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WO2025117672A1 - Indazolyl-pipéridine sulfonamides et composés apparentés et leur utilisation en thérapie - Google Patents

Indazolyl-pipéridine sulfonamides et composés apparentés et leur utilisation en thérapie Download PDF

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Publication number
WO2025117672A1
WO2025117672A1 PCT/US2024/057658 US2024057658W WO2025117672A1 WO 2025117672 A1 WO2025117672 A1 WO 2025117672A1 US 2024057658 W US2024057658 W US 2024057658W WO 2025117672 A1 WO2025117672 A1 WO 2025117672A1
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certain embodiments
compound
disease
malt1
cancer
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Inventor
Kenneth G. Carson
Yingzhi Bi
Geraldine Cirillo HARRIMAN
David J. Diller
Oscar Miguel Moradei
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Hotspot Therapeutics Inc
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Hotspot Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention provides indazolyl-piperidine sulfonamide and related compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder.
  • MALT1 mucosa-associated lymphoid tissue lymphoma translocation protein 1
  • Inflammatory disorders impact a substantial number of patients and often involve situations where the patient’s biological response to a stimulus results in the immune system attacking the body’s own cells or tissues. This can lead to abnormal inflammation and result in chronic pain, redness, swelling, stiffness, and/or damage to normal tissues. Cunent treatment options for these inflammatory disorders are not effective for all patients and/or can have substantial adverse side effects.
  • MALT1 Human mucosa-associated lymphoid tissue protein 1
  • MALT1 inhibition impairs immune suppressive function of regulatory T cells in a tumor microenvironment, implicating MALT1 inhibitors for boosting anti-tumor immunity in the treatment of solid cancers. See, for example, Isabel Hamp et al. in Expert Opinion on Therapeutic Patents (2021) vol.12, pages 1079-1096. New compounds that inhibit MALT1 are needed to treat MALT1- mediated diseases and conditions.
  • the present invention addresses the foregoing needs and provides other related advantages.
  • the invention provides indazolyl-piperidine sulfonamide and related compounds, pharmaceutical compositions, their use for inhibiting mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1), and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, or autoimmune disorder.
  • a disease or condition such as a proliferative disorder, inflammatory disorder, or autoimmune disorder.
  • one aspect of the invention provides a collection of indazolyl-piperidine sulfonamide and related compounds, such as a compound represented by Formula I: or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of indazolyl-piperidine sulfonamide and related compounds are described in the detailed description.
  • the compounds may be part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.
  • Another aspect of the invention provides a method of treating a disease or condition mediated by MALT1 in a subject.
  • the method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-A, I- B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, to a subject in need thereof to treat the disease or condition, as further described in the detailed description.
  • Another aspect of the invention provides a method of inhibiting the activity of MALT1.
  • the method comprises contacting a MALT1 with an effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, to inhibit the activity of said MALT1, as further described in the detailed description.
  • a compound described herein such as a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, to inhibit the activity of said MALT1, as further described in the detailed description.
  • a compound described herein such as a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, to inhibit the activity of said MALT1, as further described in the detailed description.
  • MALT1 mucosa-associated lymphoid tissue lymphoma translocation protein 1
  • alkyl applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March’s Advanced Organic Chemistry, 5 th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
  • aliphatic or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule.
  • aliphatic groups contain 1-6 aliphatic carbon atoms. In certain embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms.
  • aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms.
  • “cycloaliphatic” refers to a monocyclic C 3 -C 6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that 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.
  • 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 units of unsaturation, having one or more atoms in common between the two rings of the ring system.
  • the term includes any permissible ring fusion, such as ortho-fused or spirocyclic.
  • heterocyclic is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and 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, etc.
  • a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge.
  • a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen).
  • a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.
  • Exemplary bicyclic rings include: [0015]
  • Exemplary bridged bicyclics include: . [0016] The term “lower alkyl” refers to a C 1-4 straight or branched alkyl group.
  • lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
  • lower haloalkyl refers to a C 1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.
  • heteroatom means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl)).
  • unsaturated as used herein, means that a moiety has one or more units of unsaturation.
  • bivalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched, hydrocarbon chain refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.
  • alkylene refers to a bivalent alkyl group.
  • An “alkylene chain” is a polymethylene group, i.e., –(CH 2 ) n –, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3.
  • a substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • the term “-(C 0 alkylene)-“ refers to a bond. Accordingly, the term “-(C 0-3 alkylene)-” encompasses a bond (i.e.,C 0 ) and a -(C 1-3 alkylene)- group.
  • alkenylene refers to a bivalent alkenyl group.
  • a substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.
  • halogen or “halo” means F, Cl, Br, or I.
  • aryl used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members.
  • aryl may be used interchangeably with the term “aryl ring.”
  • aryl refers to an aromatic ring system which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non– aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • phenylene refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it.
  • phenylene is a bivalent phenyl group when it has two groups attached to it (e.g., “phenylene” is a trivalent phenyl group when it has three groups attached to it (e.g.,
  • arylene refers to a bivalent aryl group.
  • heteroaryl and “heteroar—,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • 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, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl and “heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where 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.
  • Nonlimiting 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.
  • a heteroaryl group may be mono– or bicyclic.
  • heteroaryl may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted.
  • heteroarylkyl refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.
  • heteroarylene refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it.
  • heteroarylene is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.
  • pyridinylene refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridinylene is a bivalent pyridine radical when it has two groups attached to it (e.g., “pyridinylene” is a trivalent pyridine radical when it has three groups attached to it (e.g., ).
  • pyridazinylene refers to a multivalent pyridazine radical having the appropriate number of open valences to account for groups attached to it.
  • pyridazinylene is a bivalent pyridazine radical when it has two groups attached to it (e.g., ).
  • pyrimidinylene refers to a multivalent pyrimidine radical having the appropriate number of open valences to account for groups attached to it.
  • pyrimidinylene is a bivalent pyrimidine radical when it has two groups attached to it (e.g., [0028]
  • heterocycle e.g., “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above.
  • nitrogen includes a substituted nitrogen.
  • the nitrogen may be N (as in 3,4–dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N– substituted pyrrolidinyl).
  • a heterocyclic ring 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.
  • saturated or partially unsaturated heterocyclic radicals include, without limitation, 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.
  • heterocycle used interchangeably herein, and also 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.
  • a heterocyclyl group may be mono– or bicyclic.
  • heterocyclylalkyl refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.
  • oxo-heterocyclyl refers to a heterocyclyl substituted by an oxo group.
  • heterocyclylene refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it.
  • 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 having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.
  • compounds of the invention may contain “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
  • Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • R* is C 1–6 aliphatic
  • R* is optionally substituted with halogen, – R ⁇ , -(haloR ⁇ ), -OH, –OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2 , or –NO 2
  • each R ⁇ is independently selected from C 1–4 aliphatic, –CH 2 Ph, –O(CH 2 ) 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, and wherein each R ⁇ is unsubstituted or where preceded by halo is substituted only with one or more halogens.
  • An optional substituent on a substitutable nitrogen is independently –R ⁇ , –NR ⁇ 2, – C(O)R ⁇ , –C(O)OR ⁇ , –C(O)C(O)R ⁇ , –C(O)CH 2 C(O)R ⁇ , -S(O) 2 R ⁇ , -S(O) 2 NR ⁇ 2 , –C(S)NR ⁇ 2 , – C(NH)NR ⁇ 2 , or –N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1–6 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 independent occurrences of R ⁇ , taken together with their intervening atom(s) form an
  • the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference.
  • Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases.
  • Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2– naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pec
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1–4 alkyl) 4 salts.
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.
  • structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, 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 compounds of the invention are within the scope of the invention.
  • the invention includes compounds that differ only in the presence of one or more isotopically enriched atoms.
  • 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, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • Chiral center(s) in a compound of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C 1 -C 12 alkyl, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • 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, etc.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “C 3 -C 6 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl.
  • cycloalkylene refers to a bivalent cycloalkyl group.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • 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.
  • 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.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • Exemplary haloalkoxyl groups include -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CF 3 , -OCF 2 CF 3 , and the like.
  • hydroxyalkoxyl refers to an alkoxyl group that is substituted with at least one hydroxyl.
  • exemplary hydroxyalkoxyl groups include -OCH 2 CH 2 OH, -OCH 2 C(H)(OH)CH 2 CH 2 OH, and the like.
  • alkoxylene refers to a bivalent alkoxyl group.
  • the symbol “ ” indicates a point of attachment.
  • any substituent or variable occurs more than one time in any constituent or the compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid.
  • Solidvate encompasses both solution-phase and isolatable solvates.
  • suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • the terms “subject” and “patient” are used interchangeably and refer to organisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and, most preferably, include humans.
  • the term “compound” refers to a quantity of molecules that is sufficient to be weighed, tested for its structural identity, and to have a demonstrable use (e.g., a quantity that can be shown to be active in an assay, an in vitro test, or in vivo test, or a quantity that can be administered to a patient and provide a therapeutic benefit).
  • IC 50 is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.
  • the term “effective amount” refers to the amount of a compound sufficient to effect beneficial or desired results (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 administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate-buffered saline solution, water, emulsions (e.g., such as oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified.
  • a 1 is a 5-6 membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms or an 8- 10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the monocyclic heteroaryl and bicyclic heteroaryl are substituted with x occurrences of R 1 ;
  • a 2 is a 5-6 membered saturated or partially unsaturated heterocyclylene containing 1 or 2 nitrogen atoms, a 5-6 membered saturated carbocyclylene, C 1-6 alkylene, or -(C 1-6 alkylene)-N(R 3 )-, wherein the heterocyclylene and carbocyclylene are substituted with y occurrences of R 4 ;
  • a 3 is a 9-10
  • variables in Formula I above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I.
  • a 1 is a 5-6 membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms or an 8-10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the monocyclic heteroaryl and bicyclic heteroaryl are substituted with x occurrences of R 1 .
  • a 1 is a 5-6 membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 5 membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 . In certain embodiments, A 1 is a 5 membered monocyclic heteroaryl containing 1 nitrogen atom, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 . In certain embodiments, A 1 is a 5 membered monocyclic heteroaryl containing 2 nitrogen atoms, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 6 membered monocyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 . In certain embodiments, A 1 is a 6 membered monocyclic heteroaryl containing 1 nitrogen atom, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 . In certain embodiments, A 1 is a 6 membered monocyclic heteroaryl containing 2 nitrogen atoms, wherein the monocyclic heteroaryl is substituted with x occurrences of R 1 .
  • A1 is an 8-10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is an 8 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is an 8 membered bicyclic heteroaryl containing 1 nitrogen atom, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is an 8 membered bicyclic heteroaryl containing 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 9 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 9 membered bicyclic heteroaryl containing 1 nitrogen atom, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 9 membered bicyclic heteroaryl containing 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 10 membered bicyclic heteroaryl containing 1 nitrogen atom, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • a 1 is a 10 membered bicyclic heteroaryl containing 2 nitrogen atoms, wherein the bicyclic heteroaryl is substituted with x occurrences of R 1 .
  • one ring of the bicyclic heteroaryl in A 1 is aromatic, and the other ring of the bicyclic heteroaryl is partially unsaturated.
  • A1 is pyrazolyl, pyridinyl, or 5,6-dihydro-4H-pyrrolo[1,2- b]pyrazolyl, each of which is substituted with x occurrences of R 1 .
  • a 1 is pyrazolyl substituted with x occurrences of R 1 .
  • a 1 is pyridinyl substituted with x occurrences of R 1 .
  • a 1 is [0072] In certain embodiments, A 1 is selected from the groups depicted in the compounds in Table 1 or 2 below.
  • A2 is a 5-6 membered saturated or partially unsaturated heterocyclylene containing 1 or 2 nitrogen atoms, a 5-6 membered saturated carbocyclylene, C 1-6 alkylene, or -(C 1-6 alkylene)-N(R 3 )-, wherein the heterocyclylene and carbocyclylene are substituted with y occurrences of R 4 .
  • a 2 is a 5-6 membered saturated or partially unsaturated heterocyclylene containing 1 or 2 nitrogen atoms,wherein the heterocyclylene is substituted with y occurrences of R 4 . In certain embodiments, A 2 is a 5 membered saturated or partially unsaturated heterocyclylene containing 1 or 2 nitrogen atoms,wherein the heterocyclylene is substituted with y occurrences of R 4 . In certain embodiments, A 2 is a 5 membered saturated or partially unsaturated heterocyclylene containing 1 nitrogen atom,wherein the heterocyclylene is substituted with y occurrences of R 4 .
  • a 2 is a 5 membered saturated or partially unsaturated heterocyclylene containing 2 nitrogen atoms,wherein the heterocyclylene is substituted with y occurrences of R 4 . In certain embodiments, A 2 is a 6 membered saturated or partially unsaturated heterocyclylene containing 1 or 2 nitrogen atoms,wherein the heterocyclylene is substituted with y occurrences of R 4 . In certain embodiments, A 2 is a 6 membered saturated or partially unsaturated heterocyclylene containing 1 nitrogen atom,wherein the heterocyclylene is substituted with y occurrences of R 4 .
  • a 2 is a 6 membered saturated or partially unsaturated heterocyclylene containing 2 nitrogen atoms,wherein the heterocyclylene is substituted with y occurrences of R 4 .
  • a 2 is a 5-6 membered saturated carbocyclylene, wherein the carbocyclylene is substituted with y occurrences of R 4 .
  • a 2 is a 5 membered saturated carbocyclylene, wherein the carbocyclylene is substituted with y occurrences of R 4 .
  • a 2 is a 6 membered saturated carbocyclylene, wherein the carbocyclylene is substituted with y occurrences of R 4 .
  • a 2 is C 1 -6 alkylene. In certain embodiments, A2 is C 1 alkylene. In certain embodiments, A 2 is C 2 alkylene. In certain embodiments, A 2 is C 3 alkylene. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(H)-. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(CH 3 )-.
  • a 2 is -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 -C(H)(CH 3 )-, -CH 2 CH 2 N(H)-, or -CH 2 CH 2 N(CH 3 )-.
  • a 2 is a piperidinylene.
  • a 2 is pyrrolidinylene.
  • a 2 is cyclohexylene.
  • a 2 is -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 -C(H)(CH 3 )-, -CH 2 CH 2 N(H)-, or -CH 2 CH 2 N(CH 3 )-.
  • a 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is -CH 2 CH 2 -. In certain embodiments, A 2 is -CH 2 CH 2 CH 2 -. In certain embodiments, A 2 is -CH 2 -C(H)(CH 3 )-. In certain embodiments, A 2 is -CH 2 CH 2 N(H)-. In certain embodiments, A 2 is -CH 2 CH 2 N(CH 3 )-. [0076] In certain embodiments, A 2 is selected from the groups depicted in the compounds in Table 1 or 2 below.
  • a 3 is a 9-10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R 5 .
  • a 3 is a 9 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R 5 .
  • a 3 is a 9 membered bicyclic heteroaryl containing 1 nitrogen atom, wherein the heteroaryl is substituted with z occurrences of R 5 .
  • a 3 is a 9 membered bicyclic heteroaryl containing 2 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R 5 . In certain embodiments, A 3 is a 10 membered bicyclic heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R 5 . In certain embodiments, A 3 is a 10 membered bicyclic heteroaryl containing 1 nitrogen atom, wherein the heteroaryl is substituted with z occurrences of R 5 .
  • a 3 is a 10 membered bicyclic heteroaryl containing 2 nitrogen atoms, wherein the heteroaryl is substituted with z occurrences of R 5 .
  • a 3 is In certain embodiments, A 3 is In certain em 3 bodiments, A is In certain embodiments, A 3 is 3 In certain embodiments, A is [0079] In certain embodiments, A 3 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0080] As defined generally above, X 1 is -N(R 2 )S(O) 2 - or -S(O) 2 N(R 2 )-.
  • X 1 is -N(R 2 )S(O) 2 -. In certain embodiments, X 1 is -S(O)2N(R 2 )-. In certain embodiments, X 1 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0081] As defined generally above, R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is C 1-4 alkyl. In certain embodiments, R 1 is C 1 alkyl. In certain embodiments, R 1 is C 2 alkyl. In certain embodiments, R 1 is C 3 alkyl.
  • R 1 is C 4 alkyl. In certain embodiments, R 1 is C 1-4 haloalkyl. In certain embodiments, R 1 is C 1 haloalkyl. In certain embodiments, R 1 is C 2 haloalkyl. In certain embodiments, R 1 is C 3 haloalkyl. In certain embodiments, R 1 is C4 haloalkyl. In certain embodiments, R 1 is -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is -(C 1 alkylene)-(cyano). In certain embodiments, R 1 is -(C 2 alkylene)-(cyano).
