GPR84 antagonists and uses thereof

Abstract

The present invention provides compounds of formula (I), compositions thereof, and methods of using them for the inhibition of GPR84 and the treatment of GPR84-mediated disorders. TIFF2024505571000765.tif38164

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 144,720, filed February 2, 2021, the contents of which are incorporated herein by reference.

[0002] Technical Field The present invention relates to compounds and methods useful for antagonizing G protein-coupled receptor 84 (GPR84). The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention, and methods of using the compositions in the treatment of various disorders. [Background technology]

[0003] G protein-coupled receptor 84 (GPR84), also known as EX33, GPCR4, and G protein-coupled receptor 84, is a medium-chain fatty acid receptor that is primarily expressed in immune cells and upregulated under inflammatory conditions.

[0004] GPR84 was isolated and characterized from human B cells as a result of an expressed sequence tag data mining strategy (Wittenberger et al. 2001. J. Mol. Biol. 307, 799-813) and using a degenerate primer reverse transcription polymerase chain reaction (RT-PCR) approach aimed at identifying novel chemokine receptors expressed in neutrophils (Yousefi S et al. 2001. J. Leukoc. Biol. 69, 1045-1052). GPR84 remained an orphan GPCR until the identification of medium-chain free fatty acids (FFAs) with carbon chain lengths of 9–14 as ligands for this receptor (Wang J et al. 2006. J. Biol. Chem. 281, 34457-34464). GPR84 has been described to be activated by capric acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0), with potencies of 5 μM, 9 μM, and 11 μM, respectively. Three small molecules have also been described to have some degree of GPR84 agonist activity: 3,3'-diindolylmethane (Wang et al. 2006), embelin (Hakak Y et al. 2007, WO2007027661(A2)), and 6-n-octylaminouracil (6-OAU) (Suzuki M et al. 2013, J. Biol. Chem. 288, 10684-10691).

[0005] GPR84 has been shown to be expressed in immune cells, including, but not limited to, polymorphonuclear leukocytes (PMNs), neutrophils, monocytes, T cells, and B cells (Hakak et al. 2007; Venkataraman C, Kuo F. 2005. Immunol. Lett. 101, 144-153; Wang et al. 2006; Yousefi et al. 2001). Higher levels of GPR84 were measured in neutrophils and eosinophils than in T cells and B cells. GPR84 expression was demonstrated in tissues that may play a role in the propagation of inflammatory responses, such as the lung, spleen, and bone marrow.

[0006] For example, in a recent review, duBois reported on the current state of treatment for pulmonary interstitial diseases such as idiopathic pulmonary fibrosis (IPF). There are nearly 300 different damaging or inflammatory causes of interstitial lung diseases that can cause diffuse pulmonary scarring, and inflammation is very likely involved in the early stages of IPF pathology (duBois RM. 2010. Nat. Rev. Drug Discov. 9, 129-140), and combination therapies including anti-inflammatory treatments may be advantageously used.

[0007] The expression of GPR84 was highly upregulated in monocytes / macrophages upon LPS stimulation (Wang et al. 2006).

[0008] GPR84 knockout (KO) mice are viable and indistinguishable from wild-type littermate controls (Venkataraman & Kuo 2005). Proliferation of T and B cells in response to various mitogens has been reported to be normal in GPR84-deficient mice (Venkataraman & Kuo 2005). T helper 2 (Th2)-differentiated T cells from GPR84 KO mice secreted higher levels of the three major Th2 cytokines, IL-4, IL-5, and IL-13, compared with wild-type littermate controls. In contrast, production of the Th1 cytokine INF-γ was similar in Th1-differentiated T cells from GPR84 KO mice and wild-type littermates (Venkataraman & Kuo 2005).

[0009] Furthermore, capric acid, undecanoic acid, and lauric acid dose-dependently increased the secretion of interleukin-12p40 subunit (IL-12p40) from LPS-stimulated RAW264.7 murine macrophage-like cells. The pro-inflammatory cytokine IL-12 plays a crucial role in promoting cell-mediated immunity and eradicating pathogens by inducing and maintaining T helper 1 (Th1) responses and inhibiting T helper 2 (Th2) responses. Medium-chain FFAs may influence the Th1 / Th2 balance through their direct action on GPR84.

[0010] Berry et al. identified a whole-blood 393-gene transcriptional signature of active tuberculosis (TB) (Berry MPR et al. 2010. Nature 466, 973-977). GPR84 was part of this whole-blood 393-gene transcriptional signature of active TB, indicating a potential role for GPR84 in infectious diseases.

[0011] GPR84 expression has also been reported in microglia, the primary immune effector cells of the central nervous system (CNS) of myelomonocytic origin (Bouchard C et al. 2007. Glia. 55, 790-800). As observed in peripheral immune cells, GPR84 expression in microglia is highly induced under inflammatory conditions, such as TNFα and IL-1 treatment, but also during endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuroinflammatory processes. These results suggest that GPR84 may be upregulated in the CNS not only during endotoxemia and multiple sclerosis, but also in all neurological conditions in which TNFα or IL-1β pro-inflammatory cytokines are produced, such as brain injury, infection, Alzheimer's disease (AD), and Parkinson's disease (PD).

[0012] GPR84 expression was also observed in adipocytes and was shown to be enhanced by inflammatory stimuli (Nagasasaki H et al. 2012. FEBS Lett. 586, 368-372). This result suggests that GPR84 expression is triggered by TNFα from infiltrating macrophages and exacerbates the vicious cycle between adiposity and diabetes / obesity, and therefore inhibition of GPR84 activity may be beneficial for the treatment of endocrine and / or metabolic diseases.

[0013] GPR84 expression is also upregulated in perineuronal microglia after nerve injury (Gamo et al., 2008. J. Neurosi. 28(46), 11980-11988). Furthermore, GPR84 knockout mice exhibit significantly reduced or completely abolished hypersensitivity to mechanical stimuli in mouse models of inflammatory and neuropathic pain (Nicol LSC et al., 2015. J. Neurosci. 35, 8959-8969). Therefore, molecules that block GPR84 activation may have the potential to produce widespread analgesia.

[0014] GPR84 expression is increased in human leukemia stem cells (LSCs) from acute myeloid leukemia (AML) patients compared with hematopoietic stem cells from healthy donors. GPR84 simultaneously enhances β-catenin signaling and the oncogenic transcriptional program essential for the establishment of MLL leukemia (Dietrich et al., 2014. Blood 124(22), 3284-3294). Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency, and impaired the reconstitution of stem cell-derived MLL leukemia, a particularly aggressive and drug-resistant subtype of AML. Targeting the oncogenic GPR84 / β-catenin signaling axis may represent a novel therapeutic strategy for AML and potentially other leukemias.

