]

[0090] In one specific embodiment, the compound of Formula I is a compound of Formula Ib:

[0091]

[0092] In a specific embodiment, R 1 is an aryl group substituted by -S(=O)2NH2 and is also optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR a R b , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy.

[0093] In a specific embodiment, R 1 is a 5-membered heteroaryl group substituted by -S(=O)2NH2 and is also optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR a R b , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy.

[0094] In a specific embodiment, R 1 is a 6-membered heteroaryl group substituted by -S(=O)2NH2 and is also optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxyl, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR a R b, wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0095] In a specific embodiment, R 1 is a (C1-C3) alkyl substituted with an aryl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0096] In a specific embodiment, R 1 is a (C1-C3) alkyl substituted with a 5-membered heteroaryl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0097] In a specific embodiment, R 1 is a (C1-C3) alkyl substituted with a 6-membered heteroaryl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NRa R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0098] In one specific embodiment, R 1 is a phenyl substituted by -S(=O)2NH2 and is also optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0099] In one specific embodiment, R 1 is a phenyl substituted by -S(=O)2NH2.

[0100] In one specific embodiment, R 1 is 4-(aminosulfonyl)phenyl.

[0101] In one specific embodiment, R 2 is a benzyl optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR c R d , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0102] In one specific embodiment, R 2 is a benzyl optionally substituted by (C1-C6) alkoxy.

[0103] In a specific embodiment, R 2 is 4-methoxybenzyl.

[0104] In a specific embodiment, R 3 is H.

[0105] In a specific embodiment, R 3 is fluorine.

[0106] In a specific embodiment, R 3 is (C1-C6)alkyl optionally substituted with one or more fluorines;

[0107] In a specific embodiment, R 3 is (C1-C6)alkoxy optionally substituted with one or more fluorines;

[0108] In a specific embodiment, ring A is phenyl, and ring A is optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR e R f , where any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy;

[0109] In a specific embodiment, ring A is a 5-membered heteroaryl, and ring A is optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR e R f , where any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy;

[0110] In a specific embodiment, ring A is a 6-membered heteroaryl, and ring A is optionally substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR e R f , where any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy;

[0111] In a specific embodiment, the compound of formula I is a compound of formula IIa:

[0112]

[0113] In a specific embodiment, the compound of formula I is a compound of formula IIb:

[0114]

[0115] In a specific embodiment, the compound of formula I is a compound of formula IIIa:

[0116]

[0117] In a specific embodiment, the compound of formula I is a compound of formula IIIb:

[0118]

[0119] In a specific embodiment, the present invention provides a compound:

[0120]

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In one embodiment, the aryl is phenyl or naphthyl.

[0123] In one embodiment, the 5-membered heteroaryl is pyrrole, furan, thiophene, pyrazole, isoxazole, oxazole, isothiazole, thiazole, or triazole.

[0124] In one embodiment, the 6-membered heteroaryl is pyridine, pyridazine, pyrimidine, or pyrazine.

[0125] Formula A

[0126] Some embodiments of the present disclosure relate to a compound of formula A or a pharmaceutically acceptable salt thereof:

[0127]

[0128] wherein the variable R 1 、R 3 、L 1 、R 10 、ring A and ring B are as defined herein.

[0129] In some embodiments, L in formula A 1 is an optionally substituted C 1-3 alkylene, such as optionally substituted methylene. When substituted, the C 1-3 alkylene can be substituted with 1-5 substituents as described herein. For example, in some embodiments, the C 1-3 alkylene can be substituted with 1, 2, 3, or 4 groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy, and NR e R f R e and R f wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, and (C1-C6)alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl, and (C1-C6)alkoxy, and wherein each R e and R f independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or R e and R f together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl being optionally substituted with one or more groups independently selected from halo and (C1-C6)alkyl.

[0130] In some embodiments, L in formula A 1 is C 1-3 alkylene, such as methylene, which may be unsubstituted or substituted with an optionally substituted alkyl, such as an optionally substituted C 1-3 alkyl.

[0131] For example, in some embodiments, the compounds of formula A may be characterized by having a structure according to formula A-1:

[0132]

[0133] Wherein:

[0134] R 4 and R 5 are each independently hydrogen or optionally substituted C 1-3 alkyl. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 and R 5 are both hydrogen.

[0135] In some embodiments, L in Formula A 1 is absent.

[0136] Ring B in Formula A is typically a cyclic structure, but in some embodiments, Ring B may also be absent. In such cases, when L in Formula A 1 is also absent, R 10 is directly attached to L 1 or a nitrogen atom.

[0137] In some embodiments, Ring B in Formula A can be an optionally substituted arylene, such as an optionally substituted phenylene or an optionally substituted naphthylene.

[0138] In some embodiments, Ring B in Formula A can also be an optionally substituted heteroarylene, such as a 5- or 6-membered heteroarylene, or a 9- or 10-membered bicyclic heteroarylene.

[0139] In some embodiments, Ring B in Formula A can also be an optionally substituted carbocyclic group.

[0140] In some embodiments, Ring B in Formula A can also be an optionally substituted heterocyclic group.

[0141] For example, in some embodiments, the compound of Formula A-1 can have Ring B, which is an optionally substituted phenylene or an optionally substituted 5- or 6-membered heteroarylene. In some specific embodiments, Ring B can be an unsubstituted phenylene.

[0142] In some embodiments, the compound of Formula A-1 can be characterized by having a structure according to Formula A-1-A:

[0143]

[0144] Wherein:

[0145] n is 0, 1, 2, or 3; and

[0146] (i) R 100Each occurrence is independently a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, a (C1-C6) alkoxy group, a (C1-C6) alkanoyl group, a (C1-C6) alkoxycarbonyl group, a (C1-C6) alkanoyloxy group, and NR e R f , where any (C1-C6) alkyl group, (C3-C6) cycloalkyl group, (C1-C6) alkoxy group, (C1-C6) alkanoyl group, (C1-C6) alkoxycarbonyl group, and (C1-C6) alkanoyloxy group are optionally substituted with one or more groups independently selected from the group consisting of a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C3-C6) cycloalkyl group, and a (C1-C6) alkoxy group, where each R e and R f are independently selected from the group consisting of H, a (C1-C6) alkyl group, a (C3-C6) cycloalkyl group, and a (C3-C6) cycloalkyl(C1-C6) alkyl group; or R e and R f together with the nitrogen to which they are attached form an aziridinyl group, an azetidinyl group, a morpholinyl group, a piperazinyl group, a pyrrolidinyl group, or a piperidinyl group, and the aziridinyl group, azetidinyl group, morpholinyl group, piperazinyl group, pyrrolidinyl group, and piperidinyl group are optionally substituted with one or more groups independently selected from a halogen group and a (C1-C6) alkyl group; or

[0147] (ii) Two adjacent Rs 100 together with the intervening atom are joined to form an optionally substituted 4- to 7-membered ring, the ring optionally containing a ring heteroatom and being aromatic or non-aromatic, and any remaining R 100 is defined in (i). For example, in some embodiments, the in formula A-1-A can be

[0148] In some embodiments, the compounds of formula A-1 can be characterized as having a structure according to formula A-1-A:

[0149]

[0150] wherein:

[0151] n is 0, 1, 2, or 3; and

[0152] (i) R 100 at each occurrence is independently a halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl, where the C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines; or

[0153] (ii) Two adjacent Rs 100 together with the intervening atom are joined to form an optionally substituted 4- to 7-membered ring, which ring optionally contains a ring heteroatom and is aromatic or non-aromatic, and any remaining Rs 100 are as defined in (i).

[0154] R 10 may be located ortho, meta or para to the C(R 4 )(R 5 ) unit in formula A-1-A. For example, in some preferred embodiments, in formula A-1-A may be wherein R 10 , R 100 and n are as defined herein.

[0155] In some embodiments, n in formula A-1-A is 0. In some embodiments, n in formula A-1-A is 1 or 2.

[0156] In some embodiments, ring B in formula A such as formula A-1 may be an optionally substituted 5- or 6-membered heteroarylene having 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur. In some embodiments, the 5- or 6-membered heteroarylene may be pyridylene. In some embodiments, the ring nitrogen atom of the 5- or 6-membered heteroarylene is optionally oxidized. Generally, when substituted, as long as the valence allows, the 5- or 6-membered heteroarylene is preferably substituted with 1 to 3 substituents. For example, in some embodiments, as long as the valence allows, the 5- or 6-membered heteroarylene may be substituted with 1 to 3 substituents, each substituent independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3- to 6-membered ring, wherein C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1 to 3 fluorines.

[0157] In some embodiments, ring B in formula A such as formula A-1 can be an optionally substituted bicyclic heteroarylene (e.g., a 9- or 10-membered bicyclic heteroarylene, such as a 5,6-bicyclic heteroarylene or a 6,6-bicyclic heteroarylene), which has 1-4 ring heteroatoms, where each ring heteroatom is independently nitrogen, oxygen, or sulfur. In some embodiments, the bicyclic heteroarylene can be a 6,6-bicyclic heteroarylene, such as a quinoline or isoquinoline ring. In some embodiments, the ring nitrogen atom of the bicyclic heteroaryl is optionally oxidized. Generally, when substituted, as long as the valence allows, the bicyclic heteroarylene is preferably substituted with 1-3 substituents. For example, in some embodiments, as long as the valence allows, the bicyclic heteroarylene can be substituted with 1-3 substituents, each independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, or a 3-6-membered ring, where C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines.

[0158] In some embodiments, ring B in formula A such as formula A-1 can be an optionally substituted 4-7-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, where each ring heteroatom is independently nitrogen, oxygen, or sulfur. For example, in some embodiments, the 4-7-membered monocyclic heterocycle can be a tetrahydropyran ring. Generally, when substituted, the 4-7-membered monocyclic heterocycle is preferably substituted with 1-3 substituents. For example, in some embodiments, the 4-7-membered monocyclic heterocycle can be substituted with 1-3 substituents, each independently selected from oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, or a nitrogen protecting group, where C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines.

[0159] Various groups are suitable for R 10 in formula A. In some embodiments according to formula A such as formula A-1, R 10 can be hydrogen. In some embodiments according to formula A such as formula A-1, R 10 can be a halogen group. In some embodiments according to formula A, R 10 can be G 1 as defined herein or O-G 1 . Other suitable definitions of R 10 are described herein.

[0160] In some embodiments, R in Formula A such as Formula A-1 or Formula A-1-A 10 is an optionally substituted 4- to 7-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur. Generally, when substituted, the 4- to 7-membered monocyclic heterocycle is preferably substituted with 1 to 3 substituents. For example, in some embodiments, the 4- to 7-membered monocyclic heterocycle can be substituted with 1 to 3 substituents, each independently selected from oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, a 3- to 6-membered ring or a nitrogen protecting group (as appropriate), wherein C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1 to 3 fluorines.

[0161] In some embodiments, R in Formula A such as Formula A-1 or Formula A-1-A 10 is an optionally substituted 5- or 6-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur. For example, in some embodiments, the 5- or 6-membered monocyclic heterocycle can be pyrrolidine, piperidine, piperazine, morpholine, etc., which can be attached to the rest of the molecule through a ring carbon atom or a ring nitrogen atom. Generally, when substituted, the 5- or 6-membered monocyclic heterocycle is preferably substituted with 1 to 3 substituents. For example, in some embodiments, the 5- or 6-membered monocyclic heterocycle can be substituted with 1 to 3 substituents, each independently selected from oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, a 3- to 6-membered ring or a nitrogen protecting group (as appropriate), wherein C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1 to 3 fluorines. In some specific embodiments, R in Formula A, such as Formula A-1 or Formula A-1-A 10 is optionally selected from:

[0162]

[0163] In some embodiments, R in Formula A such as Formula A-1 or Formula A-1-A 10is an optionally substituted 5- or 6-membered monocyclic heterocycle having 1-4 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur. For example, in some embodiments, the 5- or 6-membered heteroaryl is pyridyl or imidazole ring. In some embodiments, the ring nitrogen atom of the 5- or 6-membered heteroaryl can be optionally oxidized. Generally, when substituted, as long as the valence allows, the 5- or 6-membered heteroaryl ring is preferably substituted with 1-3 substituents. For example, in some embodiments, the 5- or 6-membered heteroaryl ring is substituted with 1-3 substituents, each substituent independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3-6 membered ring, wherein C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines. In some specific embodiments, R in Formula A, such as in Formula A-1 or Formula A-1-A 10 can be

[0164] In some embodiments, the compound of Formula A can be characterized by having a structure according to Formula A-2:

[0165]

[0166] Ring B in Formula A-2 can be those rings B as described herein, such as any of those rings B described above together with Formula A-1.

[0167] In some embodiments, Ring B in Formula A-2 is an optionally substituted phenylene, an optionally substituted heteroarylene (e.g., 5-10 membered heteroarylene, such as isoquinolinyl) or an optionally substituted naphthylene.

[0168] In some embodiments, Ring B in Formula A-2 can be an optionally substituted 5- or 6-membered heteroarylene having 1-4 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur. In some embodiments, the 5- or 6-membered heteroarylene can be pyridylene. In some embodiments, the ring nitrogen atom of the 5- or 6-membered heteroarylene is optionally oxidized. Generally, when substituted, as long as the valence allows, the 5- or 6-membered heteroarylene is preferably substituted with 1-3 substituents. For example, in some embodiments, as long as the valence allows, the 5- or 6-membered heteroarylene can be substituted with 1-3 substituents, each substituent independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3-6 membered ring, wherein C 1-4 alkyl, C 1-4 alkoxy or C1-4 The heteroalkyl is optionally substituted with 1 - 3 fluorines.

[0169] In some embodiments, ring B in formula A - 2 can be an optionally substituted bicyclic heteroarylene (e.g., a 9 - or 10 - membered bicyclic heteroarylene, such as a 5,6 - bicyclic heteroarylene or a 6,6 - bicyclic heteroarylene), having 1 - 4 ring heteroatoms, where each ring heteroatom is independently nitrogen, oxygen, or sulfur. In some embodiments, the bicyclic heteroarylene can be a 6,6 - bicyclic heteroarylene, such as a quinoline or isoquinoline ring. In some embodiments, the ring nitrogen atom of the bicyclic heteroaryl is optionally oxidized. Generally, when substituted, as long as the valence allows, the bicyclic heteroarylene is preferably substituted with 1 - 3 substituents. For example, in some embodiments, as long as the valence allows, the bicyclic heteroarylene can be substituted with 1 - 3 substituents, each independently selected from halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, or a 3 - 6 - membered ring, where C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl is optionally substituted with 1 - 3 fluorines.

[0170] For example, in some embodiments, the compound of formula A - 2 can be characterized by having a structure according to formula A - 2 - A, formula A - 2 - B, or formula A - 2 - C:

[0171]

[0172] where:

[0173] j is 0, 1, 2, 3, or 4; and

[0174] (i) R 101 is independently, each occurrence, halo, hydroxy, cyano, nitro, (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, (C1 - C6)alkanoyloxy, and NR e R f , where any (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, and (C1 - C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3 - C6)cycloalkyl, and (C1 - C6)alkoxy, where each R e and R findependently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or R e and R f together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl being optionally substituted with one or more groups independently selected from halo and (C1-C6)alkyl; or

[0175] (ii) two R 101 are joined together to form a 5- to 7-membered ring which is optionally substituted with halogen, CN, C 1-4 alkyl optionally substituted with 1-3 F, C 1-4 alkoxy optionally substituted with 1-3 F, or C 1-4 heteroalkyl optionally substituted with 1-3 F, and any remaining R 101 is as defined in (i). For example, in some embodiments, the in formula A-2-A can be For clarity, in formula A-2-A and formula A-2-C, it should be understood that the R 101 group and the R 10 group can be attached at any available position on either of the two rings.

[0176] In some embodiments, the compounds of formula A-2 can be characterized as having a structure according to formula A-2-A, formula A-2-B, or formula A-2-C:

[0177]

[0178] wherein:

[0179] j is 0, 1, 2, 3, or 4; and

[0180] (i) R 101 is independently at each occurrence halogen, CN, OH, G 2 or OG 2 wherein G 2 is independently at each occurrence C 1-4 alkyl, C 1-4 heteroalkyl, a 3- to 6-membered ring, (C 1-4 alkylene)-(3- to 6-membered ring), or (C 1-4 heteroalkylene)-(3- to 6-membered ring), wherein said C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 alkylene, or C 1-4The heteroalkylene is optionally substituted with 1 - 3 fluorines; and the 3 - 6 - membered ring is optionally substituted with a halogen, CN, a C 1-4 alkyl optionally substituted with 1 - 3 fluorines, a C 1-4 alkoxy optionally substituted with 1 - 3 fluorines or a C 1-4 heteroalkyl, or

[0181] (ii) two R 101 groups are joined together to form a 5 - 7 - membered ring which is optionally substituted with a halogen, CN, a C 1-4 alkyl optionally substituted with 1 - 3 Fs, a C 1-4 alkoxy optionally substituted with 1 - 3 Fs or a C 1-4 heteroalkyl, and any remaining R 101 is as defined in (i). For clarity, in Formula A - 2 - A and Formula A - 2 - C, it should be understood that the R 101 groups and the R 10 groups can be attached to any available position on either of the two rings.

[0182] In Formula A - 2 - A, R 10 can be in any position of the naphthalene ring. For example, in some preferred embodiments, the in Formula A - 2 - A can be wherein R 10 , R 101 and j are as defined herein.

[0183] In Formula A - 2 - B, R 10 can be in the ortho, meta or para position of the amide (N(CO)) unit. For example, in some preferred embodiments, the in Formula A - 2 - B can be wherein R 10 , R 101 and j are as defined herein.

[0184] In some embodiments, R 10 can be hydrogen and the in Formula A - 2 - C can be represented by wherein R 101 and j are as defined herein.

[0185] R 10 groups suitable for Formula A - 2 such as Formula A - 2 - A, Formula A - 2 - B or Formula A - 2 - C include those groups described herein, such as any of those groups described in connection with Formula A - 1. In some embodiments, the R 10can be hydrogen, a halogen, OH, or a C alkoxy optionally substituted with 1 - 3 Fs. For example, in some embodiments, R in Formula A-2 such as Formula A-2-A, Formula A-2-B, or Formula A-2-C 1-4 can be hydrogen. In some embodiments, R in Formula A-2 such as Formula A-2-A, Formula A-2-B, or Formula A-2-C 10 can be F or Cl. In some embodiments, R in Formula A-2 such as Formula A-2-A, Formula A-2-B, or A-2-C 10 can be an optionally substituted 5- or 6-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, where each ring heteroatom is independently nitrogen, oxygen, or sulfur, such as morpholine, 10 When substituted, the 5- or 6-membered monocyclic heterocycle is preferably substituted with 1 - 3 substituents, such as 1 - 3 substituents each independently selected from the following: oxo, halogen (e.g., F), OH, C alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, a 3 - 6-membered ring, or a nitrogen protecting group, where C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 heteroalkyl is optionally substituted with 1 - 3 fluorines. 1-4

[0186] R, R, and ring A suitable for Formula A (e.g., A-1, A-1-A, A-2, A-2-A, A-2-B, or A-2-C) include any of those described herein together with Formula I and its sub-formulas. For example, in some embodiments, R in Formula A 1 3 can be 1 In some embodiments, R in Formula A can be 3 OH. In some embodiments, ring A in Formula A can be a benzene ring. For example, in some embodiments, the compound of Formula A can be characterized by having a structure according to Formula A-3:

[0187]

[0188] In some embodiments, the compound of Formula A (including any sub-formulas herein) can be characterized by having certain stereochemistry. For example, in some embodiments, the compound of Formula A can have stereochemistry according to Formula A-E1 or Formula A-E2:

[0189]

[0190] ​​​In some embodiments, the present disclosure also provides novel specific compounds as described in the Examples section herein, including any new synthetic intermediates or target compounds, as well as their stereoisomers, their deuterated analogs, or their pharmaceutically acceptable salts.

[0191] In some embodiments, the present disclosure provides a compound selected from the following table, its stereoisomers, its deuterated analogs, or its pharmaceutically acceptable salts:

[0192]

[0193]

[0194]

[0195] Where the compound is sufficiently basic or acidic, the salts of the compounds of Formula I or Formula A can be used as intermediates for the separation or purification of the compounds of Formula I or Formula A. Additionally, it may be appropriate to administer the compounds of Formula I or Formula A as pharmaceutically acceptable acid or base salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, mesylate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0196] Salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound such as an amine with a suitable acid that provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0197] In view of the present disclosure, those skilled in the art can readily synthesize the compounds of the present disclosure. Illustrative syntheses are also shown in the Examples section.