  • R 1 is -(C 3 alkylene)-(cyano). In certain embodiments, R 1 is -(C 4 alkylene)-(cyano). In certain embodiments, R 1 is -CF 3 . In certain embodiments, R 1 is -CH 3 . In certain embodiments, R 1 is -CF 2 CH 3 . In certain embodiments, R 1 is -C(CH 3 ) 2 -CN. [0082] In certain embodiments, R 1 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0083] As defined generally above, R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is hydrogen.
  • R 2 is C 1-4 alkyl. In certain embodiments, R 2 is C1 alkyl. In certain embodiments, R 2 is C2 alkyl. In certain embodiments, R 2 is C 3 alkyl. In certain embodiments, R 2 is C 4 alkyl. In certain embodiments, R 2 is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R 2 is C1-4 alkoxyl. In certain embodiments, R 2 is -(C1 alkylene)-(C1-4 alkoxyl). In certain embodiments, R 2 is -(C 2 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 3 alkylene)-(C 1-4 alkoxyl).
  • R 2 is -(C 4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 1 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 2 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 3 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 4 alkoxyl). In certain embodiments, R 2 is -CH 3 . In certain embodiments, R 2 is -CH 2 OCH 3 . In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 1 or 2 below.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is C 1 alkyl. In certain embodiments, R 3 is C 2 alkyl. In certain embodiments, R 3 is C 3 alkyl. In certain embodiments, R 3 is C 4 alkyl. In certain embodiments, R 3 is -CH 3 . In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0085] As defined generally above, R4 represents independently for each occurrence C 1-4 alkyl or oxo. In certain embodimens, R 4 is C 1-4 alkyl.
  • R 4 is C 1 alkyl. In certain embodimens, R 4 is C 2 alkyl. In certain embodimens, R 4 is C 3 alkyl. In certain embodimens, R 4 is C 4 alkyl. In certain embodimens, R 4 is oxo. In certain embodiments, R 4 is -CH 3 . In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0086] As defined generally above, R5 represents independently for each occurrence C 1-4 alkyl or C 1-4 alkoxyl. In certain embodiments, R 5 is C 1-4 alkyl. In certain embodiments, R 5 is C 1 alkyl.
  • R 5 is C 2 alkyl. In certain embodiments, R 5 is C 3 alkyl. In certain embodiments, R 5 is C 4 alkyl. In certain embodiments, R 5 is C 1-4 alkoxyl. In certain embodiments, R 5 is C 1 alkoxyl. In certain embodiments, R 5 is C 2 alkoxyl. In certain embodiments, R 5 is C 3 alkoxyl. In certain embodiments, R 5 is C 4 alkoxyl. In certain embodiments, R 5 is -CH 3 . In certain embodiments, R 5 is -OCH 3 . In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1 or 2 below. [0087] As defined generally above, x and z are independently 0, 1, or 2.
  • x is 0. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, x is selected from the corresponding value in the groups depicted in the compounds in Table 1 or 2 below. In certain embodiments, z is selected from the corresponding value in the groups depicted in the compounds in Table 1 or 2 below. [0088] As defined generally above, y is 0 or 1. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is selected from the corresponding value in the groups depicted in the compounds in Table 1 or 2 below.
  • the description above describes multiple embodiments relating to compounds of Formula I.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the compound of Formula I is further defined by Formula Ia or Ib or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1.
  • the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I.
  • the description above describes multiple embodiments relating to compounds of Formula Ia and Ib.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the compound of Formula I is further defined by Formula Ic or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1.
  • the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I. [0093] The description above describes multiple embodiments relating to compounds of Formula Ic. The patent application specifically contemplates all combinations of the embodiments. [0094] In certain embodiments, the compound of Formula I is further defined by Formula Id or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1. In certain embodiments, the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I. [0095] The description above describes multiple embodiments relating to compounds of Formula Id. The patent application specifically contemplates all combinations of the embodiments.
  • the compound of Formula I is further defined by Formula Ie or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1.
  • the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I.
  • the description above describes multiple embodiments relating to compounds of Formula Ie. The patent application specifically contemplates all combinations of the embodiments.
  • the compound is represented by Formula If, Ig, or Ih or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1.
  • the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I.
  • the description above describes multiple embodiments relating to compounds of Formula If, Ig, and Ih.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the compound is represented by Formula Ii or Ij or a pharmaceutically acceptable salt thereof: wherein m is 0 or 1.
  • the definition of variables R 5 and A 1 is one of the embodiments described above in connection with Formula I.
  • the description above describes multiple embodiments relating to compounds of Formula Ii and Ij.
  • the patent application specifically contemplates all combinations of the embodiments.
  • Another aspect of the invention provides a compound in Table 1 or 2 below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1 or 2 below.
  • a 1 is A 2 is C 1-6 alkylene, or -(C 1-6 alkylene)-N(R 3 )-;
  • a 3 is R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or -(C 0-4 alkylene)-(cyano);
  • R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-(C 1-4 alkoxyl);
  • R 3 is hydrogen or C 1-4 alkyl;
  • R 4 represents independently for each occurrence C 1-4 alkyl or oxo;
  • R 5 represents independently for each occurrence C 1-4 alkyl or C 1-4 alkoxyl;
  • x and z are independently 0 or 1; and
  • y is 0 or 1.
  • variables in Formula I-A above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, (i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I-A.
  • A1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certa 1 in embodiments, A is selected from the groups depicted in the compounds in Table 1 below.
  • a 2 is C 1-6 alkylene, or -(C 1-6 alkylene)-X-(R 3 )-. In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is In certain embodiments, A 2 is C 1-6 alkylene. A 2 is C 1 alkylene. In certain embodiments, A 2 is C 2 alkylene.
  • a 2 is C 3 alkylene. In certain embodiments, A 2 is C 4 alkylene. In certain embodiments, A 2 is C 5 alkylene. In certain embodiments, A 2 is C 6 alkylene. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1 alkylene)- N(R 3 )-. In certain embodiments, A 2 is -(C 2 alkylene)-N(R 3 )-. In certain embodiments, A 2 is - (C 3 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1-3 alkylene)-C(H)(CH 3 )-.
  • a 2 is -(C 1 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 2 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 3 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1 alkylene)- N(R 3 )-. In certain embodiments, A 2 is -(C 2 alkylene)-N(R 3 )-. In certain embodiments, A 2 is - (C 3 alkylene)-N(R 3 )-. In certain embodiments, A 2 is - (C 3 alkylene)-N(R 3 )-.
  • a 2 is selected from the groups depicted in the compounds in Table 1 below.
  • A3 is In certain embodiments, A 3 is In certain embo 3 diments, A is In certain embodiments, A 3 is selected from the groups depicted in the compounds in Table 1 below.
  • R1 represents independently for each occurrence C1-4 alkyl, C 1-4 haloalkyl, or -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is C 1-4 alkyl. In certain embodiments, R 1 is C 1 alkyl. In certain embodiments, R 1 is C 2 alkyl. In certain embodiments, R 1 is C 3 alkyl.
  • R 1 is C 4 alkyl. In certain embodiments, R 1 is C 1-4 haloalkyl. In certain embodiments, R 1 is C 1 haloalkyl. In certain embodiments, R 1 is C 2 haloalkyl. In certain embodiments, R 1 is C 3 haloalkyl. In certain embodiments, R 1 is C 4 haloalkyl. In certain embodiments, R 1 is -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is -(C 1 alkylene)-(cyano). In certain embodiments, R 1 is -(C 2 alkylene)-(cyano).
  • R 1 is -(C 3 alkylene)-(cyano). In certain embodiments, R 1 is -(C 4 alkylene)-(cyano). In certain embodiments, R 1 is -CF 3 . In certain embodiments, R 1 is -CH 3 . In certain embodiments, R 1 is -CF 2 CH 3 . In certain embodiments, R 1 is -C(CH 3 ) 2 -CN. [0110] In certain embodiments, R1 is selected from the groups depicted in the compounds in Table 1 below. [0111] As defined generally above, R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is hydrogen.
  • R 2 is C 1-4 alkyl. In certain embodiments, R 2 is C 1 alkyl. In certain embodiments, R 2 is C 2 alkyl. In certain embodiments, R 2 is C 3 alkyl. In certain embodiments, R 2 is C 4 alkyl. In certain embodiments, R 2 is -(C 1-4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is C 1-4 alkoxyl. In certain embodiments, R 2 is -(C 1 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 2 alkylene)-(C 1-4 alkoxyl).
  • R 2 is -(C 3 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 1 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 2 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 3 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 4 alkoxyl). In certain embodiments, R 2 is -CH 3 . In certain embodiments, R 2 is -CH 2 OCH 3 .
  • R 2 is selected from the groups depicted in the compounds in Table 1 below.
  • R 3 is hydrogen or C 1-4 alkyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is C 1 alkyl. In certain embodiments, R 3 is C 2 alkyl. In certain embodiments, R 3 is C 3 alkyl. In certain embodiments, R 3 is C 4 alkyl. In certain embodiments, R 3 is -CH 3 . In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1 below. [0113] As defined generally above, R4 represents independently for each occurrence C 1-4 alkyl or oxo.
  • R 4 is C 1-4 alkyl. In certain embodiments, R 4 is C 1 alkyl. In certain embodiments, R 4 is C 2 alkyl. In certain embodiments, R 4 is C 3 alkyl. In certain embodiments, R 4 is C 4 alkyl. In certain embodiments, R 4 is oxo. In certain embodiments, R 4 is -CH 3 . In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1 below. [0114] As defined generally above, R5 represents independently for each occurrence C 1-4 alkyl or C 1-4 alkoxyl. In certain embodiments, R 5 is C 1-4 alkyl. In certain embodiments, R 5 is C 1 alkyl.
  • R 5 is C 2 alkyl. In certain embodiments, R 5 is C 3 alkyl. In certain embodiments, R 5 is C 4 alkyl. In certain embodiments, R 5 is C 1-4 alkoxyl. In certain embodiments, R 5 is C 1 alkoxyl. In certain embodiments, R 5 is C 2 alkoxyl. In certain embodiments, R 5 is C 3 alkoxyl. In certain embodiments, R 5 is C 4 alkoxyl. In certain embodiments, R 5 is -CH 3 . In certain embodiments, R 5 is -OCH 3 . In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1 below. [0115] As defined generally above, x and z are independently 0 or 1.
  • x is 0. In certain embodiments, x is 1. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, x is selected from the corresponding value in the groups depicted in the compounds in Table 1 below. In certain embodiments, z is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • y is 0 or 1. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is selected from the corresponding value in the groups depicted in the compounds in Table 1 below.
  • Another aspect of the invention provides a compound in Table 1 below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1 below.
  • a 1 is A 2 is C 1-6 alkylene, or -(C 1-6 alkylene)-N(R 3 )-;
  • a 3 is R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or -(C 0-4 alkylene)-cyano;
  • R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-(C 1-4 alkoxyl);
  • R 3 is hydrogen or C 1-4 alkyl;
  • R 4 represents independently for each occurrence C 1-4 alkyl or oxo;
  • R 5 represents independently for each occurrence C 1-4 alkyl or C 1-4 alkoxyl;
  • x and z are independently 0 or 1; and
  • y is 0 or 1 [0120]
  • the definitions of variables in Formula I-B above encompass multiple chemical groups.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above, (ii) the definition of a variable is a collection of two or more of the chemical groups selected from those set forth above, and (iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is a compound of Formula I-B.
  • a 1 is or In certain embodim 1 ents, A is .
  • a 1 is In certain embodiments, A 1 is .
  • a 1 is In certain embodiments, A 1 is selected from the groups depicted in the compounds in Table 1 below.
  • a 2 is C 1-6 alkylene, or -(C 1-6 alkylene)-X-(R 3 )-. In certain embodiments, A 2 is In certain embodiments, A 2 is 2 In certain embodiments, A is In certain embodiments, A 2 is In cer 2 tain embodiments, A is C 1-6 alkylene. A 2 is C 1 alkylene. In certain embodiments, A 2 is C 2 alkylene. In certain embodiments, A 2 is C 3 alkylene. In certain embodiments, A 2 is C 4 alkylene. In certain embodiments, A 2 is C 5 alkylene. In certain embodiments, A 2 is C 6 alkylene.
  • a 2 is -(C 1-6 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1 alkylene)- N(R 3 )-. In certain embodiments, A 2 is -(C 2 alkylene)-N(R 3 )-. In certain embodiments, A 2 is - (C 3 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1-3 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 1 alkylene)-C(H)(CH 3 )-.
  • a 2 is -(C 2 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 3 alkylene)-C(H)(CH 3 )-. In certain embodiments, A 2 is -(C 1-6 alkylene)-N(R 3 )-. In certain embodiments, A 2 is -(C 1 alkylene)- N(R 3 )-. In certain embodiments, A 2 is -(C 2 alkylene)-N(R 3 )-. In certain embodiments, A 2 is - (C 3 alkylene)-N(R 3 )-. In certain embodiments, A 2 is selected from the groups depicted in the compounds in Table 2 below.
  • a 3 is . In certain embodiments, A 3 is In certa 3 in embodiments, A is In certain embodiments, A 3 is selected from the groups depicted in the compounds in Table 2 below.
  • R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, or -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is C 1-4 alkyl. In certain embodiments, R 1 is C 1 alkyl. In certain embodiments, R 1 is C 2 alkyl. In certain embodiments, R 1 is C 3 alkyl. In certain embodiments, R 1 is C 4 alkyl.
  • R 1 is C 1-4 haloalkyl. In certain embodiments, R 1 is C 1 haloalkyl. In certain embodiments, R 1 is C 2 haloalkyl. In certain embodiments, R 1 is C 3 haloalkyl. In certain embodiments, R 1 is C 4 haloalkyl. In certain embodiments, R 1 is -(C 0-4 alkylene)-(cyano). In certain embodiments, R 1 is cyano. In certain embodiments, R 1 is -(C 1 alkylene)-(cyano). In certain embodiments, R 1 is -(C 2 alkylene)-(cyano). In certain embodiments, R 1 is -(C 3 alkylene)-(cyano).
  • R 1 is -(C 4 alkylene)-(cyano). In certain embodiments, R 1 is -CF 3 . In certain embodiments, R 1 is -CH 3 . In certain embodiments, R 1 is -CF 2 CH 3 . In certain embodiments, R 1 is -C(CH 3 ) 2 -CN. [0126] In certain embodiments, R 1 is selected from the groups depicted in the compounds in Table 2 below. [0127] As defined generally above, R 2 is hydrogen, C 1-4 alkyl, or -(C 1-4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C 1-4 alkyl.
  • R 2 is C 1 alkyl. In certain embodiments, R 2 is C 2 alkyl. In certain embodiments, R 2 is C 3 alkyl. In certain embodiments, R 2 is C 4 alkyl. In certain embodiments, R 2 is -(C 1-4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is C 1-4 alkoxyl. In certain embodiments, R 2 is -(C 1 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C2 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 3 alkylene)-(C 1-4 alkoxyl).
  • R 2 is -(C 4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 1 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 2 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 3 alkoxyl). In certain embodiments, R 2 is -(C 1 alkylene)-(C 4 alkoxyl). In certain embodiments, R 2 is -CH 3 . In certain embodiments, R 2 is -CH 2 OCH 3 . In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 2 below.
  • R3 is hydrogen or C1-4 alkyl. In certain embodiments, R3 is hydrogen. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is C 1 alkyl. In certain embodiments, R 3 is C 2 alkyl. In certain embodiments, R 3 is C 3 alkyl. In certain embodiments, R 3 is C 4 alkyl. In certain embodiments, R 3 is -CH 3 . In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 2 below. [0129] As defined generally above, R4 represents independently for each occurrence C1-4 alkyl or oxo. In certain embodiments, R 4 is C 1-4 alkyl.
  • R 4 is C 1 alkyl. In certain embodiments, R 4 is C 2 alkyl. In certain embodiments, R 4 is C 3 alkyl. In certain embodiments, R 4 is C 4 alkyl. In certain embodiments, R 4 is oxo. In certain embodiments, R 4 is -CH 3 . In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 2 below. [0130] As defined generally above, R5 represents independently for each occurrence C1-4 alkyl or C 1-4 alkoxyl. In certain embodiments, R 5 is C 1-4 alkyl. In certain embodiments, R 5 is C 1 alkyl. In certain embodiments, R 5 is C 2 alkyl.
  • R 5 is C 3 alkyl. In certain embodiments, R 5 is C 4 alkyl. In certain embodiments, R 5 is C 1-4 alkoxyl. In certain embodiments, R 5 is C 1 alkoxyl. In certain embodiments, R 5 is C 2 alkoxyl. In certain embodiments, R 5 is C 3 alkoxyl. In certain embodiments, R 5 is C 4 alkoxyl. In certain embodiments, R 5 is -CH 3 . In certain embodiments, R 5 is -OCH 3 . In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 2 below. [0131] As defined generally above, x and z are independently 0 or 1. In certain embodiments, x is 0.
