Pyrazolyl sulfonamide compounds and their use in therapy

Abstract

The present invention provides pyrazolyl sulfonamide compounds, pharmaceutical compositions, and their use for inhibiting mucosa-associated lymphoid tissue lymphoma migration protein 1 (MALT1), and their use in treating diseases or conditions, such as proliferative, inflammatory, or autoimmune disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 401,490, filed August 26, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present invention provides pyrazolyl sulfonamide compounds, pharmaceutical compositions, and their use for inhibiting mucosa-associated lymphoid tissue lymphoma migration protein 1 (MALT1), and their use in treating diseases or conditions, such as proliferative, inflammatory, or autoimmune disorders. [Background technology]

[0003] Cancer remains a significant health problem despite significant research efforts and scientific advances reported in the literature to treat this disease. Solid tumors, including prostate, breast, and lung cancer, remain widely prevalent among the world's population. Current treatment options for these cancers are not effective for all patients and / or may have significant adverse side effects. Furthermore, new therapies that achieve anti-cancer effects through different mechanisms represent opportunities to treat cancer more effectively and / or to treat cancers that have become resistant to currently available pharmaceuticals.

[0004] Inflammatory disorders affect a significant number of patients and often involve situations in which a patient's biological response to a stimulus results in the immune system attacking the body's own cells or tissues. This can cause abnormal inflammation, resulting in chronic pain, redness, swelling, stiffness, and / or damage to normal tissue. Current treatment options for these inflammatory disorders are not effective for all patients and / or can have significant adverse side effects.

[0005] Human mucosa-associated lymphoid tissue protein 1 (MALT1) is a key regulator of immune responses and an immunomodulatory target for the treatment of autoimmune and inflammatory diseases. Additionally, studies have shown that inhibiting MALT1 impairs the immunosuppressive function of regulatory T cells in the tumor microenvironment, suggesting that MALT1 inhibitors enhance antitumor immunity in the treatment of solid cancers. See, for example, Isabel Hamp et al. in Expert Opinion on Therapeutic Patents (2021) vol. 12, pp. 1079-1096.

[0006] The present invention addresses the aforementioned needs and provides other related advantages as well. Summary of the Invention

[0007] The present invention provides pyrazolyl sulfonamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma migration protein 1 (MALT1), and their use in treating diseases or conditions, such as proliferative, inflammatory, or autoimmune disorders. In particular, one aspect of the present invention provides a collection of pyrazolyl sulfonamide compounds, such as compounds represented by Formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional collections of pyrazolyl sulfonamide compounds is provided in the detailed description. The compound may be part of a pharmaceutical composition that includes a pharmaceutically acceptable carrier.

[0008] Another aspect of the present invention is a collection of pyrazolyl sulfonamide compounds, such as compounds represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined in the detailed description. Further description of additional collections of pyrazolyl sulfonamide compounds is provided in the detailed description. The compound may be part of a pharmaceutical composition that includes a pharmaceutically acceptable carrier.

[0009] Another aspect of the present invention provides a method of treating a MALT1-mediated disease or condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds described in Section I, as further described in the Detailed Description of the Invention, to treat the disease or condition.

[0010] Another aspect of the present invention provides a method for inhibiting the activity of MALT1, comprising contacting MALT1 with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I, to inhibit the activity of MALT1, as further described in the Detailed Description of the Invention. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention provides pyrazolyl sulfonamide compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma migration protein 1 (MALT1), and their use in treating diseases or conditions, such as proliferative, inflammatory, or autoimmune disorders. The practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. These techniques are described in, for example, Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992), Handbook of Experimental Immunology (D.M. Weir & C.C. Blackwell, eds.), Current Protocols in Molecular Biology (F.M. Ausubel et al., eds., 1987, and periodically updated), and "Current Protocols in Immunology" (J.E. Coligan et al., eds., 1991), each of which is incorporated herein by reference in its entirety.

[0012] Various aspects of the invention are described in the following sections, but an aspect of the invention described in a particular section is not limited to any particular section. Further, if a variable is not accompanied by a definition, the previous definition of that variable takes precedence.

[0013] definition The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and genera disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply whether a term is used alone or in combination with other terms, unless otherwise indicated. Thus, the definition of "alkyl" applies to "alkyl" and the "alkyl" portion of "-O-alkyl," etc. For purposes of this invention, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th In addition, general principles of organic chemistry are identified in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5 th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] The terms "aliphatic" or "aliphatic group," as used herein, refer to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "alicyclic"), and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0015] As used herein, the term "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated, or having one or more unsaturated units, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic," requiring one or more heteroatoms to be present in one or both rings of the bicyclic ring. Such heteroatoms may be present at ring junctions, are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a single atom or valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups described below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: [ka]

[0016] Exemplary bridged bicyclic compounds include: [ka]

[0017] The term "lower alkyl" refers to C 1-4 It refers to a straight-chain or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 It refers to a straight-chain or branched alkyl group.

[0019] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (including as in N-substituted pyrrolidinyl)).

[0020] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0021] As used herein, "divalent C 1-8 (or C 1-6 The term "saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains, which are straight or branched as defined herein.

[0022] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0023] The term "-(C alkylene)-" refers to a bond. 0-3 The term "alkylene)-" refers to a bond (i.e., C) and a -(C 1-3 alkylene)-groups.

[0024] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0025] The term "halogen" or "halo" means F, Cl, Br, or I.

[0026] The term "aryl," used alone or as part of a larger moiety, as in "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to describe the groups attached to it. For example, "phenylene" can be used interchangeably when two groups are attached to it (e.g., [ka] ), a divalent phenyl group, and "phenylene" refers to a phenylene group when three groups are attached to it (e.g., [ka] ), a trivalent phenyl group. The term "arylene" refers to a divalent aryl group.

[0027] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; groups having 6, 10, or 14 pi electrons shared in a cyclic arrangement; and groups having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-," as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups can be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0028] The term "heteroarylene" refers to a polyvalent heteroaryl group having an appropriate number of open valences to describe the groups attached to it. For example, a "heteroarylene" is a divalent heteroaryl group when two groups are attached to it, and a "heteroarylene" is a trivalent heteroaryl group when three groups are attached to it. The term "pyridinylene" refers to a polyvalent pyridine radical having an appropriate number of open valences to describe the groups attached to it. For example, "pyridinylene" is a pyridine radical when two groups are attached to it (e.g., [ka] ), a divalent pyridine radical, and "pyridinylene" refers to a pyridine radical when three groups are attached to it (e.g., [ka] ), is a trivalent pyridine radical. The term "pyrazolylene" refers to a polyvalent pyrazole radical having an appropriate number of open valences to describe the groups attached to it. For example, "pyrazolylene" is a pyrazole radical when two groups are attached to it (e.g., [ka] ), is a divalent pyrazole radical. The term "1,2,3-triazolylene" refers to a polyvalent 1,2,3-triazole radical having an appropriate number of open valences to account for the groups attached thereto. For example, "1,2,3-triazolylene" is a divalent pyrazole radical when two groups are attached thereto (e.g., [ka] ), a divalent 1,2,3-triazole radical.

[0029] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or . + It can be NR (as in N-substituted pyrrolidinyl).

[0030] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions are independently optionally substituted. The term "oxoheterocyclyl" refers to a heterocyclyl substituted by an oxo group. The term "heterocyclylene" refers to a polyvalent heterocyclyl group having the appropriate number of open valencies to describe the groups attached to it. For example, a "heterocyclylene" is a divalent heterocyclyl group when two groups are attached to it, and a "heterocyclylene" is a trivalent heterocyclyl group when three groups are attached to it.

[0031] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0032] As described herein, compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable," as used herein, refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0033] Each optional substituent on a substitutable carbon is a halogen; -(CH2) 0-4 R゜;-(CH2) 0-4 OR゜;-O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR゜;-(CH2) 0-4 CH(OR゜)2;-(CH2) 0-4 -(CH2) optionally substituted with SR°;R° 0-4 Ph; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 Ph; optionally substituted with R° -CH=CHPh; optionally substituted with R° -(CH2) 0-4 O(CH2) 0-1 -pyridyl; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R゜)2;-(CH2) 0-4 N(R゜)C(O)R゜;-N(R゜)C(S)R゜;-(CH2) 0-4 N(R゜)C(O)NR゜2; -N(R゜)C(S)NR゜2;-(CH2) 0-4N(R゜)C(O)OR゜;-N(R゜)N(R゜)C(O)R゜;-N(R゜)N(R゜)C(O)NR゜2; -N(R゜)N(R゜)C(O)OR゜;-(CH2) 0-4 C(O)R゜;-C(S)R゜;-(CH2) 0-4 C(O)OR゜;-(CH2) 0-4 C(O)SR゜; -(CH2) 0-4 C(O)OsiR゜3;-(CH2) 0-4 OC(O)R゜;-OC(O)(CH2) 0-4 SR-, SC(S)SR゜;-(CH2) 0-4 SC(O)R゜;-(CH2) 0-4 C(O)NR゜2;-C(S)NR゜2;-C(S)SR゜;-SC(S)SR゜, -(CH2) 0-4 OC(O)NR゜2;-C(O)N(OR゜)R゜;-C(O)C(O)R゜;-C(O)CH2C(O)R゜;-C(NOR゜)R゜;-(CH2) 0-4 SSR゜;-(CH2) 0-4 S(O)2R゜;-(CH2) 0-4 S(O)2OR゜;-(CH2) 0-4 OS(O)2R゜;-S(O)2NR゜2;-S(O)(NR゜)R゜;-S(O)2N=C(NR゜2)2;-(CH2) 0-4 S(O)R゜;-N(R゜)S(O)2NR゜2;-N(R゜)S(O)2R゜;-N(OR゜)R゜;-C(NH)N R゜2;-P(O)2R゜;-P(O)R゜2;-OP(O)R゜2;-OP(O)(OR゜)2;SiR゜3;-(C 1-4 Linear or branched alkylene)ON(R゜)2; or -(C 1-4 are monovalent substituents independently selected from: straight-chain or branched-chain alkylene)C(O)ON(R°)2.

[0034] Each R° is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, —CH— (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or, regardless of the above definition, two independent occurrences of R° together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from ═O and ═S; or each R° is selected from halogen, —(CH) 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OsiR ● 3. -C(O)SR ● , -(C 1-4 Straight or branched chain alkylene)C(O)OR ● , or -SSR ● is optionally substituted with a monovalent substituent independently selected from

[0035] Each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens, or the optional substituents on the saturated carbon are independently: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O- or -S(C(R * 2)) 2-3 or the divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is selected from -O(CR * 2) 2-3 O and R * Each independent occurrence of is hydrogen, C 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] R * C 1-6 If aliphatic, R * is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, wherein each R ● independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;● is unsubstituted or, when preceded by halo, substituted only with one or more halogens.

[0037] The optional substituents that can be replaced are independently -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † and each R † are independently hydrogen, C 1-6 an aliphatic, unsubstituted -Oph, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two R † independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R † But C 1-6 When it is aliphatic, R † is halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens.

[0038] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., provide a detailed description of pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and 2-hydroxy-ethanesulfonate. Examples of suitable salts include benzoate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0039] Furthermore, acids generally considered suitable for forming pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, in P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences 1977, 66(1), 1-19; P. Gould, International J. of Pharmaceutics 1986, 33, 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (on the website of the Food & Drug Administration, Washington, DC), the disclosures of which are incorporated herein by reference.

[0040] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N + (C 1-4 Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen with deuterium or tritium, or 13 C or 14 Compounds having this structure including a carbon replacement with a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the present invention.

[0042] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into their corresponding pure enantiomers (e.g., by hydrolysis). Alternatively, specific enantiomers of a compound of the present invention may be prepared by asymmetric synthesis. Furthermore, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxylic acid) functional group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation of the diastereoisomers so formed by fractional crystallization or chromatographic means known in the art, and then recovery of the pure enantiomers.

[0043] Individual stereoisomers of the compounds of the present invention may be, for example, substantially free of other isomers, or may be mixed with all or a selected number of other stereoisomers, e.g., as a racemate. The chiral center(s) in the compounds of the present invention may have either the S or R configuration, as defined by the IUPAC 1974 Recommendations. Furthermore, to the extent that the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the present invention.

[0044] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a chemical compound is referred to using both a chemical structure and a chemical name and the structure and name are ambiguous, the structure takes precedence. Also, note that any carbon and heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have a sufficient number of hydrogen atoms to satisfy the valences.

[0045] Unless otherwise specified, the term "about" refers to within ±10% of the stated value. The invention includes embodiments where a value is within ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1% of the stated value.

[0046] As used herein, the words "a" and "an" mean "one or more" and include plurals unless the context is inappropriate.

[0047] The term "alkyl" as used herein refers to C-C 12 Alkyl, C1-C 10Alkyl refers to saturated straight or branched hydrocarbons, such as straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms, referred to as C1-C6 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0048] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3 to 12, 3 to 8, 4 to 8, or 4 to 6 carbons, e.g., derived from cycloalkane, designated "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0049] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CHF, -CHF, -CF, -CHCF, -CFCF, and the like. The term "haloalkylene" refers to a divalent haloalkyl group. The term "haloalkenyl" refers to an alkenyl group substituted with at least one halogen.

[0050] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0051] The terms "alkoxyl" or "alkoxy" are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy, and the like. The term "haloalkoxyl" refers to an alkoxyl group substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCHF, -OCHF, -OCF, -OCHCF, -OCFCF, and the like. The term "hydroxyalkoxyl" refers to an alkoxyl group substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCHCHOH, -OCHC(H)(OH)CHCHOH, and the like. The term "alkoxylene" refers to a divalent alkoxyl group. The term "hydroxyalkoxyl" refers to an alkoxyl group substituted with at least one hydroxyl group. In certain embodiments, the hydroxyalkoxyl is an alkoxyl group substituted with one hydroxyl group.

[0052] The term "oxo" is art-recognized and refers to an "=O" substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0053] symbol [ka] indicates the point of attachment.

[0054] When any substituent or variable occurs more than one time in any constituent or compound of the present invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise stated.

[0055] One or more compounds of the present invention may exist in unsolvated or solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the present invention is intended to encompass both solvated and unsolvated forms. "Solvate" refers to a physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. A "hydrate" is a solvate in which the solvent molecule is HO.

[0056] As used herein, the terms "subject" and "patient" are used interchangeably and refer to an organism treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, porcine, canine, feline, etc.), and most preferably, humans.

[0057] As used herein, the term "compound" refers to a quantity of a molecule that has been weighed, tested for its structural identity, and is sufficient to have a demonstrable use (e.g., an amount that can be shown to be active in an assay, in vitro test, or in vivo test, or an amount that can be administered to a patient and provide a therapeutic benefit).

[0058] "I C 50 The term "concentration of a compound" is art-recognized and refers to the concentration of a compound needed to achieve 50% inhibition of a target.

[0059] As used herein, the term "effective amount" refers to an amount of a compound sufficient to produce a beneficial or desired result (e.g., a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications, or dosages, and is not intended to be limited to a particular formulation or route of administration.

[0060] As used herein, the term "treating" includes any effect that results in an improvement of a condition, disease, disorder, etc., e.g., alleviating, reducing, modulating, ameliorating, or eliminating, or alleviating the symptoms thereof.

[0061] As used herein, the term "pharmaceutical composition" refers to a combination of an active agent with an inert or active carrier that makes the composition particularly suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0062] As used herein, the term "pharmaceutically acceptable carrier" refers to any of the standard pharmaceutical carriers, such as phosphate buffered saline, water, emulsions (e.g., oil / water or water / oil emulsions), and various types of wetting agents. The composition may also contain stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, for example, Martin, Remington's Pharmaceutical Sciences, 15 th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0063] Throughout this specification, when compositions are described as having, including, or comprising certain components, or when processes and methods are described as having, including, or comprising certain steps, it is additionally contemplated that there are compositions of the invention that consist essentially of, or consist of, the recited components, and that there are processes and methods of the invention that consist essentially of, or consist of, the recited processing steps.

[0064] Generally, compositions specifying percentages are by weight unless otherwise specified.

[0065] I. Pyrazolyl sulfonamide compounds The present invention provides pyrazolyl sulfonamide compounds. The compounds may be used in the pharmaceutical compositions and methods of treatment described herein. Exemplary compounds are described in the following section, along with exemplary procedures for making the compounds.

[0066] Part A: One aspect of the present invention is a compound represented by formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 5-6 membered partially unsaturated heterocyclyl containing one nitrogen atom; or a 5-6 membered deuteroheteroaryl containing one nitrogen atom; and the heteroaryl, saturated heterocyclyl, and deuteroheteroaryl are each independently selected from n R6 A substituted, partially unsaturated heterocyclyl is one in which n occurrences of R 6 and one occurrence of oxo, A 2 is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 represents haloalkyl, or cyano; R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9), C 1-6 Hydroxyalkyl, -C(O)R 10 , -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3- to 7-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 4 is hydrogen, halo, C 1-4 Alkoxyl, C 1-4 alkyl, or deuterium, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 1-6 Hydroxyalkoxyl, -(q R 12 C replaced by occurrences of 3-7 cycloalkyl), -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10 , C 1-6 Hydroxyalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), -(C 1-4 Alkylene)-CN, C 2-4 Alkenyl, C 2-4 Haloalkenyl, -(C 0-4 alkylene)-(N(R 13 )(R 14 )), -(C 0-4alkylene)-(a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen), or a 6- to 7-membered saturated bicyclic heterocyclyl containing 1 nitrogen atom, and the monocyclic heterocyclyl and bicyclic heterocyclyl are each independently selected from 0, 1, or 2 R 12 ), which is replaced by occurrences of R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl, or a 4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 is replaced by an occurrence of R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 represents cycloalkyl, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 represents cycloalkyl, R 12 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, halo, hydroxyl, C 1-6 Haloalkyl, oxo, cyano, or -C(O)-(C 1-4 alkyl), or two R 12groups, together with the carbon atoms to which they are attached, form a 3- to 7-membered saturated carbocyclic ring; R 13 and R 14 are independently hydrogen or C 1-4 is alkyl, n, m, x, and y are independently 0, 1, or 2; q is 0, 1, 2, or 3.