[0015] GPR84 expression is increased 49.9-fold in M1 macrophages isolated from aortic atherosclerotic lesions of LDLR- / - mice fed a Western diet (Kadl A et al. 2010. Circ. Res. 107, 737-746). Therefore, molecules targeting GPR84 may have potential benefits for the treatment of atherosclerosis.

[0016] In experimental esophagitis, GPR84 is upregulated in esophageal tissue, primarily in epithelial cells, and is significantly reduced in rats treated with either omeprazole (a proton pump inhibitor) or STW5, an herbal preparation shown to improve esophagitis without affecting refluxate pH (Abdel-Aziz H et al. 2015. Mol. Med. 21, 1011-1024). This finding is supported by Western blot and immunohistochemistry in rat tissue and HET-1A cells, a human esophageal squamous cell line. GPR84 was also found to be significantly upregulated in esophageal biopsies from patients with grade B reflux esophagitis. Therefore, molecules that block GPR84 receptor activity may represent a new therapeutic paradigm for the treatment of esophagitis.

[0017] Thus, the identification and development of novel compounds, processes for their preparation, and their use in the preparation of pharmaceuticals would be highly desirable for patients suffering from inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0018] Additionally, the identification and development of novel compounds for use in the preparation of medicaments for the prevention and / or treatment of one or more fibrotic diseases, particularly NASH and / or IPF, remains highly desirable. Summary of the Invention

[0019] It has now been found that compounds of the present invention, and pharmaceutically acceptable compositions thereof, are effective as antagonists of GPR84. In certain embodiments, the present invention provides compounds of the formulae presented herein.

[0020] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders, or conditions associated with GPR84, including those described herein.

[0021] The compounds provided by the present invention are also useful for studying GPR84 in biological and pathological phenomena; for studying fibrotic processes occurring in body tissues; and for the comparative evaluation in vitro or in vivo of new GPR84 inhibitors or other modulators of neutrophil and macrophage chemotaxis. DETAILED DESCRIPTION OF THE INVENTION

[0022] 1. Details of Specific Embodiments of the Invention: In certain embodiments, the present invention provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, 1 , L 2 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined below and described in the embodiments herein.

[0023] In some embodiments, the present invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0024] In some embodiments, the present invention provides a method for treating a GPR84-mediated disease, disorder, or condition, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof.

[0025] 2. Compounds and definitions: The compounds of the present invention include those generally described herein and are further exemplified by the classes, subclasses, and species disclosed herein.As used herein, the following definitions shall apply unless otherwise specified.For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition.In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Edition, Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0026] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation; or a monocyclic or bicyclic hydrocarbon (also referred to herein as a "carbocycle," "alicyclic," or "cycloalkyl") that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has one point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0027] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. According to the IUPAC definition, a "bridge" is an unbranched chain of atoms, atom, or valence bond connecting two bridgeheads, where a "bridgehead" refers to any skeletal atom of the ring system that is attached to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, in which each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those described for aliphatic groups. Additionally or alternatively, the substitutable nitrogen of a bridged bicyclic group is optionally substituted. Examples of bridged bicyclic groups include: [ka]

[0028] The term "lower alkyl" refers to a C1-4 straight or branched chain alkyl group. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0029] The term "lower haloalkyl" refers to a C1-4 straight or branched chain alkyl group substituted with one or more halogen atoms.

[0030] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (in the case of 3,4-dihydro-2H-pyrrolyl), NH (in the case of pyrrolidinyl), or NR+ (in the case of N-substituted pyrrolidinyl)).

[0031] As used herein, the term "unsaturated" means that any moiety has one or more units of unsaturation.

[0032] As used herein, the term "divalent C1-8 (or C1-6) saturated or unsaturated, straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0033] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0034] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0035] The term "halogen" means F, Cl, Br, or I.

[0036] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, in which at least one ring in the system is aromatic, and in which 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, such as, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl" as used herein.

[0037] The terms "heteroaryl" and "heteroar-," used alone or as part of a larger moiety, for example, "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms, in which 6, 10, or 14 π electrons are shared in a cyclic arrangement, and in addition to carbon atoms, have 1 to 5 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. Examples of heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl groups may be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

[0038] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic radical," and "heterocycle" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety, either saturated or partially unsaturated, 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 substituted nitrogen. By way of example, in saturated or partially unsaturated rings having 0 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (e.g., 3,4-dihydro-2H-pyrrolyl), NH (e.g., pyrrolidinyl), or +NR (e.g., N-substituted pyrrolidinyl).

[0039] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or alicyclic rings such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl portions independently are optionally substituted.

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

[0041] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogen atoms of the specified moiety have been 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 multiple positions in any given structure can be substituted with multiple substituents selected from a specified group, the substituents may be the same or different at all positions. Combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when exposed to conditions that allow for its production, detection, and, in certain embodiments, its 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; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0-4 Ph (can be substituted with R°; -(CH2) 0-4 O(CH2) 0-1 Ph (can be substituted with R°; -CH=CHPh (can be substituted with R°; -(CH2) 0-4 O(CH2) 0-1-pyridyl (can be substituted by R°; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4 N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-N(R°)C(NR°)N(R°)2;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;-SiR°3;-(C 1-4 straight-chain or branched alkylene)ON(R°)2; or -(C 1-4 (linear or branched alkylene)C(O)ON(R°)2, where each R° is optionally substituted (e.g., with one, two, or more substituents) as defined below and independently represents hydrogen, C1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered, saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of R° 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] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms) are each independently —(CH) 0-2 R·, -(haloR·), -(CH2) 0-2 OH, -(CH2) 0-2 OR·, -(CH2) 0-2 CH(OR·)2; -O(HaloR·), -CN, -N3, -(CH2) 0-2 C(O)R·, -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR·, -(CH2) 0-2 SR·, -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR·, -(CH2) 0-2 NR·2, -NO2, -SiR·3, -OSiR·3, -C(O)SR·, -(C1-4 linear or branched alkylene)C(O)OR·, or -SSR · where each R· is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0-1 R is independently selected from Ph, 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 include ═O and ═S.