  • x is 1. In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, x is selected from the corresponding value in the groups depicted in the compounds in Table 2 below. In certain embodiments, z is selected from the corresponding value in the groups depicted in the compounds in Table 2 below. [0132] As defined generally above, y is 0 or 1. In certain embodiments, y is 0. In certain embodiments, y is 1. In certain embodiments, y is selected from the corresponding value in the groups depicted in the compounds in Table 2 below.
  • Another aspect of the invention provides a compound in Table 2 below, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 2.
  • Exemplary diseases or conditions mediated by MALT1 include proliferative disorders (e.g., cancer, neoplasia), inflammatory disorders (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), autoimmune disorders, fibrotic disorders, metabolic disorders, cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory responses in COVID-19 infections.
  • proliferative disorders e.g., cancer, neoplasia
  • inflammatory disorders e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • autoimmune disorders e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • fibrotic disorders e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • metabolic disorders e.g., cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory responses in COVID-19 infections.
  • the method comprises administering to a subject in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, to treat the disease or condition.
  • a compound described herein such as a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, or defined by one of the embodiments described above. Further description of exemplary diseases or conditions mediated by MALT1 is provided herein below.
  • Another aspect of the invention provides a method of inhibiting the activity of MALT1.
  • the method comprises contacting a MALT1 with an effective amount of a compound described herein, such as a compound of Formula I, I- A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, to inhibit the activity of said MALT1.
  • the compound is a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disease or condition described herein, such as an inflammatory disorder or an allergic disorder.
  • the compound is a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I) for treating a disease or condition, such as a disease or condition described herein.
  • the compound is a compound of Formula I, I-A, I- B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • the subject is a human. In certain embodiments, the subject is an adult human. In certain embodiments, the subject is a pediatric human. In certain embodiments, the subject is a geriatric human. Exemplary Diseases or Conditions
  • Exemplary diseases or conditions mediated by MALT1 include proliferative disorders (e.g, cancer, neoplasia), inflammatory disorders (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), autoimmune disorders, fibrotic disorders, metabolic disorders, cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory responses in COVID-19 infections.
  • proliferative disorders e.g, cancer, neoplasia
  • inflammatory disorders e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • autoimmune disorders e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • fibrotic disorders e.g., metabolic disorders, cardiovascular disorders, cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory responses in COVID-19 infections.
  • the disease or condition mediated by MALT1 is a proliferative disorder. In certain embodiments, the disease or condition mediated by MALT1 is inflammatory disorder. In certain embodiments, the disease or condition mediated by MALT1 is an autoimmune disorder. In certain embodiments, the disease or condition mediated by MALT1 is a fibrotic disorder. In certain embodiments, the disease or condition mediated by MALT1 is a metabolic disorder. In certain embodiments, the disease or condition mediated by MALT1 is a cardiovascular disorder. In certain embodiments, the disease or condition mediated by MALT I is a cerebrovascular disorder. In certain embodiments, the disease or condition mediated by MALT1 is a myeloid cell-driven hyper- inflammatory response in a COVID-19 infection.
  • the disease or condition mediated by MALT1 is cancer.
  • the cancer is selected from is non-small cell lung cancer (NSCLC), small cell lung cancer, colorectal cancer, rectal cancer, and pancreatic cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC), pancreatic cancer, and colorectal cancer. In certain embodiments, the cancer is selected from non-small cell lung cancer (NSCLC) and pancreatic cancer.
  • the cancer is a solid tumor. In certain embodiments, the cancer is a melanoma, carcinoma, or blastoma In certain embodiments, the cancer is a melanoma In certain embodiments, the cancer is a carcinoma In certain embodiments, the cancer is an adenocarcinoma In certain embodiments, the cancer is a blastoma.
  • the cancer is lung cancer, pancreatic cancer, colorectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, or a leukemia.
  • the cancer is lung cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colorectal cancer.
  • the cancer is breast cancer.
  • the cancer is cervical cancer.
  • the cancer is prostate cancer.
  • the cancer is gastric cancer.
  • the cancer is skin cancer.
  • the cancer is liver cancer.
  • the cancer is bile duct cancer.
  • the cancer is nervous system cancer.
  • 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.
  • the cancer is breast adenocarcinoma.
  • the cancer is lung adenocarcinoma.
  • the cancer is pancreatic adenocarcinoma.
  • the cancer is cervical adenocarcinoma.
  • the cancer is prostate adenocarcinoma.
  • the cancer is gastric adenocarcinoma.
  • the cancer is melanoma.
  • 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.
  • the cancer is glioblastoma or neuroblastoma. In certain embodiments, the cancer is glioblastoma. In certain embodiments, the cancer is neuroblastoma.
  • the cancer is lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is non-small cell lung cancer, pancreatic cancer, or colorectal cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is non-small cell lung cancer.
  • the cancer is a lymphoma or a leukemia, In certain embodiments, the cancer is a B-cell lymphoma or chronic myelocytic leukemia.
  • the cancer is a 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 ornon-Hodgkin’s disease), Waldenstrom’s macroglobulinemia, multiple myeloma, heavy chain disease, or a solid tumor such as a sarcoma or carcinoma (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcom
  • a leukemia
  • the cancer is MALT1 is Hodgkin’s lymphoma, nonHodgkin’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).
  • DLBCL diffuse large B-cell lymphoma
  • MALT lymphoma germinal center B-cell-like diffuse large B-cell lymphoma
  • PMBL primary mediastinal B-cell lymphoma
  • ABS-DLBCL activated B-cell-like diffuse large B-cell lymphoma
  • the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma
  • GBM glioblastoma multiforme
  • medulloblastoma craniopharyngioma
  • ependymoma pinealoma
  • hemangioblastoma acoustic neuroma
  • oligodendroglioma schwannoma
  • neurofibrosarcoma meningioma, melanoma
  • neuroblastoma or
  • 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, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal (PNET) tumor, or schwannoma.
  • astrocytoma e.g. Grade I - Pilocytic Astrocytoma, Grade II - Low-grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - G
  • the cancer is a type found more commonly in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, primitive neuroectodermal tumors (PNET), or rhabdoid tumor.
  • JPA juvenile pilocytic astrocytoma
  • medulloblastoma optic nerve glioma
  • pineal tumor pineal tumor
  • PNET primitive neuroectodermal tumors
  • rhabdoid tumor rhabdoid tumor.
  • the cancer is mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin’s Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphoc
  • the cancer is hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), prostate cancer, testicular cancer, gallbladder cancer, hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, Ewing sarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, gastrointestinal/stomach (GIST) cancer, lymphoma, squamous cell carcinoma of the head and neck (SCCHN), salivary gland cancer, glioma, or brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Wald
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian epithelial cancer
  • the cancer is selected from 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, ovarian epithelial cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic duct
  • the cancer is renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • the cancer is hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis- 1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom’s macroglobulinemia, or medulloblastoma.
  • HCC hepatocellular carcinoma
  • hepatoblastoma colon cancer
  • rectal cancer ovarian cancer
  • ovarian cancer ovarian
  • 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 cancer. In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is papillary serous cystadenocarcinoma. In certain embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In certain embodiments, the cancer is hepatocholangiocarcinoma.
  • HCC hepatocellular carcinoma
  • 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 cancer. 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 cancer. 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 glioma. In certain embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In certain embodiments, the cancer is neurofibromatosis-1 associated MPNST. In certain embodiments, the cancer is Waldenstrom’s macroglobulinemia. In certain embodiments, the cancer is medulloblastoma.
  • the cancer is a lymphoma. In certain embodiments, the cancer is a leukemia. In certain embodiments, the cancer is Hodgkin’s lymphoma. In certain embodiments, the cancer is non-Hodgkin’s lymphoma. In certain embodiments, the cancer is Burkitt’s lymphoma. In certain embodiments, the cancer is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the cancer is MALT lymphoma. In certain embodiments, the cancer is 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 activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL). In certain embodiments, the cancer is a hematological cancer.
  • GCB- DLBCL germinal center B-cell-like diffuse large B-cell lymphoma
  • PMBL primary mediastinal B-
  • the proliferative disease is a cancer associated with or dependent on a MALT1 fusion protein (e.g., API2-MALT1).
  • the proliferative disease is a cancer associated with dependence on B-cell lymphoma 10 (BcllO).
  • the proliferative disease is a cancer associated with dependence on caspase recruitment domain-containing protein (CARD1).
  • the proliferative disease is a cancer associated with dependence on NF-KB.
  • the cancer is a hematological malignancy.
  • Additional exemplary cancers include but are not limited to acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g, lymphangiosarcoma, lymphangioendotheliosarcoma, 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 cancer, medullary carcinoma of the breast, triple negative breast cancer (TNBC)); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adeno
  • gastric cancer e.g., stomach adenocarcinoma
  • GIST gastrointestinal stromal tumor
  • germ cell 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
  • alpha chain disease alpha chain disease, gamma chain disease, mu chain disease; hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a.
  • Wilms tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); 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 cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a.
  • HCC hepatocellular cancer
  • lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
  • myelofibrosis MF
  • chronic idiopathic myelofibrosis chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)
  • neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
  • neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor
  • osteosarcoma e.g., bone cancer
  • ovarian cancer e.g, cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
  • papillary adenocarcinoma pancreatic cancer
  • pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors
  • penile cancer
  • the cancer is a hematological malignancy.
  • hematological malignancies include but are not limited to leukemia, such as acute lymphoblastic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic 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); lymphoma, such as Hodgkin lymphoma (HL) (e.g., B- cell HL, T-cell HL) and non-Hodg
  • NHL acute lymphoblastic
  • cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary 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); lymphoma of an immune privileged site (e.g., cerebral lymphoma, ocular lymphoma, lymphoma of the placenta, lymphoma of the fetus, testicular lymphoma); a mixture of one or more leukemia/lymphoma as described above; myelodysplasia; multiple myeloma (MM); heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), polycythemia vera, Wilm’s tumor, and Ewing’s sarcoma.
  • CCL
  • said disease or condition mediated by MALT1 is a multiple myeloma.
  • said disease or condition mediated by MALT1 is a leukemia (e.g., acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, or promyelocytic leukemia).
  • leukemia e.g., acute lymphocytic leukemia, acute and chronic myelogenous leukemia, chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myelomonocytic leukemia, or promyelocytic leukemia.
  • said disease or condition mediated by MALT1 is a 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 tumors, Hodgkin's disease or non-Hodgkin’s disease).
  • said disease or condition mediated by MALT1 is myelodysplastic syndrome.
  • said disease or condition mediated by MALT1 is fibrosarcoma.
  • said disease or condition mediated by MALT1 is rhabdomyosarcoma.
  • said disease or condition mediated by MALT1 is astrocytoma. In certain embodiments, said disease or condition mediated by MALT1 is neuroblastoma. In certain embodiments, said disease or condition mediated by MALT1 is glioma and schwannomas. In certain embodiments, said disease or condition mediated by MALT1 is melanoma. In certain embodiments, said disease or condition mediated by MALT1 is seminoma. In certain embodiments, said disease or condition mediated by MALT1 is teratocarcinoma. In certain embodiments, said disease or condition mediated by MALT1 is osteosarcoma In certain embodiments, said disease or condition mediated by MALT1 is xenoderma pigmentosum.
  • said disease or condition mediated by MALT1 is keratoctanthoma. In certain embodiments, said disease or condition mediated by MALT1 is thyroid follicular cancer. In certain embodiments, said disease or condition mediated by MALT1 is Kaposi’s sarcoma. In certain embodiments, said disease or condition mediated by MALT1 is melanoma. In certain embodiments, said disease or condition mediated by MALT1 is teratoma. In certain embodiments, said disease or condition mediated by MALT1 is rhabdomyosarcoma. In certain embodiments, said disease or condition mediated by MALT1 is a metastatic and bone disorder. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the bone.
  • said disease or condition mediated by MALT1 is cancer of the mouth/pharynx. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the esophagus. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the larynx. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the stomach. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the intestine. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the colon. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the rectum.
  • said disease or condition mediated by MALT1 is cancer of the lung (e.g, non-small cell lung cancer or small cell lung cancer). In certain embodiments, said disease or condition mediated by MALT1 is cancer of the liver. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the pancreas. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the nerve. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the brain (e.g, glioma or glioblastoma multiforme). In certain embodiments, said disease or condition mediated by MALT1 is cancer of the head and neck. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the throat.
  • lung e.g, non-small cell lung cancer or small cell lung cancer.
  • said disease or condition mediated by MALT1 is cancer of the liver. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the pancreas. In certain embodiments, said disease or
  • said disease or condition mediated by MALT1 is cancer of the ovary. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the uterus. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the prostate. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the testis. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the bladder. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the kidney. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the breast. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the gall bladder.
  • said disease or condition mediated by MALT1 is cancer of the cervix. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the thyroid. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the prostate. In certain embodiments, said disease or condition mediated by MALT1 is cancer of the skin (e.g., skin squamous cell carcinoma). In certain embodiments, said disease or condition mediated by MALT1 is a solid tumor. In certain embodiments, said disease or condition mediated by MALT1 is gastric cancer. In certain embodiments, said disease or condition mediated by MALT1 is hepatocellular carcinoma. In certain embodiments, said disease or condition mediated by MALT1 is a peripheral nerve sheath tumor. In certain embodiments, said disease or condition mediated by MALT1 is pulmonary arterial hypertension.
  • the disease is a cancer associated with a viral infection.
  • the disease is a cancer resulting from infection with an oncovirus.
  • the oncovirus 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).
  • the disease is human T-lymphotropic virus.
  • the disease is Kaposi’s sarcoma-associated herpesvirus.
  • the disease is Epstein-Barr virus.
  • Leukemias and lymphomas which may be associated with an oncoviral include: for HTLV, adult T-cell leukemia; for HHV-8, Castleman’s disease and primary effusion lymphoma; and for EBV, Burkitt’s lymphoma, Hogdkin’s lymphoma, and posttransplant lymphoproliferative disease.
  • said disease or condition mediated by MALT1 is an inflammatory disorder or allergic disorder.
  • said disease or condition mediated by MALT1 is an inflammatory disorder, such as autoimmune disorders, chronic inflammatory disorders, acute inflammatory disorders, auto-inflammatory disorders, fibrotic disorders, metabolic disorders, neoplasias, cardiovascular or cerebrovascular disorders, and myeloid cell-driven hyper-inflammatory response in COVID-19 infections.
  • said disease or condition mediated by MALT1 is an allergic disorder, such as asthma and allergic rhinitis.
  • said disease or condition mediated by MALT1 is a disease or disorder of tissues and 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 Immunodeficiency Syndrome (AIDS)].
  • SLE systemic lupus erythematosus
  • ITP immune thrombocytopenic purpura
  • AHA autoimmune hemolytic anemia
  • AIN autoimmune neutropenia
  • Evans syndrome proliferative and hyperproliferative diseases, such as cancer, atherosclerosis, rheumatoid arthritis, psoria
  • said disease or condition mediated by MALT1 is an immunologically-mediated disease, such as allograft rejection (e.g., rejection of transplanted organs or tissues).
  • said disease or condition mediated by MALT1 is a tissue injury (e.g., associated with organ transplant or revascularization procedures).
  • said disease or condition mediated by MALT1 is a disease or disorder of the respiratory tract (e.g., asthma).
  • said disease or condition mediated by MALT1 is allergic rhinitis.
  • said disease or condition mediated by MALT1 is a disease or disorder of the bone and joints (e.g., arthritis, rheumatoid arthritis).
  • said disease or condition mediated by MALT1 is a disease or disorder of the skin. In certain embodiments, said disease or condition mediated by MALT1 is a disease or disorder of the gastrointestinal tract. [0179] In certain embodiments, said disease or condition mediated by MALT1 is a reversible obstructive airways disease, such as asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma). In certain embodiments, said disease or condition mediated by MALT1 is chronic or inveterate asthma (e.g., late asthma airways hyper-responsiveness). In certain embodiments, said disease or condition mediated by MALT1 is bronchitis.
  • asthma e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma
  • said disease or condition mediated by MALT1 is chronic or inveterate asthma (e.g., late asthma airways hyper-responsiveness). In certain embodiments, said disease or condition mediated by MALT
  • said disease or condition mediated by MALT1 is a condition characterized by an inflammation of the nasal mucus membrane.
  • said disease or condition mediated by MALT1 is acute rhinitis.
  • said disease or condition mediated by MALT1 is allergic rhinitis.
  • said disease or condition mediated by MALT1 is atrophic rhinitis.
  • said disease or condition mediated by MALT1 is chronic rhinitis (e.g., rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca, and rhinitis medicamentosa).
  • said disease or condition mediated by MALT1 is membranous rhinitis (e.g., croupous rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofoulous rhinitis).
  • said disease or condition mediated by MALT1 is seasonal rhinitis [e.g., rhinitis nervosa (hay fever), vasomotor rhinitis, sarcoidosis, farmer's lung, and related diseases, such as fibroid lung and idiopathic interstitial pneumonia].