[0067] The definitions of the variables in Formula I above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of the variable is a single chemical group selected from the chemical groups described above, (ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and (iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0068] In certain embodiments, the compound is a compound of Formula I:

[0069] As loosely defined above, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 5-6 membered partially unsaturated heterocyclyl containing one nitrogen atom; or a 5-6 membered deuteroheteroaryl containing one nitrogen atom; and the heteroaryl, saturated heterocyclyl, and deuteroheteroaryl are each independently selected from n R 6 A substituted, partially unsaturated heterocyclyl is one in which n occurrences of R 6 and one occurrence of oxo. 1is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 5-6 membered heteroaryl containing n R 6 In certain embodiments, A 1 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 6-membered heteroaryl containing n R 6 In certain embodiments, A 1 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is selected from n R 6 In certain embodiments, A 1 n R 6 In certain embodiments, A is a pyridinyl substituted with an occurrence of 1 n R 6 Replaced by occurrences of [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing one heteroatom selected from oxygen, nitrogen, and sulfur, and the heteroaryl is 6 In certain embodiments, A 1is a 9-10 membered bicyclic heteroaryl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3- to 10-membered saturated heterocyclyl containing one heteroatom independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3- to 10-membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 5-6 membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1 is a 5-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1is a 6-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1 is a 5-6 membered deuteroheteroaryl containing one nitrogen atom, and the deuteroheteroaryl is a 5-6 membered deuteroheteroaryl containing n R 6 In certain embodiments, A 1 is a 5-membered deuteroheteroaryl containing one nitrogen atom, and a deuteroheteroaryl is a 5-membered deuteroheteroaryl containing n R 6 In certain embodiments, A 1 is a 6-membered deuteroheteroaryl containing one nitrogen atom, and a deuteroheteroaryl is a 6-membered deuteroheteroaryl containing n R 6 In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0070] As loosely defined above, A 2 is pyrazolylene or 1,2,3-triazolylene. 2 is pyrazolylene. In certain embodiments, A 2 is 1,2,3-triazolylene. In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0071] As loosely defined above, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 is selected from the groups depicted in the compounds of Table 1 below.

[0072] As loosely defined above, A 4 is a 6-membered aromatic ring containing one nitrogen atom. 4is selected from the groups depicted in the compounds of Table 1 below.

[0073] As loosely defined above, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 In certain embodiments, R 1 is halo. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C4 alkyl. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0074] As loosely defined above, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C4 alkyl. In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C4 hydroxyalkyl. In certain embodiments, R 2 is -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0075] As loosely defined above, R 5 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or C 1-4 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5is C4 alkyl. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is -CHF. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 1-6 In certain embodiments, R 5 is —CH2CH2OCH3. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is a C3 deuteroalkyl. In certain embodiments, R 5 is a C4 deuteroalkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0076] As loosely defined above, R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4Alkynyl, -N(R 8 )(R 9 ), C 1-6 Hydroxyalkyl, -C(O)R 10 , -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is C 1-6 In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C4 alkyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is methoxy. In certain embodiments, R 3 is C alkoxyl. In certain embodiments, R 3 is C alkoxyl. In certain embodiments, R 3 is C4 alkoxyl. In certain embodiments, R 3 is C5 alkoxyl. In certain embodiments, R 3 is C6 alkoxyl. In certain embodiments, R 3 is halo. In certain embodiments, R 3is hydroxyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 -OC 3-7 In certain embodiments, R 3 is -(C 0-4 In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is -N(R 8 )(R 9 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C hydroxyalkyl. In certain embodiments, R 3 is C hydroxyalkyl. In certain embodiments, R 3 is —CH(CH)OH. In certain embodiments, R 3is C hydroxyalkyl. In certain embodiments, R 3 is C4 hydroxyalkyl. In certain embodiments, R 3 is C5 hydroxyalkyl. In certain embodiments, R 3 is C6 hydroxyalkyl. In certain embodiments, R 3 is -C(O)R 10 In certain embodiments, R 3 is —C(O)CH. In certain embodiments, R 3 is CO2R 10 In certain embodiments, R 3 is -C(O)N(R 8 )(R 9 In certain embodiments, R 3 is -N(R 8 )C(O)R 10 In certain embodiments, R 3 is -S(O2)R 10 In certain embodiments, R 3 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing one heteroatom selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is selected from the groups depicted in the compounds of Table 1 below.

[0077] As loosely defined above, R 4 is hydrogen, halo, C 1-4 Alkoxyl, C 1-4 alkyl, or deuterium. In certain embodiments, R 4is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C4 alkoxyl. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C4 alkyl. In certain embodiments, R 4 is deuterium. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0078] As loosely defined above, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 1-6 Hydroxyalkoxyl, -(q R 12 C replaced by occurrences of 3-7 cycloalkyl), -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10 , C 1-6 Hydroxyalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), -(C 1-4 Alkylene)-CN, C 2-4 Alkenyl, C 2-4 Haloalkenyl, -(C 0-4 alkylene)-(N(R 13 )(R 14 )), -(C 0-4 alkylene)-(a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen), or a 6- to 7-membered saturated bicyclic heterocyclyl containing 1 nitrogen atom, and the monocyclic heterocyclyl and bicyclic heterocyclyl are each independently selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is methyl. In certain embodiments, R 6is C alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 is C4 alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 Let q be the number of R 12 C replaced by occurrences of 3-7 In certain embodiments, R 6 is C 3-7 In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is halo. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 C is substituted with 0, 1, or 2 occurrences of hydroxyl 1-6 In certain embodiments, R 6 is substituted with one occurrence of hydroxyl C 1-6 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C4 alkoxyl. In certain embodiments, R 6 is C5 alkoxyl. In certain embodiments, R 6 is C6 alkoxyl. In certain embodiments, R 6 -OC 3-7In certain embodiments, R 6 is -N(R 8 )(R 9 In certain embodiments, R 6 is -C(O)R 7 In certain embodiments, R 6 is -C(O)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )C(O)R 10 In certain embodiments, R 6 is -S(O2)R 10 In certain embodiments, R 6 is -S(O2)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )S(O2)R 10 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is C hydroxyalkyl. In certain embodiments, R 6 is C hydroxyalkyl. In certain embodiments, R 6 is C hydroxyalkyl. In certain embodiments, R 6 is C4 hydroxyalkyl. In certain embodiments, R 6 is C5 hydroxyalkyl. In certain embodiments, R 6 is C6 hydroxyalkyl. In certain embodiments, R 6 is -(C 1-4 alkylene)-(C 1-6 In certain embodiments, R 6 is -(C 1-4 alkylene)-CN.

[0079] In certain embodiments, R 6 is replaced by 0 or 1 occurrence of halo2-4 In certain embodiments, R is alkenyl. 6 is C 2-4 In certain embodiments, R is alkenyl. 6 is C 2-4 In certain embodiments, R 6 is a C substituted with one occurrence of fluoro 2-4 In certain embodiments, R is alkenyl. 6 is -(C 0-4 alkylene)-(N(R 13 )(R 14 In certain embodiments, R 6 is -(N(R 13 )(R 14 )). In certain embodiments, R 6 is -(C1 alkylene)-(N(R 13 )(R 14 )). In certain embodiments, R 6 is -(C2 alkylene)-(N(R 13 )(R 14 )). In certain embodiments, R 6 is -(C3 alkylene)-(N(R 13 )(R 14 )). In certain embodiments, R 6 is -(C4 alkylene)-(N(R 13 )(R 14 )). In certain embodiments, R 6 is -(C 0-4 alkylene)-(0, 1, or 2 R 12 In certain embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, substituted with occurrences of 6 is -(C1 alkylene)-(0, 1, or 2 R 12 In certain embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, substituted with occurrences of 6is -(C2 alkylene)-(0, 1, or 2 R 12 In certain embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, substituted with occurrences of 6 is -(C alkylene)-(0, 1, or 2 R 12 In certain embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, substituted with occurrences of 6 is -(C4 alkylene)-(0, 1, or 2 R 12 In certain embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, substituted with occurrences of 6 is a 3- to 7-membered saturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 3- to 7-membered saturated monocyclic heterocyclyl containing one heteroatom independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 3- to 7-membered saturated monocyclic heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 3- to 7-membered partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6is a 3- to 7-membered partially unsaturated monocyclic heterocyclyl containing one heteroatom independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 3- to 7-membered partially unsaturated monocyclic heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 4-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 5-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 6-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 6-7 membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 6-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is selected from the group consisting of 0, 1, or 2 R 12 In certain embodiments, R 6 is a 6-membered saturated bicyclic heterocyclyl containing one nitrogen atom. In certain embodiments, R 6 is a 6-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is a 6-membered saturated bicyclic heterocyclyl containing one R12 In certain embodiments, R 6 is a 6-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is a heterocyclic ring system having two R 12 In certain embodiments, R 6 is a 7-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is selected from 0, 1, or 2 R 12 In certain embodiments, R 6 is a 7-membered saturated bicyclic heterocyclyl containing one nitrogen atom. In certain embodiments, R 6 is a 7-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is a 7-membered saturated bicyclic heterocyclyl containing one R 12 In certain embodiments, R 6 is a 7-membered saturated bicyclic heterocyclyl containing one nitrogen atom, and the bicyclic heterocyclyl is a heterocyclic ring system having two R 12 In certain embodiments, R 6 is —C(CH)OCH. In certain embodiments, R 6 is —CH(CH)OCH. In certain embodiments, R 6 is —CHOH. In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 1 below.

[0080] As loosely defined above, R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7cycloalkyl or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is —OH. In certain embodiments, R 7 is -O-(C 1-6 In certain embodiments, R 7 -OC 3-7 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 4-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 5-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 1 below.

[0081] As loosely defined above, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, or C 3-7 cycloalkyl or R 8 and R 9together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is hydrogen. In certain embodiments, R 8 is C 1-6 In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C4 alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C 1-6 In certain embodiments, R 8 is C hydroxyalkyl. In certain embodiments, R 8 is C hydroxyalkyl. In certain embodiments, R 8 is C hydroxyalkyl. In certain embodiments, R 8 is C4 hydroxyalkyl. In certain embodiments, R 8 is C5 hydroxyalkyl. In certain embodiments, R 8 is C6 hydroxyalkyl. In certain embodiments, R 8 is C 3-7 In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C4 alkyl. In certain embodiments, R 9is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C hydroxyalkyl. In certain embodiments, R 9 is C hydroxyalkyl. In certain embodiments, R 9 is C hydroxyalkyl. In certain embodiments, R 9 is C4 hydroxyalkyl. In certain embodiments, R 9 is C5 hydroxyalkyl. In certain embodiments, R 9 is C6 hydroxyalkyl. In certain embodiments, R 9 is C 3-7 In certain embodiments, R 8 and R 9 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 1 below.

[0082] As loosely defined above, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is C 1-6 In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C4 alkyl. In certain embodiments, R 10is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 -C 3-7 In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 1 below.

[0083] As loosely defined above, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 In certain embodiments, R 11 represents independently at each occurrence halo. In certain embodiments, R 11 represents independently at each occurrence fluoro. 11 represents independently at each occurrence hydroxyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11represents independently at each occurrence C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkoxyl. In certain embodiments, R 11 represents independently at each occurrence a C alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 represents, independently at each occurrence, a C4 alkoxyl. 11 represents independently at each occurrence a C5 alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 independently for each occurrence, C 3-7 In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 1 below.

[0084] As loosely defined above, R 12 independently for each occurrence, C 1-6 Alkyl, C 1-6 Alkoxyl, halo, hydroxyl, C 1-6 Haloalkyl, oxo, cyano, or -C(O)-(C 1-4 alkyl), or two R 12Groups, taken together with the carbon atoms to which they are attached, form a 3- to 7-membered saturated carbocyclic ring. 12 independently for each occurrence, C 1-6 In certain embodiments, R 12 represents independently at each occurrence C alkyl. In certain embodiments, R 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12 represents independently at each occurrence a C alkyl. 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12 represents independently at each occurrence a C alkyl. 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12 independently for each occurrence, C 1-6 In certain embodiments, R 12 represents independently at each occurrence C alkoxyl. In certain embodiments, R 12 represents independently at each occurrence a C alkoxyl. 12 represents independently at each occurrence a C alkoxyl. 12 represents, independently at each occurrence, a C4 alkoxyl. 12 represents independently at each occurrence a C5 alkoxyl. 12 represents independently at each occurrence a C alkoxyl. 12 represents independently at each occurrence halo. In certain embodiments, R 12 represents independently at each occurrence fluoro. 12 represents independently at each occurrence hydroxyl. In certain embodiments, R 12 independently for each occurrence, C 1-6 In certain embodiments, R 12represents independently at each occurrence C haloalkyl. In certain embodiments, R 12 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 12 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 12 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 12 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 12 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 12 represents, independently at each occurrence, oxo. In certain embodiments, R 12 represents, independently at each occurrence, cyano. 12 independently for each occurrence -C(O)-(C 1-4 In certain embodiments, two R 12 The groups, taken together with the carbon atoms to which they are attached, form a 3- to 7-membered saturated carbocyclic ring. 12 The groups, taken together with the carbon atoms to which they are attached, form a three-membered saturated carbocyclic ring. 12 The groups, taken together with the carbon atoms to which they are attached, form a four-membered saturated carbocyclic ring. 12 The groups, taken together with the carbon atoms to which they are attached, form a 5-membered saturated carbocyclic ring. In certain embodiments, two R 12 The groups, taken together with the carbon atoms to which they are attached, form a 6-membered saturated carbocyclic ring. In certain embodiments, two R 12 The groups, taken together with the carbon atoms to which they are attached, form a 7-membered saturated carbocyclic ring. 12 is selected from the groups depicted in the compounds of Table 1 below.

[0085] As loosely defined above, R 13 and R 14 are independently hydrogen or C 1-4In certain embodiments, R 13 is hydrogen and R 14 is C 1-4 In certain embodiments, R 13 is hydrogen and R 14 is methyl. In certain embodiments, R 13 and R 14 is hydrogen. 13 is hydrogen. In certain embodiments, R 13 is C 1-4 In certain embodiments, R 13 is C alkyl. In certain embodiments, R 13 is C alkyl. In certain embodiments, R 13 is C alkyl. In certain embodiments, R 13 is C4 alkyl. In certain embodiments, R 14 is hydrogen. In certain embodiments, R 14 is C 1-4 In certain embodiments, R 14 is C alkyl. In certain embodiments, R 14 is C alkyl. In certain embodiments, R 14 is C alkyl. In certain embodiments, R 14 is C4 alkyl. In certain embodiments, R 13 is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 14 is selected from the groups depicted in the compounds of Table 1 below.

[0086] As broadly defined above, n, m, x, and y are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2.

[0087] As broadly defined above, q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0088] The above description describes multiple embodiments for compounds of Formula I. This patent application specifically contemplates all combinations of embodiments.

[0089] Another aspect of the present invention is a compound represented by formula I-1 [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur; and the heteroaryl and heterocyclyl are selected from n R 6 is replaced by an occurrence of A 2is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 It stands for Halorkil or Cyano, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 4 is hydrogen, halo, or C 1-4 is alkyl, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), or -N(R 8 )S(O2)R 10 represents R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl, or a 4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 is replaced by an occurrence of R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom; R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7represents cycloalkyl, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 represents cycloalkyl, y is 0, 1, or 2; n, m, and x are independently 0, 1, or 2.

[0090] The definitions of the variables in Formula I-1 above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, i) the definition of the variable is a single chemical group selected from the chemical groups described above, ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0091] In certain embodiments, the compound is of formula I-1.

[0092] As loosely defined above, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl and heterocyclyl are each independently selected from n R 6 In certain embodiments, A 1 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 6-membered heteroaryl containing n R 6 In certain embodiments, A 1 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is selected from n R 6In certain embodiments, A 1 n R 6 In certain embodiments, A is a pyridinyl substituted with an occurrence of 1 n R 6 Replaced by occurrences of [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] is.

[0093] In certain embodiments, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing one heteroatom selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing one heteroatom independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0094] As loosely defined above, A 2 is pyrazolylene or 1,2,3-triazolylene. 2 is pyrazolylene. In certain embodiments, A 2 is 1,2,3-triazolylene.

[0095] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0096] As loosely defined above, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 is selected from the groups depicted in the compounds of Table 1 below.

[0097] As loosely defined above, A 4 is a 6-membered aromatic ring containing one nitrogen atom. 4 is selected from the groups depicted in the compounds of Table 1 below.

[0098] As loosely defined above, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 In certain embodiments, R 1 is halo. In certain embodiments, R 1is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C4 alkyl. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0099] As loosely defined above, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is methyl. In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C4 alkyl. In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C4 hydroxyalkyl. In certain embodiments, R 2 is -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0100] As loosely defined above, R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C4 alkyl. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5is a C3 deuteroalkyl. In certain embodiments, R 5 is a C4 deuteroalkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0101] In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0102] As loosely defined above, R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is C 1-6 In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is C 1-6In certain embodiments, R 3 is methoxy. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 -OC 3-7 In certain embodiments, R 3 is -(C 0-4 In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is -N(R 8 )(R 9 In certain embodiments, R 3 is CO2R 10 In certain embodiments, R 3 is -C(O)N(R 8 )(R 9 In certain embodiments, R 3 is -N(R 8 )C(O)R 10 In certain embodiments, R 3 is -S(O2)R 10 In certain embodiments, R 3is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing one heteroatom selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is selected from the groups depicted in the compounds of Table 1 below.

[0103] As loosely defined above, R 4 is hydrogen, halo, or C 1-4 In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C4 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0104] As loosely defined above, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), or -N(R 8 )S(O2)R 10 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is C 3-7 In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is halo. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 -OC 3-7 In certain embodiments, R 6 is -N(R 8 )(R 9 In certain embodiments, R 6 is -C(O)R 7 In certain embodiments, R 6 is -C(O)N(R 8 )(R 9In certain embodiments, R 6 is -N(R 8 )C(O)R 10 In certain embodiments, R 6 is -S(O2)R 10 In certain embodiments, R 6 is -S(O2)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )S(O2)R 10 In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 1 below.

[0105] As loosely defined above, R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is —OH. In certain embodiments, R 7 is -O-(C 1-6 In certain embodiments, R 7 -OC 3-7 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 4-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7is a 5-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 1 below.

[0106] As loosely defined above, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is hydrogen. In certain embodiments, R 8 is C 1-6 In certain embodiments, R 8 is C 3-7 In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C 3-7 In certain embodiments, R 8 and R 9 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 1 below.

[0107] As loosely defined above, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is C 1-6 In certain embodiments, R 10 is (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 1 below.

[0108] As loosely defined above, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 In certain embodiments, R 11 independently for each occurrence represents halo. In certain embodiments, R 11 represents independently at each occurrence fluoro. 11 represents independently at each occurrence hydroxyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6In certain embodiments, R 11 represents independently at each occurrence C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkoxyl. In certain embodiments, R 11 represents independently at each occurrence a C alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 represents, independently at each occurrence, a C4 alkoxyl. 11 represents independently at each occurrence a C5 alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 independently for each occurrence, C 3-7 In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 1 below.