[0198] Certain methods of use

[0199] As described herein, the compounds of Formula I or Formula A can be used as carbonic anhydrase inhibitors. Carbonic anhydrase (Car) is a family of metabolic enzymes that regulate pH and CO2 homeostasis (Supuran, C.T. 2008. Nat Rev Drug Discov 7:168 - 181, which is hereby incorporated by reference). The Car enzymes found in mammals are divided into four major subclasses, which are in turn composed of several isotypes: cytosolic Car (Car1, Car2, Car3, Car7, Car13), mitochondrial Car (Car5A, Car5B), secreted Car (Car6), and membrane - associated Car (Car4, Car9, Car12, Car14). Additionally, there are three other "catalytically inactive" Car isotypes (Car8, Car10, Car11) whose functions are still unclear.

[0200] Accordingly, certain embodiments of the present invention provide a method for inhibiting carbonic anhydrase (e.g., the activity or function of the enzyme) in vitro or in vivo, the method comprising contacting the carbonic anhydrase with an effective amount of a compound of Formula I or Formula A or a salt thereof (e.g., a pharmaceutically acceptable salt thereof). In certain embodiments, such methods comprise contacting a cell comprising the carbonic anhydrase. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is contacted by administering to the mammal a compound of Formula I or Formula A, a salt thereof (e.g., a pharmaceutically acceptable salt thereof).

[0201] In certain embodiments, the activity or function of the carbonic anhydrase is inhibited by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% (e.g., compared to a control, such as a cell or a mammal not contacted with the compound of Formula I or Formula A).

[0202] Certain embodiments also provide a compound of Formula I or Formula A or a salt thereof for inhibiting carbonic anhydrase in vitro or in vivo.

[0203] Certain embodiments provide the use of a compound of Formula I or Formula A or a salt thereof for the manufacture of a medicament for inhibiting carbonic anhydrase in vitro or in vivo.

[0204] In certain embodiments, the carbonic anhydrase is carbonic anhydrase (Car) 1 (see, UniProKB No P00915).

[0205] Certain embodiments also provide a method of inhibiting mast cell development and / or mast cell function (e.g., mast cell activation) in a mammal, which comprises administering to the mammal a compound of formula I or formula A or a pharmaceutically acceptable salt thereof.

[0206] Certain embodiments provide a compound of formula I or formula A or a pharmaceutically acceptable salt thereof for inhibiting mast cell development and / or mast cell function (e.g., mast cell activation).

[0207] Certain embodiments also provide the use of a compound of formula I or formula A or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting mast cell development and / or mast cell function (e.g., mast cell activation).

[0208] Certain embodiments also provide a method of treating a carbonic anhydrase-mediated disease or condition in a mammal (e.g., a human), which comprises administering to the mammal a compound of formula I or formula A or a pharmaceutically acceptable salt thereof.

[0209] Certain embodiments provide a compound of formula I or formula A or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a carbonic anhydrase-mediated disease or condition.

[0210] Certain embodiments also provide the use of a compound of formula I or formula A or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a carbonic anhydrase-mediated disease or condition.

[0211] Examples of carbonic anhydrase-mediated (e.g., mediated by carbonic anhydrase activity / function) diseases or conditions are known in the art and include, for example, mast cell-mediated diseases. For example, diseases associated with carbonic anhydrase and / or mast cells include, but are not limited to, for example, allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis, and mast cell-mediated inflammation.

[0212] In certain embodiments, the carbonic anhydrase-mediated disease or condition is an allergic disease.

[0213] The term "allergic disease" refers to a condition caused by a hypersensitivity reaction of the immune system in response to environmental exposure. Examples of allergic diseases that can be treated include, but are not limited to, asthma (e.g., fungal asthma), atopic dermatitis, contact dermatitis, chronic pruritus (prurigo), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, food allergy, and allergen-induced mastocytosis.

[0214] In certain other embodiments, the carbonic anhydrase-mediated disease or condition is a bacterial infection, a fungal infection, or a viral infection.

[0215] Non-limiting examples of bacterial infections include, for example, Klebsiella pneumoniae and Pseudomonas aeruginosa. In certain embodiments, the bacterial infection is a Gram-negative bacterial infection.

[0216] Non-limiting examples of fungal infections include infections caused by Aspergillus fumigates or other Aspergiullus species, as well as Candida species, Cryptococcus species, Histoplasma capsulatum, Pneumocystis jirovecii, and Stachybotrys chartarum.

[0217] Non-limiting examples of viral infections include HIV, SARS-CoV-2, and dengue fever.

[0218] On the other hand, a disease or condition mediated by carbonic anhydrase is mastocytosis.

[0219] As used herein, the term "mastocytosis" refers to a disease characterized by the presence of an excessive number of mast cells in various organs and tissues, including but not limited to, infection- or allergen-induced mastocytosis, cutaneous mastocytosis, indolent systemic mastocytosis, systemic mastocytosis with associated clonal hematologic non-mast cell lineage diseases (such as myelodysplastic syndrome, myeloproliferative syndrome, acute myeloid leukemia, non-Hodgkin lymphoma), aggressive systemic mastocytosis, mast cell leukemia, mast cell activation syndrome, and local mast cell proliferations (such as mast cell sarcoma and extracutaneous mastocytoma). In certain embodiments, the mastocytosis is mast cell activation syndrome.

[0220] On the other hand, a disease or condition mediated by carbonic anhydrase is mast cell-mediated inflammation.

[0221] As used herein, the term "mast cell-mediated inflammation" refers to any inflammatory response and / or pathology that is promoted or supported by mast cell development and / or activation. This includes mast cell responses promoted by exposure to allergens, infectious agents, or unknown stimuli. In certain embodiments, mast cell-mediated inflammation is caused by mastocytosis, infection (e.g., parasitic infections such as helminth parasites (e.g., Trichinella spiralis infection)), or allergy (e.g., food allergy or food allergy-like diseases). In certain embodiments, mast cell-mediated inflammation is mast cell-mediated intestinal inflammation. In certain embodiments, mast cell-mediated inflammation is mast cell-mediated airway inflammation (e.g., eosinophilic airway inflammation).

[0222] In certain embodiments, administration of a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof reduces mast cell responses such as mast cell-mediated inflammation (e.g., mast cell-mediated intestinal inflammation; or mast cell-mediated airway inflammation). In certain embodiments, the mast cell response (e.g., mast cell-mediated inflammation) is induced by allergy (such as food allergy).

[0223] In certain embodiments, the mast cell response (e.g., mast cell activation and / or mast cell-mediated inflammation) results in airway constriction. In certain embodiments, administration of a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof is capable of treating such airway constriction.

[0224] In certain embodiments, the methods described herein may further comprise administration of one or more additional therapeutic agents. For example, such agents can be used to treat diseases or conditions mediated by carbonic anhydrase (e.g., for treating allergic diseases, bacterial infections, fungal infections, viral infections, mastocytosis, and / or mast cell-mediated inflammation).

[0225] In certain embodiments, the one or more additional therapeutic agents are administered simultaneously or sequentially with a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof. In certain embodiments, the one or more additional therapeutic agents are administered simultaneously with a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof. In certain embodiments, a pharmaceutical composition / formulation comprising a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents is administered. In certain embodiments, a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof and the one or more additional therapeutic agents are administered sequentially. In certain embodiments, a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof is administered first and the one or more additional therapeutic agents are administered second. In certain embodiments, the one or more additional therapeutic agents are administered first and a compound of Formula I or Formula A or a pharmaceutically acceptable salt thereof is administered second.

[0226] In certain embodiments, the one or more additional therapeutic agents are antihistamines, steroids, immunotherapies (e.g., allergy vaccines, oral tolerance therapy, etc.), decongestants, bronchodilators, mast cell stabilizers, prostaglandin antagonists, blocking / neutralizing antibodies (e.g., anti-IgE therapy, anti-IL-4Rα therapy, or anti-SIGLEC8 therapy), and / or leukotriene modifiers. In certain embodiments, combinations of such agents are administered.

[0227] In certain embodiments, the one or more additional therapeutic agents are antihistamines. Histamine antagonists, commonly referred to as antihistamines, are a class of drugs that includes two types of medications: histamine H1-receptor antagonists and histamine H2-receptor antagonists. Antagonists of the histamine H1-receptor are used to treat nasal allergic reactions (e.g., itching, runny nose, and sneezing) and off-label for insomnia. They are sometimes also used to treat motion sickness or vertigo caused by inner ear problems. Antagonists of the histamine H2-receptor are used to treat gastric acid conditions (e.g., peptic ulcers and acid reflux). They act by binding to histamine H1 receptors in mast cells, smooth muscle, and endothelium in the body and histamine H2 receptors in the tuberomammillary nucleus of the brain or the upper gastrointestinal tract (primarily the stomach).

[0228] Non-limiting examples of antihistamines that can be used in the present invention include: acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; hydroxyzine metabolite, its prodrug), chlorpromazine, cimetidine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dechlorpheniramine, dimenhydrinate, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenadine (Allegra), hydroxyzine (Vistaril), lafutidine, levocetirizine, loratadine (Claritin), nizatidine, olopatadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, ranitidine, roxatidine, rupatadine, tiotidine, tripelennamine, and triprolidine.

[0229] In certain embodiments, the one or more additional therapeutic agents are blocking and / or neutralizing antibodies (e.g., antibodies that can be used to treat inflammation). For example, such antibodies can target IgE, IL-4Rα, or SIGLEC8.

[0230] Thus, in certain embodiments, the one or more additional therapeutic agents are anti-IgE therapy. Anti-IgE therapies that can be used in the present invention include anti-IgE therapeutic antibodies, such as monoclonal antibodies. Non-limiting examples of suitable monoclonal antibodies are omalizumab (Omalizumab) (Xolair).

[0231] In certain embodiments, the one or more additional therapeutic agents are anti-IL-4Rα therapies. Anti-IL-4R therapies useful in the present invention include anti-IL-4Rα therapeutic antibodies, such as monoclonal antibodies. Non-limiting examples of suitable antibodies are dupilumab.

[0232] In certain embodiments, the one or more additional therapeutic agents are anti-SIGLEC8α therapies. Anti-SIGLEC8 therapies useful in the present invention include anti-SIGLEC8α therapeutic antibodies, such as monoclonal antibodies. Non-limiting examples of suitable antibodies are lirentelima b.

[0233] In certain embodiments, the one or more additional therapeutic agents are prostaglandin antagonists. Prostaglandin antagonists are hormone antagonists that act on one or more prostaglandins, which are a subclass of eicosanoids that function as signaling molecules in many types of animal tissues. Non-limiting examples of prostaglandin antagonists useful in the present invention include NSAIDs and seratrodast.

[0234] In certain embodiments, the one or more additional therapeutic agents are steroids. Steroids are organic compounds that typically contain four rings arranged in a specific configuration. Steroids have two main biological functions: some steroids, such as cholesterol, are important components of cell membranes, altering membrane fluidity, and many steroids are signaling molecules that activate steroid hormone receptors. Generally, the steroid core structure consists of seventeen carbon atoms bonded into four "fused" rings: three six-membered cyclohexane rings (rings A, B, and C in the first illustration) and one five-membered cyclopentane ring (D ring). Steroids vary by the functional groups attached to this four-ring core and the oxidation state of the rings. Sterols are a form of steroid that has a hydroxyl group at position 3 and a skeleton derived from cholestane. Steroids can also be more significantly altered by changes in the ring structure (e.g., producing secosteroids, such as the ring rupture of vitamin D3).

[0235] Non-limiting examples of steroids useful in the present invention include: beclomethasone, ciclesonide, fluticasone propionate, fluticasone furoate, mometasone, budesonide, triamcinolone acetonide, dexamethasone, prednisone (deltasone), and prednisolone.

[0236] In certain embodiments, the one or more additional therapeutic agents are immunotherapies. Immunotherapy is the treatment of a disease or condition by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to initiate or enhance an immune response are classified as activating immunotherapies, while those that reduce or suppress are classified as inhibitory immunotherapies.

[0237] Non-limiting examples of immunotherapies useful in the present invention include allergy vaccines and oral tolerance therapies.

[0238] In certain embodiments, the one or more additional therapeutic agents are decongestants. A decongestant is an agent used to relieve nasal congestion in the upper respiratory tract. Non-limiting examples of decongestants useful in the present invention include pseudoephedrine, phenylephrine, and oxymetazoline.

[0239] In certain embodiments, the one or more additional therapeutic agents are bronchodilators. A bronchodilator is an agent that dilates the bronchi and bronchioles, reduces airway resistance, and increases airflow into the lungs. Non-limiting examples of bronchodilators useful in the present invention include albuterol and levalbuterol.

[0240] In certain embodiments, the one or more additional therapeutic agents are mast cell stabilizers. Mast cell stabilizers are generally cromone drugs used to prevent or control certain allergic conditions. They block the calcium channels necessary for mast cell degranulation, stabilizing the cells and thus preventing the release of histamine and related mediators. Non-limiting examples of mast cell stabilizers useful in the present invention include sodium cromoglycate, lodoxamide, and nedocromil.

[0241] In certain embodiments, the one or more additional therapeutic agents are leukotriene modifiers. A leukotriene modifier is an agent that acts as a leukotriene-related enzyme inhibitor (arachidonate 5-lipoxygenase) or a leukotriene receptor antagonist (cysteinyl leukotriene receptor) and thus counteracts the function of these inflammatory mediators. Non-limiting examples of leukotriene modifiers useful in the present invention include montelukast, zafirlukast, and zileuton.

[0242] In certain embodiments, the one or more additional therapeutic agents are tyrosine kinase inhibitors (TKIs), such as KIT inhibitors. Tyrosine kinases are enzymes that activate signal transduction cascades by phosphorylating proteins involved in those signaling processes. TKIs inhibit tyrosine kinase phosphorylation. Non-limiting examples of TKIs useful in the present invention include imatinib, sunitinib, dasatinib, nilotinib, avapritinib, and bezuclatinib.

[0243] Administration and formulation

[0244] The compounds of formula I or formula A can be formulated into pharmaceutical compositions and administered to mammalian hosts, such as human patients, in various forms suitable for the selected route of administration (i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes).

[0245] Thus, the compounds of the present invention can be administered systemically, for example orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an absorbable edible carrier. They can be encapsulated in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly into the food of the patient's diet. For oral therapeutic administration, the active compounds can be combined with one or more excipients and used in the form of ingestible tablets, troches, lozenges, capsules, elixirs, suspensions, syrups, powder tablets, etc. Such compositions and preparations should contain at least 0.1% of the active compound. Of course, the percentages of the compositions and preparations can vary and can conveniently be between about 2% and about 60% of the weight of the given unit dosage form. The amount of the active compound in such therapeutically useful compositions is an amount such that an effective dosage level will be obtained.

[0246] Tablets, troches, pills, capsules, etc. can also contain the following: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; disintegrating agents, such as corn starch, potato starch, alginic acid, etc.; lubricants, such as magnesium stearate; and sweetening agents, such as sucrose, fructose, lactose or aspartame, or flavoring agents such as peppermint, wintergreen oil or cherry flavoring can be added. When the unit dosage form is a capsule, in addition to materials of the above types, it can also contain a liquid carrier, such as a vegetable oil or polyethylene glycol. Various other substances can be present as coatings or can be present to otherwise modify the physical form of the solid unit dosage form. For example, tablets, pills or capsules can be coated with gelatin, wax, shellac or sugar, etc. Syrups or elixirs can contain the active compound, sucrose or fructose as a sweetening agent, methylparaben and propylparaben as preservatives, dyes and flavoring agents (such as cherry or orange flavoring). Of course, any substance used in the preparation of any unit dosage form should be pharmaceutically acceptable and substantially non-toxic at the amounts used. In addition, the active compounds can be incorporated into sustained release formulations and devices.

[0247] The active compounds can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compounds or their salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof, and in oils. Under ordinary storage and use conditions, these preparations contain preservatives to prevent the growth of microorganisms.

[0248] Pharmaceutical dosage forms suitable for injection or infusion may include sterile aqueous solutions or dispersions or, optionally, sterile powders containing the active ingredient encapsulated in liposomes, which are suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage. The liquid carrier or vehicle can be a solvent or a liquid dispersion medium, which includes, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glycerides, and suitable mixtures thereof. Appropriate fluidity can be maintained, for example, by forming liposomes, in the case of dispersions, by maintaining the desired particle size, or by using surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.). In many cases, it will be preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. Prolonged absorption of injectable compositions can be achieved by using agents that delay absorption (e.g., aluminum monostearate and gelatin) in the composition.

[0249] Sterile injectable solutions are prepared by incorporating the required amount of the active compound in a suitable solvent with the various other ingredients enumerated above, as required, followed by filtration sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying techniques, which yield a powder of the active ingredient plus any additional required ingredients present in the previously sterile filtered solution.

[0250] For topical application, the compounds of the present invention can be applied in pure form, i.e., when they are in a liquid state. However, it will generally be desirable to combine them with a dermatologically acceptable carrier and apply them to the skin in the form of a composition or formulation, which carrier can be solid or liquid.

[0251] Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Suitable liquid carriers include water, alcohols, or diols or water-alcohol / diol blends in which the compounds of the present invention can be optionally dissolved or dispersed at an effective level with the aid of a non-toxic surfactant. Adjuvants such as fragrances and other antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid compositions can be applied from absorbent pads for impregnating bandages and other dressings, or sprayed onto the affected area using a pump-type sprayer or an aerosol sprayer.

[0252] Thickening agents such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses, or modified minerals can also be used with the liquid carrier to form pourable pastes, gels, ointments, soaps, etc. for direct application to the skin of the user.

[0253] Examples of suitable dermatological compositions for delivering a compound of formula I or formula A to the skin are known in the art; see, for example, Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157), and Wortzman (U.S. Patent No. 4,820,508).

[0254] A suitable dose of a compound of formula I or formula A can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0255] The amount of the compound or its active salt or derivative required for use in therapy will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attending physician or clinician.

[0256] The required dose may conveniently be provided as a single dose or as divided doses administered at appropriate time intervals, such as two, three, four or more sub-doses per day. The sub-doses themselves may further be divided, for example, into multiple separate and loosely spaced administrations; such as multiple inhalations from an inhaler or multiple instillations into the eye.

[0257] The compounds of the invention may also be administered in combination with other therapeutic agents. Examples of such agents include antihistamines, steroids, immunotherapies (e.g., allergy vaccines, oral tolerance therapy, etc.), decongestants, bronchodilators, mast cell stabilizers, leukotriene modifiers, prostaglandin antagonists, and blocking / neutralizing antibodies (e.g., anti-IgE therapy, anti-IL-4Rα therapy, and anti-SIGLEC8 therapy).

[0258] Accordingly, one embodiment of the invention also provides a composition comprising a compound of formula I or formula A or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent (e.g., an additional agent as described herein), and a pharmaceutically acceptable diluent or carrier. The invention also provides a kit comprising a compound of formula I or formula A or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for administering the compound of formula I or formula A or a pharmaceutically acceptable salt thereof and one or more other therapeutic agents to an animal for treating a carbonic anhydrase-mediated disease or condition.

[0259] Non-limiting exemplary embodiments:

[0260] In some embodiments, the present disclosure provides the following non-limiting exemplary embodiments 1-48:

[0261] Embodiment 1. A compound of formula I:

[0262]

[0263] or a pharmaceutically acceptable salt thereof, wherein:

[0264] R 1 is aryl, 5 - membered heteroaryl, 6 - membered heteroaryl or (C1 - C3)alkyl substituted with aryl, 5 - membered heteroaryl or 6 - membered heteroaryl, wherein any aryl, 5 - membered heteroaryl and 6 - membered heteroaryl is substituted with - S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, (C1 - C6)alkanoyloxy and NR a R b , wherein any (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl and (C1 - C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3 - C6)cycloalkyl and (C1 - C6)alkoxy;

[0265] R 2 is H, aryl, 5 - membered heteroaryl, 6 - membered heteroaryl or (C1 - C3)alkyl optionally substituted with aryl, 5 - membered heteroaryl or 6 - membered heteroaryl, wherein any aryl, 5 - membered heteroaryl and 6 - membered heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl, (C1 - C6)alkanoyloxy and NR c R d , wherein any (C1 - C6)alkyl, (C3 - C6)cycloalkyl, (C1 - C6)alkoxy, (C1 - C6)alkanoyl, (C1 - C6)alkoxycarbonyl and (C1 - C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3 - C6)cycloalkyl and (C1 - C6)alkoxy;

[0266] R 3 is H, fluoro, hydroxy, (C1 - C6)alkyl or (C1 - C6)alkoxy, wherein any (C1 - C6)alkyl and (C1 - C6)alkoxy is optionally substituted with one or more fluoro;

[0267] Ring A is phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl, and provided that the valence allows, Ring A is optionally substituted by 1, 2, 3 or 4 groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR e R f , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy;

[0268] Each R a and R b is independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or R a and R b together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, wherein aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl and piperidinyl are optionally substituted by one or more groups independently selected from halogen and (C1-C6)alkyl;

[0269] Each R c and R d is independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or R c and R d together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl and piperidinyl being optionally substituted by one or more groups independently selected from halogen and (C1-C6)alkyl; and

[0270] Each R e and R f is independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl and (C3-C6)cycloalkyl(C1-C6)alkyl; or R e and R fTogether with the nitrogen to which they are attached, form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl or piperidinyl, and the aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl and piperidinyl are optionally substituted by one or more groups independently selected from halo and (C1-C6) alkyl.

