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WO2025072437A1 - Composés hétéroaryle et leur utilisation pour traiter des états pathologiques - Google Patents

Composés hétéroaryle et leur utilisation pour traiter des états pathologiques Download PDF

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Publication number
WO2025072437A1
WO2025072437A1 PCT/US2024/048549 US2024048549W WO2025072437A1 WO 2025072437 A1 WO2025072437 A1 WO 2025072437A1 US 2024048549 W US2024048549 W US 2024048549W WO 2025072437 A1 WO2025072437 A1 WO 2025072437A1
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Prior art keywords
alkylene
alkyl
substituted
certain embodiments
hydroxyalkyl
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Jotham Wadsworth Coe
John F. Kadow
Brian Thomas O'neill
Mark Stephen Plummer
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Alphina Therapeutics Inc
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Alphina Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/02—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 two hetero rings
    • C07D401/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • Solid tumors including prostate cancer, breast cancer, and lung cancer remain highly prevalent among the world population.
  • Current treatment options for these cancers are not effective for all patients and/or can have substantial adverse side effects.
  • new therapies that achieve an anti- cancer effect through a different mechanism present an opportunity to treat cancers more effectively and/or to treat cancers that have become resistant to currently available medicines.
  • 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.
  • Current treatment options for these inflammatory disorders are not effective for all patients and/or can have substantial adverse side effects.
  • Nicotinamide adenine dinucleotide is a cofactor that plays an important role in many physiologically essential processes, such as metabolism, energy production, DNA repair, and signaling. Nicotinamide phosphoribosyltransferase (NAmPRTase or NAMPT) is essential for the biosynthesis of NAD+. In mammals, the rate-limiting step in NAD+ biosynthesis is the salvage of NAM and conversion to nicotinamide mononucleotide (NMN) catalyzed by NAMPT. Thus, inhibition of NAMPT leads to depletion of NAD+ and a decrease in diseased cell proliferation and even diseased cell death.
  • NAD+ nicotinamide mononucleotide
  • the invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.
  • a disease or condition such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.
  • one aspect of the invention provides a collection of heteroaryl 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 heteroaryl 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 collection of heteroaryl compounds, such as a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof, where the variables are as defined in the detailed description. Further description of additional collections of heteroaryl 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 NAMPT.
  • 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-1, I-A, I-B, I-C, or I-D, to treat the disease or condition, as further described in the detailed description.
  • a compound described herein such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D
  • Another aspect of the invention provides a method of inhibiting the activity of NAMPT.
  • the method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT, as further described in the detailed description.
  • the invention provides heteroaryl compounds, pharmaceutical compositions, and their use in the treatment of a disease or condition, such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.
  • a disease or condition such as a proliferative disorder, inflammatory disorder, autoimmune disorder, or metabolic disorder.
  • the practice of the present invention employs, unless otherwise indicated, conventional techniques of organic chemistry, pharmacology, molecular biology (including recombinant techniques), cell biology, biochemistry, and immunology. Such techniques are explained in the literature, such as in “Comprehensive Organic Synthesis” (B.M. Trost & I. Fleming, eds., 1991-1992); “Handbook of experimental immunology” (D.M. Weir & C.C.
  • alkyl As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “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.
  • 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.
  • 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: [0016]
  • Exemplary bridged bicyclics include:
  • 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 C1-8 (or C1-6) 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., C0) and a -(C1-3 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 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 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.
  • 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.
  • heterocycle As used herein, the terms “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 When used in reference to a ring atom of a heterocycle, the term "nitrogen” includes a substituted nitrogen.
  • the nitrogen in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or 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 one or more 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.
  • oxo-heterocyclylene refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • 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 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.
  • R * is C1–6 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 –NO2, wherein each R ⁇ is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and 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, pect
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C1–4alkyl)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 C1-C12 alkyl, C 1 -C 10 alkyl, and C 1 -C 6 alkyl, respectively.
  • Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3- methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1- butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, 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 “C3-C6 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 -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like.
  • haloalkylene refers to a bivalent haloalkyl group.
  • hydroxyalkyl refers to an alkyl group that is substituted with at least one hydroxyl.
  • Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.
  • 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.
  • haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.
  • a cyclopentane susbstituted with an oxo group is cyclopentanone.
  • 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. “Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • the terms “subject” and “patient” are used interchangeable 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 includes humans.
  • IC50 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 an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • a compound of the invention contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts”) may be formed.
  • Such acidic and basic salts used within the scope of the invention are pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts.
  • Such salts of the compounds of the invention may be formed, for example, by reacting a compound of the invention with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • 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.
  • One aspect of the invention provides a compound represented by Formula I: or a pharmaceutically acceptable salt thereof; wherein: A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A 2 is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 ; A 3 is phenylene substituted with 0 or 1 occurrences of R 3 ; R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C1-4
  • 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 substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6- membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen. In certain embodiments, A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or . In certain embodiments, A 1 substituted with p occurrences of R 2 , wherein B 1 is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen. [0073] In certain embodiments, A 1 is substituted with p occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 or substituted with 1, 2 or 3 occurrences of R 2 .
  • a 1 is substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2, or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 . [0075] In certain embodiments, A 1 is substituted with 0 or 1 occurrences of R 2 , substituted with 1 or 2 occurrences of R 2 , or substituted with 1 or 2 occurrences of R 2 .
  • a 1 is substituted with 0 or 1 occurrence of R 2 , or substituted with 1 or 2. [0076] In certain embodiments, , each of which is substituted with p occurrences of R 2 . [0077] In certain embodiments, A 1 is substituted with p occurrences of R 2 . In certain embodiments, substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, substituted with 1 or 2 occurrences of R 2 . In certain embodiments, A 1 is substituted with 2 occurrences of R 2 . In certain embodiments, A 1 substituted with 3 occurrences of R 2 . In certain embodiments, A 1 is substituted with 4 occurrences of R 2 .
  • a 1 is substituted with p occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2, or 3 occurrences of R 2 . In certain embodiments, substituted with 0 or 1 occurrence of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 . In certain embodiments, substituted with p occurrences of R 2 . [0079] In certain embodiments, A 1 is substituted with p occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2 or 3 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1 or 2 occurrences of R 2 .
  • a 1 is substituted with 1 occurrence of R 2 .
  • a 1 is In certain emb 1 odiments, A is [0081] In certain embodiments, A 1 is In certain embodiments, certain embodiments, A 1 is , , .
  • A is In certain embodiments, A 1 is [0082] In certain embodiments, certain embodiments, A 1 is In certain embodiments, A 1 1 is In certain embodiments, A In certain embodiments, A 1 is In certain embodiments, [0083] In certain embodiments, A 1 is In certain embodiments, A 25 , , , , , [0084] In certain embodiments, A 1 is In certain e 1 mbodiments, A is [0085] In certain embodiments, A 1 is . In certain embodiments, certain embodiments, A 1 is . In certain embodiments, A 1 is In certain embodiments, A 1 is 26 [0086] In certain embodiments, A 1 is .
  • a 1 is In cer 1 1 tain embodiments, A is In certain embodiments, A is In certain embodiments 1 1 , A is In certain embodiments, A is In certain embodiments, A 1 is In certain 1 embodiments, A is In certain embodiments, A 1 is 1 In certain embodiments, A . In certain embodiments, A 1 is . In c 1 ertain embodiments, A is In certain 1 1 embodiments, A is In certain embodiments, A is selected from the groups depicted in the compounds in Table 1, below.
  • a 2 is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond; wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene.
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen.
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R 3 . In certain embodiments, A 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene. [0092] In some embodiments, A 2 is a 4-8 membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bicyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R 3 . In certain embodiments, A 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene.
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, each of which is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R 3 .
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.
  • a 2 is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from oxygen and nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bridged bicyclic carbocyclylene, each of which is substituted with 0 or 1 occurrences of R 3 ; or A 2 is a covalent bond.
  • a 2 is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a covalent bond.
  • each of which is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or wherein A 2 is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is one of the following: , wherein the nitrogen atom is attached to Z; ) o wherein the saturated carbon is attached to Z; or .
  • a 2 is each of which is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z.
  • a 2 is 2 wherein the nitrogen atom of A is attached to Z.
  • a 2 is wherein the saturated carbon is attached to Z, wherein A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is wherein the saturated carbon is attached to Z. In certain embodiments, A 2 is , each of which is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is [0100] In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein the saturated carbon of A 2 is attached to Z.
  • 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 , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is In certain embodiments, A 2 is . In certain embodiments, A 2 is . In certain embodiments, A 2 is , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is , wherein the saturated carbon of A 2 is attached to Z. [0102] In certain embodiments, A 2 is substituted with 0 occurrences of R 3 . In certain embodiments, A 2 is selected from the groups depicted in the compounds in Table 1, below.
  • a 3 is phenylene substituted with 0 or 1 occurrences of R 3 . In some embodiments, A 3 is para-phenylene substituted with 0 or 1 occurrences of R 3 . In some embodiments, A 3 is phenylene. In some embodiments, A 3 is para-phenylene. In certain embodiments, A 3 is . In some embodiments, A 3 is selected from the groups depicted in the compounds in Table 1, below. [0104] As defined generally above, R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C1-4 alkyl. In certain embodiments, R 1A , R 1B , and R 1C are hydrogen.
  • R 1A and R 1B are both hydrogen. In certain embodiments, R 1A and R 1B are both methyl. In certain embodiments, R 1A is hydrogen. In certain embodiments, at least one instance of R 1A is hydrogen. In certain embodiments, each R 1A is independently C1-4 alkyl. In certain embodiments, R 1B is hydrogen. In certain embodiments, at least one instance of R 1B is hydrogen. In certain embodiments, each R 1B is independently C 1-4 alkyl. In certain embodiments, R 1C is hydrogen. In certain embodiments, at least one instance of R 1C is hydrogen. In certain embodiments, each R 1C is independently C1-4 alkyl. In certain embodiments, R 1A is selected from the groups depicted in the compounds in Table 1, below.
  • R 1B is selected from the groups depicted in the compounds in Table 1, below.
  • R 1C is selected from the groups depicted in the compounds in Table 1, below.
  • R 2 represents independently for each occurrence halo, C1- 4 haloalkyl, C 1-4 alkoxyl, C 1-4 alkyl, or C 1-4 hydroxyalkyl.
  • R 2 represents independently for each occurrence fluoro, chloro, -CF3, -OCH3, -CH3, or -CH2OH.
  • R 2 represents independently for each occurrence halo.
  • each R 2 is independently fluoro or chloro.
  • R 2 is fluoro.
  • R 2 is chloro. In certain embodiments, R 2 is selected from the groups depicted in the compounds in Table 1, below. [0106] As defined generally above, R 3 represents independently for each occurrence halo or C1-4 alkyl. In certain embodiments, R 3 represents independently for each occurrence halo. In certain embodiments, R 3 represents independently for each occurrence C 1-4 alkyl. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is chloro. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1, below.
  • Z is one of the following: a) -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substitute
  • Z is one of the following: a) -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C
  • Z is one of the following: a) -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2- (C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-O-(C 1-4 alkyl), or -C(O)-(C 1-4 alkylene)-[O-(C 1-4 alkylene)-]y-(C1-6 alkoxyl); b) -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)- N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-6 alkyl), -C(O)-N(R 1A )-((R 1A )-(
  • Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or - N(R 1A )-C(O)-(C1-6 alkyl)
  • Z is selected from the groups above, provided that when B 1 is a 6- membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not -C(O)-(C 1-6 hydroxyalkyl). In certain embodiments, Z is selected from the groups above, provided that when B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or B 1 is substituted with 0 occurrences of R 2 , then Z is not -C(O)-(C 1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-R 4 , -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R 1B ), -C(O)- O-(C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C1-4 hydroxyalkyl), -S(O)2-(C1- 6 alkyl), -S(O) 2 -(C 3-7 cycloalkyl), -S(O) 2 -N(R 1A )(R 1B ), -S(O) 2 -N(R 1A )-C(O)-(C(O)-(C1-6
  • Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-7 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)), -C(O)-N(R 1A )-(C0-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -C(O)-N(R 1A )-(C 1-4 alkylene)-(C 3-7 cycloalkyl substituted with z
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-R 4 , -C(O)-(C 1-4 alkylene)- N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-] y -(C 1-6 alkoxyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)
  • Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)).
  • Z is -C(O)-(C 1-6 hydroxyalkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)); provided that when
  • Z is -C(O)R 4 or -C(O)-(C1-4 alkylene)-R 4 . In certain embodiments, Z is -C(O)R 4 or -C(O)-(C 1-4 alkylene)-R 4 ; provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 .
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)- (C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-O-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-[O-(C 1-4 alkylene)-] y -(C 1-6 alkoxyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyr
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1- 4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl)
  • Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)- (C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), or -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 .
  • Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl) or -C(O)-(C 1-4 alkylene)- N(R 1A )-S(O)2-(C1-4 alkyl).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , - C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or - C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)).
  • Z is -C(O)-(C 1-4 alkylene)-O-(C 1-4 alkyl) or -C(O)-(C 1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C 1-4 alkyl and one -OH) or - C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)).
  • Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C1-6 alkyl), -C(O)-N(R 1A )-(C1-4 haloalkyl), -C(O)-N(R 1A )-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R 1B )-(C1-4 alkylene)- [O-(C 1-4 alkylene)-] x -(C 1-6 alkoxyl), -C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), - C(O)-N(R 1A )-(C 1-4
  • Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-6 alkyl), -C(O)-N(R 1A )-(C 1-4 haloalkyl), -C(O)-N(R 1A )-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), -C(O)-N(R 1B )-(C1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), - C(O)-N(R 1A )-[
  • Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), or -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl).
  • Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-6 alkyl), or -C(O)-N(R 1A )-(C 1-4 haloalkyl).
  • Z is -C(O)-N(R 1A )-(C 1-4 alkylene)-O-(C 1-6 hydroxyalkyl), - C(O)-N(R 1B )-(C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R 1A )-(C1-4 alkylene)- N(R 1B )-C(O)-(C1-4 alkyl), -C(O)-N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ), - C(O)-N(R 1A )-[(C 1-4 alkylene)-O-] x -(C 1-4 alkylene)-N(R 1A )(R 1B ), - C(O)-N(R 1A )-[(C 1-4 alkylene)
  • Z is -C(O)-C(O)-N(R 1A )-R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), -C(O)- C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl),-C(O)-C(O)-N(R 1A )-S(O) 2 -(C 1-6 alkyl), - C(O)-C(O)-N(R 1A )-(C 1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R 4 , -C(O)-C(O)-OH, -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)-O-(
  • Z is -C(O)-C(O)-N(R 1A )-R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), -C(O)- C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R 4 , -C(O)-C(O)-OH, -C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)-N(R 1A )(R 1B ),
  • -C(O)-C(O)-N(R 1A )-(C 1-6 hydroxyalkyl -C(O)-C(O)- N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl).
  • Z is -C(O)-C(O)-N(R 1A )-R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), - C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R 4 , or -C(O)-C(O)-OH.
  • Z is -C(O)-C(O)-N(R 1A )- R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), -C(O)-C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl),- C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).
  • Z is -C(O)-C(O)-R 4 or -C(O)-C(O)-OH. In certain embodiments, Z is -C(O)-OH or -C(O)-O-(C1-6 alkyl).
  • Z is -C(O)-O- (C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C 1-4 hydroxyalkyl), or -C(O)-O-(C 1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ).
  • Z is -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl), -N(R 1A )- C(O)-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-4 alkylene)-N(R 1C )-C(O)-(C1-4 alkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 alkylene)-N(R 1C )-S(O)2-(C1-4 alkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R 1A )-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-N(R 1B )-(C1-4 haloalkyl), - N(R 1A )-C(O)-N(R 1B )-[(C1-4 alkylene)-O-]x-R 6 , -N(R 1A )-C(O)-N(R 1B )-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R 1A )-C(O)-(morpholinyl), or -N(R 1A )-C(O)- (azetidinyl
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R 1A )-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-N(R 1B )-(C 1-4 haloalkyl), or -N(R 1A )-C(O)-N(R 1B )-[(C1-4 alkylene)-O-]x-R 6 .
  • Z is - N(R 1A )-C(O)-N(R 1B )-(C1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R 1A )-C(O)- (morpholinyl), or -N(R 1A )-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).
  • Z is -N(R 1A )-C(O)-(C1-6 hydroxyalkyl), -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-S(O) 2 -(C 1-4 alkyl), - N(R 1A )-C(O)-(C 1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R 1A )-C(O)-O-[(C 1-4 alkylene)-O-]x-R 6 , -N(R 1A )-C(O)-O-(C1-4 alkylene)-(phenyl), or -N(R 1A )-S(O)2-R 7
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), - N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-S(O) 2 -(C 1-4 alkyl), -N(R 1A )-C(O)-O-[(C 1-4 alkylene)-O-] x - R 6 , or -N(R 1A )-S(O)2-R 7 .
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )- C(O)-(C1-4 alkyl), -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl), or -N(R 1A )-S(O)2-R 7 .
  • Z is -N(R 1A )-C(O)-(C 1-6 hydroxyalkyl), -N(R 1A )-C(O)-(C 1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), or -N(R 1A )-C(O)-O-(C1-4 alkylene)-(phenyl).
  • Z is -N(R 1A )-C(O)-(C1-6 hydroxyalkyl), -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-S(O) 2 -(C 1-4 alkyl), or -N(R 1A )-C(O)-(C 1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl).
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), -N(R 1A )-C(O)-(C1-4 alkylene)- N(R 1B )-S(O)2-(C1-4 alkyl), or -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x-R 6 .
  • Z is -N(R 1A )-C(O)-O-[(C 1-4 alkylene)-O-] x -R 6 or -N(R 1A )-C(O)-O-(C 1-4 alkylene)-(phenyl).
  • Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1- 4 alkylene)-(C1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O- ] x -R 5 , -S(O) 2 -(C 3-7 cycloalkyl), -S(O) 2 -N(R 1A )-(C 1-6 hydroxyalkyl), -S(O) 2 -N(R 1A )(R 1B ), -S(O) 2 - N(R 1A )-C(O)-(C1-6 alkyl), -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl), or -S(O)2-(C1-6 hydroxy
  • Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-4 alkylene)-(C1- 6 alkoxyl), -S(O) 2 -(C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl), -S(O) 2 -[(C 1-4 alkylene)-O-] x -R 5 , -S(O) 2 - N(R 1A )-(C 1-6 hydroxyalkyl), -S(O) 2 -N(R 1A )(R 1B ), -S(O) 2 -N(R 1A )-C(O)-(C 1-6 alkyl), -S(O) 2 - N(R 1A )-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R 1A )-C(O)-N(R 1B )(R 1C ).
  • Z is - S(O)2-(C1-6 alkyl) or -S(O)2-(C3-7 cycloalkyl). [0136] In certain embodiments, Z is -S(O) 2 -(C 1-6 hydroxyalkyl), -S(O) 2 -N(R 1A )-(C 1-6 hydroxyalkyl), -S(O)2-N(R 1A )-C(O)-(C1-6 alkyl), or -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl).
  • Z is -S(O)2-(C1-6 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)- (C 1-6 alkoxyl), -S(O) 2 -(C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl), -S(O) 2 -[(C 1-4 alkylene)-O-] x -R 5 , or - S(O)2-(C3-7 cycloalkyl).
  • Z is -S(O)2-N(R 1A )-(C1-6 hydroxyalkyl) or - S(O)2-N(R 1A )(R 1B ). In certain embodiments, Z is -S(O)2-N(R 1A )-C(O)-(C1-6 alkyl), -S(O)2- N(R 1A )-C(O)-O-(C 1-6 alkyl), or -S(O) 2 -N(R 1A )-C(O)-N(R 1B )(R 1C ).
  • Z is -S(O) 2 -[(C 1-4 alkylene)-O-] x -R 5 , -S(O) 2 -N(R 1A )-C(O)-(C 1-6 alkyl), or -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl).
  • Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R 1A )-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R 1A )-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl).
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)- (C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)), -C(O)- N(R 9 ), -C(O
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or - N(R 1A )-C(O)-(C1-6 alkyl)), -C(O)-N(R 1A
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R 1A )-R 5 , and -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R 1A )-R 5 , and -N(R 1A )-C(O)-C(O)- N(R 1B )-(C1-6 hydroxyalkyl); provided that when B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not -C(O)R 4 .
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R 1A )-(C1-6 hydroxyalkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl), -C(O)-C(O)-N(R 1A )-(C 1- 6 hydroxyalkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl); provided that when B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not -C(O)R 4 .
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo) or -N(R 1A )-C(O)-(C 1-6 hydroxyalkyl). In some embodiments, Z is - N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl) or -N(R 1A )-C(O)-(C1-6 hydroxyalkyl). [0143] In certain embodiments, Z is -C(O)R 4 .
  • Z is -C(O)R 4 , provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 .
  • Z is -C(O)-(C1-6 hydroxyalkyl).
  • Z is -C(O)-(C1-6 hydroxyalkyl), provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 .
  • Z is -C(O)-(C 1-4 alkylene)-R 4 .
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )- C(O)-(C 5-8 bridged bicyclic cycloalkyl substituted with z occurrence of R 9 ).
  • Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).
  • Z is -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)). In some embodiments, Z is - C(O)-(C 3-7 cycloalkyl gem-substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1- 6 alkyl)).
  • Z is -C(O)-N(R 1A )-(C 1-4 haloalkyl). In some embodiments, Z is - C(O)-N(R 1A )-(C 1-4 alkylene)-O-(C 1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R 1B )- (C1-4 alkylene)-[O-(C1-4 alkylene)-]x-(C1-6 alkoxyl). In some embodiments, Z is -C(O)-N(R 1A )- (C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl).
  • Z is -C(O)-N(R 1A )-[(C1-4 alkylene)-O-] x -(C 1-4 alkylene)-N(R 1A )(R 1B ). In some embodiments, Z is -C(O)-N(R 1A )-[(C 1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1B )-C(O)-O-(C1-6 alkyl).
  • Z is -C(O)- N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R 1A )-[(C 1-4 alkylene)-O-] x -(C 1-4 alkylene)-N(R 1B )-S(O) 2 -R 6 . In some embodiments, Z is -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl).
  • Z is -C(O)-N(R 1A )-(C0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R 1A )-(C 1-4 alkylene)-(C 3-7 cycloalkyl). In some embodiments, Z is -C(O)-N(R 1A )-S(O) 2 -R 7 . [0146] In some embodiments, Z is -C(O)-C(O)-N(R 1A )-R 5 .
  • Z is -C(O)- C(O)-N(R 1A )-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R 1A )(R 1B ). In some embodiments, Z is -C(O)-C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl). In some embodiments, Z is -C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl).
  • Z is -C(O)- C(O)-N(R 1A )-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R 4 . In some embodiments, Z is -C(O)-C(O)-OH. [0147] In some embodiments, Z is -C(O)-OH. In some embodiments, Z is -C(O)-O-(C1-6 alkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R 1B ).
  • Z is -C(O)-O-(C 1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))- (C 1-4 hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C 1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ). [0148] In some embodiments, Z is -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl).
  • Z is -N(R 1A )-C(O)-C(O)-N(R 1B )(R 1C ). In some embodiments, Z is -N(R 1A )-C(O)- C(O)-N(R 1B )-(C1-4 alkylene)-N(R 1C )-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R 1A )- C(O)-C(O)-N(R 1B )-(C 1-6 alkylene)-N(R 1C )-S(O) 2 -(C 1-4 alkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )(R 1C ). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C 1-4 haloalkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-[(C 1- 4 alkylene)-O-]x-R 6 . In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R 1A )-C(O)- (morpholinyl).
  • Z is-N(R 1A )-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH). [0150] In some embodiments, Z is -N(R 1A )-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl).
  • Z is - N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl). In some embodiments, Z is -N(R 1A )- C(O)-O-[(C1-4 alkylene)-O-]x-R 6 . In some embodiments, Z is -N(R 1A )-C(O)-O-(C1-4 alkylene)- (phenyl). In some embodiments, Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl).
  • Z is -N(R 1A )-S(O) 2 -R 7 . In some embodiments, Z is - N(R 1A )-S(O)2-(C0-4 alkylene)-N(R 1A )(R 1B ). In some embodiments, Z is -N(R 1A )-S(O)2-(C0-6 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl). In some embodiments, Z is -N(R 1A )-S(O)2-N(R 1B )-C(O)-O- R 8 .
  • Z is -N(R 1A )-S(O) 2 -N(R 1B )-CO 2 -(C 1-4 alkylene)-(phenyl). [0151] In some embodiments, Z is -S(O)2-(C1-6 hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O) 2 -(C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl).