[0109] As broadly defined above, y is 0, 1, or 2. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below.

[0110] As broadly defined above, n, m, and x are independently 0, 1, or 2. In certain embodiments, x is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below. In certain embodiments, m is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below. In certain embodiments, x is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below.

[0111] The above description describes multiple embodiments for compounds of formula I-1. This patent application specifically contemplates all combinations of embodiments.

[0112] In certain embodiments, the compound of formula I has formula Ia [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 The definitions of x, y and x are one of the embodiments described above in relation to Formula I.

[0113] The above description describes multiple embodiments for compounds of Formula Ia. This patent application specifically contemplates all combinations of embodiments.

[0114] In certain embodiments, the compound of formula I has formula Ib or Ic [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 The definitions of x, x, and y are one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Ib, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ic, or a pharmaceutically acceptable salt thereof.

[0115] The above description describes multiple embodiments for compounds of Formula Ib and Ic. This patent application specifically contemplates all combinations of embodiments.

[0116] In certain embodiments, the compound of formula I has formula Id or Ie [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 and the definition of x is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Id, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ie, or a pharmaceutically acceptable salt thereof.

[0117] The above description describes multiple embodiments for compounds of formula Id and Ie. This patent application specifically contemplates all combinations of embodiments.

[0118] In certain embodiments, the compound of formula I has the formula If [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 3 , R 4 , R 5 , A 1 and the definition of x is one of the embodiments described above in relation to formula I.

[0119] The above description describes multiple embodiments for compounds of formula If. This patent application specifically contemplates all combinations of embodiments.

[0120] In certain embodiments, the compound of formula I has formula Ig or Ih [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 The definitions of y and y are one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Ig, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ih, or a pharmaceutically acceptable salt thereof.

[0121] The above description describes multiple embodiments for compounds of Formula Ig and Ih. This patent application specifically contemplates all combinations of embodiments.

[0122] In certain embodiments, the compound of formula I has formula Ii, Ij, Ik, or Il [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R4 , R 5 , A 1 The definitions of , and y are one of the embodiments described above in connection with Formula I. In certain embodiments, compounds of Formula I are further defined by Formula Ii, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I are further defined by Formula Ij, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I are further defined by Formula Ik, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I are further defined by Formula Il, or a pharmaceutically acceptable salt thereof.

[0123] The above description describes multiple embodiments for compounds of Formulae Ii, Ij, Ik, and Il. This patent application specifically contemplates all combinations of embodiments.

[0124] In certain embodiments, the compound of formula I has the formula Im, In, Io, or Ip [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 3 , R 4 , R 5 , and A 1 is one of the embodiments described above in connection with Formula I. In certain embodiments, the compound of Formula I is further defined by Formula Im or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula In or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Io or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I is further defined by Formula Ip or a pharmaceutically acceptable salt thereof.

[0125] The above description describes multiple embodiments for compounds of formula Im, In, Io, and Ip. This patent application specifically contemplates all combinations of embodiments.

[0126] In certain embodiments, the compound of formula I is further defined by formula Iq or a pharmaceutically acceptable salt thereof. [ka]

[0127] In certain embodiments, the compound of formula I is further defined by formula Ir, or a pharmaceutically acceptable salt thereof. [ka]

[0128] In certain embodiments, R 6 is C 1-6 Haloalkyl, -C 1-6 Hydroxyalkyl, -(C 1-4 alkylene)-CN, or a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the monocyclic heterocyclyl is defined as one R 12 In certain embodiments, R 6 is C 1-3 haloalkyl. R 6 -C 2-6 10. The compound of claim 1, wherein R is hydroxyalkyl. 6 is -(C 2-4 In certain embodiments, R 6 is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing one or two heteroatoms independently selected from oxygen and nitrogen, and the monocyclic heterocyclyl is a 3- to 7-membered saturated or partially unsaturated monocyclic heterocyclyl containing one R 12 In certain embodiments, R 6 is tetrahydrofuranyl substituted by hydroxyl.

[0129] Another aspect of the present invention is a compound represented by formula I-2 [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9- to 10-membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 3- to 10-membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the heteroaryl and saturated heterocyclyl are selected from n R 6 A substituted, partially unsaturated heterocyclyl is one in which n occurrences of R 6 and one occurrence of oxo, A 2 is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 represents haloalkyl, or cyano; R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), C 1-6 Hydroxyalkyl, -C(O)R 10 , -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 4 is hydrogen, halo, C 1-4 Alkoxyl, or C 1-4 is alkyl, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, q R 12 C replaced by occurrences of 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10, -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10 , -C 1-6 Hydroxyalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or a 3- to 7-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is selected from 0 or 1 R 12 is replaced by R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl, or a 4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 is replaced by an occurrence of R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom; R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 represents cycloalkyl, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 represents cycloalkyl, R 12 independently for each occurrence, C 1-6 Alkyl, C 1-6 represents alkoxyl, halo, or hydroxyl; n, m, x, and y are independently 0, 1, or 2; q is 0, 1, 2, or 3.

[0130] The definitions of the variables in Formula I-2 above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of the variable is a single chemical group selected from the chemical groups described above, (ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and (iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0131] In certain embodiments, the compound is of formula I-2.

[0132] As loosely defined above, A 1 is a 5- to 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9- to 10-membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 3- to 10-membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 5- to 6-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the heteroaryl and saturated heterocyclyl are selected from n R 6 A substituted, partially unsaturated heterocyclyl is one in which n occurrences of R 6 and one occurrence of oxo. 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 5-6 membered heteroaryl containing n R 6In certain embodiments, A 1 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 6-membered heteroaryl containing n R 6 In certain embodiments, A 1 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is selected from n R 6 In certain embodiments, A 1 n R 6 In certain embodiments, A is a pyridinyl substituted with an occurrence of 1 n R 6 Replaced by occurrences of [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing one heteroatom selected from oxygen, nitrogen, and sulfur, and the heteroaryl is 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 9-10 membered bicyclic heteroaryl containing n R 6 In certain embodiments, A 1is a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3- to 10-membered saturated heterocyclyl containing one heteroatom independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3- to 10-membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the saturated heterocyclyl is a 3-10 membered saturated heterocyclyl containing n R 6 In certain embodiments, A 1 is a 5-6 membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1 is a 5-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1 is a 6-membered partially unsaturated heterocyclyl containing one nitrogen atom, and the partially unsaturated heterocyclyl is 6 and one occurrence of oxo. 1 is selected from the groups depicted in the compounds of Table 1 below.

[0133] As loosely defined above, A 2 is pyrazolylene or 1,2,3-triazolylene. 2is pyrazolylene. In certain embodiments, A 2 is 1,2,3-triazolylene. In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below.

[0134] As loosely defined above, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 is selected from the groups depicted in the compounds of Table 1 below.

[0135] As loosely defined above, A 4 is a 6-membered aromatic ring containing one nitrogen atom. 4 is selected from the groups depicted in the compounds of Table 1 below.

[0136] As loosely defined above, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 In certain embodiments, R 1 is halo. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C4 alkyl. In certain embodiments, R 1 is C 1-4In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0137] As loosely defined above, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C4 alkyl. In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C4 hydroxyalkyl. In certain embodiments, R 2 is -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0138] As loosely defined above, R 5 is hydrogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or C 1-4 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C4 alkyl. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is -CHF. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is C haloalkyl. In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 1-6 In certain embodiments, R 5 is —CH2CH2OCH3. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is a C3 deuteroalkyl. In certain embodiments, R 5is a C4 deuteroalkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0139] As loosely defined above, R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), C 1-6 Hydroxyalkyl, -C(O)R 10 , -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is C 1-6 In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is ethyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C4 alkyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C alkyl. In certain embodiments, R 3 is C3-7 In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is methoxy. In certain embodiments, R 3 is C alkoxyl. In certain embodiments, R 3 is C alkoxyl. In certain embodiments, R 3 is C4 alkoxyl. In certain embodiments, R 3 is C5 alkoxyl. In certain embodiments, R 3 is C6 alkoxyl. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C haloalkyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 -OC 3-7In certain embodiments, R 3 is -(C 0-4 In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is -N(R 8 )(R 9 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C hydroxyalkyl. In certain embodiments, R 3 is C hydroxyalkyl. In certain embodiments, R 3 is —CH(CH)OH. In certain embodiments, R 3 is C hydroxyalkyl. In certain embodiments, R 3 is C4 hydroxyalkyl. In certain embodiments, R 3 is C5 hydroxyalkyl. In certain embodiments, R 3 is C6 hydroxyalkyl. In certain embodiments, R 3 is -C(O)R 10 In certain embodiments, R 3 is —C(O)CH. In certain embodiments, R 3 is CO2R 10 In certain embodiments, R 3 is -C(O)N(R 8 )(R 9 In certain embodiments, R 3 is -N(R 8 )C(O)R 10 In certain embodiments, R 3 is -S(O2)R 10 In certain embodiments, R 3is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing one heteroatom selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is selected from the groups depicted in the compounds of Table 1 below.

[0140] As loosely defined above, R 4 is hydrogen, halo, C 1-4 Alkoxyl, or C 1-4 In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C alkoxyl. In certain embodiments, R 4 is C4 alkoxyl. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C4 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0141] As loosely defined above, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, q R 12 C replaced by occurrences of 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10 , -C 1-6 Hydroxyl alkyl, -(C 1-4 alkylene)-(C 1-6 alkoxyl), or a 3- to 7-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C haloalkyl. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 is C4 alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 is C alkyl. In certain embodiments, R 6 Let q be the number of R 12 C replaced by occurrences of 3-7 In certain embodiments, R 6 is cycloalkyl. In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is halo. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C alkoxyl. In certain embodiments, R 6 is C4 alkoxyl. In certain embodiments, R 6 is C5 alkoxyl. In certain embodiments, R 6 is C6 alkoxyl. In certain embodiments, R 6 -OC 3-7In certain embodiments, R 6 is -N(R 8 )(R 9 In certain embodiments, R 6 is -C(O)R 7 In certain embodiments, R 6 is -C(O)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )C(O)R 10 In certain embodiments, R 6 is -S(O2)R 10 In certain embodiments, R 6 is -S(O2)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )S(O2)R 10 In certain embodiments, R 6 -C 1-6 In certain embodiments, R 6 is -C1 hydroxyalkyl. In certain embodiments, R 6 is -C2 hydroxyalkyl. In certain embodiments, R 6 is —C3 hydroxyalkyl. In certain embodiments, R 6 is —C4 hydroxyalkyl. In certain embodiments, R 6 is —C5 hydroxyalkyl. In certain embodiments, R 6 is —C6 hydroxyalkyl. In certain embodiments, R 6 is -(C 1-4 alkylene)-(C 1-6 In certain embodiments, R 6 is a 3- to 7-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R6 is a 3- to 7-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6 is a 3- to 7-membered saturated heterocyclyl containing one heteroatom independently selected from oxygen and nitrogen, and the heterocyclyl is selected from zero or one R 12 In certain embodiments, R 6 is a 3- to 7-membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from zero or one R 12 In certain embodiments, R 6 is a 3- to 7-membered partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6 is a 3- to 7-membered partially unsaturated heterocyclyl containing one heteroatom independently selected from oxygen and nitrogen, and the heterocyclyl is selected from zero or one R 12 In certain embodiments, R 6 is a 3- to 7-membered partially unsaturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from zero or one R 12 In certain embodiments, R 6 is a 4-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6 is a 5-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6is a 6-membered saturated or partially unsaturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, and the heterocyclyl is selected from 0 or 1 R 12 In certain embodiments, R 6 is —C(CH)OCH. In certain embodiments, R 6 is —CH(CH)OCH. In certain embodiments, R 6 is —CHOH. In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 teeth, [ka] In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 1 below.

[0142] As loosely defined above, R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is —OH. In certain embodiments, R 7 is -O-(C 1-6 In certain embodiments, R 7 -OC 3-7 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7is a 4-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 5-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 1 below.

[0143] As loosely defined above, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is hydrogen. In certain embodiments, R 8 is C 1-6 In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C4 alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C alkyl. In certain embodiments, R 8 is C 3-7 In certain embodiments, R 9is hydrogen. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C4 alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C alkyl. In certain embodiments, R 9 is C 3-7 In certain embodiments, R 8 and R 9 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 1 below.

[0144] As loosely defined above, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is C 1-6 In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C4 alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is C alkyl. In certain embodiments, R 10 is (C 0-5Alkylene)-C 3-7 In certain embodiments, R 10 -C 3-7 In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 1 below.

[0145] As loosely defined above, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 In certain embodiments, R 11 represents independently at each occurrence halo. In certain embodiments, R 11 represents independently at each occurrence fluoro. 11 represents independently at each occurrence hydroxyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 represents independently at each occurrence a C alkyl. 11 represents independently at each occurrence a C alkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 represents independently at each occurrence a C haloalkyl. In certain embodiments, R 11 independently for each occurrence, C 1-6 In certain embodiments, R 11 represents independently at each occurrence C alkoxyl. In certain embodiments, R 11 represents independently at each occurrence a C alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 represents, independently at each occurrence, a C4 alkoxyl. 11 represents independently at each occurrence a C5 alkoxyl. 11 represents independently at each occurrence a C alkoxyl. 11 independently for each occurrence, C 3-7 In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 1 below.

[0146] As loosely defined above, R 12 independently for each occurrence, C 1-6 Alkyl, C 1-6 In certain embodiments, R represents alkoxyl, halo, or hydroxyl. 12 independently for each occurrence, C 1-6 In certain embodiments, R 12 represents independently at each occurrence C alkyl. In certain embodiments, R 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12represents independently at each occurrence a C alkyl. 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12 represents independently at each occurrence a C alkyl. 12 represents independently at each occurrence a C alkyl. In certain embodiments, R 12 independently for each occurrence, C 1-6 In certain embodiments, R 12 represents independently at each occurrence C alkoxyl. In certain embodiments, R 12 represents independently at each occurrence a C alkoxyl. 12 represents independently at each occurrence a C alkoxyl. 12 represents, independently at each occurrence, a C4 alkoxyl. 12 represents independently at each occurrence a C5 alkoxyl. 12 represents independently at each occurrence a C alkoxyl. 12 represents independently at each occurrence halo. In certain embodiments, R 12 represents independently at each occurrence fluoro. 12 represents independently at each occurrence hydroxyl. In certain embodiments, R 12 is selected from the groups depicted in the compounds of Table 1 below.

[0147] As broadly defined above, n, m, x, and y are independently 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2.

[0148] As broadly defined above, q is 0, 1, 2, or 3. In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0149] The above description describes multiple embodiments for compounds of formula I-2. This patent application specifically contemplates all combinations of embodiments.

[0150] Another aspect of the present invention provides compounds represented by formula I-2.

[0151] Part B: Another aspect of the present invention is a compound represented by formula I-3 [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl and heterocyclyl are each independently selected from n R 6 is replaced by occurrences of A 2 is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 represents haloalkyl, or cyano; R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 4 is hydrogen, halo, or C 1-4 is alkyl, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), or -N(R 8 )S(O2)R 10 represents R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl, or a 4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 is replaced by an occurrence of R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom; R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 represents cycloalkyl, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 represents cycloalkyl, y is 0, 1, or 2; n, m, and x are independently 0, 1, or 2.

[0152] The definitions of the variables in Formula I-3 above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of the variable is a single chemical group selected from the chemical groups described above, (ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and (iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0153] In certain embodiments, the compound is of formula I-3.

[0154] As loosely defined above, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl and heterocyclyl are selected from n R 6In certain embodiments, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 6-membered heteroaryl containing n R 6 In certain embodiments, A 1 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is selected from n R 6 In certain embodiments, A 1 n R 6 In certain embodiments, A is a pyridinyl substituted with an occurrence of 1 n R 6 Replaced by occurrences of [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing one heteroatom selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1is a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing one heteroatom independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 1 below.

[0155] As loosely defined above, A 2 is pyrazolylene or 1,2,3-triazolylene. 2 is pyrazolylene. In certain embodiments, A 2 is 1,2,3-triazolylene.

[0156] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 1 below. As broadly defined above, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 is selected from the groups depicted in the compounds of Table 1 below.

[0157] As loosely defined above, A 4 is a 6-membered aromatic ring containing one nitrogen atom. 4 is selected from the groups depicted in the compounds of Table 1 below.

[0158] As loosely defined above, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 In certain embodiments, R 1 is halo. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C4 alkyl. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 1 below.

[0159] As loosely defined above, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 5is C 1-4 In certain embodiments, R 5 is methyl. In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C4 alkyl. In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C4 hydroxyalkyl. In certain embodiments, R 2 is -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 1 below.

[0160] As loosely defined above, R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C4 alkyl. In certain embodiments, R 5 is C 1-4In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is a C3 deuteroalkyl. In certain embodiments, R 5 is a C4 deuteroalkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0161] In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 1 below.

[0162] As loosely defined above, R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is C 1-6 In certain embodiments, R 3is ethyl. In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is methoxy. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 is C 3-7 In certain embodiments, R 3 -OC 3-7 In certain embodiments, R 3 is -(C 0-4 In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is -N(R 8 )(R 9 In certain embodiments, R 3 is CO2R 10 In certain embodiments, R 3 is -C(O)N(R 8 )(R 9 In certain embodiments, R 3 is -N(R 8 )C(O)R 10In certain embodiments, R 3 is -S(O2)R 10 In certain embodiments, R 3 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing one heteroatom selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is selected from the groups depicted in the compounds of Table 1 below.

[0163] As loosely defined above, R 4 is hydrogen, halo, or C 1-4 In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C4 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 1 below.

[0164] As loosely defined above, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), or -N(R 8 )S(O2)R 10 In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is C 3-7 In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is halo. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 -OC 3-7 In certain embodiments, R 6 is -N(R 8 )(R 9 In certain embodiments, R 6 is -C(O)R 7In certain embodiments, R 6 is -C(O)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )C(O)R 10 In certain embodiments, R 6 is -S(O2)R 10 In certain embodiments, R 6 is -S(O2)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )S(O2)R 10 In certain embodiments, R 6 is selected from the groups depicted in the compounds of Table 1 below.

[0165] As loosely defined above, R 7 -OH, -O-(C 1-6 alkyl), or -OC 3-7 In certain embodiments, R 7 is —OH. In certain embodiments, R 7 is -O-(C 1-6 In certain embodiments, R 7 -OC 3-7 In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 1 below.