[0271] Embodiment 2. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of formula I is a compound of formula Ia:

[0272]

[0273] Embodiment 3. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of formula I is a compound of formula Ib:

[0274]

[0275] Embodiment 4. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is an aryl substituted by -S(=O)2NH2 and is further optionally substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0276] Embodiment 5. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is a 5-membered heteroaryl substituted by -S(=O)2NH2 and is further optionally substituted by one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b, wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0277] Embodiment 6. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is a 6-membered heteroaryl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0278] Embodiment 7. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is an (C1-C3) alkyl substituted with an aryl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0279] Embodiment 8. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1is a 5-membered heteroaryl-substituted (C1-C3)alkyl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR a R b , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy.

[0280] Embodiment 9. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is a 6-membered heteroaryl-substituted (C1-C3)alkyl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR a R b , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy.

[0281] Embodiment 10. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is a phenyl substituted with -S(=O)2NH2 and is further optionally substituted with one or more groups independently selected from the group consisting of halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR a R b, wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy is optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0282] Embodiment 11. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is a phenyl group substituted with -S(=O)2NH2.

[0283] Embodiment 12. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-3, wherein R 1 is 4-(aminosulfonyl)phenyl.

[0284] Embodiment 13. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-12, wherein R 2 is a benzyl group optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR c R d , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy is optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0285] Embodiment 14. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-12, wherein R 2 is a benzyl group optionally substituted by (C1-C6) alkoxy.

[0286] Embodiment 15. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-12, wherein R 2 is 4-methoxybenzyl.

[0287] Embodiment 16. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-15, wherein R 3 is H.

[0288] Embodiment 17. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-15, wherein R 3 is fluorine.

[0289] Embodiment 18. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-15, wherein R 3 is a (C1-C6) alkyl optionally substituted with one or more fluorines.

[0290] Embodiment 19. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-15, wherein R 3 is a (C1-C6) alkoxy optionally substituted with one or more fluorines.

[0291] Embodiment 20. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-19, wherein Ring A is phenyl, and Ring A is optionally substituted with 1, 2, 3 or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR e R f , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0292] Embodiment 21. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-19, wherein Ring A is a 5-membered heteroaryl, and Ring A is optionally substituted with 1, 2, 3 or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR e R f , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy are optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy.

[0293] Embodiment 22. The compound or pharmaceutically acceptable salt according to any one of Embodiments 1-19, wherein Ring A is a 6-membered heteroaryl, and Ring A is optionally substituted with 1, 2, 3 or 4 groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR e R f , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy is optionally substituted with one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy.

[0294] Embodiment 23. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of Formula I is the compound of Formula IIa:

[0295]

[0296] Embodiment 24. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of Formula I is the compound of Formula IIb:

[0297]

[0298] Embodiment 25. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of Formula I is the compound of Formula IIIa:

[0299]

[0300] Embodiment 26. The compound or pharmaceutically acceptable salt according to Embodiment 1, wherein the compound of Formula I is the compound of Formula IIIb:

[0301]

[0302] Embodiment 27. The compound:

[0303]

[0304] or a pharmaceutically acceptable salt thereof.

[0305] Embodiment 28. A pharmaceutical composition comprising the compound according to any one of Embodiments 1-27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0306] Embodiment 29. The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27, for use in medical therapy.

[0307] Embodiment 30. A method of inhibiting carbonic anhydrase in vitro or in vivo, comprising contacting the carbonic anhydrase with an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27.

[0308] Embodiment 31. A method of treating a carbonic anhydrase-mediated disease or condition in a mammal (e.g., a human), comprising administering to the mammal the compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27.

[0309] Embodiment 32. The method according to Embodiment 31, further comprising administering one or more additional therapeutic agents.

[0310] Embodiment 33. The method according to Embodiment 32, wherein the one or more additional therapeutic agents are antihistamines, steroids, decongestants, bronchodilators, mast cell stabilizers, leukotriene regulators, prostaglandin antagonists, blocking / neutralizing antibodies, and / or immunotherapy.

[0311] Embodiment 34. The method according to Embodiment 32, wherein the one or more additional therapeutic agents are antihistamines.

[0312] Embodiment 35. The method according to Embodiment 34, wherein the antihistamine is acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; metabolite of hydroxyzine, its prodrug), chlorpromazine, cimetidine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenadine (Allegra), hydroxyzine (Vistaril), lafutidine, levocetirizine, loratadine (Claritin), nizatidine, olopatadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, ranitidine, roxatidine, rupatadine, tiotidine, tripelennamine, or triprolidine.

[0313] Embodiment 36. The method according to any one of Embodiments 30-35, wherein the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit, or livestock.

[0314] Embodiment 37. The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1-27, for prophylactic or therapeutic treatment of a carbonic anhydrase-mediated disease or condition.

[0315] Use of a compound as described in any one of embodiments 1-27 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a carbonic anhydrase-mediated disease or condition.

[0316] Embodiment 39. The method, compound or use as described in any one of embodiments 30-38, wherein the disease or condition mediated by carbonic anhydrase is an allergic disease, a bacterial infection, a fungal infection, a viral infection, mastocytosis or mast cell-mediated inflammation.

[0317] Embodiment 40. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is an allergic disease.

[0318] Embodiment 41. The method, compound or use as described in embodiment 40, wherein the allergic disease is asthma (e.g., fungal asthma), atopic dermatitis, contact dermatitis, chronic pruritus (prurigo), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, food allergy or allergen-induced mastocytosis.

[0319] Embodiment 42. The method, compound or use as described in embodiment 40, wherein the allergic disease is asthma.

[0320] Embodiment 43. The method, compound or use as described in embodiment 40, wherein the allergic disease is food allergy.

[0321] Embodiment 44. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is a bacterial infection.

[0322] Embodiment 45. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is a fungal infection.

[0323] Embodiment 46. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is a viral infection.

[0324] Embodiment 47. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is mastocytosis.

[0325] Embodiment 48. The method, compound or use as described in embodiment 39, wherein the disease or condition mediated by carbonic anhydrase is mast cell-mediated inflammation.

[0326] The present invention will now be illustrated by the following non-limiting examples.

[0327] Example

[0328] Mast cells are potent innate immune cells that become activated in response to a variety of stimuli, including cytokines and antigen - antibody complexes. Once activated, mast cells release numerous effector molecules, the ability of which to promote detrimental inflammation in the context of allergy, asthma, mastocytosis, and mast cell activation syndrome has been well - characterized. Despite a clinical need, therapeutic strategies to target mast cell responses and reduce mast cell activation remain limited.

[0329] Recently, mast cell progenitors that express high levels of carbonic anhydrase (Car)1 have been identified. Using these cells, it was demonstrated that targeting Car1 with the inhibitor methazolamide (MZ) was sufficient to prevent mast cell development and mast cell - mediated inflammation. As described below, a more potent Car1 inhibitor, 4 - (3 - hydroxy - 1 - (4 - methoxybenzyl)-2 - oxoindolin - 3 - yl)benzenesulfonamide (CAR0037), was designed and synthesized. Specifically, CAR0037 was shown to be a more potent Car1 inhibitor compared to MZ and more effectively inhibited mast cell responses. Additional studies have shown that other compounds of the present disclosure may also have efficacy similar to or better than MZ and / or CAR0037 in inhibiting carbonic anhydrase. Collectively, these data indicate that the compounds of formula I or formula A described herein, including CAR0037, can be used to treat mast cell - mediated inflammation and other mast cell - mediated diseases or conditions.

[0330] Unless otherwise specifically stated or clearly contrary to context, the abbreviations used in the Examples section should be understood to have their ordinary meaning in the art.

[0331] Example 1. Preparation of 4 - (3 - hydroxy - 1 - (4 - methoxybenzyl)-2 - oxoindolin - 3 - yl)benzenesulfonamide.

[0332]

[0333] Bis(ethylene)rhodium(I) acetylacetonate (13.2 mg, 0.051 mmol, 3 mol%) and triphenyl phosphite (36.9 mg, 0.12 mmol, 7 mol%) in anhydrous dioxane were degassed under bubbling nitrogen for 10 minutes. A mixture of 1-(4-methoxybenzyl)indoline-2,3-dione (457 mg, 1.7 mmol, 1.0 equiv) and (4-sulfamoylphenyl)boronic acid (687 mg, 3.4 mmol, 2.0 equiv) in anhydrous dioxane was added to the solution. The reaction was heated at 80 °C overnight. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate (3 × 5 mL) and washed with water (2 × 10 mL). The ethyl acetate layer was separated and dried over Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography (ethyl acetate / hexane) to give the title compound as a white solid (210 mg, 29.1%). 1 1H NMR (CDCl3, 500 MHz): δ 7.76 (2H, d, J = 8.5 Hz); 7.44 (2H, d, J = 8.5); 7.27 - 7.23 (3H, m); 7.18 (1H, d, J = 7.0 Hz); 7.05 - 7.02 (1H, m); 6.87 (3H, d, J = 8.5 Hz); 5.29 (2H, d, J = 2.5 Hz); 4.95 (1H, d, 15.5 Hz); 4.78 (1H, d, J = 15.5 Hz); 4.52 (1H, s), 3.78 (3H, s). LCMS: 425.2 [M+H] + 。

[0334] The intermediate compound 1-(4-methoxybenzyl)indoline-2,3-dione was prepared as follows.

[0335]

[0336] a. 1-(4-methoxybenzyl)indoline-2,3-dione.

[0337] Under nitrogen at 0 °C, NaH (60% in mineral oil) (148 mg, 3.7 mmol, 1.1 equiv) was added to a solution of isatin (500 mg, 3.4 mmol, 1.0 equiv) in anhydrous DMF over a 15-minute period. After 30 minutes, 4-methoxybenzyl chloride (509 μL, 3.7 mmol, 1.1 equiv) was added dropwise and the reaction was stirred for an additional 8 hours. After completion, the solution was concentrated under reduced pressure and redissolved in EtOAc. The solution was washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by recrystallization from hot EtOAc / hexane to give 1-(4-methoxybenzyl)indoline-2,3-dione as an orange solid (410 mg, 45%).1 1H NMR (CDCl3, 500 MHz): δ 7.57 (1H, dd, J = 0.8, 6.8 Hz); 7.47 (1H, dt, J = 1.2, 7.6 Hz), 7.22 - 7.29 (2H, m), 7.06 (1H, dt, J = 0.4, 7.6 Hz), 6.82 - 6.88 (2H, m), 6.79 (1H, d, J = 8.0 Hz), 4.85 (2H, s), 3.77 (3H, s). LCMS: 289.7 [M+Na] + 。

[0338] Example 2. Alternative preparation of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide.

[0339] A mixture of added PMB-isatin (0.25 mmol, 1.0 equiv), arylboronic acid (0.28 mmol, 1.1 equiv), Rh2(OAc)4 (0.003 mmol, 1 mol%), [(t-Bu)3PH]BF4 (0.0075 mmol, 2.5 mol%), and anhydrous K2CO3 (0.015 mmol, 5 mol%) was evacuated and purged with nitrogen three times. DME / H2O (1 mL, 1 / 1 v / v) was added and the mixture was stirred at 90 °C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was extracted with ethyl acetate (3 × 5 mL) and washed with water (2 × 10 mL). The ethyl acetate layer was separated and dried over Na2SO4. After evaporation of the solvent, the residue was purified by flash column chromatography (ethyl acetate / hexane) to give the title compound. 1 1H NMR (CDCl3, 500 MHz): δ 7.76 (2H, d, J = 8.5 Hz); 7.44 (2H, d, J = 8.5); 7.27 - 7.23 (3H, m); 7.18 (1H, d, J = 7.0 Hz); 7.05 - 7.02 (1H, m); 6.87 (3H, d, J = 8.5 Hz); 5.29 (2H, d, J = 2.5 Hz); 4.95 (1H, d, 15.5 Hz); 4.78 (1H, d, J = 15.5 Hz); 4.52 (1H, s), 3.78 (3H, s).

[0340] Example 3. Preparation of 4-(3-fluoro-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide.

[0341]

[0342] At 0 °C, DAST (37 μL, 0.28 mmol, 1.2 eq) was added to a solution of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR-0037) (100 mg, 0.24 mmol, 1 eq) in DCM. The reaction was slowly warmed to room temperature and stirred for 2 h. After completion, the reaction was diluted in DCM and quenched with NaHCO3 (aqueous solution, saturated). The organic layer was separated, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (Hex / EtOAc) gave the title compound as a white solid (78 mg, 76.2%). LCMS: 427.2 [M+H] + 。

[0343] Example 4. Preparation of 4-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)benzenesulfonamide

[0344]

[0345] The title compound as a beige solid (160 mg, 50%) was prepared using a procedure similar to that described in Example 1, except that 1-methylindoline-2,3-dione (161 mg, 1 mmol) and (4-aminosulfonylphenyl)boronic acid (402 mg, 2.0 mmol, 2 eq) were used. LCMS: 319.2 [M+H] + 。

[0346] Example 5. Preparation of 4-(3-fluoro-1-methyl-2-oxoindolin-3-yl)benzenesulfonamide

[0347]

[0348] The title compound as a white solid (42 mg) was prepared using a procedure similar to that described in Example 3, except that 4-(3-hydroxy-1-methyl-2-oxoindolin-3-yl)benzenesulfonamide (66 mg, 0.21 mmol) was used. LCMS: 321.2 [M+H] + 。

[0349] Example 6. Preparation of 4-(1-(4-fluorobenzyl)-3-hydroxy-2-oxoindolin-3-yl)benzenesulfonamide

[0350]

[0351] In addition to using 1-(4-fluorobenzyl)indoline-2,3-dione (174 mg, 0.68 mmol) and (4-sulfamoylphenyl)boronic acid (273 mg, 1.36 mmol, 2 equiv), a procedure similar to that described in Example 1 was used to prepare the title compound as a white solid (102 mg, 36%). LCMS: 413.2 [M+H] + .

[0352] The intermediate compound 1-(4-fluorobenzyl)indoline-2,3-dione was prepared as follows.

[0353] a. 1-(4-fluorobenzyl)indoline-2,3-dione.

[0354] Using a procedure similar to that described in Example 1, subsection a, and using indoline-2,3-dione (588 mg, 4 mmol) and 4-fluorobenzyl chloride (636 mg, 4.4 mmol, 1.1 equiv), the title compound was prepared as an orange solid (708 mg, 69%). LCMS: 255.5 [M+H] + .

[0355] Example 7. Preparation of 4-(3-fluoro-1-(4-fluorobenzyl)-2-oxoindolin-3-yl)benzenesulfonamide

[0356]

[0357] In addition to using 4-(1-(4-fluorobenzyl)-3-hydroxy-2-oxoindolin-3-yl)benzenesulfonamide (40 mg, 0.10 mmol), a procedure similar to that described in Example 3 was used to prepare the title compound as a white solid (29 mg, 72%). LCMS: 415.22 [M+H] + .

[0358] Example 8. Preparation of 4-(3-hydroxy-2-oxoindolin-3-yl)benzenesulfonamide

[0359]

[0360] 4-(3-Hydroxy-2-oxo-1-tritylindolin-3-yl)benzenesulfonamide (180 mg, 0.33 mmol) was dissolved in a mixture of DCM (10 ml) and TFA (5 ml) and stirred overnight at room temperature. The reaction was determined to be complete by LCMS and concentrated under reduced pressure. The residue was dissolved in DCM and washed with 1×NaHCO3 (saturated, aqueous solution), 1× water, and 1× brine. The organic matter was dried over sodium sulfate and concentrated to give the title compound as a beige solid. LCMS: 305.1 [M+H] + .

[0361] The intermediate compound 4-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)benzenesulfonamide was prepared as follows.

[0362] a. 1-Tritylindoline-2,3-dione.

[0363] Using a procedure similar to that described in Sub-part a of Example 1 and using indoline-2,3-dione (500 mg, 3.4 mmol) and trityl chloride (1.04 g, 3.74 mmol, 1.1 eq), the title compound as a yellow / orange solid (720 mg, 55%) was prepared. LCMS: 411.9 [M+Na] + 。

[0364] b. Preparation of 4-(3-hydroxy-2-oxo-1-tritylindolin-3-yl)benzenesulfonamide.

[0365] Using a procedure similar to that described in Example 1, except using 1-tritylindoline-2,3-dione (530 mg, 1.36 mmol) and (4-aminosulfonylphenyl)boronic acid (547 mg, 2.72 mmol, 2 eq), the title compound as a yellow solid (220 mg, 29.6%) was prepared. LCMS: 568.7 [M+Na] + 。

[0366] Example 9. Preparation of 4-(1-ethyl-3-hydroxy-2-oxoindolin-3-yl)benzenesulfonamide

[0367]

[0368] Using a procedure similar to that described in Example 1, except using 1-ethylindoline-2,3-dione (176 mg, 1.0 mmol) and (4-aminosulfonylphenyl)boronic acid (402 mg, 2.0 mmol, 2 eq), the title compound as a white solid (204 mg, 61.4%) was prepared. LCMS: 333.2 [M+H] + 。

[0369] The intermediate compound 1-ethylindoline-2,3-dione was prepared as follows.

[0370] a. 1-Ethylindoline-2,3-dione.

[0371] Using a procedure similar to that described in Sub-part a of Example 1 and using isatin (1.47 g, 10 mmol, 1 equivalent) and bromoethane (0.76 ml, 10 mmol, 1 equivalent), the title compound as a bright orange solid (1.57 g, 90%) was prepared. LCMS: 176.3 [M+H] + 。

[0372] Example 10. Preparation of 4-(1-ethyl-3-fluoro-2-oxoindolin-3-yl)benzenesulfonamide

[0373]

[0374] Except for using 4-(1-ethyl-3-hydroxy-2-oxoindolin-3-yl)benzenesulfonamide (90 mg, 0.27 mmol), a procedure similar to that described in Example 3 was used to prepare the title compound as a white solid (57 mg, 63%). LCMS: 335.1 [M+H] + 。

[0375] Example 11. Synthesis of Compound NEM-4A.

[0376]

[0377] 1. Synthesis of 1-[[4-(difluoromethoxy)phenyl]methyl]isatin

[0378] A mixture of isatin (300 mg, 2.04 mmol, 1 equivalent), 1-(bromomethyl)-4-(difluoromethoxy)benzene (483.33 mg, 2.04 mmol, 1 equivalent), KI (135.39 mg, 815.60 umol, 0.4 equivalent), and K2CO3 (563.61 mg, 4.08 mmol, 2 equivalent) in DMF (5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 60 °C under a N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL), extracted with ethyl acetate (20 mL * 2), the combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product 1-[[4-(difluoromethoxy)phenyl]methyl]isatin as a red solid (350 mg, 1.15 mmol) was obtained and used in the next step without further purification. LCMS (ESI) m / z: 304.1 [M+H] +

[0379] 2. Synthesis of 4-[1-[[4-(difluoromethoxy)phenyl]methyl]-3-hydroxy-2-oxo-indolyl-3-yl]benzenesulfonamide (NEM-4A)

[0380] A mixture of 1-[[4-(difluoromethoxy)phenyl]methyl]indoline-2,3-dione (300 mg, 989.25 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (258.50 mg, 1.29 mmol, 1.3 eq.), diacetoxyrhodium (2.19 mg, 9.89 umol, 0.01 eq.), K2CO3 (6.84 mg, 49.46 umol, 0.05 eq.) and tri-tert-butylphosphonium tetrafluoroborate (8.61 mg, 29.68 umol, 0.03 eq.) in DME (3 mL), H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL) and extracted with ethyl acetate (20 mL*2). The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 8 minutes). 4-[1-[[4-(difluoromethoxy)phenyl]methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (26.50 mg, 56.57 umol, 5.72%) was obtained as a light yellow solid.