[0044] Suitable divalent substituents on saturated carbon atoms of an "optionally substituted" group include =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where 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 attached to adjacent substitutable carbon atoms of an "optionally substituted" group include -O(CR * 2) 2-3 O-, wherein R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below 1~6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Suitable substituents on the aliphatic group of R* include halogen, -R · ,-(Halo R · ), -OH, -OR · , -O(HaloR · ), -CN, -C(O)OH, -C(O)OR · , -NH2, -NHR · , -NR · 2, or -NO2, where each R · is unsubstituted or, if preceded by "halo", substituted only with one or more halogens, and independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R†)S(O)2R † wherein each R † are independently hydrogen, C which may be substituted as defined below 1~6 an aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, R † two independent occurrences of, taken together with their intervening atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] R † Suitable substituents on an aliphatic group include halogen, —R·, —(haloR·), —OH, —OR·, —O(haloR·), —CN, —C(O)OH, —C(O)OR·, —NH2, —NHR·, —NR·2, or —NO2, where each R· is unsubstituted or, if preceded by “halo”, substituted only with one or more halogens, and independently is selected from the group consisting of: C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the normal scope of sound medical judgment, and that is 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, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of salts include phosphate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0049] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N(Ci_4 alkyl) salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations, formed where appropriate using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0050] 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, R and S configurations of each asymmetric center, Z and E double bond isomers, Z and E structural isomers, etc. Thus, single stereochemical isomers of the compounds of the invention, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures, are within the scope of the invention. Unless otherwise stated, all tautomers of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structure, such as the replacement of a hydrogen with deuterium or tritium, or the replacement of a carbon with a C- or C-enriched carbohydrate, are within the scope of the invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents according to the invention.

[0051] In certain embodiments, R1 of provided compounds comprises one or more deuterium atoms. In certain embodiments, R2 of provided compounds comprises one or more deuterium atoms. In certain embodiments, R3 of provided compounds comprises one or more deuterium atoms. In certain embodiments, R4 of provided compounds comprises one or more deuterium atoms. In certain embodiments, R5 of provided compounds comprises one or more deuterium atoms. In certain embodiments, L1 of provided compounds comprises one or more deuterium atoms. In certain embodiments, L2 of provided compounds comprises one or more deuterium atoms. In certain embodiments, L3 of provided compounds comprises one or more deuterium atoms. In certain embodiments, ring A of provided compounds comprises one or more deuterium atoms. In certain embodiments, ring B of provided compounds comprises one or more deuterium atoms. In certain embodiments, ring C of provided compounds comprises one or more deuterium atoms. In certain embodiments, R of provided compounds can be substituted with one or more deuterium atoms. In certain embodiments, R of provided compounds can be substituted with one or more deuterium atoms. z may be substituted with one or more deuterium atoms. In certain embodiments, X of provided compounds may be substituted with one or more deuterium atoms.

[0052] Drawn structures represent relative configuration unless indicated as absolute configuration. The present invention contemplates individual enantiomers and racemic mixtures.

[0053] As used herein, a "GPR84 antagonist" or "GPR84 inhibitor" refers to a molecule that reduces, inhibits, or otherwise decreases one or more of the biological activities of GPR84 (e.g., Gαi signaling, increased immune cell migration, and secretion of pro-inflammatory cytokines). Antagonism using a GPR84 antagonist does not necessarily indicate complete elimination of GPR84 activity. Instead, activity may be reduced by a statistically significant amount, such as at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% reduction in GPR84 activity compared to an appropriate control. In some embodiments, a GPR84 antagonist reduces, inhibits, or otherwise decreases GPR84 activity. The compounds disclosed herein bind directly to GPR84 and inhibit its activity.

[0054] By "specific antagonist" is meant an agent that reduces, inhibits, or decreases the activity of a defined target to a greater extent than the activity 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 against 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 against a non-target. The compounds disclosed herein may or may not be specific GPR84 antagonists. Certain GPR84 antagonists reduce 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 closely related GPCRs (e.g., free fatty acid receptors (FFARs) such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other types of GPCRs (such as class A GPCRs).

[0055] The compounds of the present invention may be tethered to a detectable moiety. It will be understood that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety can be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently attached to the detectable moiety. Such moieties are well known to those skilled in the art and include groups containing carboxylate, amino, thiol, or hydroxyl moieties, to name just a few. It will be understood that such moieties can be attached directly to the provided compound or via a tethering group such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art, including 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 can be attached via strained alkynes. Methods using strained alkynes to enable rapid Cu-free click chemistry are known in the art, including those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0056] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that is detectable, such as primary labels and secondary labels. Radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), primary labels, such as mass tags and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0057] As used herein, the term "secondary label" refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radiative fluorescence resonance energy transfer (FRET), which then generates a detectable signal.

[0058] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, the 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 (BODIPYFL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY530 / 550, BODIPY558 / 568, BODIPY564 / 570, BODIPY576 / 589, BODIPY581 / 591), BODIPY630 / 650, BODIPY650 / 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'-Dimethoxyfluorescein, DM-NERF, Eosin, Erythrosine, Fluorescein, FAM, Hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), 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.

[0059] The term "mass tag" as used herein refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretic release tags such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone and its derivatives. The synthesis and usefulness of these mass tags are described in U.S. Patent Nos. 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 various lengths and base compositions, oligopeptides, oligosaccharides, and other synthetic polymers of various lengths and monomer compositions. A variety of neutral and charged organic molecules (biomolecules or synthetic compounds) in the appropriate mass range (100-2000 daltons) can also be used as mass tags.

[0060] The compounds of the present invention can be tethered to E3 ligase binding moieties. It will be understood 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). Those skilled in the art will recognize that E3 ligase binding moieties can be attached to provided compounds via suitable substituents as defined above. Such degraders have been found to be useful for targeted degradation of G protein-coupled receptors (Li et al. Acta Pharm. Sin. B. 2020, 10(9), 1669-1679).

[0061] As used herein, the term "E3 ligase binding moiety" is used interchangeably with the term "E3 ligase binder" and relates to any moiety that is capable of binding to and / or recruiting an E3 ligase (e.g., cIAP1, MDM2, cereblon, VHL, APC / C) for targeted degradation.

[0062] The compound of the present invention can be tethered to a lysosome targeting moiety.It will be understood that such a compound is useful as a degrading agent (see, for example, Banik et al.2020.Nature584,291-297).Those skilled in the art will recognize that a lysosome targeting moiety can be attached to the provided compound via a suitable substituent as defined above.Such a degrading agent has been found to be useful for the targeted degradation of secretory proteins and membrane proteins (Banik et al.2020).

[0063] As used herein, the term "lysosome targeting moiety" is used interchangeably with the term "lysosome binding moiety" and relates to any moiety that is 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.