  • said disease or condition mediated by MALT1 includes pannus formation.
  • said disease or condition mediated by MALT1 does not include pannus formation.
  • said disease or condition mediated by MALT1 is rheumatoid arthritis.
  • said disease or condition mediated by MALT1 is seronegative spondyloarthropathis (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter’s disease).
  • said disease or condition mediated by MALT1 is Behcet’s disease.
  • said disease or condition mediated by MALT1 is Sjogren’s syndrome.
  • said disease or condition mediated by MALT1 is systemic sclerosis.
  • said disease or condition mediated by MALT1 is psoriasis. In certain embodiments, said disease or condition mediated by MALT1 is systemic sclerosis. In certain embodiments, said disease or condition mediated by MALT1 is atopical dermatitis. In certain embodiments, said disease or condition mediated by MALT1 is contact dermatitis. In certain embodiments, said disease or condition mediated by MALT1 is eczematous dermatitis. In certain embodiments, said disease or condition mediated by MALT1 is seborrhoelic dermatitis. In certain embodiments, said disease or condition mediated by MALT1 is Lichen planus.
  • said disease or condition mediated by MALT1 is Pemphigus. In certain embodiments, said disease or condition mediated by MALT1 is bullous Pemphigus. In certain embodiments, said disease or condition mediated by MALT1 is epidermolysis bullosa. In certain embodiments, said disease or condition mediated by MALT1 is urticaria. In certain embodiments, said disease or condition mediated by MALT1 is angiodermas. In certain embodiments, said disease or condition mediated by MALT1 is vasculitides. In certain embodiments, said disease or condition mediated by MALT1 is erythemas. In certain embodiments, said disease or condition mediated by MALT1 is cutaneous eosinophilias.
  • said disease or condition mediated by MALT1 is uveitis. In certain embodiments, said disease or condition mediated by MALT1 is Alopecia. In certain embodiments, said disease or condition mediated by MALT1 is areata. In certain embodiments, said disease or condition mediated by MALT1 is vernal conjunctivitis.
  • said disease or condition mediated by MALT1 is Coeliac disease. In certain embodiments, said disease or condition mediated by MALT1 is proctitis. In certain embodiments, said disease or condition mediated by MALT1 is eosinophilic gastro-enteritis. In certain embodiments, said disease or condition mediated by MALT1 is mastocytosis. In certain embodiments, said disease or condition mediated by MALT1 is pancreatitis. In certain embodiments, said disease or condition mediated by MALT1 is Crohn’s disease. In certain embodiments, said disease or condition mediated by MALT1 is ulcerative colitis.
  • said disease or condition mediated by MALT1 is a food-related allergy having effects remote from the gut (e.g., migraine, rhinitis, and eczema).
  • said disease or condition mediated by MALT1 is multiple sclerosis.
  • said disease or condition mediated by MALT1 is artherosclerosis.
  • said disease or condition mediated by MALT1 is acquired immunodeficiency syndrome (AIDS).
  • said disease or condition mediated by MALT1 is lupus.
  • said disease or condition mediated by MALT1 is lupus erythematosus.
  • said disease or condition mediated by MALT1 is systemic lupus erythematosus. In certain embodiments, said disease or condition mediated by MALT1 is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition mediated by MALT1 is myasthenia gravis. In certain embodiments, said disease or condition mediated by MALT1 is type I diabetes. In certain embodiments, said disease or condition mediated by MALT1 is nephrotic syndrome. In certain embodiments, said disease or condition mediated by MALT1 is eosinophilia fasciitis. In certain embodiments, said disease or condition mediated by MALT1 is hyper IgE syndrome.
  • said disease or condition mediated by MALT1 is lepromatous leprosy. In certain embodiments, said disease or condition mediated by MALT1 is sezary syndrome. In certain embodiments, said disease or condition mediated by MALT1 is idiopathic thrombocytopenia purpura. In certain embodiments, said disease or condition mediated by MALT1 is restenosis following angioplasty. In certain embodiments, said disease or condition mediated by MALT1 is a tumor (e.g., leukemia, lymphomas). In certain embodiments, said disease or condition mediated by MALT1 is artherosclerosis.
  • said disease or condition mediated by MALT1 is acute chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition mediated by MALT1 is chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea). In certain embodiments, said disease or condition mediated by MALT1 is chronic graft-versus-host disease. [0185] In certain embodiments, said disease or condition mediated by MALT1 is an acute inflammatory disorder. In certain embodiments, said disease or condition mediated by MALT1 is an auto-inflammatory disorder.
  • said disease or condition mediated by MALT1 is a fibrotic disorder. In certain embodiments, said disease or condition mediated by MALT1 is a metabolic disorder. In certain embodiments, said disease or condition mediated by MALT1 is a neoplasia. In certain embodiments, said disease or condition mediated by MALT1 is a cardiovascular or cerebrovascular disorder. In certain embodiments, said disease or condition mediated by MALT1 is a myeloid cell-driven hyper- inflammatory response in COVID- 19 infections.
  • said disease or condition mediated by MALT1 is an autoimmune disorder. In certain embodiments, said disease or condition mediated by MALT1 is a chronic inflammatory disorder. In certain embodiments, said disease or condition mediated by MALT1 is an acute inflammatory disorder. In certain embodiments, said disease or condition mediated by MALT1 is an auto-inflammatory disorder. In certain embodiments, said disease or condition mediated by MALT1 is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an auto- inflammatory disorder.
  • said disease or condition mediated by MALT1 is an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease).
  • said disease or condition mediated by MALT1 is multiple sclerosis.
  • said disease or condition mediated by MALT1 is psoriasis.
  • said disease or condition mediated by MALT1 is arthritis.
  • said disease or condition mediated by MALT1 is rheumatoid arthritis.
  • said disease or condition mediated by MALT1 is osteoarthritis.
  • said disease or condition mediated by MALT1 is juvenile arthritis.
  • said disease or condition mediated by MALT1 is psoriatic arthritis. In certain embodiments, said disease or condition mediated by MALT1 is reactive arthritis. In certain embodiments, said disease or condition mediated by MALT1 is ankylosing spondylitis. In certain embodiments, said disease or condition mediated by MALT1 is cryopyrin-associated periodic syndromes. In certain embodiments, said disease or condition mediated by MALT1 is Muckle-Wells syndrome. In certain embodiments, said disease or condition mediated by MALT1 is familial cold auto-inflammatory syndrome. In certain embodiments, said disease or condition mediated by MALT1 is neonatal -onset multisystem inflammatory disease.
  • said disease or condition mediated by MALT1 is TNF receptor-associated periodic syndrome. In certain embodiments, said disease or condition mediated by MALT1 is acute and chronic pancreatitis. In certain embodiments, said disease or condition mediated by MALT1 is atherosclerosis. In certain embodiments, said disease or condition mediated by MALT1 is gout. In certain embodiments, said disease or condition mediated by MALT1 is a fibrotic disorder (e.g, hepatic fibrosis or idiopathic pulmonary fibrosis). In certain embodiments, said disease or condition mediated by MALT1 is nephropathy. In certain embodiments, said disease or condition mediated by MALT1 is sarcoidosis.
  • said disease or condition mediated by MALT1 is scleroderma. In certain embodiments, said disease or condition mediated by MALT1 is anaphylaxis. In certain embodiments, said disease or condition mediated by MALT1 is diabetes (e.g., diabetes mellitus type 1 or diabetes mellitus type 2). In certain embodiments, said disease or condition mediated by MALT1 is diabetic retinopathy. In certain embodiments, said disease or condition mediated by MALT1 is Still’s disease. In certain embodiments, said disease or condition mediated by MALT1 is vasculitis. In certain embodiments, said disease or condition mediated by MALT1 is sarcoidosis.
  • said disease or condition mediated by MALT1 is pulmonary inflammation. In certain embodiments, said disease or condition mediated by MALT1 is respiratory failure. In certain embodiments, said disease or condition mediated by MALT1 is acute respiratory distress syndrome. In certain embodiments, said disease or condition mediated by MALT1 is chronic eosinophilic pneumonia. In certain embodiments, said disease or condition mediated by MALT1 is wet and dry age-related macular degeneration. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune hemolytic syndromes. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune and inflammatory' hepatitis. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune neuropathy.
  • said disease or condition mediated by MALT1 is autoimmune ovarian failure. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune orchitis. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune thrombocytopenia. In certain embodiments, said disease or condition mediated by MALT1 is silicone implant-associated autoimmune disease. In certain embodiments, said disease or condition mediated by MALT1 is Sjogren’s syndrome. In certain embodiments, said disease or condition mediated by MALT1 is familial Mediterranean fever. In certain embodiments, said disease or condition mediated by MALT1 is systemic lupus erythematosus.
  • said disease or condition mediated by MALT1 is vasculitis syndromes (e.g., t. emporal, Takayasu’s and giant cell arteritis, Behcet’s disease or Wegener’s granulomatosis).
  • said disease or condition mediated by MALT1 is vitiligo.
  • said disease or condition mediated by MALT1 is secondary hematologic manifestation of autoimmune diseases (e.g., anemias).
  • said disease or condition mediated by MALT1 is drug-induced autoimmunity.
  • said disease or condition mediated by MALT1 is Hashimoto’s thyroiditis.
  • said disease or condition mediated by MALT1 is hypophysitis. In certain embodiments, said disease or condition mediated by MALT1 is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition mediated by MALT1 is metal-induced autoimmunity. In certain embodiments, said disease or condition mediated by MALT1 is myasthenia gravis. In certain embodiments, said disease or condition mediated by MALT1 is pemphigus. In certain embodiments, said disease or condition mediated by MALT1 is autoimmune deafness (e.g, Meniere’s disease). In certain embodiments, said disease or condition mediated by MALT1 is Goodpasture’s syndrome.
  • said disease or condition mediated by MALT1 is Graves’ disease. In certain embodiments, said disease or condition mediated by MALT1 is an HW-related autoimmune syndromes. In certain embodiments, said disease or condition mediated by MALT1 is Gullain-Barre disease. In certain embodiments, said disease or condition mediated by MALT1 is Addison’s disease. In certain embodiments, said disease or condition mediated by MALT1 is anti-phospholipid syndrome. In certain embodiments, said disease or condition mediated by MALT1 is asthma. In certain embodiments, said disease or condition mediated by MALT1 is atopic dermatitis. In certain embodiments, said disease or condition mediated by MALT1 is Celiac disease.
  • said disease or condition mediated by MALT1 is Cushing’s syndrome. In certain embodiments, said disease or condition mediated by MALT1 is dermatomyositis. In certain embodiments, said disease or condition mediated by MALT1 is idiopathic adrenal atrophy. In certain embodiments, said disease or condition mediated by MALT1 is idiopathic thrombocytopenia. In certain embodiments, said disease or condition mediated by MALT1 is Kawasaki syndrome. In certain embodiments, said disease or condition mediated by MALT1 is Lambert-Eaton Syndrome. In certain embodiments, said disease or condition mediated by MALT1 is pernicious anemia In certain embodiments, said disease or condition mediated by MALT1 is pollinosis.
  • said disease or condition mediated by MALT1 is polyarteritis nodosa. In certain embodiments, said disease or condition mediated by MALT1 is primary biliary cirrhosis. In certain embodiments, said disease or condition mediated by MALT1 is primary sclerosing cholangitis. In certain embodiments, said disease or condition mediated by MALT1 is Raynaud’s disease. In certain embodiments, said disease or condition mediated by MALT1 is Raynaud’s phenomenon. In certain embodiments, said disease or condition mediated by MALT1 is Reiter’s Syndrome. In certain embodiments, said disease or condition mediated by MALT1 is relapsing polychondritis.
  • said disease or condition mediated by MALT1 is Schmidt’s syndrome. In certain embodiments, said disease or condition mediated by MALT1 is thyrotoxidosis. In certain embodiments, said disease or condition mediated by MALT1 is sepsis. In certain embodiments, said disease or condition mediated by MALT1 is septic shock. In certain embodiments, said disease or condition mediated by MALT1 is endotoxic shock. In certain embodiments, said disease or condition mediated by MALT1 is exotoxin- induced toxic shock. In certain embodiments, said disease or condition mediated by MALT1 is gram negative sepsis. In certain embodiments, said disease or condition mediated by MALT1 is toxic shock syndrome.
  • said disease or condition mediated by MALT1 is glomerulonephritis. In certain embodiments, said disease or condition mediated by MALT1 is peritonitis. In certain embodiments, said disease or condition mediated by MALT1 is interstitial cystitis. In certain embodiments, said disease or condition mediated by MALT1 is hyperoxia-induced inflammations. In certain embodiments, said disease or condition mediated by MALT1 is chronic obstructive pulmonary disease (COPD). In certain embodiments, said disease or condition mediated by MALT1 is emphysema. In certain embodiments, said disease or condition mediated by MALT1 is nasal inflammation. In certain embodiments, said disease or condition mediated by MALT1 is vasculitis.
  • COPD chronic obstructive pulmonary disease
  • said disease or condition mediated by MALT1 is graft vs. host reaction (e.g., graft vs. host disease).
  • said disease or condition mediated by MALT1 is allograft rejections (e.g., acute allograft rejection or chronic allograft rejection).
  • said disease or condition mediated by MALT1 is early transplantation rejection (e.g., acute allograft rejection).
  • said disease or condition mediated by MALT1 is reperfusion injury.
  • said disease or condition mediated by MALT1 is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia).
  • said disease or condition mediated by MALT1 is a chronic infection. In certain embodiments, said disease or condition mediated by MALT1 is meningitis. In certain embodiments, said disease or condition mediated by MALT1 is encephalitis. In certain embodiments, said disease or condition mediated by MALT1 is myocarditis. In certain embodiments, said disease or condition mediated by MALT1 is gingivitis. In certain embodiments, said disease or condition mediated by MALT1 is post-surgical trauma. In certain embodiments, said disease or condition mediated by MALT1 is tissue injury. In certain embodiments, said disease or condition mediated by MALT1 is traumatic brain injury. In certain embodiments, said disease or condition mediated by MALT1 is enterocolitis.
  • said disease or condition mediated by MALT1 is sinusitis. In certain embodiments, said disease or condition mediated by MALT1 is uveitis. In certain embodiments, said disease or condition mediated by MALT1 is ocular inflammation. In certain embodiments, said disease or condition mediated by MALT1 is optic neuritis. In certain embodiments, said disease or condition mediated by MALT1 is gastric ulcers. In certain embodiments, said disease or condition mediated by MALT1 is esophagitis. In certain embodiments, said disease or condition mediated by MALT1 is peritonitis. In certain embodiments, said disease or condition mediated by MALT1 is periodontitis.
  • said disease or condition mediated by MALT1 is dermatomyositis. In certain embodiments, said disease or condition mediated by MALT1 is gastritis. In certain embodiments, said disease or condition mediated by MALT1 is myositis. In certain embodiments, said disease or condition mediated by MALT1 is polymyalgia. In certain embodiments, said disease or condition mediated by MALT1 is pneumonia. In certain embodiments, said disease or condition mediated by MALT1 is bronchitis. In certain embodiments, the disease or condition mediated by MALT1 is endometriosis. In certain embodiments, the disease or condition mediated by MALT1 is necrotizing vasculitis.
  • the disease or condition mediated by MALT1 is lymphadenitis. In certain embodiments, the disease or condition mediated by MALT1 is peri -arteritis nodosa. In certain embodiments, the disease or condition mediated by MALT1 is anti-phospholipid antibody syndrome. In certain embodiments, the disease or condition mediated by MALT1 is pemphigus vulgaris. In certain embodiments, the disease or condition mediated by MALT1 is Lyme disease. In certain embodiments, the disease or condition mediated by MALT1 is cardiomyopathy. In certain embodiments, the disease or condition mediated by MALT1 isrheumatic fever. In certain embodiments, the disease or condition mediated by MALT1 is a blistering disorder.
  • the disease or condition mediated by MALT1 is an antibody-mediated vasculitis syndrome. In certain embodiments, the disease or condition mediated by MALT1 is an immune-complex vasculitide. In certain embodiments, the disease or condition mediated by MALT1 is oedema In certain embodiments, the disease or condition mediated by MALT1 is embolism. In certain embodiments, the disease or condition mediated by MALT1 is fibrosis. In certain embodiments, the disease or condition mediated by MALT1 is silicosis. In certain embodiments, the disease or condition mediated by MALT1 is BENTA disease. In certain embodiments, the disease or condition mediated by MALT1 is berylliosis.
  • said disease or condition mediated by MALT1 is systemic sclerosis/scleroderma. In certain embodiments, said disease or condition mediated by MALT1 is lupus nephritis. In certain embodiments, said disease or condition mediated by MALT1 is connective tissue disease. In certain embodiments, said disease or condition mediated by MALT1 is wound healing. In certain embodiments, said disease or condition mediated by MALT1 is surgical scarring. In certain embodiments, said disease or condition mediated by MALT1 is spinal cord injury. In certain embodiments, said disease or condition mediated by MALT1 is CNS scarring. In certain embodiments, said disease or condition mediated by MALT1 is acute lung injury.