  • Z is - S(O)2-[(C1-4 alkylene)-O-]x-R 5 . In some embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-]x-(C1-6 alkyl). In some embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In some embodiments, Z is -S(O)2- N(R 1A )-(C 1-6 hydroxyalkyl). In some embodiments, Z is -S(O) 2 -N(R 1A )(R 1B ). In some embodiments, Z is -S(O) 2 -N(R 1A )-C(O)-(C 1-6 alkyl).
  • Z is -S(O) 2 -N(R 1A )- C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O)2-N(R 1A )-C(O)-N(R 1B )(R 1C ). [0152] In some embodiments, Z is -(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-C(O)-N(R 1A )-(C 1-6 hydroxyalkyl). In some embodiments, Z is -(C 1-4 alkylene)-N(R 1A )- C(O)-(C1-6 hydroxyalkyl).
  • Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C1-4 alkylene)-C(O)-O-(C1-6 alkyl). [0153] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R 1A . In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C 1-4 alkyl. In certain embodiments, Z is hydrogen. [0154] In certain embodiments, Z is [0155] In certain embodiments, Z is 51
  • Z is In certain embodiments, Z is 52
  • Z is ; provided that when B 1 is a 6-membered aryl ring 53 substituted with 0 or 1 occurrences of R 2 , then Z is not . In certain embodiments, Z is ; provided that when B 1 is a 6- membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not . [0158] In certain embodiments, provided that when 1 B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not .
  • Z provided t 1 hat when B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , then Z is not .
  • Z is certain embodiments, Z is In certain embodiments, Z is [0159] In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is 55 In certain embodiments, [0160] In certain embodiments, Z is . In certain embodiments, , , In certain embodiments, Z is [0161] In certain embodiments, Z is .
  • Z is , provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 . In certain embodiments, certain embodiments, certain embodiments, Z is . In certain embodiments, 56 certain embodiments, In certain embodiments, provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 . In certain embodiments, certain embodiments, certain embodiments, certain embodiments, . In certain embodiments, certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, In certain embodiments, . In certain embodiments, .
  • Z is In certain embodiments, . In certain embodiments, . In certain embodiments, . In certain embodiments, Z is In certain embodiments, Z is certain embodiments, certain embodiments, Z i In certain embodiments, Z is In certain embodiments, Z is . [0162] In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is 58
  • Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, embodiments, Z is . In certain embodiments, embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiment
  • Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is certain embodiments, Z is .
  • Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain
  • Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is 63 In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is .
  • Z is In certain embodiments, Z is [0163] In certain embodiments above for variable Z that contain -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , and/or -C(O)-(C1-6 hydroxyalkyl); it is provided that when B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or B 1 is substituted with 0 occurrences of R 2 , then Z is not -C(O)R 4 , -C(O)-(C1-6 hydroxyalkyl), or -C(O)-(C1-4 alkylene)-R 4 .
  • Z is selected from the groups depicted in the compounds in Table 1, below.
  • R 4 is C 1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo- heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is C 1-6 hydroxyalkyl.
  • R 4 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1, below.
  • R 5 is C1-6 alkyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), C1-6 alkoxyl, -(C1-6 alkylene)-N(R 1A )(R 1B ), or -(C1-6 alkylene)-N(R 1A )-C(O)-O-(C1-6 alkyl).
  • R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl, -(C 1-4 alkylene)-(C 1-4 alkoxyl), or C 1-6 alkoxyl.
  • R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 alkoxyl. In certain embodiments, R 5 is C1-6 alkyl. In certain embodiments, R 5 is -CH3. In certain embodiments, R 5 is C1-6 hydroxyalkyl. In certain embodiments, R 5 is C1-6 alkoxyl. In certain embodiments, R 5 is -(C 1-4 alkylene)-(C 1-4 alkoxyl) or -(C 1-6 alkylene)-N(R 1A )(R 1B ). In certain embodiments, R 5 is -(C1-4 alkylene)-(C1-4 alkoxyl).
  • R 5 is -(C1-6 alkylene)-N(R 1A )(R 1B ). In certain embodiments, R 5 is -(C1-6 alkylene)-N(R 1A )-C(O)-O-(C1-6 alkyl). In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1, below. [0169] As defined generally above, R 6 is C1-4 alkyl, C1-4 hydroxyalkyl, C1-4 haloalkyl, or -(C1- 4 alkylene)-(C 1-4 alkoxyl). In certain embodiments, R 6 is C 1-4 alkyl, C 1-4 hydroxyalkyl, or C 1-4 haloalkyl.
  • R 6 is C 1-4 alkyl. In certain embodiments, R 6 is -CH 3 . In certain embodiments, R 6 is C1-4 hydroxyalkyl. In certain embodiments, R 6 is C1-4 haloalkyl. In certain embodiments, R 6 is -(C1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 1, below.
  • R 7 is C1-4 alkyl, C1-4 alkoxyl, C1-6 hydroxyalkyl, -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)-N(R 1A )(R 1B ), -(C0-6 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C 1-4 alkyl, C 1-4 alkoxyl or C 1-6 hydroxyalkyl.
  • R 7 is -(C1-4 alkylene)-(C1-4 alkoxyl), -(C0-4 alkylene)- N(R 1A )(R 1B ), -(C0-6 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is -(C 0-4 alkylene)-N(R 1A )(R 1B ), -(C 0-6 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), or - N(R 1B )-C(O)-O-R 8 .
  • R 7 is -N(R 1A )(R 1B ), -N(R 1B )-C(O)-(C 1-4 alkyl), or - N(R 1B )-C(O)-O-R 8 .
  • R 7 is -(C1-4 alkylene)-N(R 1A )(R 1B ) or -(C1-6 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl).
  • R 7 is C1-4 alkyl, C1-4 alkoxyl, -(C1-4 alkylene)-(C 1-4 alkoxyl), -(C 0-4 alkylene)-N(R 1A )(R 1B ), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C1-4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R 1A )(R 1B ), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C1-4 alkyl.
  • R 7 is -CH3.
  • R 7 is C 1-4 alkoxyl. In certain embodiments, R 7 is C 1-6 hydroxyalkyl. In certain embodiments, R 7 is -(C0-4 alkylene)-N(R 1A )(R 1B ). In certain embodiments, R 7 is - N(R 1A )(R 1B ). In certain embodiments, R 7 is -(C1-4 alkylene)-N(R 1A )(R 1B ). In certain embodiments, R 7 is -N(R 1B )-C(O)-O-R 8 . In certain embodiments, R 7 is -(C 1-4 alkylene)-(C 1-4 alkoxyl).
  • R 7 is -(C 0-6 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl). In certain embodiments, R 7 is -N(R 1B )-C(O)-(C1-4 alkyl). In certain embodiments, R 7 is -(C1-6 alkylene)- N(R 1B )-C(O)-(C1-4 alkyl). In certain embodiments, R 7 is selected from the groups depicted in the compounds in Table 1, below. [0172] As defined generally above, R 8 is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R 8 is C1-4 alkyl. In certain embodiments, R 8 is -CH3.
  • R 8 is -(C 0-4 alkylene)-(phenyl). In certain embodiments, R 8 is selected from the groups depicted in the compounds in Table 1, below. [0173] As defined generally above, R 9 is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R 9 is oxo. In certain embodiments, R 9 is C 1-4 alkyl. In certain embodiments, R 9 is -CH 3 . In certain embodiments, R 9 is hydroxyl. In certain embodiments, R 9 is -C(O)-O-(C1-4 alkyl).
  • R 9 is selected from the groups depicted in the compounds in Table 1, below.
  • m and n are independently 1 or 2. In certain embodiments, m and n are 1. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, m is selected from the values represented in the compounds in Table 1, below. In certain embodiments, n is selected from the values represented in the compounds in Table 1, below. [0175] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • p is 4. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments p is 2 or 3. In certain embodiments p is 3 or 4. In certain embodiments p is 0, 1, or 2. In certain embodiments p is 1, 2, or 3. In certain embodiments, p is 2, 3, or 4. In certain embodiments p is 0, 1, 2, or 3. In certain embodiments p is 1, 2, 3, or 4. In certain embodiments, p is selected from the values represented in the compounds in Table 1, below. [0176] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4.
  • x is 5. In certain embodiments, x is selected from the values represented in the compounds in Table 1, below. [0177] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, y is selected from the values represented in the compounds in Table 1, below. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from the values represented in the compounds in Table 1, below. [0178] The description above describes multiple embodiments relating to compounds of Formula I. The patent application specifically contemplates all combinations of the embodiments.
  • Another aspect of the invention provides a compound represented by Formula I-B: or a pharmaceutically acceptable salt thereof; wherein: substituted with p occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 ;
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 ;
  • R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C1-4 alkyl;
  • R 2 represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl
  • variables in Formula I-B 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-B.
  • a 1 is substituted with p occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 or substituted with 1, 2 or 3 occurrences of R 2 . [0183] In certain embodiments, A 1 is substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 .
  • a 1 is substituted with 1, 2, or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 . [0184] In certain embodiments, A 1 is substituted with p occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2, or 3 occurrences of R 2 . In certain embodiments, substituted with 0 or 1 occurrence of R 2 . [0185] In certain embodiments, A 1 is substituted with 1, 2 or 3 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1 or 2 occurrences of R 2 .
  • a 1 is substituted with 1 occurrence of R 2 .
  • a 1 is substituted with 2, 3, or 4 occurrences of R 2 .
  • a 1 is 2 substituted with 2 occurrences of R .
  • a 1 is substituted with 3 occurrences of R 2 .
  • A is substituted with 4 occurrences of R 2 .
  • a 1 is In certain embodiments, A 1 is [0188] In certain embodiments, certain embodiments, . In certain embodiments, In certain embodiments, A 1 is [0189] In certain embodiments, .
  • a 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 [0190] In certain embodiments, A 1 is In certain emb 1 odiments, A is [0191] In certain embodiments, certain embodiments, certain embodiments, In certain embodiments, A 1 is . [0192] In certain embodiments, A 1 is . In certain embodiments, A 1 is In certain embodiments, A 1 is 1 In certain embodiments, A is In certain embodiments, A 1 i 1 s . In certain embodiments, A In certain embodiments, A 1 is . In certain embodiments, A 1 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene.
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6- membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, wherein the heterocyclylene is substituted with 1 occurrence of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen.
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene substituted with 1 occurrence of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene.
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene.
  • each of which is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or wherein A 2 is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is one of the following: , wherein the nitrogen atom is attached to Z; wherein the saturated carbon is attached to Z; or [0200]
  • a 2 is , each of which is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z.
  • a 2 is , wherein the nitrogen atom of A 2 is attached to Z.
  • a 2 is wherein the saturated carbon is attached to Z, wherein A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, wherein the saturated carbon is attached to Z. In certain embodiments, A 2 is each of which is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is . [0201] In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein the saturated carbon of A 2 is attached to Z. [0202] In certain embodiments, A 2 is . In certain embodiments, A 2 is In certain embodiments, A 2 is . In certain embodiments, A 2 is , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is .
  • a 2 is . In certain embodiments, A 2 is wherein the saturated carbon of A 2 is attached to Z. In certain embodiments, A 2 is substituted with 0 occurrences of R 3 .
  • R 3 is halo or C 1-4 alkyl. In some embodiments, R 3 is halo. In some embodiments, R 3 is C1-4 alkyl. In some embodiments, R 3 is methyl.
  • each of variables R 1A , R 1B , R 1C , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , p, x, y, z, and Z is one of the embodiments described above in connection with Formula I.
  • the description above describes multiple embodiments relating to compounds of Formula I-B. The patent application specifically contemplates all combinations of the embodiments.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen;
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R 3 ;
  • R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C 1-4 alkyl;
  • R 2 represents independently for each occurrence halo, C1-4 haloalkyl, C1-4 alkoxyl, C1-4 alkyl, or C1-4 hydroxyalkyl;
  • R 3 is halo or
  • variables in Formula I-C 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-C.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or .
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered heteroaryl ring containing 2 heteroatoms that are nitrogen. [0211] In certain embodiments, A 1 is substituted with p occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with p occurrences of R 2 or substituted with 1, 2 or 3 occurrences of R 2 .
  • a 1 is substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2, or 3 occurrences of R 2 , or substituted with 2, 3, or 4 occurrences of R 2 . In certain embodiments, A 1 is substituted with 1, 2 or 3 occurrences of R 2 , substituted with 1, 2 or 3 occurrences of R 2 . [0213] In certain embodiments, A 1 is substituted with 0 or 1 occurrences of R 2 , substituted with 1 or 2 occurrences of R 2 , or substituted with 1 or 2 occurrences of R 2 .
  • a 1 is substituted with 0 or 1 occurrence of R 2 , or substituted with 1 or 2.
  • a 1 is substituted with p occurrences of R 2 .
  • a 1 is or substituted with 2, 3, or 4 occurrences of R 2 .
  • a 1 is or substituted with 2 occurrences of R 2 .
  • a 1 is substituted with 3 occurrences of R 2 .
  • a 1 is substituted with 4 occurrences of R 2 .
  • a 1 is substituted with p occurrences of R 2 .
  • a 1 is substituted with 0 or 1 occurrence of R 2 .
  • a 1 is substituted with p occurrences of R 2 .
  • a 1 is substituted with 1, 2 or 3 occurrences of R 2 .
  • a 1 is substituted with 1 or 2 occurrences of R 2 .
  • a 1 is substituted with 1 occurrence of R 2 .
  • a 1 is , , , I 1 n certain embodiments, A is [0218] In certain embodiments, A 1 is In certain embodiments, certain embodiments, A 1 is , , or .
  • a 1 is . In certain embodiments, A 1 is [0219] In certain embodiments, certain embodiments, A 1 is In certain embodiments, A 1 is I 1 n certain embodiments, A In certain em 1 bodiments, A is In certain embodiments, [0220] In certain embodiments, A 1 is [0221] In certain embodiments, A 1 is , In certain e 1 mbodiments, A is [0222] In certain embodiments, A 1 is . In certain embodiments, A 1 is In certain embod 1 iments, A is In certain e 1 mbodiments, A is or In certain embodiments, A 1 is [0223] In certain embodiments, A 1 is . In certain embodiments, A 1 is .
  • a 1 is . In certain embodiments, A 1 is . In certain embodiments, certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodiments, A 1 is In certain embodimen 1 ts, A is In certain embodiments, A 1 is In certain em 1 bodiments, A . In certain embodiments, A 1 is In cer 1 tain embodiments, A is [0224] As defined generally above, A 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bicyclic carbocyclylene and heterocyclylene are substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene or a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene substituted with 1 occurrence of R 3 .
  • a 2 is a 5-8 membered saturated bridged bicyclic carbocyclylene.
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen, wherein the bridged bicyclic heterocyclylene is substituted with 1 occurrence of R 3 .
  • a 2 is a 5-8 membered saturated or partially unsaturated bridged bicyclic heterocyclylene containing 1 heteroatom selected from nitrogen and oxygen.
  • a 2 is each of which is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 . In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein the nitrogen atom of A 2 is attached to Z. In certain embodiments, A 2 is . In certain embodiments, A 2 is . In certain embodiments, A 2 is . In certain embodiments, A 2 is .
  • a 2 is , wherein the nitrogen atom of A 2 is attached to Z. [0228] In certain embodiments, A 2 is substituted with 0 occurrences of R 3 . [0229] As defined generally above, R 3 is halo or C 1-4 alkyl. In some embodiments, R 3 is halo. In some embodiments, R 3 is C 1-4 alkyl. In some embodiments, R 3 is methyl.
  • Z is one of the following: a) -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), - C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y- (C1-6 alkoxyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substitute
  • Z is one of the following: a) -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C
  • Z is one of the following: a) -C(O)-(C 1-6 hydroxyalkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or - N(R 1A )-C(O)-(C
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-O-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-] y -(C 1-6 alkoxyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)- (C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)), -C(O)- N(
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )- C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or - N(R 1A )-C(O)-(C1-6 alkyl)), -C(O)-N(R 1A )-
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R 1A )-R 5 , and -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl), - C(O)-C(O)-N(R 1A )-(C1-6 hydroxyalkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl).
  • variable Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variable Z is one of the embodiments described below in connection with Formula I-D. [0238] In certain embodiments, the definition of each of variables R 1A , R 1B , R 1C , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , p, x, y, and z is one of the embodiments described above in connection with Formula I. [0239] The description above describes multiple embodiments relating to compounds of Formula I-C. The patent application specifically contemplates all combinations of the embodiments.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 6-membered heteroaryl ring containing 1 or 2 heteroatoms that are nitrogen;
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic heterocyclylene containing 1 heteroatom that is nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, or a 5-8 membered saturated bridged bicyclic carbocyclylene, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 ;
  • R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C 1-4 alkyl;
  • R 2 represents independently for each occurrence halo, C1-4 haloalkyl, C1-4
  • variables in Formula I-D 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-D.
  • the definition of variable A 1 is one of the embodiments described above in connection with Formula I-C.
  • each of variables A 2 and R 3 is one of the embodiments described above in connection with Formula I-B.
  • Z is one of the following: a) -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), - C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyr
  • Z is one of the following: a) -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)- R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or - N(R 1A )-C(O)-(C)
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-(C1-4 alkylene)- N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or -C(O)-(C3-7
  • Z is -C(O)-(C 1-6 hydroxyalkyl), -C(O)-(C 1-4 alkylene)- N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)).
  • Z is -C(O)-(C1-6 hydroxyalkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)); provided that when B 1 is a 6-membere
  • Z is -C(O)R 4 or -C(O)-(C1-4 alkylene)-R 4 . In certain embodiments, Z is -C(O)R 4 or -C(O)-(C1-4 alkylene)-R 4 ; provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 .
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)- (C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH), or - C(O)-(C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)- (C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ), or -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl), or -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-R 4 .
  • Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl) or -C(O)-(C 1-4 alkylene)- N(R 1A )-S(O)2-(C1-4 alkyl).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 , - C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), or - C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O) 2 -(C 1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)).
  • Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C3-8 cycloalkyl substituted with z occurrence of R 9 ), -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C 1-4 alkyl and one -OH) or -C(O)-(C 3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)).
  • Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-6 alkyl), -C(O)-N(R 1A )-(C 1-4 haloalkyl), -C(O)-N(R 1A )-(C 1-4 alkylene)-O-(C 1-6 hydroxyalkyl), -C(O)-N(R 1B )-(C 1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), - C(O)-N(R 1A )-(C1-6 hydroxyal
  • Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C 1-6 alkyl), -C(O)-N(R 1A )-(C 1-4 haloalkyl), -C(O)-N(R 1A )-(C 1-4 alkylene)-O-(C 1-6 hydroxyalkyl), -C(O)-N(R 1B )-(C 1-4 alkylene)- [O-(C1-4 alkylene)-]x-(C1-6 alkoxyl), -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), - C(O)-N(R 1A )-(C1-6 hydroxyal
  • Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), or -C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl).
  • Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-N(R 1A )(R 1B ), -C(O)-N(R 1A )-(C1-6 alkyl), or -C(O)-N(R 1A )-(C1-4 haloalkyl).
  • Z is -C(O)-N(R 1A )-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl), - C(O)-N(R 1B )-(C 1-4 alkylene)-[O-(C 1-4 alkylene)-] x -(C 1-6 alkoxyl), -C(O)-N(R 1A )-(C 1-4 alkylene)- N(R 1B )-C(O)-(C1-4 alkyl), -C(O)-N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ), - C(O)-N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ), - C(O)-N(R 1A )-[(C1-4 alkylene)-
  • Z is -C(O)-C(O)-N(R 1A )-R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), -C(O)- C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), - C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), - C(O)-C(O)-R 4 , -C(O)-C(O)-OH, -C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)-N(R 1A )(R 1B ),
  • -C(O)-C(O)-N(R 1A )-(C 1-6 hydroxyalkyl -C(O)-C(O)- N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or - C(O)-C(O)-(C1-6 hydroxyalkyl).
  • Z is -C(O)-C(O)-N(R 1A )-R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), - C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl),-C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms), -C(O)-C(O)-R 4 , or -C(O)-C(O)-OH.
  • Z is -C(O)-C(O)-N(R 1A )- R 5 , -C(O)-C(O)-N(R 1A )(R 1B ), -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl),- C(O)-C(O)-N(R 1A )-S(O)2-(C1-6 alkyl), or -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).
  • Z is -C(O)-C(O)-R 4 or -C(O)-C(O)-OH.
  • Z is -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C1-4 hydroxyalkyl), or -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ).
  • Z is -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl), -N(R 1A )- C(O)-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-4 alkylene)-N(R 1C )-C(O)-(C 1-4 alkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 alkylene)-N(R 1C )-S(O)2-(C1-4 alkyl).
  • Z is -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl), -N(R 1A )-C(O)-C(O)-N(R 1B )- (C 1-4 alkylene)-N(R 1C )-C(O)-(C 1-4 alkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 alkylene)-N(R 1C )- S(O) 2 -(C 1-4 alkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R 1A )-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-N(R 1B )-(C1-4 haloalkyl), - N(R 1A )-C(O)-N(R 1B )-[(C 1-4 alkylene)-O-] x -R 6 , -N(R 1A )-C(O)-N(R 1B )-(C 1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl), -N(R 1A )-C(O)-(morpholinyl), or -N(R 1A )-C(O)- (azeti
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -N(R 1A )-C(O)-N(R 1B )(R 1C ), -N(R 1A )-C(O)-N(R 1B )-(C1-4 haloalkyl), or -N(R 1A )-C(O)-N(R 1B )-[(C 1-4 alkylene)-O-] x -R 6 .
  • Z is - N(R 1A )-C(O)-N(R 1B )-(C 1-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl), -N(R 1A )-C(O)- (morpholinyl), or -N(R 1A )-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).
  • Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl), - N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl), -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x- R 6 , or -N(R 1A )-S(O)2-R 7 .
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )- C(O)-(C 1-4 alkyl), -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-S(O) 2 -(C 1-4 alkyl), or -N(R 1A )-S(O) 2 -R 7 .
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl), -N(R 1A )- C(O)-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl), or -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x-R 6 .
  • Z is -S(O) 2 -(C 1-6 hydroxyalkyl), -S(O) 2 -(C 1-4 alkylene)-(C 1-6 alkoxyl), -S(O)2-(C1-4 alkylene)-C(O)-O-(C1-6 alkyl), -S(O)2-[(C1-4 alkylene)-O-]x-R 5 , -S(O)2- N(R 1A )-(C1-6 hydroxyalkyl), -S(O)2-N(R 1A )(R 1B ), -S(O)2-N(R 1A )-C(O)-(C1-6 alkyl), -S(O)2- N(R 1A )-C(O)-O-(C 1-6 alkyl), or -S(O) 2 -N(R 1A )-C(O)-N(R 1B )(R 1C ).
  • Z is - S(O)2-(C1-6 hydroxyalkyl), -S(O)2-N(R 1A )-(C1-6 hydroxyalkyl), -S(O)2-N(R 1A )-C(O)-(C1-6 alkyl), or -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl).
  • Z is -S(O)2-N(R 1A )-(C1-6 hydroxyalkyl) or -S(O) 2 -N(R 1A )(R 1B ).
  • Z is -S(O) 2 -N(R 1A )-C(O)-(C 1-6 alkyl), -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl), or -S(O)2-N(R 1A )-C(O)-N(R 1B )(R 1C ).
  • Z is -S(O)2-[(C1-4 alkylene)-O-]x-R 5 , -S(O)2-N(R 1A )-C(O)-(C1-6 alkyl), or -S(O)2- N(R 1A )-C(O)-O-(C 1-6 alkyl).
  • Z is -S(O) 2 -[(C 1-4 alkylene)-O-] x -(C 1-6 alkyl), -S(O) 2 -N(R 1A )-C(O)-(C 1-6 alkyl), or -S(O) 2 -N(R 1A )-C(O)-O-(C 1-6 alkyl).
  • Z is -(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-N(R 1A )-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-N(R 1A )-C(O)-(C1-6 hydroxyalkyl), -(C1-4 alkylene)-C(O)-OH, or - (C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl).
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R 1A )-R 5 , and -N(R 1A )-C(O)-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo), -C(O)-C(O)-N(R 1A )-R 5 , and -N(R 1A )-C(O)-C(O)- N(R 1B )-(C 1-6 hydroxyalkyl); provided that when B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or B 1 is substituted with 0 occurrences of R 2 , then Z is not - C(O)R 4 .
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C1-4 alkylene)-N(R 1A )-S(O)2-(C1-4 alkyl), -C(O)-N(R 1A )-(C1-6 hydroxyalkyl), -C(O)- C(O)-N(R 1A )-(C1-6 hydroxyalkyl), or -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl).
