Substituted pyridone GPR84 antagonists and uses thereof

Abstract

The present invention provides methods of treating cardiovascular disorders using a GPR84 antagonist compound, along with compounds and pharmaceutical compositions for use in such methods.

Description

SUBSTITUTED PYRIDONE GPR84 ANTAGONISTS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to United States Provisional Patent Application serial number 63 / 735,488, filed December 18, 2024, the contents of which are hereby incorporated by reference in their entirety.TECHNICAL FIELD OF THE INVENTION

[0002] The present invention provides methods of treating cardiovascular disorders using a GPR84 antagonist compound, along with compounds and pharmaceutical compositions for use in such methods.BACKGROUND OF THE INVENTION

[0003] The G-protein coupled receptor 84 (GPR84), also known as EX33, GPCR4, and G protein-coupled receptor 84, is a medium chain fatty acid receptor mainly expressed in immune cells and upregulated under inflammatory conditions. GPR84 was isolated and characterized from human B cells (Wittenberger et al. 2001. J. Mol. Biol. 307, 799-813.) as the result of an expressed sequence tag data mining strategy, and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach aimed to identify novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001. J. Leukoc. Biol. 69, 1045- 1052.).

[0004] GPR84 has been hypothesized to play a role in a wide variety of inflammatory and immune responses (Hakak et al. 2007; Venkataraman C, Kuo F. 2005. Immunol. Lett. 101, 144-153; Wang et al. 2006; Yousefi et al. 2001; Bouchard C et al. 2007. Glia 55, 790-800; Nagasaki H et al. 2012. FEBS Lett. 586, 368-372; Nicol LSC et al. 2015. J. Neurosci. 35, 8959-8969; Gamo et al, 2008. J. Neurosi. 28(46), 11980-11988; Abdel-Aziz H et al. 2015. Mol. Med. 21, 1011-1024; and Kadi A et al. 2010. Circ. Res. 107, 737-746). Exemplary antagonists of GPR84 are described in International Patent Application Publication Nos. WO 2022 / 167445, WO 2022 / 167457, WO / 2024 / 028363; WO 2024 / 028364; and WO 2024 / 028365.

[0005] Cardiovascular disorders, including heart disease, are the leading cause of death for men, women, and people of most racial and ethnic groups. In year 2022, 1 in every 5 deaths was attributed to cardiovascular disorders. Currently available therapeutics used for cardiovascular disorders have several pitfalls. For example, vascular endothelial growth factor (VEGF), a common therapy for treatment of atherosclerosis, is a key regulator ofangiogenesis that stimulates endothelial cell proliferation and promotes the formation of new vessels, thereby increasing blood flow to ischemic tissue and relieving vascular disease.However, VEGF also promotes nonspecific mitogenesis and potentiate angiogenesis-driven diseases such as diabetic retinopathy and certain tumors. Similarly, systemic administration of the angiogenic stimulator fibroblast growth factor can cause severe side effects due to its lack of specificity for cardiac tissue. Unfortunately, such side effects limit the utility.

[0006] Current therapy for heart failure, including congestive heart failure, focuses on increasing cardiac output without causing undue demands on the myocardium. To achieve these ends, various combinations of diuretics, vasodilators and inotropic agents are used to decrease blood volume, to decrease peripheral resistance, and to increase force of cardiac contraction. Current therapy therefore depends on balancing the effects of multiple drugs to achieve the clinical needs of individual patients, and is plagued by adverse reactions.

[0007] Therefore, the identification and development of new methods for the treatment of cardiovascular disorders would be highly desirable for patients.SUMMARY OF THE INVENTION

[0008] The present invention provides methods of treating cardiovascular disorders using a GPR84 antagonist compound, along with compounds and pharmaceutical compositions for use in such methods.

[0009] One aspect of the invention provides methods of treating a variety of cardiovascular disorders in a patient. The method comprises administering to said patient in need thereof, a therapeutically effective amount of a compound described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5. Exemplary cardiovascular disorders include acute coronary syndrome, atherosclerosis, congestive heart failure, coronary artery disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, peripheral vascular disease, stroke, thrombosis, and vascular dementia.BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is graph showing results in a mouse experiment, which analyzed for the amount of total cholesterol, as further described in Example 2. The abbreviation “CD” refers to cyclodextrin.

[0011] Figure 2 is graph showing results in a mouse experiment, which analyzed for the amount of LDL-cholesterol, as further described in Example 2. The abbreviation “CD” refers to cyclodextrin.

[0012] Figure 3 is graph showing results in a mouse experiment, which analyzed for the amount of HDL-cholesterol, as further described in Example 2. The abbreviation “CD” refers to cyclodextrin.

[0013] Figure 4 is a graph showing the mean percent reduction from baseline of total cholesterol over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI), or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0014] Figure 5 is a graph showing the mean percent reduction from baseline of non-HDL cholesterol over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI), or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0015] Figure 6 is a graph showing the mean percent reduction from baseline of ApoB over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI), or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0016] Figure 7 is a graph showing the mean percent reduction from baseline of oxidized LDL cholesterol over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI), or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0017] Figure 8 is a plot showing the percent reduction from baseline of ApoB in human subjects receiving Dose 1 compound 1-1-393 (administered to subjects with normal BMI) or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI) as a function of BMI, on day 14 of treatment.

[0018] Figure 9 is a graph showing the mean percent reduction from baseline of LDL cholesterol over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI),or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0019] Figure 10 is a plot showing the percent reduction from baseline of LDL in human subjects receiving Dose 1 compound 1-1-393 (administered to subjects with normal BMI) or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI) as a function of BMI, on day 14 of treatment.

[0020] Figure 11 is a graph showing the mean percent reduction from baseline of triglycerides over time in human subjects receiving placebo (administered to subjects with both normal and high BMI), Dose 1 compound 1-1-393 (administered to subjects with normal BMI), or Dose 2 compound 1-1-393 (administered to subjects with both normal and high BMI, with normal and high BMI groups depicted separately).

[0021] Figure 12 is a graph showing the mean percent reduction from baseline of triglycerides in fasted human subjects receiving placebo (administered to subjects with both normal and high BMI) or compound 1-1-393 (administered to subjects with high BMI), on days -1, 8, and 13 of treatment after receiving an approximately 550 kcal liquid mixed meal.DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0022] The present invention provides methods of treating cardiovascular disorders using a GPR84 antagonist compound, along with compounds and pharmaceutical compositions for use in such methods. Exemplary compounds, methods, and cardiovascular disorders are described in more detail below.1. Definitions:

[0023] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0024] The term “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. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0025] As used herein, the term “bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or 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). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such 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 bridged bicyclics include:

[0026] The term “lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0027] The term “lower haloalkyl” refers to a C1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0028] The term “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)).

[0029] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0030] As used herein, the term “bivalent Ci-s (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0031] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)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 asubstituent. Suitable substituents include those described below for a substituted aliphatic group.

[0032] The term “-(Co alkylene)-“ refers to a bond. Accordingly, the term “-(Co-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1-3 alkylene)- group.

[0033] The term “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.

[0034] The term “halogen” means F, Cl, Br, or I.

[0035] The term “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. The term “aryl” may be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, 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. The term “phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, “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). The term “arylene” refers to a bivalent aryl group.

[0036] The terms “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. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, 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, 47 / quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0037] The term “heteroarylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “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. The term “pyridinylene” refers to a multivalent pyridine radical having the appropriate number of open valences to account for groups attached to it. For example, “pyridinylene” is a bivalent pyridineradical when it has two groups attached to it (e.g.,); “pyridinylene” is a trivalentpyridine radical when it has three groups attached toit (e.g.,

[0038] 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. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, 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-di hydro-27 / pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N- substituted pyrrolidinyl).

[0039] 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.Examples of such 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. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are 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, 3 / 7-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0040] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0041] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, 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. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0042] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o4R°; -(CH2)o4OR°; -0(CH2)o-4R°, -0-(CH2)o4C(O)ORO; -(CH2)O4CH(ORO)2; -(CH2)O4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)o40(CH2)o iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o -i -pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)O4N(RO)2; -(CH2)O4N(RO)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; - N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -N(RO)C(NR°)N(RO)2;-(CH2)O 4C(O)RO; -C(S)R°; -(CH2)O 4C(O)ORO; -(CH2)O4C(O)SRO; -(CH2)O4C(O)OSiR°3; -(CH2)O 4OC(O)RO; -OC(0)(CH2)O4SRO; -SC(S)SR°; -(CH2)O4SC(O)RO; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O 4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)O 4SSRO; -(CH2)O4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O 4OS(O)2RO; -S(O)2NRO2; -(CH2)O 4S(O)RO; -N(RO)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2RO; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; -SiRo3; — (Ci-4straight or branched alkylene)O-N(R°)2; or -(Ci-4straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0043] In certain embodiments, a suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)O 4ORO; -0(CH2)O-4R°, -0-(CH2)O4C(O)ORO; -(CH2)O4CH(ORO)2; -(CH2)O 4SRO; -(CH2)O4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)o40(CH2)o i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o4N(R°)2; -(CH2)o-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O4N(RO)C(O)NR°2; -N(RO)C(S)NR°2; -(CH2)O4N(RO)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -N(RO)C(NR°)N(R°)2;-(CH2)O 4C(O)RO; -C(S)R°; -(CH2)O4C(O)ORO; -(CH2)O4C(O)SRO; -(CH2)O 4C(O)OSiR°3; -(CH2)0 4OC(O)R°; -OC(O)(CH2)0 4SR°; -SC(S)SR°; -(CH2)O 4SC(O)RO; -(CH2)O 4C(O)NRO2; -C(S)NRO2; -C(S)SR°; -SC(S)SR°, -(CH2)O4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O4SSRO; -(CH2)O 4S(O)2RO; -(CH2)O4S(O)2ORO; -(CH2)O 4OS(O)2RO; -S(O)2NRO2; -(CH2)O4S(O)RO; -N(RO)S(O)2NR°2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)NRO2; -P(O)2R°; -P(O)RO2; -OP(O)RO2; -OP(O)(ORO)2; -SiR°3; –(C1–4straight or branchedalkylene)0-N(R°)2; or-(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -0(CH2)o iPh, -CH2-(5-6 membered heteroaryl ring), or a 3-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0044] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen, -(CH2)o-2R*, -(haloR*), -(CH2)o 2OH, -(CH2)o-2OR*, -(CH2)o-2CH(OR*)2; -O(haloR’), -CN, -N3, -(CH2)0-2C(O)R*, -(CH2)o2C(O)OH, -(CH2)o-2C(O)OR*, -(CH2)O 2SR*, -(CH2)O2SH, -(CH2)O 2NH2, -(CH2)O 2NHR*, -(CH2)O 2NR*2, -NO2,-SiR*3, -OSiR*3, -C(O)SR* -(Ci^t straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0045] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR\ =NOR\ -O(C(R*2))23O-, or -S(C(R*2))23S-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR*2)2-3O-, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] Suitable substituents on the aliphatic group of R* include halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -R\ -NR -C(O)Rf, -C(O)ORf, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NRt2, -C(NH)NRt2, or -N(Rt)S(O)2Rt; wherein each R:is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, 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, notwithstanding the definition above, two independent occurrences of R taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] Suitable substituents on the aliphatic group of R1' are independently halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, -CH2PI1, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0049] As used herein, 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. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0050] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci 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.

[0051] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; 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. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

[0052] 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.Alternatively, a particular enantiomer of a compound of the present invention may be prepared by asymmetric synthesis. Still further, where the molecule contains a basicfunctional group (such as amino) or an acidic functional group (such as carboxylic acid) 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.

[0053] 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. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this invention.

[0054] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0055] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0056] The term “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, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-m ethyl- 1 -butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l-pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0057] The term “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. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0058] The term “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. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0059] The term “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.

[0060] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0061] The term “carbocyclylene” refers to a multivalent carbocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “carbocyclylene” is a bivalent carbocyclyl group when it has two groups attached to it;“carbocyclylene” is a trivalent carbocyclyl group when it has three groups attached to it.

[0062] The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, / c / V-butoxy and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term “hydroxyalkoxyl” refers to an alkoxyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkoxyl groups include -OCH2CH2OH, -OCEE HXOEOCEECEEOH, and the like. The term “alkoxylene” refers to a bivalent alkoxyl group.

[0063] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane susbsituted with an oxo group is cyclopentanone.

[0064] The symbol “ ■~vv” indicates a point of attachment.

[0065] When a chemical structure containing a ring is depicted with a substituent having a bond that crosses a ring bond, the substituent may be attached at any available position on / N I the ring. For example, the chemical structureNencompassesI, and In the context of a polycyclic fused ring, when a chemical structure containing a polycyclic fused ring is depicted with one or more substituent(s)having a bond that crosses multiple rings, the one or more substituent(s) may be independently attached to any of the rings crossed by the bond. To illustrate, the chemical

[0066] When 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.

[0067] 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. Nonlimiting examples of suitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H2O.

[0068] As used herein, a " GPR84 antagonist" or a " GPR84 inhibitor" is a molecule that reduces, inhibits, or otherwise diminishes one or more of the biological activities of GPR84 (e.g. Gai signaling, increased immune cell migration, and secretion of proinflammatory cytokines). Antagonism using the GPR84 antagonist does not necessarily indicate a total elimination of the GPR84 activity. Instead, the activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of GPR84 compared to an appropriate control. In some embodiments, the GPR84 antagonist reduces, inhibits, or otherwise diminishes the activity of GPR84. The presently disclosed compounds bind directly to GPR84 and inhibit its activity.

[0069] By "specific antagonist" is intended an agent that reduces, inhibits, or otherwise diminishes the activity of a defined target greater than that of an unrelated target. For example, a GPR84 specific antagonist reduces at least one biological activity of GPR84 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the IC50 of the antagonist for the target is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less of the IC50 of the antagonist for a non-target. The presently disclosed compounds may or may not be a specific GPR84 antagonist. A specific GPR84 antagonist reduces the biological activity of GPR84 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, the GPR84 antagonist specifically inhibits the activity of GPR84. In some of these embodiments, the IC50 of the GPR84 antagonist for GPR84 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001%, or less of the IC50 of the GPR84 antagonist for a closely related GPCR (e.g., a free fatty acid receptor (FFAR) such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other type of GPCR (e.g, a Class A GPCR).

[0070] A compound of the present invention may be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. One of ordinary skill in the art will recognize that a detectable moiety may be attached to a provided compound via a suitable substituent. As used herein, the term “suitable substituent” refers to a moiety that is capable of covalent attachment to a detectable moiety. Such moieties are well known to one of ordinary skill in the art and include groups containing, e.g., a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name but a few. It will be appreciated that such moieties may be directly attached to a provided compound or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties may be attached via click chemistry. In some embodiments, such moieties may be attached via a 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods of using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem..2006, 17, 52-57. In some embodiments, such moieties may be attached via a strained alkyne. Methods of using strained alkynes to enable rapid Cu-free click chemistry are known in the art and include those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0071] As used herein, the term “detectable moiety” is used interchangeably with the term "label" and relates to any moiety capable of being detected, e.g., primary labels and secondary labels. Primary labels, such as radioisotopes (e.g., tritium,32P,33P,35S, or14C), mass-tags, andfluorescent labels are signal generating reporter groups which can be detected without further modifications. Detectable moieties also include luminescent and phosphorescent groups.

[0072] The term “secondary label” as used herein refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for production of a detectable signal. For biotin, the secondary intermediate may include streptavi din-enzyme conjugates. For antigen labels, secondary intermediates may include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of nonradiative fluorescent resonance energy transfer (FRET), and the second group produces the detected signal.

[0073] The terms “fluorescent label”, “fluorescent dye”, and “fluorophore” as used herein refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660 and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), Carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarin, 4',5'-Dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD 700, IRD 800), JOE, Lissamine rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-Tetra-bromosulfone-fluorescein, Tetramethyl-rhodamine (TMR), Carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0074] The term “mass-tag” as used herein refers to any moiety that is capable of being uniquely detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass-tags include electrophore release tags such as N-[3-[4’-[(p-Methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic Acid, 4’-[2, 3,5,6-Tetrafluoro-4-(pentafluorophenoxyl)]methyl acetophenone, and their derivatives. The synthesis and utility of these mass-tags is described in United States Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides, oligosaccharides, andother synthetic polymers of varying length and monomer composition. A large variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds) of an appropriate mass range (100-2000 Daltons) may also be used as mass-tags.

[0075] A compound of the present invention may be tethered to an E3 ligase binding moiety. It will be appreciated that such compounds are useful as degraders (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41(5), 305-31; Ottis and Crews, ACS Chem. Biol. 2017, 12(4), 892-898.). One of ordinary skill in the art will recognize that an E3 ligase binding moiety may be attached to a provided compound via a suitable substituent as defined above. Such degraders have been found to be useful for the targeted degradation of G-protein coupled receptors (Li et al. Acta Pharm. Sin. B. 2020, 10(9), 1669-1679.).

[0076] As used herein, the term “E3 ligase binding moiety” is used interchangeably with the term “E3 ligase binder” and relates to any moiety capable of binding to and / or recruiting an E3 ligase (e.g., cIAPl, MDM2, cereblon, VHL, APC / C) for targeted degradation.

[0077] A compound of the present invention may be tethered to a lysosome targeting moiety. It will be appreciated that such compounds are useful as degraders (see, for example, Banik et al. 2020. Nature 584, 291-297.). One of ordinary skill in the art will recognize that a lysosome targeting moiety may be attached to a provided compound via a suitable substituent as defined above. Such degraders have been found to be useful for the targeted degradation of secreted and membrane proteins (Banik et al. 2020).

[0078] As used herein, the term “lysosome targeting moiety” is used interchangeably with the term "lysosome binding moiety" and relates to any moiety capable of binding to and / or recruiting a cell surface lysosome targeting receptor (e.g., cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

[0079] The terms “measurable affinity” and “measurably inhibit,” as used herein, means a measurable change in a GPR84 activity between a sample comprising a compound of the present invention, or composition thereof, and a GPR84 GPCR, and an equivalent sample comprising a GPR84 GPCR, in the absence of said compound, or composition thereof.

[0080] Throughout the description, where 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.

[0081] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.2. Therapeutic Applications

[0082] One aspect of the invention provides a method of treating a cardiovascular disorder. Another aspect of the invention provides a method of treating a cardiovascular disorder, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5, in order to treat the disorder.

[0083] A method of the invention may be used as a treatment of cardiovascular disorders in mammals that are causally related or attributable to aberrant activity of GPR84 and / or aberrant GPR84 expression and / or aberrant GPR84 distribution.

[0084] Accordingly, a compound and pharmaceutical compositions of the invention find use as therapeutics for the prophylaxis and / or treatment of cardiovascular disorders.

[0085] Accordingly, in one aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use as a medicament for treating cardiovascular disorders.

[0086] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for use in treating cardiovascular disorders.

[0087] In yet another aspect, the present invention provides a method of treating a mammal having, or at risk of having a disease disclosed herein. In a particular aspect, the present invention provides a method of treating a mammal having, or at risk of a cardiovascular disorder.

[0088] In another aspect, the present invention provides the compound of the invention, or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of a medicament for the prophylaxis and / or treatment of cardiovascular disorders.

[0089] As used herein the terms "cardiovascular disorder" and “cardiovascular disease” are used interchangeably and refer to diseases affecting the heart or blood vessels or both. In particular, cardiovascular disorders includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis; peripheral obstructivearteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality; acute coronary syndrome; congestive heart failure; coronary artery disease; dyslipidemia; hypercholesterolemia; hyperlipidemia; hypertriglyceridemia; hypoalphalipoproteinemia; peripheral vascular disease; stroke; thrombosis; and vascular dementia.

[0090] In certain embodiments, the cardiovascular disorder is selected from acute coronary syndrome, atherosclerosis, congestive heart failure, coronary artery disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, peripheral vascular disease, stroke, thrombosis, and vascular dementia.

[0091] In certain embodiments, the cardiovascular disorder is acute coronary syndrome. In certain embodiments, the cardiovascular disorder is atherosclerosis. In certain embodiments, the cardiovascular disorder is congestive heart failure. In certain embodiments, the cardiovascular disorder is coronary artery disease. In certain embodiments, the cardiovascular disorder is dyslipidemia. In certain embodiments, the cardiovascular disorder is hypercholesterolemia. In certain embodiments, the cardiovascular disorder is hyperlipidemia. In certain embodiments, the cardiovascular disorder is hypertriglyceridemia. In certain embodiments, the cardiovascular disorder is hypoalphalipoproteinemia. In certain embodiments, the cardiovascular disorder is peripheral vascular disease. In certain embodiments, the cardiovascular disorder is stroke. In certain embodiments, the cardiovascular disorder is thrombosis. In certain embodiments, the cardiovascular disorder is vascular dementia.

[0092] In certain embodiments, the cardiovascular disorder is primary hyperlipidemia and / or mixed dyslipidemia. In certain embodiments, the method reduces elevated total-C, LDL-C, ApoB, nonHDL-C, and / or TG levels. In certain embodiments, the method increases HDL-C.

[0093] In certain embodiments, the cardiovascular disorder is hypertriglyceridemia. In certain embodiments, the cardiovascular disorder is hypertriglyceridemia in a patients with primary dysbetalipoproteinemia (Type III hyperlipoproteinemia).

[0094] In certain embodiments, the cardiovascular disorder is homozygous familial hypercholesterolemia (HoFH). In certain embodiments, the method reduces LDL-C, total-C, and / or ApoB.