  • said disease or condition mediated by MALT1 is pulmonary fibrosis (e.g, idiopathic pulmonary fibrosis or cystic fibrosis). In certain embodiments, said disease or condition mediated by MALT1 is chronic obstructive pulmonary disease. In certain embodiments, said disease or condition mediated by MALT1 is adult respiratory distress syndrome. In certain embodiments, said disease or condition mediated by MALT1 is acute lung injury. In certain embodiments, said disease or condition mediated by MALT1 is drug- induced lung injury. In certain embodiments, said disease or condition mediated by MALT1 is glomerulonephritis.
  • said disease or condition mediated by MALT1 is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, said disease or condition mediated by MALT1 is hypertension-induced nephropathy. In certain embodiments, said disease or condition mediated by MALT1 is alimentary track or gastrointestinal fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is renal fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is hepatic or biliary fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma).
  • liver fibrosis e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma.
  • said disease or condition mediated by MALT1 is cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease, such as alcoholic and nonalcoholic steatosis).
  • said disease or condition mediated by MALT1 is radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary).
  • said disease or condition mediated by MALT1 is primary sclerosing cholangitis.
  • said disease or condition mediated by MALT1 is restenosis.
  • said disease or condition mediated by MALT1 is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis). In certain embodiments, said disease or condition mediated by MALT1 is opthalmic scarring. In certain embodiments, said disease or condition mediated by MALT1 is fibrosclerosis. In certain embodiments, said disease or condition mediated by MALT1 is a fibrotic cancer. In certain embodiments, said disease or condition mediated by MALT1 is fibroids. In certain embodiments, said disease or condition mediated by MALT1 is fibroma. In certain embodiments, said disease or condition mediated by MALT1 is a fibroadenoma.
  • said disease or condition mediated by MALT1 is a fibrosarcoma. In certain embodiments, said disease or condition mediated by MALT1 is transplant arteriopathy. In certain embodiments, said disease or condition mediated by MALT1 is keloid. In certain embodiments, said disease or condition mediated by MALT1 is mediastinal fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is myelofibrosis. In certain embodiments, said disease or condition mediated by MALT1 is retroperitoneal fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is progressive massive fibrosis. In certain embodiments, said disease or condition mediated by MALT1 is nephrogenic systemic fibrosis.
  • said disease or condition mediated by MALT1 is obesity. In certain embodiments, said disease or condition mediated by MALT1 is steroid-resistance. In certain embodiments, said disease or condition mediated by MALT1 is glucose intolerance. In certain embodiments, said disease or condition mediated by MALT1 is metabolic syndrome.
  • said disease or condition mediated by MALT1 is atherosclerosis. In certain embodiments, said disease or condition mediated by MALT1 is restenosis of an atherosclerotic coronary artery. In certain embodiments, said disease or condition mediated by MALT1 is acute coronary syndrome. In certain embodiments, said disease or condition mediated by MALT1 is myocardial infarction. In certain embodiments, said disease or condition mediated by MALT1 is cardiac-allograft vasculopathy. In certain embodiments, said disease or condition mediated by MALT1 is stroke. In certain embodiments, said disease or condition mediated by MALT1 is a central nervous system disorder with an inflammatory or apoptotic component.
  • said disease or condition mediated by MALT1 is Alzheimer's disease. In certain embodiments, said disease or condition mediated by MALT1 is Parkinson’s disease. In certain embodiments, said disease or condition mediated by MALT1 is Huntington’s disease. In certain embodiments, said disease or condition mediated by MALT1 is amyotrophic lateral sclerosis. In certain embodiments, said disease or condition mediated by MALT1 is spinal cord injury. In certain embodiments, said disease or condition mediated by MALT1 is neuronal ischemia. In certain embodiments, said disease or condition mediated by MALT1 is peripheral neuropathy.
  • said disease or condition mediated by MALT1 is a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2).
  • said coronavirus is SARS-CoV-2.
  • the disease or disorder associated with SARS-CoV-2 is COVID-19.
  • the disease or condition mediated by MALT1 is a rheumatic disease.
  • the disease or condition mediated by MALT1 is an inflammatory arthropathy.
  • the disease or condition mediated by MALT1 is rheumatoid arthritis, juvenile arthritis, Still’s disease, juvenile rheumatoid arthritis, systemic onset 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 onset juvenile rheumatoid arthritis, giant cell arteritis, secondary osteoarthritis from an inflammatory disease.
  • JIA juvenile Idi
  • the disease or condition mediated by MALT1 is a connective tissue disease.
  • the disease or condition mediated by MALT1 is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren’s syndrome, scleroderma (systemic sclerosis), Raynaud’s phenomenonjuvenile scleroderma, polymyositis, dermatomyositis, polymyositis-dermatomyositis, polymyalgia rheumatica, a mixed connective tissue disease, sarcoidosis, fibromyalgia, vasculitis microscopic polyangiitis, vasculitis, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss Syndrome), granulomatosis with polyangiitis (formerly known as Churg-Strauss Syndrome),
  • the disease or condition mediated by MALT1 is a neurodegenerative disease or neuroinflammatory disease.
  • the disease or condition mediated by MALT1 is multiple sclerosis, amyotropic lateral sclerosis, Guillain-Bane disease, autoimmune encephalomyelitis, Alzheimer’s disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder.
  • the disease or condition mediated by MALT1 is an inflammatory bowel disease.
  • 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.
  • the disease or condition mediated by MALT1 is an organ or cell transplant rejection.
  • the disease or condition mediated by MALT1 is graft-versus-host disease.
  • 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, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xeno transplantation.
  • the disease or condition mediated by MALT1 is an autoimmune disease of the eye.
  • the disease or condition mediated by MALT1 is Graves’ disease, noninfectious 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, conical keratitis, comeal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren’s ulcer, scleritis, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, or ocular neovascularization
  • Graves disease, noninfectious uveitis
  • the disease or condition mediated by MALT1 is an ocular manifestation of an autoimmune disease.
  • the disease or condition mediated by MALT1 is a respiratory disease.
  • the disease or condition mediated by MALT1 is asthma, chronic obstructive pulmonary disease, or acute respiratory disease.
  • the disease or condition mediated by MALT1 is diabetes. In certain embodiments, the disease or condition mediated by MALT1 is Type I diabetes mellitus, Type II diabetes mellitus, or juvenile onset diabetes.
  • Another aspect of the 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-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I), or 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-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I).
  • a compound described herein e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I.
  • the compound is a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • cell proliferation is inhibited for T-cells.
  • cell proliferation is inhibited for B-cells.
  • cell proliferation is inhibited for T-cells and B- cells.
  • Another aspect of the invention provides methods of inducing apoptosis of a cell in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I), or inducing apoptosis of a cell in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I).
  • a compound described herein e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I
  • the compound is a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • cell is a tumor cell.
  • the cell is a lymphocyte.
  • the cell is a T-cell.
  • the cell is a B-cell.
  • Another aspect of the invention provides methods of inhibiting adhesion of a cell in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I), or inhibiting adhesion of a cell in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I).
  • a compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I.
  • the compound is a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • the cell is a tumor cell.
  • the cell is a lymphocyte.
  • the cell is a T-cell.
  • the cell is a B-cell.
  • Another aspect of the invention provides methods of inhibiting activation of T-cells or B-cells in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I), or inhibiting activation of T-cells or B-cells in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I).
  • a compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I.
  • the compound is a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • Another aspect of the invention provides methods of inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or a MALT1 fusion protein in a subject by administering to the subject a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I), or inhibiting the activity of mucosa-associated lymphoid tissue lymphoma translation protein 1 (MALT1) or a MALT1 fusion protein in a biological sample by contacting the biological sample with a compound described herein (e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I).
  • a compound described herein e.g., a compound of Formula I, I-
  • the compound is a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I, or defined by one of the embodiments described above.
  • the method inhibits the protease activity of MALT1.
  • the method inhibits the protease activity of a MALT1 fusion protein (e.g., API2-MALT1).
  • the method inhibits the protease activity of MALT1 or a MALT1 fusion protein for cleavage of a peptide substrate.
  • the peptide substrate is A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1 ⁇ , or MALT1.
  • the inhibitor may selectively inhibit the protease activity of MALT1 or a MALT1 fusion protein for cleavage of a first peptide substrate over protease activity for cleavage of a second peptide substrate.
  • the first and/or second substrate is A20, Bcl10, RelB, CYLD, NIK, regnase-1, roquin-1, roquin-2, LIMA1 ⁇ , or MALT1.
  • the selectivity is between about 1.25 fold and about 5 fold. In certain embodiments, the selectivity is between about 5 fold and about 10 fold. In certain embodiments, the selectivity is between about 10 fold and about 25 fold. In certain embodiments, the selectivity is between about 25 fold and about 50 fold. In certain embodiments, the selectivity is between about 50 fold and about 100 fold. In certain embodiments, the selectivity is between about 100 fold and about 250 fold. In certain embodiments. In certain embodiments, the selectivity is between about 250 fold and about 500 fold. In certain embodiments, the selectivity is between about 500 fold and about 1000 fold. In certain embodiments, or at least about 1000 fold. III. Combination Therapy [0207] Another aspect of the invention provides for combination therapy.
  • 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 co-administering simultaneously or sequentially an effective amount of one or more additional therapeutic agents, such as those described herein.
  • the method includes co-administering one additional therapeutic agent.
  • the method includes co-administering two additional therapeutic agents.
  • One or more other therapeutic agents may be administered separately from a compound or composition of the invention, as part of a multiple dosage regimen.
  • one or more other therapeutic agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as a multiple dosage regime, one or more other therapeutic agent and a compound or composition of the invention may be administered simultaneously, sequentially or within a period of time from one another.
  • the compounds of the disclosure can be administered with one or more of a second therapeutic agent, sequentially or concurrently, either by the same route or by different routes of administration. When administered sequentially, the time between administrations is selected to benefit, among others, the therapeutic efficacy and/or safety of the combination treatment.
  • the compound of the disclosure can be administered first followed by a second therapeutic agent, or alternatively, the second therapeutic agent administered first followed by the compound of the disclosure.
  • the compound of the disclosure can be administered for the same duration as the second therapeutic agent, or alternatively, for a longer or shorter duration as the second therapeutic compound.
  • the compounds of the disclosure can be administered separately at the same time as the second therapeutic agent, by the same or different routes, or administered in a single composition by the same route.
  • the compound of the disclosure is prepared as a first pharmaceutical composition
  • the second therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously, sequentially, or separately.
  • the amount and frequency' of administration of the second therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent. See, e.g., Physicians ’ Desk Reference, 70th Ed., PDR Network, 2015; incorporated herein by reference.
  • the additional therapeutic agent is a leukotriene inhibitor, non-steroidal anti-inflammatory drug (NSAID), steroid, tyrosine kinase inhibitor, receptor kinase inhibitor, modulator of nuclear receptor family of transcription factor, HSP90 inhibitor, adenosine receptor (A 2 A) agonist, disease modifying antirheumatic drugs (DMARDS), phosphodiesterase (PDE) inhibitor, neutrophil elastase inhibitor, modulator of Axl kinase, an anti-cancer agent, anti-allergic agent, anti-nausea agent (or anti-emetic), pain reliever, cytoprotective agent, or a combination thereof.
  • NSAID non-steroidal anti-inflammatory drug
  • steroid steroid
  • tyrosine kinase inhibitor inhibitor
  • receptor kinase inhibitor modulator of nuclear receptor family of transcription factor
  • HSP90 inhibitor adenosine receptor (A 2 A) agonist
  • DARDS disease modifying antir
  • the additional therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.
  • 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 (tebentafusp), Tecvayli (teclistamab), Lunsumio (mosunetuzumab), Epkinly (epcoritamab), and Columvi (glofitamab).
  • the second therapeutic agent is a chimeric antigen receptor (CAR) T-cell therapy.
  • Exemplary CAR T-cell therapies include but are not limited to ABECMA® (idecabtagene vicleucel), BREYANZI® (lisocabtagene maraleucel), CARVYKTITM (ciltacabtagene autoleucel), KYMRIAHTM (tisagenlecleucel), TECARTUSTM (brexucabtagene autoleucel), and YESCARTATM (axicabtagene ciloleucel).
  • the second therapeutic agent is a leukotriene inhibitor.
  • leukotriene inhibitors considered for use in combination therapies of the invention include but are not limited to montelukast, zafirlukast, pranlukast, zileuton, or combinations thereof.
  • the second therapeutic agent is a an NSAID.
  • NSAIDs considered for use in combination therapies of the invention include but are not limited to acetylsalicylic acid, diflunisal, salsalate, ibuprofen, dexibuprofen, naioxen, 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, tolfenamic acid, celecoxib, or combinations thereof.
  • the second therapeutic agent is a steroid.
  • steroids considered for use in combination therapies of the invention include but are not limited to prednisone, prednisolone, methylprednisone, triacmcinolone, betamethasone, dexamethasone, and prodrugs thereof.
  • the second therapeutic agent is a tyrosine kinase inhibitor.
  • tyrosine kinase inhibitors considered for use in combination therapies of the invention include but are not limited to inhibitors of the following kinases, including, among others: JAK, Syk, JNK/SAPK, MAPK, PI-3K, and/or Ripk2.
  • 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 combinations thereof.
  • the second therapeutic agent is a Bruton Tyrosine Kinase (BTK) inhibitor.
  • BTK inhibitors considered for use in combination therapies of the invention include but are not limited to ibrutinib, acalabrutinib, pirtobrutinib, and zanubrutinib.
  • the second therapeutic agent is a receptor kinase inhibitor, including among others, an inhibitor of EGFR or HER2.
  • receptor kinase inhibitors considered for use in combination therapies of the invention include but are not limited to gefitinib, erlotinib, neratinib, lapatinib, cetuximab, panitumumab, vandetanib, necitumumab, osimertinib, trastuzumab, neratinib, lapatinib, pertuzumab, or combinations thereof.
  • the second therapeutic agent is a modulator of nuclear receptor family of transcription factors, including, among others, an inhibitor of PPAR, RXR, FXR, or LXR.
  • the inhibitor is pioglitazone, bexarotene, obeticholic acid, ursodeoxycholic acid, fexaramine, hypocholamide, or combinations thereof.
  • the second therapeutic agent is an HSP90 inhibitor.
  • HSP90 inhibitors considered for use in combination therapies of the invention include but are not limited to ganetespib, 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-dernethoxy-geldanarnycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or combinations thereof.
  • the second therapeutic agent is an adenosine receptor 2A (A2A) agonist.
  • A2A adenosine receptor 2A
  • Examples of adenosine receptor agonists considered for use in combination therapies of the invention include but are not limited to those disclosed in U.S. Pat. No. 9,067,963, which is incorporated herein by reference.
  • the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052, or combinations thereof.
  • the second therapeutic agent is selected from disease modifying antirheumatic drugs (DMARDS).
  • DMARDS disease modifying antirheumatic drugs
  • examples of DMARDS considered for use in combination therapies of the invention include but are not limited to tocilizumab, certolizumab, etanercept, adalimumab, anakinra, abatacept, infliximab, rituximab, golimumab, uteskinumab, or combinations thereof.
  • the second therapeutic agent is a phosphodiesterase (PDE) inhibitor.
  • PDE phosphodiesterase
  • Examples of phosphodiesterase inhibitor considered for use in combination therapies of the invention include but are not limited to apremilast, crisaborole, piclimilast, drotaverine, ibudulast, roflumilast, sildenafil, tadalafil, vardenafil, or combinations thereof.
  • the second therapeutic agent is a neutrophil elastase inhibitor.
  • neutrophil elastase inhibitors considered for use in combination therapies of the invention include but are not limited to sivelestat.
  • the second therapeutic agent is a modulator of Axl kinase.
  • modulators of Axl kinase considered for use in combination therapies of the invention include but are not limited to bemcentinib (BGB324 or R428), TP-0903, LY2801653, amuvatinib (MP-470), bosutinib (SKI-606), MGCD 265, ASP2215, cabozantinib (XL184), foretinib (GSK1363089/XL880), and SGI-7079.
  • the modulator of Axl kinase is a monoclonal antibody targeting AXL (e.g, YW327.6S2) or an AXL decoy receptor (e.g, GL2I.T), or glesatinib, merestinib, or a dual Flt3-Axl inhibitor such as gilteritinib.
  • AXL e.g, YW327.6S2
  • AXL decoy receptor e.g, GL2I.T
  • glesatinib, merestinib glesatinib, merestinib
  • a dual Flt3-Axl inhibitor such as gilteritinib.
  • the additional therapeutic agent is an anti-cancer agent or chemo-therapeutic agent.