[0381] 1 H NMR (400MHz, acetonitrile-d3) δ7.86-7.82(m,2H),7.54-7.49(m,2H),7.39(d,J=8.8Hz,2H),7.32(dt,J=1.3,7.8Hz,1H),7.21(dd,J=0.8,7.4Hz,1H),7.1 4(d,J=8.6Hz,2H),7.11-7.06(m,1H),6.96(d,J=7.9Hz,1H),6.75(t,J=74.2Hz,1H),5.65(s,2H),4.96-4.86(m,2H)LCMS(ESI)m / z:461.0[M+H] +

[0382] Example 12. Synthesis of compound NEM-9A.

[0383]

[0384] 1. Synthesis of 1-[(3,4-difluorophenyl)methyl]indoline-2,3-dione

[0385] NaH (326.21 mg, 8.16 mmol, 60% purity, 1.2 eq) was added to a solution of indoline-2,3-dione (1 g, 6.80 mmol, 1 eq) in DMF (10 mL) at 0 ° C, and the mixture was stirred at 0 ° C for 10 minutes, and then 4-(bromomethyl)-1,2-difluoro-benzene (1.55 g, 7.48 mmol, 955.38 uL, 1.1 eq) was added. The mixture was stirred at 20 ° C for 3 hours. The mixture was poured into 20 mL of ice-cold water, the solid was collected by filtration, washed with H2O (5 mL * 3) and dried under reduced pressure to give a crude product. The crude product 1-[(3,4-difluorophenyl)methyl]indoline-2,3-dione (900 mg, crude product) was obtained as a red solid, which was used in the next step without further purification. LCMS (ESI) m / z: 274.2 [M + H] +

[0386] 2. Synthesis of 4-[1-[(3,4-difluorophenyl)methyl]-3-hydroxy-2-oxo-indolyl-3-yl]benzenesulfonamide (NEM-9A)

[0387] A mixture of 1-[(3,4-difluorophenyl)methyl]indoline-2,3-dione (300 mg, 1.10 mmol, 1 eq.), (4-sulfamoylphenyl)boronic acid (286.91 mg, 1.43 mmol, 1.3 eq.), diacetoxyrhodium (2.43 mg, 10.98 umol, 0.01 eq.), K2CO3 (7.59 mg, 54.90 umol, 0.05 eq.) and tri-tert-butylphosphonium tetrafluoroborate (9.56 mg, 32.94 umol, 0.03 eq.) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL) and extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 8 minutes). Compound 4-[1-[(3,4-difluorophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (41.72 mg, 93.91 umol, 8.54%) was obtained as a light yellow solid.

[0388] 11H NMR (400 MHz, acetonitrile-d3) δ = 7.86 - 7.81 (m, 2H), 7.54 - 7.49 (m, 2H), 7.33 (dt, J = 1.3, 7.8 Hz, 1H), 7.30 - 7.23 (m, 2H), 7.23 - 7.20 (m, 1H), 7.16 (ddd, J = 1.9, 4.1, 6.2 Hz, 1H), 7.12 - 7.07 (m, 1H), 6.95 (d, J = 7.9 Hz, 1H), 5.65 (s, 2H), 4.96 - 4.82 (m, 2H). LCMS (ESI) m / z: 431.0 [M+H] +

[0389] Example 13. Synthesis of compound NEM-10A.

[0390]

[0391] 1. Synthesis of 4-(chloromethyl)-1-oxopyridin-1-ium

[0392] At 0 °C, m-CPBA (2.71 g, 12.54 mmol, 80% purity, 2 eq) was added to a solution of 4-(chloromethyl)pyridine (1.2 g, 9.41 mmol, 1.5 eq) in DCM (15 mL). The mixture was stirred at 20 °C for 12 h. The mixture was treated with aqueous Na2S2O3 solution (10 mL, 8 M in H2O) and extracted with DCM (3 × 10 mL). The crude product 4-(chloromethyl)-1-oxopyridin-1-ium (600 mg, crude) was obtained as a dark brown solid and was used in the next step without further purification.

[0393] 2. Synthesis of 1-[(1-oxopyridin-1-ium-4-yl)methyl]indoline-2,3-dione

[0394] A mixture of isatin (1 g, 6.80 mmol, 1 equiv), 4-(chloromethyl)-1-oxidopyridin-1-ium (975.80 mg, 6.80 mmol, 1 equiv), K2CO3 (939.34 mg, 6.80 mmol, 1 equiv), and KI (225.65 mg, 1.36 mmol, 0.2 equiv) in DMF (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C under a N2 atmosphere for 6 h. The mixture was filtered and the filtrate was purified by preparative HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water (TFA)-ACN]; B%: 1%-40%, 10 min). The compound 1-[(1-oxidopyridin-1-ium-4-yl)methyl]isatin (300 mg, 884.99 μmol, 13.02%, 75% purity) was obtained as a brown solid. LCMS (ESI) m / z: 255.2 [M+H] + ,

[0395] 3. Synthesis of 4-[3-hydroxy-1-[(1-oxidopyridin-1-ium-4-yl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (NME-10A)

[0396] A mixture of 1-[(1-oxypyridin-1-ium-4-yl)methyl]indoline-2,3-dione (250 mg, 983.32 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (395.31 mg, 1.97 mmol, 2 eq.), diacetoxyrhodium (2.17 mg, 9.83 umol, 0.01 eq.), tri-tert-butylphosphonium tetrafluoroborate (8.56 mg, 29.50 umol, 0.03 eq.) and K2CO3 (6.80 mg, 49.17 umol, 0.05 eq.) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 6 h. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (20 mL). The organic phase was separated, washed with 20 mL of NaCl aqueous solution, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-30%, 8 minutes). Compound 4-[3-hydroxy-1-[(1-oxidopyridin-1-ium-4-yl)methyl]-2-oxo-indoline-3-yl]benzenesulfonamide (16.76 mg, 39.26umol, 3.99%, 96.37% purity) was obtained as a light yellow solid.

[0397] 1 H NMR (400MHz, methanol-d4) δ8.29(d,J=7.1Hz,2H),7.91-7.85(m,2H),7.58-7.51(m,4H),7.37(dt,J=1.3,7.8Hz,1H) ,7.26(d,J=6.6Hz,1H),7.18-7.13(m,1H),7.02(d,J=7.9Hz,1H),5.09-5.00(m,2H)LCMS(ESI)m / z:412.1[M+H] +

[0398] Example 14. Synthesis of compound NEM-12A.

[0399]

[0400] 1. Synthesis of 1-[(4-methoxyphenyl)methyl]indoline-2,3-dione

[0401] A mixture of indoline-2,3-dione (300 mg, 2.04 mmol, 1 equivalent), 4-(bromomethyl)tetrahydropyran (365.09 mg, 2.04 mmol, 1 equivalent), KI (135.39 mg, 815.60 umol, 0.4 equivalent), K2CO3 (563.61 mg, 4.08 mmol, 2 equivalents) in DMF (5 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 60 ° C under N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL), extracted with ethyl acetate (20 mL * 2), and the combined organics were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product 1-(tetrahydropyran-4-ylmethyl) indoline-2,3-dione (300 mg, crude product) was obtained as a yellow solid, which was used in the next step without further purification. LCMS (ESI) m / z: 246.1 [M+H] +

[0402] 2. Synthesis of 4-[3-hydroxy-1-[(4-methoxyphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-12A)

[0403] A mixture of 1-(tetrahydropyran-4-ylmethyl)indoline-2,3-dione (300 mg, 1.22 mmol, 1 eq.), (4-sulfamoylphenyl)boronic acid (319.62 mg, 1.59 mmol, 1.3 eq.), diacetoxyrhodium (2.70 mg, 12.23 umol, 0.01 eq.), K2CO3 (8.45 mg, 61.16 umol, 0.05 eq.) and tri-tert-butylphosphonium tetrafluoroborate (10.65 mg, 36.69 umol, 0.03 eq.) in DME (2 mL) and H2O (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL) and extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 20%-50%, 8 minutes). Compound 4-[3-hydroxy-2-oxo-1-(tetrahydropyran-4-ylmethyl)indolin-3-yl]benzenesulfonamide (11.66 mg, 27.93 umol, 2.28%, 96.41% purity) was obtained as a light yellow solid.

[0404] 11H NMR (400 MHz, acetonitrile-d3) δ 7.84 - 7.80 (m, 2H), 7.51 - 7.47 (m, 2H), 7.40 (dt, J = 1.3, 7.8 Hz, 1H), 7.18 (dd, J = 0.8, 7.3 Hz, 1H), 7.13 - 7.06 (m, 2H), 5.64 (s, 2H), 3.87 (dddd, J = 2.6, 4.5, 6.7, 8.9 Hz, 2H), 3.67 - 3.53 (m, 2H), 3.34 - 3.26 (m, 2H), 2.11 - 2.02 (m, 1H), 1.66 - 1.51 (m, 2H), 1.40 - 1.27 (m, 2H) LCMS (ESI) m / z: 403.0 [M+H] +

[0405] Example 15. Synthesis of Compounds NEM-27A and 13A

[0406]

[0407] 1. Synthesis of 1-(4-Bromophenyl)indoline-2,3-dione

[0408] A mixture of indoline-2,3-dione (2 g, 13.59 mmol, 1 equiv), (4-bromophenyl)boronic acid (4.09 g, 20.39 mmol, 1.5 equiv), Cu(OAc)2 (2.47 g, 13.59 mmol, 1 equiv), and TEA (2.75 g, 27.19 mmol, 3.78 mL, 2 equiv) in DCE (10 mL) was degassed and purged with N2 three times. Then the mixture was stirred at 20 °C under a N2 atmosphere for 12 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (100 mL, 50 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 10:1 - 1:1). 1-(4-Bromophenyl)indoline-2,3-dione as a yellow solid was obtained (1.5 g, 4.96 mmol, 36.52%). LCMS (ESI) m / z: 302.1 [M+H] +

[0409] 2. Synthesis of 4-[1-(4-Bromophenyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-27A)

[0410] A mixture of 1-(4-bromophenyl)indoline-2,3-dione (500 mg, 1.65 mmol, 1 eq.), (4-sulfamoylphenyl)boronic acid (665.32 mg, 3.31 mmol, 2 eq.), diacetoxyrhodium (7.31 mg, 33.10 umol, 0.02 eq.), tri-tert-butylphosphonium tetrafluoroborate (19.21 mg, 66.20 umol, 0.04 eq.) and K2CO3 (22.87 mg, 165.50 umol, 0.1 eq.) in DME (4 mL) and H2O (4 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 3 hours. The reaction mixture was partitioned between EtOAc (60 mL) and H2O (30 mL). The organic phase was separated, washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenexluna C18 100*40mm*3um; mobile phase: [water (TFA)-ACN]; B%: 20%-65%, 8 minutes). Compound 4-[1-(4-bromophenyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (200 mg, 435.43umol, 26.31%, 100% purity) was obtained as a white solid.

[0411] 1 H NMR (400MHz, methanol-d4) δ7.89(d,J=8.5Hz,2H),7.78-7.73(m,2H),7.62(d,J=8.5Hz,2H),7.44-7.40(m,2H),7.37(d t,J=1.1,7.8Hz,1H),7.28(d,J=6.6Hz,1H),7.20-7.16(m,1H),6.92(d,J=7.9Hz,1H); LCMS(ESI)m / z:458.9[M+H] +

[0412] 3. Synthesis of 4-[3-hydroxy-1-(4-methoxyphenyl)-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-13A)

[0413] A mixture of 4-[1-(4-bromophenyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (150 mg, 326.58 μmol, 1 equiv), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (25.94 mg, 32.66 μmol, 0.1 equiv), and NaOMe (52.93 mg, 979.73 μmol, 3 equiv) in MeOH (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 70 °C under a N2 atmosphere for 12 h. H2O (3 mL) was added to the mixture, and the mixture was extracted with EtOAc (10 mL × 3). The organic layer was washed with brine (5 mL), dried over Na2SO4, and concentrated to obtain a crude product. The crude product was purified by preparative HPLC (column: Phenomenex C18 80 × 30 mm × 3 μm; mobile phase: [water (TFA)-ACN]; B%: 35% - 65%, 8 min). The compound 4-[3-hydroxy-1-(4-methoxyphenyl)-2-oxo-indolin-3-yl]benzenesulfonamide as a white solid was obtained (21.4 mg, 51.10 μmol, 15.65%, 98% purity).

[0414] 1 H NMR (400 MHz, methanol-d4) δ 7.90 - 7.88 (m, 2H), 7.62 - 7.60 (m, 2H), 7.37 - 7.34 (m, 3H), 7.26 (dd, J = 0.8, 7.4 Hz, 1H), 7.17 - 7.10 (m, 3H), 6.82 - 6.80 (d, J = 7.8 Hz, 1H), 3.87 (s, 3H) LCMS (ESI) m / z: 411.1 [M + H] +

[0415] Example 16. Synthesis of compound NEM-14A.

[0416]

[0417] 1. Synthesis of (4-morpholinophenyl)methyl 4-methylbenzenesulfonate

[0418] To a solution of (4-morpholinophenyl)methanol (500 mg, 2.59 mmol, 1 equiv) in DCM (5 mL) was added DMAP (63.22 mg, 517.49 μmol, 0.2 equiv) and TEA (785.46 mg, 7.76 mmol, 1.08 mL, 3 equiv). Then 4-methylbenzenesulfonyl chloride (542.62 mg, 2.85 mmol, 1.1 equiv) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC (dichloromethane:methanol = 10:1) indicated residual starting material and detected one major new spot with greater polarity. The solvent was removed under pressure to give a solid. The crude product (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (800 mg, crude) was obtained as a yellow solid and was used in the next step without further purification.

[0419] 2. Synthesis of 1-[(4-morpholinophenyl)methyl]indoline-2,3-dione

[0420] A mixture of indoline-2,3-dione (350 mg, 2.38 mmol, 1 equiv), (4-morpholinophenyl)methyl 4-methylbenzenesulfonate (800 mg, 2.30 mmol, 9.68×10⁻¹ equiv), KI (157.96 mg, 951.54 μmol, 0.4 equiv), and K₂CO₃ (657.54 mg, 4.76 mmol, 2 equiv) in DMF (10 mL) was degassed and purged with N₂ three times, and then the mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature and diluted with water (15 mL), and extracted with ethyl acetate (20 mL×2). The organic layer was washed with brine (5 mL), dried over Na₂SO₄ and concentrated to give a crude product. The crude product was purified by flash column (ISCO 40 g silica, 0 - 100% ethyl acetate in petroleum ether, gradient within 20 min). The compound 1-[(4-morpholinophenyl)methyl]indoline-2,3-dione was obtained as a yellow solid (350 mg, 1.09 mmol, 45.64%). LCMS (ESI) m / z: 323.2 [M+H] +

[0421] 3. Synthesis of 4-[3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-14A)

[0422] A mixture of 1-[(4-morpholinophenyl)methyl]indoline-2,3-dione (300 mg, 930.64 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (243.19 mg, 1.21 mmol, 1.3 eq.), diacetoxyrhodium (2.06 mg, 9.31 umol, 0.01 eq.), K2CO3 (6.43 mg, 46.53 umol, 0.05 eq.) and tri-tert-butylphosphonium tetrafluoroborate (8.10 mg, 27.92 umol, 0.03 eq.) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 5 hours. The reaction mixture was cooled to room temperature and diluted with water (15 mL) and extracted with ethyl acetate (20 mL*2). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative HPLC (column: Phenomenex C18 80*30mm*3um; mobile phase: [water (TFA)-ACN]; B%: 25%-55%, 8 minutes). Compound 4-[3-hydroxy-1-[(4-morpholinophenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (23.01 mg, 47.02umol, 5.05%, 98% purity) was obtained as a light yellow solid. 1 H NMR (400MHz, acetonitrile-d3) δ7.84-7.82(d,J=8.4,2H),7.52-7.50(d,J=8.4,2H),7.34-7.29(m,3H),7.22-7.18(m,1H),7.12-7.05(m, 3H),6.96(d,J=8.0Hz,1H),5.66(s,2H),4.86(d,J=2.6Hz,2H),3.86-3.80(m,4H),3.25-3.19(m,4H)LCMS(ESI)m / z:480.1[M+H] + .

[0423] Example 17. Synthesis of compound NEM-15A.

[0424]

[0425] 1. Synthesis of 2-(6-methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0426] A mixture of 1-bromo-6-methoxynaphthalene (800 mg, 3.37 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.11 g, 4.39 mmol, 1.3 equiv), Pd(dppf)Cl2·CH2Cl2 (551.10 mg, 674.84 μmol, 0.2 equiv), and KOAc (993.46 mg, 10.12 mmol, 3 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C under a N2 atmosphere for 3 h. After cooling to room temperature, the reaction mixture was filtered through a Celite pad, and the Celite was rinsed with ethyl acetate (20 mL × 3). The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc = 50:1 to 2:1) to give 2-(6-methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a yellow solid (780 mg, 2.74 mmol, 81.35%). LCMS (ESI) m / z: 285.3 [M+H] + 。

[0427] 2. Synthesis of (6-methoxy-1-naphthyl)boronic acid

[0428] To a solution of 2-(6-methoxy-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 2.64 mmol, 1 equiv) in THF (5 mL) were added NaIO4 (2.26 g, 10.56 mmol, 585.02 μL, 4 equiv), NH4OAc (813.80 mg, 10.56 mmol, 4 equiv), and H2O (5 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by adding Na2SO3 (10 mL) at 0 °C, then diluted with H2O (10 mL) and extracted with EtOAc 50 mL (25 mL × 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel (petroleum ether / EtOAc = 30:1 to 1:10) to give a solid. The compound (6-methoxy-1-naphthyl)boronic acid was obtained as a yellow solid (300 mg, 1.49 mmol, 56.26%). LCMS (ESI) m / z: 203.2 [M+H] +

[0429] 3. Synthesis of 1-(6-methoxy-1-naphthyl)indoline-2,3-dione

[0430] A mixture of (6-methoxy-1-naphthyl)boronic acid (300 mg, 1.49 mmol, 1 equiv), indoline-2,3-dione (284.04 mg, 1.93 mmol, 1.3 equiv), Cu(OAc)2 (269.74 mg, 1.49 mmol, 1 equiv), and TEA (300.54 mg, 2.97 mmol, 413.40 μL, 2 equiv) in DCE (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 20 °C under a N2 atmosphere for 3 h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (20 mL, 10 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The crude product was purified by flash column chromatography on silica gel (petroleum ether / EtOAc = 30:1 to 1:1) to afford 1-(6-methoxy-1-naphthyl)indoline-2,3-dione as a yellow solid (150 mg, 494.54 μmol, 33.30%). LCMS (ESI) m / z: 304.2 [M+H] +

[0431] 4. Synthesis of 4-[3-hydroxy-1-(6-methoxy-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-15A)

[0432] A mixture of 1-(6-methoxy-1-naphthyl)indoline-2,3-dione (100 mg, 329.69 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (132.54 mg, 659.39 umol, 2 eq.), K2CO3 (4.56 mg, 32.97 umol, 0.1 eq.), diacetoxyrhodium (7.29 mg, 32.97 umol, 0.1 eq.) and tri-tert-butylphosphonium tetrafluoroborate (9.57 mg, 32.97 umol, 0.1 eq.) in DME (1 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 3 hours. The reaction mixture was cooled to room temperature and diluted with water (5 mL) and extracted with ethyl acetate (10 mL*2). The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give a crude product. The crude product was purified by preparative HPLC (column: C18-1 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 15%-60%, 8 minutes) to give 4-[3-hydroxy-1-(6-methoxy-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (6.05 mg, 12.98 umol, 3.94%) as a light yellow solid.

[0433] 1 H NMR (400MHz, methanol-d4) δ8.01-7.91(m,3H),7.79-7.69(m,2.4H),7.67-7.58(m,1H),7.45-7.36(m,3H), 7.35-7.08(m,3.6H),6.45(dd,J=7.8,14.1Hz,1H),3.94(d,J=8.5Hz,3H)LCMS(ESI)m / z:461.0[M+H] +

[0434] Example 18. Synthesis of compound NEM-19A.

[0435]

[0436] 1. Synthesis of 1-[4-(chloromethyl)phenyl]piperidine

[0437] At 0 °C, SOCl2 (933.01 mg, 7.84 mmol, 568.91 μL, 5 equiv) was added to a solution of [4-(1-piperidinyl)phenyl]methanol (300 mg, 1.57 mmol, 1 equiv) in DCM (3 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product 1-[4-(chloromethyl)phenyl]piperidine (300 mg, crude) as a white solid was obtained and used in the next step without further purification.