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl), -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O)
  • Z is -C(O)R 4 . In certain embodiments, Z is -C(O)R 4 , provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 . In certain embodiments, Z is -C(O)-(C 1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-6 hydroxyalkyl), provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 .
  • Z is -C(O)-(C 1-4 alkylene)-R 4 . In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R 4 , provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 . [0269] In some embodiments, Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-C(O)-(C 1-4 alkyl).
  • Z is -C(O)-(C 1-4 alkylene)-N(R 1A )-S(O) 2 -(C 1-4 alkyl). In some embodiments, Z is - C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-R 4 . In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R 1A )- C(O)-(C 3-8 cycloalkyl substituted with z occurrence of R 9 ).
  • Z is -C(O)- (C 1-4 alkylene)-N(R 1A )-C(O)-(C 3-8 cycloalkyl substituted with one -OH). In some embodiments, Z is -C(O)-(C1-4 alkylene)-N(R 1A )-C(O)-(C5-8 bridged bicyclic cycloalkyl substituted with z occurrence of R 9 ). In some embodiments, Z is -C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C 1-4 alkyl and one -OH).
  • Z is -C(O)- (C3-7 cycloalkyl substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C1-6 alkyl)). In some embodiments, Z is -C(O)-(C3-7 cycloalkyl gem-substituted with one -N(R 1A )-S(O)2-(C1-6 alkyl) or -N(R 1A )-C(O)-(C 1-6 alkyl)).
  • Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R 1A )-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl substituted with 1 occurrence of halo). In some embodiments, Z is -C(O)-N(R 1A )(R 1B ). In some embodiments, Z is -C(O)-N(R 1A )-(C 1-6 alkyl).
  • Z is -C(O)-N(R 1A )-(C1-4 haloalkyl). In some embodiments, Z is - C(O)-N(R 1A )-(C1-4 alkylene)-O-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R 1B )- (C 1-4 alkylene)-[O-(C 1-4 alkylene)-] x -(C 1-6 alkoxyl). In some embodiments, Z is -C(O)-N(R 1A )- (C1-4 alkylene)-N(R 1B )-C(O)-(C1-4 alkyl).
  • Z is -C(O)-N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ). In some embodiments, Z is -C(O)-N(R 1A )-[(C1-4 alkylene)-O-] x -(C 1-4 alkylene)-N(R 1B )-C(O)-O-(C 1-6 alkyl).
  • Z is -C(O)- N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1B )-C(O)-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1B )-S(O)2-R 6 . In some embodiments, Z is -C(O)-N(R 1A )-(C 1-4 alkylene)-N(R 1B )-S(O) 2 -(C 1-4 alkyl).
  • Z is -C(O)-N(R 1A )-(C 0-4 alkylene)-(tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -C(O)-N(R 1A )-(C1-4 alkylene)-(C3-7 cycloalkyl). In some embodiments, Z is -C(O)-N(R 1A )-S(O)2-R 7 . [0271] In some embodiments, Z is -C(O)-C(O)-N(R 1A )-R 5 .
  • Z is -C(O)- C(O)-N(R 1A )-(C1-6 hydroxyalkyl). In some embodiments, Z is -C(O)-C(O)-N(R 1A )(R 1B ). In some embodiments, Z is -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-N(R 1A )-C(O)-(C1-4 alkyl). In some embodiments, Z is -C(O)-C(O)-N(R 1A )-S(O) 2 -(C 1-6 alkyl).
  • Z is -C(O)- C(O)-N(R 1A )-(C1-4 alkylene)-(5-membered heteroaryl containing 1-4 nitrogen atoms). In some embodiments, Z is -C(O)-C(O)-R 4 . In some embodiments, Z is -C(O)-C(O)-OH. [0272] In some embodiments, Z is -C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)-N(R 1A )(R 1B ).
  • Z is -C(O)-O-(C 1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))- (C1-4 hydroxyalkyl). In some embodiments, Z is -C(O)-O-(C1-4 alkylene)-(5-membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ). [0273] In some embodiments, Z is -N(R 1A )-C(O)-C(O)-N(R 1B )-(C1-6 hydroxyalkyl).
  • Z is -N(R 1A )-C(O)-C(O)-N(R 1B )(R 1C ). In some embodiments, Z is -N(R 1A )-C(O)- C(O)-N(R 1B )-(C 1-4 alkylene)-N(R 1C )-C(O)-(C 1-4 alkyl). In some embodiments, Z is -N(R 1A )- C(O)-C(O)-N(R 1B )-(C1-6 alkylene)-N(R 1C )-S(O)2-(C1-4 alkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-(C1-6 hydroxyalkyl substituted with 0 or 1 occurrence of halo). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C 1-6 hydroxyalkyl). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )(R 1C ). In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C1-4 haloalkyl).
  • Z is -N(R 1A )-C(O)-N(R 1B )-[(C1- 4 alkylene)-O-]x-R 6 . In some embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-(C1-4 alkylene)- (tetrahydrofuranyl or tetrahydropyranyl). In some embodiments, Z is -N(R 1A )-C(O)- (morpholinyl).
  • Z is-N(R 1A )-C(O)-(azetidinyl, pyrrolidinyl, or piperidinyl, each of which is substituted with one C1-4 alkyl and one -OH).
  • Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl).
  • Z is -N(R 1A )-C(O)-(C1-4 alkylene)-N(R 1B )-S(O)2-(C1-4 alkyl).
  • Z is -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x-R 6 .
  • Z is - N(R 1A )-S(O) 2 -R 7 .
  • Z is -N(R 1A )-S(O) 2 -(C 0-4 alkylene)-N(R 1A )(R 1B ).
  • Z is -N(R 1A )-S(O) 2 -(C 0-6 alkylene)-N(R 1B )-C(O)-(C 1-4 alkyl).
  • Z is -N(R 1A )-S(O)2-N(R 1B )-C(O)-O-R 8 . In some embodiments, Z is -N(R 1A )- S(O)2-N(R 1B )-CO2-(C1-4 alkylene)-(phenyl). [0276] In some embodiments, Z is -S(O) 2 -(C 1-6 hydroxyalkyl). In some embodiments, Z is - S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl). In some embodiments, Z is -S(O)2-(C1-4 alkylene)-C(O)-O- (C1-6 alkyl).
  • Z is -S(O)2-[(C1-4 alkylene)-O-]x-R 5 . In some embodiments, Z is -S(O) 2 -[(C 1-4 alkylene)-O-] x -(C 1-6 alkyl). In some embodiments, Z is -S(O) 2 -N(R 1A )-(C 1-6 hydroxyalkyl). In some embodiments, Z is -S(O)2-N(R 1A )(R 1B ). In some embodiments, Z is - S(O)2-N(R 1A )-C(O)-(C1-6 alkyl).
  • Z is -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl). In some embodiments, Z is -S(O) 2 -N(R 1A )-C(O)-N(R 1B )(R 1C ). [0277] In some embodiments, Z is -(C 1-6 hydroxyalkyl). In some embodiments, Z is -(C 1-4 alkylene)-C(O)-N(R 1A )-(C1-6 hydroxyalkyl). In some embodiments, Z is -(C1-4 alkylene)-N(R 1A )- C(O)-(C1-6 hydroxyalkyl).
  • Z is -(C1-4 alkylene)-C(O)-OH. In some embodiments, Z is -(C 1-4 alkylene)-C(O)-O-(C 1-6 alkyl). [0278] In some embodiments, Z is a 5-membered oxo-heterocyclyl containing 2 ring heteroatoms independently selected from nitrogen and oxygen, wherein the oxo-heterocyclyl is substituted with one R 1A . In some embodiments, Z is oxazolidinonyl or imidazolidinonyl substituted with one C1-4 alkyl.
  • Z is In certain embodiments, Z is 109 provided that if B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 , then Z is not . [0280] In certain embodiments, Z is provided that if B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 , then Z is not .
  • Z is not if B is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 , then Z is not . In certain embodiments, provided that if B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 , then Z is not . In certain embodiments, Z In certain embodiments, Z is In certain embodiments, Z is [0282] In certain embodiments, Z is In certain embodiments, Z is 111 , In certain embodiments, Z is .
  • Z is [0283] In certain embodiments, Z is ; provided that if B 1 is a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 , then Z is not . [0284] In certain embodiments, Z is . In certain embodiments, Z is ; provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 . In certain embodiments, Z is certain embodiments, certain embodiments, embodiments, . In certain embodiments, .
  • Z is ; provided that B 1 is not a 6-membered aryl ring substituted with 0 or 1 occurrences of R 2 , or substituted with 0 occurrences of R 2 . In certain embodiments, certain embodiments, certain embodiments, . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, 113 In certain embodiments, Z is In certain embodiments, Z is .
  • Z is In certain embodiments, Z In certain embodiments, [0285] In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z In certain embodiments, Z is , In certain embodiments, Z is [0286] As generally defined above, z is 1, 2 or 3. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3. [0287] In certain embodiments, the definition of each of variables R 1A , R 1B , R 1C , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , p, and x is one of the embodiments described above in connection with Formula I.
  • Another aspect of the invention provides a compound represented by Formula I-1: (I-1) or a pharmaceutically acceptable salt thereof; wherein: A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur; A 2 is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 ; R 1A , R 1B ,
  • variables in Formula I-1 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-1.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered aryl ring.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur.
  • a 1 is substituted with p occurrences of R 2 , wherein B 1 is a 5-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. In certain embodiments, A 1 is substituted with p occurrences of R 2 , wherein B 1 is a 6-membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur. [0293] In certain embodiments, each of which is substituted by p occurrences of halo. In certain embodiments, A 1 substituted by p occurrences of halo. In certain embodiments, A 1 is substituted by p occurrences of halo.
  • a 1 is substituted by p occurrences of halo. In certain embodiments, A 1 is substituted by p occurrences of halo. [0294] In certain embodiments, A 1 is In 1 certain embodiments, A In certain embodiments, A 1 is In certain embodiments, A 1 In certain embodiments, A 1 is In certain embodiments, A 1 In certain embodiments, A 1 is In certain embodiments, A 1 In certain embodiments, A 1 is In c 1 ertain embodiments, A is In certain embodiments, A 1 is In certain embodiments, A 1 is .
  • a 1 is In certai 1 n e mbodiments, A In certain embodimen 1 1 ts, A is In certain embodiments, A is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • a 2 is a 6-membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, a 5-8 membered saturated bicyclic carbocyclylene, or a covalent bond, wherein the heterocyclylene, monocyclic carbocyclylene, and bicyclic carbocyclylene are substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6- membered saturated or partially unsaturated heterocyclylene containing 1 heteroatom selected from nitrogen, wherein the heterocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 6-membered saturated or partially unsaturated monocyclic carbocyclylene, wherein the monocyclic carbocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a 5-8 membered saturated bicyclic carbocyclylene, wherein the bicyclic carbocyclylene is substituted with 0 or 1 occurrences of R 3 .
  • a 2 is a covalent bond.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is each of which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C1-4 alkyl.
  • R 1A is hydrogen.
  • R 1A is C1-4 alkyl.
  • R 1B is hydrogen.
  • R 1B is C 1-4 alkyl.
  • R 1C is hydrogen.
  • R 1C is C1-4 alkyl.
  • R 1A and R 1B are both hydrogen.
  • R 1A and R 1B are both methyl.
  • R 1A is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • R 2 represents independently for each occurrence halo. In certain embodiments, R 2 is fluoro or chloro. In certain embodiments, R 2 is fluoro. In certain embodiments, R 2 is chloro. In certain embodiments, R 2 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0298] As defined generally above, R 3 is halo or C1-4 alkyl. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is C1-4 alkyl. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is chloro. In certain embodiments, R 3 is methyl.
  • R 3 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-OH, - C(O)-O-(C 1-6 alkyl), -C(O)-N(R 1A )(R 1B ), -C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)- N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C1-4 hydroxyalkyl), -S(O)2-(C1-6 alkyl), -S(O)2-(C3-7 cycloalkyl), -S(O)2-N(R 1A )(R 1B
  • Z is In certain embodiments, Z is , In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiment
  • Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is .
  • Z i . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiment
  • Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . ain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is . In certain embodiments, . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is [0301] In certain embodiments, Z is -C(O)R 4 .
  • Z is -C(O)-(C1-4 alkylene)-R 4 . In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R 1A )(R 1B ). In certain embodiments, Z is - C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)-N(R 1A )(R 1B ).
  • Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O) 2 -N(R 1A )(R 1B ). In certain embodiments, Z is -S(O) 2 -N(R 1A )- C(O)-(C1-6 alkyl).
  • Z is -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R 1A )-C(O)-N(R 1B )(R 1C ). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-] x -R 5 . In certain embodiments, Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom).
  • Z is -N(R 1A )-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x- R 6 . In certain embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-[(C 1-4 alkylene)-O-] x -R 6 . In certain embodiments, Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl).
  • Z is -C(O)- N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ). In certain embodiments, Z is -N(R 1A )- C(O)-N(R 1B )-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-] y -(C 1-6 alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH.
  • Z is -C(O)-C(O)-N(R 1A )(R 1B ). In certain embodiments, Z is -N(R 1A )-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R 1A )-R 5 . In certain embodiments, Z is -N(R 1A )-C(O)-C(O)-N(R 1B )(R 1C ). In certain embodiments, Z is -C(O)-N(R 1A )-S(O) 2 -R 7 .
  • Z is -N(R 1A )-S(O)2-R 7 . In certain embodiments, Z is -C(O)-C(O)-N(R 1A )- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).
  • Z is -C(O)-O-(C 1- 4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ).
  • Z is hydrogen.
  • Z is -C(O)-N(R 1A )-(C 1-4 alkylene)-O-(C 1-6 hydroxyalkyl).
  • Z is -C(O)N(R 1B )-(C1-4 alkylene)-[O-(C1-4 alkylene)-]y-(C1-6 alkoxyl).
  • Z is -N(R 1A )-S(O)2-N(R 1B )-CO2-(C1-4 alkylene)-phenyl. [0303] In certain embodiments, Z is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • R 4 is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is C 1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is C 1-6 hydroxyalkyl.
  • R 4 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5-7 membered di-oxo-heterocyclyl containing 1 or 2 heteroatoms independently selected from sulfur, nitrogen, and oxygen. In certain embodiments, R 4 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0305] As defined generally above, R 5 is C 1-6 alkyl, C 1-6 hydroxyalkyl, -(C 1-4 alkylene)-(C 1-4 alkoxyl), or C1-6 alkoxyl.
  • R 5 is C1-6 alkyl, C1-6 hydroxalkyl, or C1-6 alkoxyl. In certain embodiments, R 5 is C1-6 alkyl. In certain embodiments, R 5 is C1-6 hydroxalkyl. In certain embodiments, R 5 is C 1-6 alkoxyl. In certain embodiments, R 5 is -(C 1-4 alkylene)-(C1-4 alkoxyl). In certain embodiments, R 5 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0306] As defined generally above, R 6 is C 1-4 alkyl, C 1-4 hydroxyalkyl, or C 1-4 haloalkyl. In certain embodiments, R 6 is C 1-4 alkyl.
  • R 6 is C 1-4 hydroxyalkyl. In certain embodiments, R 6 is C1-4 haloalkyl. In certain embodiments, R 6 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0307] As defined generally above, R 7 is C 1-4 alkyl, C 1-4 alkoxyl, -(C 1-4 alkylene)-(C 1-4 alkoxyl), -(C0-4 alkylene)-N(R 1A )(R 1B ), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C1- 4 alkyl, C1-4 alkoxyl, -(C0-4 alkylene)-N(R 1A )(R 1B ), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C 1-4 alkyl.
  • R 7 is C 1-4 alkoxyl.
  • R 7 is -(C0-4 alkylene)-N(R 1A )(R 1B ).
  • R 7 is -N(R 1B )-C(O)- O-R 8 .
  • R 7 is -(C1-4 alkylene)-(C1-4 alkoxyl).
  • R 7 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • R 8 is C 1-4 alkyl or -(C 0-4 alkylene)-(phenyl). In certain embodiments, R 8 is C1-4 alkyl. In certain embodiments, R 8 is -(C0-4 alkylene)-(phenyl). In certain embodiments, R 8 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below.
  • R 9 is oxo, C1-4 alkyl, hydroxyl, or -C(O)-O-(C1-4 alkyl). In certain embodiments, R 9 is oxo.
  • R 9 is C1-4 alkyl. In certain embodiments, R 9 is hydroxyl. In certain embodiments, R 9 is -C(O)-O-(C 1-4 alkyl). In certain embodiments, R 9 is selected from the groups depicted in compounds I-1 through I-180 in Table 1, below. [0310] As defined generally above, m is 1 or 2. In certain embodiments, m is 1. In certain embodiments, m is 2. [0311] As defined generally above, n is 1 or 2. In certain embodiments, n is 1. In certain embodiments, n is 2. [0312] As defined generally above, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.
  • p is 4. In certain embodiments, p is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0313] As defined generally above, x is 1, 2, 3, 4, or 5. In certain embodiments, x is 1. In certain embodiments, x is 2. In certain embodiments, x is 3. In certain embodiments, x is 4. In certain embodiments, x is 5. In certain embodiments, x is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0314] As defined generally above, y and z are independently 1, 2, or 3. In certain embodiments, y is 1.
  • y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below. In certain embodiments, y is 2. In certain embodiments, y is 3. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is selected from a corresponding value in the groups depicted in compounds I-1 through I-180 in Table 1, below. [0315] The description above describes multiple embodiments relating to compounds of Formula I-1. The patent application specifically contemplates all combinations of the embodiments. [0316] In certain embodiments, the compound of Formula I is further defined by Formula Ia: or a pharmaceutically acceptable salt thereof.
  • the definition of variables A 1 , A 2 , R 1 , and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A 1 , A 2 , R 1 , and Z is one of the embodiments described above in connection with Formula I-1. [0317] In certain embodiments, the compound of Formula I is further defined by Formula Ib: or a pharmaceutically acceptable salt thereof, wherein: B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R 2 .
  • variables A 2 , R 1 , and Z are one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables A 2 , R 1 , and Z is one of the embodiments described above in connection with Formula I-1. [0319] In certain embodiments, each of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo. In certain embodiments, B 1 is [0320] The description above describes multiple embodiments relating to compounds of Formula 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: B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R 2 .
  • B 1 is a 6-membered aryl ring or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms independently selected from nitrogen and sulfur, wherein the aryl and heteroaryl are substituted with p occurrences of R 2 .
  • the definition of variables A 2 , R 1 , and Z is one of the embodiments described above in connection with Formula I.
  • the definition of variables A 2 , R 1 , and Z is one of the embodiments described above in connection with Formula I-1.
  • B 1 is each of which is substituted by 0, 1, 2, 3, or 4 occurrences of halo.
  • B 1 is [0322]
  • the description above describes multiple embodiments relating to compounds of Formula Ic. The patent application specifically contemplates all combinations of the embodiments.
  • the compound of Formula I is further defined by Formula Id: or a pharmaceutically acceptable salt thereof, wherein X is -C(H)- or -N-. In certain embodiments, X is -C(H)-. In certain embodiments, X is -C(R 2 )-, and the aromatic ring of the isoindoline is substituted with 0, 1, 2, or 3 additional occurrences of R 2 .
  • X is -C(R 2 )-, and the aromatic ring of the isoindoline is not substituted with any additional occurrences of R 2 .
  • X is -C(R 2 )-, and the aromatic ring of the isoindoline is substituted with 1 additional occurrence of R 2 .
  • X is -C(R 2 )-, and the aromatic ring of the isoindoline is substituted with 2 additional occurrences of R 2 .
  • X is -N-.
  • the definition of variables A 2 , R 2 , p, and Z is one of the embodiments described above in connection with Formula I.
  • the definition of variables A 2 , R 2 , p, and Z is one of the embodiments described above in connection with Formula I-1.
  • the compound of Formula I is further defined by Formula Ie: or a pharmaceutically acceptable salt thereof, wherein Y and Q each represent independently N or S.
  • the definition of variables A 2 and Z is one of the embodiments described above in connection with Formula I.
  • the definition of variables A 2 and Z is one of the embodiments described above in connection with Formula I-1.
  • the compound of Formula I is further defined by Formula If, Ig, Ih, or Ii: or a pharmaceutically acceptable salt thereof.
  • the definition of variables R 2 , p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R 2 , p, and Z is one of the embodiments described above in connection with Formula I-1. [0326] In certain embodiments, the compound of Formula I is further defined by Formulae Ij or Ik: or a pharmaceutically acceptable salt thereof. In certain embodiments, the definition of variables R 2 , p, and Z is one of the embodiments described above in connection with Formula I. In certain embodiments, the definition of variables R 2 , p, and Z is one of the embodiments described above in connection with Formula I-1.
  • the compound of Formula I is further defined by Formula Il: or a pharmaceutically acceptable salt thereof.
  • the definition of variable Z is one of the embodiments described above in connection with Formula I.
  • the definition of variable Z is one of the embodiments described above in connection with Formula I-1.
  • Another aspect of the invention provides a compound represented by Formula I-A: (I-A) or a pharmaceutically acceptable salt thereof; wherein: A 1 is each of which is substituted by p occurrences of halo; A 2 is a covalent bond; or A 2 is each of which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z; R 1A , R 1B , and R 1C represent independently for each occurrence hydrogen or C1-4 alkyl; R 3 is halo or C 1-4 alkyl; Z is -C(O)R 4 , -C(O)-(C1-4 alkylene)-R 4 , -C(O)-OH, -C(O)-O-(C1-6 alkyl), -C(O)- N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R
  • 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.
  • a 1 is , , , or , each of which is substituted by p occurrences of halo.
  • a 1 is substituted by p occurrences of halo. In certain embodiments, A 1 is substituted by p occurrences of halo. In certain embodiments, A 1 is substituted by p occurrences of halo. In certain embodiments, A 1 is substituted by p occurrences of halo. In certain embodiments, A 1 is In certain 139 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 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 certain embodiments, A 1 is In certain embodiments, In certain embodiments, certain embodiments, certain embodiments, A 1 is .
  • a 1 is certain embodiments, A 1 is selected from the groups depicted in the compounds in Table 1, below.
  • a 2 is a covalent bond; or , which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is a covalent bond.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is substituted with 0 or 3 1 occurrences of R , wherein ***is the point of attachment to Z.
  • a 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z. In certain embodiments, A 2 is , each of which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • a 2 is selected from the groups depicted in the compounds in Table 1, below.
  • R 1A , R 1B , and R 1C each represent independently for each occurrence hydrogen or C 1-4 alkyl.
  • R 1A is hydrogen.
  • R 1A is C1-4 alkyl.
  • R 1B is hydrogen.
  • R 1B is C 1-4 alkyl.
  • R 1C is hydrogen.
  • R 1C is C 1-4 alkyl.
  • R 1A and R 1B are both hydrogen.
  • R 1A and R 1B are both methyl.
  • R 1A is selected from the groups depicted in the compounds in Table 1, below.
  • R 3 is halo or C 1-4 alkyl. In certain embodiments, R 3 is halo. In certain embodiments, R 3 is C 1-4 alkyl. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is chloro. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is selected from the groups depicted in the compounds in Table 1, below.
  • Z is -C(O)R 4 , -C(O)-(C 1-4 alkylene)-R 4 , -C(O)-OH, -C(O)-O- (C1-6 alkyl), -C(O)-N(R 1A )(R 1B ), -C(O)-O-(C1-4 alkylene)-O-(C1-4 alkylene)-N(R 1A )(R 1B ), -C(O)- O-(C 1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C 1-4 hydroxyalkyl), -S(O) 2 -(C 1- 6 alkyl), -S(O) 2 -(C 3-7 cycloalkyl), -S(O) 2 -N(R 1A )(R 1B ), -S(O) 2 -N(R 1A )-C(O)-C(O)-C
  • Z is hydrogen. In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is or . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is , , In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, certain embodiments, Z is . In certain embodiments, certain embodiments, Z i . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z is In certain embodiments, . In certain embodiments, Z
  • Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiment
  • Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z i . In certain embodiments, Z is . In certain embodiments, Z i . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is certain embodiments, Z is . In certain embodiments, Z is certain embodiments
  • Z is ain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain embodiments, Z is . In certain
  • Z is In certain embodiments, Z is In certain embodiments, Z is [0337] In certain embodiments, Z is -C(O)R 4 . In certain embodiments, Z is -C(O)-(C1-4 alkylene)-R 4 . In certain embodiments, Z is -C(O)-OH. In certain embodiments, Z is -C(O)-O- (C1-6 alkyl). In certain embodiments, Z is -C(O)-N(R 1A )(R 1B ). In certain embodiments, Z is - C(O)-O-(C 1-4 alkylene)-O-(C 1-4 alkylene)-N(R 1A )(R 1B ).