[0166] As loosely defined above, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is hydrogen. In certain embodiments, R 8is C 1-6 In certain embodiments, R 8 is C 3-7 In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C 3-7 In certain embodiments, R 8 and R 9 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is selected from the groups depicted in the compounds of Table 1 below. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 1 below.

[0167] As loosely defined above, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is C 1-6 In certain embodiments, R 10 is (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 1 below.

[0168] As broadly defined above, y is 0, 1, or 2. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below.

[0169] As broadly defined above, n, m, and x are independently 0, 1, or 2. In certain embodiments, n and x are independently 0, 1, or 2. In certain embodiments, x is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below. In certain embodiments, m is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below. In certain embodiments, x is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below.

[0170] The above description describes multiple embodiments for compounds of formula I-3. This patent application specifically contemplates all combinations of embodiments.

[0171] In certain embodiments, the compound is a compound of formula I-4 [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl and heterocyclyl are selected from n R 6 is replaced by an occurrence of A 2 is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 It stands for Halorkil or Cyano, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 4is hydrogen, halo, or C 1-4 is alkyl, R 6 , independently for each occurrence, halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), or -N(R 8 )S(O2)R 10 represents R 7 -OH, -O-(C 1-6 alkyl), or -OC 3-7 is cycloalkyl, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom; R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 represents cycloalkyl, y is 0, 1, or 2; n and x are independently 0, 1, or 2.

[0172] The above description describes multiple embodiments for compounds of formula I-4. This patent application specifically contemplates all combinations of embodiments.

[0173] In certain embodiments, the compound of formula I-4 has formula Ia-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 , x, and y are one of the embodiments described above in connection with formula I-4.

[0174] The above description describes multiple embodiments for compounds of formula Ia-4. This patent application specifically contemplates all combinations of embodiments.

[0175] In certain embodiments, the compound of formula I-4 has formula Ib-4 or Ic-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 The definitions of x, x, and y are one of the embodiments described above in connection with Formula I-4. In certain embodiments, the compound of Formula I-4 is further defined by Formula Ib-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I-4 is further defined by Formula Ic-4, or a pharmaceutically acceptable salt thereof.

[0176] The above description describes multiple embodiments for compounds of formula Ia-4 and Ib-4. This patent application specifically contemplates all combinations of embodiments.

[0177] In certain embodiments, the compound of formula I-4 is Id-4 or Ie-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 and the definition of x is one of the embodiments described above in connection with formula I-4. In certain embodiments, the compound of formula I-4 is further defined by formula Id-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula I-4 is further defined by formula Ie-4, or a pharmaceutically acceptable salt thereof.

[0178] The above description describes multiple embodiments for compounds of formula Id-4 and Ie-4. This patent application specifically contemplates all combinations of embodiments.

[0179] In certain embodiments, the compound of formula I-4 has the formula If-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 3 , R 4 , R 5 , A 1 and the definition of x is one of the embodiments described above in relation to formula I-4.

[0180] The above description describes multiple embodiments for compounds of formula If-4. This patent application specifically contemplates all combinations of embodiments.

[0181] In certain embodiments, the compound of formula I-4 is Ig-4 or Ih-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 and the definition of y is one of the embodiments described above in connection with formula I-4. In certain embodiments, the compound of formula I-4 is further defined by formula Ig-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of formula I-4 is further defined by formula Ih-4, or a pharmaceutically acceptable salt thereof.

[0182] The above description describes multiple embodiments for compounds of formula Ig-4 and Ih-4. This patent application specifically contemplates all combinations of embodiments.

[0183] In certain embodiments, the compound of formula I-4 has formula Ii-4, Ij-4, Ik-4, or Il-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 2 , R 3 , R 4 , R 5 , A 1 and y are one of the embodiments described above in connection with Formula I-4. In certain embodiments, compounds of Formula I-4 are further defined by Formula Ii-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I-4 are further defined by Formula Ij-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I-4 are further defined by Formula Ik-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, compounds of Formula I-4 are further defined by Formula Il-4, or a pharmaceutically acceptable salt thereof.

[0184] The above description describes multiple embodiments for compounds of formula Ii-4, Ij-4, Ik-4, and Il-4. This patent application specifically contemplates all combinations of embodiments.

[0185] In certain embodiments, the compound of formula I-4 has the formula Im-4, In-4, Io-4, or Ip-4 [ka] or a pharmaceutically acceptable salt thereof. In certain embodiments, the variable R 1 , R 3 , R 4 , R 5 , and A 1 is one of the embodiments described above in connection with Formula I-1. In certain embodiments, the compound of Formula I-4 is further defined by Formula Im-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I-4 is further defined by Formula In-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I-4 is further defined by Formula Io-4, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound of Formula I-4 is further defined by Formula Ip-4, or a pharmaceutically acceptable salt thereof.

[0186] The above description describes multiple embodiments for compounds of formula Im-4, In-4, Io-4, and Ip-4. This patent application specifically contemplates all combinations of embodiments.

[0187] Part C: Another aspect of the present invention provides a compound in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 1 below. In certain embodiments, the compound is any one of compounds I-1 to I-90 in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-1 to I-90 in Table 1 below. In certain embodiments, the compound is any one of compounds I-91 to I-485 in Table 1 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds I-91 to I-485 in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

[0188] In certain embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0189] Part D: Another aspect of the present invention is a compound represented by formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl and heterocyclyl are each independently selected from n R 6 is replaced by an occurrence of A 2 is pyrazolylene or 1,2,3-triazolylene, A 3 teeth, [ka] and A 4 is a six-membered aromatic ring containing one nitrogen atom, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 represents haloalkyl, or cyano; R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 ) and R 5 is hydrogen, C1-4 Alkyl, or C 1-4 is a deuteroalkyl; R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6 Deuteroalkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , or -S(O2)R 10 represents R 4 is hydrogen, halo, or C 1-4 is alkyl, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C 1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo; R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7 cycloalkyl, or a 4- to 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 is replaced by an occurrence of R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom; R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 represents cycloalkyl, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 represents cycloalkyl, y is 0, 1, or 2; n, m, and x are independently 0, 1, or 2.

[0190] The definitions of the variables in Formula II above encompass multiple chemical groups. The present application contemplates embodiments in which, for example, (i) the definition of the variable is a single chemical group selected from the chemical groups described above, (ii) the definition of the variable is a collection of two or more chemical groups selected from the chemical groups described above, and (iii) the compound is defined by a combination of the variables defined by (i) or (ii).

[0191] In certain embodiments, the compound is a compound of formula II.

[0192] As loosely defined above, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl and heterocyclyl are selected from n R 6 In certain embodiments, A 1 is a 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is a 6-membered heteroaryl containing n R 6 In certain embodiments, A 1 is pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, each of which is selected from n R 6 In certain embodiments, A 1 n R 6 In certain embodiments, A is a pyridinyl substituted with an occurrence of 1 n R 6 Replaced by occurrences of [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] In certain embodiments, A 1 teeth, [ka] is.

[0193] In certain embodiments, A 1 is a 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, or a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heteroaryl is selected from n R 6 In certain embodiments, A 1 is a 5-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heteroaryl is selected from n R 6 In certain embodiments, A 1is a 9-10 membered bicyclic heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing one heteroatom selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 9-10 membered bicyclic heteroaryl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur. 1 is a 3-10 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing one heteroatom independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is a 3-10 membered saturated heterocyclyl containing three heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is a heterocyclyl having n R 6 In certain embodiments, A 1 is selected from the groups depicted in the compounds of Table 2 below.

[0194] As loosely defined above, A 2 is pyrazolylene or 1,2,3-triazolylene. 2 is pyrazolylene. In certain embodiments, A 2is 1,2,3-triazolylene.

[0195] In certain embodiments, A 2 teeth, [ka] In certain embodiments, A 2 teeth, [ka] is.

[0196] In certain embodiments, A 2 is selected from the groups depicted in the compounds of Table 2 below.

[0197] As loosely defined above, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 teeth, [ka] is.

[0198] In certain embodiments, A 3 teeth, [ka] In certain embodiments, A 3 is selected from the groups depicted in the compounds of Table 2 below.

[0199] As loosely defined above, A 4 is a 6-membered aromatic ring containing one nitrogen atom. 4 is selected from the groups depicted in the compounds of Table 2 below.

[0200] As loosely defined above, R 1 independently for each occurrence, halo, C 1-4 Alkyl, C 1-4 In certain embodiments, R 1 is halo. In certain embodiments, R 1 is F. In certain embodiments, R 1 is Cl. In certain embodiments, R 1 is Br. In certain embodiments, R 1 is I. In certain embodiments, R 1 is C 1-4 In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C alkyl. In certain embodiments, R 1 is C4 alkyl. In certain embodiments, R 1 is C 1-4In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is C haloalkyl. In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is selected from the groups depicted in the compounds of Table 2 below.

[0201] As loosely defined above, R 2 is hydrogen, C 1-4 Alkyl, C 2-4 hydroxyalkyl, or -(C 1-6 alkylene)-N(R 8 )(R 9 In certain embodiments, R 2 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is methyl. In certain embodiments, R 2 is C 1-4 In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C alkyl. In certain embodiments, R 2 is C4 alkyl. In certain embodiments, R 2 is C 2-4 In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C hydroxyalkyl. In certain embodiments, R 2 is C4 hydroxyalkyl. In certain embodiments, R 2 is -(C 1-6 alkylene)-N(R8 )(R 9 In certain embodiments, R 2 is selected from the groups depicted in the compounds of Table 2 below.

[0202] As loosely defined above, R 5 is hydrogen, C 1-4 Alkyl, or C 1-4 In certain embodiments, R 5 is hydrogen. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C alkyl. In certain embodiments, R 5 is C4 alkyl. In certain embodiments, R 5 is C 1-4 In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is C deuteroalkyl. In certain embodiments, R 5 is a C3 deuteroalkyl. In certain embodiments, R 5 is a C4 deuteroalkyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 2 below.

[0203] In certain embodiments, R 5 is selected from the groups depicted in the compounds of Table 2 below.

[0204] As loosely defined above, R 3 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuteroalkyl, C 1-6 Alkoxyl, C 1-6Deuteroalkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, -(C 0-4 Alkylene)-CN, Cyano, C 2-4 Alkynyl, -N(R 8 )(R 9 ), -CO2R 10 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , or -S(O2)R 10 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is ethyl. In certain embodiments, C 3-7 In certain embodiments, R 3 is cyclopropyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is methoxy. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 is C 1-6 In certain embodiments, R 3 -OC 3-7 In certain embodiments, R 3 is -(C 0-4 In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is C 2-4 In certain embodiments, R 3 is -N(R 8 )(R9 In certain embodiments, R 3 is CO2R 10 In certain embodiments, R 3 is -C(O)N(R 8 )(R 9 In certain embodiments, R 3 is -N(R 8 )C(O)R 10 In certain embodiments, R 3 is -S(O2)R 10 In certain embodiments, R 3 is selected from the groups depicted in the compounds of Table 2 below.

[0205] As loosely defined above, R 4 is hydrogen, halo, or C 1-4 In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is halo. In certain embodiments, R 4 is F. In certain embodiments, R 4 is Cl. In certain embodiments, R 4 is Br. In certain embodiments, R 4 is I. In certain embodiments, R 4 is C 1-4 In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C alkyl. In certain embodiments, R 4 is C4 alkyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds of Table 2 below.

[0206] As loosely defined above, R 6 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, Cyano, C1-6 Alkoxyl, C 3-7 Cycloalkyl, -OC 3-7 Cycloalkyl, C 3-7 Halocycloalkyl, C 3-7 Hydroxycycloalkyl, -N(R 8 )(R 9 ), -C(O)R 7 , -C(O)N(R 8 )(R 9 ), -N(R 8 )C(O)R 10 , -S(O2)R 10 , -S(O2)N(R 8 )(R 9 ), -N(R 8 )S(O2)R 10 or a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 6 is C 1-6 In certain embodiments, R 6 is —CF. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 is methyl. In certain embodiments, R 6 is C 3-7 In certain embodiments, R 6 is cyclopropyl. In certain embodiments, R 6 is halo. In certain embodiments, R 6 is hydroxyl. In certain embodiments, R 6 is cyano. In certain embodiments, R 6 is C 1-6 In certain embodiments, R 6 -OC 3-7 In certain embodiments, R 6 is C 3-7 In certain embodiments, R 6 is C3-7 In certain embodiments, R 6 is -N(R 8 )(R 9 In certain embodiments, R 6 is -C(O)R 7 In certain embodiments, R 6 is -C(O)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )C(O)R 10 In certain embodiments, R 6 is -S(O2)R 10 In certain embodiments, R 6 is -S(O2)N(R 8 )(R 9 In certain embodiments, R 6 is -N(R 8 )S(O2)R 10 In certain embodiments, R 3 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing one heteroatom selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 3 is a 3-7 membered saturated heterocyclyl containing two heteroatoms independently selected from oxygen and nitrogen, wherein the heterocyclyl is substituted with 0 or 1 halo. 6 is selected from the groups depicted in the compounds of Table 2 below.

[0207] As loosely defined above, R 7 -OH, -O-(C 1-6 alkyl), -OC 3-7cycloalkyl or a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is —OH. In certain embodiments, R 7 is -O-(C 1-6 In certain embodiments, R 7 -OC 3-7 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen, and sulfur, and the heterocyclyl is selected from m R 11 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing one heteroatom selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is 11 In certain embodiments, R 7 is a 4-6 membered saturated heterocyclyl containing two heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is a 4-6 membered saturated heterocyclyl containing m R 11 In certain embodiments, R 7 is selected from the groups depicted in the compounds of Table 2 below.

[0208] As loosely defined above, R 8 and R 9 are independently hydrogen, C 1-6 Alkyl or C 3-7 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is hydrogen. In certain embodiments, R 8 is C 1-6 In certain embodiments, R 8 is C 3-7In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is C 1-6 In certain embodiments, R 9 is C 3-7 In certain embodiments, R 8 and R 9 together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring containing one nitrogen atom. 8 is selected from the groups depicted in the compounds of Table 2 below. In certain embodiments, R 9 is selected from the groups depicted in the compounds of Table 2 below.

[0209] As loosely defined above, R 10 independently for each occurrence, C 1-6 Alkyl or (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is C 1-6 In certain embodiments, R 10 is (C 0-5 Alkylene)-C 3-7 In certain embodiments, R 10 is selected from the groups depicted in the compounds of Table 2 below.

[0210] As loosely defined above, R 11 independently for each occurrence halo, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxyl, or C 3-7 In certain embodiments, R 11 is halo. In certain embodiments, R 11 is F. In certain embodiments, R 11 is Cl. In certain embodiments, R 11 is Br. In certain embodiments, R11 is I. In certain embodiments, R 11 is hydroxyl. In certain embodiments, R 11 is C 1-6 In certain embodiments, R 11 is C alkyl. In certain embodiments, R 11 is C alkyl. In certain embodiments, R 11 is C alkyl. In certain embodiments, R 11 is C4 alkyl. In certain embodiments, R 11 is C alkyl. In certain embodiments, R 11 is C alkyl. In certain embodiments, R 11 is C 1-6 In certain embodiments, R 11 is C 1-6 In certain embodiments, R 11 is C 3-7 In certain embodiments, R 11 is selected from the groups depicted in the compounds of Table 2 below.

[0211] As broadly defined above, y is 0, 1, or 2. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is selected from the corresponding values ​​in the groups depicted for the compounds in Table 2 below.

[0212] As broadly defined above, n, m, and x are independently 0, 1, or 2. In certain embodiments, n and x are independently 0, 1, or 2. In certain embodiments, n and x are independently 0, 1, or 2. In certain embodiments, x is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is selected from the corresponding values ​​in the groups depicted for the compounds in Table 2 below. In certain embodiments, m is selected from the corresponding values ​​in the groups depicted for the compounds in Table 1 below. In certain embodiments, x is selected from the corresponding values ​​in the groups depicted for the compounds in Table 2 below.

[0213] The above description describes multiple embodiments for compounds of Formula II. This patent application specifically contemplates all combinations of embodiments.

[0214] Part E: Another aspect of the present invention provides a compound in Table 2 below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound in Table 2. In certain embodiments, the compound is any one of compounds II-1 to II-20 in Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is any one of compounds II-1 to II-20 in Table 2. In certain embodiments, the compound is compound II-21 in Table 2, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is compound II-21 in Table 2. [Table 2-1] [Table 2-2] [Table 2-3]

[0215] Methods for preparing the compounds described herein are illustrated in the following synthetic schemes. The schemes are provided for the purpose of illustrating the invention and are not intended to limit the scope or spirit of the invention. Starting materials shown in the schemes can be obtained from commercial sources or prepared based on literature procedures.

[0216] In the schemes, it is understood by one skilled in the art of organic synthesis that the functional groups present on various portions of the molecule must be compatible with the reagents and reactions proposed. Substituents incompatible with the reaction conditions will be apparent to one skilled in the art, and alternative methods (e.g., use of protecting groups or alternative reactions) are suggested accordingly. Protecting group chemistry and strategies are described, for example, in Protecting Groups in Organic Synthesis, 3 rd Edition, TW Greene and PGMWuts, John Wiley & Sons, 1999 and Greene's Protective Groups in Organic Synthesis, 5 th Ed., (Peter G.M.Wuts, John Wiley & Sons: 2014), both of which are incorporated herein by reference in their entireties.

[0217] The synthetic route illustrated in Scheme 1 is a basic method for preparing pyrazolylsulfonamides C. Reaction of pyrazolylsulfonyl chloride A with amine B provides pyrazolylsulfonamide C. [ka]

[0218] The modular synthetic route illustrated in Scheme 1 can be adapted to provide additional pyridinyl sulfonamide compounds by performing functional group transformations on intermediate and final compounds. Such functional group transformations are described, for example, in Comprehensive Organic Synthesis (B.M. Trost & I. Fleming, eds., 1991-1992), Organic Synthesis, 3 rd Ed. (Michael B. Smith, Wavefunction, Inc., Irvine: 2010), Modern Methods of Organic Synthesis, 4 th Ed. (William Carruthers and Iain Coldham, Cambridge University Press, Cambridge: 2004), March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 8 th Ed., (Michael B. Smith, John Wiley&Sons, New York: 2020), and Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3 rd Ed. (Richard C. Larock, ed., John Wiley & Sons, New York: 2018), and are well known in the art.