[0095] Another aspect of the invention provides a method of slowing the progression of atherosclerosis as part of a treatment strategy to lower total-C and LDL-C as an adjunct to diet in a patient (e.g., a pediatric patient 10 to 17 years of age) having heterozygous familial hypercholesterolemia (HeFH), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5. In certain embodiments, the method reduces elevated total-C, LDL-C and / or ApoB. In certain embodiments, the patient has failed an adequate trial of diet therapy.

[0096] Another aspect of the invention provides a method of reducing the risk of myocardial infarction, stroke, and / or arterial revascularization procedures in a patient without clinically evident Congenital heart disease, but with multiple risk factors, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0097] Another aspect of the invention provides a method of reducing low-density lipoprotein cholesterol (LDL-C) in adults with hypercholesterolemia (including heterozygous familial hypercholesterolemia (HeFH), the method comprising administering to a patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0098] Another aspect of the invention provides a method of reducing the risk of major adverse cardiovascular events (e.g., cardiovascular death, myocardial infarction, stroke, or coronary revascularization) in an adult human patient at increased risk for these events who are unable to take recommended statin therapy (e.g., those not taking a statin), the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0099] Another aspect of the invention provides a method of reducing the risk of myocardial infarction (MI), stroke, revascularization procedures, and angina in an adult patient with multiple risk factors for coronary heart disease (CHD) but without clinically evident CHD, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0100] Another aspect of the invention provides a method of reducing the risk of myocardial infarction and stroke in an adult patient with type 2 diabetes mellitus with multiple risk factors for myocardial infarction but without clinically evident myocardial infarction, the method comprising administering to the patient in need thereof atherapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0101] Another aspect of the invention provides a method of reducing the risk of non-fatal myocardial infarction, fatal and non-fatal stroke, revascularization procedures, hospitalization for congestive heart failure, and angina in adults with clinically evident myocardial infarction, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0102] Another aspect of the invention provides a method of reducing low-density lipoprotein (LDL-C) in an adult patient with primary hyperlipidemia, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula I-1, I-2, I-3, I-4, or I-5.

[0103] Another aspect of the invention provides a method of reducing low-density lipoprotein (LDL-C) in an adult or pediatric patients aged 10 years and older with heterozygous familial hypercholesterolemia (HeFH), the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0104] Another aspect of the invention provides a method of reducing low-density lipoprotein (LDL-C) an adult or pediatric patient aged 10 years and older with homozygous familial hypercholesterolemia, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0105] Another aspect of the invention provides a method of treating an adult patient with primary dysbetalipoproteinemia, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0106] Another aspect of the invention provides a method of treating an adult patient with hypertriglyceridemia, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5.

[0107] Another aspect of the invention provides a method of treating a medical disorder selected from diabetic complications, metabolic syndrome, retinopathy, and chronic kidney disease, the method comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compounds described herein, such as a compound of Formula 1-1, 1-2, 1-3, 1-4, or 1-5, in order to treat the disorder.

[0108] In certain embodiments, the medical disorder is chronic kidney disease. In certain embodiments, the medical disorder is diabetic complications. In certain embodiments, the medical disorder is metabolic syndrome. In certain embodiments, the medical disorder is retinopathy.

[0109] In certain embodiments, the patient is a human. In certain embodiments, the patient is an adult human.

[0110] In certain embodiments, the patient has a Body Mass Index > 25 kg / m2. In certain embodiments, the patient has a Body Mass Index > 28 kg / m2. In certain embodiments, the patient has a Body Mass Index > 30 kg / m2. In certain embodiments, the patient has a Body Mass Index in the range of 30 kg / m2to 35 kg / m2.2. Description of Exemplary GPR84 Antagonist Compounds

[0111] In certain aspects, the invention provides a method of treating a cardiovascular disorder in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of Formula 1-1, 1-2, 1-3, 1-4, or 1-5 to treat the cardiovascular disorder, wherein the cardiovascular disorder is acute coronary syndrome, atherosclerosis, congestive heart failure, coronary artery disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, peripheral vascular disease, stroke, thrombosis, or vascular dementia;wherein Formula 1-1 is represented by:or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturatedor partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a C1-6aliphatic; each of which is substituted with q instances of R5; and (ii) hydrogen, -CN, or -OR;each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, - NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, - CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, - OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, - N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; ortwo R2groups are optionally taken together to form =0;two R4groups are optionally taken together to form =0;two R5groups are optionally taken together to form =0;two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; two R4groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or arylfused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; ortwo R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;each Rzis independently selected from an optionally substituted group selected from C1-6aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of R3is independently selected from:(a) hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, - C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, - N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN; or(b) an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R3groups are optionally taken together to form =0 or =S; ortwo R3groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or L1is one of the following:(a) a C1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2- - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;L2and L3are independently one of the following:(a) a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2- - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on vicinal carbons are taken together with the vicinal carbons to form an optionally substituted 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring or heterocyclic ring, wherein the heterocyclic ring has, in addition to the vicinal carbons, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, or 4; andq is 0, 1, 2, 3, or 4;wherein Formula 1-2 is represented by:X11-2or a pharmaceutically acceptable salt thereof, wherein:R1is -O-(C1-5alkylene)-Z1or Y1;R2represents independently for each occurrence C 1-4 alkyl or Y2;R3is one of the following:(a) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl;(b) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or(c) Y3;R4represents independently for each occurrence hydrogen or methyl;R5and R8each represent independently for each occurrence halo, C1-4 alkyl, C1-4haloalkyl, Ci- 4 alkoxyl, or C3-6 cycloalkyl;R6and R9each represent independently for each occurrence hydrogen or C1-4 alkyl;R7is C2-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8- 11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl;A1is phenylene, pyridinylene, or piperidinylene, each of which is substituted with q occurrences of R8; or A1is Y4;X1is O or S;Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R4)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R5;Z2is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Z3is hydroxyl, Ci-4alkoxyl, -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic);L1is Ci-4 alkylene, C3-4 haloalkylene, Ci-4hydroxyalkylene, cyclopropylene, or Y5;Y1is one of the following:(a) -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;(b) -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2; (c) -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or(d) -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5;Y2represents independently for each occurrence C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; Y3is one of the following:(a) -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,C=^, -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)- (C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl;(b) -O-(C1-8alkylene)-Z3or hydroxyl; or(c) -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;N.5-iY4is -C C-, cyclohexylene,, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2;Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-; andm, n, p, and q represent independently 0, 1, or 2; andwherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5;wherein Formula 1-3 is represented by:1-3or a pharmaceutically acceptable salt thereof, wherein:Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and a C1–6aliphatic; each of which is substituted with p instances of R4; and (ii) hydrogen;each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, - NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, - CR2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, - N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; ortwo R2groups are optionally taken together to form =0;two R4groups are optionally taken together to form =0;two R5groups are optionally taken together to form =0;two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;each instance of Rzis independently selected from an optionally substituted group selected from C1-6aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3is hydrogen or an optionally substituted C1–6aliphatic group; ortwo R3groups are optionally taken together to form =0; oran R2group and an R3group are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated or partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;L1is one of the following:(a) a C1–6bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1–3 methylene units of the chain are independently and optionally replaced with –O–, –Cy–, –C(O)–, –C(S)–, –C(R)2–, –CH(R)–, –CH(OR)–, –C(F)2–, –N(R)–, –S–, –S(O)–, or –S(O)2–; or(b) a covalent bond;each -Cy- is independently an optionally substituted bivalent ring selected from phenylene; 3- 7 membered saturated or partially unsaturated carbocyclylene; 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-11 membered saturated or partially unsaturated spiro orbridged bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L2is a covalent bond or a Ci-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CR(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, -CH(CR3)-, -C=(CH2)-, or-S(O)2-;L3is one of the following:(a) a Ci-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;X is one of the following:(a) a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partiallay unsaturated bridged or spiro cyclic, bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl; each of which is substituted with q instances of R5; or(b) -CH2(OR), -CH(R)(OR), or -C(R)2(OR);each instance of R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R groups on the same atom are optionally taken together with the atom to form an optionally substituted 3-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, 4, or 5; andq is 0, 1, 2, 3, 4, or 5;wherein Formula 1-4 is represented by:1-4or a pharmaceutically acceptable salt thereof, wherein:R2is -(C2-4alkynylene)-(C3-7cycloalkyl), -(C2-4alkynylene)-(C1-3alkylene)-(C1-6alkoxyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C1-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2;R3represents independently for each occurrence halo, C1-4 alkyl, C 1 -4 haloalky 1, C1-4 alkoxyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -N(R7)(R8), or Y3;R4and R5are independently C1-6 alkyl or C1-2 deuteroalkyl, or R4and R5are taken together with their intervening atom(s) to form a 3-5 membered saturated carbocyclic ring;R6is C1-6 alkyl or C3-6 cycloalkyl;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;A1is or Y4, wherein ** is a point of attachment to A2;A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Y5; wherein the phenylene and heteroarylene are substituted with n occurrences of R3;L1is a C1-3 alkylene;is -C(O)N(R7)(R8), -N(R7)C(O)(R6), -CO2R7Y2is -C=C-(Ci-3alkylene)-N(R7)SO2-R6, -C=C-(Ci-3alkylene)-SO2-N(R7)(R8), -C=C-(C0-3 alkylene)-N(R7)C(O)R6, -C=C-(Co-3 alkylene)-C(O)N(R7)(R8), -C=C-(Ci-3alkylene)-0-(C3-6 cycloalkyl), -C=C-(Ci-3 alkylene)-O-(Ci-s haloalkyl), -C=C-(Ci-s haloalkyl), -C=C-(cyclobutyl), -C=C-(C(CH3)2(OH)), -C=C-(hydroxycyclopropyl), -C=C-(Ci-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C=C-(Ci-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C=C-(Ci-3 alkylene)-(triazolyl optionally substituted by one phenyl which is optionally substituted by one C1-3 alkyl), -C=C-(C1-3 alkyl ene)-(imidazolylene)-(phenylene)-N(R7)(R8),OH(C-|_3alkylene)-N(R7)— N, -(azetidinylene substituted with 1 or 2 occurrences of Ci-4 alkyl)-Z2, -(azetidinyl substituted with one C1-4 haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one C1-3 alkylene-O-C3-6 cycloalkyl), -(azetidinyl substituted with one C1-4 haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one -(Co-4alkylene)-(Ci-4haloalkoxyl)), -(C0-3 alkylene)-CN, -(C2 alkynylene)-CN, C1-4 haloalkyl, -(C0-3 alkylene)-C(O)N(R7)(R8), -O-(Ci-3 alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(Ci-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (C1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (Ci-4alkylene)-(C3-6 cycloalkyl), or hydrogen;Y3is -N(R7)(C1-4deuteroalkyl) or -N(C1-4deuteroalkyl)2;R6, wherein ** is a point of attachment to A'Y5isN F substituted with n occurrences of R3;zHs Ci -10 aliphatic, -(C0-3 alkylene)-(3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 1, 2, or 3 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C0-3 alkylene)-(5-6membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -N(R7)-(CI-IO optionally substituted aliphatic)-, or Ci-6 hydroxyalkyl;Z2is one of the following:(a) 3-7 membered saturated heterocyclyl substituted 1 or 2 occurrences of R3, (b) -(Co-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or(c) 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0, 1, or 2;wherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5; and**provided that whenY4is VN^N, then R3is not methyl;wherein Formula 1-5 is represented by:1-5or a pharmaceutically acceptable salt thereof, wherein:A1is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-membered unsaturated oxo-heterocyclylene containing 1 nitrogen atom; or phenylene; each of which is substituted with m occurrences of R3;A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is substituted with n occurrences of R4;L1is a Ci-6 bivalent straight or branched saturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-;L2is -C(O)N(R5)-, -N(R6)C(O)-, -N(R6)-, -N(R6)-(CI-4alkylene)-, -(Ci-4alkylene)-N(R6)-, -S(O)2N(R5)-, -N(R6)S(O)2-, -CO2-, or -OC(O)-;R1is -C(O)N(R7)(R8), a 6-11 membered saturated or partially unsaturated, bridged or spirocyclic, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each of said bicyclic heterocyclic ring and monocyclic heterocyclic ring are substituted with q instances of R9;R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl) or hydrogen;R3represents independently for each occurrence C1-6 alkyl or halo;R4represents independently for each occurrence C1-6 alkyl, halo, hydroxyl, C1-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8);R5is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen; or R5and one occurrence of R4are taken together with their intervening atoms to form a 5-6 membered ring containing 1 nitrogen atom;R6is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;R9represents independently for each occurrence C1-6 alkyl, halo, hydroxyl, C1-6 alkoxyl, or C3-6 cycloalkyl; andm, n, and q are independently 0, 1, or 2;R9O NNR4represents independently for each occurrence halo, hydroxyl, C1-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8).Part A: First Set of GPR84 Antagonist Compounds

[0112] In certain aspects, the methods described here comprise the administration of a compound of Formula 1-1 to a patient in need thereof. In certain embodiments, the compound is a compound of the following Formula 1-1:(R2)m7B) [ cor an N-oxide, or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a C1-6aliphatic; each of which is substituted with q instances of R5; and (ii) hydrogen, -CN, or -OR;each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, - NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, - CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, - OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, - N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; ortwo R2groups are optionally taken together to form =0;two R4groups are optionally taken together to form =0;two R5groups are optionally taken together to form =0;two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; two R4groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; ortwo R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are optionally taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; each Rzis independently selected from an optionally substituted group selected from C1-6aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of R3is independently selected from:(a) hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, - C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(0)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, - N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN; or(b) an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R3groups are optionally taken together to form =0 or =S; ortwo R3groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;L1is one of the following:(a) a Ci-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2- - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;L2and L3are independently one of the following:(a) a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2- - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / ortwo R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on vicinal carbons are taken together with the vicinal carbons to form an optionally substituted 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring or heterocyclic ring, wherein the heterocyclic ring has, in addition to the vicinal carbons, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, or 4; andq is 0, 1, 2, 3, or 4.

[0113] As defined generally above, Ring A is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0114] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, two R2groups are taken together to form =0 and Ring A is a pyridone ring. In some embodiments, Ring A is piperazine ring. In some embodiments, Ring A is a pyridine ring.(R2)m

[0116] In some embodiments, Ring A is in some embodiments, Ring A isipH

[0117] In some embodiments, Ring A is (R2)™. In some embodiments, Ring A is(R")m(R2)m

[0118] In some embodiments, Ring A is In some embodiments, Ring A is (R2)m(R2)m

[0119] In some embodiments, Ring A isIn some embodiments, Ring A isNHIn some embodiments, Ring A is. In some embodiments, Ring A(R2)m| — N N — |

[0120] In some embodiments, RingA is ' /

[0121] In some embodiments, RingA is. In some embodiments,the < on the left side of Ring A is connected to L1and the< on the right side of Ring A isconnected to L2. In some embodiments, the‘ on the right side of Ring A is connected to L1and the * on the left side of Ring A is connected to L2.

[0122] In some embodiments, two R2groups are taken together to form =0 and Ring A is (R2)O-20. In some embodiments, two R2groups are taken together to form =0 and RingIn some embodiments, two R2groups are taken together to form =0 andRing A is (R)°-2. In some embodiments, two R2groups are taken together to form =0(R2)0-2^HKI— 'and Ring A is0. In some embodiments, two R2groups are taken together to form an optionally substituted aryl ring and Ring A with said optionally substituted aryl ring fusedthereto isIn some embodiments, two R2groups are taken together to form an optionally substituted aryl ring and Ring A with said optionally substituted aryl ring fusedthereto isv. In some embodiments,< is attached to L2. In some OHS5Hembodiments, two R2groups are taken together to form =0 and Ring Ais (R2)O-2 [NOHsome embodiments, two R2groups are taken together to form =0 and RingA is

[0123] In some embodiments, Ring A is selected from those depicted in Table 1, below.

[0124] As defined generally above, Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl.

[0125] In some embodiments, Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0126] In some embodiments, Ring B is an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0127] In some embodiments, Ring B is phenyl.

[0128] In some embodiments, RingB is In some embodiments, Ring B isIn some embodiments, Ring B isIn some embodiments, Ring BIn some embodiments, Ring B is In some embodiments, RingIn some embodiments, Ring B is In some embodiments,In some embodiments, Ring B is In someembodiments, RingB is In some embodiments, RingB issome embodiments, RingB is In some embodiments, RingB isIn some embodiments, RingB is In some embodiments, RingB isIn some embodiments, RingB is In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B In some embodiments, Ring B is In some embodiments, Ring In some embodiments, Ring B is In some embodiments, Ring B is In some embodiments, Ring B is In some (R3)n embodiments, RingB is In some embodiments, RingB isembodiments, RingB is In some embodiments, RingB is In some embodiments, RingB is In some embodiments, RingB is some embodiments, RingB is (RIn some embodiments, RingB isIn some embodiments, RingB is In some embodiments, RingB isIn some embodiments, RingB is,(R3)n

[0129] In some embodiments, RingB is ' '. In some embodiments, Ring B is

[0131] In some embodiments, two R3groups are taken together to form =0 and Ring B is O(R )o-2 insome embodiments, two R3groups are taken together to form =0 and Ring Bis(R3)O-2 in some embodiments, two R3groups are taken together to form =0 and Ring O(R3)-1ZNH B is * ' In some embodiments, two R3groups are taken together to form =0 j? (R3)O-2and Ring B is ' '. In some embodiments, two R3groups are taken together toform =0 and Ring Bis (R3)O-2 In some embodiments, two R3groups are taken togetherto form =0 and RingB is (R3)0-2. In some embodiments, two R3groups are takentogether to form =0 and Ring Bis In some embodiments, two R3groups aretaken together to form =0 and Ring Bis In some embodiments, two R3groups ONare taken together to form =0 and Ring Bis (R )o-2 insome embodiments, two R3Ogroups are taken together to form =0 and Ring Bis In some embodiments,(R3)O-2 two R3groups are taken together to form =0 and RingB is In someembodiments, two R3groups are taken together to form =0 and RingB is In some embodiments, two R3groups are taken together to form =0 and Ring B isIn some embodiments, two R3groups are taken together to form =0 andIn some embodiments, two R3groups are taken together to form =0Ojf -j] - (R3)0-2and RingB is. In some embodiments, two R3groups are taken togetherto form =0 and RingB is In some embodiments, two R3groups are taken togetherto form =0 and RingB is In some embodiments, two R3groups are taken(R3)O-2together to form =0 and Ring Bis

[0132] In some embodiments, two R3groups are taken together to form =0 and Ring B isM XCi(R3)0-2.

[0133] In some embodiments, two sets of R3groups are taken together to each form =0Oand RingB is. In some embodiments, two sets of R3groups are taken together Oto each form =0 and RingB is 0. In some embodiments, the* on the left side ofRing B is connected to L2and theon the right side of Ring B is connected to L3. In someembodiments, theon the right side of Ring B is connected to L2and theon the left side of Ring B is connected to L3.

[0134] In some embodiments, Ring B is selected from those depicted in Table 1, below.

[0135] As defined generally above, Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0136] In some embodiments, Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring C is an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independentlyselected from nitrogen, oxygen, and sulfur). In some embodiments, Ring C is an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.o(R4)

[0137] In some embodiments, RingC is 'p. In some embodiments, Ring C is0 o / □4\YR' / p 4). In some embodiments, Ring C is '7p. In some embodiments, Ring°\V(R4)PC is. In some embodiments, RingC is )p. In some embodiments,o.(R4)Ring Cis',p. In some embodiments, RingC is (R)p. In some embodiments,(R4)P Ring C isIn some embodiments, Ring C is(R4)P. In some embodiments, Ring C isIn some embodiments, Ring C is(R4)P In some embodiments, Ring C is0(R4)' 'p. In some embodiments, Ring C isp. In some embodiments, Ring Co o'p. In some embodiments, Ring C isp. In some embodiments,some embodiments, In some embodiments, Ring C is(R4)PIn some embodiments, Ring C is. In some embodiments,(R4)P Ring C isIn some embodiments, Ring C is< R4)P-E H embodiments, Ring C isHIn some embodiments, Ring C issome embodiments, Ring C isIn some embodiments, RingC is (R4)PIn some embodiments, Ring C isIn some embodiments, RingC is-N(R4)p-f H In some embodiments, RingC is In some embodiments, Ring C is0(R4)P. In some embodiments, RingC is In some embodiments, Ring C is® N^ ® N^. In some embodiments, Ring C is. In some embodiments,Ring C isIn some embodiments, Ring C is. In some embodiments, RingC isNin some embodiments, Ring C isN in some embodiments,Ring C isO. In some embodiments, Ring C is® In some embodiments, Ring C. In some embodiments, Ring C is. In some embodiments, RingC is

[0138] In some embodiments, Ring C is selected from those depicted in Table 1, below.

[0139] As defined generally above, R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a Ci-6 aliphatic; each of which is substituted with q instances of R5; and (ii) hydrogen, -CN, or -OR.

[0140] In some embodiments, R1is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring which is substituted with q instances of R5. In some embodiments, R1is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is substituted with q instances of R5. In some embodiments, R1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is substituted with q instances of R5. In some embodiments, R1is phenyl which is substituted with q instances of R5. In some embodiments, R1is a C1-6aliphatic group substituted with q instances of R5.

[0141] In some embodiments, R1is hydrogen. In some embodiments, R1is -CN. In some embodiments, R1is -OR.

[0142] In some embodiments, R1is methyl. In some embodiments, R1is. In someembodiments, R1is[n someembodiments, R1is— " A. In some embodiments,R1isFSCIn some embodiments, R1isIn some embodiments,R1is. In some embodiments,R1is ' 'qIn some embodiments,R1is In some, (R5)q embodiments,R1is In some embodiments,R is In someOembodiments,R1is

[0143] In some embodiments, R1is -OMe. In some embodiments, R1is cyano.