[0064] As used herein, the terms "measurable affinity" and "measurable inhibition" refer to a measurable change in GPR84 activity between a sample containing a compound of the present invention or a composition thereof and GPR84 GPCR and an equivalent sample containing GPR84 GPCR in the absence of the compound or composition thereof.

[0065] 3. Description of Exemplary Embodiments As noted above, in certain embodiments, the present invention provides compounds of formula I: [ka] or 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 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 carbocycle; Ring B is a 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1 is selected from (i) a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 11-membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and C 1~6 Aliphatic; each is R 4 is substituted with p instances of; and (ii) is hydrogen; R 2 , R 4 , and R 5 Each instance of is independently hydrogen, deuterium, or R z, 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 The Two R's 2 the groups optionally taken together form =O; The Two R's 4 the groups optionally taken together form =O; The Two R's 5 the groups optionally taken together form =O; The Two R's 2 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The Two R's 4 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's 5 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R z An instance of C 1~6Independently selected from optionally substituted groups selected from aliphatic, phenyl; 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 3 is hydrogen, or optionally substituted by C 1~6 is an aliphatic group; or The Two R's 3 groups optionally taken together to form =O; or R 2 Groups and R 3 groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated, partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is one of the following: (a)C 1~6 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein 1 to 3 methylene units of the chain are independently optionally replaced by -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-; (b) Covalent bonding; each -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3- to 7-membered saturated or partially unsaturated carbocyclylene; a 4- to 7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 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- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 is a covalent bond or C 1~4a divalent linear or branched saturated or unsaturated hydrocarbon chain, wherein one to two methylene units of the chain are independently and optionally replaced by -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-; L 3 is one of the following: (a)C 1~4 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; (b) Covalent bonding; X is one of the following: (a) a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bridged or spirocyclic bicyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; or phenyl; each of which is selected from q R 5 be replaced with an instance of; or (b) -CH2(OR), -CH(R)(OR), or -C(R)2(OR); Each instance of R is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic; phenyl; an 8- to 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same atom optionally taken together with the atom 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; q is 0, 1, 2, 3, 4, or 5).

[0066] As generally defined 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 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 carbocycle;

[0067] 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 heterocycle 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 carbocycle.

[0068] In some embodiments, ring A is [ka] In some embodiments, the left side of ring A is [ka] L 1 is connected to the right side of ring A. [ka] L 2 In some embodiments, the right side of ring A is connected to [ka] L 1 is connected to the left side of ring A. [ka] L 2 is connected to.

[0069] In some embodiments, ring A is selected from those shown in Table 1 below.

[0070] As generally defined above, Ring B is a 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0071] In some embodiments, Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] In some embodiments, Ring B is a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0073] In some embodiments, ring B is [ka] is.

[0074] In some embodiments, two R 3 The groups together form =O and ring B is [ka] In some embodiments, two R 3 The groups together form =O and ring B is [ka] In some embodiments, two R 3 The groups together form =O and ring B is [ka] In some embodiments, the left side of ring B is [ka] L 2 and on the right side of ring B [ka] L 3 In some embodiments, the right side of ring B is connected to [ka] L 2 is connected to the left side of ring B. [ka] L 3 is connected to.

[0075] In some embodiments, ring B is selected from those shown in Table 1 below.

[0076] As generally defined above, R 1 is selected from (i) a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 11-membered saturated or partially unsaturated spiro bicyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and C 1~6 Aliphatic; each is R 4 is substituted with p instances of; and (ii) is hydrogen.

[0077] In some embodiments, R 1 pR 4 In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with an instance of 1 pR 4 In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR4 In some embodiments, R is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR 4 In some embodiments, R is a 7- to 11-membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR 4 C being replaced with an instance of 1~6 In some embodiments, R 1 pR 4 In some embodiments, R is phenyl substituted with an instance of 1 is hydrogen.

[0078] In some embodiments, R 1 teeth, [ka] is.

[0079] In some embodiments, two R 4 The groups together form =O and R 1 teeth, [ka] In some embodiments, two R 4 The groups together form =O and R 1 teeth, [ka] In some embodiments, two R 4 The groups together form =O and R 1 teeth, [ka] is.

[0080] In some embodiments, two sets of R 4 The groups together form =O, and R 1 teeth, [ka] is.

[0081] In some embodiments, R 1 teeth, [ka] In some embodiments, -L 1 -R 1 teeth, [ka] is.

[0082] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0083] As generally defined above, R 2 , R 4 , and R 5 Each instance of is independently hydrogen, deuterium, or R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0084] In some embodiments, R 2 is hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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( In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -P(O)(R)NR, -P(O)(R)OR, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -Si(OR). ... 2 is hydrogen. In some embodiments, R 2 is R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0085] In some embodiments, R 2are methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, -CF3, -OCH3, -N(CH3)2, -OCH2CH2OH, -CH2CF3, -C(O)CH3, -S(O)CH3, -S(O)2CH3, -OiPr, -SCH3, -CN, -C(O)NH2, -C(O)OCH3, -CH2OH, -CH2CN, -CO2H, -OCF3, -OCHF2, [ka] is.

[0086] In some embodiments, R 2 is selected from those shown in Table 1 below.

[0087] As generally defined above, R 4 is hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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( In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -P(O)(R)NR, -P(O)(R)OR, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -Si(OR). ... 4 is hydrogen. In some embodiments, R 4 is R z, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0088] In some embodiments, R 4 are methyl, fluoro, -OCH3, -N(CH3)2, -OH, -CF3, -C(O)NH2, -CN, [ka] is.

[0089] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0090] As generally defined above, R 5 is hydrogen, deuterium, R z, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0091] In some embodiments, R 5 is methyl, fluoro, [ka] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0092] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0093] As generally defined above, two R 2 The groups optionally join together to form =O.

[0094] In some embodiments, two R 2 The groups together form =O.

[0095] As generally defined above, two R 4 The groups optionally join together to form =O.

[0096] In some embodiments, two R 4 The groups together form =O.

[0097] As generally defined above, two R 5 The groups optionally join together to form =O.

[0098] In some embodiments, two R 5 The groups together form =O.

[0099] As generally defined above, two R 2 The groups optionally together with their intervening atoms form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0100] In some embodiments, two R 2 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0101] As generally defined above, two R 4The groups optionally together with their intervening atoms form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0102] In some embodiments, two R 4 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0103] As generally defined above, two R 5 The groups optionally together with their intervening atoms form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0104] In some embodiments, two R 5 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0105] As generally defined above, each R z are independently selected from optionally substituted groups selected from C1-6 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.

[0106] In some embodiments, R z is C 1~6Selected from optionally substituted groups selected from aliphatic; phenyl; 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0107] In some embodiments, R z is selected from those shown in Table 1 below.