  • Z is -C(O)-O- (C1-4 alkylene substituted with 1 occurrence of -N(R 1A )(R 1B ))-(C1-4 hydroxyalkyl). In certain embodiments, Z is -S(O)2-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-(C3-7 cycloalkyl). In certain embodiments, Z is -S(O) 2 -N(R 1A )(R 1B ). In certain embodiments, Z is -S(O) 2 -N(R 1A )- C(O)-(C1-6 alkyl).
  • Z is -S(O)2-N(R 1A )-C(O)-O-(C1-6 alkyl). In certain embodiments, Z is -S(O)2-N(R 1A )-C(O)-N(R 1B )(R 1C ). In certain embodiments, Z is -S(O)2-[(C1-4 alkylene)-O-] x -R 5 . In certain embodiments, Z is -N(R 1A )-C(O)-(C 1-4 alkylene)-(5-6 membered saturated heterocyclyl containing 1 oxygen atom).
  • Z is -N(R 1A )-C(O)- O-(C1-4 alkylene)-(phenyl). In certain embodiments, Z is -N(R 1A )-C(O)-O-[(C1-4 alkylene)-O-]x- R 6 . In certain embodiments, Z is -N(R 1A )-C(O)-N(R 1B )-[(C 1-4 alkylene)-O-] x -R 6 . In certain embodiments, Z is -C(O)-N(R 1A )-(C 1-6 hydroxyalkyl).
  • Z is -C(O)- N(R 1A )-[(C1-4 alkylene)-O-]x-(C1-4 alkylene)-N(R 1A )(R 1B ). In certain embodiments, Z is -N(R 1A )- C(O)-N(R 1B )-[(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-(C1-4 alkylene)-[O-(C1-4 alkylene)-] y -(C 1-6 alkoxyl). In certain embodiments, Z is -C(O)-C(O)-OH.
  • Z is -C(O)-C(O)-N(R 1A )(R 1B ). In certain embodiments, Z is -N(R 1A )-C(O)-(C1-6 hydroxyalkyl). In certain embodiments, Z is -C(O)-C(O)-N(R 1A )-R 5 . In certain embodiments, Z is -N(R 1A )-C(O)-C(O)-N(R 1B )(R 1C ). In certain embodiments, Z is -C(O)-N(R 1A )-S(O) 2 -R 7 .
  • Z is -N(R 1A )-S(O)2-R 7 . In certain embodiments, Z is -C(O)-C(O)-N(R 1A )- S(O)2-(C1-6 alkyl), -S(O)2-(C1-4 alkylene)-(C1-6 alkoxyl), -C(O)-C(O)-N(R 1A )-(C1-4 alkylene)-(5 membered heteroaryl containing 1-4 nitrogen atoms).
  • Z is -C(O)-O-(C 1- 4 alkylene)-(5 membered saturated heterocyclyl containing 1 nitrogen atom and 1 oxygen atom, wherein the heterocyclyl is substituted with z occurrences of R 9 ).
  • Z is hydrogen.
  • Z is selected from the groups depicted in the compounds in Table 1, below. [0338] As defined generally above, R 4 is C1-6 hydroxyalkyl, a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, or a 3-7 membered saturated carbocyclyl, wherein the heterocyclyl and carbocyclyl are substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is C1-6 hydroxyalkyl. In certain embodiments, R 4 is a 3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 3 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 5 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 6-membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 7 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 3-7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 3 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 4 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 5 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl.
  • R 4 is a 6-membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is a 7 membered saturated carbocyclyl, wherein the carbocyclyl is substituted with 0 or 1 occurrences of hydroxyl. In certain embodiments, R 4 is selected from the groups depicted in the compounds in Table 1, below. [0339] As defined generally above, R 5 is C 1-6 alkyl, C 1-6 hydroxalkyl, or C 1-6 alkoxyl. In certain embodiments, R 5 is C1-6 alkyl. In certain embodiments, R 5 is C1-6 hydroxalkyl.
  • R 5 is C1-6 alkoxyl. In certain embodiments, R 5 is selected from the groups depicted in the compounds in Table 1, below. [0340] As defined generally above, R 6 is C1-4 alkyl, C1-4 hydroxyalkyl, or C1-4 haloalkyl. In certain embodiments, R 6 is C1-4 alkyl. In certain embodiments, R 6 is C1-4 hydroxyalkyl. In certain embodiments, R 6 is C 1-4 haloalkyl. In certain embodiments, R 6 is selected from the groups depicted in the compounds in Table 1, below.
  • R 7 is C 1-4 alkyl, C 1-4 alkoxyl, -(C 0-4 alkylene)- N(R 1A )(R 1B ), or -N(R 1B )-C(O)-O-R 8 .
  • R 7 is C1-4 alkyl.
  • R 7 is C1-4 alkoxyl.
  • R 7 is -(C0-4 alkylene)-N(R 1A )(R 1B ).
  • R 7 is -N(R 1B )-C(O)-O-R 8 .
  • R 7 is selected from the groups depicted in the compounds in Table 1, below.
  • R 8 is C1-4 alkyl or -(C0-4 alkylene)-(phenyl). In certain embodiments, R 8 is C 1-4 alkyl. In certain embodiments, R 8 is -(C 0-4 alkylene)-(phenyl). In certain embodiments, R 8 is selected from the groups depicted in the compounds in Table 1, below. [0343] As defined generally above, R 9 is oxo, C 1-4 alkyl, or -C(O)-O-(C 1-4 alkyl). In certain embodiments, R 9 is oxo. In certain embodiments, R 9 is C 1-4 alkyl. In certain embodiments, R 9 is -C(O)-O-(C1-4 alkyl).
  • R 9 is selected from the groups depicted in the compounds in Table 1, below.
  • p is 0, 1, 2, 3, or 4.
  • p is 1.
  • p is 2.
  • p is 3.
  • p is 4.
  • p is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.
  • x is 1, 2, 3, 4, or 5.
  • x is 1.
  • x is 2.
  • x is 3.
  • x is 4.
  • x is 5.
  • x is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.
  • y and z are independently 1, 2, or 3.
  • y is 1.
  • y is 2.
  • y is 3.
  • y is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.
  • z is 1.
  • z is 2.
  • z is 3.
  • z is selected from a corresponding value in the groups depicted in the compounds in Table 1, below.
  • the definitions of 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).
  • Exemplary Specific Compounds [0349]
  • the compound is a compound in Table 1 or a pharmaceutically acceptable salt thereof.
  • the compound is a compound in Table 1.
  • the compound is a compound selected from I-1 through I- 180 in Table 1, or a pharmaceutically acceptable salt thereof.
  • the compound is a compound selected from I-1 through I-180 in Table 1. TABLE 1.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3.
  • the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the biochemical assays in Table 3.
  • the compound is a compound in Table 1, wherein the compound has at least one activity of “A” in one of the biochemical assays in Table 3.
  • the compound is a compound in Table 1, wherein the compound has at least one activity of “A” or “B” in one of the cell-based assays in Table 3.
  • the compound is a compound in Table 1, wherein the compound has at least one activity of “A” in one of the cell- based assays in Table 3.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B.
  • the compound is a compound in Table 1, wherein the compound is a compound of Formula I-B.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- C.
  • the compound is a compound in Table 1, wherein the compound is a compound of Formula I-C.
  • the compound is a compound in Table 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I- D. In certain embodiments, the compound is a compound in Table 1, wherein the compound is a compound of Formula I-D. [0353] In certain embodiments, the compound is a compound in the table below, or a pharmaceutically acceptable salt thereof: 216
  • the compound is a compound in the table above. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-B. In certain embodiments, the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-C. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-C.
  • the compound is a compound in the table above, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula I-D. In certain embodiments, the compound is a compound in the table above, wherein the compound is a compound of Formula I-D.
  • the compound is one of the following: Synthetic Methods [0356] Methods for preparing compounds described herein are illustrated in the following synthetic Scheme. The Scheme is given for the purpose of illustrating the invention, and not intended to limit the scope or spirit of the invention. Starting materials shown in the Scheme can be obtained from commercial sources or can be prepared based on procedures described in the literature. [0357] Scheme 1 illustrates a general method for preparing heteroaryl compounds F.
  • Amine A is coupled with a protected piperidine or other suitable reagent (e.g., a cyclohexane, bicyclo[2.2.2.]octane, dihydropyridine, etc.) using, for example, a Suzuki or Stille coupling to afford compound B.
  • a protected piperidine or other suitable reagent e.g., a cyclohexane, bicyclo[2.2.2.]octane, dihydropyridine, etc.
  • a Suzuki or Stille coupling to afford compound B.
  • Compound B is reacted with an acyl chloride to form carbamate C.
  • Carbamate C is then reacted with an optionally substituted isoindoline or other heteroaryl compound (e.g., a pyrrolo-pyridine, pyrrolo-pyrazine, a pyrolo-thiazole, etc.) to form protected isoindoline compound D.
  • heteroaryl compounds described herein such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I, provide therapeutic benefits to subjects suffering a disease or condition mediated by NAMPT. Description of exemplary therapeutic applications are provided herein below.
  • One aspect of the invention provides a method of treating a disease or condition mediated by NAMPT.
  • 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-1, I-A, I-B, I-C, or I-D, to treat the disease or condition.
  • a therapeutically effective amount of a compound described herein such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D
  • Another aspect of the invention provides a method of inhibiting the activity of NAMPT.
  • the method comprises contacting a NAMPT with an effective amount of a compound described herein, such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, to inhibit the activity of said NAMPT.
  • a proliferative disorder e.g., cancer, neoplasia
  • inflammatory disorder e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • autoimmune disorder e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder
  • fibrotic disorder e.g., metabolic disorder, cardiovascular disorder, cerebrovascular disorder, and myeloid cell-driven hyper-inflammatory response in a COVID-19 infection.
  • the disease or condition mediated by NAMPT is a NAPRT- negative cancer.
  • the disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease.
  • the disease or condition mediated by NAMPT is inflammatory bowel disease.
  • the heteroaryl compounds described herein provide therapeutic benefits to subjects suffering from cancer (e.g., pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia), intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis.
  • cancer e.g., pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia
  • intestinal or inflammatory bowel disease diseases of
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D 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 a proliferative disorder, inflammatory disorder, or metabolic disorder.
  • a compound described herein such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I
  • the subject is a human.
  • 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 and disorders include but are not limited to those described herein.
  • the disease or condition is a proliferative disorder (e.g., cancer, neoplasia), an inflammatory disorder (e.g., chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder), an autoimmune disorder, a fibrotic disorder, a metabolic disorder, a cardiovascular disorder, a cerebrovascular disorder, or a myeloid cell-driven hyper- inflammatory response in COVID-19 infections.
  • the proliferative disease is cancer.
  • the proliferative disease is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, lymphoma, leukemia, or a combination thereof.
  • the disease or condition is an inflammatory disorder (e.g., intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis, nephropathy, fibrosis, or sepsis.
  • an inflammatory disorder e.g., intestinal or inflammatory bowel disease, diseases of overactive T-cells, psoriasis, neurodegenerative diseases, acute kidney disease, inflammation, stroke, acute infarct, inflammatory bowel disease, acute lung injury, rheumatoid arthritis,
  • the disease or condition is a NAPRT- negative cancer.
  • the disease or condition is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease.
  • the disease or condition is inflammatory bowel disease.
  • Exemplary proliferative diseases include but are not limited to those described herein.
  • the proliferative disease or condition to be treated or prevented using the compounds described herein is cancer.
  • 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), medulloblasto
  • 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.
  • 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- Hodgkin lymphoma (HL)
  • said disease or condition is a cancer.
  • said disease or condition is an angiogenesis disorder.
  • said disease or condition is a multiple myeloma.
  • said disease or condition 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).
  • the cancer is a solid tumor, leukemia, or lymphoma.
  • the cancer is ovarian cancer, uterine cancer, endometrial cancer, cervical cancer, prostate cancer, testicular cancer, breast cancer, brain cancer, lung cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, colon cancer, rectal cancer, skin cancer, sebaceous gland carcinoma, bile duct and gallbladder cancers, liver cancer, pancreatic cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, or thyroid cancer.
  • said disease or condition 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 is myelodysplastic syndrome.
  • said disease or condition is fibrosarcoma.
  • said disease or condition is rhabdomyosarcoma.
  • said disease or condition is astrocytoma.
  • said disease or condition is neuroblastoma.
  • said disease or condition is glioma and schwannomas. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is seminoma. In certain embodiments, said disease or condition is teratocarcinoma. In certain embodiments, said disease or condition is osteosarcoma. In certain embodiments, said disease or condition is xenoderma pigmentosum. In certain embodiments, said disease or condition is keratoctanthoma. In certain embodiments, said disease or condition is thyroid follicular cancer. In certain embodiments, said disease or condition is Kaposi's sarcoma. In certain embodiments, said disease or condition is melanoma. In certain embodiments, said disease or condition is teratoma.
  • said disease or condition is rhabdomyosarcoma. In certain embodiments, said disease or condition is a metastatic and bone disorder. In certain embodiments, said disease or condition is cancer of the bone. In certain embodiments, said disease or condition is cancer of the mouth/pharynx. In certain embodiments, said disease or condition is cancer of the esophagus. In certain embodiments, said disease or condition is cancer of the larynx. In certain embodiments, said disease or condition is cancer of the stomach. In certain embodiments, said disease or condition is cancer of the intestine. In certain embodiments, said disease or condition is cancer of the colon. In certain embodiments, said disease or condition is cancer of the rectum.
  • said disease or condition is cancer of the lung (e.g., non-small cell lung cancer or small cell lung cancer). In certain embodiments, said disease or condition is cancer of the liver. In certain embodiments, said disease or condition is cancer of the pancreas. In certain embodiments, said disease or condition is cancer of the nerve. In certain embodiments, said disease or condition is cancer of the brain (e.g., glioma or glioblastoma multiforme). In certain embodiments, said disease or condition is cancer of the head and neck. In certain embodiments, said disease or condition is cancer of the throat. In certain embodiments, said disease or condition is cancer of the ovary. In certain embodiments, said disease or condition is cancer of the uterus.
  • said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the testis. In certain embodiments, said disease or condition is cancer of the bladder. In certain embodiments, said disease or condition is cancer of the kidney. In certain embodiments, said disease or condition is cancer of the breast. In certain embodiments, said disease or condition is cancer of the gall bladder. In certain embodiments, said disease or condition is cancer of the cervix. In certain embodiments, said disease or condition is cancer of the thyroid. In certain embodiments, said disease or condition is cancer of the prostate. In certain embodiments, said disease or condition is cancer of the skin (e.g., skin squamous cell carcinoma). In certain embodiments, said disease or condition is a solid tumor.
  • said skin e.g., skin squamous cell carcinoma
  • said disease or condition is a solid tumor.
  • said disease or condition is gastric cancer. In certain embodiments, said disease or condition is hepatocellular carcinoma. In certain embodiments, said disease or condition is a peripheral nerve sheath tumor. In certain embodiments, said disease or condition is pulmonary arterial hypertension. [0376] In certain embodiments, the disease is a cancer associated with a viral infection. In certain embodiments, the disease is a cancer resulting from infection with an 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, Hodgkin’s lymphoma, and post-transplant lymphoproliferative disease.
  • said disease or condition is an inflammatory disorder or allergic disorder.
  • said disease or condition 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 is an allergic disorder, such as asthma and allergic rhinitis.
  • said disease or condition 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, psoriasis, id
  • said disease or condition is an immunologically-mediated disease, such as allograft rejection (e.g., rejection of transplanted organs or tissues).
  • said disease or condition is a tissue injury (e.g., associated with organ transplant or revascularization procedures).
  • said disease or condition is a disease or disorder of the respiratory tract (e.g., asthma).
  • said disease or condition is allergic rhinitis.
  • said disease or condition is a disease or disorder of the bone and joints (e.g., arthritis, rheumatoid arthritis).
  • said disease or condition is a disease or disorder of the skin.
  • said disease or condition is a disease or disorder of the gastrointestinal tract.
  • diseases of the respiratory tract include but are not limited to those described herein.
  • said disease or condition is a reversible obstructive airways disease, such as asthma (e.g., bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and dust asthma).
  • said disease or condition is chronic or inveterate asthma (e.g., late asthma airways hyper-responsiveness).
  • said disease or condition is bronchitis.
  • said disease or condition is a condition characterized by an inflammation of the nasal mucus membrane.
  • said disease or condition is acute rhinitis.
  • said disease or condition is allergic rhinitis. In certain embodiments, said disease or condition is atrophic rhinitis. In certain embodiments, said disease or condition is chronic rhinitis (e.g., rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca, and rhinitis medicamentosa). In certain embodiments, said disease or condition is membranous rhinitis (e.g., croupous rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofoulous rhinitis).
  • membranous rhinitis e.g., croupous rhinitis, fibrinous rhinitis, pseudomembranous rhinitis, and scrofoulous rhinitis.
  • said disease or condition 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].
  • rhinitis e.g., rhinitis nervosa (hay fever), vasomotor rhinitis, sarcoidosis, farmer's lung, and related diseases, such as fibroid lung and idiopathic interstitial pneumonia.
  • exemplary diseases of the bone and joints include but are not limited to those described herein.
  • said disease or condition includes pannus formation.
  • said disease or condition does not include pannus formation.
  • said disease or condition is rheumatoid arthritis.
  • said disease or condition is seronegative spondyloarthropathis (e.g., ankylosing spondylitis, psoriatic arthritis, and Reiter's disease).
  • said disease or condition is Behcet's disease.
  • said disease or condition is Sjogren's syndrome.
  • said disease or condition is systemic sclerosis.
  • Exemplary diseases and disorders of the skin include but are not limited to those described herein.
  • said disease or condition is psoriasis.
  • said disease or condition is systemic sclerosis.
  • said disease or condition is dermatitis.
  • said disease or condition is atopical dermatitis. In certain embodiments, said disease or condition is contact dermatitis. In certain embodiments, said disease or condition is eczematous dermatitis. In certain embodiments, said disease or condition is seborrhoetic dermatitis. In certain embodiments, said disease or condition is Lichen planus. In certain embodiments, said disease or condition is Pemphigus. In certain embodiments, said disease or condition is bullous Pemphigus. In certain embodiments, said disease or condition is epidermolysis bullosa. In certain embodiments, said disease or condition is urticaria. In certain embodiments, said disease or condition is angiodermas. In certain embodiments, said disease or condition is vasculitides.
  • said disease or condition is erythemas. In certain embodiments, said disease or condition is cutaneous eosinophilias. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is alopecia. In certain embodiments, said disease or condition is areata. In certain embodiments, said disease or condition is alopecia areata. In certain embodiments, said disease or condition is vernal conjunctivitis. [0382] Exemplary diseases and disorders of the gastrointestinal tract include but are not limited to those described herein. In certain embodiments, said disease or condition is Coeliac disease. In certain embodiments, said disease or condition is proctitis.
  • said disease or condition is eosinophilic gastro-enteritis. In certain embodiments, said disease or condition is mastocytosis. In certain embodiments, said disease or condition is pancreatitis. In certain embodiments, said disease or condition is Crohn's disease. In certain embodiments, said disease or condition is ulcerative colitis. In certain embodiments, said disease or condition is a food-related allergy having effects remote from the gut (e.g., migraine, rhinitis, and eczema). [0383] Exemplary diseases and disorders of other tissues and systemic disease include but are not limited to those described herein. In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is atherosclerosis.
  • said disease or condition is acquired immunodeficiency syndrome (AIDS).
  • said disease or condition is lupus.
  • said disease or condition is lupus erythematosus.
  • said disease or condition is systemic lupus erythematosus.
  • said disease or condition is Hashimoto's thyroiditis.
  • said disease or condition is myasthenia gravis.
  • said disease or condition is type I diabetes.
  • said disease or condition is nephrotic syndrome.
  • said disease or condition is eosinophilia fasciitis.
  • said disease or condition is hyper IgE syndrome.
  • said disease or condition is lepromatous leprosy. In certain embodiments, said disease or condition is sezary syndrome. In certain embodiments, said disease or condition is idiopathic thrombocytopenia purpura. In certain embodiments, said disease or condition is restenosis following angioplasty. In certain embodiments, said disease or condition is a tumor (e.g., leukemia, lymphomas). In certain embodiments, said disease or condition is atherosclerosis. [0384] Exemplary allograft rejections include but are not limited to those described herein. In certain embodiments, said disease or condition is acute chronic allograft rejection (e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea).
  • acute chronic allograft rejection e.g., following transplantation of kidney, heart, liver, lung, bone marrow, skin, or cornea.
  • said disease or condition 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 is chronic graft-versus-host disease. [0385] In certain embodiments, said disease or condition is an acute inflammatory disorder. In certain embodiments, said disease or condition is an auto-inflammatory disorder. In certain embodiments, said disease or condition is a fibrotic disorder. In certain embodiments, said disease or condition is a metabolic disorder. In certain embodiments, said disease or condition is a neoplasia. In certain embodiments, said disease or condition is a cardiovascular or cerebrovascular disorder.
  • said disease or condition is a myeloid cell- driven hyper-inflammatory response in COVID-19 infections.
  • said disease or condition is an autoimmune disorder.
  • said disease or condition is a chronic inflammatory disorder.
  • said disease or condition is an acute inflammatory disorder.
  • said disease or condition is an auto-inflammatory disorder.
  • said disease or condition is a combination of one, two, or all three of a chronic inflammatory disorder, an acute inflammatory disorder, and an auto-inflammatory disorder.
  • Exemplary autoimmune and/or inflammatory and/or auto-inflammatory disorders include but are not limited to those described herein.
  • said disease or condition is an inflammatory bowel disease (e.g., ulcerative colitis or Crohn’s disease). In certain embodiments, said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is psoriasis. In certain embodiments, said disease or condition is arthritis. In certain embodiments, said disease or condition is rheumatoid arthritis. In certain embodiments, said disease or condition is osteoarthritis. In certain embodiments, said disease or condition is juvenile arthritis. In certain embodiments, said disease or condition is psoriatic arthritis. In certain embodiments, said disease or condition is reactive arthritis. In certain embodiments, said disease or condition is ankylosing spondylitis.
  • inflammatory bowel disease e.g., ulcerative colitis or Crohn’s disease.
  • said disease or condition is multiple sclerosis. In certain embodiments, said disease or condition is psoriasis. In certain embodiments, said disease or condition is arthritis. In certain embodiments, said disease or condition is rheumatoi
  • said disease or condition is cryopyrin-associated periodic syndromes. In certain embodiments, said disease or condition is Muckle-Wells syndrome. In certain embodiments, said disease or condition is familial cold auto-inflammatory syndrome. In certain embodiments, said disease or condition is neonatal-onset multisystem inflammatory disease. In certain embodiments, said disease or condition is TNF receptor-associated periodic syndrome. In certain embodiments, said disease or condition is acute and chronic pancreatitis. In certain embodiments, said disease or condition is atherosclerosis. In certain embodiments, said disease or condition is gout. In certain embodiments, said disease or condition is a fibrotic disorder (e.g., hepatic fibrosis or idiopathic pulmonary fibrosis).
  • a fibrotic disorder e.g., hepatic fibrosis or idiopathic pulmonary fibrosis.
  • said disease or condition is nephropathy. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is scleroderma. In certain embodiments, said disease or condition is anaphylaxis. In certain embodiments, said disease or condition is diabetes (e.g., diabetes mellitus type 1 or diabetes mellitus type 2). In certain embodiments, said disease or condition is diabetic retinopathy. In certain embodiments, said disease or condition is Still's disease. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is sarcoidosis. In certain embodiments, said disease or condition is pulmonary inflammation. In certain embodiments, said disease or condition is respiratory failure.
  • said disease or condition is acute respiratory distress syndrome. In certain embodiments, said disease or condition is chronic eosinophilic pneumonia. In certain embodiments, said disease or condition is wet and dry age-related macular degeneration. In certain embodiments, said disease or condition is autoimmune hemolytic syndromes. In certain embodiments, said disease or condition is autoimmune and inflammatory hepatitis. In certain embodiments, said disease or condition is autoimmune neuropathy. In certain embodiments, said disease or condition is autoimmune ovarian failure. In certain embodiments, said disease or condition is autoimmune orchitis. In certain embodiments, said disease or condition is autoimmune thrombocytopenia. In certain embodiments, said disease or condition is silicone implant-associated autoimmune disease.
  • said disease or condition is Sjogren's syndrome. In certain embodiments, said disease or condition is familial Mediterranean fever. In certain embodiments, said disease or condition is systemic lupus erythematosus. In certain embodiments, said disease or condition is vasculitis syndromes (e.g., temporal, Takayasu’s and giant cell arteritis, Behcet’s disease or Wegener's granulomatosis). In certain embodiments, said disease or condition is vitiligo. In certain embodiments, said disease or condition is ichthyosis. In certain embodiments, said disease or condition is secondary hematologic manifestation of autoimmune diseases (e.g., anemias).