[0219] II. Therapeutic Uses of Pyrazolyl Sulfonamide Compounds The compounds described herein are useful for treating diseases or conditions mediated by MALT1. Exemplary diseases or conditions mediated by MALT1 include proliferative disorders (e.g., cancer, neoplasms), inflammatory disorders (e.g., chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders), autoimmune disorders, fibrotic disorders, metabolic disorders, cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyperinflammatory responses in COVID-19 infection.

[0220] Thus, one aspect of the present invention provides a method for treating a disease or condition mediated by MALT1 in a subject. The method includes administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I, to a subject in need thereof to treat the disease or condition. In certain embodiments, the compound is a compound of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or as defined by one of the above embodiments. Further description of exemplary diseases or conditions mediated by MALT1 is provided herein below.

[0221] Another aspect of the present invention provides a method for inhibiting the activity of MALT1. The method comprises contacting MALT1 with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I, to inhibit the activity of MALT1. In certain embodiments, the compound is a compound of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments.

[0222] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I) in the manufacture of a medicament. In certain embodiments, the medicament is for treating a disease or condition described herein, such as an inflammatory disorder or an allergic disorder. In certain embodiments, the compound is a compound of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or as defined by one of the above embodiments.

[0223] Another aspect of the present invention provides the use of a compound described herein (such as a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein. In certain embodiments, the compound is a compound of Formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments.

[0224] In certain embodiments, the subject is a human. In certain embodiments, the subject is an adult. In certain embodiments, the subject is a child. In certain embodiments, the subject is a geriatric.

[0225] Exemplary Diseases or Conditions Exemplary diseases or conditions mediated by MALT1 include proliferative disorders (e.g., cancer, neoplasms), inflammatory disorders (e.g., chronic inflammatory disorders, acute inflammatory disorders, autoinflammatory disorders), autoimmune disorders, fibrotic disorders, metabolic disorders, cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyperinflammatory responses in COVID-19 infection.

[0226] In certain embodiments, the MALT1-mediated disease or condition is a proliferative disorder. In certain embodiments, the MALT1-mediated disease or condition is an inflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is an autoimmune disorder. In certain embodiments, the MALT1-mediated disease or condition is a fibrotic disorder. In certain embodiments, the MALT1-mediated disease or condition is a metabolic disorder. In certain embodiments, the MALT1-mediated disease or condition is a cardiovascular disorder. In certain embodiments, the MALT1-mediated disease or condition is a cerebrovascular disorder. In certain embodiments, the MALT1-mediated disease or condition is a myeloid cell-driven hyperinflammatory response in COVID-19 infection.

[0227] In certain embodiments, the MALT1-mediated disease or condition is cancer.

[0228] In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), small cell lung cancer, colon cancer, rectal cancer, and pancreatic cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, and colon cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC) and pancreatic cancer.

[0229] In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is melanoma, carcinoma, or blastoma. In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is carcinoma. In certain embodiments, the cancer is adenocarcinoma. In certain embodiments, the cancer is blastoma.

[0230] In certain embodiments, the cancer is lung cancer, pancreatic cancer, colon cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, or leukemia. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is cervical cancer. In certain embodiments, the cancer is prostate cancer. In certain embodiments, the cancer is gastric cancer. In certain embodiments, the cancer is skin cancer. In certain embodiments, the cancer is liver cancer. In certain embodiments, the cancer is bile duct cancer. In certain embodiments, the cancer is a nervous system cancer.

[0231] In certain embodiments, the cancer is lymphoma or leukemia, hi certain embodiments, the cancer is B-cell lymphoma or chronic myelocytic leukemia.

[0232] In certain embodiments, the cancer is breast adenocarcinoma, lung adenocarcinoma, pancreatic adenocarcinoma, cervical adenocarcinoma, colorectal adenocarcinoma, prostate adenocarcinoma, gastric adenocarcinoma, melanoma, lung squamous cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, glioblastoma, or neuroblastoma. In certain embodiments, the cancer is breast adenocarcinoma. In certain embodiments, the cancer is lung adenocarcinoma. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is cervical adenocarcinoma. In certain embodiments, the cancer is prostate adenocarcinoma. In certain embodiments, the cancer is gastric adenocarcinoma.

[0233] In certain embodiments, the cancer is melanoma.

[0234] In certain embodiments, the cancer is lung squamous cell carcinoma, hepatocellular carcinoma, or cholangiocarcinoma. In certain embodiments, the cancer is lung squamous cell carcinoma. In certain embodiments, the cancer is hepatocellular carcinoma. In certain embodiments, the cancer is cholangiocarcinoma.

[0235] In certain embodiments, the cancer is glioblastoma or neuroblastoma. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma.

[0236] In certain embodiments, the cancer is lung cancer, pancreatic cancer, or colon cancer. In certain embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colon cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer.

[0237] In certain embodiments, the cancer is selected from the group consisting of leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors, such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma). otheliosarcoma), synovium, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung carcinoma, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0238] In certain embodiments, the MALT1-mediated disease or condition is Hodgkin's lymphoma, non-Hodgkin's lymphoma, Burkitt's lymphoma, diffuse large B-cell lymphoma (DLBCL), MALT lymphoma, germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL), primary mediastinal B-cell lymphoma (PMBL), or activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL).

[0239] In certain embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0240] In certain embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I—pilocytic astrocytoma, Grade II—low-grade astrocytoma, Grade III—anaplastic astrocytoma, or Grade IV—glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal tumor (PNET), or schwannoma. In certain embodiments, the cancer is a type more commonly found in children than adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor.

[0241] In certain embodiments, the cancer is mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, gastric cancer, gastrointestinal (stomach, colorectum, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0242] In certain embodiments, the cancer is hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, gastrointestinal / gastric (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma, or brain tumor, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0243] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube carcinoma, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0244] In certain embodiments, the cancer is renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian carcinoma carcinoma), or fallopian tube cancer; serous papillary cystadenocarcinoma or uterine serous papillary carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepato-cholangiocarcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain tumor; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; and medulloblastoma.

[0245] In certain embodiments, the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian cancer, fallopian tube cancer, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain tumor, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0246] In certain embodiments, the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube carcinoma, serous papillary cystadenocarcinoma, uterine serous papillary carcinoma (UPSC), hepatic cholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0247] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In certain embodiments, the cancer is hepatoblastoma. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is rectal cancer. In certain embodiments, the cancer is ovarian cancer or ovarian carcinoma. In certain embodiments, the cancer is ovarian epithelial carcinoma. In certain embodiments, the cancer is fallopian tube carcinoma. In certain embodiments, the cancer is papillary serous cystadenocarcinoma. In certain embodiments, the cancer is uterine serous adenocarcinoma (UPSC). In certain embodiments, the cancer is hepatocholangiocarcinoma. In certain embodiments, the cancer is soft tissue and bone synovial sarcoma. In certain embodiments, the cancer is rhabdomyosarcoma. In certain embodiments, the cancer is osteosarcoma. In certain embodiments, the cancer is anaplastic thyroid carcinoma. In certain embodiments, the cancer is adrenocortical carcinoma. In certain embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is a glioma. In certain embodiments, the cancer is a malignant peripheral nerve sheath tumor (MPNST). In certain embodiments, the cancer is a neurofibromatosis-1-associated MPNST. In certain embodiments, the cancer is Waldenstrom's macroglobulinemia. In certain embodiments, the cancer is a medulloblastoma.

[0248] In certain embodiments, the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is a Hodgkin's lymphoma. In certain embodiments, the cancer is a non-Hodgkin's lymphoma. In certain embodiments, the cancer is a Burkitt's lymphoma. In certain embodiments, the cancer is a diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the cancer is a MALT lymphoma. In certain embodiments, the cancer is a germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) or primary mediastinal B-cell lymphoma (PMBL). In certain embodiments, the cancer is an activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). In certain embodiments, the cancer is a hematological cancer.

[0249] In certain embodiments, the proliferative disease is a cancer associated with or dependent on a MALT1 fusion protein (e.g., API2-MALT1). In certain embodiments, the proliferative disease is a cancer associated with dependency on B-cell lymphoma 10 (Bcl10). In certain embodiments, the proliferative disease is a cancer associated with dependency on caspase recruitment domain-containing protein (CARD1). In certain embodiments, the proliferative disease is a cancer associated with dependency on NF-κB. In certain embodiments, the cancer is a hematological malignancy.

[0250] Additional exemplary cancers include acoustic neuroma; adenocarcinoma; adrenal carcinoma; anal carcinoma; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendothelial sarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary carcinoma, cancer, medullary carcinoma of the breast, triple-negative breast cancer (TNBC); brain tumors (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue carcinoma; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., , uterine cancer, uterine sarcoma); esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell carcinoma; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); Hemangioblastoma; Hypopharyngeal carcinoma; Inflammatory myofibroblastic tumor; Immune cell amyloidosis; Kidney cancer (e.g., nephroblastoma, also known as Wilms' tumor, renal cell carcinoma); Liver cancer (e.g., hepatocellular carcinoma (HCC), malignant liver cancer); Lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); Leiomyosarcoma (LMS); Mastocytosis (e.g., systemic mastocytosis); Muscle carcinoma; Myelodysplastic syndrome (MDS); Mesothelioma; Myeloproliferative disorders ( MPDs) (e.g., polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (AMM), also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors);Osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian germ cell carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine (small Intestinal cancer; sweat gland carcinoma; synovial tumor; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; vulvar cancer (e.g., Paget's disease of the vulva); Burkitt's lymphoma; primary intraocular lymphoma; classical Hodgkin's lymphoma; acute mixed lineage leukemia; T-cell lymphoma; nasal T-cell lymphoma; enteropathic T-cell lymphoma; subcutaneous panniculitis-like T-cell lymphoma, blastic NK-cell lymphoma; T-cell prolymphocytic leukemia, and NK-cell leukemia.

[0251] In certain embodiments, the cancer is a hematological malignancy. Exemplary hematological malignancies include leukemias, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myeloid leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), acute non-lymphocytic leukemia (ANLL), acute promyelocytic leukemia (APL), and acute myelomonocytic leukemia (AMMoL); lymphomas, such as Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell B-cell NHL, such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphoma (MCL), and non-Hodgkin's lymphoma (NHL) (e.g., diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL, e.g., activated B-cell (ABC) DLBCL (ABC-DLBCL))). lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, Waldenstrom's macroglobulinemia (WM, lymphoplasmacytic lymphoma), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, central nervous system (CNS) lymphomas (e.g., , primary CNS lymphoma and secondary CNS lymphoma); and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy-type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); lymphomas of immune-privileged sites (e.g., cerebral lymphoma, ocular lymphoma, placental lymphoma, fetal lymphoma, testicular lymphoma); mixed leukemia / lymphoma of one or more of the above; myelodysplasia; multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), polycythemia vera, Wilms' tumor, and Ewing's sarcoma.

[0252] In certain embodiments, the MALT1-mediated disease or condition is multiple myeloma. In certain embodiments, the MALT1-mediated disease or condition is leukemia (e.g., acute lymphocytic leukemia, acute and chronic myeloid leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, or promyelocytic leukemia).

[0253] In certain embodiments, the MALT1-mediated disease or condition is lymphoma (e.g., B-cell lymphoma, T-cell lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma, mast cell tumor, Hodgkin's disease, or non-Hodgkin's disease). In certain embodiments, the MALT1-mediated disease or condition is myelodysplastic syndrome. In certain embodiments, the MALT1-mediated disease or condition is fibrosarcoma. In certain embodiments, the MALT1-mediated disease or condition is rhabdomyosarcoma. In certain embodiments, the MALT1-mediated disease or condition is astrocytoma. In certain embodiments, the MALT1-mediated disease or condition is neuroblastoma. In certain embodiments, the MALT1-mediated disease or condition is glioma and schwannoma. In certain embodiments, the MALT1-mediated disease or condition is melanoma. In certain embodiments, the MALT1-mediated disease or condition is seminoma. In certain embodiments, the MALT1-mediated disease or condition is teratocarcinoma. In certain embodiments, the MALT1-mediated disease or condition is osteosarcoma. In certain embodiments, the MALT1-mediated disease or condition is xeroderma pigmentosum. In certain embodiments, the MALT1-mediated disease or condition is keratoacanthoma. In certain embodiments, the MALT1-mediated disease or condition is follicular thyroid carcinoma. In certain embodiments, the MALT1-mediated disease or condition is Kaposi's sarcoma. In certain embodiments, the MALT1-mediated disease or condition is melanoma. In certain embodiments, the MALT1-mediated disease or condition is teratocarcinoma. In certain embodiments, the MALT1-mediated disease or condition is rhabdomyosarcoma. In certain embodiments, the MALT1-mediated disease or condition is a metastatic bone disorder.In certain embodiments, the MALT1-mediated disease or condition is bone canal. In certain embodiments, the MALT1-mediated disease or condition is oral / pharyngeal cancer. In certain embodiments, the MALT1-mediated disease or condition is esophageal cancer. In certain embodiments, the MALT1-mediated disease or condition is laryngeal cancer. In certain embodiments, the MALT1-mediated disease or condition is gastric cancer. In certain embodiments, the MALT1-mediated disease or condition is intestinal cancer. In certain embodiments, the MALT1-mediated disease or condition is colon cancer. In certain embodiments, the MALT1-mediated disease or condition is rectal cancer. In certain embodiments, the MALT1-mediated disease or condition is lung cancer (e.g., non-small cell lung cancer or small cell lung cancer). In certain embodiments, the MALT1-mediated disease or condition is liver cancer. In certain embodiments, the MALT1-mediated disease or condition is pancreatic cancer. In certain embodiments, the MALT1-mediated disease or condition is neural cancer. In certain embodiments, the MALT1-mediated disease or condition is brain cancer (e.g., glioma or glioblastoma multiforme). In certain embodiments, the MALT1-mediated disease or condition is head and neck cancer. In certain embodiments, the MALT1-mediated disease or condition is throat cancer. In certain embodiments, the MALT1-mediated disease or condition is ovarian cancer. In certain embodiments, the MALT1-mediated disease or condition is uterine cancer. In certain embodiments, the MALT1-mediated disease or condition is prostate cancer. In certain embodiments, the MALT1-mediated disease or condition is testicular cancer. In certain embodiments, the MALT1-mediated disease or condition is bladder cancer.In certain embodiments, the MALT1-mediated disease or condition is kidney cancer. In certain embodiments, the MALT1-mediated disease or condition is breast cancer. In certain embodiments, the MALT1-mediated disease or condition is gallbladder cancer. In certain embodiments, the MALT1-mediated disease or condition is cervical cancer. In certain embodiments, the MALT1-mediated disease or condition is thyroid cancer. In certain embodiments, the MALT1-mediated disease or condition is prostate cancer. In certain embodiments, the MALT1-mediated disease or condition is skin cancer (e.g., cutaneous squamous cell carcinoma). In certain embodiments, the MALT1-mediated disease or condition is a solid tumor. In certain embodiments, the MALT1-mediated disease or condition is gastric cancer. In certain embodiments, the MALT1-mediated disease or condition is hepatocellular carcinoma. In certain embodiments, the MALT1-mediated disease or condition is peripheral nerve sheath tumor. In certain embodiments, the MALT1-mediated disease or condition is pulmonary arterial hypertension.

[0254] In certain embodiments, the disease is a cancer associated with a viral infection. In certain embodiments, the disease is a cancer resulting from infection with an oncogenic virus. In certain embodiments, the oncogenic virus is hepatitis A, hepatitis B, hepatitis C, human T-lymphotropic virus (HTLV), human papillomavirus (HPV), Kaposi's sarcoma-associated herpesvirus (HHV-8), Merkel cell polyomavirus, or Epstein-Barr virus (EBV). In certain embodiments, the disease is a human T-lymphotropic virus. In certain embodiments, the disease is Kaposi's sarcoma-associated herpesvirus. In certain embodiments, the disease is Epstein-Barr virus. Leukemias and lymphomas that may be associated with oncogenic viruses include HTLV, adult T-cell leukemia; HHV-8, Castleman's disease, and primary effusion lymphoma; and EBV, Burkitt's lymphoma, Hodgkin's lymphoma, and post-transplant lymphoproliferative disease.

[0255] In certain embodiments, the MALT1-mediated disease or condition is an inflammatory disorder or an allergic disorder. In certain embodiments, the MALT1-mediated disease or condition includes an inflammatory disorder, such as an autoimmune disorder, a chronic inflammatory disorder, an acute inflammatory disorder, an autoinflammatory disorder, a fibrotic disorder, a metabolic disorder, a neoplasm, a cardiovascular or cerebrovascular disorder, and a myeloid cell-driven hyperinflammatory response in COVID-19 infection. In certain embodiments, the MALT1-mediated disease or condition is an allergic disorder, such as asthma and allergic rhinitis.

[0256] In certain embodiments, the MALT1-mediated disease or condition is a tissue disease or disorder and a systemic disease (e.g., systemic lupus erythematosus (SLE), immune thrombocytopenic purpura (ITP); autoimmune hemolytic anemia (AHA); autoimmune neutropenia (AIN); Evans syndrome; proliferative and hyperproliferative diseases, such as cancer, atherosclerosis, rheumatoid arthritis, psoriasis, idiopathic pulmonary fibrosis, scleroderma, cirrhosis of the liver, and acquired immune deficiency syndrome (AIDS)). In certain embodiments, the MALT1-mediated disease or condition is an immune-mediated disease, such as allograft rejection (e.g., rejection of a transplanted organ or organ). In certain embodiments, the MALT1-mediated disease or condition is tissue injury (e.g., associated with organ transplantation or revascularization). In certain embodiments, the MALT1-mediated disease or condition is a disease or disorder of the airway (e.g., asthma). In certain embodiments, the MALT1-mediated disease or condition is allergic rhinitis. In certain embodiments, the MALT1-mediated disease or condition is a disease or disorder of the bone and joints (e.g., arthritis, rheumatoid arthritis). In certain embodiments, the MALT1-mediated disease or condition is a skin disease or disorder. In certain embodiments, the MALT1-mediated disease or condition is a gastrointestinal disease or disorder.