  • anti-cancer agents considered for use in combination therapies of the invention include but are not limited 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, adezelesin, anthracyclin, carzelesin, bizelesin, dolastatin, auristatins, duocarmycin, eleutherobin, taxols such as paclitaxel or docetaxel,
  • the additional therapeutic agent is selected from 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® orNEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (actin
  • the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HD AC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof.
  • the compounds of the present invention are combined with another therapeutic agent selected from vemurafinib, debrafinib, LGX818, trametinib, MEK162, LEE011, PD-0332991, panobinostat, verinostat, romidepsin, cetuximab, gefitinib, erlotinib, lapatinib, panitumumab, vandetanib, INC280, everolimus, simolimus, BMK120, BYL719 or CLR457, or a combination thereof.
  • the additional therapeutic agent is selected based on the disease or condition that is being treated.
  • the additional therapeutic agent is selected from aldesleukin (e.g., PROLEUKIN®), dabrafenib (e.g., TAFINLAR®), dacarbazine, recombinant interferon alfa-2b (e.g., INTRON® A), ipilimumab, trametinib (e.g., MEKINIST®), peginterferon alfa-2b (e.g., PEGINTRON®, SYLATRONTM), vemurafenib (e.g., ZELBORAF®)), and ipilimumab (e.g., YERVOY®).
  • aldesleukin e.g., PROLEUKIN®
  • dabrafenib e.g., TAFINLAR®
  • dacarbazine recombinant interferon alfa-2b (e.
  • the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), carboplatin (PARAPLATIN®), cyclophosphamide (CYTOXAN®, NEOSAR®), cisplatin (PLATINOL®, PLATINOL- AQ®), doxorubicin hydrochloride liposome (DOXIL®, DOX-SL®, EV ACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).
  • doxorubicin hydrochloride Adriamycin®
  • carboplatin PARAPLATIN®
  • CYTOXAN® cyclophosphamide
  • PLATINOL- AQ® cisplatin
  • DOXIL® DOX-SL®
  • EV ACET® EV ACET®
  • LIPODOX® gemcitabine hydroch
  • the additional therapeutic agent is selected from doxorubicin hydrochloride (Adriamycin®), cabozantinib-S-malate (COMETRIQ®), and vandetanib (CAPRELSA®).
  • 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 ziv- aflibercept (ZALTRAP®).
  • fluorouracil e.g., ADRUCIL®, EFUDEX®, FLUOROPLEX®
  • bevacizumab AVASTIN®
  • irinotecan hydrochloride CAMPTOSTAR®
  • capecitabine XELODA®
  • cetuximab ERBITUX®
  • the additional therapeutic agent is selected from methotrexate, methotrexate LPF (e.g., FOLEX®, FOLEX 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®).
  • methotrexate LPF e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE
  • the other therapeutic agent may be selected from fluorouracil (ADRUCIL®), EFUDEX®, FLUOROPLEX®), erlotinib hydrochloride (TARCEVA®), gemcitabine hydrochloride (GEMZAR®), and mitomycin or mitomycin C (MITOZYTREXTM, MUTAMYCIN®).
  • the additional therapeutic agent is selected from bleomycin (BLENOXANE®), cisplatin (PLATINOL®, PLATINOL-AQ®) and topotecan hydrochloride (HYCAMTIN®).
  • 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®).
  • methotrexate LPF e.g., FOLEX®, FOLEX PFS®, Abitrexate®, MEXATE®, MEXATE-AQ®
  • fluorouracil ADRUCIL®, EFUDEX®, FLUOROPLEX®
  • BLENOXANE® cetuximab
  • cisplatin PATINOL®, PLATINOL-AQ®
  • docetaxel TXOTER
  • 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®).
  • anti-allergic agents may be administered to minimize the risk of an allergic reaction.
  • Suitable anti-allergic agents include corticosteroids, such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g., BECLOVENT®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, 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 RED®, METICORTEN® and ORASONE®
  • corticosteroids such as dexamethasone (e.g., DECADRON®), beclomethasone (e.g.
  • antiemetics may be administered in preventing nausea (upper stomach) and vomiting.
  • Suitable anti-emetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HC1 (KYTRIL®), lorazepam (ATIVAN®, dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.
  • medication to alleviate the pain experienced during the treatment period is prescribed to make the patient more comfortable.
  • Common over-the- counter analgesics such TYLENOL®, are often used.
  • Opioid analgesic drugs such as hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., VICODIN®), morphine (e.g., ASTRAMORPH® or AVINZA®), oxycodone (e.g., OXYCONTIN® or PERCOCET®), oxymorphone hydrochloride (OP ANA®), and fentanyl (e.g., DURAGESIC®) are also useful for moderate or severe pain.
  • hydrocodone/paracetamol or hydrocodone/acetaminophen e.g., VICODIN®
  • morphine e.g., ASTRAMORPH® or AVINZA®
  • oxycodone e.g., OXYCON
  • cytoprotective agents such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like
  • Suitable cytoprotective agents include amifostine (ETHYOL®), glutamine, dimesna (TAVOCEPT®), mesna (MESNEX®), dexrazoxane (ZINECARD® or TOTECT®), xaliproden (XAPRILA®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • a compound of the present invention may be used in combination with known therapeutic processes, for example, with the administration of hormones or in radiation therapy.
  • a compound of the present invention may be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • the doses and dosage regimen of the active ingredients used in the combination therapy may be determined by an attending clinician.
  • the compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating the disease or condition.
  • the compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I) and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating the disease or condition.
  • the compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I
  • the additional therapeutic agent(s) are present in the same composition, which is suitable for oral administration.
  • the compound described herein e.g., a compound of Formula I, I-A, I-B, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or other compounds in Section I
  • the additional therapeutic agent(s) may act additively or synergistically.
  • a synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy.
  • a lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • the invention provides pharmaceutical compositions, which comprise a therapeutically -effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable carriers (additives) and/or diluents.
  • the pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pess
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I) and a pharmaceutically acceptable carrier.
  • a compound described herein e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I
  • a pharmaceutically acceptable carrier e.g., a compound of Formula I, I-A, I-B, la, lb, Ic, Id, le, If, Ig, Ih, li, or Ij, or other compounds in Section I
  • ‘therapeutically effective amount” means that amount of a compound, material, or composition comprising a compound of the present invention which is effective for producing some desired therapeutic effect in at least a sub-population of cells in an animal at a reasonable benefit/risk ratio applicable to any medical treatment.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • 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, 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 active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • 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.
  • 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.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a 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 pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically -acceptable carriers, such as sodium citrate or di calcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and sur
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which 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 of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which 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.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isosteaiyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microciystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isosteaiyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microciystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • 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
  • Dosage forms for the 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 which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper 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 either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • 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.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as poly lactide-poly glycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. 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 which are compatible with body tissue.
  • biodegradable polymers such as poly lactide-poly glycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0. 1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • 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 of skill in the art.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the compounds are administered at about 0.01 mg/kg to about 200 mg/kg, more preferably at about 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5 mg/kg to about 50 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the invention further provides a unit dosage form (such as a tablet or capsule) comprising a indazolyl-piperidine sulfonamide or related compound described herein in a therapeutically effective amount for the treatment of a disease or condition described herein.
  • a unit dosage form such as a tablet or capsule
  • a indazolyl-piperidine sulfonamide or related compound described herein in a therapeutically effective amount for the treatment of a disease or condition described herein.
  • Another aspect of the invention provides a medical kit comprising, for example, (i) a compound described herein, and (ii) instructions for use according to a method described herein.
  • Step 1 Synthesis of 1-1: A mixture of tert-butyl 4-(chlorosulfonyl)piperidine-1- carboxylate (2 g, 7.048 mmol, 1 equiv) and imidazole (1.44 g, 21.144 mmol, 3 equiv) in DCM (5 mL) was stirred for 2 h at 0 °C under a nitrogen atmosphere.
  • Step 2 Synthesis of 1-2: A mixture of tert-butyl 4-(imidazole-1-sulfonyl)piperidine- 1-carboxylate (3 g, 9.512 mmol, 1 equiv) and triflate ester (7.80 g, 47.560 mmol, 5 equiv) in DCM (10 mL) was stirred for 1 h at 0 °C under a nitrogen atmosphere. The precipitated solids were collected by filtration and washed with EtOAc (3x5 mL). The resulting mixture was concentrated under vacuum.
  • Step 3 Synthesis of 1-3: A mixture of 3-[1-(tert-butoxycarbonyl)piperidin-4- ylsulfonyl]-1-methylimidazol-1-ium triflate (2.80 g, 5.840 mmol, 1.03 equiv) and 6-methoxy- 1-methylindazol-7-amine (1 g, 5.643 mmol, 1.00 equiv) in MeCN (30 mL) was stirred overnight at 90 °C under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30mL).
  • Step 4 Synthesis of 1-4: A mixture of tert-butyl 4-[(6-methoxy-1-methylindazol-7- yl)sulfamoyl]piperidine-1-carboxylate (2 g, 4.711 mmol, 1 equiv) and TFA (6 mL) in DCM (6 mL) was stirred for 2 h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 30mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 5 Synthesis of 1-5: To a stirred mixture of 5-bromo-3-(trifluoromethyl)-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ pyrazole (3.19 g, 9.248 mmol, 2 equiv), N-(6-methoxy-1- methylindazol-7-yl)piperidine-4-sulfonamide (1.5 g, 4.624 mmol, 1.00 equiv), tBuXPhos Pd G3 (367.32 mg, 0.462 mmol, 0.1 equiv), and t-BuXPhos (196.36 mg, 0.462 mmol, 0.1 equiv) in dioxane (7 mL) was added potassium tert-butoxide (1.56 g, 13.872 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 6 Synthesis of N-(6-methoxy-1-methylindazol-7-yl)-1-[5-(trifluoromethyl)- 2H-pyrazol-3-yl]piperidine -4-sulfonamide of (I-1): A mixture of N-(6-methoxy-1- methylindazol-7-yl)-1-[5-(trifluoromethyl)-2- ⁇ [2-(trimethylsilyl)ethoxy] methyl ⁇ pyrazol-3- yl]piperidine-4-sulfonamide (80 mg, 0.136 mmol, 1 equiv) and TFA (1 mL) in DCM (1 mL) was stirred for 2 h at room temperature under a nitrogen atmosphere.
  • Step 1 Synthesis of 2-1: A solution of 3-bromo-5-(trifluoromethyl)-1H-pyrazole (500 mg, 2.33 mmol, 1 equiv),NaH (111.63 mg, 4.652 mmol, 2 equiv) and SEMCl (465.32 mg, 2.79 mmol, 1.2 equiv) in THF (23 mL) was stirred for 4 h from 0 °C to room temperature.
  • Step 2 Synthesis of 2-2: A solution of 2-1 (86.5 mg, 0.28 mmol, 1 equiv), N-(6- methoxy-1-methylindazol-7-yl)pyrrolidine-3-sulfonamide (86.5 mg, 0.279 mmol, 1 equiv), Cs 2 CO 3 (311.46 mg, 0.96 mmol, 3.43 equiv), Ephos (52.17 mg, 010 mmol, 0.35 equiv) and EPhos Pd G 4 (51.20 mg, 0.06 mmol, 0.20 equiv) in dioxane (15 mL) was stirred overnight at 90 °C. After the reaction was complete, the resulting mixture was diluted with water (20 mL).
  • Step 3 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-1-(5- (trifluoromethyl)-1H-pyrazol-3-yl)pyrrolidine-3-sulfonamide (I-2): A solution of 2-2 (50 mg, 0.044 mmol, 1 equiv) in TFA (2 mL) and DCM (4 mL) was stirred overnight at room temperature.
  • Step 2 Synthesis of 3-4: A mixture of 2-chloropyridine-4-sulfonyl chloride (200 mg, 0.94 mmol, 1 equiv) and 1-methylindazol-7-amine (138.8 mg, 0.94 mmol, 1 equiv) in pyridine (2 mL) was stirred for 12 hours at 80 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (1x30 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of 3-5: A mixture of 2-chloro-N-(1-methylindazol-7-yl)pyridine-4- sulfonamide (116 mg, 0.359 mmol, 1 equiv) and KOH (60.49 mg, 1.077 mmol, 3 equiv) in t- BuOH (1.5 mL) was stirred for 4 hours at 100 °C. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x20 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of N-(1-methylindazol-7-yl)-2-oxo-1-[5-(trifluoromethyl)-2H- pyrazol-3-yl]pyridine-4-sulfonamide (I-3): To a stirred solution of N-(1-methylindazol-7- yl)-2-oxo-1H-pyridine-4-sulfonamide (100 mg, 0.329 mmol, 1 equiv), 3-bromo-5- (trifluoromethyl)-2H-pyrazole (211.92 mg, 0.987 mmol, 3 equiv), and Cs 2 CO 3 (321.19 mg, 0.987 mmol, 3 equiv) in DMSO (2
  • the resulting mixture was stirred at 110 °C under a nitrogen atmosphere overnight.
  • the resulting mixture was diluted with water (20 mL).
  • the resulting mixture was extracted with CH 2 Cl 2 (3 x20 mL).
  • the combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 1 Synthesis of 5-1: A solution of 1-methylindazol-7-amine (500 mg, 3.397 mmol, 1 equiv) in THF (10 mL) was treated with LDA (4.25 mL, 8.492 mmol, 2.5 equiv) for 30 min at -40°C under a nitrogen atmosphere followed by the addition of tert-butyl 3- (chlorosulfonyl)pyrrolidine-1-carboxylate (1007.99 mg, 3.737 mmol, 1.1 equiv) dropwise at - 40 °C.
  • Step 2 Synthesis of 5-2: A solution of 5-1 (490 mg, 1.524 mmol, 1 equiv) and HCl(gas) in 1,4-dioxane (4 M, 10 mL) was stirred for 1 hour at room temperature. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.5-2 (200 mg, crude) was obtained as a red brown solid.
  • Step 3 Synthesis of 5-3: A solution of 5-2 (200 mg, 0.713 mmol, 1 equiv), 2-chloro- 4-(trifluoromethyl)pyridine (12.95 mg, 0.072 mmol, 2 equiv) and Cs 2 CO 3 (929.75 mg, 2.852 mmol, 4 equiv) in DMF (5 mL) was stirred overnight at 80 °C. The residue was diluted with water (20 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 20 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Step 1 Synthesis of 7-1: To a stirred solution of 1-methylindazol-7-amine (1.5 g, 10.192 mmol, 1 equiv) and 3-chloropropane-1-sulfonyl chloride (3.61 g, 20.384 mmol, 2.00 equiv) in pyridine (10 mL) was added DMAP (124.51 mg, 1.019 mmol, 0.10 equiv) in portions at room temperature under a nitrogen atmosphere.
  • 1-methylindazol-7-amine 1.5 g, 10.192 mmol, 1 equiv
  • 3-chloropropane-1-sulfonyl chloride 3.61 g, 20.384 mmol, 2.00 equiv
  • DMAP (124.51 mg, 1.019 mmol, 0.10 equiv
  • Step 2 Synthesis N-(1-methyl-1H-indazol-7-yl)-3-(4-(trifluoromethyl)-1H- pyrazol-1-yl)propane-1-sulfonamide (I-7): To a stirred solution of 3-chloro-N-(1- methylindazol-7-yl)propane-1-sulfonamide (200 mg, 0.695 mmol, 1 equiv) and 4- (trifluoromethyl)-1H-pyrazole (141.87 mg, 1.042 mmol, 1.5 equiv) in DMF (5 mL) was added Cs 2 CO 3 (679.36 mg, 2.085 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • the crude product (80 mg) was purified by prep-HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05%NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 15% B to 40% B in 7min; wave length: 254 nm/220 nm; RT1(min): 8.52) to afford N-(1-methylindazol-7-yl)-3-[4- (trifluoromethyl)pyrazol-1-yl]propane-1-sulfonamide (I-7, 11.9 mg, 4.42%) as a white solid.
  • Step 1 Synthesis of 8-1: To a stirred mixture of 1-methylindazol-7-amine (2 g, 13.589 mmol, 1 equiv) in pyridine (100 mL) was added 2-(1,3-dioxoisoindol-2-yl)ethanesulfonyl chloride (5.58 g, 20.384 mmol, 1.5 equiv) in portions at room temperature under an air atmosphere.
  • Step 2 Synthesis of 8-2: To a stirred mixture of 8-1 (300 mg, 0.780 mmol, 1 equiv) in EtOH (80 mL) was added hydrazine hydrate (78.14 mg, 1.560 mmol, 2 equiv) in portions at room temperature under an air atmosphere. The resulting mixture was stirred overnight at room temperature. The crude product was re-crystallized from PE/EtOH (10:1100mL) to afford 8-2 (102 mg, 51.39%) as a white solid.