  • autoimmune diseases e.g., anemias
  • said disease or condition is drug-induced autoimmunity. In certain embodiments, said disease or condition is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition is hypophysitis. In certain embodiments, said disease or condition is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition is metal-induced autoimmunity. In certain embodiments, said disease or condition is myasthenia gravis. In certain embodiments, said disease or condition is pemphigus. In certain embodiments, said disease or condition is autoimmune deafness (e.g., Meniere's disease). In certain embodiments, said disease or condition is Goodpasture's syndrome. In certain embodiments, said disease or condition is Graves’ disease.
  • said disease or condition is Hashimoto’s thyroiditis. In certain embodiments, said disease or condition is hypophysitis. In certain embodiments, said disease or condition is idiopathic thrombocytic pupura. In certain embodiments, said disease or condition is metal
  • said disease or condition is an HW-related autoimmune syndromes. In certain embodiments, said disease or condition is Guillain-Barre disease. In certain embodiments, said disease or condition is Addison’s disease. In certain embodiments, said disease or condition is anti-phospholipid syndrome. In certain embodiments, said disease or condition is asthma. In certain embodiments, said disease or condition is atopic dermatitis. In certain embodiments, said disease or condition is Celiac disease. In certain embodiments, said disease or condition is Cushing’s syndrome. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is idiopathic adrenal atrophy.
  • said disease or condition is idiopathic thrombocytopenia. In certain embodiments, said disease or condition is Kawasaki syndrome. In certain embodiments, said disease or condition is Lambert-Eaton Syndrome. In certain embodiments, said disease or condition is pernicious anemia. In certain embodiments, said disease or condition is pollinosis. In certain embodiments, said disease or condition is polyarteritis nodosa. In certain embodiments, said disease or condition is primary biliary cirrhosis. In certain embodiments, said disease or condition is primary sclerosing cholangitis. In certain embodiments, said disease or condition is Raynaud’s disease. In certain embodiments, said disease or condition is Raynaud’s phenomenon.
  • said disease or condition is Reiter’s Syndrome. In certain embodiments, said disease or condition is relapsing polychondritis. In certain embodiments, said disease or condition is Schmidt’s syndrome. In certain embodiments, said disease or condition is thyrotoxidosis. In certain embodiments, said disease or condition is sepsis. In certain embodiments, said disease or condition is septic shock. In certain embodiments, said disease or condition is endotoxic shock. In certain embodiments, said disease or condition is exotoxin-induced toxic shock. In certain embodiments, said disease or condition is gram negative sepsis. In certain embodiments, said disease or condition is toxic shock syndrome. In certain embodiments, said disease or condition is glomerulonephritis.
  • said disease or condition is peritonitis. In certain embodiments, said disease or condition is interstitial cystitis. In certain embodiments, said disease or condition is hyperoxia-induced inflammations. In certain embodiments, said disease or condition is chronic obstructive pulmonary disease (COPD). In certain embodiments, said disease or condition is emphysema. In certain embodiments, said disease or condition is nasal inflammation. In certain embodiments, said disease or condition is vasculitis. In certain embodiments, said disease or condition is graft vs. host reaction (e.g., graft vs. host disease). In certain embodiments, said disease or condition is allograft rejections (e.g., acute allograft rejection or chronic allograft rejection).
  • COPD chronic obstructive pulmonary disease
  • said disease or condition is early transplantation rejection (e.g., acute allograft rejection). In certain embodiments, said disease or condition is reperfusion injury. In certain embodiments, said disease or condition is pain (e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia). In certain embodiments, said disease or condition is a chronic infection. In certain embodiments, said disease or condition is meningitis. In certain embodiments, said disease or condition is encephalitis. In certain embodiments, said disease or condition is myocarditis. In certain embodiments, said disease or condition is gingivitis. In certain embodiments, said disease or condition is post-surgical trauma. In certain embodiments, said disease or condition is tissue injury.
  • pain e.g., acute pain, chronic pain, neuropathic pain, or fibromyalgia
  • said disease or condition is a chronic infection.
  • said disease or condition is meningitis.
  • said disease or condition is encephalitis.
  • said disease or condition is myocardi
  • said disease or condition is traumatic brain injury. In certain embodiments, said disease or condition is enterocolitis. In certain embodiments, said disease or condition is sinusitis. In certain embodiments, said disease or condition is uveitis. In certain embodiments, said disease or condition is ocular inflammation. In certain embodiments, said disease or condition is optic neuritis. In certain embodiments, said disease or condition is gastric ulcers. In certain embodiments, said disease or condition is esophagitis. In certain embodiments, said disease or condition is peritonitis. In certain embodiments, said disease or condition is periodontitis. In certain embodiments, said disease or condition is dermatomyositis. In certain embodiments, said disease or condition is gastritis.
  • said disease or condition is myositis. In certain embodiments, said disease or condition is polymyalgia. In certain embodiments, said disease or condition is pneumonia. In certain embodiments, said disease or condition is bronchitis. In certain embodiments, the disease or condition is endometriosis. In certain embodiments, the disease or condition is necrotizing vasculitis. In certain embodiments, the disease or condition is lymphadenitis. In certain embodiments, the disease or condition is peri-arteritis nodosa. In certain embodiments, the disease or condition is anti-phospholipid antibody syndrome. In certain embodiments, the disease or condition is pemphigus vulgaris. In certain embodiments, the disease or condition is Lyme disease.
  • the disease or condition is cardiomyopathy. In certain embodiments, the disease or condition is rheumatic fever. In certain embodiments, the disease or condition is a blistering disorder. In certain embodiments, the disease or condition is an antibody-mediated vasculitis syndrome. In certain embodiments, the disease or condition is an immune-complex vasculitide. In certain embodiments, the disease or condition is oedema. In certain embodiments, the disease or condition is embolism. In certain embodiments, the disease or condition is fibrosis. In certain embodiments, the disease or condition is silicosis. In certain embodiments, the disease or condition is BENTA disease. In certain embodiments, the disease or condition is berylliosis.
  • Exemplary fibrotic disorders include but are not limited to those described herein.
  • said disease or condition is systemic sclerosis/scleroderma.
  • said disease or condition is lupus nephritis.
  • said disease or condition is connective tissue disease.
  • said disease or condition is wound healing.
  • said disease or condition is surgical scarring.
  • said disease or condition is spinal cord injury.
  • said disease or condition is CNS scarring.
  • said disease or condition is acute lung injury.
  • said disease or condition is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis or cystic fibrosis).
  • said disease or condition is chronic obstructive pulmonary disease. In certain embodiments, said disease or condition is adult respiratory distress syndrome. In certain embodiments, said disease or condition is acute lung injury. In certain embodiments, said disease or condition is drug- induced lung injury. In certain embodiments, said disease or condition is glomerulonephritis. In certain embodiments, said disease or condition is kidney disease. In certain embodiments, said disease or condition is chronic kidney disease (e.g., diabetic nephropathy). In certain embodiments, said disease or condition is hypertension-induced nephropathy. In certain embodiments, said disease or condition is alimentary track or gastrointestinal fibrosis. In certain embodiments, said disease or condition is renal fibrosis.
  • said disease or condition is hepatic or biliary fibrosis.
  • said disease or condition is liver fibrosis (e.g., nonalcoholic steatohepatitis, hepatitis C, or hepatocellular carcinoma).
  • said disease or condition is cirrhosis (e.g., primary biliary cirrhosis or cirrhosis due to fatty liver disease, such as alcoholic and nonalcoholic steatosis).
  • said disease or condition is radiation-induced fibrosis (e.g., head and neck, gastrointestinal or pulmonary).
  • said disease or condition is primary sclerosing cholangitis.
  • said disease or condition is restenosis.
  • said disease or condition is cardiac fibrosis (e.g., endomyocardial fibrosis or atrial fibrosis).
  • said disease or condition is ophthalmic scarring.
  • said disease or condition is fibrosclerosis.
  • said disease or condition is a fibrotic cancer.
  • said disease or condition is fibroids.
  • said disease or condition is fibroma.
  • said disease or condition is a fibroadenoma.
  • said disease or condition is a fibrosarcoma.
  • said disease or condition is transplant arteriopathy.
  • said disease or condition is keloid. In certain embodiments, said disease or condition is mediastinal fibrosis. In certain embodiments, said disease or condition is myelofibrosis. In certain embodiments, said disease or condition is retroperitoneal fibrosis. In certain embodiments, said disease or condition is progressive massive fibrosis. In certain embodiments, said disease or condition is nephrogenic systemic fibrosis. [0389] Exemplary metabolic disorders include but are not limited to those described herein. In certain embodiments, said disease or condition is obesity. In certain embodiments, said disease or condition is steroid-resistance. In certain embodiments, said disease or condition is glucose intolerance. In certain embodiments, said disease or condition is metabolic syndrome.
  • Exemplary cardiovascular or cerebrovascular disorders include but are not limited to those described herein.
  • said disease or condition is atherosclerosis.
  • said disease or condition is restenosis of an atherosclerotic coronary artery.
  • said disease or condition is acute coronary syndrome.
  • said disease or condition is myocardial infarction.
  • said disease or condition is cardiac-allograft vasculopathy.
  • said disease or condition is stroke.
  • said disease or condition is a central nervous system disorder with an inflammatory or apoptotic component.
  • said disease or condition is Alzheimer's disease.
  • said disease or condition is Parkinson's disease.
  • said disease or condition is Huntington’s disease. In certain embodiments, said disease or condition is amyotrophic lateral sclerosis. In certain embodiments, said disease or condition is spinal cord injury. In certain embodiments, said disease or condition is neuronal ischemia. In certain embodiments, said disease or condition is peripheral neuropathy.
  • said disease or condition is a disease or disorder associated with a coronavirus (e.g., SARS-CoV-2). In certain embodiments, said coronavirus is SARS-CoV-2. In certain embodiments, the disease or disorder associated with SARS-CoV-2 is COVID-19. [0392] In certain embodiments, the disease or condition is a rheumatic disease.
  • the disease or condition is an inflammatory arthropathy.
  • the disease or condition 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 osteoarthriti
  • the disease or condition is a connective tissue disease.
  • the disease or condition is lupus, systemic lupus erythematosus, juvenile systemic lupus erythematosus, nephritis, Sjögren's syndrome, scleroderma (systemic sclerosis), Raynaud's phenomenon, juvenile 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 Wegener's granulomatosis),
  • the disease or condition is multiple sclerosis, amyotropic lateral sclerosis, Guillain-Barre disease, autoimmune encephalomyelitis, Alzheimer's disease, major depressive disorder, traumatic brain injury, epilepsy, Parkinson’s disease, or bipolar disorder.
  • the disease or condition is an inflammatory bowel disease (IBD).
  • the disease or condition 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 is a skin autoimmune disorder.
  • the disease or condition is psoriasis. In certain embodiments, the disease or condition is eczema. In certain embodiments, the disease or condition is plaque psoriasis, Guttate psoriasis, psoriatic epidermal hyperplasia, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, atopic dermatitis, eczema dermatitis, dermatitis, rosacea, pruritus, alopecia areata, vitiligo, epidermal hyperplasia, juvenile dermatomyositis, dermatomyositis, or hidradenitis suppurativa.
  • said disease or condition is hidradenitis suppurativa.
  • the disease or condition is an organ or cell transplant rejection.
  • the disease or condition is graft-versus-host disease.
  • the disease or condition 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 is an autoimmune disease of the eye.
  • the disease or condition 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, corneal 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 [0399] In certain embodiments, the disease or condition is an ocular
  • the disease or condition is a respiratory disease. In certain embodiments, the disease or condition is asthma, chronic obstructive pulmonary disease, or acute respiratory disease. [0401] In certain embodiments, the disease or condition is diabetes. In certain embodiments, the disease or condition is Type I diabetes mellitus, Type II diabetes mellitus, or juvenile onset diabetes.
  • the disease or condition is thyroid cancer, duodenal, neuroendocrine carcinoma (NEC), uterine cancer, small cell lung cancer (SCLC), hepatocellular carcinoma, mesothelioma, breast cancer, sarcoma, ovarian cancer, renal cell carcinoma, rectal cancer, head and neck cancer, prostate cancer, pancreatic cancer, melanoma, colorectal cancer, cervix cancer, non-small cell lung cancer (NSCLC), cholangiocarcinoma, or endometrial cancer.
  • the disease or condition is an autoimmune disease or atherosclerosis.
  • the disease or condition is ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin’s disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atopic dermatitis, psoriasis, systemic lupus erythematosus, multiple Sclerosis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephritis, metabolic Syndrome, non-Small cell lung cancer, Small cell lung cancer
  • the disease or condition is cancer, an autoimmune disease, viral disease, fungal disease, neurological/neurodegenerative disorder, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
  • the disease or condition is a carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including Small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gallbladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and pro myelocytic leukemia; tumors of mes
  • NAMPT inhibitors show promise in immunosuppression of auto-immune disease, decreasing hyperactivation of the immune system in IBD (Gerner et al. in Gut 2018; 67:1813-1823), Psoriasis (Arroyo et al. in Int. J. Mol.
  • NAMPT expression has also been positively correlated with markers of inflammation, and NAMPTi decreases the expression of these same inflammation markers (Gerner et al. in Gut 2018; 67:1813-1823).
  • NAMPT NAMPT inhibitors
  • NAMPT is also found to be upregulated in COPD and negatively correlated with lung function (Huang Y, Niu Y, Wang X, Li X, He Y and Liu X (2024) in Identification of novel biomarkers related to neutrophilic inflammation in COPD. Front. Immunol.).
  • NAMPT knockdown has been shown to reduce atherosclerosis by promoting cholesterol efflux and macrophage RCT through the PPARa-LXRa-ABCA1/G1 pathway both in vitro and in vivo (Li et al. in Scientific Reports volume 6, Article number: 26746 (2016)).
  • GVHD graft-versus-host disease
  • NAMPT inhibition strongly attenuates symptoms of GVHD in in vivo models and depletes NAD levels in activated T-cells (Gerner RR et al. in Leukemia 2020; 34(7):1885-1897).
  • NAMPT inhibitors are understood to provide a benefit in treating rheumatoid arthritis (Lv, R., Yu, J. & Sun, Q. in Future Oncol. (Lond. Engl.) 16(10), 541–458; and Liu, X. et al. in Gene 712(143911), 143911).
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) in the manufacture of a medicament.
  • the medicament is for treating a disorder described herein, such as cancer.
  • Another aspect of the invention provides for the use of a compound described herein (such as a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) for treating a medical disorder, such as a medical disorder described herein, such as cancer.
  • Compounds described herein may also be used as a component in an antibody-drug conjugate.
  • compounds described herein may be conjugated to an antibody to form an antibody-drug conjugate.
  • the antibody-drug conjugate may be used to treat disorder and conditions described herein.
  • III. Combination Therapy Another aspect of the invention provides for combination therapy.
  • Heteroaryl compounds described herein e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I
  • additional therapeutic agents may be used in combination with additional therapeutic agents to treat diseases or conditions, such as an inflammatory disorder.
  • 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. Alternatively, 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.
  • 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 an additional 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 additional 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, and the additional therapeutic agent prepared as a second pharmaceutical composition, where the first pharmaceutical composition and the additional pharmaceutical composition are administered simultaneously, sequentially, or separately.
  • the amount and frequency of administration of the additional therapeutic agent can used standard dosages and standard administration frequencies used for the particular therapeutic agent.
  • 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, anticoagulant, antiplatelet agent and dual antiplatelet therapy, angiotensin- converting enzyme (ACE) inhibitor, angiotensin II receptor blocker, angiotensin receptor- n
  • the additional therapeutic agent is an anti-cancer agent, an analgesic, an anti-inflammatory agent, or a combination thereof.
  • the additional therapeutic agent is a leukotriene inhibitor. Examples of 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 additional therapeutic agent is a 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 additional 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 additional therapeutic agent is a tyrosine kinase inhibitor. Examples of 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 additional 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 additional 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 additional 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-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, or combinations thereof.
  • the additional therapeutic agent is an adenosine receptor 2A (A2A) agonist.
  • A2A adenosine receptor 2A
  • 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.
  • the adenosine receptor agonist is LNC-3050, LNC-3015, LNC-3047, LNC-3052, or combinations thereof.
  • the additional therapeutic agent is selected from disease modifying antirheumatic drugs (DMARDS). 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 additional 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 additional therapeutic agent is a neutrophil elastase inhibitor. Examples of neutrophil elastase inhibitors considered for use in combination therapies of the invention include but are not limited to sivelestat.
  • the additional 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.
  • 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, cyclophosphamide, doxorubicin, vincristine, prednisone or pred
  • 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® or NEOSAR®), cytarabine, cytosine arabinoside (CYTOSAR-U®), cytarabine liposome injection (DEPOCYT®), dacarbazine (DTIC-Dome®), dactinomycin (act
  • the additional therapeutic agent is capable of inhibiting BRAF, MEK, CDK4/6, SHP-2, HDAC, EGFR, MET, mTOR, PI3K or AKT, or a combination thereof.
  • 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®, EVACET®, LIPODOX®), gemcitabine hydrochloride (GEMZAR®), topotecan hydrochloride (HYCAMTIN®), and paclitaxel (TAXOL®).
  • doxorubicin hydrochloride Adriamycin®
  • carboplatin PARAPLATIN®
  • CYTOXAN® cyclophosphamide
  • PLATINOL-AQ® cisplatin
  • DOXIL® DOX-SL®
  • EVACET® EVACET®
  • LIPODOX® gemcitabine hydrochloride
  • 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 additional 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 T
  • 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®).
  • the additional therapeutic agent is a PARP inhibitor, a dihydrofolate reductase inhibitor (e.g., pemetrexed), or a BCL-2 inhibitor (e.g., ventoclax).
  • the additional therapeutic agent is Temozolomide, Venetoclax, Niraparib, 5-Fluoruracil, Paclitaxel, Gemcitabine, Olaparib, Pemetrexed, Bortezomib, Etoposide, TRAIL, Ibrutinib, Vorinostat, FX-11, Rituxumab, Cisplatin, Indoximod, or a pharmaceutically acceptable salt thereof.
  • the additional therapeutic agent is anti-PD1 agent, such as an anti-PD1 antibody.
  • the additional therapeutic agent is a DNA interactive agent (such as cisplatin or doxorubicin)); a taxane (e.g.
  • a topoisomerase II inhibitor such as etoposide
  • a topoisomerase I inhibitor such as irinotecan (or CPT-11), camptostar, or topotecan
  • a tubulin interacting agent such as paclitaxel, docetaxel or the epothilones
  • a hormonal agent such as tamoxifen
  • a thymidilate synthase inhibitor such as 5-fluorouracil or 5-FU
  • an anti-metabolite such as methoxtrexate
  • an alkylating agent such as temozolomide, cyclophosphamide
  • a farnesyl protein transferase inhibitor such as, SARASARTM.(4-2-4- (11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5- 6cyclohepta 1.2-bipyridin-11-yl--1- pipe
  • anti-cancer also known as anti-neoplastic
  • anti-cancer agents include but are not limited to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, BuSulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, FloXuri dine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATINR), Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mito mycin-C.
  • the additional therapeutic agent is an inhibitor of DNA Polymerase Theta (PolO) activity such as molecules described in WO 2023/233295 and WO 2024/121290.
  • the additional therapeutic agent is a Pol Theta inhibitor and a PARP inhibitor.
  • patients may experience allergic reactions to the compounds of the present invention and/or other anti-cancer agent(s) during or after administration. Therefore, anti-allergic agents may be administered to minimize the risk of 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®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate; e.g., DURAL
  • anti-emetics may be administered in preventing nausea (upper stomach) and vomiting.
  • Suitable anti-emetics include aprepitant (EMEND®), ondansetron (ZOFRAN®), granisetron HCl (KYTRIL®), lorazepam (ATIVAN®. dexamethasone (DECADRON®), prochlorperazine (COMPAZINE®), casopitant (REZONIC® and Zunrisa®), and combinations thereof.
  • EMEND® aprepitant
  • ZOFRAN® ondansetron
  • KYTRIL® granisetron HCl
  • lorazepam ATIVAN®.
  • DECADRON® dexamethasone
  • prochlorperazine COMPAZINE®
  • casopitant REZONIC® and Zunrisa®
  • 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 (OPANA®), 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., OXYCONTIN® or PERCOCET®
  • OPANA® oxymorphone hydrochloride
  • fentanyl e.g., DURAGESIC®
  • 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).
  • the second therapeutic agent is an anticoagulant.
  • anticoagulants considered for use in combination therapies of the invention include but are not limited to apixaban, dabigatran, edoxaban, heparin, rivaroxaban, warfarin, or combinations thereof.
  • the second therapeutic agent is an antiplatelet agent and dual antiplatelet therapy. Examples of antiplatelet agents and dual antiplatelet therapy considered for use in combination therapies of the invention include but are not limited to aspirin, clopidogrel, dipyridamole, prasugrel, ticagrelor, or combinations thereof.
  • the second therapeutic agent is an angiotensin-converting enzyme (ACE) inhibitor.
  • ACE angiotensin-converting enzyme
  • angiotensin-converting enzyme (ACE) inhibitors considered for use in combination therapies of the invention include but are not limited to benazepril, captopril, enalapril, fosinopril, lisinopril, moexipril, perindopril, quinapril, ramipril, trandolapril, or combinations thereof.
  • the second therapeutic agent is an angiotensin II receptor blocker.
  • angiotensin II receptor blockers considered for use in combination therapies of the invention include but are not limited to azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan, or combinations thereof.
  • the second therapeutic agent is an angiotensin receptor- neprilysin inhibitor.
  • angiotensin receptor-neprilysin inhibitors considered for use in combination therapies of the invention include but are not limited to sacubitril/valsartan.
  • the second therapeutic agent is a beta blocker.
  • beta blockers considered for use in combination therapies of the invention include but are not limited to acebutolol, atenolol, betaxolol, bisoprolol/hydrochlorothiazide, bisoprolol, metoprolol, nadolol, propranolol, sotalol, or combinations thereof.
  • the second therapeutic agent is a combined alpha- and beta- blocker. Examples of combined alpha- and beta-blockers considered for use in combination therapies of the invention include but are not limited to carvedilol, labetalol hydrochloride, or combinations thereof.
  • the second therapeutic agent is a calcium channel blocker.
  • Examples of calcium channel blockers considered for use in combination therapies of the invention include but are not limited to amlodipine, diltiazem, felodipine, nifedipine, nimodipine, nisoldipine, verapamil, or combinations thereof.
  • the second therapeutic agent is a cholesterol-lowering medication.
  • the second therapeutic agent is a diuretic.
  • diuretics considered for use in combination therapies of the invention include but are not limited to acetazolamide, amiloride, bumetanide, chlorothiazide, chlorthalidone, furosemide, hydro- chlorothiazide, indapamide, metalozone, spironolactone, torsemide, or combinations thereof.
  • the second therapeutic agent is a vasodilator.
  • vasodilators considered for use in combination therapies of the invention include but are not limited to isosorbide dinitrate, isosorbide mononitrate, hydralazine, nitroglycerin, minoxidil, or combinations thereof.
  • the second therapeutic agent is an antiarrhythmic agent.
  • antiarrhythmic agent considered for use in combination therapies of the invention include but are not limited to Class Ia antiarrhythmic agents (e.g., quinidine, ajmaline, procain amide, dispyramide, sparteine), Class Ib antiarrhythmic agents (e.g., lidocaine, phenytoin, mexiletine, tocainide), Class Ic antiarrhythmic agents (e.g., encainide, flecainide, propafenone, moricizine), Class II antiarrhythmic agents (e.g., carvedilol, propranolol, esmolol, timolol, metoprolol, atenolol, bisoprolol, nebivolol), Class III antiarrhythmic agents (e.g., amiodarone, sotalol, ibutilide, dofetilide, dronedarone, E-4031, vernakalant), Class IV antiarrhythmic
  • the second therapeutic agent is an agent used to treat a metabolic disorder.
  • metabolic disorder agents considered for use in combination therapies of the invention include but are not limited to statins (e.g., atorvastatin, simvastatin, rosuvastatin), cholesterol absorption inhibitors (e.g., ezetimibe), insulin-sensitizing agents (e.g., rosiglitazone, metformin), GLP-1 receptor agonists (e.g., exenatide), DPP-4 inhibitors (e.g., sitagliptin), thiazolidinediones (e.g., pioglitazone), or combinations thereof.