[0257] In certain embodiments, the MALT1-mediated disease or condition is a reversible obstructive airway disease, such as asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust-induced asthma). In certain embodiments, the MALT1-mediated disease or condition is chronic or chronic asthma (e.g., late asthmatic airway hyperresponsiveness). In certain embodiments, the MALT1-mediated disease or condition is bronchitis. In certain embodiments, the MALT1-mediated disease or condition is a condition characterized by inflammation of the nasal mucosa. In certain embodiments, the MALT1-mediated disease or condition is acute rhinitis. In certain embodiments, the MALT1-mediated disease or condition is allergic rhinitis. In certain embodiments, the MALT1-mediated disease or condition is atrophic rhinitis. In certain embodiments, the MALT1-mediated disease or condition is chronic rhinitis (e.g., caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, rhinitis sicca, and rhinitis medicamentosa). In certain embodiments, the MALT1-mediated disease or condition is membranous rhinitis (e.g., croupus rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofulous rhinitis). In certain embodiments, the MALT1-mediated disease or condition is seasonal rhinitis (e.g., neurogenic rhinitis (hay fever), vasomotor rhinitis, sarcoidosis, farmer's lung, and related diseases such as pulmonary fibrosis and idiopathic interstitial pneumonia).

[0258] In certain embodiments, the MALT1-mediated disease or condition involves pannus formation. In certain embodiments, the MALT1-mediated disease or condition does not involve pannus formation. In certain embodiments, the MALT1-mediated disease or condition is rheumatoid arthritis. In certain embodiments, the MALT1-mediated disease or condition is a seronegative spondyloarthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's disease). In certain embodiments, the MALT1-mediated disease or condition is Behçet's disease. In certain embodiments, the MALT1-mediated disease or condition is Sjögren's syndrome. In certain embodiments, the MALT1-mediated disease or condition is systemic sclerosis.

[0259] In certain embodiments, the MALT1-mediated disease or condition is psoriasis. In certain embodiments, the MALT1-mediated disease or condition is systemic sclerosis. In certain embodiments, the MALT1-mediated disease or condition is systemic sclerosis. In certain embodiments, the MALT1-mediated disease or condition is contact dermatitis. In certain embodiments, the MALT1-mediated disease or condition is eczematous dermatitis. In certain embodiments, the MALT1-mediated disease or condition is seborrheic dermatitis. In certain embodiments, the MALT1-mediated disease or condition is lichen planus. In certain embodiments, the MALT1-mediated disease or condition is pemphigus. In certain embodiments, the MALT1-mediated disease or condition is bullous pemphigus. In certain embodiments, the MALT1-mediated disease or condition is epidermolysis bullosa. In certain embodiments, the MALT1-mediated disease or condition is urticaria. In certain embodiments, the MALT1-mediated disease or condition is angioderma. In certain embodiments, the MALT1-mediated disease or condition is vasculitis. In certain embodiments, the MALT1-mediated disease or condition is erythema. In certain embodiments, the MALT1-mediated disease or condition is cutaneous eosinophilia. In certain embodiments, the MALT1-mediated disease or condition is uveitis. In certain embodiments, the MALT1-mediated disease or condition is alopecia. In certain embodiments, the MALT1-mediated disease or condition is alopecia areata. In certain embodiments, the MALT1-mediated disease or condition is vernal conjunctivitis.

[0260] In certain embodiments, the MALT1-mediated disease or condition is celiac disease. In certain embodiments, the MALT1-mediated disease or condition is proctitis. In certain embodiments, the MALT1-mediated disease or condition is eosinophilic gastroenteritis. In certain embodiments, the MALT1-mediated disease or condition is mastocytosis. In certain embodiments, the MALT1-mediated disease or condition is pancreatitis. In certain embodiments, the MALT1-mediated disease or condition is Crohn's disease. In certain embodiments, the MALT1-mediated disease or condition is ulcerative colitis. In certain embodiments, the MALT1-mediated disease or condition is a food allergy with effects remote from the gastrointestinal tract (e.g., migraine, rhinitis, and eczema).

[0261] In certain embodiments, the MALT1-mediated disease or condition is multiple sclerosis. In certain embodiments, the MALT1-mediated disease or condition is arthrosclerosis. In certain embodiments, the MALT1-mediated disease or condition is acquired immune deficiency syndrome (AIDS). In certain embodiments, the MALT1-mediated disease or condition is lupus. In certain embodiments, the MALT1-mediated disease or condition is lupus erythematosus. In certain embodiments, the MALT1-mediated disease or condition is systemic lupus erythematosus. In certain embodiments, the MALT1-mediated disease or condition is Hashimoto's thyroiditis. In certain embodiments, the MALT1-mediated disease or condition is myasthenia gravis. In certain embodiments, the MALT1-mediated disease or condition is type 1 diabetes. In certain embodiments, the MALT1-mediated disease or condition is nephrotic syndrome. In certain embodiments, the MALT1-mediated disease or condition is eosinophilic fasciitis. In certain embodiments, the MALT1-mediated disease or condition is hyper-IgE syndrome. In certain embodiments, the MALT1-mediated disease or condition is leprosy. In certain embodiments, the MALT1-mediated disease or condition is Sézary syndrome. In certain embodiments, the MALT1-mediated disease or condition is idiopathic thrombocytopenic purpura. In certain embodiments, the MALT1-mediated disease or condition is post-angioplasty restenosis. In certain embodiments, the MALT1-mediated disease or condition is a tumor (e.g., leukemia, lymphoma). In certain embodiments, the MALT1-mediated disease or condition is arthrosclerosis.

[0262] In certain embodiments, the MALT1-mediated disease or condition is acute or chronic allograft rejection (e.g., after kidney, heart, liver, lung, bone marrow, skin, or diaphragm transplantation). In certain embodiments, the MALT1-mediated disease or condition is chronic allograft rejection (e.g., after kidney, heart, liver, lung, bone marrow, skin, or diaphragm transplantation). In certain embodiments, the MALT1-mediated disease or condition is chronic graft-versus-host disease.

[0263] In certain embodiments, the MALT1-mediated disease or condition is an acute inflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is an autoinflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is a fibrotic disorder. In certain embodiments, the MALT1-mediated disease or condition is a metabolic disorder. In certain embodiments, the MALT1-mediated disease or condition is a neoplasm. In certain embodiments, the MALT1-mediated disease or condition is a cardiovascular or cerebrovascular disorder. In certain embodiments, the MALT1-mediated disease or condition is a myeloid cell-driven hyperinflammatory response in COVID-19 infection.

[0264] In certain embodiments, the MALT1-mediated disease or condition is an autoimmune disorder. In certain embodiments, the MALT1-mediated disease or condition is a chronic inflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is an acute inflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is an autoinflammatory disorder. In certain embodiments, the MALT1-mediated disease or condition is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an autoinflammatory disorder.

[0265] In certain embodiments, the MALT1-mediated disease or condition is inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease). In certain embodiments, the MALT1-mediated disease or condition is multiple sclerosis. In certain embodiments, the MALT1-mediated disease or condition is psoriasis. In certain embodiments, the MALT1-mediated disease or condition is arthritis. In certain embodiments, the MALT1-mediated disease or condition is rheumatoid arthritis. In certain embodiments, the MALT1-mediated disease or condition is osteoarthritis. In certain embodiments, the MALT1-mediated disease or condition is juvenile arthritis. In certain embodiments, the MALT1-mediated disease or condition is psoriatic arthritis. In certain embodiments, the MALT1-mediated disease or condition is reactive arthritis. In certain embodiments, the MALT1-mediated disease or condition is ankylosing spondylitis. In certain embodiments, the MALT1-mediated disease or condition is cryopyrin-associated periodic syndrome. In certain embodiments, the MALT1-mediated disease or condition is Muckle-Wells syndrome. In certain embodiments, the MALT1-mediated disease or condition is familial cold autoinflammatory syndrome. In certain embodiments, the MALT1-mediated disease or condition is neonatal-onset multisystem inflammatory disease. In certain embodiments, the MALT1-mediated disease or condition is TNF receptor-associated periodic syndrome. In certain embodiments, the MALT1-mediated disease or condition is acute and chronic pancreatitis. In certain embodiments, the MALT1-mediated disease or condition is atherosclerosis. In certain embodiments, the MALT1-mediated disease or condition is gout. In certain embodiments, the MALT1-mediated disease or condition is a fibrotic disorder (e.g., liver fibrosis or idiopathic pulmonary fibrosis).In certain embodiments, the MALT1-mediated disease or condition is nephropathy. In certain embodiments, the MALT1-mediated disease or condition is sarcoidosis. In certain embodiments, the MALT1-mediated disease or condition is scleroderma. In certain embodiments, the MALT1-mediated disease or condition is anaphylaxis. In certain embodiments, the MALT1-mediated disease or condition is diabetes (e.g., type 1 diabetes or type 2 diabetes). In certain embodiments, the MALT1-mediated disease or condition is diabetic retinopathy. In certain embodiments, the MALT1-mediated disease or condition is Still's disease. In certain embodiments, the MALT1-mediated disease or condition is vasculitis. In certain embodiments, the MALT1-mediated disease or condition is sarcoidosis. In certain embodiments, the MALT1-mediated disease or condition is pulmonary inflammation. In certain embodiments, the MALT1-mediated disease or condition is respiratory failure. In certain embodiments, the MALT1-mediated disease or condition is acute respiratory distress syndrome. In certain embodiments, the MALT1-mediated disease or condition is chronic eosinophilic pneumonia. In certain embodiments, the MALT1-mediated disease or condition is wet and dry age-related macular degeneration. In certain embodiments, the MALT1-mediated disease or condition is autoimmune hemolytic syndrome. In certain embodiments, the MALT1-mediated disease or condition is autoimmune and inflammatory hepatitis. In certain embodiments, the MALT1-mediated disease or condition is autoimmune neuropathies. In certain embodiments, the MALT1-mediated disease or condition is autoimmune ovarian failure. In certain embodiments, the MALT1-mediated disease or condition is autoimmune orchitis.In certain embodiments, the MALT1-mediated disease or condition is autoimmune thrombocytopenia. In certain embodiments, the MALT1-mediated disease or condition is silicone implant-associated autoimmune disease. In certain embodiments, the MALT1-mediated disease or condition is Sjögren's syndrome. In certain embodiments, the MALT1-mediated disease or condition is familial Mediterranean fever. In certain embodiments, the MALT1-mediated disease or condition is systemic lupus erythematosus. In certain embodiments, the MALT1-mediated disease or condition is a vasculitic syndrome (e.g., temporal arteritis, Takayasu's arteritis, giant cell arteritis, Behçet's disease, or Wegener's granulomatosis). In certain embodiments, the MALT1-mediated disease or condition is vitiligo. In certain embodiments, the MALT1-mediated disease or condition is a secondary hematological manifestation of an autoimmune disease (e.g., anemia). In certain embodiments, the MALT1-mediated disease or condition is drug-induced autoimmunity. In certain embodiments, the MALT1-mediated disease or condition is Hashimoto's thyroiditis. In certain embodiments, the MALT1-mediated disease or condition is hypophysitis. In certain embodiments, the MALT1-mediated disease or condition is idiopathic thrombocytopenic purpura. In certain embodiments, the MALT1-mediated disease or condition is metal-induced autoimmunity. In certain embodiments, the MALT1-mediated disease or condition is myasthenia gravis. In certain embodiments, the MALT1-mediated disease or condition is pemphigus. In certain embodiments, the MALT1-mediated disease or condition is autoimmune hearing loss (e.g., Meniere's disease). In certain embodiments, the MALT1-mediated disease or condition is Goodpasture's syndrome. In certain embodiments, the MALT1-mediated disease or condition is Graves' disease.In certain embodiments, the MALT1-mediated disease or condition is HW-associated autoimmune syndrome. In certain embodiments, the MALT1-mediated disease or condition is Guillain-Barré disease. In certain embodiments, the MALT1-mediated disease or condition is Addison's disease. In certain embodiments, the MALT1-mediated disease or condition is antiphospholipid syndrome. In certain embodiments, the MALT1-mediated disease or condition is asthma. In certain embodiments, the MALT1-mediated disease or condition is atopic dermatitis. In certain embodiments, the MALT1-mediated disease or condition is celiac disease. In certain embodiments, the MALT1-mediated disease or condition is Cushing's syndrome. In certain embodiments, the MALT1-mediated disease or condition is dermatomyositis. In certain embodiments, the MALT1-mediated disease or condition is idiopathic adrenal atrophy. In certain embodiments, the MALT1-mediated disease or condition is idiopathic thrombocytopenia. In certain embodiments, the MALT1-mediated disease or condition is Kawasaki syndrome. In certain embodiments, the MALT1-mediated disease or condition is Lambert-Eaton syndrome. In certain embodiments, the MALT1-mediated disease or condition is pernicious anemia. In certain embodiments, the MALT1-mediated disease or condition is hay fever. In certain embodiments, the MALT1-mediated disease or condition is polyarteritis nodosa. In certain embodiments, the MALT1-mediated disease or condition is primary biliary cirrhosis. In certain embodiments, the MALT1-mediated disease or condition is primary sclerosing cholangitis. In certain embodiments, the MALT1-mediated disease or condition is Raynaud's disease. In certain embodiments, the MALT1-mediated disease or condition is Raynaud's phenomenon.In certain embodiments, the MALT1-mediated disease or condition is Reiter's syndrome. In certain embodiments, the MALT1-mediated disease or condition is relapsing polychondritis. In certain embodiments, the MALT1-mediated disease or condition is Schmidt's syndrome. In certain embodiments, the MALT1-mediated disease or condition is thyrotoxicosis. In certain embodiments, the MALT1-mediated disease or condition is sepsis. In certain embodiments, the MALT1-mediated disease or condition is septic shock. In certain embodiments, the MALT1-mediated disease or condition is endotoxic shock. In certain embodiments, the MALT1-mediated disease or condition is exotoxin-induced toxic shock. In certain embodiments, the MALT1-mediated disease or condition is Gram-negative sepsis. In certain embodiments, the MALT1-mediated disease or condition is toxic shock syndrome. In certain embodiments, the MALT1-mediated disease or condition is glomerulonephritis. In certain embodiments, the MALT1-mediated disease or condition is peritonitis. In certain embodiments, the MALT1-mediated disease or condition is interstitial cystitis. In certain embodiments, the MALT1-mediated disease or condition is hyperoxia-induced inflammation. In certain embodiments, the MALT1-mediated disease or condition is chronic obstructive pulmonary disease (COPD). In certain embodiments, the MALT1-mediated disease or condition is emphysema. In certain embodiments, the MALT1-mediated disease or condition is rhinitis. In certain embodiments, the MALT1-mediated disease or condition is vasculitis. In certain embodiments, the MALT1-mediated disease or condition is graft-versus-host rejection (e.g., graft-versus-host disease).In certain embodiments, the MALT1-mediated disease or condition is allograft rejection (e.g., acute allograft rejection or chronic allograft rejection). In certain embodiments, the MALT1-mediated disease or condition is early transplant rejection (e.g., acute allograft rejection). In certain embodiments, the MALT1-mediated disease or condition is reperfusion injury. In certain embodiments, the MALT1-mediated disease or condition is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In certain embodiments. In certain embodiments, the MALT1-mediated disease or condition is a chronic infection. In certain embodiments, the MALT1-mediated disease or condition is meningitis. In certain embodiments, the MALT1-mediated disease or condition is encephalitis. In certain embodiments, the MALT1-mediated disease or condition is myocarditis. In certain embodiments, the MALT1-mediated disease or condition is gingivitis. In certain embodiments, the MALT1-mediated disease or condition is post-surgical trauma. In certain embodiments, the MALT1-mediated disease or condition is tissue injury. In certain embodiments, the MALT1-mediated disease or condition is traumatic brain injury. In certain embodiments, the MALT1-mediated disease or condition is enteritis. In certain embodiments, the MALT1-mediated disease or condition is sinusitis. In certain embodiments, the MALT1-mediated disease or condition is uveitis. In certain embodiments, the MALT1-mediated disease or condition is ocular inflammation. In certain embodiments, the MALT1-mediated disease or condition is optic neuritis. In certain embodiments, the MALT1-mediated disease or condition is gastric ulcer. In certain embodiments, the MALT1-mediated disease or condition is esophagitis. In certain embodiments, the MALT1-mediated disease or condition is peritonitis. In certain embodiments, the MALT1-mediated disease or condition is periodontitis. In certain embodiments, the MALT1-mediated disease or condition is dermatomyositis. In certain embodiments, the MALT1-mediated disease or condition is gastritis. In certain embodiments, the MALT1-mediated disease or condition is myositis. In certain embodiments, the MALT1-mediated disease or condition is polymyalgia. In certain embodiments, the MALT1-mediated disease or condition is pneumonia.In certain embodiments, the MALT1-mediated disease or condition is bronchitis. In certain embodiments, the MALT1-mediated disease or condition is endometriosis. In certain embodiments, the MALT1-mediated disease or condition is necrotizing vasculitis. In certain embodiments, the MALT1-mediated disease or condition is lymphadenitis. In certain embodiments, the MALT1-mediated disease or condition is periarteritis nodosa. In certain embodiments, the MALT1-mediated disease or condition is antiphospholipid syndrome. In certain embodiments, the MALT1-mediated disease or condition is pemphigus vulgaris. In certain embodiments, the MALT1-mediated disease or condition is Lyme disease. In certain embodiments, the MALT1-mediated disease or condition is cardiomyopathy. In certain embodiments, the MALT1-mediated disease or condition is rheumatic fever. In certain embodiments, the MALT1-mediated disease or condition is bullous disease. In certain embodiments, the MALT1-mediated disease or condition is antibody-mediated vasculitis syndrome. In certain embodiments, the MALT1-mediated disease or condition is immune complex vasculitis. In certain embodiments, the MALT1-mediated disease or condition is edema. In certain embodiments, the MALT1-mediated disease or condition is embolism. In certain embodiments, the MALT1-mediated disease or condition is fibrosis. In certain embodiments, the MALT1-mediated disease or condition is silicosis. In certain embodiments, the MALT1-mediated disease or condition is BENTA disease. In certain embodiments, the MALT1-mediated disease or condition is beryllium disease.