[0108] As generally defined above, R 3 is hydrogen or optionally substituted C 1~6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1~6 In some embodiments, R 3 is methyl. In some embodiments, R 3 is selected from those shown in Table 1 below.

[0109] As generally defined above, two R 3 The groups optionally join together to form =O. In some embodiments, two R 3 The groups together form =O.

[0110] As generally defined above, R 2 Groups and R 3 The groups optionally together with their intervening atoms form a 5-8 membered saturated, partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0111] In some embodiments, R 2 Groups and R 3 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0112] As generally defined above, L 1 is (a)C 1~6 wherein one to three methylene units of the chain are independently optionally replaced by -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.

[0113] In some embodiments, L 1 is (a)C 1~6 wherein 1 to 3 methylene units of the chain are independently optionally replaced by -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-.

[0114] In some embodiments, L 1 is a covalent bond.

[0115] In some embodiments, L 1 teeth, [ka] [ka] [ka] In some embodiments, L 1 to the left of [ka] is R 1 connected to L 1 to the right of [ka] is connected to ring A. In some embodiments, L 1 to the left of [ka] is R 1 connected to L 1 to the left of [ka] is connected to ring A.

[0116] In some embodiments, L 1 is selected from those shown in Table 1 below.

[0117] As generally defined above, each -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3- to 7-membered saturated or partially unsaturated carbocyclylene; a 4- to 7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 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- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0118] In some embodiments, -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3-7 membered saturated or partially unsaturated carbocyclylene; a 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.

[0119] In some embodiments, -Cy- is selected from those shown in Table 1 below.

[0120] As generally defined above, L 2 is a covalent bond or C 1~4 wherein one to two methylene units of the chain are independently and optionally replaced by -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-.

[0121] In some embodiments, L 2 is the coupling due to supply coupling.

[0122] In some embodiments, L 2 is a covalent bond or C 1~4 wherein one to two methylene units of the chain are independently and optionally replaced by -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-.

[0123] In some embodiments, L 2 teeth, [ka] is.

[0124] In some embodiments, L 2 is selected from those shown in Table 1 below.

[0125] As generally defined above, L 3 is (a)C 1~4wherein one to two methylene units of the chain are independently optionally replaced by -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.

[0126] In some embodiments, L 3 is C 1~4 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0127] In some embodiments, L3 is a covalent bond.

[0128] In some embodiments, L 3 teeth, [ka] In some embodiments, L 3 to the left of [ka] is connected to ring B, and L 3 to the right of [ka] is connected to X. In some embodiments, L 3 to the left of [ka] is connected to ring B, and L 3 to the left of [ka] is connected to X.

[0129] In some embodiments, L 3 is selected from those shown in Table 1 below.

[0130] As generally defined above, X is any one of the following: (a) a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bridged or spirocyclic bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle 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 carbocycle; or phenyl; each of which is selected from q R 5 or (b) -CH2(OR), -CH(R)(OR), or -C(R)2(OR).

[0131] In some embodiments, X is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bridged or spirocyclic bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle 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 carbocycle; or phenyl; each of which is selected from q R 5is replaced with an instance of

[0132] In some embodiments, X is —CH 2 (OR), —CH(R)(OR), or —C(R) 2 (OR).

[0133] In some embodiments, X is [ka] [ka] is.

[0134] In some embodiments, two R 5 The groups together form =O and X is [ka] is.

[0135] In some embodiments, two sets of R 5 The groups together form =O, and X is [ka] is.

[0136] In some embodiments, X is selected from those shown in Table 1 below.

[0137] Each instance of R may independently be hydrogen, or C, as generally defined above. 1~6an optionally substituted group selected from aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or 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; or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or; two R groups on the same nitrogen are optionally combined 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.

[0138] In some embodiments, R is hydrogen. In some embodiments, R is independently hydrogen, or C 1~6 an optionally substituted group selected from aliphatic; phenyl; an 8- to 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0139] In some embodiments, two R groups on the same nitrogen, taken together with the nitrogen, 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.

[0140] In some embodiments, R is selected from those shown in Table 1 below.

[0141] Generally, m is 0, 1, 2, 3, or 4, as defined above.

[0142] In some embodiments, m is 0, 1, 2, 3, or 4. 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.

[0143] In some embodiments, m is selected from those shown in Table 1 below.

[0144] Generally, n is 0, 1, 2, 3, or 4, as defined above.

[0145] In some embodiments, n is 0, 1, 2, 3, or 4. 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.

[0146] In some embodiments, n is selected from those shown in Table 1 below.

[0147] Generally, p is 0, 1, 2, 3, 4, or 5, as defined above.

[0148] In some embodiments, p is 0, 1, 2, 3, 4, or 5. 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 5.

[0149] In some embodiments, p is selected from those shown in Table 1 below.

[0150] Generally, q is 0, 1, 2, 3, 4, or 5 as defined above.

[0151] In some embodiments, q is 0, 1, 2, 3, 4, or 5. 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 5.

[0152] In some embodiments, q is selected from those shown in Table 1 below.

[0153] In some embodiments, the present invention provides compounds of formula I, wherein ring A is phenyl, ring B is triazolyl, and L 2 is a covalent bond), to provide a compound of formula Ia: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0154] In some embodiments, the present invention provides compounds of Formula I, wherein Ring A is pyridyl, Ring B is triazolyl, and L 2 is a covalent bond), and providing a compound of formula Ib-1, Ib-2, or Ib-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3, X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0155] In some embodiments, the present invention provides compounds of formula I, wherein ring A is thiophenyl, ring B is triazolyl, and L 2 is a covalent bond), to provide a compound of formula Ic: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0156] In some embodiments, the present invention provides compounds of formula I, wherein L 1 is acetylenyl, and L 2 is a covalent bond, ring A is phenyl, thiophenyl, or pyridyl, and ring B is triazolyl, resulting in a compound of formula If-1, If-2, If-3, If-4, If-5, If-6, If-7, If-8, or If-9: [ka] or a pharmaceutically acceptable salt thereof, wherein L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0157] In some embodiments, the present invention provides compounds of formula I, wherein ring B is triazolyl and L 3is methylene and X is oxetanyl, providing a compound of formula Ig-1, Ig-2, or Ig-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0158] In some embodiments, the present invention provides compounds of formula I, wherein ring B is triazolyl and L 3 is methylene and X is furanyl, providing a compound of formula Ih-1, Ih-2, or Ih-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0159] In some embodiments, the present invention provides compounds of formula I, wherein ring B is triazolyl and L 3 is methylene and X is tetrahydropyranyl, providing a compound of formula Ii-1, Ii-2, or Ii-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0160] In some embodiments, the present invention provides compounds of formula I, wherein ring B is triazolyl and L 3 is methylene and X is 1,4-dioxanyl, providing a compound of formula Ij-1, Ij-2, or Ij-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0161] In some embodiments, the present invention provides compounds of formula I, wherein ring B is triazolyl, ring A is phenyl, and L 2 is selected from —O—, —N(H)—, —N(Ac)—, —N(CH3)—, —S—, —S(O)—, or —S(O)2—), providing a compound of formula Ik-1: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0162] In certain embodiments, the compound of formula I is a compound of formula Ik-2: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0163] In certain embodiments, the compound of formula is a compound of formula Ik-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 3 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0164] In certain embodiments, the compound of formula I is a compound of formula Ik-4, Ik-5, or Ik-6: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , R 1 , R 2 , R 3 , R 5 Each of m, q, and n, both alone and in combination, is as defined above and as described in the embodiments herein. In certain embodiments, in Ik-5 and Ik-6, q is not 0 and R 5 is not hydrogen.