  • statins e.g., atorvastatin, simvastatin, rosuvastatin
  • cholesterol absorption inhibitors e.g., ezetimibe
  • insulin-sensitizing agents e.g., rosiglitazone, metformin
  • GLP-1 receptor agonists e.g
  • 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-1, I-A, I-B, I-C, or I-D or other compounds in Section I
  • 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-1, I-A, I-B, I-C, or I-D or other compounds in Section I
  • 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-1, I-A, I-B, I-C, or I-D 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-1, I-A, I-B, I-C, or I-D 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. IV.
  • 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.
  • 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 pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D, or other compounds in Section I) and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier e.g., a pharmaceutically acceptable carrier.
  • 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, emulsifiers and lubricants, 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.
  • 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.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • 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 dicalcium 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;
  • the pharmaceutical 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 such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-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.
  • compositions may be formulated for rapid release, e.g., freeze-dried. They 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. Examples of 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, corn, 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 and
  • 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 isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline 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.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such 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, eye ointments, powders, solutions and the like, 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.
  • These 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. [0494] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. 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.
  • the compounds of the present invention When 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.
  • parenteral administration 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 intrasternal 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, intracisternally 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.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • 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.
  • 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 heteroaryl substituted phenylpyrimidinone or related compound described herein in a therapeutically effective amount for the treatment of a medical disorder described herein. V.
  • kits comprising a therapeutically effective amount of a compound described herein (e.g., a compound of Formula I, I-1, I-A, I-B, I-C, or I-D or other compounds in Section I), a pharmaceutically acceptable carrier, vehicle or diluent, and optionally at least one additional therapeutic agent listed above.
  • the kit further comprises instructions, such as instructions for treating a disease described herein.
  • Embodiment 2 The compound of embodiment 1, wherein the compound is a compound of Formula I.
  • Embodiment 3 The compound of embodiment 1 or 2, wherein R 1A is hydrogen.
  • Embodiment 4. The compound of any one of embodiments 1-3, wherein R 2 is fluoro or chloro.
  • Embodiment 5. The compound of any one of embodiments 1-3, wherein R 2 is fluoro.
  • Embodiment 6. The compound of any one of embodiments 1-5, wherein A 1 is each of which is substituted by p occurrences of halo.
  • Embodiment 7. The compound of any one of embodiments 1-5, wherein A 1 is , , [0517] Embodiment 8.
  • Embodiment 9 The compound of any one of embodiments 1-5, wherein A 1 is [0518] Embodiment 9. The compound of any one of embodiments 1-5, wherein A 1 is 267 [0519] Embodiment 10. The compound of any one of embodiments 1-9, wherein A 2 is , , , , , , each of which is substituted with 0 or 1 occurrences of R 3 , or a covalent bond, wherein ***is the point of attachment to Z. [0520] Embodiment 11. The compound of embodiment 1, wherein the compound is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof. [0521] Embodiment 12.
  • Embodiment 17 The compound of embodiment 1, wherein the compound is a compound of Formula Ie: or a pharmaceutically acceptable salt thereof, wherein Y and Q each represent independently N or S.
  • Embodiment 18 The compound of any one of embodiments 1-17, wherein A 2 is , each of which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • Embodiment 19 The compound of embodiment 1, wherein the compound is a compound of Formula If, Ig, Ih, or Ii, or a pharmaceutically acceptable salt thereof: [0529] Embodiment 20.
  • Embodiment 21 The compound of embodiment 1, wherein the compound is a compound of Formula Il: or a pharmaceutically acceptable salt thereof.
  • Embodiment 22 The compound of embodiment 1, wherein the compound is a compound of Formula Il: or a pharmaceutically acceptable salt thereof.
  • Embodiment 23 The compound of embodiment 22, wherein the compound is a compound of Formula I-A.
  • Embodiment 24 The compound of embodiment 22 or 23, wherein A 1 is .
  • Embodiment 25 The compound of embodiment 22 or 23, wherein A 1 is [0535]
  • Embodiment 26 The compound of any one of embodiments 1-25, wherein A 2 is each of which is substituted with 0 or 1 occurrences of R 3 , wherein ***is the point of attachment to Z.
  • Embodiment 27 The compound of any one of embodiments 1-26, wherein is hydrogen.
  • Embodiment 28 The compound of any one of embodiments 1-26, wherein is hydrogen.
  • Embodiment 33 The compound of any one of embodiments 1-26, wherein Z is , , , [0543] Embodiment 34.
  • Embodiment 38 A compound in Table 1 herein, or a pharmaceutically acceptable salt thereof. [0548] Embodiment 39.
  • Embodiment 40 A method for treating a disease or condition mediated by NAMPT, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-38 to treat the disease or condition.
  • Embodiment 41 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is a proliferative disorder.
  • Embodiment 42 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is an inflammatory disorder.
  • Embodiment 43 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is a metabolic disorder.
  • Embodiment 44 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is selected from cancer, neoplasia, chronic inflammatory disorder, acute inflammatory disorder, auto-inflammatory disorder, metabolic disorder, and a combination thereof.
  • Embodiment 45 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is cancer.
  • Embodiment 46 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is cancer.
  • the cancer is pancreatic cancer, melanoma, glioma, lung cancer, colon cancer, rectal cancer, breast cancer, cervical cancer, prostate cancer, gastric cancer, skin cancer, liver cancer, bile duct cancer, nervous system cancer, a lymphoma, leukemia, ovarian cancer, uterine cancer, endometrial cancer, testicular cancer, brain cancer, oral cancer, esophageal cancer, head and neck cancer, stomach cancer, sebaceous gland carcinoma, gallbladder cancer, bladder cancer, urinary tract cancer, kidney cancer, eye cancer, thyroid cancer, urothelial cancer, colorectal cancer, or glioblastoma multiforme.
  • Embodiment 47 Embodiment 47.
  • Embodiment 48 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is allergic rhinitis, nasal inflammation, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, emphysema, chronic eosinophilic pneumonia, adult respiratory distress syndrome, sinusitis, allergic conjunctivitis, idiopathic pulmonary fibrosis, atopic dermatitis, asthma, allergic rhinitis, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, endometriosis, eczema, psoriasis, rosacea, or lupus erythematosus.
  • COPD chronic obstructive pulmonary disease
  • Embodiment 49 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is multiple sclerosis, ankylosing spondylitis, arthritis, osteoarthritis, juvenile arthritis, reactive arthritis, rheumatoid arthritis, psoriatic arthritis, acquired immunodeficiency syndrome (AIDS), Coeliac disease, psoriasis, chronic graft-versus-host disease, acute graft-versus- host disease, Crohn’s disease, inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, Celiac Sprue, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjogren’s syndrome, scleroderma, ulcerative colitis, asthma, uveitis, rosacea, dermatitis, alopecia areata, vitiligo, arthritis, Type 1 diabetes, lupus erythematosus, systemic l
  • Embodiment 50 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is psoriasis, dermatitis, vitiligo, ichthyosis, alopecia areata, epidermolysis bullosa, hidradenitis suppurativa, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, or kidney disease.
  • Embodiment 51 The method of embodiment 40, wherein said disease or condition mediated by NAMPT is inflammatory bowel disease (IBD).
  • Embodiment 52 Embodiment 52.
  • Embodiment 53 A method of inhibiting the activity of NAMPT, comprising contacting a NAMPT with an effective amount of a compound of any one of embodiments 1-38 to inhibit the activity of said NAMPT.
  • Method A X-Bridge BEH C-18 (3x50 mmx2.5mm); mobile phase: A; 0.025% formic acid in H2O; B; ACN; injection volume: 2 ⁇ L; flow rate: 1.2 mL/min; column temperature: 50 o C; gradient: 2% B to 98% B in 2.2 min, hold until 3 min, at 3.2 min B conc. is 2% until up to 4 min.
  • Method B X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A; 0.025% formic acid in H2O; B; ACN; injection volume: 2 ⁇ L; flow rate: 1.2 mL/min; column temperature: 50 o C; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min.
  • Method C X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A; 0.05% formic acid in H2O: ACN (95:5); B: 0.05% formic acid in ACN; injection volume: 2 ⁇ L; flow rate: 1.2 mL/min; column temperature: 50 o C; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min.
  • Method D X-select CSH C18 (3x50 mmx2.5 ⁇ m); mobile phase: A: 2mM in ammonium bicarbonate; B: ACN; injection volume:2 ⁇ L; flow rate:1.2 mL/min; column temperature: 50 o C; gradient: 0% B to 98% B in 2 min, hold until 3 min, at 3.2 min B conc. is 0 % until up to 4 min.
  • Method E X-Select CSH-C18 (3.0x50mm, 2.5 ⁇ m); mobile phase: A: 2.5mM; NH 4 HCO 3 in water; mobile phase: B: ACN; injection volume: 2 ⁇ L; (gradient) T/B%:0.0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2; flow rate: 1 ml/min; column temp.: 40 °C.
  • Method F CORTECS UPLC C18 (3x30) mm, 1.6 ⁇ m; flow rate: 0.85 mL/min; mobile phase A: 0.05% formic acid in water; mobile phase B: 0.05% formic acid in ACN; injection volume: 2 ⁇ L; column temp.: 45 °C; gradient program (time/%B): 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3.
  • Method G X-select CSH 18 (3x50 mmx2.5mm); mobile phase: A: 0.05% TFA in H2O; B: 0.05% TFA in ACN; injection volume: 2 ⁇ L; flow rate: 1mL/min; column temperature: 40 o C; gradient (time/%B): 0.0/2, 0.3/2, 2/98, 2.8/98, 3.0/2, 3.7/2.
  • Method H X-Select CSH-C18 (3.0x50mm, 2.5 ⁇ m); mobile phase: A: 2.5mM NH 4 HCO 3 in water + 5% ACN; mobile phase: B: 100% ACN; injection volume: 2 ⁇ L; gradient: time/B%: 0.0/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2; flow rate: 1 ml/min; column Temp.: 40 °C.
  • Method I X-Select CSH C18, (50mm*3.0mm, 2.5 ⁇ m); mobile phase A: 0.05% formic acid in water; mobile phase B: 0.05% formic acid in acetonitrile; flow rate: 1.0mL/min; column temperature: 40 °C; gradient (time/B%): 0.01/2, 0.3/2, 2.0/98, 2.8/98, 3.0/2, 3.7/2.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (1-3): A mixture of compound 1-1 (25 g, 145.3 mmol), compound 1-2 (49.43 g, 159.9 mmol), and Cs 2 CO 3 (95.2 g, 290.7 mmol) in 1,4-dioxane: H 2 O (1:1, 250 mL) was degassed with argon for 5 min.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1-4): To a stirred solution of compound 1-3 (15.0 g, 54.71 mmol) in methanol (150 mL) was added 10% palladium on carbon (50% wet, 5.82 g) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine-1- carboxylate (1-6): To a stirred solution of compound 1-4 (25.00 g, 90.45 mmol) in DCM (250 mL) was added pyridine (14.69 mL, 180.9 mmol) and DMAP (1.12 g, 9.04 mmol) and the reaction mixture was stirred at room temperature, followed by addition of compound 1-5 (15.58 g, 99.49 mmol) at 0 o C.
  • reaction mixture was then the reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and the precipitated solids were filtered and dried under reduced pressure to afford the title compound 1-6 (20.5 g, 51.7 mmol, 57.20% yield) as an off white solid.
  • Step 4 Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl)piperidine-1-carboxylate (1-8): To a stirred solution of compound 1-6 (28.00 g, 70.62 mmol) and compound 1-7 (14.71 g, 84.74 mmol) in DMF (140 mL) at room temperature was added DIPEA (61.7 mL, 353.1 mmol) and then the reaction mixture was stirred at 90 o C for 4 h under a nitrogen atmosphere.
  • the reaction mixture was diluted with ice cold water, the precipitated solid was filtered, washed with n-heptane (2 x 60 mL), and dried under reduced pressure to afford the title compound 1-8 (15.00 g, 34.13 mmol, 48.33% yield) as an off-white solid.
  • Step 5 Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (1-9): To a stirred solution of compound 1-8 (15.00 g, 34.13 mmol) in 1,4-dioxane (75 mL) was added 4 M HCl in 1,4-dioxane (85.32 mL, 341.3 mmol) at 0 o C and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of 4-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-137): To stirred solution of compound 1-9 (22.00 g, 64.82 mmol), 2-hydroxy-2-methylpropanoic acid 1-10 (10.12 g, 97.23 mmol) in DMF (20 mL) were added DIPEA (56.6 mL, 324.1 mmol), followed by HATU (50.82 g, 129.6 mmol) at 0 o C.
  • the resulting mixture was stirred at room temperature for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was poured into ice-cold water and a gummy solid precipitated out. The solid was collected by filtration and dissolved in 10% MeOH-DCM. The resulting mixture was filtered to remove undissolved solids, and the filtrate was concentrated and a gummy solid was obtained. This gummy solid was washed by MeOH and the solid material was collected by filtration. This solid material was dissolved in 10% MeOH- DCM at 60 o C. This mixture was left at rt. After a few hours, solids precipitated out, which were collected by filtration.
  • HPLC Rt 7.728 min, purity: 98.79%; method: HPLC_X-Bridge; column: X-Bridge C18 (4.6*150) mm x 5 ⁇ m, mobile phase: A – 5 mm ammonium bicarbonate in water B – acetonitrile, injection volume: 5.0 ⁇ L, flow rate: 1.0 mL/minute, gradient: time(min)/ B Conc.: 0.01/5, 1.0/5, 8.0/100, 12.0/100, 14.0/5, 18.0/5.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (1-3): A mixture of compound 1-1 (10.0 g, 58.13 mmol), compound 1-2 (21.57 g, 69.76 mmol), and Cs2CO3 (37.78 g, 116.26 mmol) in 1,2-Dioxane: H2O (70:30, 100 mL) was degassed with argon for 5 minutes.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (1-4): To a stirred solution of compound 1-3 (5.0 g, 18.22 mmol) in ethanol (50 mL) was added 10% palladium on carbon (0.73 g) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 100 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (1-6): To a stirred solution of compound 1-4 (4.3 g, 16 mmol) in DCM (50 mL) was added pyridine (2.5 mL, 31 mmol) and DMAP (0.19 g, 1.6 mmol) and the reaction mixture was stirred at room temperature and then compound 1-5 (2.3 mL, 19 mmol) was added at 0 o C and then the reaction mixture was stirred at room temperature for 2 h under a nitrogen atmosphere.
  • Step 4 Synthesis of tert-butyl 4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (1-8): To a stirred solution of compound 1-6 (6.9 g, 17 mmol) and compound 1-7 (3.10 g, 19 mmol) in DMF (30 mL) at room temperature was added DIPEA (15 mL, 87 mmol) and then the reaction mixture was stirred at 80 o C for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 5 Synthesis of 4-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide (1-9): To a stirred solution of compound 1-8 (3.8 g, 8.6 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (22 mL, 86 mmol) at 0 o C and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of 4-fluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)piperidin-4- yl)phenyl)isoindoline-2-carboxamide (I-137): To stirred solution of compound 1-9 (1.5 g, 4.4 mmol), 2-hydroxy-2-methylpropanoic acid 1-10 (0.55 g, 5.3 mmol), and HATU (2.6 g, 6.6 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (2.3 mL, 13 mmol) at 0 °C and the reaction mixture was stirred at room temperature for 16 h under a nitrogen atmosphere.
  • N,N-diisopropylethylamine 2.3 mL, 13 mmol
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (2-3): To a mixture of compound 2-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 o C. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was collected by filtration and dried under reduced pressure to afford the title crude compound 2-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (2-4): To a stirred solution of compound 2-3 (1.0 g, 4.01 mmol) in t-BuOH (10 mL) was added Boc-anhydride (1.57 g, 7.12 mmol) followed by DMAP (0.15 g, 1.20 mmol) at 0 o C.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (2-5): To a stirred solution of compound 2-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g 1.41 mmol) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (2-7): To a stirred solution of compound 2-5 (0.25 g, 0.908 mmol) in DCM (10 mL) were added pyridine (0.15 mL, 1.816 mmol) followed by phenyl chloroformate 2- 6 (0.17 g, 1.09 mmol) at 0 o C and then the reaction mixture was stirred at rt for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido) phenyl)cyclohexane-1-carboxylate (2-9): To a stirred solution of compound 2-7 (0.3 g, 0.849 mmol) and compound 2-8 (0.14 g, 1.02 mmol) in DMF (5 mL) was added DIPEA (0.45 mL, 2.55 mmol) at rt and then the reaction mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4-fluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (2-10): To the stirred solution of compound 2-9 (0.15 g, 0.342 mmol) in DCM (5 mL), was added trifluoroacetic acid (TFA) (1 mL) at 0 o C. The reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the reaction was directly concentrated under reduced pressure to afford the crude compound 2-10 (0.125 g, 0.33 mmol, 95.56% yield) as a light brown solid.
  • TFA trifluoroacetic acid
  • Step 8 Synthesis of tert-butyl (N-((1r,4r)-4-(4-(4-fluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carbonyl)sulfamoyl)carbamate (I-67): To a stirred solution of compound 2-10 (0.15 g, 0.392 mmol) in DMF (2 mL) at 0 o C were added DIPEA (0.35 mL, 1.96 mmol) and HATU (0.226 g, 0.588 mmol).
  • Step 9 Synthesis of 4-fluoro-N-(4-((1r,4r)-4-(sulfamoylcarbamoyl) cyclohexyl) phenyl)isoindoline-2-carboxamide (I-53): To a stirred solution of compound I-67 (0.025 g, 0.045 mmol) in DCM (1 mL), was added 4 M HCl in 1,4-dioxane (2 mL) at 0 o C and the reaction mixture was stirred at rt for 16 h.
  • Prep-HPLC purification method column: X-select 18(250*30MM*5U); mobile phase A: 0.1% FA in water; mobile phase B: ACN; flow rate: 25 mL/min; gradient (time/%B) 0/15, 3/15, 10/35, 20/48, 25/53, 35/60, 40/68, 45/75, 55/85, 60/98.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (3-3): A mixture of compound 3-1 (2.00 g, 11.6 mmol), compound 3-2 (4.31 g, 14.0 mmol), and Cs2CO3 (11.4 g, 34.9 mmol) in 1,4-dioxane:H2O (1:1) (20 mL) was degassed with argon for 5 min.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (3-4): To a stirred solution of compound 3-3 (2.00 g, 7.29 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.155 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was concentrated under reduced pressure to afford the title crude compound 3-4 (1.6 g, 5.8 mmol, 79% yield) as an off white solid.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (3-6): To a stirred solution of compound 3-4 (0.8 g, 2.89 mmol) in DCM (10 mL) at 0 o C were added pyridine (0.46 mL, 0.72 mmol) and compound 3-5 (0.54 g, 3.473 mmol) followed by DMAP (0.035 g, 0.289 mmol).
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (3-8): To a stirred solution of compound 3-6 (1.12 g, 2.82 mmol) in DMF (4 mL) were added compound 3-7 (0.465 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at rt. The resulting mixture was heated to 80 o C for 16 h.
  • Step 6 Synthesis of methyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (3-11): To a stirred solution of compound 3-9 (0.5 g, 1.33 mmol) in DCM (10 mL) was added triethylamine (0.560 mL, 4.00 mmol) at 0 ⁇ C, followed by dropwise addition of methyl 2-chloro-2-oxoacetate 3-10 (0.196 g, 1.60 mmol), and the reaction mixture was stirred at rt for 16 h.
  • Step 7 Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin- 1-yl)-2-oxoacetic acid (I-52): To a stirred solution of compound 3-11 (0.18 g, 0.423 mmol) in THF: MeOH: H 2 O (1:1:1, 3 ml) was added LiOH (0.016 g, 0.635 mmol) at 0 o C and the resulting mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the MeOH and THF were evaporated under reduced pressure.
  • Prep-HPLC purification method preparative column: X-select; mobile phase A: 0.1% FA; mobile phase B: ACN; flow rate 25 ml/min; gradient (time/%B) 0/5, 3/5, 10/15, 15/30, 20/40, 25/50, 35/70, 45/90, 50/98.
  • Step 1 Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (4-3): A mixture of compound 4-1 (5.0 g, 24.75 mmol), compound 4-2 (9.47 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min.
  • Step 2 Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (4-4): To a stirred solution of compound 4-3 (1.5 g, 4.9 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (5 mL, 20 mmol) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated sequentially with diethyl ether (10 mL) and then with n-pentane (5 mL x 2).
  • Step 3 Synthesis of 3-hydroxy-3-methyl-1-(4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)butan-1-one (4-6): To a stirred solution of compound 4-4 (1.0 g, 4.89 mmol) in DMF (20 mL) were added compound 4-5 (0.69 g, 5.87 mmol), EDC.HCl (1.4 g, 7.34 mmol), HOBt (1.01 g, 7.34 mmol) and DIPEA (2.57 mL, 14.69 mmol) at rt, and the reaction mixture was then the reaction mixture was stirred at rt for 16 h.
  • Step 4 Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-3-methyl butan-1-one (4-7): To a stirred solution of compound 4-6 (1.0 g, 3.28 mmol) in MeOH (30 mL) was added 10% palladium on carbon (50% wet, 0.36 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of phenyl (4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)carbamate (4-9): To a stirred solution of compound 4-7 (0.83 g, 3.00 mmol) in DCM (20 mL) were added pyridine (0.74 mL, 9.01 mmol) and compound 4-8 (0.57 g, 3.60 mmol) at 0 o C and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 6 Synthesis of 4,6-difluoro-N-(4-(1-(3-hydroxy-3-methylbutanoyl)piperidin- 4-yl)phenyl)isoindoline-2-carboxamide (I-51): To a stirred solution of compound 4-9 (0.2 g, 0.504 mmol) in DMF (5 mL) were added compound 4-10 (0.094 g, 0.605 mmol) and DIPEA (0.264 mL, 1.51 mmol) at rt and the resulting mixture was stirred at 60 o C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc.
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (5-2): To a stirred solution of compound 5-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g, 31 mmol) at rt.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (5-3): To a mixture of compound 5-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 o C. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid were filtered and dried under reduced pressure to afford the title crude compound 5-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (5-4): To a stirred solution of compound 5-3 (1.0 g, 4.01 mmol) in t-BuOH (10 mL) were added Boc-anhydride (1.57 g, 7.12 mmol), followed by DMAP (0.15 g, 1.20 mmol) at 0 o C.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (5-5): To a stirred solution of compound 5-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g 1.41 mmol) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl) amino) phenyl) cyclohexane-1-carboxylate (5-7): To a stirred solution of compound 5-5 (0.35 g, 1.271 mmol) in DCM (5 mL) were added pyridine (0.21 mL, 2.54 mmol) followed by phenyl chloroformate 5-6 (0.24 g, 1.52 mmol) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (5-9): To a stirred solution of compound 5-7 (0.4 g, 1.01 mmol) and compound 5-8 (0.188 g, 1.21 mmol) in DMF (10 mL) was added DIPEA (0.9 mL, 5.06 mmol) at rt. The reaction mixture was then the reaction mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (I-50): To the stirred solution of compound 5-9 (0.2 g, 0.438 mmol) in DCM (10 mL), was added trifluoroacetic acid (TFA) (1 mL) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. after completion of the reaction (monitored by TLC), The organic layer was mixed with water and extracted with EtOAc.
  • TFA trifluoroacetic acid
  • injections 7 (5.5 mg /inj) column: iCellulose 5 (30 x 250*4.6mm, 5u); mobile phase A: n-Hexane; mobile phase B: IPA; eluent A: 50% & B: 50%; total flow rate (mL/min): 38 min; detection: 245 nm.
  • Step 1 Synthesis of tert-butyl (4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (6-3): A mixture of compound of compound 6-1 (5.0 g, 24.75 mmol), compound 6- 2 (9.60 g 29.70 mmol) and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min.
  • Step 2 Synthesis of 4'-nitro-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-amine (6-4): To a stirred solution of compound 6-3 (5.8 g, 18 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (45 mL, 180 mmol) slowly at 0 o C and then the reaction mixture was stirred at rt for 6 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n- pentane (5 mL x 2).
  • Step 3 Synthesis of 2-hydroxy-2-methyl-N-(4’-nitro-2,3,4,5-tetrahydro-[1,1’- biphenyl]-4-yl)propenamide (6-6): To a stirred solution of compound 6-4 (5.0 g, 15 mmol) and compound 6-5 (1.9 g, 18 mmol) in DMF (10 mL) were added EDC.HCl (4.5 g, 23 mmol) and HOBt (3.2 g, 23 mmol), followed by DIPEA (8.0 mL, 46 mmol) at 0 o C and then the reaction mixture was stirred at rt for 16 h.