[0144] In some embodiments, R1is selected from those depicted in Table 1, below.

[0145] As defined generally above, each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, - N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR, or -P(O)R2.

[0146] In some embodiments, R2is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR, or -P(O)R2.

[0147] In some embodiments, R2is methyl. In some embodiments, R2is fluoro. In some embodiments, R2is bromo.

[0148] In some embodiments, R2is selected from those depicted in Table 1, below.

[0149] In some embodiments, R4is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR2, –CF2R, –CF3, –CR2(OR), –CR2(NR2), –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –C(S)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –Si(OR)R2, –SiR3, –P(O)(R)NR2, –P(O)(R)OR or –P(O)R2.

[0150] In some embodiments, R4is hydrogen.

[0151] In some embodiments, R4is selected from those depicted in Table 1, below.

[0152] In some embodiments, R5is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR2, –CF2R, –CF3, –CR2(OR), –CR2(NR2), –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –C(S)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –Si(OR)R2, –SiR3, –P(O)(R)NR2, –P(O)(R)OR or –P(O)R2.

[0153] In some embodiments, R5is methyl. In some embodiments, R5is fluoro, In someembodiments, R5is. In some embodiments, R5is.

[0154] In some embodiments, R5is selected from those depicted in Table 1, below.

[0155] As defined generally above, two R2groups are optionally taken together to form =0.

[0156] In some embodiments, two R2groups are taken together to form =0.

[0157] As defined generally above, two R4groups are optionally taken together to form =0.

[0158] In some embodiments, two R4groups are taken together to form =0.

[0159] As defined generally above, two R5groups are optionally taken together to form =0.

[0160] In some embodiments, two R5groups are taken together to form =0.

[0161] As defined generally above, two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0162] In some embodiments, two R2groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0163] As defined generally above, two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0164] In some embodiments, two R4groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0165] As defined generally above, two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0166] In some embodiments, two R5groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0167] As defined generally above, each Rzis independently selected from an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0168] In some embodiments, Rzis an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0169] In some embodiments, Rzis selected from those depicted in Table 1, below.

[0170] As defined generally above, R3is independently selected from: (a) hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN; or (b) an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R3groups are optionally taken together to form =0; or two R3groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partiallyunsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0171] In some embodiments, R3is hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R,-CF3, -CR2(OR),-CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N®OR, -OC(O)R, -OC(O)NR2, -C(S)NR2,-N(R)C(O)OR, --N(R)C(O)R, -N(R)C(O)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -S(NR)(O)R, -N(R)S(O)R, or -N(R)CN.

[0172] In some embodiments, R3is an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0173] In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In someembodiments, R3is chloro. In some embodiments, R3is. In some embodiments, R3is '. In some embodiments, R3is '.O

[0174] In some embodiments, R3is -CF3. In some embodiments, R3is Y^NMe2 In °> r°some embodiments, R3is. In some embodiments, R3is '

[0175] In some embodiments, two R3groups are taken together to form =0 or =S. In some embodiments, two R3groups are taken together to form =0. In some embodiments, two R3groups are taken together to form =S.

[0176] In some embodiments, two R3groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0177] In some embodiments, two R3groups are taken together with their interveningatoms to formIn some embodiments, two R3groups are taken together with theirintervening atoms to form

[0178] In some embodiments, R3is selected from those depicted in Table 1, below.

[0179] As defined generally above, L1is one of the following: (a) a C1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) a covalent bond.

[0180] In some embodiments, L1is a C1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, -S(O)-, or-S(O)2-

[0181] In some embodiments, L1is a covalent bond.O

[0182] In some embodiments, L1is. In some embodiments, L1is. Insome embodiments, L1is. In some embodiments, L1is. In someembodiments, L1is' O. In some embodiments, L1is' ® '. In someembodiments, L1isz°y. In some embodiments, L1isV'0'x- / . In someembodiments, L1isf5OV. In some embodiments, L1isV°K5. In someembodiments, L1is. In some embodiments, L1is. In someO 0embodiments, L1is. In some embodiments, L1is. In someembodiments, L1is'. In some embodiments, L1isv. In / H H 1 so e m o i e tN m b mN e d n s, L isz. In some embodiments, L1isIn some embodiments, L1is. In some embodiments, L1isIn some embodiments,L1is In some embodiments, L1isIn some embodiments, L1is O In some embodiments, H e, HHn0n ° L1is O. In some embodiments, L1is °. In someembodiments, the< on the left side of L1is connected to R1and the< on the right side ofL1is connected to Ring A. In some embodiments, the< on the right side of L1is connectedto R1and the < on the left side of L1is connected to Ring A.

[0183] In some embodiments, L1is selected from those depicted in Table 1, below.

[0184] As defined generally above, L2and L3are independently one of the following: (a) a Ci-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) a covalent bond.

[0185] In some embodiments, L2is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, -S(O)-, or-S(O)2-

[0186] In some embodiments, L2is a covalent bond.

[0187] In some embodiments, L2isIn some embodiments, L2issome embodiments, L2isIn some embodiments, L2is. In someembodiments, L2isIn some embodiments, L2isembodiments, L2isIn some embodiments, L2is. In some embodiments,HCL HCL. In some embodiments, L2is In some embodiments, L2isHChIn some embodiments, L2is. In some embodiments, L2is. In someembodiments,L2is.

[0188] In some embodiments, L2is selected from those depicted in Table 1, below.

[0189] In some embodiments, L3is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, -S(O)-, or-S(O)2-

[0190] In some embodiments, L3is a covalent bond.

[0191] In some embodiments, L3isin some embodiments, L3is.In some embodiments, L3is. In some embodiments, L3isIn someembodiments, L3is. In some embodiments, L3is. In some embodiments,the < on the left side of L3is connected to Ring B and the? on the right side of L3isconnected to Ring C. In some embodiments, the \ 7 on the right side of L is connected toRing B and the< on the left side of L is connected to Ring C.

[0192] In some embodiments, L3is selected from those depicted in Table 1, below.

[0193] As defined generally above, each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen,oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or two R groups on vicinal carbons are optionally taken together with the vicinal carbons to form an optionally substituted 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring or heterocyclic ring, wherein the heterocyclic ring has, in addition to the vicinal carbons, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0194] In some embodiments, R is hydrogen.

[0195] In some embodiments, R is an optionally substituted group selected from Ci-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0196] In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0197] In some embodiments, two R groups on vicinal carbons are optionally taken together with the vicinal carbons to form an optionally substituted 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring or heterocyclic ring, wherein the heterocyclic ring has, in addition to the vicinal carbons, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0198] In some embodiments, R is selected from those depicted in Table 1, below.

[0199] As defined generally above, m is 0, 1, 2, 3, or 4.

[0200] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0201] In some embodiments, m is selected from those depicted in Table 1, below.

[0202] As defined generally above, n is 0, 1, 2, 3, or 4.

[0203] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0204] In some embodiments, n is selected from those depicted in Table 1, below.

[0205] As defined generally above, p is 0, 1, 2, 3, or 4.

[0206] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0207] In some embodiments, p is selected from those depicted in Table 1, below.

[0208] As defined generally above, q is 0, 1, 2, 3, or 4.

[0209] In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4.

[0210] In some embodiments, q is selected from those depicted in Table 1, below.

[0211] In some embodiments, the compound of Formula 1-1 is notembodiments, the compound of Formula 1-1 is not. In some embodiments, the compound of Formula 1-1 is notO

[0212] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is oxetanyl, to provide a compound of Formula I-l-a-1, 1-l-a-2, or I-l-a-3:I-l-a-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0213] In some embodiments, the present invention provides a compound of fFormula 1-1, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is furanyl, to provide a compound of formula I-l-b-1, 1-l-b-2, or I-l-b-3:I-l-b-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0214] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is tetrahydropyranyl, to provide a compound of formula I-l-c-1, 1-l-c-2, or I-l-c-3:I-l-c-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0215] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is 1,4-dioxanyl, to provide a compound of formula I-l-d-1, 1-l-d-2, or I-l-d-3:I-l-d-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0216] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; and two R3groups are taken together to form =0; to provide a compound of formula I-l-e-1, 1-l-e-2, or I-l-e-3:or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0217] In some embodiments, the present invention provides a compound of Formula 1-1,wherein L1is==; Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; and two R3groups are taken together to form =0; to provide a compound of formula I-l-f-1, 1-l-f-2, or I-l-f-3:I-l-f-3or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0218] In some embodiments, the present invention provides a compound of formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is oxetanyl; to provide a compound of formula I-l-g-1, 1-1-g-2, or I-l-g-3:I-l-g-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0219] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is furanyl, to provide a compound of formula I-l-h-1, 1-1-h-2, or I-l-h-3:I-l-h-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0220] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is tetrahydropyranyl; to provide a compound of formula I-l-i-1, I-l-i-2, or I-l-i-3:I-l-i-1 I-l-i-2I-l-i-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0221] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is 1,4-dioxanyl; to provide a compound of formula I-l-j-1, I-l-j-2, or I-l-j-3:I-l-j-1 I-l-j-2(R4)0-2I-l-j-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0222] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is oxetanyl, to provide a compound of formula II-l-a-1, II-l-a-2, or II-l-a-3:II-l-a-1 II-l-a-2II-l-a-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0223] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is furanyl, to provide a compound of formula II-l-b-1, II-l-b-2, or II-l-b-3:II-l-b-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0224] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is tetrahydropyranyl, to provide a compound of formula II-l-c-1, II-l-c-2, or II-l-c-3:II-l-c-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0225] In some embodiments, the present invention provides a compound of Formula 1-1, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is 1,4-dioxanyl, to provide a compound of formula II-l-d-1, II-l-d-2, or II-l-II-l-d-1 II-l-d-2II-l-d-3or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0226] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; and two R3groups are taken together to form =0; to provide a compound of formula II-l-e-1, II-l-e-2, or II-1-e- 3:II-l-e-3or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0227] In some embodiments, the present invention provides a compound of Formula 1-1,wherein L1is; Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; and two R3groups are taken together to form =0; to provide a compound of formula II-l-f-1, II-l-f-2, or II-l-f-3:II-l-f-1 II-l-f-2II-l-f-3or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0228] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is oxetanyl; to provide a compound of formula II-1-g- 1, II-l-g-2, or II-l-g-3:or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0229] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is furanyl, to provide a compound of formula II-1-h- 1, II-l-h-2, or II-l-h-3:II-l-h-1 II-l-h-2II-l-h-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0230] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is tetrahydropyranyl; to provide a compound of formula II-l-II-l, II-1-II-2, or II-1-II-3:II-l-II-l II-1-II-2II-1-II-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0231] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is 1,4-dioxanyl; to provide a compound of formula II-1-j-l, II-l-j-2, or II-l-j-3:II-l-j-1 II-l-j-2II-l-j-3or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0232] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl; Ring B is pyrimidinone or pyrimidinethione; two R3groups are taken together to form =0 or =S; an additional R3group and an R2group together form CH2CH2— £wherein the left and right represent points of attachment to Ring A and Ring B, respectively; and Ring C is as defined above; to provide a compound of formula III- 1-a-l or III-l-a-2:(R2)0-3 (R2)0-3III-l-a-1 III-l-a-2 or a pharmaceutically acceptable salt thereof, wherein each of L1, L3, R1, R2, R3, R4, p, and Ring C is as defined above and described in embodiments herein, both singly and in combination.

[0233] In some embodiments, the present invention provides a compound of formula 1-1, wherein Ring A is phenyl; Ring B is pyridinone or pyridinethione; two R3groups are taken together to form =0 or =S; an additional R3group and an R2group together form CH2CH2— £wherein the left and right represent points of attachment to Ring A andRing B, respectively; and Ring C is as defined above; to provide a compound of formula III- 1-b-l or III-l-b-2:III-l-b-1 III-l-b-2 or a pharmaceutically acceptable salt thereof, wherein each of L1, L3, R1, R2, R3, R4, p, and Ring C is as defined above and described in embodiments herein, both singly and in combination.

[0234] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl; Ring B is pyridinone or pyridinethione; two R3groups are taken together to form =0 or =S; an additional R3group and an R2group together form CH2CH2— Iwherein the left and right represent points of attachment to Ring A and Ring B, respectively; and Ring C is as defined above; to provide a compound of Formula III-1-c-l or III-l-c-2:III-l-c-1 III-l-c-2 or a pharmaceutically acceptable salt thereof, wherein each of L1, L3, R1, R2, R3, R4, p, and Ring C is as defined above and described in embodiments herein, both singly and in combination.

[0235] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl; Ring B is pyrimidinone or pyrimidinethione; two R3groups are taken together to form =0 or =S; an additional R3group and an R2group together form OCH2CH2-| |wherein the left and right represent points of attachment to Ring A and Ring B, respectively; and Ring C is as defined above; to provide a compound of Formula III-1-d-l or III-l-d-2:(R2)0-3 (R2)0-3 III-l-d-1 III-l-d-2 or a pharmaceutically acceptable salt thereof, wherein each of L1, L3, R1, R2, R3, R4, m, p, and Ring C is as defined above and described in embodiments herein, both singly and in combination.

[0236] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is phenyl; Ring B is pyridinone; two R3groups are taken together to form =0; and Ring C is as defined above; to provide a compound of Formula III-l-e-1:III-l-e-1or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, n, p, and Ring C is as defined above and described in embodiments herein, both singly and in combination. Insome embodiments, Ring C and it R substituent(s) isN. In some embodiments, Ring Cand it R4substituent(s) isIn some embodiments, Ring C and it R4substituent(s) is(R4)PIn some embodiments, Ring C and it R4substituent(s) is. In someembodiments, Ring C and it R4substituent(s) is

[0237] In some embodiments, the present invention provides a compound of Formula 1-1, wherein Ring A is pyridinone wherein two R2groups are taken together to form =0 and oneR2group is methyl; Ring B is phenyl; and Ring C is cyclopropyl; to provide a compound of Formula III-l-f-1:R1^III-l-f-1or a pharmaceutically acceptable salt thereof, wherein each of R, R1, R2, R3, R4, n, and p is as defined above and described in embodiments herein, both singly and in combination.

[0238] In certain embodiments, the present invention provides a compound of formula I- 1-1*:or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein:Ring A is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- 6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a C1-6aliphatic; each of which is substituted with q instances of R5; and (ii) hydrogen, -CN, or -OR;each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, - NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, - CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, - OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, - N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; ortwo R2groups are optionally taken together to form =0;two R4groups are optionally taken together to form =0;two R5groups are optionally taken together to form =0;two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each Rzis independently selected from an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;each instance of R3is independently selected from:(a) hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, - S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, - C(0)N(R)0R, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, - N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN; or(b) an optionally substituted selected from Ci-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R3groups are optionally taken together to form =0; ortwo R3groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0- 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; L1is one of the following:(a) a Ci-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;L2and L3are independently one of the following:(a) a Ci-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated,partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, or 4; andq is 0, 1, 2, 3, or 4.

[0239] Compounds may be more specifically defined by reference to certain variables associated with Formula 1-1-1*. For example, in some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0240] In some embodiments, two R2groups are taken together to form =0 and Ring A is a pyridone ring. In some embodiments, Ring A is piperazine ring. In some embodiments, Ring A is a pyridine ring.(R2)m

[0241] In some embodiments, Ring Ais Insomeembodiments, Ring A is(r 2)mX / H' '. In some embodiments, Ring A is (R. In some embodiments, Ring A(R2)mZ \ N-^.s / _ ( / A _is (R. In some embodiments, Ring A is \= / . In some embodiments, RingIn some embodiments, Ring A isIn some embodiments,(R2)mRing A isIn some embodiments, Ring A is(RIn some (R2)m |— N ' N— | embodiments, RingA is In some embodiments, RingA is ’ / . In (R2)O-2some embodiments, two R2groups are taken together to form =0 and RingA is0(R2)O-2In some embodiments, two R2groups are taken together to form =0 and RingA is ° In some embodiments, two R2groups are taken together to form =0 and Ring A is(R2)O-2 insome embodiments, two R2groups are taken together to form =0 and Ring (R2)O-2A is0

[0242] In some embodiments, Ring A is selected from those depicted in Table 1, below.

[0243] In some embodiments, Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring B is phenyl.(R3)n

[0244] In some embodiments, Ring B isIn some embodiments, Ring B isIn some embodiments, Ring B isIn some embodiments, RingIn some embodiments, Ring B is In some embodiments,In some embodiments, Ring B is In someembodiments, Ring B is In some embodiments, Ring B is some embodiments, RingB is In some embodiments, RingB is In some embodiments, RingB is In some embodiments, RingB is In some embodiments, RingB is In some embodiments, Ring B isIn some embodiments, Ring B is In some embodiments, Ring BIn some embodiments, RingIn some embodiments, Ring B is In some embodiments,In some embodiments, Ring B is In someembodiments, RingB is In some embodiments, RingB isIn some embodiments, Ring B isIn some embodiments, Ring B isIn some embodiments, Ring B is In some embodiments, RingIn some embodiments, Ring B is In some embodiments,In some embodiments, Ring B is In some embodiments,Ring Bis In some embodiments, RingB is

[0245]

[0246] (R3)n Ring Bis. In some embodiments, Ring B is(R3)n In some embodiments, Ring B is. In some embodiments, Ring B is

[0247] In some embodiments, two R3groups are taken together to form =0 and Ring B isIn some embodiments, two R3groups are taken together to form =0 and Ring B is (R3)0-2In some embodiments, two R3groups are taken together to form =0 andIn some embodiments, two R3groups are taken together to form -2=0 and RingB is In some embodiments, two R3groups are taken togetherto form =0 and RingB is In some embodiments, two R3groups are takentogether to form =0 and Ring Bis In some embodiments, two R3groups aretaken together to form =0 and Ring Bis In some embodiments, two R3groupsare taken together to form =0 and Ring Bis In some embodiments, two R3groups are taken together to form =0 and Ring Bistwo R3groups are taken together to form =0 and RingB is In some(R3)0-2embodiments, two R3groups are taken together to form =0 and RingB is In some embodiments, two R3groups are taken together to form =0 and Ring B isIn some embodiments, two R3groups are taken together to form =0 and Ring Bis (R3)0-2. In some embodiments, two R3groups are taken together to form =0 andIn some embodiments, two R3groups are taken together to form =0In some embodiments, two R3groups are taken togetherto form =O and Ring B iso form =0 and Ring B is In some embodiments, two R3groups are taken togetherto form =0 and Ring Bistogether to form =0 and Ring Bis

[0248] In some embodiments, two R3groups are taken together to form =0 and Ring B is1-2

[0249] In some embodiments, two sets of R3groups are taken together to each form =0Oand RingB is0In some embodiments, two sets of R3groups are taken together ONto each form =0 and Ring Bis

[0250] In some embodiments, Ring B is selected from those depicted in Table 1, below.

[0251] In some embodiments, Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring C is phenyl. In some embodiments, Ring C is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring C is an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0252] In some embodiments, RingC isp. In some embodiments, Ring C isO O(R YR4)'4)'p. In some embodiments, Ring C is ' 'p. In some embodiments, Ring(R4)PC is. In some embodiments, RingC is (R)p. In some embodiments,ORing C is(R)p. In some embodiments, Ring C is( 'R4) 'Dp. T In some0(R4)P. In some embodiments, Rin(R4)P embodiments, Ring C is g C isOCk\J-(R4)' 'p. In some embodiments, Ring C is In some embodiments, RingC is / R4)' 'p. In some embodiments, Ring C is (R)p. In some embodiments,O O(R4)Ring C isk'p. In some embodiments, Ring C is ( 'R4) 'Dp. T In someembodiments, Ring CisIn some embodiments, RingC is (R4)P

[0253] In some embodiments, Ring C is selected from those depicted in Table 1, below.

[0254] In some embodiments, R1is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring which is substituted with q instances of R5. In some embodiments, R1is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is substituted with q instances of R5. In some embodiments, R1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur which is substituted with q instances of R5. In some embodiments, R1is phenyl which is substituted with q instances of R5. In some embodiments, R1is a C1-6aliphatic group substituted with q instances of R5.

[0255] In some embodiments, R1is hydrogen. In some embodiments, R1is -CN. In some embodiments, R1is -OR. In some embodiments, R1is methyl. In some embodiments, R1is. In some embodiments, R1is . In some embodiments, R1is. Insome embodiments, R1isIn some embodiments, R1isIn someembodiments,R1is In some embodiments,R1is In some embodiments,R1is (R)q. In some embodiments, R1isq. In some embodiments, R1is -OMe. In some embodiments, R1is cyano. In some embodiments, R1is selected from those depicted in Table 1, below.

[0256] In some embodiments, R2is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, -SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR2, –CF2R, –CF3, –CR2(OR), –CR2(NR2), –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –C(S)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –Si(OR)R2, –SiR3, –P(O)(R)NR2, –P(O)(R)OR or –P(O)R2. In some embodiments, R2is methyl. In some embodiments, R2is fluoro. In some embodiments, R2is bromo. In some embodiments, R2is selected from those depicted in Table 1, below.

[0257] In some embodiments, R4is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR2, –CF2R, –CF3, –CR2(OR), –CR2(NR2), –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –C(S)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –Si(OR)R2, –SiR3, –P(O)(R)NR2, –P(O)(R)OR or –P(O)R2. In some embodiments, R4is hydrogen. In some embodiments, R4is selected from those depicted in Table 1, below.