  • Step 3 Synthesis of N-(1-methyl-1H-indazol-7-yl)-2-((4-(trifluoromethyl)pyridin- 2-yl)amino)ethane-1-sulfonamide (I-8): To a stirred mixture of 8-2 (50 mg, 0.197 mmol, 1 equiv) and 2-fluoro-4-(trifluoromethyl)pyridine (32.46 mg, 0.197 mmol, 1 equiv) in DMSO (10 mL) was added K 2 CO 3 (81.52 mg, 0.591 mmol, 3 equiv) in portions at 100 °C under an air atmosphere. The resulting mixture was stirred for an additional 3 h at 100 °C.
  • the crude product (50 mg) was purified by prep-HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05%NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 44% B in 7 min; wave length: 254 nm/220 nm; RT1(min): 8.9) to afford N-(1-methyl-1H- indazol-7-yl)-2-((4-(trifluoromethyl)104 yridine-2-yl)amino)ethane-1-sulfonamide (I-8, 40.9 mg, 51.41%) as a white solid.
  • Step 1 Synthesis of 9-1: To a stirred solution of 2-(1,3-dioxoisoindol-2- yl)ethanesulfonyl chloride (324 mg, 1.184 mmol, 1.00 equiv) and DMAP (14.5 mg, 0.119 mmol, 0.10 equiv) in pyridine (5 mL) was added 6-methoxy-1-methylindazol-7-amine (210 mg, 1.185 mmol, 1 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 2 Synthesis of 9-2: To a stirred mixture of 9-1 (420 mg, 1.013 mmol, 1 equiv) in EtOH (15 mL) was added hydrazine hydrate (300 uL, 6.172 mmol, 6.09 equiv) in portions at room temperature under an air atmosphere. The resulting mixture was stirred for an additional 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column: C18 silica gel; mobile phase: MeCN in water (10 mmol/L NH 4 HCO 3 ), 20% to 23% gradient in 15 min; detector: UV 220 nm.
  • Step 3 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-2-((4- (trifluoromethyl)pyridin-2-yl)amino)ethane-1-sulfonamide (I-9): A solution of 9-2 (150 mg, 0.528 mmol, 1 equiv) in DMSO (10 mL) was treated with K 2 CO 3 (220 mg, 1.592 mmol, 3.02 equiv) for 5 min at room temperature under a nitrogen atmosphere followed by the addition of 2-fluoro-4-(trifluoromethyl)pyridine (100 uL, 0.821 mmol, 1.56 equiv) dropwise at room temperature.
  • the crude product (100 mg) was purified by prep-HPLC with the following conditions (column: Xbridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05%NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 29% B to 56% B in 7 min; wave length: 254 nm/220 nm; RT1(min): 7.59; number of runs: 2) to afford N-(6-methoxy-1-methyl-1H-indazol-7-yl)-2-((4- (trifluoromethyl)pyridine-2-yl)amino)ethane-1-sulfonamide (I-9, 47.2 mg, 20.71%) as a white solid.
  • Step 2 Synthesis of 10-2: A mixture of benzyl 4-[(1-methylindazol-7-yl)sulfamoyl] piperidine-1-carboxylate (350 mg, 0.817 mmol, 1.00 equiv) and Pd/C (43 mg, 0.408 mmol, 0.50 equiv) in EtOAc (5 mL) was stirred overnight at room temperature under a hydrogen atmosphere.
  • Step 3 Synthesis of 10-3: A mixture of N-(1-methylindazol-7-yl)piperidine-4- sulfonamide (200 mg, 0.442 mmol, 1.00 equiv), 5-bromo-3-(trifluoromethyl)-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ pyrazole (228 mg, 0.663 mmol, 1.50 equiv), EPhos (47 mg, 0.08 mmol, 0.20 equiv), EPhos Pd G4 (40 mg, 0.04 mmol, 0.10 equiv) and Cs 2 CO 3 (431 mg, 1.32 mmol, 3.00 equiv) in dioxane (2 mL) was stirred overnight at 90 °C under a nitrogen atmosphere.
  • Step 4 Synthesis of N-(1-methyl-1H-indazol-7-yl)-1-(3-(trifluoromethyl)-1H- pyrazol-5-yl)piperidine-4-sulfonamide (I-10): To a stirred mixture of N-(1-methylindazol- 7-yl)-1-[5-(trifluoromethyl)-2- ⁇ [2-(trimethylsilyl) ethoxy] methyl ⁇ pyrazol-3-yl] piperidine-4- sulfonamide (70 mg, 0.125 mmol, 1.00 equiv) in DCM (2 mL) was added HCl(gas) in 1,4- dioxane (1 mL) dropwise at 0 °C under a nitrogen atmosphere.
  • Step 2 Synthesis of 11-2: A solution of 11-1 (190 mg, 0.414 mmol, 1 equiv) and Pd/C (2.20 mg, 0.021 mmol, 0.05 equiv) in EA (5 mL) was stirred for 15 h at room temperature under a hydrogen atmosphere.
  • Step 3 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-1-(4- (trifluoromethyl)pyridin-2-yl)piperidine-4-sulfonamide (I-11): A solution of 11-2 (90 mg, 0.277 mmol, 1 equiv) in DMSO (9 mL) was treated with K 2 CO 3 (115 mg, 0.832 mmol, 3.00 equiv) for 5 min at room temperature under a nitrogen atmosphere followed by the addition of 2-fluoro-4-(trifluoromethyl)pyridine (69 mg, 0.418 mmol, 1.51 equiv) dropwise at room temperature.
  • Step 2 Synthesis of 12-4: A solution of tert-butyl 3-[(6-methoxy-1-methylindazol-7- yl)sulfamoyl]pyrrolidine-1-carboxylate (220 mg, 0.536 mmol, 1 equiv) in HCl(gas) in 1,4- dioxane (4 M, 3 mL) was stirred for 1 hour at room temperature. The resulting mixture was concentrated under reduced pressure. This resulted in N-(6-methoxy-1-methylindazol-7- yl)pyrrolidine-3-sulfonamide (12-4, 182 mg, crude) as a brown solid.
  • Step 3 Synthesis of 12-6: A solution of N-(6-methoxy-1-methylindazol-7- yl)pyrrolidine-3-sulfonamide (160 mg, 0.516 mmol, 1 equiv), Cs 2 CO 3 (503.89 mg, 1.548 mmol, 3 equiv) and 2-fluoro-4-(trifluoromethyl)pyridine (93.62 mg, 0.568 mmol, 1.1 equiv) in DMF (5 mL) was stirred overnight at 80 °C. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x50 mL).
  • Step 1 Synthesis of 14-1: To a stirred solution of 1-methylindazol-7-amine (300 mg, 2.038 mmol, 1 equiv) and 2-chloroethanesulfonyl chloride (498.40 mg, 3.057 mmol, 1.5 equiv) in ACN (10 mL) was added pyridine (483.69 mg, 6.114 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 2 Synthesis of N-(1-methyl-1H-indazol-7-yl)-2-(4-(trifluoromethyl)-1H- pyrazol-1-yl)ethane-1-sulfonamide (I-14): To a stirred solution of N-(1-methylindazol-7- yl)ethenesulfonamide (280 mg, 1.180 mmol, 1 equiv) and 4-(trifluoromethyl)-1H-pyrazole (240.86 mg, 1.770 mmol, 1.50 equiv) in DMF (8 mL) was added Cs 2 CO 3 (1.16 g, 3.560 mmol, 3.02 equiv) in portions at room temperature under a nitrogen atmosphere.
  • the crude product (50 mg) was purified by prep-HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 )+0.05%NH 3 .H 2 O, mobile phase B: ACN; flow rate: 60 mL/min; gradient: 17% B to 44% B in 7min; wave length: 254 nm/220 nm; RT1(min): 8.9) to afford 2-(methyl(4- (trifluoromethyl)pyridin-2-yl)amino)-N-(1-methyl-1H-indazol-7-yl)ethane-1-sulfonamide (I- 15, 14.8 mg, 28.20%) as a white solid.
  • Step 1 Synthesis of 16-1: To a stirred solution of 6-methoxy-1-methylindazol-7-amine (100mg, 0.564 mmol, 1 equiv) and 2-bromoethanesulfonyl chloride (140.5mg, 0.676 mmol, 1.2 equiv) in MeCN (3 mL) was added pyridine (4.46mg, 0.056 mmol, 0.1 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 2 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-2-(4- (trifluoromethyl)-1H-pyrazol-1-yl)ethane-1-sulfonamide (I-16): To a stirred solution of N- (6-methoxy-1-methylindazol-7-yl) ethenesulfonamide (150 mg, 0.561 mmol, 1 equiv) and 4- (trifluoromethyl)-1H-pyrazole (152.72 mg, 1.122 mmol, 2 equiv) in DMF (2 mL) was added Cs 2 CO 3 (548.52 mg, 1.683 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 1 Synthesis of 21-1: To a stirred solution of 6-methoxy-1-methylindazol-7-amine (100 mg, 0.564 mmol, 1 equiv) and prop-2-ene-1-sulfonyl chloride (119.00 mg, 0.846 mmol, 1.5 equiv) in pyridine (2 mL) was added DMAP (6.89 mg, 0.056 mmol, 0.1 equiv).
  • Step 2 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-2-(4- (trifluoromethyl)-1H-pyrazol-1-yl)propane-1-sulfonamide (I-21): To a stirred solution of N-(6-methoxy-1-methylindazol-7-yl) prop-2-ene-1-sulfonamide (90 mg, 0.320 mmol, 1 equiv) and 4-(trifluoromethyl)-1H-pyrazole (87.06 mg, 0.640 mmol, 2 equiv) in DMF (2 mL) was added t-BuOK (71.80 mg, 0.640 mmol, 2 equiv).
  • the crude product (110 mg) was purified by prep- HPLC with the following conditions (column: XBridge Prep OBD RP18 column, 19*250 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: MeOH; flow rate: 25 mL/min; gradient: 45% B to 70% B in 9 min; wave length: 220 nm; RT1(min): 8.85) to afford N-(6-methoxy-1-methylindazol-7-yl)-2-[4-(trifluoromethyl)pyrazol-1- yl]propane-1-sulfonamide (I-21, 57.4 mg, 41.57%) as a light pink solid.
  • Step 2 Synthesis of 22-2: To a stirred solution of 3-chloro-N-(6-methoxy-1- methylindazol-7-yl) propane-1-sulfonamide (150 mg, 0.566 mmol, 1 equiv) and K 2 CO 3 (234.84 mg, 1.698 mmol, 3 equiv) in THF (5 mL) was added PMBCl (106.45 mg, 0.679 mmol, 1.2 equiv). The resulting mixture was stirred overnight at 50 °C under a nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (2 x 100 mL).
  • Step 3 Synthesis of 22-3: A solution of 4-(trifluoromethyl)-1H-pyrazole (18.64 mg, 0.138 mmol, 2 equiv) in DMF (2 mL) was treated with NaH (2.47 mg, 0.104 mmol, 1.5 equiv) for 30 min at 0 °C under a nitrogen atmosphere followed by the addition of 3-chloro-N-(6- methoxy-1-methylindazol-7-yl)-N-[(4-methoxyphenyl)methyl]propane-1-sulfonamide (30 mg, 0.069 mmol, 1 equiv). The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere.
  • Step 4 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-3-(4- (trifluoromethyl)-1H-pyrazol-1-yl)propane-1-sulfonamide (I-22): To a solution of N-(6- methoxy-1-methylindazol-7-yl)-N-[(4-methoxyphenyl)methyl]-3-[4- (trifluoromethyl)pyrazol-1-yl]propane-1-sulfonamide (20 mg, 0.037 mmol, 1 equiv) in MeOH (5 mL) was added Pd/C (10%, 0.04 g) under a nitrogen atmosphere in a 25 mL round-bottom flask.
  • Step 1 Synthesis of 24-1: To a stirred solution of 2-(1,3-dioxoisoindol-2- yl)ethanesulfonyl chloride (1 g, 3.654 mmol, 1.08 equiv) and DMAP (42 mg, 0.344 mmol, 0.10 equiv) in pyridine (10 mL) was added 6-methoxy-1-methylindazol-7-amine (600 mg, 3.386 mmol, 1 equiv) in portions at room temperature under a nitrogen atmosphere.
  • Step 2 Synthesis of 24-2: A solution of 24-1 (1.19 g, 2.871 mmol, 1 equiv) in THF (20 mL) was treated with NaH (0.14 g, 3.617 mmol, 1.26 equiv, 60%) for 30 min at 0 °C under a nitrogen atmosphere followed by the addition of [2-(chloromethoxy)ethyl]trimethylsilane (0.72 g, 4.306 mmol, 1.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for 1 h at room temperature under a nitrogen atmosphere. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL).
  • Step 3 Synthesis of 24-3: To a stirred mixture of 24-2 (1 g, 1.836 mmol, 1 equiv) in EtOH (40 mL) was added hydrazine hydrate (0.55 g, 11.016 mmol, 6 equiv) in portions at room temperature under an air atmosphere. The resulting mixture was stirred for an additional 3 h at room temperature. The resulting mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of 24-4: To a stirred solution of 24-3 (470 mg, 1.134 mmol, 1 equiv) and K 2 CO 3 (470.02 mg, 3.402 mmol, 3 equiv) in DMSO (20 mL) was added 2-fluoro-4- (trifluoromethyl)pyridine (374.30 mg, 2.268 mmol, 2 equiv) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 15 h at 60 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
  • Step 5 Synthesis of 24-5: A solution of 24-4 (350 mg, 0.625 mmol, 1 equiv) in THF (10 mL) was treated with NaH (35 mg, 0.875 mmol, 1.40 equiv, 60%) for 30 min at 0 °C under a nitrogen atmosphere followed by the addition of MeI (80 uL, 1.285 mmol, 2.05 equiv) dropwise at 0 °C. The resulting mixture was stirred for 5 h at room temperature under a nitrogen atmosphere. The reaction was quenched with sat. NH 4 Cl (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure.
  • Step 6 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-2-(methyl(4- (trifluoromethyl)pyridin-2-yl)amino)ethane-1-sulfonamide (I-24): A solution of 24-5 (100 mg, 0.174 mmol, 1 equiv) in HCl(gas) in 1,4-dioxane (10 mL, 164.564 mmol, 1888.24 equiv) was stirred for 2 h at 50 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure.
  • the crude product (60 mg) was purified by prep-HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 7 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05%NH 3 H 4 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 9% B to 32% B in 7min; wave length: 254 nm/222 nm; RT1(min): 6.63; number of runs: 2) to afford 1-(5,6-dihydro-4H-pyrrolo[1,2- b]pyrazol-3-yl)-N-(6-methoxy-1-methyl-1H-indazol-7-yl)piperidine-4-sulfonamide (I-25, 5.1 mg, 3.80%) as a brown solid.
  • the crude product (50 mg) was purified by prep-HPLC with the following conditions (column: XBridge Shield RP18 OBD column, 30*150 mm, 7 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05%NH 3 H 4 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 9% B to 32% B in 7min; wave length: 254 nm/222 nm; RT1(min): 6.63; number of runs: 2) to afford 1- (5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)-N-(1-methyl-1H-indazol-7-yl)piperidine-4- sulfonamide (I-27, 4.1 mg, 3.01%) as a white solid.
  • Step 2 Synthesis of 28-2: To a stirred solution of N-(6-methoxy-1-methylindazol-7- yl)-1-(1-methylpyrazol-3-yl)-N- ⁇ [2-(trimethylsilyl) ethoxy] methyl ⁇ piperidine-4- sulfonamide (20 mg, 0.037 mmol, 1 equiv) in DCM (3 mL) was added TFA (0.5 mL) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification.
  • Step 3 Synthesis of N-(6-methoxy-1-methyl-1H-indazol-7-yl)-1-(1-methyl-1H- pyrazol-3-yl)piperidine-4-sulfonamide (I-28): To a stirred solution of N-(hydroxymethyl)- N-(6-methoxy-1-methylindazol-7-yl)-1-(1-methylpyrazol-3-yl) piperidine-4-sulfonamide (10 mg, 0.023 mmol, 1 equiv) in MeCN (3 mL) was added NH 3 ⁇ H 2 O (3 mL) dropwise at room temperature under a nitrogen atmosphere.
  • Step 1 Synthesis of 29-1: A solution of 4-bromo-3-methyl-1H-indazole (1 g, 4.738 mmol, 1 equiv) in THF (15 mL) was treated with t-BuOK (1.59 g, 14.214 mmol, 3 equiv) for 5 min at 0 °C under a nitrogen atmosphere followed by the addition of SEM-Cl (2.10 mL, 11.845 mmol, 2.5 equiv) dropwise at 0 °C. The resulting mixture was stirred for an additional 1 h at room temperature. The resulting mixture was extracted with CH 2 Cl 2 (3 x 20 mL).