[0438] 2. Synthesis of 1-[[4-(1-piperidinyl)phenyl]methyl]indoline-2,3-dione

[0439] To a solution of 1-[4-(chloromethyl)phenyl]piperidine (250 mg, 1.19 mmol, 1 equiv) in DMF (4 mL) were added K2CO3 (329.52 mg, 2.38 mmol, 2 equiv), KI (197.89 mg, 1.19 mmol, 1 equiv) and indoline-2,3-dione (175.39 mg, 1.19 mmol, 1 equiv). The mixture was stirred at 60 °C for 3 h. The reaction mixture was partitioned between EtOAc (50 mL) and bromine (30 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 10 g silica gel flash column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 50 mL / min). The compound 1-[[4-(1-piperidinyl)phenyl]methyl]indoline-2,3-dione (140 mg, crude) as a yellow solid was obtained. LCMS (ESI) m / z: 321.2 [M+H] +

[0440] 3. Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(1-piperidinyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-19A)

[0441] A mixture of 1-[[4-(1-piperidinyl)phenyl]methyl]indoline-2,3-dione (100 mg, 312.13 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (94.11 mg, 468.19 umol, 1.5 eq.), tri-tert-butylphosphonium tetrafluoroborate (3.62 mg, 12.49 umol, 0.04 eq.), diacetoxyrhodium (1.38 mg, 6.24 umol, 0.02 eq.) and K2CO3 (43.14 mg, 312.13 umol, 1 eq.) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 3 hours. The reaction mixture was partitioned between EtOAc (30 mL) and H2O (10 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-60%, 8 minutes). The compound 4-[3-hydroxy-2-oxo-1-[[4-(1-piperidinyl)phenyl]methyl]indoline-3-yl]benzenesulfonamide (11.5 mg, 23.61 umol, 7.56%, 98.03% purity) was obtained as a white solid.

[0442] 1 H NMR (400MHz, acetonitrile-d3) δ7.83(d,J=8.5Hz,2H),7.50(d,J=8.5Hz,2H),7.43-7.36(m,4H),7.35-7.30(m,1H),7.21(d,J=7.4Hz,1H),7.12-7. 06(m,1H),6.96(d,J=8.0Hz,1H),5.68(s,2H),4.91(d,J=2.8Hz,2H),3.39-3.32(m,4H),1.87(td,J=5.7,10.9Hz,4H),1.71-1.63(m,2H)

[0443] Example 19. Synthesis of compound NEM-23A.

[0444]

[0445] 1. Synthesis of 4-[4-(chloromethyl)phenyl]pyridine

[0446] At 0 °C, SOCl2 (963.47 mg, 8.10 mmol, 587.48 μL, 5 equiv) was added to a solution of [4-(4-pyridyl)phenyl]methanol (300 mg, 1.62 mmol, 1 equiv) in DCM (5 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product 4-[4-(chloromethyl)phenyl]pyridine (300 mg, crude product), which was a yellow solid, was used in the next step without further purification. LCMS (ESI) m / z: 204.3 [M+H] +

[0447] 2. Synthesis of 1-[[4-(4-pyridyl)phenyl]methyl]indoline-2,3-dione

[0448] To a solution of 4-[4-(chloromethyl)phenyl]pyridine (150 mg, 736.50 μmol, 1 equiv), indoline-2,3-dione (108.36 mg, 736.50 μmol, 1 equiv) in DMF (4 mL) was added K2CO3 (203.58 mg, 1.47 mmol, 2 equiv) and KI (12.23 mg, 73.65 μmol, 0.1 equiv). The mixture was stirred at 60 °C for 3 h. The reaction mixture was partitioned between EtOAc (20 mL) and bromine (5 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 10 g Silica gel flash column, eluent was 0 - 100% ethyl acetate / petroleum ether gradient, 50 mL / min). The compound 1-[[4-(4-pyridyl)phenyl]methyl]indoline-2,3-dione (140 mg, 445.38 μmol, 60.47%) was obtained as a yellow solid. LCMS (ESI) m / z: 315.2 [M+H] +

[0449] 3. Synthesis of 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-23A)

[0450] A mixture of 1-[[4-(4-pyridyl)phenyl]methyl]indoline-2,3-dione (100 mg, 318.13 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (95.92 mg, 477.20 umol, 1.5 eq.), tri-tert-butylphosphonium tetrafluoroborate (3.69 mg, 12.73 umol, 0.04 eq.), diacetoxyrhodium (1.41 mg, 6.36 umol, 0.02 eq.) and K2CO3 (4.40 mg, 31.81 umol, 0.1 eq.) in DME (1 mL) and H2O (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 3 hours. The reaction mixture was partitioned between EtOAc (20 mL) and H2O (5 mL). The organic phase was separated, washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 8 minutes). Compound 4-[3-hydroxy-2-oxo-1-[[4-(4-pyridyl)phenyl]methyl]indoline-3-yl]benzenesulfonamide (10.5 mg, 22.27 umol, 7.00%, 100% purity) was obtained as a yellow solid.

[0451] 1 H NMR (400MHz, methanol-d4) δ8.66(br d,J=6.1Hz,2H),7.94(br d,J=6.3Hz,2H),7.85(br dd,J=8.3,16.3Hz,4H),7.55(br t,J=9.2Hz,4H),7.33(br t,J=7.7Hz,1H),7.24(br d,J=7.4Hz,1H),7.15-7.09(m,1H),7.02(d,J=7.9Hz,1H),5.14-5.02(m,2H).

[0452] Example 20. Synthesis of compound NEM-26A.

[0453]

[0454] 1. Synthesis of 6-(chloromethyl)quinoline

[0455] At 0 °C, SOCl2 (3.28 g, 27.57 mmol, 2 mL, 8.78 eq) was added to a solution of 6 - quinolinylmethanol (500 mg, 3.14 mmol, 1 eq) in CH3CN (12 mL). The mixture was stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure. The crude product 6 - (chloromethyl)quinoline (300 mg, crude) was obtained as a pale yellow solid and was used in the next step without further purification. LCMS (ESI) m / z: 178.3 [M + H] + .

[0456] 2. Synthesis of 1 - (6 - quinolinylmethyl)indoline - 2,3 - dione

[0457] To a solution of 6 - (chloromethyl)quinoline (300 mg, 1.69 mmol, 1 eq) in DMF (3 mL) were added indoline - 2,3 - dione (248.49 mg, 1.69 mmol, 1 eq), K2CO3 (466.83 mg, 3.38 mmol, 2 eq) and KI (28.04 mg, 168.89 μmol, 0.1 eq). The mixture was stirred at 60 °C for 3 h. H2O (5 mL) was added to the reaction mixture and it was extracted with EtOAc (10 mL * 3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography ( 10 g Silica gel flash column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 50 mL / min). The compound 1 - (6 - quinolinylmethyl)indoline - 2,3 - dione (150 mg, crude) was obtained as a yellow solid. LCMS (ESI) m / z: 289.3 [M + H] +

[0458] 3. Synthesis of 4 - [3 - hydroxy - 2 - oxo - 1 - (6 - quinolinylmethyl)indolin - 3 - yl]benzenesulfonamide (NEM - 26A)

[0459] A mixture of 1-(6-quinolylmethyl)indolin-2,3-dione (140 mg, 485.61 umol, 1 eq.), (4-sulfamoylphenyl)boric acid (146.42 mg, 728.41 umol, 1.5 eq.), tri-tert-butylphosphonium tetrafluoroborate (5.64 mg, 19.42 umol, 0.04 eq.), diacetoxyrhodium (2.15 mg, 9.71 umol, 0.02 eq.) and K2CO3 (67.11 mg, 485.61 umol, 1 eq.) in DME (3 mL) and H2O (3 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90° C. under N2 atmosphere for 3 hours. H2O (5 mL) was added to the reaction mixture, and extracted with EtOAc (10 mL*3). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 18%-48%, 8 minutes). The compound 4-[3-hydroxy-2-oxo-1-(6-quinolylmethyl)indolin-3-yl]benzenesulfonamide (10.5 mg, 23.05 umol, 4.75%, 97.78% purity) was obtained as a white solid.

[0460] 1 H NMR (400MHz, methanol-d4) δ8.83(dd,J=1.5,4.3Hz,1H),8.31(d,J=8.0Hz,1H),8.01(d,J=8.8Hz,1H),7.93(s,1H),7.87(d,J=8.5Hz,2H),7.77(dd ,J=1.8,8.8Hz,1H),7.59-7.51(m,3H),7.33-7.27(m,1H),7.24(d,J=7.0Hz,1H),7.14-7.08(m,1H),7.03(d,J=7.9Hz,1H),5.25-5.13(m,2H)

[0461] Example 21. Synthesis of compound NEM-20A.

[0462]

[0463] 1. Synthesis of 4-[1-[[4-(4,4-difluoro-1-piperidinyl)phenyl]methyl]-3-hydroxy-2-oxo-indolyl-3-yl]benzenesulfonamide (NEM-20A)

[0464] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxoindolin-3-yl]benzenesulfonamide (130 mg, 274.64 μmol, 1 equiv), 4,4-difluoropiperidine (49.90 mg, 411.97 μmol, 1.5 equiv), BrettPhos Pd G3 (49.79 mg, 54.93 μmol, 0.2 equiv), and sodium 2-methyl-2-propanolate (2 M, 274.64 μL, 2 equiv) in t-AmylOH (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 5%-35%, 8 min). The compound 4-[1-[[4-(4,4-difluoro-1-piperidinyl)phenyl]methyl]-3-hydroxy-2-oxoindolin-3-yl]benzenesulfonamide was obtained as a white solid (21.2 mg, 41.28 μmol, 15.03% yield).

[0465] 1 H NMR (400 MHz, chloroform-d) δ 7.87 - 7.82 (m, 2H), 7.53 - 7.47 (m, 2H), 7.33 - 7.29 (m, 1H), 7.26 - 7.19 (m, 3H), 7.10 - 7.05 (m, 1H), 6.94 (br d, J = 6.1 Hz, 2H), 6.89 (d, J = 7.9 Hz, 1H), 5.04 - 4.94 (m, 3H), 4.78 (d, J = 15.4 Hz, 1H), 3.85 (br s, 1H), 3.36 (br t, J = 5.6 Hz, 4H), 2.12 (br s, 4H) MS (M+H) + = 514.1.

[0466] Example 22. Synthesis of Compounds NEM-30A and NEM-21A.

[0467]

[0468] 1. Synthesis of tert-Butyl 4-[4-(Hydroxymethyl)phenyl]piperidine-1-carboxylate

[0469] At 0 °C, BH3·THF (1 M, 8.51 mL, 2 equivalents) was added dropwise to a solution of 4-(1-tert-butoxycarbonyl-4-piperidyl)benzoic acid (1.3 g, 4.26 mmol, 1 equivalent) in THF (15 mL). The mixture was stirred at 20 °C for 12 h. The mixture was quenched with 5% aqueous NH4Cl solution (10 mL) and extracted with ethyl acetate (30 mL). The organic layer was washed with aqueous NaHCO3 solution (25 mL), dried over Na2SO4 and concentrated. The compound tert-butyl 4-[4-(hydroxymethyl)phenyl]piperidine-1-carboxylate (1 g, crude product) was obtained as a white solid and was used in the next step without further purification.

[0470] 2. Synthesis of tert-butyl 4-[4-(bromomethyl)phenyl]piperidine-1-carboxylate

[0471] To a solution of tert-butyl 4-[4-(hydroxymethyl)phenyl]piperidine-1-carboxylate (500 mg, 1.72 mmol, 1 equivalent) in DCM (10 mL) were added PPh3 (585.09 mg, 2.23 mmol, 1.3 equivalents) and CBr4 (739.77 mg, 2.23 mmol, 1.3 equivalents). The mixture was stirred at 20 °C for 12 h. The mixture was concentrated under reduced pressure. The crude product tert-butyl 4-[4-(bromomethyl)phenyl]piperidine-1-carboxylate (500 mg, crude product) was obtained as a brown oil and was used in the next step without further purification.

[0472] 3. Synthesis of tert-butyl 4-[4-[(2,3-dioxoindolin-1-yl)methyl]phenyl]piperidine-1-carboxylate

[0473] To a solution of indoline-2,3-dione (150 mg, 1.02 mmol, 1 eq.), tert-butyl 4-[4-(bromomethyl)phenyl]piperidine-1-carboxylate (361.19 mg, 1.02 mmol, 1 eq.) in CH3CN (5 mL) was added K2CO3 (281.80 mg, 2.04 mmol, 2 eq.) and KI (16.92 mg, 101.95 umol, 0.1 eq.). The mixture was stirred at 20 °C for 12 hours. The mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 x 5 mL). The organic layer was washed with brine (3 mL), dried over Na2SO4 and concentrated to give a crude product. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 45%-75%, 8 minutes). The compound tert-butyl 4-[4-[(2,3-dioxoindolin-1-yl)methyl]phenyl]piperidine-1-carboxylate (130 mg, 309.16umol, 30.32% yield) was obtained as a yellow solid.

[0474] 4. Synthesis of tert-butyl 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperidine-1-carboxylate (NEM-30A)

[0475] A mixture of tert-butyl 4-[4-[(2,3-dioxoindol-1-yl)methyl]phenyl]piperidine-1-carboxylate (120 mg, 285.37 umol, 1 eq.), (4-sulfamoylphenyl)boronic acid (114.73 mg, 570.75 umol, 2 eq.), tri-tert-butylphosphonium tetrafluoroborate (2.48 mg, 8.56 umol, 0.03 eq.), diacetoxyrhodium (630.65 ug, 2.85 umol, 0.01 eq.) and K2CO3 (1.97 mg, 14.27 umol, 0.05 eq.) in H2O (2 mL) and DME (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100° C. under N2 atmosphere for 5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 minutes). The compound 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperidine-1-carboxylic acid tert-butyl ester (35 mg, 60.59umol, 21.23% yield) was obtained as a white solid.

[0476] 1 1H NMR (400 MHz, methanol-d4) δ 7.85 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.33 - 7.28 (m, 3H), 7.24 - 7.18 (m, 3H), 7.11 - 7.06 (m, 1H), 6.98 (d, J = 7.9 Hz, 1H), 4.99 - 4.88 (m, 2H), 4.19 (br d, J = 13.3 Hz, 2H), 2.85 (br s, 2H), 2.70 (tt, J = 3.4, 12.1 Hz, 1H), 1.78 (br s, 2H), 1.63 - 1.50 (m, 2H), 1.49 - 1.45 (m, 9H)

[0477] 5. 4-[3-Hydroxy-2-oxo-1-[[4-(4-piperidinyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-21A)

[0478] A mixture of tert-butyl 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperidine-1-carboxylate (28 mg, 48.47 μmol, 1 equiv) in HCl / EtOAc (4 M, 1.87 mL, 154.05 equiv) was stirred at 20 °C under a N2 atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 5% - 35%, 8 min). Compound 4-[3-Hydroxy-2-oxo-1-[[4-(4-piperidinyl)phenyl]methyl]indolin-3-yl]benzenesulfonamide was obtained as a pale yellow solid (20 mg, 41.88 μmol, 86.40% yield).

[0479] 1 1H NMR (400 MHz, methanol-d4) δ 7.86 - 7.84 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.38 - 7.35 (m, 2H), 7.33 - 7.23 (m, 3H), 7.20 - 7.16 (m, 1H), 7.10 - 7.05 (m, 1H), 7.01 - 6.95 (m, 1H), 4.99 - 4.88 (m, 2H), 3.50 - 3.47 (m, 2H), 3.16 - 3.09 (m, 2H), 2.91 - 2.85 (m, 1H), 2.07 - 2.03 (m, 2H), 1.90 - 1.84 (m, 2H) MS (M + H) + = 478.0

[0480] Example 23. Synthesis of compounds NEM-32A and NEM-22A.

[0481]

[0482] 1. Synthesis of 1-[(4-bromophenyl)methyl]indoline-2,3-dione

[0483] To a solution of indoline-2,3-dione (1 g, 6.80 mmol, 1 eq.), 1-bromo-4-(bromomethyl)benzene (1.70 g, 6.80 mmol, 1 eq.) in CH3CN (10 mL), K2CO3 (1.88 g, 13.60 mmol, 2 eq.) and KI (112.83 mg, 680.00 umol, 0.1 eq.) were added. The mixture was stirred at 20 °C for 12 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether). Compound 1-[(4-bromophenyl)methyl]indoline-2,3-dione (1.5 g, 4.74 mmol, 69.77% yield) was obtained as a red solid.

[0484] 2. Synthesis of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide

[0485] A mixture of [4-(tert-butylaminosulfonyl)phenyl]boronic acid (400 mg, 1.27 mmol, 1 eq.), (4-sulfamoylphenyl)boronic acid (382.92 mg, 1.91 mmol, 1.5 eq.), diacetoxyrhodium (5.61 mg, 25.40 umol, 0.02 eq.), tri-tert-butylphosphonium tetrafluoroborate (14.74 mg, 50.80 umol, 0.04 eq.) and KCO (17.55 mg, 127.00 umol, 0.1 eq.) in DME (3 mL) and H O (3 mL) was degassed and purged with N 3 times, and then the mixture was stirred at 90° C. under N atmosphere for 3 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and H O (30 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether). Compound 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (300 mg, 633.80 umol, 49.91% yield) was obtained as a yellow solid.

[0486] 3. Synthesis of tert-butyl 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperazine-1-carboxylate (NEM-32A)

[0487] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxoindolin-3-yl]benzenesulfonamide (150 mg, 316.90 μmol, 1 equiv), tert-butyl piperazine-1-carboxylate (118.04 mg, 633.80 μmol, 2 equiv), BrettPhos PdG3 (57.45 mg, 63.38 μmol, 0.2 equiv), and sodium 2-methyl-2-propanolate (2 M, 475.35 μL, 3 equiv) in t-AmylOH (5 mL) was degassed and purged with N2 three times. The mixture was then stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*40 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min). The compound tert-butyl 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperazine-1-carboxylate was obtained as a light yellow solid (30 mg, 47.36 μmol, 14.94% yield).

[0488] H NMR (400 MHz, acetonitrile-d3) δ 7.87-7.78 (m, 2H), 7.55-7.48 (m, 2H), 7.30 (dt, J = 1.3, 7.8 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.20-7.16 (m, 1H), 7.08-7.03 (m, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.93-6.89 (m, 2H), 5.74-5.56 (m, 2H), 4.88-4.77 (m, 2H), 3.53-3.46 (m, 4H), 3.10-3.04 (m, 4H), 1.43 (s, 9H).

[0489] 4. Synthesis of 4-[3-hydroxy-2-oxo-1-[(4-piperazin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (NEM-22A)

[0490] A mixture of tert-butyl 4-[4-[[3-hydroxy-2-oxo-3-(4-sulfamoylphenyl)indolin-1-yl]methyl]phenyl]piperazine-1-carboxylate (20 mg, 34.56 μmol, 1 equiv) in HCl / EtOAc (4 M, 2.00 mL, 231.47 equiv) was stirred at 20 °C under a N2 atmosphere for 1 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 μm; mobile phase: [water (HCl)-ACN]; B%: 1%-30%, 8 min). Compound 4-[3-hydroxy-2-oxo-1-[(4-piperazin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide was obtained as a pale yellow solid (8.1 mg, 16.34 μmol, 47.27% yield).

[0491] 1 H NMR (400 MHz, methanol-d4) δ 7.88 - 7.82 (m, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.35 - 7.28 (m, 3H), 7.23 - 7.18 (m, 1H), 7.12 - 7.06 (m, 1H), 7.03 - 6.98 (m, 3H), 4.97 - 4.92 (m, 1H), 4.82 (s, 1H), 3.42 - 3.38 (m, 4H), 3.38 - 3.33 (m, 4H) MS (M+H)+ = 479.1

[0492] Example 24. Synthesis of compound NEM-24A.

[0493]

[0494] 1. Synthesis of 4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide (NEM-24A)

[0495] A mixture of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxoindolin-3-yl]benzenesulfonamide (130 mg, 274.64 μmol, 1 equiv), pyrrolidine (29.30 mg, 411.97 μmol, 34.39 μL, 1.5 equiv), BrettPhos Pd G3 (49.79 mg, 54.93 μmol, 0.2 equiv), and sodium 2-methylpropan-2-olate (2 M, 274.64 μL, 2 equiv) in t-AmylOH (2 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 40%-70%, 8 min). Compound 4-[3-hydroxy-2-oxo-1-[(4-pyrrolidin-1-ylphenyl)methyl]indolin-3-yl]benzenesulfonamide was obtained as an off-white solid (2.3 mg, 4.96 μmol, 1.81% yield).

[0496] 1 H NMR (400 MHz, chloroform-d) δ 7.79 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.22 (brs, 1H), 7.15 - 7.10 (m, 3H), 7.01 - 6.93 (m, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.53 - 6.43 (m, 2H), 4.92 (d, J = 14.9 Hz, 1H), 4.78 (s, 2H), 4.71 - 4.58 (m, 1H), 3.43 (s, 1H), 3.20 (s, 4H), 1.99 - 1.89 (m, 4H) MS (M+H) + = 464.1。

[0497] Example 25. Synthesis of compound NEM-25A.