[0165] In certain embodiments, the compound of formula I is a compound of formula Il-1, Il-2, or Il-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , R 1 , and R 2 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein.

[0166] In certain embodiments, the compound of formula I is a compound of formula Im-1, Im-2, or Im-3: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , R 1 , R 2 , R 3 , L 3 and X, both alone and in combination, are as defined above and described in the embodiments herein.

[0167] In certain embodiments, the compound of formula I is a compound of formula In-1, In-2, or In-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein.

[0168] In certain embodiments, the compound of formula I is a compound of formula Io-1, Io-2, or Io-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R on the right side of the formula in this paragraph, both alone and in combination, is as defined above and as described in the embodiments herein. 2 is H, and R is meta to the nitrogen of pyridine (ring B). 2 is not H.

[0169] In certain embodiments, the compound of formula I is a compound of formula Ip-1, Ip-2, or Ip-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of these, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, in the formulas of this paragraph, R is meta to the point of attachment to the triazole (and para to the N of the pyridine). 2 is not H.

[0170] In certain embodiments, the compound of formula I is a compound of formula Iq-1, Iq-2, or Iq-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R in the formulas of this paragraph 2 R on the left side of 2 is H.

[0171] In certain embodiments, the compound of formula I is a compound of formula Ir-1, Ir-2, or Ir-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R on the right side of the formula in this paragraph, both alone and in combination, is as defined above and as described in the embodiments herein. 2 (in brackets) is H, and R is ortho to the nitrogen of pyridine (ring B). 2 is not H. In some embodiments, the R ortho to the pyridine N in the formula of this paragraph is 2is methyl.

[0172] In certain embodiments, the compound of formula I is a compound of formula Is-1, Is-2, or Is-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R in the formulas of this paragraph 2 R on the right side of 2 (down) is H. In some embodiments, R in the formulas of this paragraph 2 R on the left side of 2 (Upward) is not H.

[0173] In certain embodiments, the compound of formula I is a compound of formula It-1, It-2, or It-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R in the formulas of this paragraph 2 R on the right side of 2 is H. In some embodiments, in the formulas of this paragraph, R that is meta to the point of attachment to the triazole 2 is not H.

[0174] In certain embodiments, the compound of formula I is a compound of formula Iu-1, Iu-2, or Iu-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of R, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, R1 is cyclopropyl or -CHOR. In some embodiments, this R is H or methyl. In some embodiments, the R on the right side of the formula in this paragraph is 2 is H, and R is shown ortho to the triazole attachment point. 2 is not H.

[0175] In certain embodiments, the compound of formula I is a compound of formula Iv-1, Iv-2, or Iv-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of R, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, R 1 is cyclopropyl or -CHOR. In some embodiments, this R is H or methyl. In some embodiments, the R on the right side of the formula in this paragraph is 2 is H, and R is meta to the nitrogen of pyridine (ring B). 2 is not H.

[0176] In certain embodiments, the compound of formula I is a compound of formula Iw-1, Iw-2, or Iw-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of R, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, R 1 is cyclopropyl or -CHOR. In some embodiments, this R is H or methyl. In some embodiments, the R on the right side of the formula in this paragraph is 2 is H, and R is para to the pyridine nitrogen. 2 is not H.

[0177] In certain embodiments, the compound of formula I is a compound of formula Ix-1, Ix-2, or Ix-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R on the right side of the formula in this paragraph, both alone and in combination, is as defined above and as described in the embodiments herein. 2 is H. In some embodiments, R 1 is cyclopropyl or —CHOR. In some embodiments, R is H or methyl.

[0178] In certain embodiments, the compound of formula I is a compound of formula Iy-1, Iy-2, or Iy-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R on the right side of the formula in this paragraph, both alone and in combination, is as defined above and as described in the embodiments herein. 2 is H, and R is ortho to the pyridine nitrogen. 2 is not H. In some embodiments, R 1 is cyclopropyl or —CHOR. In some embodiments, R is H or methyl.

[0179] In certain embodiments, the compound of formula I is a compound of formula Iz-1, Iz-2, or Iz-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the groups, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, the group of formula R in this paragraph 2 R on the right side of2 (Downward R 2 In some embodiments, R 1 is cyclopropyl or —CHOR. In some embodiments, R is H or methyl.

[0180] In certain embodiments, the compound of Formula I is a compound of formula I-aa-1, I-aa-2, or I-aa-3: [ka]

[0181] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R groups in the formulae of this paragraph are 2 R on the right side of 2 is H. In some embodiments, R 1 is cyclopropyl or —CHOR. In some embodiments, R is H or methyl.

[0182] In certain embodiments, the compound of formula I is a compound of formula I-bb-1, I-bb-2, or I-bb-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, the R, ortho to the triazole attachment site of the formulas in this paragraph, 2 R to the right of 2 is H.

[0183] In certain embodiments, the compound of formula I is a compound of formula I-cc-1, I-cc-2, or I-cc-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein.

[0184] In certain embodiments, the compound of formula I is a compound of formula I-dd-1, I-dd-2, or I-dd-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the following, both alone and in combination, is as defined above and described in the embodiments herein.

[0185] In certain embodiments, the compound of formula I is a compound of formula I-ee-1, I-ee-2, or I-ee-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, the R, ortho to the pyridine nitrogen of the formula in this paragraph, 2 0 to 2 R's to the right of 2 is H.

[0186] In certain embodiments, the compound of formula I is a compound of formula I-ff-1, I-ff-2, or I-ff-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R groups in the formulae of this paragraph are 2 R on the right side of 2 (downward) is H.