  • Step 2 Synthesis of 29-2: To a stirred solution of benzyl 4-sulfamoylpiperidine-1- carboxylate (300 mg, 1.005 mmol, 1 equiv), Cs 2 CO 3 (982.83 mg, 3.015 mmol, 3 equiv) and 4- bromo-3-methyl-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ indazole (411.84 mg, 1.206 mmol, 1.2 equiv) in dioxane (4 mL) were added GPhos Pd G6 TES (95.07 mg, 0.100 mmol, 0.1 equiv) and GPhos (53.97 mg, 0.100 mmol, 0.1 equiv) at room temperature under a nitrogen atmosphere.
  • Step 3 Synthesis of 29-3: A solution of benzyl 4-[(3-methyl-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazol-4-yl)sulfamoyl]piperidine-1-carboxylate (270 mg, 0.483 mmol, 1 equiv) and Pd/C (51.4 mg, 4.830 mmol, 1 equiv) in IPA (6 mL) was stirred for 2 h at room temperature under a hydrogen atmosphere. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of 29-4: To a stirred solution of N-(3-methyl-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazol-4-yl) piperidine-4-sulfonamide (125 mg, 0.294 mmol, 1 equiv), t-BuOK (99.10 mg, 0.882 mmol, 3 equiv) and 5-bromo-3-(trifluoromethyl)-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ pyrazole (304.88 mg, 0.882 mmol, 3 equiv) in dioxane (4 mL) were added t-BuXPhos (25.00 mg, 0.059 mmol, 0.2 equiv) and t-BuBrettPhos Pd G3 (50.30 mg, 0.059 mmol, 0.2 equiv) at room temperature under a nitrogen atmosphere.
  • t-BuXPhos 25.00 mg, 0.059 mmol
  • Step 5 Synthesis of N-(3-methyl-1H-indazol-4-yl)-1-(3-(trifluoromethyl)-1H- pyrazol-5-yl)piperidine-4-sulfonamide (I-29): A solution of N-(3-methyl-1- ⁇ [2- (trimethylsilyl)ethoxy]methyl ⁇ indazol-4-yl)-1-[5-(trifluoromethyl)-2- ⁇ [2- (trimethylsilyl)ethoxy] methyl ⁇ pyrazol-3-yl]piperidine-4-sulfonamide (23 mg, 0.033 mmol, 1 equiv) and trifluoroacetaldehyde (1.5 mL) in DCM (2 mL) was stirred for 1 h at room temperature under a nitrogen atmosphere.
  • the crude product (15 mg) was purified by prep- HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 3 +0.05% NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 13% B to 38% B in 8 min; wave length: 220 nm; RT1(min): 8.15) to afford N-(3-methyl-1H-indazol-4-yl)-1-[5-(trifluoromethyl)-2H-pyrazol-3- yl]piperidine-4-sulfonamide (I-29, 2.9 mg, 19.99%) as a white solid.
  • EXAMPLE 30 SYNTHESIS OF 1-(4-(2-CYANOPROPAN-2-YL)PYRIDIN-2-YL)-N- (1-METHYL-1H-INDAZOL-7-YL)PIPERIDINE-4-SULFONAMIDE (I-30) [0359] To a stirred solution of N-(1-methylindazol-7-yl) piperidine-4-sulfonamide (100 mg, 0.340 mmol, 1 equiv) and 2-(2-fluoropyridin-4-yl)-2-methylpropanenitrile (66.93 mg, 0.408 mmol, 1.2 equiv) in DMF (3 mL) was added t-BuOK (114.36 mg, 1.020 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • the resulting mixture was stirred for 8 h at 80 °C under a nitrogen atmosphere.
  • the resulting mixture was diluted with water (20 mL).
  • the resulting mixture was extracted with EtOAc (3 x 10 mL).
  • the combined organic layers were washed with brine (2 x 10 mL) and dried over anhydrous Na 2 SO 4 .
  • the resulting mixture was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 40% to 53% gradient in 10 min; detector: UV 254 nm.
  • the resulting mixture was concentrated under reduced pressure.
  • EXAMPLE 32 SYNTHESIS OF 1-(4-(1,1-DIFLUOROETHYL)PYRIDIN-2-YL)-N- (1-METHYL-1H-INDAZOL-7-YL)PIPERIDINE-4-SULFONAMIDE (I-32) [0361] To a stirred mixture of N-(1-methylindazol-7-yl)piperidine-4-sulfonamide (70 mg, 0.238 mmol, 1 equiv) and 2-chloro-4-(1,1-difluoroethyl)pyridine (42.23 mg, 0.238 mmol, 1 equiv) in DMF (2 mL) was added Cs 2 CO 3 (232.44 mg, 0.714 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere.
  • the resulting mixture was stirred overnight at 140 °C under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic layers were concentrated under reduced pressure.
  • the crude product was purified by prep-HPLC with the following conditions (column: Xselect CSH C18 OBD column 30*150mm 5 ⁇ m; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 24% B to 51% B in 7 min; wave length: 254 nm/220 nm; RT1(min): 7.17; number of runs: 2) to afford 1-[4-(1,1-difluoroethyl)pyridin-2-yl]-N-(1-methylindazol-7- yl)piperidine-4-sulfonamide (I-32, 13 mg, 12.39%) as an off-white solid.
  • Step 2 Synthesis of 33-2: To a stirred mixture of 4-hydroxycyclohexyl 4- methylbenzenesulfonate (20 g, 73.981 mmol, 1 equiv) and 4-(trifluoromethyl)-1H-pyrazole (20.13 g, 147.962 mmol, 2 equiv) in DMF (400 mL) was added Cs 2 CO 3 (72.31 g, 221.943 mmol, 3 equiv) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for an additional 5 h at 80 °C. The desired product could be detected by LCMS.
  • Step 3 Synthesis of 33-3: To a stirred solution of 4-[4-(trifluoromethyl)pyrazol-1- yl]cyclohexan-1-ol (1.2 g, 5.123 mmol, 1 equiv) in pyridine (20 mL) was added TsCl (1.95 g, 10.246 mmol, 2 equiv) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 4 h at room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of 33-4: To a stirred solution of 4-[4-(trifluoromethyl)pyrazol-1- yl]cyclohexyl 4-methylbenzenesulfonate (1 g, 2.575 mmol, 1 equiv) in DMF (20 mL) was added 1-(potassiosulfanyl)ethanone (735.05 mg, 6.438 mmol, 2.5 equiv) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for an additional 4 h at 75 °C. The desired product could be detected by LCMS. The reaction was quenched by the addition of water (20 mL) at 0 °C.
  • Step 5 Synthesis of 33-5: To a stirred mixture of 1-( ⁇ 4-[4-(trifluoromethyl)pyrazol-1- yl]cyclohexyl ⁇ sulfanyl)ethanone (300 mg, 1.026 mmol, 1 equiv) and 2 M HCl (0.15 mL, 0.298 mmol, 0.29 equiv) in MeCN (5 mL) was added NCS (548.15 mg, 4.104 mmol, 4 equiv) in portions at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 4 h at room temperature. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure.
  • Step 6 Synthesis of 33-6: To a stirred solution of 6-methoxy-1-methylindazol-7- amine (103.51 mg, 0.584 mmol, 1 equiv) in THF (8 mL) were added LDA (2 M in THF) (0.58 mL, 1.168 mmol, 2 equiv) dropwise at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for an additional 30 min at 0 °C. To the above mixture was added 4-[4- (trifluoromethyl)pyrazol-1-yl]cyclohexane-1-sulfonyl chloride (185 mg, 0.584 mmol, 1 equiv) dropwise at 0 °C.
  • the resulting mixture was stirred for an additional 4 h at room temperature.
  • the desired product could be detected by LCMS.
  • the reaction was quenched by the addition of NH 4 Cl (aq.) (10mL) at 0 °C.
  • the resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were concentrated under reduced pressure.
  • EXAMPLE 34 SYNTHESIS OF 1-(4-(2-CYANOPROPAN-2-YL)PYRIDIN-2-YL)-N- (6-METHOXY-1-METHYL-1H-INDAZOL-7-YL)PIPERIDINE-4-SULFONAMIDE (I- 35) .
  • the desired product could be detected by LCMS.
  • the resulting mixture was diluted with water (50 mL).
  • the resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL).
  • the combined organic layers were concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column: C18 silica gel; mobile phase: MeCN in water, 0% to 50% gradient in 30 min; detector: UV 254 nm.
  • the resulting mixture was concentrated under reduced pressure. This resulted in 36-1 (180 mg, 17.59%) as a brown oil.
  • Step 2 Synthesis of 36-2: A solution of 36-1 (180 mg, 0.421 mmol, 1 equiv) and Pd/C (49.29 mg, 0.463 mmol, 1.1 equiv) in IPA (5 mL) was stirred for 4 h at room temperature under a hydrogen atmosphere. The desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.36-2 (120 mg, 97.14%) was obtained as a light yellow oil.
  • Step 3 Synthesis of 36-3: A solution of 36-2 (120 mg, 0.409 mmol, 1 equiv) 5-bromo- 3-(trifluoromethyl)-1- ⁇ [2-(trimethylsilyl)ethoxy]methyl ⁇ pyrazole (564.82 mg, 1.636 mmol, 4 equiv) tBuXPhos Pd G3 (64.98 mg, 0.082 mmol, 0.2 equiv) t-BuXPhos (34.74 mg, 0.082 mmol, 0.2 equiv) and t-BuOK (137.69 mg, 1.227 mmol, 3 equiv) in dioxane (5 mL) was stirred overnight at 90 °C under a nitrogen atmosphere.
  • the desired product could be detected by LCMS.
  • the resulting mixture was diluted with water (10 mL).
  • the resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL).
  • the combined organic layers were washed with brine (10 mL) and dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • the residue was purified by reversed-phase flash chromatography with the following conditions: column: C18 silica gel; mobile phase: MeCN in water (10 mmol/L NH 4 HCO 3 ), 0% to 100% gradient in 40 min; detector: UV 254 nm. This resulted in 36-3 (100 mg, 50.91%) as a reddish brown oil.
  • Step 4 Synthesis of N-(1-methyl-1H-indol-7-yl)-1-(3-(trifluoromethyl)-1H- pyrazol-5-yl)piperidine-4-sulfonamide (I-36): A solution of 36-3 (100 mg, 0.179 mmol, 1 equiv) in AcOH (100 mL)/THF (10 mL)/H 2 O (20 mL) was stirred overnight at 70 °C. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were concentrated under reduced pressure.
  • the obtained product (20 mg) was further purified by prep-HPLC with the following conditions (column: XBridge Prep OBD C18 column, 30*150 mm, 5 ⁇ m; mobile phase A: water (10 mmol/L NH 4 HCO 4 +0.5%NH 3 H 2 O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 31% B to 56% B in 7min; wave length: 254/220 nm; RT1(min): 7.05) to afford N-(1-methyl-1H-indol-7-yl)-1-(3-(trifluoromethyl)-1H-pyrazol-5-yl)piperidine-4- sulfonamide (I-36, 1.8 mg, 2.30%) as a light brown solid.
  • EXAMPLE 36 SYNTHESIS OF N-(6-METHOXY-1-METHYL-1H-INDAZOL-7- YL)-4-(4-(TRIFLUOROMETHYL)-1H-PYRAZOL-1-YL)CYCLOHEXANE-1- SULFONAMIDE (I-37) [0374] To a stirred solution of 6-methoxy-1-methylindazol-7-amine (103.5 mg, 0.584 mmol, 1.00 equiv) in THF (8 mL) were added LDA (2 M in THF, 0.58 mL, 0.005 mmol, 2 equiv) dropwise at 0 °C under a nitrogen atmosphere.
  • EXAMPLE 38 MALT1 INHIBITION ASSAY AND NF-KB REPORTER ASSAY
  • Exemplary compounds were evaluated for inhibition of MALT1 activity and activity in an NF-kB reporter Assay. Experimental procedures and results are provided below. Part I – Assay for Inhibition of MALT1 Activity [0377] Inhibition of MALT1 activity by the presence of small molecules was evaluated using MALT-1 Fluorogenic Peptide Cleavage Assay. The assay utilizes a quenched AMC-labelled peptide that contains the MALT-1 recognition sequence and cleavage site (LRSR).
  • LRSR quenched AMC-labelled peptide that contains the MALT-1 recognition sequence and cleavage site
  • N-2-hydroxyethylpiperazine-N-2-ethane sulfonic acid HEPMS (1 M, pH 7.5, stored at 4 °C), sodium citrate (stored at RT), tris(2- carboxyethyl)phosphine hydrochloride (T-CEP) (500 mM, stored at -20 °C), ethylenediaminetetraacetic acid (EDTA) (500 mM, stored at RT), dimethylsulfoxide (DMSO, stored at RT), 3-[(3-cholamidopropyl)dimethylammonio]-1-propane sulphate (CHAPS) (stored at RT), dimethylsulfoxide (HEPES) (1 M, pH 7.5, stored at 4 °C), sodium citrate (stored at RT), tris(2- carboxyethyl)phosphine hydrochloride (T-CEP) (500 mM, stored at -20 °C), ethylenediaminetetraace
  • the standard reagent formulations used in this assay were prepared and stored as follows.
  • a 1.1 M solution of sodium citrate (161.3 g, 500 mL) was prepared and stored at room temperature.
  • a 10% (w/v) CHAPS solution (2.0 g, 20 mL) was prepared and stored at 4 °C.
  • a 500 mM HEPES solution having pH of 6.89 was prepared from 200 mL of a 1 M HEPES solution having a pH of 7.5 using concentrated hydrochloric acid and brought to a final volume of 400 mL with MILLI-Q ® H 2 O.
  • the substrate, 10 mM Ac-LRSR-AMC Peptide was prepared (10 mg, 1.370 mL DMSO) and stored at -20 °C.
  • MALT-1 was thawed and kept on ice. Peptide substrate was thawed on the bench under ambient conditions. A MALT-1 enzyme working stock was prepared from Avi-tagged FL MALT-1 (40 nM in a prepared reagent volume of 16.5 ⁇ L) and the reaction buffer (13.0 mL). MALT1 working stock (5 ⁇ L) was added to each well of the microplate. MALT-1 was pre- incubated with compounds for 30 minutes at room temperature. [0382] Two substrate working stocks (Km and 10xKm) were prepared.
  • the 1xKm substrate was prepared from Ac-LRSR-AMC Peptide (50 ⁇ M in a prepared reagent volume of 35.0 ⁇ L) and the reaction buffer (6.965 mL).
  • the 10x Km substrate was prepared from Ac-LRSR-AMC Peptide (280 ⁇ M in a prepared reagent volume of 196.0 ⁇ L) and the reaction buffer (6.804 mL).
  • the reaction was initiated by the addition of substrate working stock (5 ⁇ L, 50 ⁇ M) to Km plates and the addition of substrate working stock (5 ⁇ L 280 ⁇ M) to 10xKm plates. The plates were covered and incubated on the bench at room temperature for 90 minutes.
  • Fluorescence intensity was determined using a CLARIOstar microplate reader (BMG LABTECH) using the optimised AMC mode. Before taking readings, a 70% gain was applied on the neutral control well. Compound data were normalised to %Inhibition and used to plot sigmoidal concentration response curves to yield various parameters including IC 50 .
  • Part II – NF-kB Reporter Assay [0384] Jurkat cells were maintained in complete RPMI 1640 media supplemented with 10% FBS. Prior to the assay, 120 nL of the serial diluted compound was added in each well of 384- well flat bottom white plate (Corning #3570) by using liquid handler Echo550.
  • Jurkat cells were harvested by centrifugation at 120g for 10 min and resuspended in fresh RPMI 1640 media without serum.30 ⁇ L of cells (25,000 cells) were seeded in each well of 384-well plate containing compound. After 1hr incubation at 37oC in a 5% CO 2 incubator, 10 ⁇ L of diluted aCD3/aCD28/PMA (final concentration at 5 ⁇ g/mL, 5 ⁇ g/mL and 0.03 ⁇ g/mL, respectively) in RPMI 1640 without serum were added to each well. After incubation at 37oC in 5% CO 2 for 4 hr, 30 ⁇ L of One-Glo reagent (Promega #E6120) was added into each well.
  • aCD3/aCD28/PMA final concentration at 5 ⁇ g/mL, 5 ⁇ g/mL and 0.03 ⁇ g/mL, respectively

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un indazolyl-pipéridine sulfonamide et des composés apparentés, des compositions pharmaceutiques, leur utilisation pour inhiber la protéine 1 de translocation du lymphome lymphoïde associé aux muqueuses (MALT1), et leur utilisation dans le traitement d'une maladie ou d'un état, tel qu'un trouble prolifératif, un trouble inflammatoire ou un trouble auto-immun.
PCT/US2024/057658 2023-12-01 2024-11-27 Indazolyl-pipéridine sulfonamides et composés apparentés et leur utilisation en thérapie Pending WO2025117672A1 (fr)

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WO2006002284A1 (fr) * 2004-06-22 2006-01-05 Rigel Pharmaceuticals, Inc. Inhibiteurs de l'ubiquitine ligase
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