[0258] In some embodiments, R5is hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, –SR, –NR2, –S(O)2R, –S(O)2NR2, –S(O)R, –S(O)NR2, –CF2R, –CF3, –CR2(OR), –CR2(NR2), –C(O)R, –C(O)OR, –C(O)NR2, –C(O)N(R)OR, –OC(O)R, –OC(O)NR2, –C(S)NR2, –N(R)C(O)OR, –N(R)C(O)R, –N(R)C(O)NR2, –N(R)C(NR)NR2, –N(R)NR2, –N(R)S(O)2NR2, –N(R)S(O)2R, –N=S(O)R2, –S(NR)(O)R, –N(R)S(O)R, –N(R)CN, –Si(OR)R2, –SiR3, –P(O)(R)NR2, –P(O)(R)OR or –P(O)R2.

[0259] In some embodiments, R5is methyl. In some embodiments, R5is fluoro, In someembodiments, R5is. In some embodiments, R5is.

[0260] In some embodiments, R5is selected from those depicted in Table 1, below.

[0261] As defined generally above, two R2groups are optionally taken together to form =0.

[0262] In some embodiments, two R2groups are taken together to form =0.

[0263] As defined generally above, two R4groups are optionally taken together to form =0.

[0264] In some embodiments, two R4groups are taken together to form =0.

[0265] As defined generally above, two R5groups are optionally taken together to form =0.

[0266] In some embodiments, two R5groups are taken together to form =0.

[0267] As defined generally above, two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0268] In some embodiments, two R2groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0269] As defined generally above, two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0270] In some embodiments, two R4groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0271] In some embodiments, two R5groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0272] In some embodiments, Rzis an optionally substituted group selected from Ci-6 aliphatic; phenyl; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Rzis selected from those depicted in Table 1, below.

[0273] In some embodiments, R3is hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R,-CF3, -CR2(OR),-CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN. In some embodiments, R3is an optionally substituted selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R3is methyl. In some embodiments, R3is ethyl. In some embodiments, R3is chloro. In someembodiments, R3is . In some embodiments, R3is . In some embodiments, R3

[0274] In some embodiments, R3is -CF3. In some embodiments, R3issome embodiments, R3isIn some embodiments, R3is. In some embodiments, two R3groups are taken together to form =0. In some embodiments, two R3groups are taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0275] In some embodiments, two R3groups are taken together with their interveningatoms to formIn some embodiments, two R3groups are taken together with theirintervening atoms to form

[0276] In some embodiments, R3is selected from those depicted in Table 1, below.

[0277] In some embodiments, L1is a C1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, — S(O)—, or -S(O)2- In some embodiments, L1is a covalent bond. In someembodiments, L1isIn some embodiments, L1isIn some embodiments,L1is In some embodiments, L1isIn some embodiments, L1isIn some embodiments, L1isIn some embodiments, L1isIn some embodiments, L1is In some embodiments,In some embodiments, L1isembodiments, L1isIn some embodiments, L1is. In some H o embodiments,L1is0. In some embodiments, L1is O

[0278] In some embodiments, L1is selected from those depicted in Table 1, below.

[0279] In some embodiments, L2is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, — S(O)—, or -S(O)2- In some embodiments, L2is a covalent bond. In someembodiments, L2is. In some embodiments, L2is. In some embodiments,L2is. In some embodiments, L2is. In some embodiments, L2is0. In some embodiments, L2isf 0'. In some embodiments, L2isIn some embodiments, L2is. In some embodiments, L2is. In someembodiments, L2is In some embodiments, L2is In some embodiments, HO^L2is ' '.

[0280] In some embodiments, L2is selected from those depicted in Table 1, below.

[0281] In some embodiments, L3is a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2--N(R)-, -S-, — S(O)—, or -S(O)2- In some embodiments, L3is a covalent bond. In someembodiments, L3is'0'. In some embodiments, L3is0. In someO Oembodiments, L3isH. In some embodiments, L3isH. In someembodiments,L3is.

[0282] In some embodiments, L3is selected from those depicted in Table 1, below.

[0283] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from Ci-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same nitrogen are taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is selected from those depicted in Table 1, below.

[0284] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, is selected from those depicted in Table 1, below. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is selected from those depicted in Table 1, below. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is selected from those depicted in Table 1, below. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 3. In some embodiments, q is 4. In some embodiments, q is selected from those depicted in Table 1, below.

[0285] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is oxetanyl, to provide a compound of formula I-1-a-1*, I-1-a-2*, or I-1-a-3*:I-1-a-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0286] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is furanyl, to provide a compound of formula I-1-b-1*, I-1-b-2*, or I-1-b-3*:I-1-b-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0287] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is tetrahydropyranyl, to provide a compound of Formula I-1-c-1*, I-1-c-2*, or I-l-c-3*:I-1-c-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0288] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyridone, two R3groups are taken together to form =0, and Ring C is 1,4-dioxanyl, to provide a compound of formula I-1-d-1*, I-1-d-2*, or I-1-d-3*:I-1-d-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0289] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; and two R3groups are taken together to form =0; to provide a compound of Formula I-1-e-1*, I-1-e-2*, or I-1-e-3*:I-1-e-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0290] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L1is J == J; Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; and two R3groups are taken together to form =0; to provide a compound of formula I-1-f-1*, I-I-1-f-2*or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0291] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is oxetanyl; to provide a compound of formula I-1-g-1*, I-1-g-2*, or I-1-g-3*:I-1-g-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0292] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is furanyl, to provide a compound of fFormula I-1-h-1*, I-1-h-2*, or I-1-h-3*:I-1-h-1* I-1-h-2*I-1-h-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0293] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is tetrahydropyranyl; to provide a compound of formula I-1-i-1*, I-1-i-2*, or I-1-i-3*:I-1-i-1* I-1-i-2*I-1-i-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0294] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyridone; two R3groups are taken together to form =0; and Ring C is 1,4-dioxanyl; to provide a compound of Formula I-1-j-1*, I-1-j-2*, or I-1-j-3*:I-1-j-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0295] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is oxetanyl, to provide a compound of formula II-l-a-1*, II-1-a-2*, or II-1-a-3*:II-1-a-2*II-1-a-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0296] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form=0, and Ring C is furanyl, to provide a compound of formula II-l-b-1*, II-l-b-2*, or II-1-b-3*:II-1-b-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0297] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is tetrahydropyranyl, to provide a compound of Formula II-l-c-1*, II-l-c-2*, or II-1-c-3*:II-1-c-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0298] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L3is -OCH2-, Ring B is pyrimidone, two R3groups are taken together to form =0, and Ring C is 1,4-dioxanyl, to provide a compound of Formula II-l-d-1*, II-l-d-2*, or II-1-d-3*:II-1-d-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring A, L1, L2, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0299] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; and two R3groups are taken together to form =0; to provide a compound of Formula II-l-e-1*, II-l-e-2*, or II-1-e-3*:II-1-e-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0300] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein L1is ’ ’; Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; and two R3groups are taken together to form =0; to provide a compound of Formula II-1-f- 1*, II-1-f-2*, or II-1-f-3*:II-1-f-3*or a pharmaceutically acceptable salt thereof, wherein each of Ring C, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0301] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is oxetanyl; to provide a compound of Formula II-l-g-1*, II-l-g-2*, orII-1-g-3*:II-1-g-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0302] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is furanyl, to provide a compound of Formula II-1-h- 1*, II-l-h-2*, or II-1-h-3*:II-1-h-1*(R2)mII-1-h-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0303] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups are taken together to form =0; and Ring C is tetrahydropyranyl; to provide a compound of Formula II-1-II-1*, II-1-II-2*, or II-1-II-3*II-1-II-1*II-1-II-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0304] In some embodiments, the present invention provides a compound of Formula 1-1-1*, wherein Ring A is phenyl, thiophenyl, or pyridyl; Ring B is pyrimidone; two R3groups aretaken together to form =0; and Ring C is 1,4-dioxanyl; to provide a compound of Formula II- 1-j-l*, II-1-j-2*, or II-1-j-3*:II-1-j-3*or a pharmaceutically acceptable salt thereof, wherein each of L1, L2, L3, R1, R2, R3, R4, m, and p is as defined above and described in embodiments herein, both singly and in combination.

[0305] Exemplary compounds of the invention are set forth in Table 1, below. In certain embodiments, the compound is selected from those disclosed in Table 1, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 1, below.Table 1. Selected CompoundsCompoundStructure No.1-1-2210 -1-1-222zZ-0z / —T / o / =1-1-223 oO_ _ o o0 -1-1-2241-1-22511-1-276 1 jfj 11Enantiomer I1-1-277 A 1 JOT 11Cr°^Enantiomer IICompoundStructureNo.0 - 1-1-2780 - 1-1-279o Il JO 1-1-280f f YY. N. _ A / 1-1-2960 - 1-1-297 A rci\7 0 - 1-1-298CroJ^ \ - 0 - 1-1-299u0 - 1-1-300 0^OJOOOCompoundStructureNo.1-1-3011-1-302o - 1-1-3030 - 1-1-3040=1-1-316NHMe l^N O O1-1-3170 - 1-1-318\7 OH1-1-319< >< O N JCompoundStructure No.011-1-320 / 1-1-321 = Zz^ 2 o o zZ- 2 / °== - 1-1-322 o op zb0E1-1-3231-1-324o1-1-325 Cr°^ V % 1-1-326 Cr°^ V x 1-1-327CompoundStructureNo.OH1-1-328< 0 N0 - 1-1-3290 - 1-1-3460T1-1-346 r0 - 1-1-3471-1-348.^XdCL>70E1-1-349s>.rXccLNJ>70E1-1-350 _N^0jiooL^7CompoundStructureNo.1-1-3510 -1-1-352V1-1-3531-1-3541-1-355(VV6XVNH \Z o -1-1-356>7 0 -1-1-357r v 0 -1-1-358^7CompoundStructureNo.1-1-359'N>71-1-360Z z=4zV fj-zZ~o o o o ^ 2 °=1-1-361 o C C 4 Co°=°° / / / Zz z z z / / / / fa1-1-3621-1-3631-1-3641-1-3651-1-376IllCompoundStructureNo.1-1-377o - 1-1-378s 71-1-379 ^rA A ^0 - 1-1-3800T °^v 1-1-381-V A A / 1-1-382s - 1-1-3830 - 1-1-384 A AF FCompoundStructureNo.o =1-1-385F1-1-386o =1-1-387CroJ^ °\,0 zo1-1-38801-1-389o =1-1-390N^ XOOC1-1-391CompoundStructure No.o =1-1-3920E1-1-393ZpXooL 0 - 1-1-3940T1-1-395 H2N^OZO0L 0 - 1-1-396

[0306] In certain embodiments, the compound is compound I-1-393 or a pharmaceutically acceptable salt thereof:(I-1-393). In certain embodiments, the compound is compound I-1-39.

[0307] In certain embodiments, the compound is a compound described in international patent application WO 2022 / 167445, the contents of which are hereby incorporated by reference. Compounds described herein above may be prepared according to, or based on, procedures described in WO 2022 / 167445.Part B: Second Set of GPR84 Antagonist Compounds

[0308] In certain aspects, the methods described here comprise the administration of a compound of Formula I-2 to a patient in need thereof. In certain embodiments, the compound is a compound of the following Formula I-2:1-2or a pharmaceutically acceptable salt thereof, wherein:R1is -O-(C1-5alkylene)-Z1or Y1;R2represents independently for each occurrence C 1-4 alkyl or Y2;R3is one of the following:(a) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl;(b) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or(c) Y3;R4represents independently for each occurrence hydrogen or methyl;R5and R8each represent independently for each occurrence halo, C1-4 alkyl, C1-4haloalkyl, Ci- 4 alkoxyl, or C3-6 cycloalkyl;R6and R9each represent independently for each occurrence hydrogen or C1-4 alkyl;R7is C2-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8- 11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl;A1is phenylene, pyridinylene, or piperidinylene, each of which is substituted with q occurrences of R8; or A1is Y4;X1is O or S;Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R4)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R5;Z2is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Z3is hydroxyl, C1-4 alkoxyl, -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic);L1is C1-4 alkylene, C3-4 haloalkylene, Ci-4hydroxyalkylene, cyclopropylene, or Y5;Y1is one of the following:(a) -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;(b) -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2;(c) -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or(d) -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5;Y2represents independently for each occurrence C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl; Y3is one of the following:(a) -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,C=t^, -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)- (C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl;(b) -O-(C1-8alkylene)-Z3or hydroxyl; or(c) -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;Y4is -C=C-, cyclohexylene,, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2;Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-; andm, n, p, and q represent independently 0, 1, or 2;wherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5.

[0309] The definitions of variables in Formula I-2 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).

[0310] In certain embodiments, the compound is a compound of Formula I-2.

[0311] As defined generally above, R1is -O-(C1-5alkylene)-Z1or Y1. In some embodiments, R1is -O-(C1-5alkylene)-Z1. In some embodiments, R1is Y1. In someembodiments, R1is -O-(C1-3alkylene)-Z1or Y1. In some embodiments, R1is -O-(C3-5alkylene)-Z1or Y1. In some embodiments, R1is -OCH2-Z1or Y1. In some embodiments, R1is -O-(C1-3alkylene)-Z1. In some embodiments, R1is -O-(C3-5alkylene)-Z1. In some embodiments, R1is -OCH2-Z1.

[0312] In some embodiments R1isIn someembodiments R1isIn some embodiments R1is

[0313] In some embodiments, R1is selected from those disclosed in Table 2 below.

[0314] As defined generally above, R2represents independently for each occurrence Ci-4 alkyl or Y2. In some embodiments, R2represents independently for each occurrence Ci-4 alkyl. In some embodiments, R2represents independently for each occurrence Y2. In some embodiments, R2represents independently for each occurrence C1-2 alkyl or Y2. In some embodiments, R2represents independently for each occurrence C1-2 alkyl. In some embodiments, R2is methyl. In some embodiments R2is ethyl. In some embodiments, R2is propyl. In some embodiments, R2is isopropyl. In some embodiments, R2is butyl. In some embodiments, R2is isobutyl. In some embodiments, R2is Y2, and Y2represents independently for each occurrence C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl. In some embodiments, R2is Y2, and Y2represents independently for each occurrence C1-4 haloalkyl or Ci-4 alkoxyl. In some embodiments, R2is Y2, and Y2represents independently for each occurrence C3-6 cycloalkyl.

[0315] In some embodiments, R2is selected from those disclosed in Table 2 below.

[0316] As defined generally above, R3is one of the following:(a) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl;(b) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or(c) Y3.

[0317] In some embodiments, R3is one of the following:(a) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl; or(b) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0318] In some embodiments, R3is one of the following:• -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), - (phenylene)-(C3-6 cycloalkyl), or -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl); or• -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0319] In some embodiments, R3is -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkylene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl. In some embodiments, R3is -(C2-4 alkynylene)-(C3-6 cycloalkyl). In some embodiments, R3is -C=C-(C3-6 cycloalkyl). In some embodiments, R3is -(C2-4 alkynylene)-(cyclopropyl). In some embodiments, R3is -(C2-4 alkenylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(Co-4 alkylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(phenylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl). In some embodiments, R3is -C=C-(Ci-4 alkyl). In some embodiments, R3is C1-6 alkyl.

[0320] In some embodiments, R3is-C(H)=C(H)-(cyclopropyl), -(C0-2 alkylene)-(cyclopropyl), -(phenylene)-(cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl), or -C=C-(Ci-4 alkyl). In some embodiments, R3is. In some embodiments, R3is -C(H)=C(H)-(cyclopropyl). In some embodiments, R3is -(C0-2 alkylene)-(cyclopropyl). In some embodiments, R3is -(phenylene)-(cyclopropyl). In some embodiments, R3is -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl). In some embodiments, R3is -C=C-(C 1-4 alkyl). In some embodiments, R3is Ci-6 alkoxyl, C1-6 haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3is Ci-6 alkoxyl. In some embodiments, R3is Ci-6 haloalkoxyl. In some embodiments, R3is -0-(Co-6 alkylene)-phenyl. In some embodiments, R3is -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3is Y3. In some embodiments, R3is Y3, and Y3is -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4haloalkyl, and hydroxyl). In some embodiments, R3is Y3,and Y3is -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,C=C^, or C1-4 haloalkyl. In some embodiments, R3is Y3, and Y3is -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)-(C1-4 haloalkyl), or -(phenylene)-(Ci-4 haloalkyl). In some embodiments, R3is Y3, and Y3is -O-(Ci-8alkylene)-Z3or hydroxyl.

[0321] In some embodiments, R3is selected from those depicted in Table 2.

[0322] As defined generally above, R4represents independently for each occurrence hydrogen or methyl. In some embodiments, R4is hydrogen. In some embodiments, R4is methyl. In some embodiments, R4is selected from those depicted in Table 2.

[0323] As defined generally above, R5and R8each represent independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R5represents independently for each occurrence halo, C1-4 alkyl, C 1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R5represents independently for each occurrence halo. In some embodiments, R5represents independently for each occurrence C1-4 alkyl. In some embodiments, R5represents independently for each occurrence C 1-4 haloalkyl. In some embodiments, R5represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R5represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R5represents independently for each occurrence methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. In some embodiments, R5represents independently for each occurrence methoxy, chloro, fluoro, or trifluoromethyl. In some embodiments, R5represents independently for each occurrence chloro, fluoro, or trifluoromethyl. In some embodiments, R5represents independently for each occurrence methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R5represents independently for each occurrence methyl, ethyl, or isopropyl.

[0324] In some embodiments, R5is methoxy. In some embodiments, R5is chloro. In some embodiments, R5is fluoro. In some embodiments, R5is methyl. In some embodiments, R5isethyl. In some embodiments, R5is isopropyl. In some embodiments, R5is cyclopropyl. In some embodiments, R5is trifluoromethyl.

[0325] In some embodiments, R5is independently for each occurrence selected from those depicted in Table 2.

[0326] As defined generally above, R6and R9each represent independently for each occurrence hydrogen or Ci-4 alkyl. In some embodiments, R6represents independently for each occurrence hydrogen or Ci-4 alkyl. In some embodiments, R6represents independently for each occurrence Ci-4 alkyl. In some embodiments, R6is hydrogen. In some embodiments, R6represents independently for each occurrence methyl or hydrogen. In some embodiments, R6is methyl. In some embodiments R6is selected from those depicted in Table 2.

[0327] As defined generally above, R7is C2-6 alkyl, C1-4haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl.

[0328] In some embodiments, R7is C3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl.

[0329] In some embodiments, R7is C2-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl.

[0330] In some embodiments, R7is C2-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are takentogether with the nitrogen atom to which they are attached to form an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and Ci-4 alkyl.

[0331] In some embodiments, R7is C2-6 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said cycloalkyl and heterocyclic ring are substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7is C2-6 alkyl. In some embodiments, R7is C2-4 alkyl. In some embodiments, R7is C1-4 haloalkyl. In some embodiments, R7is C1-2 haloalkyl. In some embodiments, R7is C3-6 cycloalkyl substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7is C3-6 cycloalkyl. In some embodiments, R7is cyclopropyl. In some embodiments, R7is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said ring is substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7is a 4-6 membered saturated monocyclic heterocyclic ring having 1 nitrogen or oxygen atom; wherein said ring is substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R7is a 4-6 membered saturated monocyclic heterocyclic ring having 1 nitrogen or oxygen atom.

[0332] In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein each ring is substituted with p substituents independently selected from halo and C1-4 alkyl.

[0333] In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom; wherein said ring is substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring containing 1 nitrogen atom; wherein said ring is substituted with p substituents independently selected from halo and C1-4 alkyl. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form a 3-7 membered ringcontaining 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form a 5-6 membered saturated ring containing 1 nitrogen atom. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said ring is substituted with p substituents independently selected from halo and Ci-4 alkyl. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form an 8-11 membered saturated spirocyclic ring containing 2 nitrogen atoms; wherein said ring is substituted with p substituents independently selected from halo and Ci-4 alkyl. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form an 8-11 membered spirocyclic ring containing 2 nitrogen atoms. In some embodiments, R7and R6are taken together with the nitrogen atom to which they are attached to form an 8-11 membered saturated spirocyclic ring containing 2 nitrogen atoms.

[0334] In some embodiments, R7is selected from those depicted in Table 2.

[0335] As defined generally above, R5and R8each represent independently for each occurrence halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R8represents independently for each occurrence halo, C1-4 alkyl, C 1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl.

[0336] In some embodiments, R8represents independently for each occurrence halo. In some embodiments, R8represents independently for each occurrence C1-4 alkyl. In some embodiments, R8represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R8represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R8represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R8represents independently for each occurrence methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. In some embodiments, R8represents independently for each occurrence methoxy, chloro, fluoro, or trifluoromethyl. In some embodiments, R8represents independently for each occurrence chloro, fluoro, or trifluoromethyl. In some embodiments, R8represents independently for each occurrence methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R8represents independently for each occurrence methyl, ethyl, or isopropyl.

[0337] In some embodiments, R8is methoxy. In some embodiments, R8is chloro. In some embodiments, R8is fluoro. In some embodiments, R8is methyl. In some embodiments, R8is ethyl. In some embodiments, R8is isopropyl. In some embodiments, R8is cyclopropyl. In some embodiments, R8is trifluoromethyl.

[0338] In some embodiments, R8is independently for each occurrence selected from those depicted in Table 2.

[0339] As defined generally above, R6and R9each represent independently for each occurrence hydrogen or Ci-4 alkyl. In some embodiments, R9represents independently for each occurrence hydrogen or Ci-4 alkyl. In some embodiments, R9represents independently for each occurrence Ci-4 alkyl. In some embodiments, R9is hydrogen. In some embodiments, R9represents independently for each occurrence methyl or hydrogen. In some embodiments, R9is methyl. In some embodiments R9is selected from those depicted in Table 2.