  • EDC.HCl 4.5 g, 23 mmol
  • HOBt 3.2 g, 23 mmol
  • DIPEA 8.0 mL, 46 mmol
  • Step 4 Synthesis of N-(4-(4-aminophenyl)cyclohexyl)-2-hydroxy-2- methylpropanamide (6-7): To a stirred solution of compound 6-6 (4.0 g, 13 mmol) in ethanol (40 mL) was added 10% Pd/C (50% wet, 0.14 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethanol.
  • Step 5 Synthesis of phenyl (4-(4-(2-hydroxy-2-methylpropanamido)cyclohexyl) phenyl)carbamate (6-9): To a stirred solution of compound 6-7 (3.10 g, 11.2 mmol) in DCM (2 mL) was added pyridine (1.82 mL, 22.4 mmol) at rt.
  • Step 6 Synthesis of 4,6-difluoro-N-(4-(4-(2-hydroxy-2-methylpropanamido) cyclohexyl)phenyl)isoindoline-2-carboxamide (I-49): To a stirred solution of compound 6-9 (0.1 g, 0.25 mmol) in DMF (5 mL) were added compound 6-10 (0.047 g, 0.30 mmol) and DIPEA (0.22 mL, 1.26 mmol) at rt and the reaction mixture was stirred at 70 o C for 16 h.
  • Step 7 Chiral Prep-HPLC purification to afford First-Eluting Isomer (I-142) and Second-Eluting Isomer (I-143): Chiral prep-HPLC purification method: No. of injections 19 (8 mg /Inj), column: Chiral pack IG (30 x 250*4.6 mm, 5u), mobile phase A: MeOH mobile phase B: ACN, eluent A: 10% & B: 90%. total flow rate (mL/min): 48 min.
  • Step 1 Synthesis of (4-(dimethylamino)pyridin-1-ium-1-carbonyl)(N,N- dimethylsulfamoyl)amide (7-9): To a stirred solution of compound 7-1a (0.5 g, 4.027 mmol) in ACN (5 mL) were added compound 7-2b (0.98 g, 8.054 mmol) and diphenyl carbonate (0.96 g, 4.429 mmol) at 0 o C.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (7-3): A mixture of compound of compound 7-1 (5.00 g, 29.06 mmol), compound 7- 2 (10.19 g, 31.97 mmol), and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1,110 mL) was degassed with argon for 5 minutes. Pd(dppf)Cl 2 .DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at room temperature.
  • reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under vacuum to obtain the crude mixture. The crude mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (7-5): To a stirred solution of compound 7-3 (2.0 g, 7.28 mmol) in DCM (20 mL) were added pyridine (1.17 mL, 14.58 mmol) and compound 7-4 (1.37 g, 8.74 mmol), followed by DMAP (0.089 g, 0.73) at 0 o C and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (7-7): To a stirred solution of compound 7-5 (2.35 g, 5.96 mmol) in DMF (4 mL) were added compound 7-6 (0.89 g, 6.55 mmol) and DIPEA (5.20 mL, 29.8 mmol) at rt and the reaction mixture was stirred at 80 o C for 16 h.
  • Step 5 Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (7-8): To a stirred solution of compound 7-7 (2.4 g, 5.5 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (20 mL) dropwise at 0 o C and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of N-(4-(1-((N,N-dimethylsulfamoyl)carbamoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-48): To a stirred solution of compound 7-8 (0.3 g, 0.80 mmol) in CAN (10 mL), were added DIPEA (0.155 mL, 0.88 mmol), followed by compound 7-9 (0.22 g, 0.80 mmol) at 0 o C. The reaction mixture was then the reaction mixture was stirred at 50 o C for 16 h.
  • Prep-HPLC purification method preparative column: X select C18 mobile phase A: 10 mM ammonium acetate in water; mobile phase B: 100 % ACN; flow rate: 25 ml/min; gradient 0/2, 5/2, 10/6, 30/25.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (8-3): A mixture of compound of compound 8-1 (5.00 g, 29.06 mmol), compound 8- 2 (10.19 g, 31.97 mmol), and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 min.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (8-4): To a stirred solution of compound 8-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (8-6): To a stirred solution of compound 8-4 (5.0 g, 18.09 mmol) in DCM (20 mL) were added pyridine (2.90 mL, 36.18 mmol) and compound 8-5 (3.39 g, 21.71 mmol), followed by DMAP (0.232 g, 1.80 mmol)) at 0 o C and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (8-8): To a stirred solution of compound 8-6 (3.5 g, 8.8 mmol) in DMF (30 mL), were added compound 8-7 (1.7 g, 9.7 mmol) and DIPEA (7.23 mL, 44 mmol) at rt and then the reaction mixture was stirred at 90 °C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (8-9): To a stirred solution of compound 8-8 (1.8 g, 4.1 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) drop-wise at 0 o C and then the reaction mixtue was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (8-11): To a stirred solution of compound 8-9 (0.1 g, 0.295 mmol) in DCM (5 mL), were added DBU (0.23 g, 1.47 mmol) and DMAP (0.004 g, 0.029 mmol) at 0 o C. After 10 min, 2-chloroethane-1-sulfonyl chloride 8-10 (0.11 g, 0.67 mmol) was added and the reaction mixture was stirred at rt for 3 h.
  • Step 7 Synthesis of 5-fluoro-N-(4-(1-((2-(2-(2-(2-(2-(2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy) ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-47): To a stirred solution of sodium hydride (0.019 g, 0.47 mmol) in DMF (5 mL), was added 2,2'-(ethane-1,2- diylbis(oxy))bis(ethan-1-ol) 8-12 (0.042 g, 0.28 mmol). After 10 min, compound 8-11 (0.1 g, 0.233 mmol) was added at rt.
  • reaction was stirred at rt for 16 h and then the reaction mixture was stirred at 60 o C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Prep-HPLC purification method preparative column: x-select, mobile phase A: 0.1% FA mobile phase B: ACN; flow rate 25 ml/min; gradient (time/%B) 0/5, 3/5, 10/15, 15/30, 20/40, 25/50, 35/70, 45/90, 50/98.
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (9-2): To a stirred solution of compound 9-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added Triethylamine (6.7 mL) and 10% palladium on carbon (50% wet,3.3 g) at rt.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (9-3): To a mixture of compound 9-2 (2.0 g, 9.79 mmol) and potassium nitrate (0.29 g, 2.94 mmol) was added sulphuric acid (20 mL, 45.6 mmol) dropwise at 0 o C. The reaction mixture was stirred for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered and dried under reduced pressure to afford the title crude compound 9-3 (1.7 g, 6.8 mmol, 70% yield) as a white solid.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (9-4): To a stirred solution of compound 9-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added Boc-anhydride (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 o C and then the reaction mixture was stirred at 80 o C for 3 h.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (9-5): To a stirred solution of compound 9-4 (0.5 g, 1.64 mmol) in ethanol (20 mL) was added 10% palladium on carbon (50% wet, 0.15 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (9-7): To a stirred solution of compound 9-5 (0.35 g, 1.271 mmol) in DCM (5 mL) was added pyridine (0.21 mL, 2.54 mmol), followed by phenyl chloroformate 9-6 (0.24 g, 1.52 mmol) at 0 o C, and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (9-9): To a stirred solution of compound 9-7 (0.5 g, 1.26 mmol) and compound 9-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) and the mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (9-10): To the stirred solution of compound 9-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 o C. The reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with pentane (5 mL x 2).
  • Step 8 Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-((3-hydroxy-2,2-dimethylpropyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-46): To a stirred solution of the compound 9-10 (0.2 g, 0.499 mmol) in DMF (5 mL) were added DIPEA (0.44 mL, 2.498 mmol) and HATU (0.288 g, 0.749 mmol) at 0 o C.
  • Step 1 Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (10-3): A mixture of compound 10-1 (5.0 g, 24.75 mmol), compound 10-2 (9.47 g, 29.70 mmol), and Cs2CO3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H2O (50:50, 100 mL) was degassed with argon for 5 min. Pd2(dba)3 (1.168 g, 1.24 mmol) and X-Phos (1.17 g, 2.47 mmol), was added to the reaction mixture at rt.
  • reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step 2 Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (10-4): To a stirred solution of compound 10-3 (1.5 g, 4.9 mmol) in 1,4-dioxane (10 mL) was added HCl in 1,4-dioxane (5 mL, 20 mmol) at 0 o C and then the mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure. The residue was then triturated with diethyl ether (10 mL) and then with n-pentane (5 mL x 2).
  • Step 3 Synthesis of 3-hydroxy-3-methyl-1-(4-(4-nitrophenyl)-3,6-dihydropyridin- 1(2H)-yl)butan-1-one (10-6): To a stirred solution of compound 10-4 (1.0 g, 4.89 mmol) in DMF (20 mL) were added compound 10-5 (0.69 g, 5.87 mmol), EDC.HCl (1.4 g, 7.34 mmol), HOBt (1.01 g, 7.34 mmol) and DIPEA (2.57 mL, 14.69 mmol) at rt and the reaction mixture was stirred for 16 h.
  • Step 4 Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-3- methylbutan-1-one (10-7): To a stirred solution of compound 10-6 (1.0 g, 3.28 mmol) in MeOH (30 mL) was added 10% palladium on carbon (50% wet, 0.36 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of phenyl (4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)carbamate (10-9): To a stirred solution of compound 10-7 (0.83 g, 3.00 mmol) in DCM (20 mL) were added pyridine (0.74 mL, 9.01 mmol) and compound 10-8 (0.57 g, 3.60 mmol) at 0 o C and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 6 Synthesis of 3-fluoro-N-(4-(1-(3-hydroxy-3-methylbutanoyl)piperidin-4- yl)phenyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxamide (I-45): To a stirred solution of compound 10-9 (0.2 g, 0.50 mmol) in DMF (1 mL) were added 3-fluoro-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine (compound 10-10, 0.084 g, 0.60 mmol) and DIPEA (0.26 mL, 1.51 mmol) dropwise at rt.
  • reaction mixture was then the reaction mixture was stirred at 60 ⁇ C for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (11-3): A mixture of compound of compound 11-1 (5.00 g, 29.06 mmol), compound 11-2 (10.19 g, 31.97 mmol) and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 min. Pd(dppf)Cl 2 .DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at rt.
  • reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (11-4): To a stirred solution of compound 11-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (11-6): To a stirred solution of compound 11-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at rt.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (11-8): To a stirred solution of compound 11-6 (1.12 g, 2.82 mmol) in DMF (30 mL) were added compound 11-7 (0.46 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at rt.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (11-9): To a stirred solution of compound 11-8 (1.8 g, 4.1 mmol) in DCM (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) dropwise at 0 o C and then the reaction mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)sulfonyl)carbamate (I-44): To a stirred solution of compound 11-9 (0.4 g, 1.17 mmol) in DCM (10 mL) were added compound 18-9 (0.36 g, 1.17 mmol) and DIPEA (0.31 mL, 1.76 mmol) at rt and then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 1 Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (12-3): A mixture of compound 12-1 (5.0 g, 24.75 mmol), compound 12-2 (9.47 g 29.03 mmol), and Cs 2 CO 3 (24.2 g, 74.26 mmol) in 1,4-dioxane:H 2 O (50:50, 100 mL) was degassed with argon for 5 min. X-Phos (1.2 g, 2.47) and Pd2(dba)3 (1.16 g, 1.24 mmol) were added to the reaction mixture at rt.
  • reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred to 90 o C and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude. The crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step 2 Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (12-4): To a stirred solution of compound 12-3 (0.6 g, 1.97 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (3 mL, 12 mmol) dropwise at 0 o C and then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 3 Synthesis of 3-hydroxy-2,2-dimethyl-1-(4-(4-nitrophenyl)-3,6-dihydro pyridin-1(2H)-yl)propan-1-one (12-6): To a stirred solution of compound 12-4 (0.4 g, 1.95 mmol) and compound 12-5 (0.31 g, 2.35 mmol) in DMF (5 mL) were added EDC.HCl (0.44, 2.35 mmol) and HOBt (0.40 g, 2.35 mmol), followed by DIPEA (1.03 mL, 5.87 mmol) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 16 h.
  • Step 4 Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-3-hydroxy-2,2-dimethyl propan-1-one (12-7): To a stirred solution of compound 12-6 (0.5 g, 1.57 mmol) in MeOH (8 mL) was added 10% Pd/C (50% wet, 0.3 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with MeOH.
  • Step 5 Synthesis of phenyl (4-(1-(3-hydroxy-2,2-dimethylpropanoyl)piperidin-4- yl)phenyl)carbamate (12-9): To a stirred solution of compound 12-7 (0.3 g, 1.03 mmol) in DCM (10 mL) were added pyridine (0.25 mL, 3.09 mmol), followed by compound 12-8 (0.196 g, 1.24 mmol) at 0 o C and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 6 Synthesis of 4,6-difluoro-N-(4-(1-(3-hydroxy-2,2-dimethylpropanoyl) piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-34): To a stirred solution of compound 12- 9 (0.2 g, 0.504 mmol) in DMF (5 mL) were added compound 12-10 (0.094 g, 0.605 mmol) and DIPEA (0.264 mL, 1.51 mmol) at rt. The reaction was then the reaction mixture was stirred at 60 o C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (13-3): A mixture of compound of compound 13-1 (5.00 g, 29.06 mmol), compound 13-2 (10.19 g, 31.97 mmol) and K3PO4 (20.15 g, 93.012 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd(dppf)Cl 2 .DCM (1.21 g, 1.45 mmol) was added to the reaction mixture at rt.
  • the reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 16 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude.
  • the crude was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • the crude was purified by CombiFlash (Nexgen-300) chromatography using a 24 g silica gel cartridge and 20 - 35% EtOAc in heptane as the eluent to afford the title compound 13-3 (4.0 g, 14.58 mmol, 50.15% yield) as an off white solid.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (13-4): To a stirred solution of compound 13-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (50% wet, 2.5 g) and the reaction mixture was stirred at rt for 16 h under a hydrogen atmosphere at 50 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (13-6): To a stirred solution of compound 13-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at rt, and compound 13-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol)) were added at 0 o C, and then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (13-8): To a stirred solution of compound 13-6 (2.0 g, 5.04 mmol) in DMF (20 mL) were added compound 13-7 (0.96 g, 5.54 mmol) and DIPEA (4.35 mL, 25.22 mmol) at rt and then the reaction mixture was heated to 90 o C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (13-9): To a stirred solution of compound 13-8 (1.7 g, 3.9 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14.62 mL, 58.5 mmol) slowly at 0 o C and then the reaction mixture was stirred at rt for 1 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidin-1-yl)-2-oxoacetate (13-11): To a stirred solution of compound 13-9 (1.0 g, 2.66 mmol) in DCM (20 mL) was added DIPEA (1.40 mL, 8.00 mmol) at 0 °C, followed by ethyl 2-chloro-2- oxo-acetate 13-10 (0.364 g, 2.66 mmol) dropwise and the reaction mixture was then the reaction mixture was stirred to rt for 16 h.
  • Step 7 Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)piperidin- 1-yl)-2-oxoacetic acid (13-12): To a stirred solution of compound 13-11 (0.32 g, 0.728 mmol) in 1,4-dioxane (4.6 ml) was added a 1 M NaOH solution (4.6 mL) and the resulting reaction mixture was stirred at rt for 5 h. After completion of the reaction (monitored by TLC), the volatiles were evaporated under reduced pressure.
  • Step 8 Synthesis of 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-33): To the stirred solution of compound 13-12 (0.1 g, 0.2431 mmol) in DCM (2 mL) at rt was added DIPEA (0.13 mL, 0.729 mmol) and 50% T3P in EtOAc (2 equiv., 0.486 mmol).
  • Prep-HPLC purification method preparative column: x-select C18 (250x30mm, 5 ⁇ ), mobile phase A: 0.1% FA in water mobile phase B: ACN, flow rate: 25, gradient (time/%B) 0/5, 3/5, 20/50, 33/70, 45/88, 60/98.
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (14-2): To a stirred solution of compound 14-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (14-3): To a mixture of compound 14-2 (4.0 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol) was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 o C. The reaction mixture was stirred at 0 o C for 30 min.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (14-4): To a stirred solution of compound 14-3 (5 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added Boc-anhydride (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 o C and then the reaction mixture was stirred at 80 o C for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with cold water and extracted with EtOAc.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (14-5): To a stirred solution of compound 14-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl) amino)phenyl) cyclohexane-1-carboxylate (14-7): To a stirred solution of compound 14-5 (1.5 g, 5.4 mmol) in DCM (15 mL) at 0 o C were added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 14-6 (1.0 g, 6.5 mmol). The reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carbox amido)phenyl)cyclohexane-1-carboxylate (14-9): To a stirred solution of compound 14-7 (0.5 g, 1.26 mmol) and compound 14-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) at rt and then the reaction mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (14-10): To the stirred solution of compound 14-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 8 Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-(methylcarbamoyl)cyclohexyl) phenyl)isoindoline-2-carboxamide (I-32): To the stirred solution of the compound 14-10 (0.2 g, 0.499 mmol) in the DMF (5 mL) was added DIPEA (0.44 mL, 2.49 mmol) and HATU (0.28 g, 0.749 mmol) at 0 o C. After 5 min, methylamine 14-11 (0.019 g, 0.599 mmol) was added. The reaction mixture stirred at rt for 16 h.
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (15-2): To a stirred solution of compound 15-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt. The reaction mixture was stirred at 50 o C for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (15-3): To a mixture of compound 15-2 (4 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol), was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 o C. The reaction mixture was stirred at 0 o C for 30 min.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (15-4): To a stirred solution of compound 15-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added di-tert-butyl decarbonate (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 o C. Then, the reaction mixture was stirred at 80 o C for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (15-5): To a stirred solution of compound 15-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexane-1-carboxylate (15-7): To a stirred solution of compound 15-5 (1.5 g, 5.4 mmol) in DCM (15 mL) at 0 °C was added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 15-6 (1.0 g, 6.5 mmol). The reaction was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carbox amido)phenyl)cyclohexane-1-carboxylate (15-9): To a stirred solution of compound 15-7 (0.5 g, 1.26 mmol) and compound 15-8 (0.235 g, 1.52 mmol) in DMF (5 mL) at rt was added DIPEA (1.12 mL, 6.32 mmol), and then the reaction mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido) phenyl)cyclohexane-1-carboxylic acid (15-10): To the stirred solution of compound 15-9 (0.4 g, 0.876 mmol) in DCM (10 mL), was added trifluoroacetic acid (3 mL) at 0 o C. The reaction mixture was then the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 8 Synthesis of 4,6-difluoro-N-(4-((1r,4r)-4-((2-hydroxy-2-methylpropyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-31): To a stirred solution of compound 15-10 (0.1 g, 0.249 mmol) in the DMF (5 mL), was added DIPEA (0.22 mL, 1.25 mmol) and HATU (0.14 g, 0.374 mmol) at 0 o C. After 5 min, 1-amino-2-methylpropan-2-ol 15- 11 (0.027 g 0.299 mmol) was added.
  • reaction mixture was then the reaction mixture was stirred at rt for 16 h. After completion of the reaction (monitored by TLC), The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (16-2): To a stirred solution of compound 16-1 (10.0 g, 41.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (50% wet, 3.3 g) at rt.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (16-3): A mixture of compound 16-2 (4 g, 19.58 mmol) and potassium nitrite (0.59 g, 5.874 mmol) was added sulphuric acid (40 mL, 91.2 mmol) dropwise at 0 o C. The reaction mixture was stirred at 0 o C for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and the precipitated solid was filtered off and dried under reduced pressure to afford the title crude compound 16-3 (2.1 g, 8.4 mmol, 43% yield) as a white solid.
  • Step 3 Synthesis of tert-butyl (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylate (16-4): To a stirred solution of compound 16-3 (5.0 g, 20.06 mmol) in t-butyl alcohol (40 mL) was added di-terrt-butyl dicarbonate (21.89 g, 100.3 mmol), followed by DMAP (0.742 g, 6.017 mmol) at 0 o C and then the reaction mixture was stirred at 80 o C for 3 h.
  • Step 4 Synthesis of tert-butyl (1r,4r)-4-(4-aminophenyl)cyclohexane-1- carboxylate (16-5): To a stirred solution of compound 16-4 (2.3 g, 7.5 mmol) in ethanol (25 mL) was added 10% palladium on carbon (50% wet, 0.5 g) and the reaction mixture was stirred at rt for 16 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc.
  • Step 5 Synthesis of tert-butyl (1r,4r)-4-(4-((phenoxycarbonyl)amino)phenyl) cyclohexane-1-carboxylate (16-7): To a stirred solution of compound 16-5 (1.5 g, 5.4 mmol) in DCM (15 mL) was added pyridine (0.88 mL, 11 mmol), followed by phenyl chloroformate 16-6 (1.0 g, 6.5 mmol) at 0 o C and the reaction mixture was then the reaction mixture was stirred at rt for 16 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 6 Synthesis of tert-butyl (1r,4r)-4-(4-(4,6-difluoroisoindoline-2- carboxamido)phenyl)cyclohexane-1-carboxylate (16-9): To a stirred solution of compound 16- 7 (0.5 g, 1.26 mmol), and compound 16-8 (0.235 g, 1.52 mmol) in DMF (5 mL) was added DIPEA (1.12 mL, 6.32 mmol) at rt and then the reaction mixture was stirred at 80 o C for 1 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 7 Synthesis of (1r,4r)-4-(4-(4,6-difluoroisoindoline-2-carboxamido)phenyl) cyclohexane-1-carboxylic acid (16-10): To the stirred solution of compound 16-9 (0.4 g, 0.876 mmol) in DCM (10 mL) was added trifluoroacetic acid (3 mL) at 0 o C. The reaction mixture stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 8 Synthesis of 4,6-difluoro-N-(4-((1s,4s)-4-((2-(2-hydroxyethoxy)ethyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-30): To the stirred solution of the compound 16-10 (0.1 g, 0.249 mmol) in the DMF (2 mL), were added DIPEA (0.22 mL, 1.25 mmol) and HATU (0.15 g, 0.374 mmol) at 0 o C. After 5 min, 2-(2-aminoethoxy)ethan-1-ol 16-11 (0.032 g 0.299 mmol) was added.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (17-3): A mixture of compound 17-1 (10.0 g, 58.13 mmol), compound 17-2 (20.38 g, 63.94 mmol), and K3PO4 (37.77 g, 174.40 mmol) in 1,2-DME: H2O (70:30) (60 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.42 g, 2.90 mmol) was added to the reaction mixture at rt.
  • reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 o C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (17-5): To a solution of compound 17-3 (5.0 g, 18.22 mmol) in DCM (100 mL) was added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol) and the reaction mixture was stirred at rt. Then compound 17-4 (3.42 g, 21.87 mmol) was added at 0 o C and then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere.
  • Step 3 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (17-7): To a stirred solution of compound 17-5 (3.0 g, 7.60 mmol) and compound 17-6 (1.25 g, 9.12 mmol) in DMF (30 mL) at rt was added DIPEA (13.28 mL, 76.05 mmol), and then the reaction mixture was stirred at 80 o C for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 4 Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide, hydro chlorine (17-8): To a stirred solution of compound 17-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14 mL, 57 mmol) at 0 o C and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 5 Synthesis of ethyl 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetate (17-10): To stirred solution of compound 17-8 (1.0 g, 2.68 mmol), in DMF (20 mL), was added DIPEA (1.41 mL, 8.04 mmol), followed by ethyl 2- chloro-2-oxoacetate 17-9 (0.366 g, 2.68 mmol) at 0 o C and the reaction mixture was stirred at rt for 3 h.
  • Step 6 Synthesis of 2-(4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridin-1(2H)-yl)-2-oxoacetic acid (I-27): To a stirred solution of compound 17-10 (0.32 g, 0.731 mmol) in 1,4-dioxane (4.6 mL) was added a 1 N NaOH solution (4.6 mL) at room temperature and the reaction mixture was stirred at room temperature for 5 h.
  • Step 7 Synthesis of 5-fluoro-N-(4-(1-(2-((2-hydroxy-2-methylpropyl)amino)-2- oxoacetyl)-1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-29): To a stirred solution of compound I-27 (0.1 g, 0.244 mmol) in DCM (2 mL) was added DIPEA (0.13 mL0.733 mmol) and 50% T3P in EtOAc (0.32 g 0.488 mmol) at rt.
  • Prep-HPLC purification method preparative column: x-select C-18 (250x30mm, 5 ⁇ ) mobile phase A: 0.1% FA in water mobile phase B: ACN, flow rate 20 mL/min, gradient (time/%B) 0/10, 2/10, 10/25, 25/45, 30/80, 35/98.