[0498]

[0499] 1. Synthesis of 1-[4-(chloromethyl)phenyl]imidazole

[0500] At 0 °C, SOCl2 (1.71 g, 14.35 mmol, 1.04 mL, 5 eq) was added to a solution of (4-imidazol-1-ylphenyl)methanol (500 mg, 2.87 mmol, 1 eq) in DCM (6 mL). The mixture was stirred at 20 °C for 3 h. The mixture was concentrated under reduced pressure. The mixture was diluted with ethyl acetate (20 mL) and washed with saturated aqueous NaHCO3 at 0 °C until pH = 7. The organic layer was washed with brine (5 mL), dried over Na2SO4 and concentrated to give the crude product. Compound 1-[4-(chloromethyl)phenyl]imidazole (500 mg, crude product) was obtained as a white solid and used directly without further purification.

[0501] 2. Synthesis of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide

[0502] At -70 °C, n-BuLi (2 M, 1.36 mL, 4 eq) was added dropwise to a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (397.19 mg, 1.36 mmol, 2 eq) in THF (4 mL). After addition, the mixture was stirred at this temperature for 30 min, and then indoline-2,3-dione (100 mg, 679.67 umol, 1 eq) in THF (4 mL) was added dropwise to the above solution at -70 °C. The resulting mixture was stirred at -70 °C for 1.5 h. The mixture was quenched with saturated NH4Cl (5 mL) and extracted with EtOAc (10 mL x 3). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, 100 - 200 mesh, 0 - 100% ethyl acetate in petroleum ether). Compound N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 277.45 umol, 40.82%) was obtained as a white solid.

[0503] 1 H NMR (400 MHz, acetonitrile-d3) δ 8.50 (br s, 1H), 7.84 - 7.76 (m, 2H), 7.54 - 7.47 (m, 2H), 7.32 (dt, J = 1.3, 7.7 Hz, 1H), 7.18 - 7.13 (m, 1H), 7.08 - 6.97 (m, 2H), 5.59 (s, 1H), 4.66 (s, 1H), 1.13 (s, 9H)

[0504] 3. Synthesis of N-tert-butyl-4-[3-hydroxy-1-[(4-imidazol-1-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide

[0505] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (50 mg, 138.72 μmol, 1 equiv) in DMF (1 mL) was added K2CO3 (38.35 mg, 277.45 μmol, 2 equiv) and 1-[4-(chloromethyl)phenyl]imidazole (32.07 mg, 166.47 μmol, 1.2 equiv). The mixture was stirred at 60 °C for 12 h. The resulting mixture was filtered and the combined filtrate was purified by preparative HPLC (column: Waters Xbridge BEH C18 100*30 mm*10 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 25%-55%, 8 min). The compound N-tert-butyl-4-[3-hydroxy-1-[(4-imidazol-1-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide was obtained as a white solid (30 mg, 55.17 μmol, 39.77% yield, 95% purity).

[0506] 1H NMR (400 MHz, methanol-d4) δ = 8.12 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.58 - 7.49 (m, 7H), 7.33 (s, 1H), 7.23 (s, 1H), 7.14 (s, 2H), 7.04 (s, 1H), 5.04 (s, 2H), 1.16 (s, 9H)

[0507] 4. Synthesis of 4-[3-hydroxy-1-[(4-imidazol-1-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-25A)

[0508] To a solution of N-tert-butyl-4-[3-hydroxy-1-[(4-imidazol-1-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 58.07 μmol, 1 equiv) in DCM (1 mL) was added TFA (2.31 g, 20.26 mmol, 1.5 mL, 348.87 equiv). The mixture was stirred at 60 °C for 2 h. The reaction mixture was cooled to 20 °C. The solvent was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 80*30 mm*3 μm; mobile phase: [water (TFA)-ACN]; B%: 5%-35%, 8 min). The compound 4-[3-hydroxy-1-[(4-imidazol-1-ylphenyl)methyl]-2-oxo-indolin-3-yl]benzenesulfonamide was obtained as a yellow solid (13.7 mg, 22.73 μmol, 39.14% yield, TFA salt). 11H NMR (400 MHz, acetonitrile-d3) δ 8.68 (s, 1H), 7.89 - 7.82 (m, 2H), 7.66 (br s, 1H), 7.48 (br s, 1H), 7.62 - 7.46 (m, 7H), 7.34 (dt, J = 1.3, 7.8 Hz, 1H), 7.23 (dd, J = 0.7, 7.4 Hz, 1H), 7.16 - 7.07 (m, 1H), 6.99 (d, J = 7.9 Hz, 1H), 5.68 (s, 2H), 5.07 - 4.95 (m, 2H). MS (M + H) + = 461.1

[0509] Example 26. Synthesis of Compound NEM-34A

[0510]

[0511] 1. Synthesis of (6-Fluoro-1-naphthyl) trifluoromethanesulfonate

[0512] To a solution of 6-fluoronaphthalen-1-ol (500 mg, 3.08 mmol, 1 equiv) in DCM (5 mL) was added DIEA (1.59 g, 12.33 mmol, 2.15 mL, 4 equiv) and Tf2O (1.74 g, 6.17 mmol, 1.02 mL, 2 equiv). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (30 mL) and extracted with DCM (15 mL * 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica chromatography (ISCO; 12 g SepaFlash silica flash column, eluent 0 - 15% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound (6-fluoro-1-naphthyl) trifluoromethanesulfonate was obtained as a colorless oil (0.85 g, 2.89 mmol, 93.70% yield).

[0513] 2. Synthesis of 2-(6-Fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0514] A mixture of (6-fluoro-1-naphthyl) trifluoromethanesulfonate (674.9 mg, 2.29 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.33 g, 9.18 mmol, 4 equiv), cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (280.99 mg, 344.08 μmol, 0.15 equiv), TEA (928.45 mg, 9.18 mmol, 1.28 mL, 4 equiv) in dioxane (6 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 40 g SepaFlash silica gel rapid column, eluent: 0 - 10% ethyl acetate / petroleum ether gradient, 40 mL / min). Compound 2-(6-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a pale yellow oil (0.5 g, 1.84 mmol, 80.10% yield) was obtained. 1 1H NMR (400 MHz, chloroform-d) δ 8.82 - 8.76 (m, 1H), 8.05 - 8.03 (m, 1H), 7.90 - 7.86 (d, J = 8.4, 1H), 7.53 - 7.42 (m, 2H), 7.34 - 7.28 (m, 1H), 1.43 (s, 12H).

[0515] 3. Synthesis of (6-fluoro-1-naphthyl)boronic acid

[0516] To a solution of 2-(6-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (470 mg, 1.73 mmol, 1 equiv) in THF (9 mL) and H2O (3 mL) was added NH4OAc (199.70 mg, 2.59 mmol, 1.5 equiv) and NaIO4 (1.85 g, 8.64 mmol, 478.53 μL, 5 equiv). The mixture was stirred at 20 °C for 2 h. The mixture was acidified to pH = 6 by dropwise addition of hydrochloric acid (1 M, 10 mL) at 0 °C, and the reaction mixture was concentrated. The solid was collected by filtration and dried under reduced pressure. (6-fluoro-1-naphthyl)boronic acid as a white solid (350 mg, crude product) was obtained.

[0517] 4. Synthesis of N-tert-butyl-4-[1-(6-fluoro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide

[0518] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 equiv), (6-fluoro-1-naphthyl)boronic acid (105.42 mg, 554.90 μmol, 2 equiv), TEA (56.15 mg, 554.90 μmol, 77.23 μL, 2 equiv), pyridine (43.89 mg, 554.90 μmol, 44.79 μL, 2 equiv) and Cu(OAc)2 (100.79 mg, 554.90 μmol, 2 equiv) in DCE (2 mL) was degassed and purged with O2 three times, and then the mixture was stirred at 20 °C under an O2 atmosphere for 12 h. 10 mL of water was added to the mixture, and the mixture was extracted with dichloromethane (10 mL * 3), and the combined extracts were washed with brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash silica gel rapid column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound N-tert-butyl-4-[1-(6-fluoro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (0.07 g, 138.73 μmol, 50.00% yield) was obtained as a pale yellow solid. MS (M + H) + = 505.0

[0519] 5. 4-[1-(6-Fluoro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-34A)

[0520] To a solution of N-tert-butyl-4-[1-(6-fluoro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (50 mg, 99.09 μmol, 1 equiv) in DCM (1 mL) was added TFA (1.93 g, 16.88 mmol, 1.25 mL, 170.37 equiv). The mixture was stirred at 50 °C for 1 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [water (TFA)-ACN]; B%: 35% - 65%, 8 min). The compound 4-[1-(6-fluoro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (8.5 mg, 15.11 μmol, 15.25% yield, TFA salt) was obtained as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 8.08 - 8.06 (m, 1H), 7.94 - 7.89 (m, 2H), 7.80 - 7.65 (m, 4.5H), 7.66 - 7.56 (m, 1.5H), 7.47 - 7.24 (m, 3H), 7.23 - 7.11 (m, 1H), 6.48 (dd, J = 7.8, 10.6 Hz, 1H), 5.68 (br d, J = 5.6 Hz, 2H). MS (M + H)+ = 449.0.

[0521] Example 27. Synthesis of Compound NEM-35A

[0522]

[0523] 1. Synthesis of (6-Chloro-1-naphthyl) trifluoromethanesulfonate

[0524] To a solution of 6-chloronaphthalen-1-ol (500 mg, 2.80 mmol, 1 equiv) in DCM (6 mL) was added DIEA (1.45 g, 11.20 mmol, 1.95 mL, 4 equiv) and Tf2O (1.58 g, 5.60 mmol, 923.74 μL, 2 equiv). The mixture was stirred at 20 °C for 2 h. 10 mL of water was added to the mixture, and the mixture was extracted with dichloromethane (10 mL * 3). The combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash silica gel flash column, eluent 0 - 10% ethyl acetate / petroleum ether gradient, 80 mL / min). The compound (6-chloro-1-naphthyl) trifluoromethanesulfonate was obtained as a pale yellow oil (0.83 g, 2.67 mmol, 95.44% yield). 1 1H NMR (400 MHz, chloroform-d) δ 8.03 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.60 (dd, J = 2.0, 9.1 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.50 - 7.45 (m, 1H)

[0525] 2. Synthesis of 2-(6-Chloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0526] A mixture of (6-chloro-1-naphthyl) trifluoromethanesulfonate (830 mg, 2.67 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.71 g, 10.69 mmol, 4 equiv), TEA (1.08 g, 10.69 mmol, 1.49 mL, 4 equiv), cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (218.17 mg, 267.16 μmol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 90 °C under N2 atmosphere for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash silica gel rapid column, eluent: 0 - 1% ethyl acetate / petroleum ether gradient, 40 mL / min). Compound 2-(6-chloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was obtained as a pale yellow oil (0.7258 g, 2.52 mmol, 94.14% yield). 1 1H NMR (400 MHz, chloroform-d) δ 8.73 (d, J = 9.1 Hz, 1H), 8.08 (dd, J = 1.2, 6.8 Hz, 1H), 7.87 - 7.79 (m, 2H), 7.53 - 7.44 (m, 2H), 1.43 (s, 12H)

[0527] 3. Synthesis of (6-chloro-1-naphthyl)boronic acid

[0528] To a solution of 2-(6-chloro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (725 mg, 2.51 mmol, 1 equiv) in THF (9 mL) and H2O (3 mL) was added NaIO4 (2.69 g, 12.56 mmol, 696.07 μL, 5 equiv) and NH4OAc (290.48 mg, 3.77 mmol, 1.5 equiv). The mixture was stirred at 20 °C for 2 h. The mixture was acidified to pH = 6 by dropwise addition of hydrochloric acid (1 M, 10 mL) at 0 °C. The reaction mixture was concentrated and the solid was collected by filtration. (6-Chloro-1-naphthyl)boronic acid was obtained as a white solid (300 mg, crude product).

[0529] 4. Synthesis of N-tert-butyl-4-[1-(6-chloro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide

[0530] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (100 mg, 277.45 μmol, 1 equiv), (6-chloro-1-naphthyl)boronic acid (103.09 mg, 499.41 μmol, 1.8 equiv), TEA (56.15 mg, 554.90 μmol, 77.24 μL, 2 equiv), pyridine (43.89 mg, 554.90 μmol, 44.79 μL, 2 equiv) and Cu(OAc)2 (100.79 mg, 554.90 μmol, 2 equiv) in DCE (1 mL) was degassed and purged with O2 three times, then the mixture was stirred at 20 °C under an O2 atmosphere for 12 h. 5 mL of water was added to the mixture, the mixture was extracted with DCM (10 mL * 3), and the combined extracts were washed with brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions, column: Phenomenex C18 80 * 40 mm * 3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 50%-80%, 8 min). The compound N-tert-butyl-4-[1-(6-chloro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide was obtained as a pale yellow solid (50 mg, 95.96 μmol, 34.59% yield). MS (M + H) + = 521.1

[0531] 5. 4-[1-(6-Chloro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NE M-35A)

[0532] To a solution of N-tert-butyl-4-[1-(6-chloro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 57.58 μmol, 1 equiv) in DCM (1 mL) was added TFA (2.31 g, 20.26 mmol, 1.50 mL, 351.86 equiv). The mixture was stirred at 50 °C for 1 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75 * 30 mm * 3 μm; mobile phase: [water (TFA)-ACN]; B%: 35%-65%, 8 min). The compound 4-[1-(6-chloro-1-naphthyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide was obtained as a yellow solid (12.5 mg, 26.62 μmol, 46.23% yield). 11H NMR (400 MHz, acetonitrile-d3) δ 8.11 (dd, J = 2.1, 7.8 Hz, 1H), 8.05 (dd, J = 5.0, 8.3 Hz, 1H), 7.97 - 7.87 (m, 2H), 7.78 - 7.69 (m, 3.5H), 7.64 (dd, J = 0.9, 7.3 Hz, 1H), 7.55 (td, J = 2.7, 9.0 Hz, 1H), 7.49 - 7.44 (m, 0.5H), 7.40 - 7.24 (m, 2H), 7.22 - 7.12 (m, 1H), 6.48 (dd, J = 7.9, 10.1 Hz, 1H), 5.68 (br d, J = 5.5 Hz, 2H). MS (M + H)+ = 464.9

[0533] Example 28. Synthesis of Compound NEM-36A

[0534]

[0535] 1. Synthesis of 1-benzyloxy-6-bromo-naphthalene

[0536] To a solution of 6-bromonaphthalen-1-ol (1 g, 4.48 mmol, 1 equiv) and chloromethylbenzene (1.70 g, 13.45 mmol, 1.55 mL, 3 equiv) in DMF (10 mL) was added K2CO3 (1.86 g, 13.45 mmol, 3 equiv) and KI (74.42 mg, 448.30 μmol, 0.1 equiv). The mixture was stirred at 80 °C for 12 h. The reaction mixture was cooled to room temperature and diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica gel, 0 - 20% ethyl acetate in petroleum ether gradient, 40 mL / min). Compound 1-benzyloxy-6-bromo-naphthalene was obtained as a yellow oil (1.3 g, 4.15 mmol, 92.59% yield).

[0537] 2. Synthesis of 4-(5-benzyloxy-2-naphthyl)morpholine

[0538] A mixture of 1-benzyloxy-6-bromo-naphthalene (1.3 g, 4.15 mmol, 1 equiv), morpholine (723.25 mg, 8.30 mmol, 730.55 uL, 2 equiv), t-BuOK (931.55 mg, 8.30 mmol, 2 equiv), and tris(tert-butyl)phosphine palladium (424.26 mg, 830.17 umol, 0.2 equiv) in toluene (15 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 110 °C under a N2 atmosphere for 3 h. 20 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (30 mL * 2), and the combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica gel, 0 - 20% ethyl acetate in petroleum ether gradient, 40 mL / min). The compound 4-(5-benzyloxy-2-naphthyl)morpholine as a yellow solid (1 g, 3.13 mmol, 75.43% yield) was obtained.

[0539] 3. Synthesis of 6-morpholinonaphthalen-1-ol

[0540] Under a N2 atmosphere, Pd / C (1 g, 10% purity) was added to a solution of 4-(5-benzyloxy-2-naphthyl)morpholine (1 g, 3.13 mmol, 1 equiv) in MeOH (15 mL). The suspension was degassed and purged with H2 three times. The mixture was stirred at 20 °C under H2 (15 Psi) for 12 h. The suspension was filtered through a celite pad and the filter cake was washed with MeOH (20 mL × 3). The filtrate was concentrated under reduced pressure to give a residue. The compound 6-morpholinonaphthalen-1-ol as a gray solid (600 mg, crude product) was obtained, which was used in the next step without further purification.

[0541] 4. Synthesis of (6-morpholin-1-ylnaphthalen-1-yl) trifluoromethanesulfonate

[0542] To a solution of 6-morpholinonaphthalen-1-ol (542.7 mg, 2.37 mmol, 1 equiv) in DCM (5 mL) was added DIEA (1.22 g, 9.47 mmol, 1.65 mL, 4 equiv) and Tf2O (1.34 g, 4.73 mmol, 781.09 uL, 2 equiv). The mixture was stirred at 20 °C for 2 h. 15 mL of water was added to the mixture, and the mixture was extracted with dichloromethane (15 mL * 3), and the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0 - 15% ethyl acetate in petroleum ether, gradient over 20 min). The compound (6-morpholin-1-ylnaphthalen-1-yl) trifluoromethanesulfonate as a pale yellow oil (0.7288 g, 2.02 mmol, 85.21% yield) was obtained.

[0543] 5. Synthesis of 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]morpholine

[0544] A mixture of (6-morpholin-1-ylnaphthalen-1-yl) trifluoromethanesulfonate (700 mg, 1.94 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.97 g, 7.75 mmol, 4 equiv), TEA (784.12 mg, 7.75 mmol, 1.08 mL, 4 equiv), cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (158.20 mg, 193.73 umol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under a N2 atmosphere for 12 h. 10 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL * 3), and the combined extracts were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0 - 15% ethyl acetate in petroleum ether gradient, 80 mL / min). The compound 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthyl]morpholine as a pale yellow oil (700 mg, 1.24 mmol, 63.91% yield, 60% purity) was obtained. 11H NMR (400 MHz, chloroform-d) δ 8.67 (d, J = 9.3 Hz, 1H), 7.91 (dd, J = 1.3, 6.9 Hz, 1H), 7.80 (d, J = 8.1 Hz, 1H), 7.41 (dd, J = 6.9, 8.1 Hz, 1H), 7.35 - 7.28 (m, 1H), 7.15 - 7.09 (m, 1H), 3.98 - 3.89 (m, 4H), 3.34 - 3.23 (m, 4H), 1.46 - 1.40 (s, 12H)

[0545] 6. Synthesis of (6 - Morpholin - 1 - naphthyl)boronic acid

[0546] At 20 °C, NaIO4 (2.05 g, 9.58 mmol, 530.87 μL, 5 equiv) and NH4OAc (147.70 mg, 1.92 mmol, 1 equiv) were added in one portion to a solution of 4 - [5 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) - 2 - naphthyl]morpholine (650 mg, 1.92 mmol, 1 equiv) in THF (1 mL) and H2O (0.3 mL), and the mixture was kept for 12 h. The mixture was acidified to pH = 6 by dropwise addition of hydrochloric acid (1 M, 100 mL) at 0 °C. The crude product was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH4HCO3) - ACN]; B%: 5% - 35%, 8 min). The compound (6 - morpholin - 1 - naphthyl)boronic acid as a brown solid was obtained (20 mg, 77.79 μmol, 4.06% yield).

[0547] 7. Synthesis of N - tert - butyl - 4 - (3 - hydroxy - 2 - oxo - indolin - 3 - yl)benzenesulfonamide

[0548] At -70 °C, n-BuLi (2.5 M, 14.68 mL, 4 eq) was added dropwise to a solution of 4-bromo-N-tert-butyl-benzenesulfonamide (5.36 g, 18.35 mmol, 2 eq) in THF (30 mL) within 5 minutes. After the addition, the mixture was stirred at this temperature for 30 minutes, and then indoline-2,3-dione (1.35 g, 9.18 mmol, 1 eq) in THF (20 mL) was added dropwise at -70 °C. The resulting mixture was stirred at -70 °C for 1.5 hours. The reaction mixture was poured into 50 mL of ice-cold aqueous NH4Cl solution at 0 °C, and the mixture was extracted with ethyl acetate (50 mL × 3), and the combined extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica gel, 0 - 100% gradient of ethyl acetate in petroleum ether, 40 mL / min). The compound N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide as a yellow solid was obtained (0.9 g, 2.50 mmol, 27.21% yield).