[0340] As defined generally above, A1is phenylene, pyridinylene, or piperidinylene, each of which is substituted with q occurrences of R8; or A1is Y4.

[0341] In some embodiments, A1is phenylene, pyridinylene, or piperidinylene, each of which is substituted with q occurrences of R8. In some embodiments, A1is pyridinylene or piperidinylene, each of which is substituted with q occurrences of R8. In some embodiments, A1is Y4.

[0342] In some embodiments, A1is phenylene substituted with q occurrences of R8. In some embodiments, A1is pyridinylene substituted with q occurrences of R8. In some embodiments, A1is piperidinylene substituted with q occurrences of R8. In some embodiments, A1is phenylene substituted with 1 occurrence of R8. In some embodiments, A1is pyridinylene substituted with 1 occurrence of R8. In some embodiments, A1is piperidinylene substituted with 1 occurrence of R8. In some embodiments, A1is phenylene. In some embodiments, A1is pyridinylene. In some embodiments, A1is piperidinylene.

[0343] In some embodiments, A1is Y4, and Y4is -C=C-, cyclohexylene,oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl,or -N(R6)2. In some embodiments, A1is Y4, and Y4is -C=C-, cyclohexylene,, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl,or -N(R6)2. In some embodiments, A1is Y4, and Y4isoxazolylene, pyridazinylene, azetidinylene, or pyrrolidinylene.

[0344] In some embodiments, A1is orIn some embodiments,

[0345] In some embodiments, A1is selected from those depicted in Table 2.

[0346] As defined generally above, X1is O or S. In some embodiments X1is O. In some embodiments X1is S. In some embodiments, X1is selected from those depicted in Table 2.

[0347] As defined generally above, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R4)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R5.

[0348] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl and heterocyclic rings are substituted with n occurrences of R5.

[0349] In some embodiments, Z1is phenyl or -C(O)N(R4)2; wherein the phenyl ring is substituted with n occurrences of R5.

[0350] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R5.

[0351] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroarylis substituted with n occurrences of R5. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heterocyclic ring is substituted with n occurrences of R5. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocyclic ring is substituted with n occurrences of R5. In some embodiments, Z1is phenyl; wherein the phenyl is substituted with n occurrences of R5. In some embodiments, Z1is -C(O)N(R4)2. In some embodiments, Z1is -C(O)N(CH3)2.

[0352] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z1is phenyl.

[0353] In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms; wherein the heteroaryl is substituted with n occurrences of R5. In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms. In some embodiments, Z1is pyrimidinyl. In some embodiments, Z1is pyrimidin-2-yl.

[0354] In some embodiments, Z1is selected from those depicted in Table 2.

[0355] As defined generally above, Z2is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0356] In some embodiments, Z2is a 5-6 membered heteroaryl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z2is a 5-6 membered heteroaryl having 2 or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0357] In some embodiments, Z2is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z2is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms. In some embodiments, Z2is a 5-membered heteroaryl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z2is pyridinyl. In some embodiments, Z2is a 5-membered heteroaryl having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z2is a 6-membered heteroaryl having 2 nitrogen atoms. In some embodiments, Z2is pyrimidinyl. In some embodiments, Z2is pyrimidin-2-yl.

[0358] In some embodiments, Z2is selected from those depicted in Table 2.

[0359] As defined generally above, Z3is hydroxyl, Ci-4 alkoxyl, -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic).

[0360] In some embodiments, Z3is hydroxyl, Ci-4 alkoxyl, -N(R9)2, or -C(O)N(R9)2. In some embodiments, Z3is hydroxyl or Ci-4 alkoxyl. In some embodiments, Z3is -N(R9)2 or -C(O)N(R9)2.

[0361] In some embodiments, Z3is Ci-4 alkoxyl, -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic).

[0362] In some embodiments, Z3is -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic).

[0363] In some embodiments, Z3is hydroxyl. In some embodiments, Z3is Ci-4 alkoxyl. In some embodiments, Z3is methoxy. In some embodiments, Z3is -N(R9)2. In some embodiments, Z3is -N(CH3)2. In some embodiments, Z3is -C(O)N(R9)2. In some embodiments, Z3is a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic). In some embodiments, Z3is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0364] In some embodiments, Z3is selected from those depicted in Table 2.

[0365] As defined generally above, L1is Ci-4 alkylene, C3-4 haloalkylene, C1-4 hydroxyalkylene, cyclopropylene, or Y5.

[0366] In some embodiments, L1is C1-4 alkylene, C3-4 haloalkylene, Ci-4hydroxyalkylene, or cyclopropylene. In some embodiments, L1is C1-4 alkylene, C3-4 haloalkylene, or C1-4 hydroxyalkylene. In some embodiments, L1is C3-4 haloalkylene, C1-4 hydroxyalkylene, or cyclopropylene.

[0367] In some embodiments, L1is C1-4 alkylene. In some embodiments, L1is C1-2 alkylene. In some embodiments, L1is -C(H)(CH3)-. In some embodiments, L1is C3-4 haloalkylene. In some embodiments, L1is C1-4 hydroxyalkylene. In some embodiments, L1is C1-2 hydroxyalkylene. In some embodiments, L1is cyclopropylene. In some embodiments, L1is Y5.

[0368] In some embodiments, L1is Y5, and Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-.

[0369] In some embodiments, L1is selected from those depicted in Table 2, below.

[0370] As defined generally above, Y1is one of the following:(a) -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;(b) -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2; (c) -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or(d) -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0371] In some embodiments, Y1is one of the following:(a) -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;(b) -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2; or (c) -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5.

[0372] In some embodiments, Y1is one of the following:• -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;• -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2; or• -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0373] In some embodiments, Y1is one of the following:• -O-(C1-5alkylene)-C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(C1-5alkylene)-CO2R6;• -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or• -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0374] In some embodiments, Y1is one of the following:• -O-(C1-5haloalkylene)-N(R6)2, -O-(C1-5alkylene)-(C3-6cycloalkylene)-N(R6)2, or -O-(C1-5alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2;• -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or• -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0375] In some embodiments, Y1is one of the following:• -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or• -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0376] In some embodiments, Y1is -O-(Ci-s alkylene)-C(O)N(R6)(R7), -O-(Ci-s alkylene)-SO2N(R6)2, or -O-(Ci-s alkylene)-CO2R6. In some embodiments, Y1is -O-(Ci-s alkylene)-C(O)N(R6)(R7). In some embodiments, Y1is -OCH2-C(O)N(R6)(R7), -OCH2-SO2N(R6)2, or -OCH2-CO2R6. In some embodiments, Y1is -OCH2-C(O)N(R6)(R7).

[0377] In some embodiments, Y1is -O-(Ci-s haloalkylene)-N(R6)2, -O-(Ci-5 alkylene)-(C3-6 cycloalkylene)-N(R6)2, or -O-(Ci-s alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2. In some embodiments, Y1is -OCH2-N(R6)2, -OCH2-(C3-6 cycloalkylene)-N(R6)2, or -OCH2-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2.

[0378] In some embodiments, Y1is -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5.

[0379] In some embodiments, Y1is -O-(Ci-s alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(CI-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

[0380] In some embodiments, Y1is selected from those depicted in Table 2.

[0381] As defined generally above, Y2represents independently for each occurrence C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl. In some embodiments, Y2represents independently for each occurrence C1-3 haloalkyl or C1-3 alkoxyl.

[0382] In some embodiments, Y2represents independently for each occurrence C1-4 haloalkyl. In some embodiments, Y2is trifluoromethyl. In some embodiments, Y2represents independently for each occurrence C1-4 alkoxyl. In some embodiments, Y2is methoxy. In some embodiments, Y2represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, Y2is cyclopropyl. In some embodiments, Y2is independently for each occurrence selected from those depicted in Table 2.

[0383] As defined generally above, Y3is one of the following:(a) -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,C=C structure (image), -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)- (C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl;(b) -O-(C1-8alkylene)-Z3or hydroxyl; or(c) -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0384] In some embodiments, Y3is one of the following:(a) -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,C=C structure (image), -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)- (C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl; or(b) -O-(C1-8alkylene)-Z3or hydroxyl.

[0385] In some embodiments, Y3is one of the following:• -O-(Ci-8 alkylene)-Z3or hydroxyl; or• -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0386] In some embodiments, Y3is one of the following:-(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-s aliphatic), -C=C-CN,^^1, -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)- (C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl; or• -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0387] In some embodiments, Y3is -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,-(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)-(Ci-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl. In someembodiments, Y3is -C=C-C=C-(Ci-5 aliphatic), -C=C-CN,or C 1-4 haloalkyl. In some embodiments, Y3is -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), -(C3-6 cycloalkylene)-(Ci-4 haloalkyl), or -(phenylene)-(Ci-4 haloalkyl).

[0388] In some embodiments, Y3is -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl). In some embodiments, Y3is -C=C-C=C-(Ci-s aliphatic). In some embodiments, Y3is -C=C-CN. Insome embodiments, Y3is. In some embodiments, Y3is -(C3-6 cycloalkylene)-(C3- 6 cycloalkyl). In some embodiments, Y3is -(C3-6 cycloalkylene)-(Ci-4 haloalkyl). In some embodiments, Y3is -(phenylene)-(Ci-4 haloalkyl). In some embodiments, Y3is C 1-4 haloalkyl.

[0389] In some embodiments, Y3is -O-(Ci-8 alkylene)-Z3or hydroxyl. In some embodiments, Y3is -O-(Ci-8 alkylene)-Z3. In some embodiments, Y3is hydroxyl.

[0390] In some embodiments, Y3is -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), or-N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Y3is -N(R9)2. In some embodiments, Y3is -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl).In some embodiments, Y3is -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0391] In some embodiments, Y3is selected form those depicted in Table 2.

[0392] As defined generally above, Y4is -C=C-, cyclohexylene,oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2.

[0393] In some embodiments, Y4is cyclohexylene,, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2.

[0394] In some embodiments, Y4is, oxazolylene, pyridazinylene, azetidinylene, or pyrrolidinylene. In some embodiments, Y4is -C=C-, cyclohexylene,, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2.

[0395] In some embodiments, Y4is -C=C-. In some embodiments, Y4is cyclohexylene. Insome embodiments, Y4is. In some embodiments, Y4issome embodiments, Y4is. In some embodiments, Y4is oxazolylene. In some embodiments, Y4is pyridazinylene. In some embodiments, Y4is azetidinylene. In some embodiments, Y4is pyrrolidinylene. In some embodiments, Y4is phenylene substituted with 1 cyano, hydroxyl, or -N(R6)2.

[0396] In some embodiments, Y4is selected from those depicted in Table 2.

[0397] As defined generally above, Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-. In some embodiments, Y5is C2-4alkenylene or C1-2 haloalkylene. In some embodiments, Y5is C1-2 haloalkylene or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-. In some embodiments, Y5is C2-4 alkenylene or -(C 1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-.

[0398] In some embodiments, Y5is C2-4 alkenylene. In some embodiments, Y5is C1-2 haloalkylene. In some embodiments, Y5is -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-. In some embodiments, Y5is selected from those depicted in Table 2.

[0399] As defined generally above, m, n, p, and q represent independently 0, 1, or 2.

[0400] In some embodiments, m, n, p, and q represent independently 1, or 2. In some embodiments, m, n, p, and q represent independently 0 or 1. In some embodiments, m, n, p, and q represent independently 0 or 2.

[0401] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments m is selected from those depicted in Table 2.

[0402] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments n is selected from those depicted in Table 2.

[0403] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments p is selected from those depicted in Table 2.

[0404] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments q is selected from those depicted in Table 2.

[0405] As defined generally above, the compound of formula 1-2 contains at least one occurrence of Y1, Y2, Y3, Y4, or Y5. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y2, Y3, Y4, or Y5. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y1, Y3, Y4, or Y5. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y1, Y2, Y4, or Y5. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y1, Y2, Y3, or Y5. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y1, Y2, Y3, or Y4.

[0406] In some embodiments, the compound of formula 1-2 contains Y1. In some embodiments, the compound of formula 1-2 contains at least one occurrence of Y2. In someembodiments, the compound of formula 1-2 contains Y3. In some embodiments, the compound of formula 1-2 contains Y4. In some embodiments, the compound of formula 1-2 contains Y5.

[0407] In some embodiments, the present invention provides a compound of formula I-2-aor a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, L1, and A1is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula I-2-a.

[0408] In some embodiments, the present invention provides a compound of formula I-2-b, I-2-c, or I-2-d:I-2-b I-2-c I-2-d or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, A1, Y1, Y3, and Y4is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula I-2-b, I-2-c, or I-2-d.

[0409] In some embodiments, the present invention provides a compound of formula 1-2-c-1, I-2-c-2, I-2-d-1, or I-2-d-2:or a pharmaceutically acceptable salt thereof, wherein each of R3, A1, Y3, and Y4is as defined above and described in embodiments herein, both singly and in combination. In someembodiments, the compound is a compound of formula I-2-c-1, I-2-c-2, I-2-d-1, or I-2-d-2.

[0410] In some embodiments, the present invention provides a compound of formula I-2-b-1, I-2-b-2, I-2-d-3, or I-2-d-4:I-2-d-3 I-2-d-4or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Y1, and Y3is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula I-2-b-1, I-2-b-2, I-2-d-3, or I-2-d-4.

[0411] In some embodiments, the present invention provides a compound of formula I-2-b-3 or I-2-c-3:I-2-b-3 I-2-c-3or a pharmaceutically acceptable salt thereof, wherein each of R1, A1, Y1, and Y4is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula I-2-b-3 or I-2-c-3.

[0412] The description above describes multiple embodiments relating to compounds of formula I-2. The patent application specifically contemplates all combinations of the embodiments.

[0413] As described above, in certain embodiments, the present invention provides a compound of formula II-2:II-2or a pharmaceutically acceptable salt thereof, wherein:R1is -(C2-4 alkynylene)-(C3-6 cycloalkyl);R2represents independently for each occurrence C1-4 alkyl, C1-4haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;R3is one of the following:(a) hydrogen;(b) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl; or(c) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur);R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;A1is phenylene or a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said phenylene and heteroarylene are substituted with n occurrences of R4;X1is O or S;L1is C1-4 alkylene, C1-4haloalkylene, Ci-4hydroxyalkylene, or cyclopropylene; and m and n represent independently 0, 1, or 2.

[0414] The definitions of variables in formula II-2 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).

[0415] In certain embodiments, the compound is a compound of formula II-2.

[0416] As defined generally above, R1is -(C2-4 alkynylene)-(C3-6 cycloalkyl). In someembodiments, R1is -C=C-(C3-6 cycloalkyl). In some embodiments, R1is==. In some embodiments, R1is selected from those depicted in Table 3, below.

[0417] As defined generally above, R2represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In someembodiments, R2represents independently for each occurrence C1-4 alkyl or C1-4haloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or Ci-4alkoxyl.

[0418] In some embodiments, R2represents independently for each occurrence C1-4 alkyl. In some embodiments, R2is methyl. In some embodiments, R2represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R2is trifluoromethyl. In some embodiments, R2represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R2is methoxy. In some embodiments, R2represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is selected from those depicted in Table 3, below.

[0419] As defined generally above, R3is one of the following:(a) hydrogen;(b) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl; or(c) C1-6 alkoxyl, Ci-ehaloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0420] In some embodiment, R3is hydrogen. In some embodiments, R3is one of the following:• -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(Ci-4 alkyl), or C1-6 alkyl; or• C1-6 alkoxyl, C1-6 haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0421] In some embodiments, R3is -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkylene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(C 1-4 alkyl), or C1-6 alkyl.

[0422] In some embodiments, R3is -(C2-4 alkynylene)-(C3-6 cycloalkyl). In some embodiments, R3is -C=C-(C3-6 cycloalkyl). In some embodiments, R3is -(C2-4 alkynylene)-(cyclopropyl). In some embodiments, R3is -(C2-4 alkenylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(C0-4 alkylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(phenylene)-(C3-6 cycloalkyl). In some embodiments, R3is -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl). In some embodiments, R3is -C=C-(Ci-4 alkyl). In some embodiments, R3is C1-6 alkyl.

[0423] In some embodiments, R3is<^, -C(H)=C(H)-(cyclopropyl), -(C0-2 alkylene)-(cyclopropyl), -(phenylene)-(cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl), or -C=C-(Ci-4 alkyl). In some embodiments, R3is j — <1?. In some embodiments, R is -C(H)=C(H)-(cyclopropyl). In some embodiments, R3is -(C0-2 alkylene)-(cyclopropyl). In some embodiments, R3is -(phenylene)-(cyclopropyl). In some embodiments, R3is -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl). In some embodiments, R3is -C=C-(Ci-4 alkyl).

[0424] In some embodiments, R3is C1-6 alkoxyl, C1-6 haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R3is C1-6 alkoxyl. In some embodiments, R3is C1-6 haloalkoxyl. In some embodiments, R3is -0-(Co-6 alkylene)-phenyl. In some embodiments, R3is -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0425] In some embodiments, R3is -C=C-(C3-6 cycloalkyl). In some embodiments, R1is — <1s. In some embodiments, R is selected from those depicted in Table 3, below.

[0426] As defined generally above, R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R4represents independently for each occurrence halo. In some embodiments, R8represents independently for each occurrence C1-4 alkyl. In some embodiments, R4represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R4represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R4represents independently for each occurrence C3-6 cycloalkyl.

[0427] In some embodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. In someembodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, or isopropyl.

[0428] In some embodiments, R4is methoxy. In some embodiments, R4is chloro. In some embodiments, R4is fluoro. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is isopropyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is trifluoromethyl. In some embodiments, R4is selected from those depicted in Table 3, below.

[0429] As defined generally above, A1is phenylene or a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said phenylene and heteroarylene are substituted with n occurrences of R4.

[0430] In some embodiments, A1is phenylene substituted with n occurrences of R4. Insome embodiments, A1is phenylene. In some embodiments, A1is XX A

[0431] In some embodiments, A1is a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said phenylene and heteroaryl are substituted with n occurrences of R4. In some embodiments, A1is a 5-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said heteroarylene is substituted with n occurrences of R4. In some embodiments, A1is a 6-membered heteroarylene having 1, 2, or 3 nitrogen, atoms; wherein said heteroarylene is substituted with n occurrences of R4. In some embodiments, A1is pyridinylene or pyrimidinylene, each of which is substituted with n occurrences of R4.

[0432] In some embodiments, A1is a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 5-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 6-membered heteroarylene having 1, 2, or 3 nitrogen, atoms. In some embodiments, A1is pyridinylene or pyrimidinylene.

[0433] In some embodiments, A1is selected from those depicted in Table 3, below.

[0434] As defined generally above, X1is O or S. In some embodiments, X1is O. In some embodiments, X1is S. In some embodiments, X1is selected from those depicted in Table 3, below.

[0435] As defined generally above, L1is Ci-4 alkylene, Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene. In some embodiments, L1is Ci-4 alkylene, Ci-4 haloalkylene, or Ci-4 hydroxyalkylene. In some embodiments, L1is Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene.

[0436] In some embodiments, L1is Ci-4 alkylene. In some embodiments, L1is C1-2 alkylene. In some embodiments, L1is -C(H)(CH3)-. In some embodiments, L1is C1-4 haloalkylene. In some embodiments, L1is C1-2 haloalkylene. In some embodiments, L1is -C(H)(CF3)-. In some embodiments, L1is C1-4 hydroxyalkylene. In some embodiments, L1is C1-2 hydroxyalkylene. In some embodiments, L1is cyclopropylene. In some embodiments, L1is selected from those depicted in Table 3, below.

[0437] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments m is selected from those depicted in Table 3, below.

[0438] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments n is selected from those depicted in Table 3, below.

[0439] In some embodiments, the present invention provides a compound of formula II-2-a. L1.NII-2-aor a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, L1, and A1is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula II-2-a.

[0440] In some embodiments, the present invention provides a compound of formula II-2-b, II-2-c, or II-2-d:II-2-b II-2-c II-2-dor a pharmaceutically acceptable salt thereof, wherein each of R1, R3, and A1is as defined above and described in embodiments herein, both singly and in combination. In some embodiments, the compound is a compound of formula II-2-b, II-2-c, or II-2-d.

[0441] The description above describes multiple embodiments relating to compounds of formula II-2. The patent application specifically contemplates all combinations of the embodiments.

[0442] As described above, in certain embodiments, the present invention provides a compound of formula III-2:III-2or a pharmaceutically acceptable salt thereof, wherein:R1is -O-(Ci-5 alkylene)-1;R2represents independently for each occurrence C1-4 alkyl, C1-4haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;R3represents independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl;R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;A1is a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X1is O or S;Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturatedmonocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R3)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4;L1is C1-4 alkylene, C1-4haloalkylene, Ci-4hydroxyalkylene, or cyclopropylene; and m and n represent independently 0, 1, or 2.

[0443] The definitions of variables in formula III-2 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).

[0444] In certain embodiments, the compound is a compound of formula III-2.

[0445] As defined generally above, R1is -O-(Ci-s alkylene)-1. In some embodiments, R1is. In some embodiments, R1is. In someembodiments, R1isIn some embodiments, R1is selected from those depicted in Table 4, below.

[0446] As defined generally above, R2represents independently for each occurrence Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C1-4 haloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C 1-4 alkoxyl.

[0447] In some embodiments, R2represents independently for each occurrence C1-4 alkyl. In some embodiments, R2is methyl. In some embodiments, R2represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R2is trifluoromethyl. In some embodiments, R2represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R2is methoxy. In some embodiments, R2represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is selected from those depicted in Table 4, below.