[0266] In certain embodiments, the MALT1-mediated disease or condition is systemic sclerosis / scleroderma. In certain embodiments, the MALT1-mediated disease or condition is lupus nephritis. In certain embodiments, the MALT1-mediated disease or condition is a connective tissue disease. In certain embodiments, the MALT1-mediated disease or condition is wound healing. In certain embodiments, the MALT1-mediated disease or condition is surgical scarring. In certain embodiments, the MALT1-mediated disease or condition is spinal cord injury. In certain embodiments, the MALT1-mediated disease or condition is CNS scarring. In certain embodiments, the MALT1-mediated disease or condition is acute lung injury. In certain embodiments, the MALT1-mediated disease or condition is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis). In certain embodiments, the MALT1-mediated disease or condition is chronic obstructive pulmonary disease. In certain embodiments, the MALT1-mediated disease or condition is adult respiratory distress syndrome. In certain embodiments, the MALT1-mediated disease or condition is acute lung injury. In certain embodiments, the MALT1-mediated disease or condition is drug-induced lung injury. In certain embodiments, the MALT1-mediated disease or condition is The MALT1-mediated disease or condition is glomerulonephritis. In certain embodiments, the MALT1-mediated disease or condition is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, the MALT1-mediated disease or condition is hypertension-induced nephropathy. In certain embodiments, the MALT1-mediated disease or condition is gastrointestinal or gastrointestinal fibrosis. In certain embodiments, the MALT1-mediated disease or condition is renal fibrosis. In certain embodiments, the MALT1-mediated disease or condition is hepatic or biliary fibrosis.In certain embodiments, the MALT1-mediated disease or condition is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma). In certain embodiments, the MALT1-mediated disease or condition is liver cirrhosis (e.g., primary biliary cirrhosis or cirrhosis resulting from fatty liver disease, such as alcoholic and nonalcoholic steatosis). In certain embodiments, the MALT1-mediated disease or condition is radiation-induced fibrosis (e.g., head and neck, gastrointestinal, or pulmonary). In certain embodiments, the MALT1-mediated disease or condition is primary sclerosing cholangitis. In certain embodiments, the MALT1-mediated disease or condition is restenosis. In certain embodiments, the MALT1-mediated disease or condition is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis). In certain embodiments, the MALT1-mediated disease or condition is ocular scarring. In certain embodiments, the MALT1-mediated disease or condition is fibrosclerosis. In certain embodiments, the MALT1-mediated disease or condition is fibrous carcinoma. In certain embodiments, the MALT1-mediated disease or condition is fibroid. In certain embodiments, the MALT1-mediated disease or condition is fibroadenoma. In certain embodiments, the MALT1-mediated disease or condition is fibrosarcoma. In certain embodiments, the MALT1-mediated disease or condition is transplant arteriopathy. In certain embodiments, the MALT1-mediated disease or condition is keloid. In certain embodiments, the MALT1-mediated disease or condition is mediastinal fibrosis. In certain embodiments, the MALT1-mediated disease or condition is myelofibrosis. In certain embodiments, the MALT1-mediated disease or condition is retroperitoneal fibrosis.In certain embodiments, the MALT1-mediated disease or condition is progressive massive fibrosis. In certain embodiments, the MALT1-mediated disease or condition is nephrogenic systemic fibrosis.

[0267] In certain embodiments, the MALT1-mediated disease or condition is obesity. In certain embodiments, the MALT1-mediated disease or condition is steroid resistance. In certain embodiments, the MALT1-mediated disease or condition is impaired glucose tolerance. In certain embodiments, the MALT1-mediated disease or condition is metabolic syndrome.

[0268] In certain embodiments, the MALT1-mediated disease or condition is atherosclerosis. In certain embodiments, the MALT1-mediated disease or condition is atherosclerotic coronary restenosis. In certain embodiments, the MALT1-mediated disease or condition is acute coronary syndrome. In certain embodiments, the MALT1-mediated disease or condition is myocardial infarction. In certain embodiments, the MALT1-mediated disease or condition is cardiac allograft vasculopathy. In certain embodiments, the MALT1-mediated disease or condition is stroke. In certain embodiments, the MALT1-mediated disease or condition is a central nervous system disorder with an inflammatory or apoptotic component. In certain embodiments, the MALT1-mediated disease or condition is Alzheimer's disease. In certain embodiments, the MALT1-mediated disease or condition is Parkinson's disease. In certain embodiments, the MALT1-mediated disease or condition is Huntington's disease. In certain embodiments, the disease or condition mediated by MALT1 is amyotrophic lateral sclerosis. In certain embodiments, the disease or condition mediated by MALT1 is spinal cord injury. In certain embodiments, the disease or condition mediated by MALT1 is neuronal ischemia. In certain embodiments, the disease or condition mediated by MALT1 is peripheral neuropathy.

[0269] In certain embodiments, the MALT1-mediated disease or condition is a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2). In certain embodiments, the coronavirus is SARS-CoV-2. In certain embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19.

[0270] In certain embodiments, the MALT1-mediated disease or condition is a rheumatic disease. In certain embodiments, the MALT1-mediated disease or condition is an inflammatory arthropathy. In certain embodiments, the disease or condition mediated by MALT1 is rheumatoid arthritis, juvenile arthritis, Still's disease, juvenile rheumatoid arthritis, systemic rheumatoid arthritis, pauciarticular rheumatoid arthritis, pauciarticular juvenile rheumatoid arthritis, polyarticular rheumatoid arthritis, enteropathic arthritis, juvenile Reiter's syndrome, ankylosing spondylitis, juvenile ankylosing spondylitis, SEA syndrome, reactive arthritis (reactive arthropathy), psoriatic arthropathy, juvenile enteropathic arthritis, polymyalgia rheumatica, enteropathic spondylitis, juvenile idiopathic arthritis (JIA), juvenile psoriatic arthritis, juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, giant cell arteritis, osteoarthritis secondary to inflammatory diseases.

[0271] In certain embodiments, the MALT1-mediated disease or condition is a connective tissue disease, such as lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjogren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile scleroderma, polymyositis, dermatomyositis, polymyalgia rheumatica, mixed connective tissue disease, sarcoidosis, fibromyalgia, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis), polyarteritis nodosa, Henoch-Schönlein purpura, idiopathic thrombotic thrombocytopenic purpura, juvenile vasculitis, ... These include polyarteritis nodosa (also known as panarteritis nodosa Kussmaul disease, Kussmaul-Meyer disease, or PAN), serum sickness, myasthenia gravis, Takayasu's arteritis, Behçet's disease, Kawasaki disease (mucocutaneous lymph node syndrome), Buerger's disease (thromboangiitis obliterans), Vogt-Koyanagi-Harada disease, Addison's disease, Hashimoto's thyroiditis, primary biliary sclerosis, autoimmune hepatitis, chronic aggressive hepatitis, nonalcoholic fatty liver disease, sclerosing cholangitis, membranous glomerulopathy, polymyositis, atherosclerosis, autoimmune hemolytic anemia, autoimmune orchitis, and Goodpasture's disease.

[0272] In certain embodiments, the disease or condition mediated by MALT1 is a neurodegenerative disease or a neuroinflammatory disease. In certain embodiments, the disease or condition mediated by MALT1 is multiple sclerosis, amyotrophic lateral sclerosis, Guillain-Barré syndrome, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson's disease, or bipolar disorder.

[0273] In certain embodiments, the disease or condition mediated by MALT1 is inflammatory bowel disease. In certain embodiments, the disease or condition mediated by MALT1 is Crohn's disease, ulcerative colitis, celiac sprue, celiac disease, proctitis, eosinophilic gastroenteritis, autoimmune atrophic gastritis of pernicious anemia, or mastocytosis.

[0274] In certain embodiments, the disease or condition mediated by MALT1 is a skin autoimmune disorder.In certain embodiments, the disease or condition mediated by MALT1 is psoriasis.In certain embodiments, the disease or condition mediated by MALT1 is eczema.In certain embodiments, the disease or condition mediated by MALT1 is psoriasis vulgaris, guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, atopic dermatitis, eczematous dermatitis, dermatitis, rosacea, pruritus, alopecia areata, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa.

[0275] In certain embodiments, the disease or condition mediated by MALT1 is organ or cell transplant rejection.In certain embodiments, the disease or condition mediated by MALT1 is graft-versus-host disease.In certain embodiments, the disease or condition mediated by MALT1 is chronic graft-versus-host disease, acute graft-versus-host disease, or organ or cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, pancreatic islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea, or xenotransplantation.

[0276] In certain embodiments, the MALT1-mediated disease or condition is an ocular autoimmune disease. In certain embodiments, the MALT1-mediated disease or condition is Graves' disease, non-infectious uveitis, dry eye syndrome, sympathetic ophthalmia, Cogan's syndrome, keratoconjunctivitis, vernal conjunctivitis, uveitis (e.g., uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, keratoconus, corneal epithelial degeneration, corneal leukoplakia, ocular premphigus, Mooren's ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenosis, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization.

[0277] In certain embodiments, the MALT1-mediated disease or condition is an ocular manifestation of an autoimmune disease.

[0278] In certain embodiments, the MALT1-mediated disease or condition is a respiratory disease. In certain embodiments, the MALT1-mediated disease or condition is asthma, chronic obstructive pulmonary disease, or acute respiratory disease.

[0279] In certain embodiments, the MALT1-mediated disease or condition is diabetes. In certain embodiments, the MALT1-mediated disease or condition is type I diabetes, type II diabetes, or juvenile-onset diabetes.

[0280] Additional methods Another aspect of the present invention provides methods of inhibiting cell proliferation in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I), or methods of inhibiting cell proliferation in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I). In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments. In certain embodiments, cell proliferation is inhibited for T cells. In certain embodiments, cell proliferation is inhibited for B cells. In certain embodiments, cell proliferation is inhibited for T cells and B cells.

[0281] Another aspect of the present invention provides a method of inducing apoptosis of cells in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I), or a method of inducing apoptosis of cells in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I). In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments. In certain embodiments, the cell is a tumor cell. In certain embodiments, the cell is a lymphocyte. In certain embodiments, the cell is a T cell. In certain embodiments, the cell is a B cell.

[0282] Another aspect of the present invention provides methods of inhibiting cell adhesion in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I), or methods of inhibiting cell adhesion in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I). In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments. In certain embodiments, the cell is a tumor cell. In certain embodiments, the cell is a lymphocyte. In certain embodiments, the cell is a T cell. In certain embodiments, the cell is a B cell.

[0283] Another aspect of the present invention provides methods of inhibiting T cell or B cell activation in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I), or methods of inhibiting T cell or B cell activation in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I). In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments.

[0284] Another aspect of the invention provides methods for inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or MALT1 fusion proteins in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I), or for inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or MALT1 fusion proteins in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I). In certain embodiments, the compound is a compound of formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, Ij, Ik, Il, Im, In, Io, Ip, Ia-4, Ib-4, Ic-4, Id-4, Ie-4, If-4, Ig-4, Ih-4, Ii-4, Ij-4, Ik-4, Il-4, Im-4, In-4, Io-4, Ip-4, or defined by one of the above embodiments. In certain embodiments, the method inhibits the protease activity of MALT1. In certain embodiments, the method inhibits the protease activity of a MALT1 fusion protein (e.g., API2-MALT1). In certain embodiments, the method inhibits the protease activity of MALT1 or a MALT1 fusion protein for cleavage of a peptide substrate. In certain embodiments, the peptide substrate is A20, Bcl10, RelB, CYLD, NIK, Regnase 1, Roquin 1, Roquin 2, LIMA1a, or MALT1. The inhibitor may selectively inhibit the protease activity of a MALT1 or MALT1 fusion protein for cleavage of a first peptide substrate over the protease activity for cleavage of a second peptide substrate. In certain embodiments, the first and / or second substrate is A20, Bcl10, RelB, CYLD, NIK, Regnase 1, Roquin 1, Roquin 2, LIMA1a, or MALT1. In certain embodiments, the selectivity is about 1.25-fold to about 5-fold. In certain embodiments, the selectivity is about 5-fold to about 10-fold. In certain embodiments, the selectivity is about 10-fold to about 25-fold.In certain embodiments, the selectivity is about 25-fold to about 50-fold. In certain embodiments, the selectivity is about 50-fold to about 100-fold. In certain embodiments, the selectivity is about 100-fold to about 250-fold. In certain embodiments, the selectivity is about 250-fold to about 500-fold. In certain embodiments, the selectivity is about 500-fold to about 1000-fold. In certain embodiments, the selectivity is at least about 1000-fold.

[0285] III. Combination Therapy Another aspect of the present invention provides combination therapy. The pyrazolyl sulfonamides described herein (e.g., compounds of Formula I, I-1, I-2, I-3, I-4, II, or other compounds in Section I) or their pharmaceutically acceptable salts may be used in combination with an additional therapeutic agent to treat a disease or condition, such as an inflammatory disorder.

[0286] Thus, in some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents.

[0287] One or more other therapeutic agents may be administered separately from the compounds or compositions of the invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. When administered as a multiple dose regimen, the one or more other therapeutic agents and the compounds or compositions of the invention may be administered simultaneously, sequentially, or within a period of each other.

[0288] In certain embodiments, the compound of the present disclosure can be administered sequentially or concurrently with one or more second therapeutic agents, either by the same administration route or by different administration routes. When administered sequentially, the time between administrations is selected to benefit, among other things, the therapeutic efficacy and / or safety of the combined treatment. In certain embodiments, the compound of the present disclosure can be administered first, followed by the second therapeutic agent, or alternatively, the second therapeutic agent can be administered first, followed by the compound of the present disclosure. In certain embodiments, the compound of the present disclosure can be administered for the same period as the second therapeutic agent, or alternatively, can be administered for a longer or shorter period than the second therapeutic compound.

[0289] When administered concurrently, the compound of the present disclosure can be administered simultaneously with the second therapeutic agent, by the same or different route, separately, or in a single composition by the same route. In certain embodiments, the compound of the present disclosure is prepared as a first pharmaceutical composition, and the second therapeutic agent is prepared as a second pharmaceutical composition, and the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately. In certain embodiments, the dosage and administration frequency of the second therapeutic agent can be the standard dosage and administration frequency used for the specific therapeutic agent. For example, see Physicians' Desk Reference, 70, incorporated herein by reference. th Ed., PDR Network, 2015.

[0290] In certain embodiments, the additional therapeutic agent is a leukotriene inhibitor, a nonsteroidal anti-inflammatory drug (NSAID), a steroid, a tyrosine kinase inhibitor, a receptor kinase inhibitor, a modulator of the nuclear receptor family of transcription factors, an HSP90 inhibitor, an adenosine receptor (A2A) agonist, a disease-modifying antirheumatic drug (DMARD), a phosphodiesterase (PDE) inhibitor, a neutrophil elastase inhibitor, a modulator of Axl kinase, an anti-cancer agent, an anti-allergic agent, an anti-emetic agent (or anti-emetic), a pain-relieving agent, a cytoprotective agent, or a combination thereof. In certain embodiments, the additional therapeutic agent is an anti-cancer agent, an analgesic agent, an anti-inflammatory agent, or a combination thereof.

[0291] In certain embodiments, the second therapeutic agent is a leukotriene inhibitor. Examples of leukotriene inhibitors contemplated for use in the combination therapy of the present invention include, but are not limited to, montelukast, zafirlukast, pranlukast, zileuton, or combinations thereof.

[0292] In certain embodiments, the second therapeutic agent is NSAID.The example of NSAID that is considered for use in the combination therapy of the present invention includes but is not limited to acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, nioxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, phenylbutazone, mefenamic acid, meclofenamic acid, flufenamic acid, trofenamic acid, celecoxib or combinations thereof.

[0293] In certain embodiments, the second therapeutic agent is a steroid. Examples of steroids contemplated for use in the combination therapy of the present invention include, but are not limited to, prednisone, prednisolone, methylprednisone, triaccinolone, betamethasone, dexamethasone, and prodrugs thereof.

[0294] In certain embodiments, the second therapeutic agent is a tyrosine kinase inhibitor. Examples of tyrosine kinase inhibitors contemplated for use in the combination therapies of the present invention include, but are not limited to, inhibitors of kinases including JAK, Syk, JNK / SAPK, MAPK, PI-3K, and / or Ripk2, among others. In certain embodiments, the tyrosine kinase inhibitor is ruxolitinib, tofacitinib, oclactinib, filgotinib, ganotinib, lestaurtinib, momelotinib, pacritinib, upadacitinib, peficitinib, fedratinib, bentamapimod, D-JNKI-1 (XG-102, AM-111), ponatinib, WEHI-345, OD36, GSK583, idelalisib, copanlisib, taselisib, duvelisib, alpelisib, umbralisib, dactolisib, CUDC-907, entospletinib, fostamatinib, or a combination thereof. In certain embodiments, the second therapeutic agent is a Bruton's tyrosine kinase (BTK) inhibitor. Examples of BTK inhibitors contemplated for use in the combination therapies of the present invention include, but are not limited to, ibrutinib, acalabrutinib, pirtobrutinib, and zanubrutinib.

[0295] In certain embodiments, the second therapeutic agent is a receptor kinase inhibitor, including, among others, an inhibitor of EGFR or HER2. Examples of receptor kinase inhibitors contemplated for use in the combination therapy of the present invention include, but are not limited to, gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or combinations thereof.

[0296] In certain embodiments, the second therapeutic agent is a modulator of the nuclear receptor family of transcription factors, including, among others, an inhibitor of PPAR, RXR, FXR, or LXR. In certain embodiments, the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fexaramine, hypocholamide, or a combination thereof.

[0297] In certain embodiments, the second therapeutic agent is an HSP90 inhibitor. Examples of HSP90 inhibitors that are considered for use in the combination therapy of the present invention include but are not limited to ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or combinations thereof.

[0298] In certain embodiments, the second therapeutic agent is an adenosine receptor 2A (A2A) agonist.The example of adenosine receptor agonist that is considered for use in the combination therapy of the present invention includes but is not limited to those disclosed in United States Patent No. 9,067,963, which is incorporated herein by reference.In certain embodiments, the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052, or a combination thereof.

[0299] In certain embodiments, the second therapeutic agent is selected from disease-modifying antirheumatic drugs (DMARDs). Examples of DMARDs that are considered for use in the combination therapy of the present invention include but are not limited to tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, uteskinumab, or combinations thereof.

[0300] In certain embodiments, the second therapeutic agent is a phosphodiesterase (PDE) inhibitor. Examples of phosphodiesterase inhibitors contemplated for use in the combination therapy of the present invention include, but are not limited to, apremilast, crisaborole, piclimilast, drotaverine, ibudrust, roflumilast, sildenafil, tadalafil, vardenafil, or a combination thereof.

[0301] In certain embodiments, the second therapeutic agent is a neutrophil elastase inhibitor. Examples of neutrophil elastase inhibitors contemplated for use in the combination therapy of the present invention include, but are not limited to, sivelestat.

[0302] In certain embodiments, the second therapeutic agent is an Axl kinase modulator. Examples of Axl kinase modulators contemplated for use in the combination therapies of the present invention include, but are not limited to, bemcentinib (BGB324 or R428), TP-0903, LY2801653, amuvatinib (MP-470), bosutinib (SKI-606), MGCD265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089 / XL880), and SGI-7079. In certain embodiments, the Axl kinase modulator is a monoclonal antibody targeting AXL (e.g., YW327.6S2) or an AXL decoy receptor (e.g., GL2I.T), or a dual Flt3-Axl inhibitor such as glesatinib, merestinib, or gilteritinib.