[0187] In certain embodiments, the compound of formula I is a compound of formula I-gg-1, I-gg-2, or I-gg-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R groups in the formulae of this paragraph are 2 R on the right side of 2 is H.

[0188] In certain embodiments, the compound of formula I is a compound of formula I-hh-1, I-hh-2, or I-hh-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of the R groups, both alone and in combination, is as defined above and as described in the embodiments herein. In some embodiments, R groups in the formulae of this paragraph are 2 R on the right side of 2 is H, and R is ortho to the triazole attachment 2 is not H.

[0189] In certain embodiments, the compound of formula I is a compound of formula I-hh-1, I-hh-2, or I-hh-3: [ka] or a pharmaceutically acceptable salt thereof, wherein R 2 Each of these, both alone and in combination, is as defined above and as described in embodiments herein. In some embodiments, the R 2 0 to 3 R's on the right 2 is H. In some embodiments, R ortho to the point of attachment of the phenyl to ring B 2is not H. In some embodiments, ring B is [ka] is.

[0190] In certain embodiments, the compound of formula I is a compound of formula I-ii-1 or I-ii-2: [ka] and pharmaceutically acceptable salts thereof (wherein R 2’ is R 2 In some embodiments, R 2’ is -NR2. In some embodiments, R 2’ is -N(CH3)2.

[0191] In certain embodiments, the compound of formula I is a compound of any one of formulas I-jj-1 or I-jj-2: [ka] or a pharmaceutically acceptable salt thereof.

[0192] In certain embodiments, the compound of formula I is a compound of any one of formula I-kk-1 or I-kk-2: [ka] a pharmaceutically acceptable salt thereof (wherein R 2’ is R 2 In some embodiments, R 2’ is -NR2. In some embodiments, R 2’ is -N(CH3)2.

[0193] In certain embodiments, the compound of formula I is a compound of any one of formulas I-ll-1 or I-ll-2: [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, one R 2 is F.

[0194] In certain embodiments, the present invention provides a compound of formula I-1* [ka] or 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; Ring B is a 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 1 is selected from (i) a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 11-membered saturated or partially unsaturated spiro bicyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and C 1~6 Aliphatic; each is R 4 is substituted with p instances of; and (ii) is hydrogen; R 2 , R 4 , and R 5 Each instance of is independently hydrogen, deuterium, or R z, 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 The Two R's 2 the groups optionally taken together form =O; The Two R's 4 the groups optionally taken together form =O; The Two R's 5 the groups optionally taken together form =O; The Two R's 2 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; The Two R's 4 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or The Two R's 5 groups, optionally taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R zare independently selected from optionally substituted groups selected from C1-6 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; R 3 is hydrogen, or optionally substituted by C 1~6 is an aliphatic group; or The Two R's 3 groups optionally taken together to form =O; or R 2 Groups and R 3 groups optionally taken together with their intervening atoms form a 5-8 membered saturated, partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L 1 is one of the following: (a)C 1~6 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein 1 to 3 methylene units of the chain are independently optionally replaced by -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-; (b) Covalent bonding; each -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3-7 membered saturated or partially unsaturated carbocyclylene; a 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 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; L 2 is a covalent bond, C 1~4a divalent linear or branched saturated or unsaturated hydrocarbon chain of formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; L 3 is one of the following: (a)C 1~4 a divalent linear or branched saturated or unsaturated hydrocarbon chain of the formula: wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-; (b) Covalent bonding; X is one of the following: (c) a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; or phenyl; each of which is selected from q R 5 be replaced with an instance of; or (d) -CH2(OR), -CH(R)(OR), or -C(R)2(OR); Each instance of R is independently hydrogen or C 1~6an optionally substituted group selected from aliphatic; phenyl; an 8- to 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen optionally taken together with the nitrogen 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, 4, or 5; q is 0, 1, 2, 3, 4, or 5).

[0195] The compounds of formula I-1* can be more specifically defined. For example, 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring A is phenyl. In some embodiments, ring A is a 3-7 membered saturated or partially unsaturated monocyclic carbocycle.

[0196] In some embodiments, ring A is [ka] is.

[0197] In some embodiments, ring A is selected from those shown in Table 1 below.

[0198] In some embodiments, Ring B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 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.

[0199] In some embodiments, ring B is [ka] is.

[0200] In some embodiments, two R 3 The groups together form =O and ring B is [ka] In some embodiments, two R 3 The groups together form =O and ring B is [ka] In some embodiments, two R 3 The groups together form =O and ring B is [ka] is.

[0201] In some embodiments, ring B is selected from those shown in Table 1 below.

[0202] In some embodiments, R 1 pR 4 In some embodiments, R is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring substituted with an instance of 1 pR 4In some embodiments, R is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR 4 In some embodiments, R is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR 4 In some embodiments, R is a 7- to 11-membered saturated or partially unsaturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with instances of 1 pR 4 C being replaced with an instance of 1~6 In some embodiments, R 1 pR 4 In some embodiments, R is phenyl substituted with an instance of 1 is hydrogen.

[0203] In some embodiments, R 1 teeth, [ka] is.

[0204] In some embodiments, two R 4 The groups together form =O and R 1 teeth, [ka] In some embodiments, two R 4 The groups together form =O and R 1 teeth, [ka] In some embodiments, two R 4 The groups together form =O and R1 teeth, [ka] is.

[0205] In some embodiments, two sets of R groups together each form =O, and R 1 teeth, [ka] is.

[0206] In some embodiments, R 1 is selected from those shown in Table 1 below.

[0207] In some embodiments, R 2 is hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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.

[0208] In some embodiments, R 2are methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, -CF3, -OCH3, -N(CH3)2, -OCH2CH2OH, -CH2CF3, -C(O)CH3, -S(O)CH3, -S(O)2CH3, -OiPr, -SCH3, -CN, -C(O)NH2, -C(O)OCH3, -CH2OH, -CH2CN, -CO2H, -OCF3, -OCHF2, [ka] In some embodiments, R 2 is selected from those shown in Table 1 below.

[0209] In some embodiments, R 4 is hydrogen, deuterium, R z , halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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( In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -P(O)(R)NR, -P(O)(R)OR, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -Si(OR). ... 4 are methyl, fluoro, -OCH3, -N(CH3)2, -OH, -CF3, -C(O)NH2, -CN, [ka] In some embodiments, R 4 is selected from those shown in Table 1 below.