[0549] 8. Synthesis of N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide

[0550] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (28 mg, 77.69 μmol, 1 eq) and (6-morpholino-1-naphthyl)boronic acid (19.97 mg, 77.69 μmol, 1 eq) in DCE (1 mL) were added pyridine (6.14 mg, 77.69 μmol, 6.27 μL, 1 eq), TEA (7.86 mg, 77.69 μmol, 10.81 μL, 1 eq) and Cu(OAc)2 (14.11 mg, 77.69 μmol, 1 eq), and the mixture was stirred at 20 °C under an O2 atmosphere for 12 hours. The suspension was filtered through a pad of Celite and the filter cake was washed with dichloromethane (2 mL × 3). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica gel, 0 - 50% gradient of ethyl acetate in petroleum ether, 40 mL / min). The compound N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide as a yellow solid was obtained (10 mg, 10.50 μmol, 13.51% yield, 60% purity).

[0551] 9. Synthesis of 4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-36A)

[0552] To a solution of N-tert-butyl-4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide (10 mg, 10.50 μmol, 60% purity, 1 eq) in DCM (0.5 mL) was added dropwise TFA (385.00 mg, 3.38 mmol, 0.25 mL, 321.72 eq). The mixture was stirred at 45 °C for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 20%-50%, 8 min). Compound 4-[3-hydroxy-1-(6-morpholino-1-naphthyl)-2-oxo-indolin-3-yl]benzenesulfonamide was obtained as a white solid (1.8 mg, 3.49 μmol, 33.26% yield). 1 H NMR (400 MHz, acetonitrile-d3) δ 7.96 - 7.87 (m, 3H), 7.71 (dd, J = 8.6, 10.9 Hz, 2H), 7.64 - 7.52 (m, 2H), 7.33 (br d, J = 17.6 Hz, 6H), 7.21 - 7.11 (m, 1H), 6.47 (dd, J = 7.9, 11.8 Hz, 1H), 5.70 (br d, J = 6.0 Hz, 2H), 3.85 - 3.79 (m, 4H), 3.26 (td, J = 5.0, 10.5 Hz, 4H). MS (M+H)+ = 515.95

[0553] Example 29. Synthesis of Compound NEM-37A

[0554]

[0555] 1. Synthesis of 5,7,14-trioxatetracyclo[9.2.1.02,10.04,8]tetradeca-2(10),3,8,12-tetraene

[0556] At -70 °C, n-BuLi (2 M, 4.29 mL, 1.2 equiv) was added dropwise within 5 minutes to a stirred solution of 5,6-dibromo-1,3-benzodioxole (2 g, 7.15 mmol, 308.64 μL, 1 equiv) and freshly distilled furan (2.43 g, 35.73 mmol, 2.60 mL, 5 equiv) in toluene (20 mL). The reaction mixture was stirred for 10 minutes and then warmed to -40 °C. Stirring was continued for an additional 2 hours. The mixture was quenched with 10 mL of 1 N aqueous HCl, then diluted with 100 mL of H2O and extracted with ethyl acetate (50 mL * 2). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue. The crude product 5,7,14-trioxatetracyclo[9.2.1.02,10.04,8]tetradeca-2(10),3,8,12-tetraene (1 g, 4.25 mmol, 59.50% yield, 80% purity) was obtained as a white solid and was used in the next step without further purification.

[0557] Synthesis of benzo[f][1,3]benzodioxol-5-ol

[0558] To a solution of 5,7,14-trioxatetracyclo[9.2.1.02,10.04,8]tetradeca-2(10),3,8,12-tetraene (1.2 g, 6.38 mmol, 1 equiv) in DCM (12 mL) was added copper(II) bis(trifluoromethanesulfonate) (115.32 mg, 318.85 μmol, 0.050 equiv). The reaction mixture was degassed three times with N2 and stirred for 2 hours at 25 °C under a N2 atmosphere. 15 mL of water was added to the mixture, the mixture was extracted with DCM (15 mL * 3), the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The compound benzo[f][1,3]benzodioxol-5-ol (1.7 g, crude product) was obtained as a pale yellow oil.

[0559] Synthesis of benzo[f][1,3]benzodioxol-5-yl trifluoromethanesulfonate

[0560] To a solution of benzo[f][1,3]benzodioxol-5-ol (1.6 g, 8.50 mmol, 1 equiv) in DCM (15 mL) at 0 °C was added DIEA (4.40 g, 34.01 mmol, 5.92 mL, 4 equiv) and Tf2O (4.80 g, 17.01 mmol, 2.81 mL, 2 equiv). The mixture was stirred at 20 °C for 2 h. 35 mL of water was added to the mixture, and the mixture was extracted with DCM (25 mL * 3), and the combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash silica gel rapid column, eluent: 0 - 15% ethyl acetate / petroleum ether gradient, 80 mL / min). The compound benzo[f][1,3]benzodioxol-5-yl trifluoromethanesulfonate was obtained as a pale yellow oil (2.3 g, 7.18 mmol, 84.47% yield). 1 H NMR (400 MHz, chloroform-d) δ 7.66 - 7.59 (m, 1H), 7.31 - 7.27 (m, 2H), 7.22 (s, 1H), 7.13 (s, 1H), 6.07 (s, 2H)

[0561] 4. Synthesis of 2-benzo[f][1,3]benzodioxol-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0562] Benzof[f][1,3]benzodioxol-5-yl trifluoromethanesulfonate (1 g, 3.12 mmol, 1 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.96 g, 15.61 mmol, 5 equiv), TEA (1.26 g, 12.49 mmol, 1.74 mL, 4 equiv), cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (255.01 mg, 312.26 μmol, 0.1 equiv) in dioxane (10 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C under N2 atmosphere for 12 h. 10 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (10 mL * 3), and the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash silica gel fast column, eluent: 0 - 15% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound 2-benzof[f][1,3]benzodioxol-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid was obtained (1.7 g, 2.85 mmol, 91.30% yield, 50% purity). 1 H NMR (400 MHz, chloroform-d) δ 8.19 (s, 1H), 7.93 (d, J = 6.9 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.36 - 7.30 (m, 1H), 7.14 - 7.09 (d, J = 3.6 Hz, 1H), 6.04 (s, 2H), 1.41 (s, 12H).

[0563] 5. Synthesis of benzof[f][1,3]benzodioxol-5-ylboronic acid

[0564] To a solution of 2-benzof[f][1,3]benzodioxol-5-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.5 g, 5.03 mmol, 1 equiv) in THF (3 mL) and H2O (1 mL) was added portionwise NaIO4 (5.38 g, 25.16 mmol, 1.39 mL, 5 equiv), NH4OAc (581.72 mg, 7.55 mmol, 1.5 equiv). The mixture was stirred at 20 °C for 5 h. The mixture was acidified to pH = 6 by dropwise addition of hydrochloric acid (1 M, 10 mL) at 0 °C. The reaction mixture was concentrated, then the reaction mixture was filtered and the filter cake was concentrated under reduced pressure. The compound benzof[f][1,3]benzodioxol-5-ylboronic acid as a brown solid was obtained (320 mg, crude product).

[0565] 6. Synthesis of 4-(1-benzo[f][1,3]benzodioxol-5-yl-3-hydroxy-2-oxo-indolin-3-yl)-N-tert-butyl-benzenesulfonamide

[0566] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (150 mg, 416.17 μmol, 1 equiv), benzo[f][1,3]benzodioxol-5-ylboronic acid (179.78 mg, 832.35 μmol, 2 equiv), TEA (84.22 mg, 832.35 μmol, 115.85 μL, 2 equiv), pyridine (65.84 mg, 832.35 μmol, 67.18 μL, 2 equiv) and Cu(OAc)2 (151.18 mg, 832.35 μmol, 2 equiv) in DCM (2 mL) was degassed and purged with O2 three times, and then the mixture was stirred at 20 °C under an O2 atmosphere for 12 h. 5 mL of water was added to the mixture, and the mixture was extracted with DCM (5 mL × 3), and the combined extracts were washed with brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 25 g SepaFlash silica gel rapid column, eluent: 0 - 100% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound 4-(1-benzo[f][1,3]benzodioxol-5-yl-3-hydroxy-2-oxo-indolin-3-yl)-N-tert-butyl-benzenesulfonamide was obtained as a pale yellow oil (42 mg, 55.41 μmol, 13.31% yield, 70% purity).

[0567] 7. 4-(1-benzo[f][1,3]benzodioxol-5-yl-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (NEM-37A)

[0568] To a solution of 4-(1-benzo[f][1,3]benzodioxol-5-yl-3-hydroxy-2-oxo-indolin-3-yl)-N-tert-butyl-benzenesulfonamide (42 mg, 79.16 μmol, 1 equiv) in DCM (1 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 341.25 equiv). The mixture was stirred at 50 °C for 12 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna 80*30 mm*3 um; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 8 min). The compound 4-(1-benzo[f][1,3]benzodioxol-5-yl-3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide as a yellow solid was obtained (3.5 mg, 7.38 μmol, 9.32% yield, 100% purity). 1 H NMR (400 MHz, acetonitrile-d3) δ 7.94 - 7.85 (m, 3H), 7.70 (t, J = 8.9 Hz, 2H), 7.55 - 7.46 (m, 1H), 7.45 - 7.41 (m, 1H), 7.39 - 7.24 (m, 3H), 7.22 - 7.11 (m, 1H), 7.05 - 7.01 (m, 0.5H), 6.74 - 6.70 (m, 0.5H), 6.51 - 6.45 (m, 1H), 6.09 - 6.00 (m, 2H), 5.74 - 5.62 (m, 2H). MS (M+H)+ = 475.0

[0569] Example 30. Synthesis of Compound NEM-38A

[0570]

[0571] 1. Synthesis of N-tert-butyl-4-[3-hydroxy-1-(5-isoquinolinyl)-2-oxo-indolin-3-yl]benzenesulfonamide

[0572] A mixture of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (200 mg, 554.90 μmol, 1 equiv), 5-isoquinolinylboronic acid (287.95 mg, 1.66 mmol, 3 equiv), Cu(OAc)2 (201.57 mg, 1.11 mmol, 2 equiv), TEA (112.30 mg, 1.11 mmol, 154.47 μL, 2 equiv) and pyridine (87.78 mg, 1.11 mmol, 89.58 μL, 2 equiv) in DCM (5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 50 °C under N2 atmosphere for 3 h. 5 mL of water was added to the mixture, and the mixture was extracted with DCM (20 mL × 2), and the combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex C18 80*40 mm*3 μm; mobile phase: [water (NH4HCO3)-ACN]; B%: 30%-50%, 8 min). The compound N-tert-butyl-4-[3-hydroxy-1-(5-isoquinolinyl)-2-oxo-indolin-3-yl]benzenesulfonamide (35 mg, 71.78 μmol, 12.94% yield) was obtained as a yellow solid. MS (M+H)+ = 488.1

[0573] 2. Synthesis of 4-[3-hydroxy-1-(5-isoquinolinyl)-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-38A)

[0574] TFA (1.15 g, 10.13 mmol, 750.00 μL, 164.63 equiv) was added to a solution of N-tert-butyl-4-[3-hydroxy-1-(5-isoquinolinyl)-2-oxo-indolin-3-yl]benzenesulfonamide (30 mg, 61.53 μmol, 1 equiv) in DCM (1 mL). The mixture was stirred at 50 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 75*30 mm*3 μm; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 8 min). The compound 4-[3-hydroxy-1-(5-isoquinolinyl)-2-oxo-indolin-3-yl]benzenesulfonamide (17.7 mg, 32.42 μmol, 52.69% yield, TFA salt) was obtained as a yellow solid. 11H NMR (400 MHz, acetonitrile-d3) δ 9.58 (br d, J = 6.8 Hz, 1H), 8.59 - 8.48 (m, 1H), 8.47 - 8.40 (m, 1H), 8.08 (br d, J = 7.4 Hz, 1H), 8.01 (brt, J = 8.1 Hz, 1H), 7.96 - 7.88 (m, 2H), 7.85 (br s, 0.5H), 7.76 - 7.69 (m, 2H), 7.64 (br s, 0.5H), 7.41 - 7.28 (m, 2H), 7.22 (dd, J = 7.6, 11.1 Hz, 1H), 6.59 - 6.51 (m, 1H), 5.70 (br d, J = 6.4 Hz, 2H). MS (M + H)+ = 432.0

[0575] Example 31. Synthesis of Compound NEM-41A

[0576]

[0577] 1. Synthesis of 4-[1-(1,3-Benzodioxol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide

[0578] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (110 mg, 305.19 μmol, 1 equiv) in DMF (2 mL) was added K2CO3 (126.54 mg, 915.58 μmol, 3 equiv) and 5-(chloromethyl)-1,3-benzodioxole (52.06 mg, 305.19 μmol, 1 equiv), and the mixture was stirred at 60 °C for 12 h. 5 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 2), and the combined extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0 - 60% ethyl acetate in petroleum ether, gradient in 20 min). Compound 4-[1-(1,3-benzodioxol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide was obtained as a yellow solid (60 mg, 121.32 μmol, 39.75% yield).

[0579] 2. Synthesis of 4-[1-(1,3-Benzodioxol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide (NEM-41A)

[0580] To a solution of 4-[1-(1,3-benzodioxol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (60 mg, 121.32 μmol, 1 equiv) in DCM (1 mL) was added TFA (660.00 mg, 5.79 mmol, 428.57 μL, 47.71 equiv). The mixture was stirred at 50 °C for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 80*30 mm*3 μm; mobile phase: [water (TFA)-ACN]; B%: 30%-60%, 8 min) to give the desired compound. The compound 4-[1-(1,3-benzodioxol-5-ylmethyl)-3-hydroxy-2-oxo-indolin-3-yl]benzenesulfonamide as a yellow solid was obtained (9.5 mg, 20.58 μmol, 16.96% yield). 1 H NMR (400 MHz, methanol-d4) δ 7.86 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 7.32 (dt, J = 1.1, 7.7 Hz, 1H), 7.20 (d, J = 7.0 Hz, 1H), 7.13 - 7.05 (m, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.91 - 6.82 (m, 2H), 6.77 (d, J = 7.9 Hz, 1H), 5.97 - 5.87 (d, J = 1.6 Hz, 2H), 4.87 (s, 2H). MS (M+H)+ = 439.1

[0581] Example 32. Synthesis of Compound NEM-45A

[0582]

[0583] 1. Synthesis of 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide

[0584] To a solution of N-tert-butyl-4-(3-hydroxy-2-oxo-indolin-3-yl)benzenesulfonamide (200 mg, 554.90 μmol, 1 equiv) and K2CO3 (191.72 mg, 1.39 mmol, 2.5 equiv) in DMF (2 mL) was added 1-bromo-4-(bromomethyl)benzene (166.42 mg, 665.88 μmol, 1.2 equiv). The mixture was then stirred at 60 °C for 3 h. 5 mL of water was added to the mixture, and the mixture was extracted with ethyl acetate (10 mL * 3), and the combined extracts were washed with brine (6 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash silica gel rapid column, eluent 0 - 100% ethyl acetate / petroleum ether gradient, 50 mL / min). Compound 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide was obtained as a pale yellow solid (0.295 g, 501.47 μmol, 90.37% yield, 90% purity). MS (M+H)+ = 529.1

[0585] 2. Synthesis of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[2-(trifluoromethyl)-4-pyridinyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide

[0586] 4-[1-[(4-bromophenyl)methyl]-3-hydroxy-2-oxo-indolin-3-yl]-N-tert-butyl-benzenesulfonamide (60 mg, 113.33 μmol, 1 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine (34.04 mg, 124.66 μmol, 1.1 equiv), K3PO4 (48.11 mg, 226.65 μmol, 2 equiv), cyclopentyl(diphenyl)phosphane; dichloromethane; palladium dichloride; iron (18.51 mg, 22.67 umol, 0.2 equiv) in a mixture in DME (1 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 °C under a N2 atmosphere for 12 h. 5 mL of water was added to the mixture, the mixture was extracted with ethyl acetate (5 mL * 3), and the combined extracts were washed with brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 12 g SepaFlash silica gel rapid column, eluent 0 - 100% ethyl acetate / petroleum ether gradient, 40 mL / min). The compound N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 83.94 μmol, 74.07% yield) was obtained as a pale yellow solid. MS (M+H)+ = 596.3

[0587] 3. 4-[3-Hydroxy-2-oxo-1-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (NEM-45A)

[0588] TFA (3.07 g, 26.92 mmol, 2 mL, 320.74 equiv) was added to a solution of N-tert-butyl-4-[3-hydroxy-2-oxo-1-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (50 mg, 83.94 μmol, 1 equiv) in DCM (1 mL). Then the mixture was stirred at 50 °C for 3 h. The mixture was evaporated under reduced pressure. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10 um; mobile phase: [water (NH4HCO3)-ACN]; gradient: 30% - 65% B in 8 min). The compound 4-[3-hydroxy-2-oxo-1-[[4-[2-(trifluoromethyl)-4-pyridyl]phenyl]methyl]indolin-3-yl]benzenesulfonamide (5 mg, 9.27 μmol, 15.46% yield) was obtained as a white solid. 11H NMR (400 MHz, acetonitrile-d3) δ 8.76 (d, J = 5.1 Hz, 1H), 8.03 (s, 1H), 7.89 - 7.83 (m, 3H), 7.79 (d, J = 8.4 Hz, 2H), 7.56 - 7.50 (m, 4H), 7.33 (dt, J = 1.3, 7.8 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.09 (dt, J = 0.8, 7.5 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 5.65 (br s, 2H), 5.01 (d, J = 4.4 Hz, 2H), 4.81 (s, 1H). MS (M + H)+ = 540.2

[0589] Biological Example 1. Biological evaluation

[0590] To evaluate the ability of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (Examples 1 and 2) to effectively inhibit Car1 enzyme activity, a stopped-flow assay was performed and its half-maximal inhibitory concentration (IC 50 ) was determined and compared with the known Car enzyme inhibitor MZ. Using the stopped-flow assay, it was determined that 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide is more effective than the established inhibitor MZ in inhibiting Car1 (Table 1). These results strongly suggest that 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide is much more effective than MZ in inhibiting mast cell development and thus has significant therapeutic potential.

[0591] Table 1. IC of Car enzyme inhibitors 50

[0592]

[0593] To further test the ability of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide to inhibit mast cell development, an established mast cell culture assay (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663-73) was used. As a positive control for mast cell development, bone marrow cells were isolated from mouse femurs and cultured for seven days in the presence of 10 ng / mL IL-3 and vehicle (1:10, DMSO / RPMI complete medium) and mast cells were identified as (c-Kit+FceRIa+CD49b- cells) by flow cytometry analysis. To determine the mast cell inhibitory ability, cultures were treated with increasing doses of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037) (0.5 uM, 2.5 uM and 10 uM), and its effect was compared with that of MZ used at 30 ug / mL (126.97 uM) (the peak effective range of which was based on previous studies (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663-73)). Treatment with IL-3 led to an increase in the number of mast cells compared to the vehicle-treated control ( Figure 1 ). Additionally, while vehicle alone showed no effect, treatment with MZ led to a significant reduction in the number of mast cells as previously reported ( Figure 1 ) (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663-73). Importantly, 10 uM of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide inhibited mast cell development as effectively as 126.97 uM of MZ. These data are consistent with our stopped-flow analysis (Table 1) and demonstrate that 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide is a more potent inhibitor of in vitro mast cell responses than MZ.

[0594] Stop-flow and in vitro studies indicate that the novel compound 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide is a more potent inhibitor of Car1 than MZ and is thus a more effective inhibitor of mast cell development. However, it remains unknown whether 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037) is also more effective than MZ in inhibiting in vivo mast cell responses. To address this question, a Trichinella-induced mastocytosis model was used, and the ability of MZ and 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide to inhibit intestinal mast cell responses was directly compared (Henry, E.K. et al., J Exp Med, 2016.213(9): pp. 1663-73). Briefly, mice were infected with Trichinella and treated with vehicle, MZ, or 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide, and intestinal mast cells were quantified via esterase staining and histological analysis (Henry, E.K. et al., J Exp Med, 2016.213(9): pp. 1663-73). As previously reported, mice infected with Trichinella showed a significantly increased mast cell response in the presence of vehicle (Henry, E.K. et al., J ExpMed, 2016.213(9): pp. 1663-73). Importantly, mice treated with MZ at 2 mg / day (a lower dose than that required to inhibit mast cell responses in previously published studies) (Henry, E.K. et al., J Exp Med, 2016.213(9): pp. 1663-73) showed no change in the mast cell response after infection ( Figure 2 ). In contrast, mice treated with 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide at 2 mg / day showed a significant decrease in the number of intestinal mast cells ( Figure 2 ). These data are consistent with the in vitro assay and further demonstrate that 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide is a more potent inhibitor of mast cells than MZ and thus has significant therapeutic potential.