[0448] As defined generally above, R3represents independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl or C1-4 haloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence hydrogen, C1-4 alkyl, or C1-4 haloalkyl. In some embodiments, R3represents independently for each occurrence hydrogen or C1-4 alkyl. In some embodiments, R3represents independently for each occurrence hydrogen or methyl.

[0449] In some embodiments, R3is hydrogen. In some embodiments, R3represents independently for each occurrence C1-4 alkyl. In some embodiments, R3is methyl. In some embodiments, R3represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R3represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R3is selected from those depicted in Table 4, below.

[0450] As defined generally above, R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R4represents independently for each occurrence halo. In some embodiments, R8represents independently for each occurrence C1-4 alkyl. In some embodiments, R4represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R4represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R4represents independently for each occurrence C3-6 cycloalkyl.

[0451] In some embodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, or isopropyl.

[0452] In some embodiments, R4is methoxy. In some embodiments, R4is chloro. In some embodiments, R4is fluoro. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is isopropyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is trifluoromethyl. In some embodiments, R4is selected from those depicted in Table 4, below.

[0453] As defined generally above, A1is a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 5-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 6-membered heteroarylene having 1, 2, or 3 nitrogen, atoms. In some embodiments, A1is pyridinylene or pyrimidinylene. In some embodiments, A1is pyridinylene. In some embodiments, A1is pyrimidinylene. In some embodiments, A1is selected from those depicted in Table 4, below.

[0454] As defined generally above, X1is O or S. In some embodiments, X1is O. In some embodiments, X1is S. In some embodiments, X1is selected from those depicted in Table 4, below.

[0455] As defined generally above, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R3)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4.

[0456] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl and heterocyclic rings are substituted with n occurrences of R4.

[0457] In some embodiments, Z1is phenyl or -C(O)N(R3)2; wherein the phenyl ring is substituted with n occurrences of R4.

[0458] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4.

[0459] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl is substituted with n occurrences of R4. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heterocyclic ring is substituted with noccurrences of R4. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocyclic ring is substituted with n occurrences of R4. In some embodiments, Z1is phenyl; wherein the phenyl is substituted with n occurrences of R4. In some embodiments, Z1is -C(O)N(R3)2. In some embodiments, Z1is -C(O)N(CH3)2.

[0460] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z1is phenyl.

[0461] In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms; wherein the heteroaryl is substituted with n occurrences of R4. In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms. In some embodiments, Z1is pyrimidinyl. In some embodiments, Z1is pyrimidin-2-yl.

[0462] In some embodiments, Z1is selected from those depicted in Table 4, below.

[0463] As defined generally above, L1is Ci-4 alkylene, Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene. In some embodiments, L1is Ci-4 alkylene, Ci-4 haloalkylene, or Ci-4 hydroxyalkylene. In some embodiments, L1is Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene.

[0464] In some embodiments, L1is Ci-4 alkylene. In some embodiments, L1is C1-2 alkylene. In some embodiments, L1is -C(H)(CH3)-. In some embodiments, L1is C1-4 haloalkylene. In some embodiments, L1is C1-2 haloalkylene. In some embodiments, L1is -C(H)(CF3)-. In some embodiments, L1is C1-4 hydroxyalkylene. In some embodiments, L1is C1-2 hydroxyalkylene. In some embodiments, L1is cyclopropylene. In some embodiments, L1is selected from those depicted in Table 4, below.

[0465] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments m is selected from those depicted in Table 4, below.

[0466] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In someembodiments, n is 1 or 2. In some embodiments n is selected from those depicted in Table 4, below.

[0467] As described above, in certain embodiments, the present invention provides a compound of formula III-2-1:I A1,2-III-2-1or a pharmaceutically acceptable salt thereof, wherein:R1is -O-(Ci-5 alkylene)-1;R2represents independently for each occurrence C1-4 alkyl, C1-4haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;R3represents independently for each occurrence hydrogen, C 1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl;R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;A1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;X1is O or S;Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R3)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4;L1is C1-4 alkylene, C1-4haloalkylene, Ci-4hydroxyalkylene, or cyclopropylene; and m and n represent independently 0, 1, or 2.

[0468] The definitions of variables in formula III-2-1 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).

[0469] In certain embodiments, the compound is a compound of formula III-2-1.

[0470] As defined generally above, R1is -O-(Ci-s alkylene)-1. In some embodiments, R1is. In some embodiments, R1is. In someembodiments, R1isIn some embodiments, R1is selected from those depicted in Table 4, below.

[0471] As defined generally above, R2represents independently for each occurrence C1-4 alkyl, Ci-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C1-4 haloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl. In some embodiments, R2represents independently for each occurrence C1-4 alkyl or C 1-4 alkoxyl.

[0472] In some embodiments, R2represents independently for each occurrence C1-4 alkyl. In some embodiments, R2is methyl. In some embodiments, R2represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R2is trifluoromethyl. In some embodiments, R2represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R2is methoxy. In some embodiments, R2represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R2is cyclopropyl. In some embodiments, R2is selected from those depicted in Table 4, below.

[0473] As defined generally above, R3represents independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl, C1-4 haloalkyl, or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl or C1-4 haloalkyl. In some embodiments, R3represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl. In some embodiments, R3represents independently for each occurrence hydrogen, C1-4 alkyl, or C1-4 haloalkyl. In some embodiments, R3represents independently for each occurrence hydrogen or C1-4 alkyl. In some embodiments, R3represents independently for each occurrence hydrogen or methyl.

[0474] In some embodiments, R3is hydrogen. In some embodiments, R3represents independently for each occurrence C1-4 alkyl. In some embodiments, R3is methyl. In some embodiments, R3represents independently for each occurrence C1-4 haloalkyl. In someembodiments, R3represents independently for each occurrence C3-6 cycloalkyl. In some embodiments, R3is selected from those depicted in Table 4, below.

[0475] As defined generally above, R4represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl. In some embodiments, R4represents independently for each occurrence halo. In some embodiments, R8represents independently for each occurrence C1-4 alkyl. In some embodiments, R4represents independently for each occurrence C1-4 haloalkyl. In some embodiments, R4represents independently for each occurrence C1-4 alkoxyl. In some embodiments, R4represents independently for each occurrence C3-6 cycloalkyl.

[0476] In some embodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence methoxy, chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence chloro, fluoro, or trifluoromethyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, isopropyl, or cyclopropyl. In some embodiments, R4represents independently for each occurrence methyl, ethyl, or isopropyl.

[0477] In some embodiments, R4is methoxy. In some embodiments, R4is chloro. In some embodiments, R4is fluoro. In some embodiments, R4is methyl. In some embodiments, R4is ethyl. In some embodiments, R4is isopropyl. In some embodiments, R4is cyclopropyl. In some embodiments, R4is trifluoromethyl. In some embodiments, R4is selected from those depicted in Table 4, below.

[0478] As defined generally above, A1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, A1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen, atoms. In some embodiments, A1is pyridinyl or pyrimidinyl. In some embodiments, A1is pyridinyl. In some embodiments, A1is pyrimidinyl. In some embodiments, A1is selected from those depicted in Table 4, below.

[0479] As defined generally above, X1is O or S. In some embodiments, X1is O. In some embodiments, X1is S. In some embodiments, X1is selected from those depicted in Table 4, below.

[0480] As defined generally above, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or -C(O)N(R3)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4.

[0481] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl and heterocyclic rings are substituted with n occurrences of R4.

[0482] In some embodiments, Z1is phenyl or -C(O)N(R3)2; wherein the phenyl ring is substituted with n occurrences of R4.

[0483] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R4.

[0484] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl is substituted with n occurrences of R4. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heterocyclic ring is substituted with n occurrences of R4. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocyclic ring is substituted with n occurrences of R4. In some embodiments, Z1is phenyl; wherein the phenyl is substituted with n occurrences of R4. In some embodiments, Z1is -C(O)N(R3)2. In some embodiments, Z1is -C(O)N(CH3)2.

[0485] In some embodiments, Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z1is a 5-6 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z1is phenyl.

[0486] In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms; wherein the heteroaryl is substituted with n occurrences of R4. In some embodiments, Z1is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms. In some embodiments, Z1is pyrimidinyl. In some embodiments, Z1is pyrimidin-2-yl.

[0487] In some embodiments, Z1is selected from those depicted in Table 4, below.

[0488] As defined generally above, L1is Ci-4 alkylene, Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene. In some embodiments, L1is Ci-4 alkylene, Ci-4 haloalkylene, or Ci-4 hydroxyalkylene. In some embodiments, L1is Ci-4 haloalkylene, Ci-4 hydroxyalkylene, or cyclopropylene.

[0489] In some embodiments, L1is Ci-4 alkylene. In some embodiments, L1is C1-2 alkylene. In some embodiments, L1is -C(H)(CH3)-. In some embodiments, L1is C1-4 haloalkylene. In some embodiments, L1is C1-2 haloalkylene. In some embodiments, L1is -C(H)(CF3)-. In some embodiments, L1is C1-4 hydroxyalkylene. In some embodiments, L1is C1-2 hydroxyalkylene. In some embodiments, L1is cyclopropylene. In some embodiments, L1is selected from those depicted in Table 4, below.

[0490] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments m is selected from those depicted in Table 4, below.

[0491] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments n is selected from those depicted in Table 4, below.

[0492] Exemplary compounds of the invention are set forth in Tables 2, 3, 4, 5, and 6. In certain embodiments, the compound is selected from those disclosed in Tables 2, 3, 4, 5, and 6, below. Exemplary compounds of the invention are set forth in Table 2, below. In certain embodiments, the compound is selected from those disclosed in Table 2, below, or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 2, below.Table 2. Selected CompoundsCompoundChemical StructureNo.o =I-2-1o z 0 x / ’""0 Z / —p O0I-2-2o o0O Q t>°0 Y 'imI-2-3D0z / I-2-4ifN^ T)Me 0001I-2-5I-2-6o =I-2-7° ^070F II '■I-2-800\7

[0493] Exemplary compounds of the invention are set forth in Table 3, below. In certain embodiments, the compound is selected from those disclosed in Table 3, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 3, below.

[0494] Exemplary compounds of the invention are set forth in Table 4, below. In certain embodiments, the compound is selected from those disclosed in Table 4, below, or apharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 4, below.Table 4. Selected CompoundsCompoundChemical StructureNo.I-2-96I-2-97p p ( ( o. o.ZZ—— ^ ^

[0495] Exemplary compounds of the invention are set forth in Table 5, below. In certain embodiments, the compound is selected from those disclosed in Table 5, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected\from those disclosed in Table 5, below.

[0496] Exemplary compounds of the invention are set forth in Table 6, below. In certain embodiments, the compound is selected from those disclosed in Table 6, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 6, below.Table 6. Selected CompoundsCompound No. Chemical Structure01I-2-219kA0 ^>-701I-2-2300J xI-2-241A-A AJA0^\7

[0497] In certain embodiments, the compound is a compound described in international patent application WO 2024 / 028365, the contents of which are hereby incorporated by reference. Compounds described herein above may be prepared according to, or based on, procedures described in WO 2024 / 028365.Part C: Third Set of GPR84 Antagonist Compounds

[0498] In certain aspects, the methods described here comprise the administration of a compound of Formula 1-3 to a patient in need thereof. In certain embodiments, the compound is a compound of the following Formula 1-3:1-3or a pharmaceutically acceptable salt thereof, wherein:Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and a C1–6aliphatic; each of which is substituted with p instances of R4; and (ii) hydrogen;each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, - NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, - CR2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, - N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, - N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or two R2groups are optionally taken together to form =0;two R4groups are optionally taken together to form =0;two R5groups are optionally taken together to form =0;two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;each instance of Rzis independently selected from an optionally substituted group selected from C1-6aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;R3is hydrogen or an optionally substituted C1–6aliphatic group; ortwo R3groups are optionally taken together to form =0; oran R2group and an R3group are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated or partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;L1is one of the following:(a) a C1–6bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1–3 methylene units of the chain are independently and optionally replaced with –O–, –Cy–, –C(O)–, –C(S)–, –C(R)2–, –CH(R)–, –CH(OR)–, –C(F)2–, –N(R)–, –S–, –S(O)–, or –S(O)2–; or(b) a covalent bond;each –Cy– is independently an optionally substituted bivalent ring selected from phenylene; 3–7 membered saturated or partially unsaturated carbocyclylene; 4–7 membered saturated or partially unsaturated heterocyclylene having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7–11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclylene having 1–2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5–6 membered heteroarylene having 1–4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;L2is a covalent bond or a C1–4bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1–2 methylene units of the chain are independently and optionally replaced with –O–, –C(O)–, –C(S)–, –C(R)2– –CH(R)–, –CR(OR)–, –C(F)2–, –N(R)–, –S–, –S(O)–, –CH(CR3)–, –C=(CH2)– or –S(O)2–;L3is one of the following:(a) a C1-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2- - N(R)-, -S-, -S(O)-, or-S(O)2-; or(b) a covalent bond;X is one of the following:(a) a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partiallay unsaturated bridged or spiro cyclic, bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partiallay unsaturated bridged tricyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl; each of which is substituted with q instances of R5; or(b) -CH2(OR), -CH(R)(OR), or -C(R)2(OR);each instance of R is independently hydrogen, or an optionally substituted group selected from C1–6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1- 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; ortwo R groups on the same atom are optionally taken together with the atom to form an optionally substituted 3-7 membered monocyclic saturated, partiallyunsaturated, or heteroaryl ring having, in addition to the atom, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;m is 0, 1, 2, 3, or 4;n is 0, 1, 2, 3, or 4;p is 0, 1, 2, 3, 4, or 5; andq is 0, 1, 2, 3, 4, or 5.

[0499] The definitions of variables in Formula 1-3 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).

[0500] In certain embodiments, the compound is a compound of Formula 1-3.

[0501] As defined generally above, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.

[0502] In some embodiments, Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Ring A is phenyl. In some embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, Ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring.to L1and the on the right side of Ring A is connected to L2. In some embodiments, theon the right side of Ring A is connected to L1and the‘ on the left side of Ring A is connected to L2.

[0504] In some embodiments, Ring A is selected from those depicted in Table 7, below.

[0505] As defined generally above, Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0506] In some embodiments, Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0507] In some embodiments, Ring B is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0509] In some embodiments, two R3groups are taken together to form =0 and Ring B is (R3)0-2Nl f q. In some embodiments, two R groups are taken together to form =0 and Ring In some embodiments, two R3groups are taken together to form =0 and. In some embodiments, the < on the left side of Ring B is connected to L2and the< on the right side of Ring B is connected to L3. In someembodiments, theon the right side of Ring B is connected to L2and theon the left side of Ring B is connected to L3.

[0510] In some embodiments, Ring B is selected from those depicted in Table 7, below.

[0511] Exemplary compounds of the invention are set forth in Table 7, below. In certain embodiments, the compound is selected from those disclosed in Table 7, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 7, below.

[0512] In certain embodiments, the compound is a compound described in international patent application WO 2022 / 167457, the contents of which are hereby incorporated by reference. Compounds described herein above may be prepared according to, or based on, procedures described in WO 2022 / 167457.Part D: Second Set of GPR84 Antagonist Compounds

[0513] In certain aspects, the methods described here comprise the administration of a compound of Formula 1-4 to a patient in need thereof. In certain embodiments, the compound is a compound of the following Formula 1-4:1-4or a pharmaceutically acceptable salt thereof, wherein:R2is -(C2-4alkynylene)-(C3-7cycloalkyl), -(C2-4alkynylene)-(C1-3alkylene)-(C1-6alkoxyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C1-4alkylene)-(5-6membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2;R3represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -N(R7)(R8), or Y3;R4and R5are independently C1-6 alkyl or C1-2 deuteroalkyl, or R4and R5are taken together with their intervening atom(s) to form a 3-5 membered saturated carbocyclic ring;R6is C1-6 alkyl or C3-6 cycloalkyl;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;V-Nxz> NA1is ’Nor Y4, wherein ** is a point of attachment to A2;A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Y5; wherein the phenylene and heteroarylene are substituted with n occurrences of R3;L1is a C1-3 alkylene;Y1is -C(O)N(R7)(R8), -N(R7)C(O)(R6), -CO2R7,Y2is -C≡C-(C1-3alkylene)-N(R7)SO2-R6, -C≡C-(C1-3alkylene)-SO2-N(R7)(R8), -C≡C-(C0-3alkylene)-N(R7)C(O)R6, -C≡C-(C0-3alkylene)-C(O)N(R7)(R8), -C≡C-(C1-3alkylene)-O-(C3-6cycloalkyl), -C≡C-(C1-3alkylene)-O-(C1-5haloalkyl), -C≡C-(C1-5haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C1-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C≡C-(C1-3alkylene)-N(R7)-(C0-3alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C≡C-(C1-3alkylene)-(triazolyl optionally substituted by one phenyl which is optionally substituted by one C1-3alkyl), -C≡C-(C1-3alkylene)-(imidazolylene)-(phenylene)-N(R7)(R8),occurrences of Ci-4alkyl)-Z2, -(azetidinyl substituted with one C1-4haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one C1-3 alkylene-O-C3-6 cycloalkyl), -(azetidinyl substituted with one C1-4haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one -(Co-4 alkylene)-(C 1-4 haloalkoxyl)), -(C0-3 alkyl ene)-CN, -(C2 alkynylene)-CN, C1-4haloalkyl, -(C0-3 alkylene)-C(O)N(R7)(R8), -O-(Ci-3alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(Ci-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (C1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (Ci-4alkylene)-(C3-6 cycloalkyl), or hydrogen;Y3is -N(R7)(C1-4deuteroalkyl) or -N(C1-4deuteroalkyl)2;of attachment to A2;Y5issubstituted with n occurrences of R3;Z1is C1-10aliphatic, -(C0-3alkylene)-(3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl issubstituted with 1, 2, or 3 groups independently selected from Ci-6 alkyl and Ci-6 hydroxyalkyl), -N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(Co-3 alkylene)- (5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -N(R7)-(C1-10optionally substituted aliphatic)-, or C1-6hydroxyalkyl;Z2is one of the following:(a) 3-7 membered saturated heterocyclyl substituted 1 or 2 occurrences of R3, (b) -(Co-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or(c) 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0, 1, or 2;wherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5; and**provided that when Y4is ’, then R3is not methyl.

[0514] The definitions of variables in Formula 1-4 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).

[0515] In certain embodiments, the compound is a compound of Formula 1-4.O\z°

[0516] As defined generally above,R1is [structure] or Y1. In some embodiments, R1is. In some embodiments, R1is Y1. In some embodiments, R1is Y1, and Y1is -C(O)N(R7)(R8), -N(R7)C(O)(R6), -CO2R7,is Y1, and Y1is -C(O)N(R7)(R8). In some embodiments, R1is Y1, and Y1is -N(R7)C(O)(R6)or -CO2R7. In some embodiments, R1is Y1, and Y1is, or. In some embodiments, R1is Y1, and

[0517] In some embodiments, R1is selected from those depicted in Table 8.

[0518] As defined generally above, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl), -(C2-4 alkynylene)-(Ci-3alkylene)-(Ci-6alkoxyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2. In some embodiments, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl). In some embodiments, R2is -(C2-4alkynylene)-(Ci-3 alkylene)-(Ci-6 alkoxyl). In some embodiments, R2is -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxy alkyl). In some embodiments, R2is -(7-9 memberedsaturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from Ci-6 alkyl and Ci-6 hydroxy alkyl). In some embodiments, R2is -(3-7 membered saturated heterocyclyl ene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen). In some embodiments, R2is Y2.

[0519] In some embodiments, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

[0520] In some embodiments, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl) or -(C2-4 alkynylene)-(Ci-3 alkylene)-(Ci-6 alkoxyl). In some embodiments, R2is -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

[0521] In some embodiments, R2is Y2, and Y2is -C≡C-(C1-3alkylene)-N(R7)SO2-R6, -C≡C-(C1-3alkylene)-SO2-N(R7)(R8), -C≡C-(C0-3alkylene)-N(R7)C(O)R6, -C≡C-(C0-3alkylene)-C(O)N(R7)(R8), -C≡C-(C1-3alkylene)-O-(C3-6cycloalkyl), -C≡C-(C1-3alkylene)-O-(C1-5haloalkyl), -C≡C-(C1-5haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C1-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C≡C-(C1-3alkylene)-N(R7)-(C0-3alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C≡C-(C1-3alkylene)-(triazolyl optionally substituted by one phenyl which isoptionally substituted by one C1-3 alkyl), -C=C-(Ci-3 alkylene)-(imidazolylene)-(phenylene)-of Ci-4alkyl)-Z2, -(azetidinyl substituted with one C1-4haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one C1-3 alkylene-O-Cs-6 cycloalkyl), -(azetidinyl substituted with one C1-4haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one -(Co-4alkylene)-(Ci-4haloalkoxyl)), -(C0-3 alkylene)-CN, -(C2 alkynylene)-CN, C1-4haloalkyl, -(C0-3 alkylene)-C(O)N(R7)(R8), -O-(Ci-3alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(Ci-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (C1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (Ci-4 alkyl ene)-(C3-6 cycloalkyl), or hydrogen.