[0303] In certain embodiments, the second therapeutic agent is a bispecific antibody, such as a bispecific antibody that binds to a tumor-specific antigen. Exemplary bispecific antibodies include, but are not limited to, Blincyto (blinatumomab), Kimmtrak (tebentafsp), Tecvayli (teclistamab), Lunsumio (mosunetuzumab), Epkinly (epcolitamab), and Columvi (glofitamab).

[0304] In certain embodiments, the second therapeutic agent is a chimeric antigen receptor (CAR) T-cell therapy. Exemplary CAR T-cell therapy agents include, but are not limited to, ABECMA® (idecabutagen bicleucel), BREYANZI® (lisocabbutagen malareucel), CARVYKTI™ (siltacabbutagen autolucel), KYMRIAH™ (tisagenlecleucel), TECARTUST™ (brexcabbutagen autolucel), and YESCARTA™ (axicabbutagen ciloreucel).

[0305] In certain embodiments, the additional therapeutic agent is an anti-cancer or chemotherapeutic agent. Examples of anti-cancer agents contemplated for use in the combination therapy of the present invention include erlotinib, bortezomib, fulvestrant, sunitib, imatinib mesylate, letrozole, finasunate, platins such as oxaliplatin, carboplatin, and cisplatin, finasunate, fluorouracil, rapamycin, leucovorin, lapatinib, lonafamib, sorafenib, gefitinib, camptothecin, topotecan, bryostatin, adzesin, anthracyclines, and the like. Other alkylating agents such as cyclophosphamide, doxorubicin, vincristine, prednisone or prednisolone, mechlorethamine, chlorambucil, and ifosfamide, antimetabolites such as azathioprine or mercaptopurine, other microtubule inhibitors (vinca alkaloids such as vincristine, vinblastine, vinorelbine, and vindesine), and taxols such as vincristine, carzelesin, bizelesin, dolastatins, auristatins, duocarmycins, eleutherobin, paclitaxel, or docetaxel, Other cytotoxins such as podophyllotoxins (etoposide, teniposide, etoposide phosphate, and epipodophyllotoxin), topoisomerase inhibitors, actinomycin, daunorubicin, valrubicin, idarubicin, edrecolomab, epirubicin, bleomycin, plicamycin, and mitomycin, as well as other anti-cancer antibodies (cetuximab, bevacizumab, ibritumomab, abagovomab, adecatumumab, afutuzumab, alacizumab, alemtuzumab, anatumomab, apolizumab, bavituximab, belimumab, Mab, bivatuzumab mertansine, blinatumomab, brentuximab vedotin, cantuzumab mertansine, catechumanab, cetuximab, sitatuzumab bogatox, cixutumumab, clivatuzumab tetraxetan, conatumumab, dacetuzumab, daclizumab, detumomab, ecromeximab, edrecolomab, elotuzumab, epratuzumab, ertumaxomab, etaracizumab, faretuzumab, figitumumab, frezolimumab, galiximab, gembatumumab vedotin, gemtuzumab, ibritumomab tiuxetan,Inotuzumab ozogamicin, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab, lintuzumab, lucatumumab, rumilicimab, mapatumumab, matuzumab, milatuzumab, mitumomab, nacolomab butafenatox, naptumomab estafenatox, necitumumab, nimotuzumab, ofatumumab, olara tuzumab, oportuzumab monatox, oregovomab, panitumumab, pemtumomab, pertuzumab, pintumomab, pritumumab, ramucirumab, rilotumumab, lobatumumab, rituximab, sibrotuzumab, tacatuzumab tetraxetan, tapritumomab paptox, tenatumomab, ticilimumab, tigatuzumab, tositumomab, or 131 I-tositumomab, trastuzumab, tremelimumab, tuocuzumab-celmoleukin, veltuzumab, visilizumab, volociximab, votumumab, zalutumumab, zanolimumab, IGN-101, MDX-010, ABX-EGR, EMD72000, ior-t1, MDX-220, MRA, H-11 scFv, huJ591, TriGem, TriAb, R3, MT-201, G-250, ACA-125, Onyvax-105, CD:-960, Cea-Vac, BrevaRex AR54, IMC-1C11, GlioMab-H, ING-1, anti-LCG Mab, MT-103, KSB-303, Therex, KW2871, anti-HMI.24, anti-PTHrP, 2C4 antibody, SGN-30, TRAIL-RI Mab, prostate cancer antibody, H22xKi-r, ABX-Mai, Imuteran, Monopharm-C), and antibody drug conjugates comprising any of the above agents (particularly the auristatins MMAE and MMAF, maytansinoids such as DM-1, calicheamicin, or various cytotoxins).

[0306] In certain embodiments, the additional therapeutic agent is anastrozole (ARIMIDEX®), bicalutamide (CASODEX®), bleomycin sulfate (BLENOXANE®), busulfan (MYLERAN®), busulfan injection (BUSULFEX®), capecitabine (XELODA®), N4-pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (PARAPLATIN®), carmustine (BiCNU®), chlorambucil (LEUKERAN®), cisplatin (PLATINOL®), cladribine (LEUSTATIN®), cyclophosphamide (CYTOXAN® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (actinomycin D, COSMEGAN®), daunorubicin hydrochloride (CERUBIDINE®), (Trademark), daunorubicin citrate liposome injection (DAUNOXOME®), dexamethasone, docetaxel (TAXOTERE®), doxorubicin hydrochloride (ADRIAMYCIN®, RUBEX®), etoposide (VEPESID®), fludarabine phosphate (FLUDARA®), 5-fluorouracil (ADRUCIL®, EFUDEX®), flutamide (EULEXIN®), tezacitibine, gemcitabine (difluorodeoxycytidine), hydrochloride xyurea (HYDREA®), idarubicin (IDAMYCIN®), ifosfamide (IFEX®), irinotecan (CAMPTOSAR®), L-asparaginase (ELSPAR®), leucovorin calcium, melphalan (ALKERAN®), 6-mercaptopurine (PURINETHOL®), methotrexate (FOLEX®), mitoxantrone (NOVANTRONE®), gemtuzumab ozogamicin (MYLOTARG™),Selected from paclitaxel (TAXOL®), nanoparticle albumin-bound paclitaxel (ABRAXANE®), phoenix (Yttrium 90 / MX-DTPA), pentostatin, polifeprosan 20 with carmustine implant (GLIADEL®), tamoxifen citrate (NOLVADEX®), teniposide (VUMON®), 6-thioguanine, thiotepa, tirapazamine (TIRAZONE®), injectable topotecan hydrochloride (HYCAMPTIN®), vinblastine (VELBAN®), vincristine (ONCOVIN®), and vinorelbine (NAVELBINE®).

[0307] In certain embodiments, the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4 / 6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K, or AKT, or a combination thereof. In certain embodiments, the compound of the present invention is combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, belinstat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719, or CLR457, or a combination thereof.

[0308] In certain embodiments, the additional therapeutic agent is selected based on the disease or condition being treated. For example, in the treatment of melanoma, the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alpha-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), pegylated interferon alpha-2b (e.g., PEGINTRON®, SYLATRON™), vemurafenib (e.g., ZELBORAF®), and ipilimumab (e.g., YERVOY®).

[0309] For the treatment of ovarian cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL-AQ®), doxorubicin hydrochloride liposomal (DOXIL®, DOX-SL®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).

[0310] For the treatment of thyroid cancer, the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).

[0311] For the treatment of colon cancer, the additional therapeutic agent is selected from fluorouracil (e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®), bevacizumab (AVASTIN®), irinotecan hydrochloride (CAMPTOSTAR®), capecitabine (XELODA®), cetuximab (ERBITUX®), oxaliplatin (ELOXATIN®), leucovorin calcium (WELLCOVORIN®), regorafenib (STIVARGA®), panitumumab (VECTIBIX®), and dib-aflibercept (ZALTRAP®).

[0312] For the treatment of lung cancer, the additional therapeutic agent may be methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX Selected from PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), paclitaxel (TAXOL®), paclitaxel albumin-stabilized nanoparticle formulation (ABRAXANE®), afatinib dimaleate (GILOTRIF®), pemetrexed disodium (ALIMTA®), bevacizumab (AVASTIN®), carboplatin (PARAPLATIN®), cisplatin (PLATINOL®, PLATINOL-AQ®), crizotinib (XALKORI®), erlotinib hydrochloride (TARCEVA®), gefitinib (IRESSA®), and gemcitabine hydrochloride (GEMZAR®).

[0313] For the treatment of pancreatic cancer, other therapeutic agents may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®).

[0314] For the treatment of cervical cancer, the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®), and topotecan hydrochloride (HYCAMTIN®).

[0315] For the treatment of head and neck cancer, the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®), fluorouracil (ADRUCIL®, EFUDEX®, FLUOROPLEX®), bleomycin (BLENOXANE®), cetuximab (ERBITUX®), cisplatin (PLATINOL®, PLATINOL-AQ®), and docetaxel (TAXOTERE®).

[0316] For the treatment of leukemia, including chronic myelomonocytic leukemia (CMML), the additional therapeutic agent is selected from bosutinib (BOSULIF®), cyclophosphamide (CYTOXAN®, NEOSAR®), cytarabine (CYTOSAR-U®, TARABINE PFS®), dasatinib (SPRYCEL®), imatinib mesylate (GLEEVEC®), ponatinib (ICLUSIG®), nilotinib (TASIGNA®), and omacetaxine mepesuccinate (SYNRIBO®).

[0317] In some cases, patients may experience allergic reactions to the compounds of the present invention and / or other anti-cancer agent(s) during or after administration. Therefore, anti-allergic agents may be administered to minimize the risk of allergic reactions. Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, and hydrocortisone sodium phosphate; e.g., ALA-CORT®, hydrocortisone phosphate, Solu-CORTEF®, HYDROCORT Acetate®, and LANACORT®), prednisolone (e.g., DELTA-Cortel®, ORAPRED®, PEDIAPRED®, and PRELONE®), prednisone (e.g., DELTASONE®, LIQUID TRIPOLYPHOSPHATE), and TRIPOLYPHOSPHATE. RED®, METICORTEN®, and ORASONE®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., DURALONE®, MEDRALONE®, MEDROL®, M-PREDNISOL®, and SOLU-MEDROL®); antihistamines, e.g., diphenhydramine (e.g., BENADRYL®), hydroxyzine, and cyproheptadine; and bronchodilators, e.g., the beta-adrenergic receptor agonists, albuterol (e.g., PROVENTIL®), and terbutaline (BRETHINE®).

[0318] In other cases, patients may experience nausea during and after administration of the compounds of the present invention and / or other anticancer agent(s). Therefore, antiemetic agents may be administered to prevent nausea (upper stomach) and vomiting. Suitable antiemetic agents include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®), dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitan (REZONIC® and Zunrisa®), and combinations thereof.

[0319] In still other cases, medications to alleviate pain experienced during treatment are prescribed to make patients more comfortable. Common over-the-counter pain relievers, such as TYLENOL®, are often used. Opioid pain relievers, such as hydrocodone / paracetamol or hydrocodone / acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OPANA®), and fentanyl (e.g., DURAGESIC®), are also useful for moderate or severe pain.

[0320] Additionally, cytoprotective agents (e.g., neuroprotectants, free radical scavengers, cardioprotectants, anthracycline extravasation neutralizers, nutrients, etc.) may be used as adjunctive therapy to protect normal cells from treatment toxicity and limit organ toxicity. Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, dimemuna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor, and folinic acid).

[0321] In yet another aspect, the compounds of the present invention may be used in combination with known therapeutic processes, for example, with the administration of hormones or with radiation therapy. In certain cases, the compounds of the present invention may be used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0322] The dosage and dosing schedule of the active ingredients used in the combination therapy can be determined by the attending clinician. In certain embodiments, a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I) and the additional therapeutic agent(s) are administered at doses typically used when such agents are used as monotherapy to treat a disease or condition. In other embodiments, a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I) and the additional therapeutic agent(s) are administered at doses lower than those typically used when such agents are used as monotherapy to treat a disease or condition. In certain embodiments, a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds of Section I) and the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.

[0323] In certain embodiments, a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I) and the additional therapeutic agent(s) may act additively or synergistically. A synergistic combination may allow for lower dosages of one or more agents of the combination therapy and / or less frequent administration of one or more agents. Lower dosages or less frequent administration of one or more agents may reduce the toxicity of the treatment without reducing the efficacy of the treatment.

[0324] IV. Pharmaceutical Composition and Dosage Considerations As mentioned above, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of one or more of the above-described compounds formulated with one or more pharmaceutically acceptable carriers (excipients) and / or diluents. The pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for: (1) oral administration, e.g., drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., buccal, sublingual, and those intended for systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, e.g., by subcutaneous, intramuscular, intravenous, or epidural injection, e.g., as a sterile solution or suspension, or sustained-release formulation; (3) topical application, e.g., as a cream, ointment, or controlled-release patch or spray applied to the skin; (4) vaginal or rectal administration, e.g., as a suppository, cream, or foam; (5) sublingual; (6) ocular; (7) transdermal; or (8) nasal administration. In certain embodiments, the present invention provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula I, I-1, I-2, I-3, I-4, or II, or other compounds in Section I) and a pharmaceutically acceptable carrier.

[0325] As used herein, the phrase "therapeutically effective amount" means an amount of a compound, material, or composition containing a compound of the invention that is effective to produce some desired therapeutic effect in at least a subpopulation of cells in an animal, at a reasonable benefit / risk ratio applicable to any medical treatment.

[0326] The phrase "pharmaceutically acceptable" is employed herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0327] Wetting agents, emulsifiers, and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and fragrances, preservatives, and antioxidants may also be present in the composition. Examples of pharmaceutically acceptable antioxidants include (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0328] Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, and / or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated and the particular mode of administration. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of the active ingredient, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent.

[0329] In certain embodiments, formulations of the invention comprise an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle-forming agents such as bile acids, and polymeric carriers such as polyesters and polyanhydrides, and a compound of the invention. In certain embodiments, the above-described formulations render the compounds of the invention orally bioavailable.

[0330] Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0331] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, usually sucrose and acacia or tragacanth), powder, granules, each containing a predetermined amount of a compound of the present invention as the active ingredient, or as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as a pastille (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or mouthwash, etc. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0332] In solid dosage forms of the present invention for oral administration (e.g., capsules, tablets, pills, dragees, powders, granules, lozenges, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, e.g., glycerol; and (4) disintegrants, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates. and sodium carbonate, (5) solvents such as paraffin, (6) absorption enhancers such as quaternary ammonium compounds, and surfactants such as poloxamer and sodium lauryl sulfate, (7) wetting agents such as cetyl alcohol, glycerol monostearate, and nonionic surfactants, (8) absorbents such as kaolin and bentonite clay, (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid, and mixtures thereof, (10) coloring agents, and (11) controlled-release agents such as crospovidone or ethylcellulose. In the case of capsules, tablets, and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-shell gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0333] Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), surfactants, or dispersants. Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine.

[0334] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropylmethylcellulose, other polymer matrices, liposomes, and / or microspheres to provide the desired release profile. They may also be formulated for rapid release, for example, lyophilized. They may also be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be composed to release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0335] The liquid dosage form for oral administration of the compound of the present invention includes pharmaceutically acceptable emulsion, microemulsion, solution, suspension, syrup and elixir.In addition to active ingredient, liquid dosage form may contain inert diluent commonly used in the art, such as water or other solvent, solubilizer, emulsifier, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oil (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol and fatty acid ester of sorbitan, and mixtures thereof.

[0336] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0337] Suspensions may contain, in addition to the active compound, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0338] Formulations of pharmaceutical compositions of the invention for rectal or vaginal administration may be provided as suppositories, which may be prepared by mixing one or more compounds of the invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity, releasing the active compound(s).

[0339] Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such carriers as are known in the art to be appropriate.

[0340] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0341] The ointments, pastes, creams, and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0342] Powders and sprays can contain, in addition to the compounds of the present invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0343] Transdermal patches have the additional advantage of providing controlled delivery of the compound of the present invention to the body.Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium.Absorption enhancers can also be used to increase the flux of the compound across the skin.The rate of such flux can be controlled by providing a rate-controlling membrane or dispersing the compound in a polymer matrix or gel.

[0344] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of the present invention.

[0345] Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions immediately before use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0346] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0347] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of microbial action on the target compounds can be ensured by including various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid, etc. It may also be desirable to include isotonic agents, such as sugars and sodium chloride, in the compositions. In addition, prolonged absorption of injectable pharmaceutical forms may be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[0348] In some cases, in order to prolong the effect of a drug, it is desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.Thus, the absorption rate of the drug depends on its dissolution rate, which in turn depends on the crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0349] Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the drug-to-polymer ratio and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0350] When the compounds of the present invention are administered to humans and animals as pharmaceuticals, they may be administered as they are or, for example, in combination with a pharmaceutically acceptable carrier, as a pharmaceutical composition containing 0.1 to 99% (more preferably, 10 to 30%) of the active ingredient.

[0351] The preparations of the present invention can be administered orally, parenterally, topically, or rectally. They are naturally administered in a form suitable for each administration route. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion, or inhalation, by topical administration with lotion or ointment, and by rectal administration with suppositories. Oral administration is preferred.

[0352] The phrases "parenteral administration" and "administered parenterally" as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intra-arterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intrathecal, and intrasternal injection and infusion.

[0353] The phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally," as used herein, refer to administration of a compound, drug, or other material other than directly into the central nervous system, e.g., subcutaneous administration, so that it enters the patient's system and therefore is subject to metabolic and other similar processes.

[0354] These compounds may be administered to humans and other animals for treatment by any suitable route of administration, including orally, nasally, e.g., by spray, rectally, intravaginally, parenterally, intracisternally, and topically, including buccal and sublingually, as by powders, ointments, or drops.

[0355] Regardless of the route of administration selected, the compounds of the present invention, which may be used in a suitable hydrated form, and / or the pharmaceutical compositions of the present invention are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0356] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0357] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the invention employed, or its ester, salt, or amide, the route of administration, the timing of administration, the rate of excretion or metabolism of the particular compound employed, the rate and extent of absorption, the duration of treatment, other drugs, compounds, and / or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health, and medical history of the patient being treated, and similar factors well known in the medical arts.

[0358] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian may start dosages of the compounds of the present invention used in the pharmaceutical composition at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0359] In general, a suitable daily dose of a compound of the present invention will be that amount of compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the factors described above. Preferably, the compound is administ...

Claims

[Claim 1] The invention described in the specification.

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