[0595] To evaluate the ability of the representative compounds of the present invention to effectively inhibit mast cell development, in vitro mast cell cultures were performed as previously described (Henry et al.), and the percentage of inhibition at 10 μm was measured. The results are shown in the table below.

[0596]

[0597]

[0598] Other compounds were evaluated using a stopped-flow assay, and the table below shows the IC 50 values:

[0599] Table 2. IC of other Car enzyme inhibitors 50

[0600] Compound IC50 (nM) NEM-9A 51.3 NEM-10A 33.8 NEM-12A 62.5 NEM-14A 34.0 NEM-15A 35.3 NEM-23A 77 NEM-24A 44.3 NEM-37A 5.3

[0601] * The control MZ used in these assays showed an IC of approximately 26 - 39 nM 50 .

[0602] In addition, representative compounds were tested in a mast cell culture assay, and the results are shown as the percentage of inhibition (POI) based on the number of MCs. Overall, based on viability observations, all tested compounds showed low toxicity / non-toxicity.

[0603] Table 3. POI of other Car enzyme inhibitors at 15 uM*

[0604]

[0605]

[0606] * The control MZ at 126 uM used in these assays showed a POI ranging from approximately 78% to 100%. As used herein, "uM" refers to micromolar or μM.

[0607] The POI data further showed that the inhibitory effect of 10 uM NEM-14A on the number of mast cells was comparable to that of the 126 uM control MZ. 15 uM NEM-14A showed a significantly higher inhibitory effect than 126 uM MZ, p = 0.0046 (Student's t-test). The POI data also showed that both 10 uM and 15 uM NEM-15A showed a significantly higher inhibitory effect on the number of mast cells than 126 uM MZ, with p = 0.02 and 0.0049 respectively by Student's t-test. In addition, NEM-23A was found to inhibit the number of mast cells at 5 uM, 10 uM, and 15 uM, all at levels comparable to that of the 126 uM MZ. Further titration showed that NEM-23A inhibited the number of mast cells by nearly 50% at 250 nM and even at 100 nM, see Figure 3 .

[0608] Discussion

[0609] With the development of new technologies and techniques, our ability to understand hematopoiesis and lineage commitment events continues to improve. Thus, recent studies are beginning to reshape the traditional models of stem cell development and are identifying previously unappreciated therapeutic targets. Previous studies have identified a mast cell progenitor defined by its high expression of the enzyme Car1 (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663 - 73; Inclan-Rico, J.M. et al., PLoS Pathogens, 2020. 16(5): pp. e1008579). These studies have also demonstrated that inhibition of Car1 is sufficient to prevent mast cell development. Defining the developmental checkpoints of mast cells has important scientific and clinical implications. Mast cells are strategically located at barrier surfaces and are powerful producers of inflammatory molecules in response to diverse stimuli (Voehringer, D., Nat Rev Immunol, 2013. 13(5): pp. 362 - 75). Thus, mast cells are key players in several disease states, including allergy, asthma, mastocytosis, mast cell activation syndrome, and anaphylaxis (Henry, E.K. et al., J Exp Med, 2016. 213(9): pp. 1663 - 73; Voehringer, D., Nat Rev Immunol, 2013. 13(5): pp. 362 - 75). Collectively, these studies suggest that Car1 inhibitors could be used to treat several forms of mast cell-mediated inflammation.

[0610] Previous studies have demonstrated that the Car enzyme inhibitor MZ can prevent murine and human mast cell development. The studies presented here describe the design and synthesis of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037), a Car1 inhibitor that is much more potent than MZ at inhibiting Car1. Importantly, the ability of 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide to inhibit Car1 correlates with its effective potential to inhibit mast cell responses in vitro and in vivo. Collectively, these studies demonstrate that the Car1 inhibitor 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide outperforms MZ both in its ability to inhibit Car1 enzyme activation and mast cell development and has substantial therapeutic potential for treating mast cell-mediated diseases. Further studies have shown that compounds such as NEM-14A, 15-A, and 23-A effectively inhibit Car1 enzyme activation and can inhibit mast cell development at lower doses.

[0611] Materials and Methods

[0612] Stopped-flow: IC50 The values were established using an SX20 stopped-flow spectrometer from Applied Biophysics. In one syringe of the SX20, recombinant human Car1 was maintained at a concentration of 9 μM in sodium phosphate buffer and inhibitors were added to the solution at 0 nM, 10 nM, 20 nM, 80 nM, and 100 nM. In the second syringe, a saturated CO2 solution was mixed with 0.2 mM phenol red. This series of dilutions allowed for the evaluation of the rate of CO2 metabolism by Car1 in the absence of inhibitors and allowed for the determination of whether the process was inhibited with the addition of increasing concentrations of the compound.

[0613] In vitro mast cell development: Briefly, 1×10 6 bone marrow resident progenitor cells were isolated from mouse femurs and cultured for 5 days in complete medium supplemented with 10 ng / mL rIL-3. Mast cells were analyzed by flow cytometry and identified by the expression of the surface molecules FcεRIα and c-Kit. In addition to IL-3, the cultures were treated with vehicle or increasing concentrations of the Car enzyme inhibitor at the indicated concentrations.

[0614] Trichinella infection: Mice were infected via oral gavage with 500 Trichinella muscle larvae and treated daily intraperitoneally with vehicle (1:5, DMSO / PBS), 2 mg MZ, or 2 mg 4-(3-hydroxy-1-(4-methoxybenzyl)-2-oxoindolin-3-yl)benzenesulfonamide (CAR0037); mice were sacrificed between days 10 post-infection and the mast cell response in the small intestine was evaluated by esterase staining as previously described (Henry, E.K. et al., J Exp Med, 2016.213(9): pp. 1663-73).

[0615] The following exemplify representative pharmaceutical dosage forms containing a compound of formula I or formula A (“Compound X”) for use in the treatment or prevention of humans.

[0616]

[0617]

[0618] The above preparations can be obtained by conventional procedures known in the pharmaceutical art.

[0619] The Overview and Abstract sections may set forth one or more but not all exemplary embodiments of the invention as contemplated by the inventors and are not, therefore, intended to limit the invention and the appended claims in any way.

[0620] The present invention has been described above by means of functional building blocks that illustrate the implementation of specific functions and their relationships. For the sake of convenience in description, the boundaries of these functional building blocks have been arbitrarily defined herein. Alternative boundaries may be defined as long as the specific functions and their relationships are appropriately performed.

[0621] Regarding aspects of the present invention described as a genus, all individual species are separately considered to be independent aspects of the present invention. If an aspect of the present invention is described as "comprising" a feature, embodiments are also considered to "consist of" or "consist essentially of" that feature.

[0622] The foregoing description of specific embodiments will fully disclose the general nature of the present invention, so that others can, without departing from the general concept of the present invention, readily modify and / or adapt such specific embodiments for various applications by applying knowledge within the scope of the art. Accordingly, such adaptations and modifications are intended to be within the meaning and scope of the equivalents of the disclosed embodiments based on the teachings and guidance presented herein. It should be understood that the language or terminology herein is for the purpose of description and not of limitation, and thus those skilled in the art will interpret the terms or terminology of this specification according to the teachings and guidance.

[0623] The breadth and scope of the present invention should not be limited by any of the above exemplary embodiments.

[0624] All of the individual aspects, embodiments, and options described herein can be combined in any and all variations.

[0625] All publications, patents, and patent applications mentioned in this specification are hereby incorporated by reference as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein to the extent set forth. To the extent that any meaning or definition of a term in this document conflicts with the same term's meaning or definition in a document incorporated by reference, the meaning or definition given to the term in this document shall govern.

[0626] The present invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many changes and modifications can be made while remaining within the spirit and scope of the present invention.

Claims

1. A compound of formula A or a pharmaceutically acceptable salt thereof: Wherein: R 1 is an aryl, 5-membered heteroaryl, 6-membered heteroaryl or (C1-C3) alkyl substituted by aryl, 5-membered heteroaryl or 6-membered heteroaryl, wherein any aryl, 5-membered heteroaryl and 6-membered heteroaryl is substituted by -S(=O)2NH2 and is further optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl, (C1-C6) alkanoyloxy and NR a R b , wherein any (C1-C6) alkyl, (C3-C6) cycloalkyl, (C1-C6) alkoxy, (C1-C6) alkanoyl, (C1-C6) alkoxycarbonyl and (C1-C6) alkanoyloxy is optionally substituted by one or more groups independently selected from the group consisting of: halo, hydroxy, cyano, nitro, (C3-C6) cycloalkyl and (C1-C6) alkoxy; R 3 is H, fluorine, hydroxy, (C1-C6)alkyl or (C1-C6)alkoxy, where any (C1-C6)alkyl and (C1-C6)alkoxy are optionally substituted by one or more fluorines; Ring A is phenyl, a 5-membered heteroaryl or a 6-membered heteroaryl, and provided that the valence allows, ring A is optionally substituted by 1, 2, 3 or 4 groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkanoyloxy and NR e R f , wherein any (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl and (C1-C6)alkanoyloxy is optionally substituted by one or more groups independently selected from the group consisting of: halogen, hydroxy, cyano, nitro, (C3-C6)cycloalkyl and (C1-C6)alkoxy; Ring B is absent and is an optionally substituted carbocyclic group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclic group; L 1 Absent or optionally substituted C 1-3 alkylene; R 10 is hydrogen, a halogen group, a hydroxyl group, a cyano group, a nitro group, NH2, COOH, CONH2, S(O)2NH2, G 1 、OG 1 、NHG 1 、NG 1 G 1 、C(O)G 1 、C(O)OG 1 、C(O)NHG 1 、C(O)NG 1 G 1 、S(O)2G 1 、S(O)2NHG 1 or S(O)2NG 1 G 1 wherein G 1 is, independently at each occurrence, an optionally substituted (C1-C6)alkyl, an optionally substituted (C1-C6)heteroalkyl, an optionally substituted 3-7 membered carbocycle, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclic group, Each R a and R b are independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or R a and R b together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, said aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl being optionally substituted with one or more groups independently selected from halo and (C1-C6)alkyl; and Each R e and R f are independently selected from the group consisting of: H, (C1-C6)alkyl, (C3-C6)cycloalkyl, and (C3-C6)cycloalkyl(C1-C6)alkyl; or R e and R f together with the nitrogen to which they are attached form aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, or piperidinyl, and the aziridinyl, azetidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and piperidinyl are optionally substituted with one or more groups independently selected from halo and (C1-C6)alkyl.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that Has a structure according to formula A-1: Wherein: R 4 and R 5 each independently is hydrogen or optionally substituted C 1-3 alkyl.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is an optionally substituted phenyl group or an optionally substituted 5- or 6-membered heteroaryl group.

4. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is an unsubstituted phenyl group.

5. The compound or a pharmaceutically acceptable salt thereof according to claim 2, characterized in that Has a structure according to formula A-1-A: Wherein: n is 0, 1, 2 or 3; and (i)R 100 is, independently at each occurrence, a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C1-C6)alkyl group, a (C3-C6)cycloalkyl group, a (C1-C6)alkoxy group, a (C1-C6)alkanoyl group, a (C1-C6)alkoxycarbonyl group, a (C1-C6)alkanoyloxy group and NR e R f , where any (C1-C6)alkyl group, (C3-C6)cycloalkyl group, (C1-C6)alkoxy group, (C1-C6)alkanoyl group, (C1-C6)alkoxycarbonyl group and (C1-C6)alkanoyloxy group is optionally substituted by one or more groups independently selected from the group consisting of a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C3-C6)cycloalkyl group and a (C1-C6)alkoxy group, where R e and R f is defined in claim 1; or (ii) R 100 is independently, at each occurrence, halogen, OH, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl, wherein said C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1 - 3 fluorines; or (iii) Two adjacent Rs 100 together with the intervening atom are joined to form an optionally substituted 4- to 7-membered ring which is optionally heterocyclic and is aromatic or non-aromatic, and any remaining Rs 100 are as defined in (i) or (ii).

6. The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein n is 0.

7. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-6, wherein R 10 is an optionally substituted 4-7 membered monocyclic heterocycle having 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur, and when substituted, the 4-7 membered monocyclic heterocycle is preferably substituted with 1-3 substituents, such as 1-3 substituents each independently selected from the following: oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, a 3-6 membered ring or a nitrogen protecting group, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines.

8. The compound according to any one of claims 2-6 or a pharmaceutically acceptable salt thereof, wherein R 10 is an optionally substituted 5- or 6-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur, such as pyrrolidine, piperidine, piperazine, morpholine, etc., and when substituted, the 5- or 6-membered monocyclic heterocycle is preferably substituted with 1-3 substituents, such as 1-3 substituents each independently selected from the following: oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl, a 3-6 membered ring or a nitrogen protecting group, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines.

9. A compound according to any one of claims 2-6 or a pharmaceutically acceptable salt thereof, wherein R 10 is an optionally substituted 5- or 6-membered heteroaryl ring having 1-4 ring heteroatoms, each ring heteroatom independently being nitrogen, oxygen or sulfur, such as a pyridyl or imidazole ring, wherein the ring nitrogen atom is optionally oxidized, and when substituted, and provided that the valency permits, the 5- or 6-membered heteroaryl ring is preferably substituted by 1-3 substituents, such as 1-3 substituents each independently selected from the following: halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3-6 membered ring, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted by 1-3 fluorines.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-6, wherein R 10 is selected from:

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-6, wherein R 10 is 12. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is an optionally substituted 5- or 6-membered heteroarylene having 1 to 4 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur, such as pyridylene, wherein the ring nitrogen atom is optionally oxidized, and wherein when substituted, and provided that the valency permits, the 5- or 6-membered heteroarylene is preferably substituted with 1 to 3 substituents, such as 1 to 3 substituents each independently selected from the following: halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3- to 6-membered ring, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1 to 3 fluorines.

13. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is an optionally substituted bicyclic heteroarylene having 1-4 ring heteroatoms, wherein each ring heteroatom is independently nitrogen, oxygen or sulfur, such as a 6,6-bicyclic heteroaryl ring, for example a quinoline or isoquinoline ring, wherein the ring nitrogen atom is optionally oxidized, and wherein when substituted, and provided that the valency permits, the bicyclic heteroarylene is preferably substituted with 1-3 substituents, such as 1-3 substituents each independently selected from the following: halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 heteroalkyl or a 3-6 membered ring, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted with 1-3 fluorines.

14. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein ring B is an optionally substituted 4- to 7-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, each ring heteroatom independently being nitrogen, oxygen or sulfur, such as a tetrahydropyran ring, etc., and when substituted, the 4- to 7-membered monocyclic heterocycle is preferably substituted by 1 to 3 substituents, such as 1 to 3 substituents each independently selected from the following: oxo, halogen (e.g., F), OH, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl or a nitrogen protecting group, wherein the C 1-4 alkyl, C 1-4 alkoxy or C 1-4 heteroalkyl is optionally substituted by 1 to 3 fluorines.

15. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 12 - 14, wherein R 10 is hydrogen.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-15, wherein R 4 is hydrogen.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2-16, wherein R 5 is hydrogen.

18. The compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that Has a structure according to formula A-2:

19. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein ring B is an optionally substituted phenyl group, an optionally substituted heteroaryl group (e.g., 5-10 membered heteroaryl group such as isoquinolinyl) or an optionally substituted naphthyl group.

20. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein Has a structure according to formula A-2-A, formula A-2-B or formula A-2-C: Wherein: j is 0, 1, 2, 3 or 4; and (i)R 101 is, independently at each occurrence, a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C1-C6)alkyl group, a (C3-C6)cycloalkyl group, a (C1-C6)alkoxy group, a (C1-C6)alkanoyl group, a (C1-C6)alkoxycarbonyl group, a (C1-C6)alkanoyloxy group and NR e R f , wherein any (C1-C6)alkyl group, (C3-C6)cycloalkyl group, (C1-C6)alkoxy group, (C1-C6)alkanoyl group, (C1-C6)alkoxycarbonyl group and (C1-C6)alkanoyloxy group is optionally substituted by one or more groups independently selected from the group consisting of a halogen group, a hydroxyl group, a cyano group, a nitro group, a (C3-C6)cycloalkyl group and a (C1-C6)alkoxy group, wherein R e and R f is defined in claim 1; or (ii)R 101 is independently, at each occurrence, halogen (e.g., F, Cl, Br, etc.), CN, OH, G 2 or OG 2 , where G 2 is independently, at each occurrence, C 1-4 alkyl, C 1-4 heteroalkyl, a 3- to 6-membered ring, (C 1-4 alkylene)-(3- to 6-membered ring) or (C 1-4 heteroalkylene)-(3- to 6-membered ring), wherein the C 1-4 alkyl, C 1-4 heteroalkyl, C 1-4 alkylene or C 1-4 heteroalkylene is optionally substituted with 1 to 3 fluorines; and the 3- to 6-membered ring is optionally substituted with halogen, CN, C 1-4 alkyl optionally substituted with 1 to 3 Fs, C 1-4 alkoxy optionally substituted with 1 to 3 Fs or C 1-4 heteroalkyl optionally substituted with 1 to 3 Fs, or (iii) Two Rs 101 are joined together to form a 5- to 7-membered ring, which is optionally substituted by halogen, CN, C 1-4 alkyl optionally substituted by 1 to 3 Fs, C 1-4 alkoxy optionally substituted by 1 to 3 Fs or C 1-4 heteroalkyl, and any remaining Rs 101 are defined in (i) or (ii).

21. The compound according to any one of claims 18-20 or a pharmaceutically acceptable salt thereof, wherein R 10 is hydrogen, halogen, OH or C 1-4 alkoxy optionally substituted with 1-3 Fs, or R 10 is an optionally substituted 5- or 6-membered monocyclic heterocycle having 1 or 2 ring heteroatoms, where each ring heteroatom is independently nitrogen, oxygen or sulfur, such as morpholine, 22. The compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein R 1 is 23. The compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein R 3 is OH.

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-23, characterized in that Has a structure according to formula A-3:

25. A compound selected from the following table, its stereoisomers, its deuterated analogs or its pharmaceutically acceptable salts:

26. The said compound: Or its pharmaceutically acceptable salt.

27. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26 and a pharmaceutically acceptable excipient.

28. A method for inhibiting carbonic anhydrase in vitro or in vivo, which comprises contacting the carbonic anhydrase with an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26.

29. A method for treating a carbonic anhydrase-mediated disease or condition in a mammal (e.g., a human), which comprises administering to the mammal the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-26.

30. The method according to claim 29, which further comprises administering one or more additional therapeutic agents.

31. The method according to claim 30, wherein the one or more additional therapeutic agents are antihistamines, steroids, decongestants, bronchodilators, mast cell stabilizers, leukotriene regulators, prostaglandin antagonists, blocking / neutralizing antibodies and / or immunotherapy.

32. The method according to claim 31, wherein the one or more additional therapeutic agents are antihistamines.

33. The method according to claim 32, wherein the antihistamine is acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine (Zyrtec; metabolite of hydroxyzine, prodrug thereof), chlorpromazine, cimetidine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, diphenhydramine (Benadryl), ebastine, embramine, famotidine, fexofenadine (Allegra), hydroxyzine (Vistaril), lafutidine, levocetirizine, loratadine (Claritin), nizatidine, olopatadine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, ranitidine, roxatidine, rupatadine, tiotidine, tripelennamine or triprolidine.

34. The method according to any one of claims 29 - 33, wherein the mammal is a human, mouse, rat, dog, cat, hamster, guinea pig, rabbit or livestock.

35. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is an allergic disease, bacterial infection, fungal infection, viral infection, mastocytosis or mast cell-mediated inflammation.

36. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is an allergic disease.

37. The method according to claim 36, wherein the allergic disease is asthma (e.g., allergic bronchopulmonary aspergillosis), atopic dermatitis, contact dermatitis, chronic pruritus (pruritus), urticaria, hay fever, allergic conjunctivitis, allergic rhinitis, anaphylaxis, eosinophilic esophagitis, food allergy or allergen-induced mastocytosis.

38. The method according to claim 36, wherein the allergic disease is asthma.

39. The method according to claim 36, wherein the allergic disease is food allergy.

40. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is a bacterial infection.

41. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is a fungal infection.

42. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is a viral infection.

43. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is mastocytosis.

44. The method according to any one of claims 29 - 34, wherein the disease or condition mediated by carbonic anhydrase is mast cell-mediated inflammation.

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