  • Step 1 Synthesis of tert-butyl ((4-(dimethyl-l4-azaneylidene)pyridin-1(4H)- yl)sulfonyl)carbamate (18-9): To a stirred solution of 2-methylpropan-2-ol (18-1a) (0.5 g, 6.746 mmol) in DCM (5 mL) were added chlorosulfonyl isocyanate (18-2b) (0.9547 g, 6.746 mmol) and compound (18-3c) (1.648 g, 13.49 mmol) at 0 o C.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylatecarbamate (18-3): A mixture of compound 18-1 (10.0 g, 58.13 mmol), compound 18-2 (20.38 g, 63.94 mmol), and K 3 PO 4 (37.77 g, 174.40 mmol) in 1,2-DME: H 2 O (70:30) (60 mL) was degassed with argon for 5 min. Pd(dppf)Cl2.DCM (2.42 g, 2.90 mmol) was added to the reaction mixture at rt.
  • reaction mixture was stirred for 15 min while degassing with argon, and then the reaction mixture was stirred at 90 o C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with EtOAc. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (18-5): To a stirred solution of compound 18-3 (5.0 g, 18.22 mmol) in DCM (20 mL) were added pyridine (2.92 mL, 36.44 mmol) and DMAP (0.22 g, 1.82 mmol), followed by compound 18-4 (3.42 g, 21.87 mmol) at 0 o C. Then the reaction mixture was stirred at rt for 2 h under a nitrogen atmosphere.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridine-1(2H)-carboxylate (18-7): To a stirred solution of compound 18-5 (3.0 g, 7.60 mmol) and compound 18-6 (1.25 g, 9.12 mmol) in DMF (30 mL) at rt was added DIPEA (13.28 mL, 76.05 mmol), then the reaction mixture was stirred at 80 o C for 3 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with EtOAc.
  • Step 5 Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydro chlorine (18-8): To a stirred solution of compound 18-7 (2.5 g, 5.7 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (14 mL, 57 mmol) at 0 o C and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (18-10): To a stirred solution of compound 18-8 (0.3 g, 0.889 mmol) in DCM (8 mL) were added compound 18-9 (0.26 g, 0.889 mmol) and DIPEA (0.23 mL, 1.334 mmol) at rt and then the reaction mixture was stirred at rt for 16 h.
  • Step 7 Synthesis of 5-fluoro-N-(4-(1-sulfamoyl-1,2,3,6-tetrahydropyridin-4- yl)phenyl)isoindoline-2-carboxamide (18-11): To a stirred solution of compound 18-10 (0.2 g, 0.38 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (1.99 mL, 7.98 mmol) at 0 o C and the reaction mixture was stirred at rt for 2 h. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 8 Synthesis of N-(4-(1-(N-acetylsulfamoyl)-1,2,3,6-tetrahydropyridin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-28): To a stirred solution of compound 18-11 (0.12 g.0.288 mmol) in DCM (6 mL) was added triethylamine (0.121 mL, 0.864 mmol) and acetic anhydride (0.0412 mL, 0.432 mmol) at 0 o C. The reaction mixture was allowed to stir at rt for 2 h.
  • Prep-HPLC purification method preparative column: x- select C18(250*30mm,5 ⁇ ), mobile phase A: 0.1% FA in water, mobile phase B: ACN, flow rate 25 mL/min, gradient (time/%B) 0/15, 3/15, 10/40, 15/50, 20/55, 25/60, 30/65, 35/70, 50/98.
  • EXAMPLE 19 SYNTHESIS OF N-(4-((1R,4R)-4-((2-(2-(DIMETHYLAMINO)ETHOXY) ETHYL)CARBAMOYL)CYCLOHEXYL)PHENYL)ISOINDOLINE-2-CARBOXAMIDE FIRST-ELUTING ISOMER (I-132)
  • Step 1 Synthesis of (1r,4r)-4-phenylcyclohexane-1-carboxylic acid (21-2): To a stirred solution of compound 21-1 (10.0 g, 44.89 mmol) in methanol (50 mL) were added triethylamine (6.7 mL) and 10% palladium on carbon (3.5 g, 33.66 mmol) at room temperature. The reaction mixture was stirred at 50 o C for 18 h under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The combined organic layers were concentrated under reduced pressure.
  • Step 2 Synthesis of (1r,4r)-4-(4-nitrophenyl)cyclohexane-1-carboxylic acid (21-3): A mixture of compound 21-2 (4.0 g, 19.58 mmol) in nitrobenzene (10 mL), were added sulfuric acid (2.07 ml, 39.16 mmol) and nitric acid (1.63 mL, 39.16 mmol) dropwise at 0 o C. The reaction mixture was stirred for 1 hour.
  • Step 3 Synthesis of (1r,4r)-N-(2-(2-(dimethylamino)ethoxy)ethyl)-4-(4- nitrophenyl)cyclohexane-1-carboxamide (21-5): To A stirred solution of compound 21-3 (2.0 g, 8.03 mmol), 2-(2-aminoethoxy)-N,N-dimethylethan-1-amine 21-4 (2.0 g, 9.62 mmol) and HATU (4.55 g, 12.04 mmol) in DMF (10 mL) was added diisopropylethylamine (2.8 mL, 16.06 mmol) at 0 o C and the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere.
  • Step 4 Synthesis of (1r,4r)-4-(4-aminophenyl)-N-(2-(2-(dimethylamino) ethoxy)ethyl)cyclohexane-1-carboxamide (21-6): To a stirred solution of compound 21-5 (2 g, 5.50 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.44 g, 4.12 mmol) and the reaction mixture was stirred at room temperature for 16 hours under hydrogen gas at 100 psi in an autoclave. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate.
  • Step 5 Synthesis of phenyl (4-((1r,4r)-4-((2-(2-(dimethylamino)ethoxy) ethyl)carbamoyl)cyclohexyl)phenyl)carbamate (21-8): To a stirred solution of compound 21-6 (1.6 g, 4.79 mmol) in DCM (20 mL) at 0 o C were added pyridine (1.16 mL, 14.39 mmol) followed by phenyl chloroformate 21-7 (0.89 g, 5.74 mmol) and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere.
  • Step 6 Synthesis of N-(4-((1r,4r)-4-((2-(2-(dimethylamino)ethoxy)ethyl) carbamoyl)cyclohexyl)phenyl)isoindoline-2-carboxamide (I-132): To a stirred solution of compound 21-8 (1.0 g, 2.20 mmol) and compound 21-9 (0.32 g, 2.64 mmol) in DMF (10 mL) at room temperature was added diisopropylethylamine (0.42 mL, 4.40 mmol) and then the reaction mixture was stirred at 80 o C for 3 h under a nitrogen atmosphere.
  • Step 1 Synthesis of tert-butyl (4'-amino-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4- yl)carbamate (22-3): A stirred mixture of compound 22-1 (5.06 g, 29.2 mmol), compound 22-2 (9.4 g, 29.2 mmol), and Cs 2 CO 3 (19 g, 58.4 mmol) in 1,4-dioxane:H 2 O (50:50, 100 mL) was degassed with argon for 5 minutes.
  • Step 2 Synthesis of tert-butyl (4-(4-aminophenyl)cyclohexyl)carbamate (22-4): To a stirred solution of compound 22-3 (6.2 g, 20.15 mmol) in ethanol (20 mL) was added 10% palladium on carbon ( 2.28 g, 201.5 mmol ) and the reaction mixture was stirred at room temperature for 16 h under hydrogen gas at 50 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl (4-(4-((phenoxycarbonyl)amino) phenyl) cyclohexyl)carbamate (22-6): To a stirred solution of compound 22-4 (2.15 g, 8.6 mmol) in DCM (30 mL) was added pyridine (1.4 mL, 17.2 mmol) and DMAP (0.10 g, 0.86 mmol) and were stirred at room temperature before compound 22-5 (1.3 mL, 10.3 mmol) was added at 0 o C. The reaction mixture was then stirred at room temperature for 6 hours under a nitrogen atmosphere.
  • Step 4 Synthesis of tert-butyl (4-(4-(isoindoline-2-carboxamido)phenyl) cyclohexyl)carbamate (22-8): To a stirred solution of compound 22-6 (4.7 g, 11.4 mmol) and compound 22-7 (2.0 g, 12.6 mmol) in DMF (40 mL) at room temperature was added DIPEA (3.8 mL, 34.2 mmol) and then the reaction mixture was stirred at 80 o C for 4 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 5 Synthesis of N-(4-(4-aminocyclohexyl)phenyl)isoindoline-2-carboxamide hydrochloride (22-9): To a stirred solution of compound 22-8 (4.0 g, 9.19 mmol) in 1,4-dioxane (40 mL) was added 4 M HCl in 1,4-dioxane (23 mL, 91.9 mmol) at 0 o C and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of N-(4-(4-(sulfamoylamino)cyclohexyl)phenyl)isoindoline-2- carboxamide (I-129): A stirred solution of compound 22-9 (0.05 g, 0.23 mmol) and sulfamide (0.2 g, 1.7 mmol) in 1,4-dioxane (5 mL) at room temperature was heated to 120 o C and stirred for 8 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with 10% MeOH in DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 7 Synthesis of tert-butyl (N-(4-(4-(isoindoline-2-carboxamido)phenyl) cyclohexyl)sulfamoyl)carbamate (I-128): To a stirred solution of compound I-129 (0.085 g, 0.205 mmol) in DCM (5 mL) was added triethylamine (0.031 g, 0.307 mmol) and Boc-anhydride (0.054 g, 0.246 mmol) at room temperature and stirred at room temperature for 5 h under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 1 Synthesis of tert-butyl ((4-(dimethyl-l4-azaneylidene)pyridin-1(4H)- yl)sulfonyl)carbamate (23-9): To a stirred solution of 2-methylpropan-2-ol (23-1a) (0.5 g, 6.746 mmol) in DCM (5 mL) was added chlorosulfonyl isocyanate (23-2b) (0.95 g, 6.746 mmol) and N,N-dimethylpyridin-4-amine (1.648 g, 13.49 mmol) at 0 o C
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (23-3): A mixture of compound 23-1 (10.0 g, 58.13 mmol), compound 23-2 (21.57 g, 69.75 mmol), and Cs 2 CO 3 (40.3 g, 186.02 mmol) in 1,2-DME:H 2 O (10:1, 110 mL) was degassed with argon for 5 minutes. Pd2(dppf)Cl2 (2.238 g, 2.90 mmol) was added to the reaction mixture at room temperature.
  • reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite pad and washed with ethyl acetate. The organic layer was mixed with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified by CombiFlash chromatography (eluting with 35% EtOAc in heptane) to afford the title compound 23-3 (9.0 g, 32.80 mmol, 56.42% yield) as an off white solid.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (23-5): To a stirred solution of compound 23-3 (6.0 g, 22 mmol) in DCM (100 mL) was added pyridine (3.6 mL, 44 mmol) and DMAP (0.27 g, 2.2 mmol) at room temperature and then compound 23-4 (3.3 mL, 26 mmol) was added at 0 o C. Then the reaction mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)-3,6- dihydropyridine-1(2H)-carboxylate (23-7): To a stirred solution of compound 23-5 (2.35 g, 5.96 mmol) and compound 23-6 (0.89 g, 6.55 mmol) in DMF (25 mL) at room temperature was added DIPEA (5.20 mL, 29.8 mmol) and then the reaction mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with ethyl acetate.
  • Step 5 Synthesis of 5-fluoro-N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl) isoindoline-2-carboxamide hydrochloride (23-8): To a stirred solution of compound 23-7 (2.4 g, 5.5 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (20.62 mL, 82.5 mmol) at 0 o C and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of tert-butyl ((4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl)- 3,6-dihydropyridin-1(2H)-yl)sulfonyl)carbamate (I-108): To a stirred solution of compound 23-8 (0.5 g, 1.482 mmol) and compound 23-9 (0.45 g, 1.482 mmol) in DCM (10 mL) were added DIPEA (0.39 mL, 2.223 mmol) and HATU (0.16 g, 0.40 mmol) at room temperature and then the reaction mixture was stirred at room temperature for 16 hours.
  • DIPEA 0.39 mL, 2.223 mmol
  • HATU HATU
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (24-3): A mixture of compound of compound 24-1 (2.00 g, 11.6 mmol), compound 24-2 (4.31 g, 14.0 mmol) and Cs 2 CO 3 (11.4 g, 34.9 mmol) in 1,4-dioxane:H 2 O (1:1, 20 mL) was degassed with argon for 5 minutes.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (24-4): To a stirred solution of compound 24-3 (2.50 g, 9.1 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.5 g, 4.69 mmol) and the reaction mixture was stirred at room temperature for 16 h under a hydrogen atmosphere at 50 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (24-6): To a stirred solution of compound 24-4 (2.40 g, 8.68 mmol) in DCM (30 mL) was added pyridine (1.4 mL, 17.4 mmol) at room temperature, and compound 24-5 (1.27 mL, 10.4 mmol) and DMAP (0.010 g, 0.086 mmol) were added at 0 o C, and then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (24-8): To a stirred solution of compound 24-6 (3.1 g, 7.8 mmol) in DMF (30 mL) were added compound 24-7 (1.3 g, 9.4 mmol) and DIPEA (5.5 mL, 31 mmol) at room temperature and then the reaction mixture was stirred at 80 o C for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice cold water and extracted with EtOAc.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (24-9): To a stirred solution of compound 24-8 (4.0 g, 9.1 mmol) in DCM (40 mL) was added 4 M HCl in 1,4-dioxane (22.75 mL, 91 mmol) slowly at 0 o C and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (24-11): To a stirred solution of compound 24-9 (0.2 g, 0.562 mmol) in DCM (4 mL) was added triethylamine (0.23 mL, 1.68 mmol), followed by compound 24-10 (0.107 g, 0.844 mmol) drop wise at 0 ⁇ C and the reaction mixture was stirred to room temperature for 16 h.
  • Step 7 Synthesis of 5-fluoro-N-(4-(1-((2-(2-(2-methoxyethoxy)ethoxy)ethyl) sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-93): To the stirred solution sodium hydride (0.018 g, 0.698 mmol) in THF (4 mL) was added 2-(2-methoxyethoxy)ethan-1-ol 24-12 (0.067 g, 0.558 mmol) at 0 ⁇ C and the reaction mixture was stirred for 30 min, and then compound 24-11 (0.2 g, 0.465 mmol) was added at room temperature.
  • the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude.
  • the crude was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure.
  • the crude compound was purified by Prep HPLC purification to afford the desired compound 5-fluoro-N-(4-(1-((2-(2-(2- methoxyethoxy)ethoxy)ethyl)sulfonyl)piperidin-4-yl)phenyl)isoindoline-2-carboxamide (I-93, 18 mg, 0.032 mmol, 7.03% yield) as an off white solid.
  • LCMS 550 (M+H), Rt 1.40 min, 99.88%; method details: column: CORTECS UPLC C18 (3*30)mm, 1.6um flow rate: 0.85 mL/min; mobile phase A: 0.05% TFA in water mobile phase B: 0.05% TFA in acetonitrile column temp.: 45°C; gradient program time/B: 0.0/3, 0.1/3,1.4/97, 2.0/97, 2.05/3,2.5/3.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (25-3): A mixture of compound of compound 25-1 (5.00 g, 29.06 mmol), compound 25-2 (10.19 g, 31.97 mmol) and K 3 PO 4 (20.15 g, 93.012 mmol) in 1,2-DME:H 2 O (10:1, 110 mL) was degassed with argon for 5 minutes.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (25-4): To a stirred solution of compound 25-3 (5.0 g, 18.22 mmol) in methanol (20 mL) was added 10% palladium on carbon (2.5 g) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (25-6): To a stirred solution of compound 25-4 (5.0 g, 18.09 mmol) in DCM (2 mL) were added pyridine (2.90 mL, 36.18 mmol) at room temperature, and compound 25-5 (3.39 g, 21.71 mmol) and DMAP (0.232 g, 1.80 mmol)) were added at 0 o C. The reaction mixture was then stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (25-8): To a stirred solution of compound 25-6 (3.50 g, 8.8 mmol) in DMF (30 mL) were added compound 25-7 (1.7 g, 9.7 mmol) and DIPEA (7.43 mL, 44 mmol) at room temperature and then the reaction mixture was heated to 90 o C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (25-9): To a stirred solution of compound 25-8 (1.8 g, 4.1 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 41 mmol) slowly at 0 o C and the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of 5-fluoro-N-(4-(1-(vinylsulfonyl)piperidin-4-yl)phenyl) isoindoline-2-carboxamide (25-11): To a stirred solution of compound 25-9 (0.4 g, 1.125 mmol) in DCM (20 mL) was added DBU (4.71 g, 31 mmol) at 0 ⁇ C, followed by compound 25-10 (0.214 g, 1.68 mmol) dropwise and the reaction mixture was stirred at room temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was directly evaporated under reduced pressure.
  • Step 7 Synthesis of N-(4-(1-((2,5,8,11-tetraoxatridecan-13-yl)sulfonyl)piperidin-4- yl)phenyl)-5-fluoroisoindoline-2-carboxamide (I-88): To a stirred solution of NaH (60%) (0.0490 g, 1.013 mmol) in THF (15 mL) were added 2-(2-(2-methoxyethoxy)ethoxy)ethan-1-ol 25-12 (0.133 g, 0.810 mmol) followed by compound 25-11 (0.29 g, 0.675 mmol) at room temperature and then the reaction mixture was stirred at room temperature at for 16 hours.
  • Mobile phase A 0.05% FA in water
  • mobile phase B 0.05% FA in acetonitrile column temp.: 45°C
  • gradient program time/B 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3.
  • Step 1 Synthesis of tert-butyl 4-(4-aminophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (26-3): A mixture of compound of compound 26-1 (2.00 g, 11.6 mmol), compound 26-2 (4.31 g, 14.0 mmol), and Cs 2 CO 3 (11.4 g, 34.9 mmol) in 1,4-dioxane:H 2 O (1:1, 20 mL) was degassed with argon for 5 minutes.
  • Step 2 Synthesis of tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (26-4): To a stirred solution of compound 26-3 (2.00 g, 7.29 mmol) in ethanol (20 mL) was added 10% palladium on carbon (0.155 g, 1.46 mmol) and the reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 50 psi in an autoclave.
  • Step 3 Synthesis of tert-butyl 4-(4-((phenoxycarbonyl)amino)phenyl)piperidine- 1-carboxylate (26-6): To a stirred solution of compound 26-4 (0.8 g, 2.89 mmol) in DCM (2 mL) were added pyridine (0.46 mL, 0.72 mmol) at room temperature and compound 26-5 (0.54 g, 3.473 mmol). DMAP (0.035 g, 0.289 mmol) was added at 0 o C, then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with water and extracted with DCM.
  • Step 4 Synthesis of tert-butyl 4-(4-(5-fluoroisoindoline-2-carboxamido)phenyl) piperidine-1-carboxylate (26-8): To a stirred solution of compound 26-6 (1.12 g, 2.82 mmol) in DMF (4 mL) were added compound 26-7 (0.465 g, 3.39 mmol) and DIPEA (4.93 mL, 28.2 mmol) at room temperature and heated at 80 o C for 16 hours.
  • the reaction mixture was quenched with ice cold water, and the precipitated solids were filtered and washed with diethyl ether and n-pentane and dried under reduced pressure to afford the title compound 26-8 (0.85 g, 1.934 mmol, 68.5% yield) as a brown solid.
  • Step 5 Synthesis of 5-fluoro-N-(4-(piperidin-4-yl)phenyl)isoindoline-2- carboxamide hydrochloride (26-9): To a stirred solution of compound 26-8 (0.85 g, 1.934 mmol) in 1,4-dioxane (10 mL) was added 4 M HCl in 1,4-dioxane (9.52 mL, 38 mmol) slowly at 0 o C and the reaction mixture was stirred at room temperature for 8 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 6 Synthesis of N-(4-(1-(2-(dimethylamino)-2-oxoacetyl)piperidin-4-yl) phenyl)-5-fluoroisoindoline-2-carboxamide (I-85): To the stirred solution of 26-9 (0.08 g, 0.212 mmol) in DMF (1 mL) were added 2-(dimethylamino)-2-oxoacetic acid 26-10 (0.037 g, 0.698 mmol), HATU (0.1251 g, 0.3192 mmol) and DIPEA (0.11 mL, 0.63 mmol) at 0 ⁇ C and the reaction mixture was stirred for 8 hours.
  • Mobile phase A 0.05% FA in water
  • mobile phase B 0.05% FA in acetonitrile
  • column temp. 45°C
  • gradient program time/B 0.0/3, 0.1/3, 1.4/97, 2.0/97, 2.05/3, 2.5/3.
  • Step 1 Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (27-3): A mixture of compound of compound 27-1 (2.0 g, 9.90 mmol), compound 27-2 (3.67 g, 11.88 mmol), and Cs2CO3 (6.48 g, 19.80 mmol) in 1,2-DME:H2O (10:1, 110 mL) was degassed with argon for 5 minutes. X-Phos (0.48 g, 0.99 mmol) and Pd2(dba)3 (0.47 g, 0.49 mmol) were added to the reaction mixture at room temperature.
  • the reaction mixture was stirred for 15 minutes while degassing with argon, and then the reaction mixture was heated to 90 o C and stirred for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were evaporated under vacuum to obtain the crude.
  • the crude was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • the crude was purified by Combi flash chromatography using 50-60% EtOAc in heptane as the eluent to afford the title compound 27-3 (2.2 g, 7.2 mmol, 73% yield) as a pale-yellow solid.
  • Step 2 Synthesis of 4-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (27-4): To a stirred solution of compound 27-3 (2.2 g, 7.2 mmol) in 1,4-dioxane (20 mL) was added 4 M HCl in 1,4-dioxane (18 mL, 72 mmol) slowly at 0 o C and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (monitored by TLC), the volatiles were removed under reduced pressure.
  • Step 3 Synthesis of 2-hydroxy-2-methyl-1-(4-(4-nitrophenyl)piperidin-1- yl)propan-1-one (27-6): To a stirred solution of compound 27-4 (2.0 g, 8.31 mmol) in DMF (20 mL) were added compound 27-5 (1.03 g, 9.97 mmol) and DIPEA (4.35 mL, 24.92 mmol) at room temperature and the reaction mixture was stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure.
  • Step 4 Synthesis of 1-(4-(4-aminophenyl)piperidin-1-yl)-2-hydroxy-2- methylpropan-1-one (27-7): To a stirred solution of compound 27-6 (1.0 g, 3.44 mmol) in DMF (10 mL) was added 4,4'-bipyridine (0.026 g, 0.17 mmol).
  • Step 5 Synthesis of phenyl (4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)carbamate (27-9): To a stirred solution of compound 27-7 (0.62 g, 2.38 mmol) in DCM (13 mL) was added pyridine (0.38 mL, 4.74 mmol) at room temperature. Compound 27-8 (0.45 g, 2.858 mmol) and DMAP (0.029 g, 0.238 mmol) were added at 0 o C then the reaction mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere.
  • reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was triturated with diethyl ether and n-pentane. The solids were filtered and dried under reduced pressure to afford the title compound 27-9 (0.63 g, 1.656 mmol, 69.53% yield) as a pale brown solid.
  • Step 6 Synthesis of 4,6-difluoro-N-(4-(1-(2-hydroxy-2-methylpropanoyl)-1,2,3,6- tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide (I-75): To a stirred solution of compound 27-9 (0.07 g, 0.184 mmol) in DMF (1 mL) were added compound 27-10 (0.034 g, 0.221 mmol) and DIPEA (0.16 mL, 0.92 mmol) at room temperature and heated at 80 o C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with ice cold water and extracted with EtOAc.
  • mobile phase A 0.05% FA in water
  • mobile phase B 0.05% FA in acetonitrile
  • gradient program time/B 0.0/3, 0.1/3,1.4/97, 2.0/97, 2.05/3, 2.5/3.
  • Step 1 Synthesis of tert-butyl 4-(4-nitrophenyl)-3,6-dihydropyridine-1(2H)- carboxylate (28-3): A mixture of compound of compound 28-1 (2.0 g, 9.90 mmol), compound 28-2 (3.67 g, 11.88 mmol) and Cs 2 CO 3 (6.48 g, 19.80 mmol) in 1,2-DME:H 2 O (10:1, 110 mL) was degassed with argon for 5 minutes.

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Abstract

L'invention concerne des composés hétéroaryle, des compositions pharmaceutiques et leur utilisation pour traiter une maladie ou un état pathologique, par exemple un trouble prolifératif, un trouble inflammatoire, un trouble auto-immun ou un trouble métabolique.
PCT/US2024/048549 2023-09-26 2024-09-26 Composés hétéroaryle et leur utilisation pour traiter des états pathologiques Pending WO2025072437A1 (fr)

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