[0522] Another aspect of the invention provides a compound of formula II-4:R1— L1— (^A^)— L2— R2(II-4)or a pharmaceutically acceptable salt thereof, wherein:R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl), -(C2-4alkynylene)-(Ci-3 alkylene)-(Ci-6 alkoxyl), -(C2-4 alkynylene)-(phenyl substituted with 0, 1, or 2 occurrences ofR10), -(C2-4 alkynylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogenand oxygen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R10), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from Ci-6 alkyl and Ci-6 hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from Ci-6 alkyl and C1-6hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2;R3represents independently for each occurrence halo, Ci-4 alkyl, Ci-4 haloalkyl, Ci-4 alkoxyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -N(R7)(R8), or Y3;R4and R5are independently C1-6 alkyl or C1-2 deuteroalkyl, or R4and R5are taken together with their intervening atom(s) to form a 3-5 membered saturated carbocyclic ring;R6is C1-6 alkyl or C3-6 cycloalkyl;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;R9is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl;R10represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, or C3-6 cycloalkyl;**A1is ’ bl or Y4, wherein ** is a point of attachment to L2;A2is phenylene or Y5, wherein the phenylene is substituted with n occurrences of R3; L1is a C1-3 alkylene;L2is -N(R9)-, Y6, or C1-4 alkylene substituted by C1-4 alkoxyl;membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted by 0, 1, or 2 occurrences of R10;Y2is -C=C-(Ci-3alkylene)-N(R7)SO2-R6, -C=C-(Ci-3alkylene)-SO2-N(R7)(R8), -C=C-(Co-3 alkylene)-N(R7)C(O)R6, -C=C-(Co-3 alkylene)-C(O)N(R7)(R8), -C=C-(Ci-3alkylene)-N(R7)(R8), -C=C-(CI-3alkylene)-O-(C3-6 cycloalkyl), -C=C-(Ci-3alkylene)-O-(Ci-5haloalkyl), -C=C-(Ci-5haloalkyl), -C=C-(cyclobutyl), -C=C-(C(CH3)2(OH)), -C=C-(hydroxycyclopropyl), -C=C-(Ci-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C=C-(Ci-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C=C-(Ci-3 alkylene)-(triazolyl optionally substituted by one phenyl(azetidinylene substituted with 1 or 2 occurrences of Ci-4alkyl)-Z2, -(azetidinyl substituted with one Ci-4 haloalkyl and one Ci-4 alkyl), -(azetidinyl substituted with one Ci-4 alkyl and one C1-3 alkylene-O-Cs-e cycloalkyl), -(azetidinyl substituted with one Ci-4 haloalkyl and one Ci-4 alkyl), -(azetidinyl substituted with one Ci-4 alkyl and one Ci-4 haloalkoxy)-, -(C0-3 alkylene)-CN, -(C2alkynylene)-CN, Ci-4 haloalkyl, -(C0-3 alkylene)-C(O)N(R7)(R8), -O-(CI-3alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(CI-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (C1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C0-4 alkylene)-(C3-6 cycloalkyl), Ci-4alkoxyl, C1-6 hydroxyalkyl, or hydrogen;Y3is -N(R7)(CI-4 deuteroalkyl) or -N(Ci-4deuteroalkyl)2;Y5is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene is substituted with n occurrences of R3;Y6is (a) -C=C- or -(Ci-4alkylene)(C(H)(Ci-4 alkoxyl)-, (b) C2-4 alkylene substituted by 0 or 1 C3-5 cycloalkyl, (c) C1-4 alkylene substituted by -S-C1-4 alkyl, or (d) -CH2- or -O-;Z1is C1-10aliphatic, -(C0-3alkylene)-(3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 1, 2, or 3 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C0-3 alkylene)- (5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or C1-6 hydroxyalkyl;Z2is one of the following:(a) 3-7 membered saturated heterocyclyl substituted 1 or 2 occurrences of R3, (b) -(C0-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or(c) 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0, 1, or 2;wherein there is at least one occurrence of Y1, Y2, Y3, Y4, Y5, or Y6; and**V-Nxz> Nprovided that if A1is ’Nand Y6is -CH2- or -O-, then R3is not methyl.

[0523] The definitions of variables in Formula II-4 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).

[0524] In certain embodiments, the compound is a compound of Formula II-4.

[0525] As generally defined above,R1is or Y1. In certain embodiments, R1isIn certain embodiments, R1is Y1.

[0526] In some embodiments, R1is selected from those depicted in Table 9.

[0527] As generally defined above, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl), -(C2-4 alkynylene)-(Ci-3alkylene)-(Ci-6alkoxyl), -(C2-4 alkynylene)-(phenyl substituted with 0, 1, or 2 occurrences of R10), -(C2-4alkynylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R10), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2. In certain embodiments, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl) or -(C2-4 alkynylene)-(Ci-3 alkylene)-(Ci-6 alkoxyl). In certain embodiments, R2is -(C2-4 alkynylene)-(phenyl substituted with 0, 1, or 2 occurrences ofR10), -(C2-4alkynylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R10), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen). In certain embodiments, R2is Y2. In certain embodiments, R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl). In certain embodiments, R2is -(C2-4 alkynylene)-(Ci-3 alkylene)-(Ci-6 alkoxyl). In certain embodiments, R2is -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl). In certain embodiments, R2is -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6 hydroxy alkyl). In certain embodiments, R2is -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen). In some embodiments, R2is -(C2-4 alkynylene)-(phenyl substituted with 0, 1, or 2 occurrences of R10). In some embodiments, R2is -(C2-4 alkynylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is substituted with 0, 1, or 2 occurrences of R10). In some embodiments, R2is selected from those depicted in Table 9.

[0528] In certain embodiments, the compound of Formula II-4 is a compound of Formula IIa-4 or IIb-4 or a pharmaceutically acceptable salt thereof:IIa-4 IIb-4.

[0529] In certain embodiments, the present invention provides a compound of formula III-4:(III-4)or a pharmaceutically acceptable salt thereof, wherein:R2is -(C2-4alkynylene)-(C3-7cycloalkyl), -(C2-4alkynylene)-(C1-3alkylene)-(C1-6alkoxyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6alkyl and C1-6hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C1-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), -C(=N(R7)2)N(R7)2, or Y2;R3represents independently for each occurrence halo, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -N(R7)(R8), or Y3;R4and R5are independently C1-6 alkyl or C1-2 deuteroalkyl, or R4and R5are taken together with their intervening atom(s) to form a 3-5 membered saturated carbocyclic ring;R6is C1-6 alkyl or C3-6 cycloalkyl;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom, wherein the ring is substituted by 0, 1, or 2 occurrence of hydroxyl;**V-Nxz> NA1is ’Nor Y4, wherein ** is a point of attachment to A2;A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Y5; wherein the phenylene and heteroarylene are substituted with n occurrences of R3;L1is a Ci-3 alkylene, C1-3 haloalkylene, or a covalent bond;is -C(O)N(R7)(R8), -N(R7)C(O)(R6), -CO2R7,, 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a -C(O)-(5-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur), wherein the heteroaryl and heterocyclyl are substituted with 0, 1, or 2 occurrences of R3;Y2is -C=C-(Ci-3alkylene)-N(R7)SO2-R6, -C=C-(Ci-3alkylene)-SO2-N(R7)(R8), -C=C- (C0-3 alkylene)-N(R7)C(O)R6, -C=C-(Co-3 alkylene)-C(O)N(R7)(R8), -C=C-(Ci-3alkylene)- O-(C3-6 cycloalkyl), -C=C-(Ci-3 alkylene)-O-(Ci-s haloalkyl), -C=C-(Ci-s haloalkyl), - C=C-(cyclobutyl), -C=C-(C(CH3)2(OH)), -C=C-(hydroxy cyclopropyl), -C=C-(Ci-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C=C- (C1-3 alkyl ene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C=C-(Ci-3 alkylene)-(triazolyl optionally substituted by one phenyl which is optionally substituted by one C1-3 alkyl), -C=C-(Ci-3 alkylene)-(imidazolylene)-(phenylene)-N(R7)(R8),, -(azetidinylene substituted with 1 or 2 occurrences of Ci-4alkyl)-Z2, -(azetidinyl substituted with one C1-4haloalkyl and one Ci-4 alkyl), -(azetidinyl substituted with one Ci-4 alkyl and one C1-3 alkylene-O-C3-6 cycloalkyl), -(azetidinyl substituted with one C1-4haloalkyl and one C1-4 alkyl), -(azetidinyl substituted with one C1-4 alkyl and one -(Co-4 alkylene)-(C 1-4 haloalkoxyl)), -(C0-3 alkyl ene)-CN, -(C2 alkynylene)-CN, C1-4haloalkyl, -(C0-3 alkylene)-C(O)N(R7)(R8), -O-(Ci-3alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(Ci-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (C1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (Ci-4alkylene)-(C3-6 cycloalkyl), hydrogen, or a 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted by 0, 1, 2, or 3 occurrences of R3;Y3is -N(R7)(C1-4deuteroalkyl) or -N(C1-4deuteroalkyl)2;R6, a 5-6 membered saturated heterocyclene containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a 5-6 membered heteroarylene containing 2 or 3heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein ** is a point of attachment to A2;Y5issubstituted with n occurrences of R3;Z1is C1-10aliphatic, -(Co-3 alkylene)-(3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 1, 2, or 3 groups independently selected from Ci-6 alkyl and Ci-6 hydroxyalkyl), -N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(Co-3 alkylene)- (5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -N(R7)-(C1-10optionally substituted aliphatic)-, or C1-6hydroxyalkyl;Z2is one of the following:(d) 3-7 membered saturated heterocyclyl substituted 1 or 2 occurrences of R3, (e) -(Co-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or(f) 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; andn is 0, 1, or 2.

[0530] The definitions of variables in Formula III-4 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).

[0531] In certain embodiments, L1is a C1-3 alkylene. In certain embodiments, L1is a C1-3 haloalkylene. In certain embodiments, L1is a covalent bond.

[0532] In certain embodiments, R2is Y2, wherein Y2is a 5-6 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said heteroaryl is substituted by 0, 1, 2, or 3 occurrences of R3.

[0533] Exemplary compounds of the invention are set forth in Tables 8, 9, and 10, below. In certain embodiments, the compound is selected from those disclosed in Table 8, 9, or 10, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 8, 9, or 10, below. In certain embodiments, the compound is selected from those disclosed in Table 8, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 8, below.Table 8. Selected Compounds

[0534] Exemplary compounds of the invention are set forth in Table 9, below. In certain embodiments, the compound is selected from those disclosed in Table 9, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 9, below.Table 9. Selected CompoundsCompoundChemical StructureNo.1-4-29 < S> XT0- / N=NZ — K X" N1-4-43N' Jhr

[0535] Exemplary compounds of the invention are set forth in Table 10, below. In certain embodiments, the compound is selected from those disclosed in Table 10, below, or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is selected from those disclosed in Table 10, below.M C TZ \—7 °'Table 10. Selected Compounds Compound z ^Chemical StructureNo. VA / / i Q # v1-4-2 XzCQdo v1-4-20

[0536] In certain embodiments, the compound is a compound described in international patent application WO 2024 / 028364, the contents of which are hereby incorporated by reference. Compounds described herein above may be prepared according to, or based on, procedures described in WO 2024 / 028364.Part E: Second Set of GPR84 Antagonist Compounds

[0537] In certain aspects, the methods described here comprise the administration of a compound of Formula 1-5 to a patient in need thereof. In certain embodiments, the compound is a compound of the following Formula 1-5:1-5or a pharmaceutically acceptable salt thereof, wherein:A1is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-membered unsaturated oxo-heterocyclylenecontaining 1 nitrogen atom; or phenylene; each of which is substituted with m occurrences of R3;A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is substituted with n occurrences of R4;L1is a Ci-6 bivalent straight or branched saturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-;L2is -C(O)N(R5)-, -N(R6)C(O)-, -N(R6)-, -N(R6)-(CI-4alkylene)-, -(Ci-4alkylene)-N(R6)-, -S(O)2N(R5)-, -N(R6)S(O)2-, -CO2-, or -OC(O)-;R1is -C(O)N(R7)(R8), a 6-11 membered saturated or partially unsaturated, bridged or spirocyclic, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each of said bicyclic heterocyclic ring and monocyclic heterocyclic ring are substituted with q instances of R9;R2is -(C2-4alkynylene)-(C3-7cycloalkyl) or hydrogen;R3represents independently for each occurrence Ci-6 alkyl or halo;R4represents independently for each occurrence Ci-6 alkyl, halo, hydroxyl, Ci-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8);R5is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen; or R5and one occurrence of R4are taken together with their intervening atoms to form a 5-6 membered ring containing 1 nitrogen atom;R6is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen;R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;R9represents independently for each occurrence C1-6 alkyl, halo, hydroxyl, C1-6 alkoxyl, or C3-6 cycloalkyl; andm, n, and q are independently 0, 1, or 2;INwherein if R1, L1, A1and L2taken together formN"N, then n is 1 or 2, and R4represents independently for each occurrence halo, hydroxyl, Ci-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8).

[0538] The definitions of variables in Formula 1-5 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).

[0539] In certain embodiments, the compound is a compound of Formula 1-5.

[0540] As defined generally above, A1is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-membered unsaturated oxo-heterocyclylene containing 1 nitrogen atom; or phenylene; each of which is substituted with m occurrences of R3. In some embodiments, A1is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene is substituted with m occurrences of R3. In some embodiments, A1is a 6-membered unsaturated oxo-heterocyclylene containing 1 nitrogen atom, wherein the oxo-heterocyclylene is substituted with m occurrences of R3. In some embodiments, A1is phenylene substituted with m occurrences of R3. In some embodiments, A1is 1,2,3-triazolylene, imidazolylene, pyrrolylene, pyrazolylene, oxazolylene, thiazolylene, or pyridinylene, each of which is substituted with m occurrences of R3. In some embodiments, A1is 1,2,3-triazolylene substituted with m occurrences of R3.

[0541] In some embodiments, A1is, which is substituted with m occurrencesofR3. In some embodiments,A1isH, which is substituted with m occurrences of R3.In some embodiments, A1is, which is substituted with m occurrences of R3,wherein **** is a point of attachment to L2. In some embodiments, A1is ““, which is substituted with m occurrences of R3, wherein **** is a point of attachment to L2.

[0542] In some embodiments, A1issubstituted with m occurrences of R3.

[0543] In some embodiments, A1is. In some embodiments,A1is. In some embodiments,A1is

[0544] In some embodiments, A1is selected from those depicted in Table 11, below.

[0545] As defined generally above, A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is substituted with n occurrences of R4. In some embodiments, A2is phenylene substituted with n occurrences of R4. In some embodiments, A2is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur wherein the heteroarylene is substituted with n occurrences of R4. In some embodiments, A2is a 9-10 membered partially saturated carbocyclylene; substituted with n occurrences of R4. In some embodiments, A2issubstituted with n occurrences of R4. In some embodiments, A2issubstituted with n occurrences of R4.

[0546] In some embodiemnts, A2is pyridinylene substituted with n occurrences of R4.

[0547] In some embodiments, A2is, each of which is substituted with n occurrences of R4, wherein ** is the point of attachment to R2. In some embodiments, A2is selec...

Claims

1. CLAIMS1. A method of treating a cardiovascular disorder in a patient, comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of Formula 1-1, 1-2, 1-3, 1-4, or 1-5, to treat the cardiovascular disorder, wherein the cardiovascular disorder is acute coronary syndrome, atherosclerosis, congestive heart failure, coronary artery disease, dyslipidemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, hypoalphalipoproteinemia, peripheral vascular disease, stroke, thrombosis, or vascular dementia;3.wherein Formula 1-1 is represented by:

5. 7.1-18.or an N-oxide, or a pharmaceutically acceptable salt thereof, wherein:9.Ring A is phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;10.Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or phenyl;11.Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8- 10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;12.R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a C1-6aliphatic; each of which is substituted with q instances of R5; and (ii) hydrogen, -CN, or -OR;13.each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, - CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R,- CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, - OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, - S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, -P(O)(R)NR2, - P(O)(R)OR or -P(O)R2; or14.two R2groups are optionally taken together to form =0;15.two R4groups are optionally taken together to form =0;16.two R5groups are optionally taken together to form =0;17.two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;18.two R4groups are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or19.two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5groups are taken together with their intervening atoms to form a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;20.each Rzis independently selected from an optionally substituted group selected from C1-6aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;21.each instance of R3is independently selected from:22.(a) hydrogen, deuterium, halogen, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, - S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, - N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, -N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, - N(R)CN; or23.(b) an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or24.two R3groups are optionally taken together to form =0 or =S; or two R3groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or25.L1is one of the following:26.(a) a C1-5 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, - CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or-S(O)2-; or (b) a covalent bond;27.L2and L3are independently one of the following:28.(a) a C1-3 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, - CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or-S(O)2-; or (b) a covalent bond;29.each R is independently hydrogen, or an optionally substituted group selected from C1-6aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or30.two R groups on the same nitrogen are optionally taken together with the nitrogen to form an optionally substituted 4-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and / or31.two R groups on vicinal carbons are taken together with the vicinal carbons to form an optionally substituted 3-7 membered monocyclic saturated or partially unsaturated carbocyclic ring or heterocyclic ring, wherein the heterocyclic ring has, in addition to the vicinal carbons, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;32.m is 0, 1, 2, 3, or 4;33.n is 0, 1, 2, 3, or 4;34.p is 0, 1, 2, 3, or 4; and35.q is 0, 1, 2, 3, or 4;36.wherein Formula 1-2 is represented by:37.I A138.,240. 42.1-243.or a pharmaceutically acceptable salt thereof, wherein: R1is -O-(C1-5alkylene)-Z1or Y1;44.R2represents independently for each occurrence C1-4 alkyl or Y2;45.R3is one of the following:46.(d) -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co- 4 alkyl ene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(C 1-4 alkyl), or C1-6 alkyl;47.(e) C1-6alkoxyl, C1-6haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or48.(f) Y3;49.R4represents independently for each occurrence hydrogen or methyl;50.R5and R8each represent independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl;51.R6and R9each represent independently for each occurrence hydrogen or C1-4 alkyl; R7is C2-6 alkyl, C 1-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R7and R6are taken together with the nitrogen atom to which they are attached to form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spirocyclic ring containing 2 nitrogen atoms; wherein said cycloalkyl and each ring are substituted with p substituents independently selected from halo and C1-4 alkyl;52.A1is phenylene, pyridinylene, or piperidinylene, each of which is substituted with q occurrences of R8; or A1is Y4;53.X1is O or S;54.Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or - C(O)N(R4)2; wherein the heteroaryl, heterocyclic, and phenyl rings are substituted with n occurrences of R5; Z2is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;55.Z3is hydroxyl, Ci-4alkoxyl, -N(R9)2, -C(O)N(R9)2, or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(Ci-6 aliphatic);56.L1is Ci-4 alkylene, C3-4 haloalkylene, C1-4 hydroxyalkylene, cyclopropylene, or Y5; Y1is one of the following:57.(e) -O-(Ci-5 alkylene)-C(O)N(R6)(R7), -O-(Ci-5alkylene)-SO2N(R6)2, or-O-(Ci- 5 alkyl ene)-CO2R6;58.(f) -O-(Ci-5 haloalkylene)-N(R6)2, -O-(Ci-5 alkylene)-(C3-6 cycloalkylene)- N(R6)2, or -O-(Ci-5 alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2;59.(g) -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or60.(h) -O-(C1-5alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(C1-4alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5;61.Y2represents independently for each occurrence C1-4 haloalkyl, Ci-4 alkoxyl, or C3-6 cycloalkyl;62.Y3is one of the following:63.(d) -(C2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, and hydroxyl), -C=C-C=C-(Ci-564.aliphatic), -C=C-CN,65.

66. -(C3-6 cycloalkylene)-(C3-6 cycloalkyl), - (C3-6 cycloalkylene)-(C 1-4 haloalkyl), -(phenylene)-(Ci-4 haloalkyl), or C1-4 haloalkyl;67.(e) -O-(Ci-8alkylene)-Z3or hydroxyl; or68.(f) -N(R9)2, -(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)- (C3-6 cycloalkyl), or -N(R9)C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y4is -C=C-, cyclohexylene,69.

70. oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein said phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2; Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-; and71.m, n, p, and q represent independently 0, 1, or 2; and72.wherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5;73.wherein Formula 1-3 is represented by:

75. 77.1-378.or a pharmaceutically acceptable salt thereof, wherein:79.Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring;80.Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;81.R1is selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and a C1–6aliphatic; each of which is substituted with p instances of R4; and (ii) hydrogen;82.each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, - CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R,- CF3, -CR2(CN), -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, - C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -C(S)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)NR2, -N(R)S(O)2NR2, -N(R)S(O)2R, - N=S(O)R2, -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R2, -SiR3, - P(O)(R)NR2, -P(O)(R)OR or -P(O)R2; or83.two R2groups are optionally taken together to form =0;84.two R4groups are optionally taken together to form =0;85.two R5groups are optionally taken together to form =0;86.two R2groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;87.two R4groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or88.two R5groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur;89.each instance of Rzis independently selected from an optionally substituted group selected from C1-6 aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;90.R3is hydrogen or an optionally substituted C1-6 aliphatic group; or91.two R3groups are optionally taken together to form =0; or92.an R2group and an R3group are optionally taken together with their intervening atoms to form an optionally substituted 5-8 membered saturated or partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;93.L1is one of the following:94.(a) a Ci-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-3 methylene units of the chain are independently and optionally replaced with -O-, -Cy-, -C(O)-, -C(S)-, -C(R)2- -CH(R)-, -CH(OR)-, -C(F)2- -N(R)-, -S-, -S(O)-, or -S(O)2-; or (b) a covalent bond;95.each -Cy- is independently an optionally substituted bivalent ring selected from phenylene; 3-7 membered saturated or partially unsaturated carbocyclylene; 4-7 membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;96.L2is a covalent bond or a Ci-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, - CR(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, -CH(CR3)-, -C=(CH2)-, or-S(O)2-97.L3is one of the following:98.(a) a Ci-4 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, - CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or-S(O)2-; or (b) a covalent bond;99.X is one of the following:100.(c) a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partiallay unsaturated bridged or spiro cyclic, bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8- 10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or phenyl; each of which is substituted with q instances of R5; or101.(d) -CH2(OR), -CH(R)(OR), or -C(R)2(OR);102.each instance of R is independently hydrogen, or an optionally substituted group selected from Ci-6 aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or103.two R groups on the same atom are optionally taken together with the atom to form an optionally substituted 3-7 membered monocyclic saturated, partially unsaturated, or heteroaryl ring having, in addition to the atom, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;104.m is 0, 1, 2, 3, or 4;105.n is 0, 1, 2, 3, or 4;106.p is 0, 1, 2, 3, 4, or 5; and107.q is 0, 1, 2, 3, 4, or 5;108.wherein Formula 1-4 is represented by:109.R1— L1— A2-R2111. 113.1-4114.or a pharmaceutically acceptable salt thereof, wherein: ox„o115.R116. 117.1is ' / V’AAor Y1;118.R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl), -(C2-4 alkynylene)-(Ci-3 alkylene)-(Ci-ealkoxyl), -(3-7 membered saturated heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6hydroxyalkyl), -(7-9 membered saturated spirocyclic heterocyclyl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclyl is substituted with 0, 1, or 2 groups independently selected from C1-6 alkyl and C1-6hydroxyalkyl), -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(Ci-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y2;119.R3represents independently for each occurrence halo, C1-4 alkyl, C1-4 haloalkyl, Ci-4alkoxyl, C3-6 cycloalkyl, -O-C3-6 cycloalkyl, -N(R7)(R8), or Y3;120.R4and R5are independently C1-6 alkyl or C1-2 deuteroalkyl, or R4and R5are taken together with their intervening atom(s) to form a 3-5 membered saturated carbocyclic ring;121.R6is C1-6 alkyl or C3-6 cycloalkyl;122.R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;123.**124.V-Nxz> N125.A126. 127.1is N or Y4, wherein ** is a point of attachment to A2;128.A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Y5; wherein the phenylene and heteroarylene are substituted with n occurrences of R3;129.L1is a C1-3 alkylene; Y1is -C(O)N(R7)(R8), -N(R7)C(O)(R6), -CO2R7,131.

132. Y2is -C=C-(Ci-3alkylene)-N(R7)SO2-R6, -C=C-(Ci-3alkylene)-SO2-N(R7)(R8), -C=C-(CO-3 alkylene)-N(R7)C(O)R6, -C=C-(Co-3 alkylene)-C(O)N(R7)(R8), -C=C-(Ci-3 alkylene)-O-(C3-6 cycloalkyl), -C=C-(Ci-3 alkylene)-O-(Ci-s haloalkyl), -C=C-(Ci-5haloalkyl), -C=C-(cyclobutyl), -C=C-(C(CH3)2(OH)), -C=C-(hydroxycyclopropyl), -C=C-(Ci-3alkylene)-N(R7)(4-6 membered saturated heterocyclyl containing 1 oxygen atom), -C=C-(Ci-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -C=C-(Ci-3 alkylene)-(triazolyl optionally substituted by one phenyl which is optionally substituted by one C1-3 alkyl), -C=C-(Ci-3 alkylene)-(imidazolylene)-(phenylene)-N(R7)(R8),133.OH134.(Ci-3alkylene)-N(R7)— N136.

137. , -(azetidinylene substituted with 1 or 2 occurrences of Ci-4alkyl)-Z2, -(azetidinyl substituted with one Ci-4 haloalkyl and one Ci-4 alkyl), -(azetidinyl substituted with one Ci-4 alkyl and one Ci-3 alkylene-O-C3-6 cycloalkyl), -(azetidinyl substituted with one Ci-4 haloalkyl and one Ci-4 alkyl), -(azetidinyl substituted with one Ci-4 alkyl and one -(Co-4 alkylene)-(Ci-4haloalkoxyl)), -(Co-3 alkylene)-CN, -(C2alkynylene)-CN, Ci-4 haloalkyl, -(C0-3 alkyl ene)-C(O)N(R7)(R8), -O-(Ci-3alkylene)-C(O)N(R7)(R8), -N(R7)-(CI-3alkylene)-C(O)N(R7)(R8), C3-7 cycloalkyl, -(7-10 membered spirocyclic hydroxy-substituted saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R7)-(CI-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur), phenyl, benzyl, (Ci-4alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C1-4 alkylene)-(C3-6 cycloalkyl), or hydrogen;138.Y3is -N(R7)(CI-4 deuteroalkyl) or -N(CI-4 deuteroalkyl)2;140.

141. , or, wherein ** is a point of attachment to A2;142.Y5is143.

144. N F substituted with n occurrences of R3;145.Z1is Ci -10 aliphatic, -(C0-3 alkylene)-(3-7 membered saturated heterocyclyl containing 1, 2, or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclyl is substituted with 1, 2, or 3 groups independently selected from C1-6 alkyl and C1-6 hydroxyalkyl), -N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -(C0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), -N(R7)-(CI-IO optionally substituted aliphatic)-, or C1-6 hydroxyalkyl;146.Z2is one of the following:147.(d) 3-7 membered saturated heterocyclyl substituted 1 or 2 occurrences ofR3, (e) -(Co-3 alkylene)-N(R7)-(Co-3 alkylene)-(5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur), or148.(f) 5-6 membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and n is 0, 1, or 2;149.wherein there is at least one occurrence of Y1, Y2, Y3, Y4, or Y5; and150.**151.provided that when152.

153. Y4is, then R3is not methyl; and154.wherein Formula 1-5 is represented by:

156. 158.1-5159.or a pharmaceutically acceptable salt thereof, wherein:160.A1is a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-membered unsaturated oxo-heterocyclylene containing 1 nitrogen atom; or phenylene; each of which is substituted with m occurrences of R3;161.A2is phenylene, a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is substituted with n occurrences of R4;162.L1is a Ci-6 bivalent straight or branched saturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-;163.L2is -C(O)N(R5)-, -N(R6)C(O)-, -N(R6)-, -N(R6)-(CI-4alkylene)-, -(Ci-4alkylene)-N(R6)-, -S(O)2N(R5)-, -N(R6)S(O)2-, -CO2-, or -OC(O)-;164.R1is -C(O)N(R7)(R8), a 6-11 membered saturated or partially unsaturated, bridged or spirocyclic, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein each of said bicyclic heterocyclic ring and monocyclic heterocyclic ring are substituted with q instances of R9;165.R2is -(C2-4 alkynylene)-(C3-7 cycloalkyl) or hydrogen;166.R3represents independently for each occurrence C1-6 alkyl or halo;167.R4represents independently for each occurrence C1-6 alkyl, halo, hydroxyl, Ci-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8);168.R5is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen; or R5and one occurrence of R4are taken together with their intervening atoms to form a 5-6 membered ring containing 1 nitrogen atom;169.R6is C1-6 alkyl, C3-6 cycloalkyl, or hydrogen;170.R7and R8each represent independently for each occurrence hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; or R7and R8are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;171.R9represents independently for each occurrence C1-6 alkyl, halo, hydroxyl, Ci-6 alkoxyl, or C3-6 cycloalkyl; and172.m, n, and q are independently 0, 1, or 2;173.Rg N174.N175.wherein if R1, L1, A1and L2taken together form176.

177. N'", then n is 1 or 2, and R4represents independently for each occurrence halo, hydroxyl, Ci-6 alkoxyl, C3-6 cycloalkyl, or -N(R7)(R8).

2. The method of claim 1, wherein the compound is a compound of Formula 1-1, or a pharmaceutically acceptable salt thereof.

3. The method of claim 2, wherein the compound is any one of formula I-l-a-1, 1- l-a-2, 1-l-a-3, 1-l-b-1, 1-l-b-2, I-l-b-3, 1-l-c-1, 1-l-c-2, 1-l-c-3, 1-l-d-1, I-l-d-2, or I-l-d-3:(R2)m O180.(R2)m O181.I-l-a-2 I-l-a-1182.(R2)m O (R2)m O183.I-l-b-1 (R2)m O (R2)m O184.(R2)m O (R2)m O185.(R3)0-2 (R3)0-2186.(R2)m O (R2)m O187.I-l-d-1188.

189. I-l-c-3190.

191. or a pharmaceutically acceptable salt thereof.

4. The method of claim 2, wherein the compound is any one of formulae I-l-e-1, 1-193.(R2)m / R4\ / o (R )p194.(R3)O-2195.( / / R2)mn o ( (RR4) )p196.(R3)0-2197.(R2)m / o (R4)p / (R2)mr o. t (RR*t )p R1-L1198.(R3)0-2 (R3)O-2199.(R2)m0(R4)p / / (R2)m„ O ( (RR^ )p R1^=200.(R3)0-2 (R3)O-2201.

202. or a pharmaceutically acceptable salt thereof. The method of claim 2, wherein the compound is any one of formulae I-l-g-1, 1-203.I-l-j-2, or I-l-j-3:204.(R2)m205.(R3)O-2 (R4)O-2206.(R2)m207.(R3)O-2208.(R2)m / o (R4)P R1-L1209.I? (R4)O-2 (R3)0-2210.(R )m zo4\ / o y 'p T0(R4)_211.(R3)0-2 (R3)0-2212.

213. (Rd)o-2215.

216. (Rd)0-2217.I-l-i-3 I-l-j-1219.

220. (R4)0-2221.I-l-j-2 I-l-j-3 or a pharmaceutically acceptable salt thereof.

6. The method of claim 2, wherein the compound is any one of formulae II-l-a-1, II-l-a-2, II-l-a-3, II-l-b-1, II-l-b-2, II-l-b-3, II-l-c-1, II-l-c-2, II-l-c-3, II-l-d-1, II-l-d-2, or II-1-d-3:

224. 226.II-l-a-1 II-l-a-2 II-l-a-3227.II-l-b-2229. 231.II-l-d-2 II-l-d-3 or a pharmaceutically acceptable salt thereof.

7. The method of claim 2, wherein the compound is any one of formulae II-l-e-1, II-l-e-2, II-l-e-3, II-l-f-1, II-l-f-2, or II-l-f-3:

234.

235. II-l-e-1 II-l-e-2236.II-l-e-3 II-l-f-1238. 240.II-l-f-2 II-l-f-3 or a pharmaceutically acceptable salt thereof.

8. The method of claim 2, wherein the compound is any one of formulae II-l-g-1, II-l-g-2, II-l-g-3, II-l-h-1, II-l-h-2, II-l-h-3, II-l-i-1, II-l-i-2, II-l-i-3, II-l-j-1, II-l-j-2, or II-l-j-3:242.II-l-g-1 II-l-g-2243.II-l-g-3 II-l-h-1244.II-l-h-2 II-l-h-3246.

247. II-l-i-1 II-l-i-2249.

250. II-l-i-3 II-l-j-1252.

253. II-l-j-2 II-l-j-3 or a pharmaceutically acceptable salt thereof.

9. The method of claim 2, wherein the compound is of formula III-l-e-1:

256. 258.III-l-e-1259.or a pharmaceutically acceptable salt thereof.

10. The method of claim 2, wherein the compound is of formula III-l-f-1:

261. 263.or a pharmaceutically acceptable salt thereof.

11. The method of claim 2, 3, or 6, wherein the Ring A is phenyl; a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. The method of claim 2, 3, or 6, wherein Ring A and its R2substituents is266.0268.

269.

13. The method of claim 12, wherein two R2groups are taken together to form =0 and Ring A is271.

14. The method of claim 2, wherein Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

15. The method of claim 2, wherein Ring B and its R3substituents is276.

278.

279.

16. The method of claim 15, wherein two R3groups are taken together to form =0 and Ring B is280.

281. o282.(R3)0-2284.

17. The method of claim 16, wherein two sets of R3groups are taken together to each O o287.N N288.form =0 and Ring289.

290. B is O or O18. The method of any one of claims 2, 4, 7, 9, or 14-17, wherein Ring C is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; a 4-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; an 8-10 membered bicyclic heteroaromatic ring (having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

19. The method of any one of claims 2, 4, 7, 9, or 14-17, wherein Ring C and its R4294.

296.

20. The method of any one of claims 2-8 or 10-19, wherein R1is a group selected from (i) a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a Ci-6 aliphatic; each of which is substituted with q instances of R5; and (ii) -CN or -OR.

21. The method of any one of claims 2-8 or 10-19, wherein R1is methyl, -OMe, -CN,300.

301.

22. The method of any one of claims 2-8 or 11-21, wherein L1is a covalent bond,303.

304.

23. The method of any one of claims 2-8 or 11-22, wherein L2is a covalent bond,305.

306.

24. The method of any one of claims 2, 4, 5, 7, 8, or 11-13, wherein L3is a covalent307.bond,308.

25. The method of any one of claims 2-8, 11, or 12, wherein m is 1, 2, 3, or 4.

26. The method of any one of claims 2, 14, or 15, wherein n is 1, 2, 3, or 4.

27. The method of any one of claims 2-26, wherein p is 1, 2, 3, or 4.

28. The method of claim 2, wherein Ring A is phenyl; Ring B is a 6-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Ring C is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R1is a 3-7 membered saturated monocyclic carbocyclic ring; each instance of R2, R4, and R5is independently hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, -SR, or -NR2; each Rzis an optionally substituted C1-6 aliphatic; each instance of R3is independently hydrogen, halogen, or -OR; or two R3groups are optionally taken together to form =0; L1is a C1-5 bivalent straight or branched unsaturated hydrocarbon chain; L2and L3are independently a C1-3 bivalent straight or branched saturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -0-; each R is independently hydrogen or an optionally substituted C1-6 aliphatic; m is 0, 1, or 2; n is 2, 3, or 4; and p is 0, 1, or 2.

29. The method of claim 2, wherein the compound is represented by315.m o316.LV.0317.3319. 321.or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein R1is a 3-7 membered saturated monocyclic carbocyclic ring; each instance of R2and R4is independently hydrogen, deuterium, Rz, halogen, -CN, -NO2, -OR, -SR, or -NR2; each Rzis an optionally substituted C1-6 aliphatic; each instance of R3is independently hydrogen, halogen, or -OR; L1is a Ci-5 bivalent straight or branched unsaturated hydrocarbon chain; L2and L3are independently a C1-3 bivalent straight or branched saturated hydrocarbon chain wherein 1 methylene unit of the chain is optionally replaced with -O-; each R is independently hydrogen or an optionally substituted C1-6 aliphatic; m is 0, 1, or 2; and p is 0, 1, or 2.

31. The method of claim 1, wherein the compound is a compound of Formula 1-2 or pharmaceutically acceptable salt thereof.

32. The method of claim 1, wherein the compound is a compound of Formula 1-2.

33. The method of claim 31, wherein the compound is a compound of Formula 1-2-325.N I A1327.

328. >2329.I-2-a330.or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the compound is a compound of formula I-2-a.

35. The method of any one of claims 31-34, wherein R2represents independently for each occurrence Ci-4 alkyl.

36. The method of any one of claims 31-34, wherein R2is Y2, and Y2represents independently for each occurrence C1-4haloalkyl, Ci-4alkoxyl, or C3-6 cycloalkyl.

37. The method of any one of claims 31-36, wherein L1is C1-4 alkylene.

38. The method of any one of claims 31-36, wherein L1is C3-4 haloalkylene, C1-4 hydroxyalkylene, or cyclopropylene.

39. The method of any one of claims 31-36, wherein L1is Y5, and Y5is C2-4 alkenylene, C1-2 haloalkylene, or -(C1-4 alkylene substituted with C1-4 alkoxyl or C3-6 cycloalkyl)-.

40. The method of claim 31, wherein the compound is a compound of formula I-2-b, I-2-c, or I-2-d:

338.

339. or a pharmaceutically acceptable salt thereof.

41. The method of claim 40, wherein the compound is a compound of formula I-2-b, I-2-c, or I-2-d42. The method of any one of claims 31-41, wherein R1is -O-(C1-5alkylene)-Z1.

43. The method of any one of claims 31-42, wherein Z1is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the heteroaryl is substituted with n occurrences of R5.

44. The method of any one of claims 31-42, wherein Z1is -C(O)N(R4)2.

45. The method of any one of claims 31-41, wherein R1is344.

347.

348. O46. The method of any one of claims 31-41, wherein R1is Y1.

47. The method of any one of claims 31-41 or 46, wherein Y1is -O-(Ci-5 alkylene)- C(O)N(R6)(R7), -O-(C1-5alkylene)-SO2N(R6)2, or -O-(Ci-5alkylene)-CO2R6.

48. The method of any one of claims 31-41 or 46, wherein Y1is -OCH2- C(O)N(R6)(R7).

49. The method of any one of claims 31-41 or 46-48, wherein R7is C2-6alkyl, Ci-4 haloalkyl, C3-6 cycloalkyl, or a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said cycloalkyl and heterocyclic ring are substituted with p substituents independently selected from halo and C1-4 alkyl.

50. The method of any one of claims 31-41 or 46-48, wherein R7and R6are taken together with the nitrogen atom to which they are attached to form a 3-7membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, wherein said ring is substituted with p substituents independently selected from halo and Ci-4 alkyl.

51. The method of any one of claims 31-41 or 46, wherein Y1is -O-(Ci-5 haloalkylene)-N(R6)2, -O-(Ci-5 alkylene)-(C3-6 cycloalkylene)-N(R6)2, or -O-(Ci-s alkylene)-(3-7 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R6)2.

52. The method of any one of claims 31-41 or 46, wherein Y1is one of the following:355.• -S-(C1-5alkylene)-Z2, -O-C(O)-Z2, or -N(R6)C(O)-Z2; wherein each Z2is substituted with n occurrences of R5; or356.• -O-(Ci-5 alkylene)-Z2, wherein Z2is substituted with (i) one -N(R6)SO2-(CI- 4 alkyl) or -N(R6)SO2-(C1-4haloalkyl), and (ii) n occurrences of R5.

53. The method of any one of claims 31-41 or 46, or 52, wherein Z2is pyrimidinyl.

54. The method of any one of claims 31-53, wherein A1is phenylene substituted with q occurrences of R8.

55. The method of any one of claims 31-53, wherein A1is359. 361.R8363.

56. The method of any one of claims 31-53, wherein A1is pyridinylene or piperidinylene, each of which is substituted with q occurrences of R8.

57. The method of any one of claims 31-53, wherein A1is Y4.

58. The method of any one of claims 31-53 or 57, wherein Y4is -C=C-,369.

370. phenylene is substituted with 1 cyano, hydroxyl, or -N(R6)2.

59. The method of any one of claims 31-53 or 57, wherein Y4is372.

373. oxazolylene, pyridazinylene, azetidinylene, or pyrrolidinylene.

60. The method of any one of claims 31-59, wherein R3is -(C2-4 alkynylene)-(C3-6 cycloalkyl), -(C2-4 alkenylene)-(C3-6 cycloalkyl), -(Co-4 alkylene)-(C3-6 cycloalkyl), -(phenylene)-(C3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C3-6 cycloalkyl), -C=C-(C 1-4 alkyl), or C1-6 alkyl.

61. The method of any one of claims 31-59, wherein R3is -C(H)=C(H)-(cyclopropyl), -(C0-2 alkylene)-(cyclopropyl), -(phenylene)- (cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)- (cyclopropyl), or -C=C-(Ci-4 alkyl).

62. The method of any one of claims 31-59, wherein R3is376.

377. *.

63. The method of any one of claims 31-59, wherein R3is C1-6 alkoxyl, C1-6 haloalkoxyl, -0-(Co-6 alkylene)-phenyl, or -0-(Co-6 alkylene)-(5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

64. The method of any one of claims 31-59, wherein R3is Y3.

65. The method of any one of claims 31-59 or 64, wherein Y3is -(C2-4 alkynylene)- (cyclopropyl substituted with 1 or 2 groups independently selected from halo, Ci- 4 alkyl, C1-4haloalkyl, and hydroxyl).

66. The method of any one of claims 31-59 or 64, wherein Y3is -C=C-C=C-(Ci-5382.aliphatic),383.

384. -C=C-CN,C=^, or C1-4haloalkyl.

67. The method of any one of claims 31-59 or 64, wherein Y3is -(C3-6 cycloalkylene)- (C3-6 cycloalkyl), -(C3-6 cycloalkylene)-(Ci-4 haloalkyl), or -(phenylene)-(Ci-4 haloalkyl).

68. The method of any one of claims 31-59 or 64, wherein Y3is -O-(Ci-8 alkylene)- Z3or hydroxyl.

69. The method of claim 1, wherein the compound is selected from those described in Tables 1-12.

70. The method of claim 1, wherein the compound is o -388.o n0390.

391. or a pharmaceutically acceptable salt thereof.

71. The method of any one of claims 1 -70, wherein the patient has a Body Mass Index > 25 kg / m2.

72. The method of any one of claims 1-70, wherein the patient has a Body Mass Index > 28 kg / m2.

73. The method of any one of claims 1 -70, wherein the patient has a Body Mass Index > 30 kg / m2.

74. The method of any one of claims 1-70, wherein the patient has a Body Mass Index in the range of 30 kg / m2to 35 kg / m2.

75. The method of any one of claims 1-74, wherein the cardiovascular disease is dyslipidemia.

76. The method of any one of claims 1-74, wherein the cardiovascular disease is hypercholesterolemia.

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