[0210] In some embodiments, R 5 is hydrogen, deuterium, R z, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -CF2R, -CF3, -CR2(CN), -CR 2(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( In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -P(O)(R)NR, -P(O)(R)OR, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -P(O)R. In some embodiments, R is -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, -Si(OR)R, or -Si(OR). ... 5 is methyl, fluoro, [ka] is.

[0211] In some embodiments, R 5 is selected from those shown in Table 1 below.

[0212] In some embodiments, two R 2 The groups together form =O. As generally defined above, two R 4 The groups are optionally joined together to form =O. In some embodiments, two R 4 The groups together form =O. As generally defined above, two R 5 The groups are optionally joined together to form =O. In some embodiments, two R 5 The groups together form =O.

[0213] In some embodiments, two R 2 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0214] In some embodiments, two R 4 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0215] In some embodiments, two R 5 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated, or aryl-fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0216] In some embodiments, R z is C 1~6 Selected from optionally substituted groups selected from aliphatic; phenyl; 4-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0217] In some embodiments, R z is selected from those shown in Table 1 below.

[0218] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is an optionally substituted C 1~6 It is an aliphatic group.

[0219] In some embodiments, R 3 is methyl.

[0220] In some embodiments, R 3 is selected from those shown in Table 1 below.

[0221] In some embodiments, two R 3 The groups together form =O.

[0222] In some embodiments, R 2 Groups and R 3 The groups, taken together with their intervening atoms, form a 5-8 membered saturated, partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0223] In some embodiments, L 1 is (a)C 1~6 wherein 1 to 3 methylene units of the chain are independently 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. In some embodiments, L 1 is (a)C 1~6 wherein 1 to 3 methylene units of the chain are independently optionally replaced by -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-.

[0224] In some embodiments, L 1 is a covalent bond.

[0225] In some embodiments, L 1 teeth, [ka] [ka] [ka] is.

[0226] In some embodiments, L 1 is selected from those shown in Table 1 below.

[0227] In some embodiments, -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3- to 7-membered saturated or partially unsaturated carbocyclylene; a 4- to 7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 11-membered saturated or partially unsaturated spiro bicyclic heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, -Cy- is selected from those shown in Table 1 below.

[0228] In some embodiments, L 2 is a covalent bond, or C 1~4 wherein one to two methylene units of the chain are independently 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, L 2 is a bond by a covalent bond. In some embodiments, L 2 is C 1~4 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0229] In some embodiments, L 2 teeth, [ka] is.

[0230] In some embodiments, L 2is selected from those shown in Table 1 below.

[0231] In some embodiments, L 3 is C 1~4 wherein one to two methylene units of the chain are independently optionally replaced by -O-, -C(O)-, -C(S)-, -C(R)2-, -CH(R)-, -CH(OR)-, -C(F)2-, -N(R)-, -S-, -S(O)-, or -S(O)2-.

[0232] In some embodiments, L3 is a covalent bond.

[0233] In some embodiments, L 3 teeth, [ka] is.

[0234] In some embodiments, L 3 is selected from those shown in Table 1 below.

[0235] In some embodiments, X is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle 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 carbocycle; or phenyl; each of which is selected from q R 5 In some embodiments, X is -CH2(OR), -CH(R)(OR), or -C(R)2(OR).

[0236] In some embodiments, X is [ka] [ka] is.

[0237] In some embodiments, two R 5 The groups together form =O and X is [ka] is.

[0238] In some embodiments, two sets of R 5 The groups together form =O, and X is [ka] In some embodiments, X is selected from those shown in Table 1 below.

[0239] In some embodiments, R is hydrogen. In some embodiments, R is independently hydrogen, or C 1~6 an optionally substituted group selected from aliphatic; phenyl; an 8- to 10-membered bicyclic aryl ring, a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring; or a 4- to 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0240] In some embodiments, two R groups on the same nitrogen, taken together with the nitrogen, 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.

[0241] In some embodiments, R is selected from those shown in Table 1 below.

[0242] In some embodiments, m is 0, 1, 2, 3, or 4. 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, m is selected from those shown in Table 1 below.

[0243] In some embodiments, n is 0, 1, 2, 3, or 4. 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 shown in Table 1 below.

[0244] In some embodiments, p is 0, 1, 2, 3, 4, or 5. 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 5. In some embodiments, p is selected from those shown in Table 1 below.

[0245] In some embodiments, q is 0, 1, 2, 3, 4, or 5. 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 5. In some embodiments, q is selected from those shown in Table 1 below.

[0246] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring A is phenyl, ring B is triazolyl, and L2 is a covalent bond), to provide a compound of formula Ia*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0247] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring A is pyridyl, ring B is triazolyl, and L 2 is a covalent bond), and providing a compound of formula Ib-1*, Ib-2*, or Ib-3*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0248] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring A is thiophenyl, ring B is triazolyl, and L 2 is a covalent bond), to provide a compound of formula Ic*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 3 , R 1 , R 2 , R 3, X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0249] In some embodiments, the present invention provides compounds of formula I-1*, wherein L 1 is acetylenyl, and L 2 is a covalent bond, ring A is phenyl, thiophenyl, or pyridyl, and ring B is triazolyl, resulting in a compound of formula If-1*, If-2*, If-3*, If-4*, If-5*, If-6*, If-7*, If-8*, or If-9*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 3 , R 1 , R 2 , R 3 , X, m, and n, both alone and in combination, are as defined above and described in the embodiments herein.

[0250] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring B is triazolyl and L 3 is methylene and X is oxetanyl, providing compounds of formula Ig-1*, Ig-2*, or Ig-3*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0251] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring B is triazolyl and L 3 is methylene and X is furanyl, providing compounds of formula Ih-1*, Ih-2*, or Ih-3*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0252] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring B is triazolyl and L 3 is methylene and X is tetrahydropyranyl, providing compounds of formula Ii-1*, Ii-2*, or Ii-3*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0253] In some embodiments, the present invention provides compounds of formula I-1*, wherein ring B is triazolyl and L 3 is methylene and X is 1,4-dioxanyl, providing compounds of formula Ij-1*, Ij-2*, or Ij-3*: [ka] or a pharmaceutically acceptable salt thereof, wherein L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , m, n, and q, both alone and in combination, are as defined above and described in the embodiments herein.

[0254] Exemplary compounds of the present invention are shown in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-78

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

Table 1-115

Table 1-116

Table 1-117

Table 1-118

Table 1-119

Table 1-120

Table 1-121

Table 1-122

Table 1-123

Table 1-124

Table 1-125

Table 1-126

Table 1-127

Table 1-129

Table 1-131

[0255] In some embodiments, the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, excipient, or diluent.

[0256] In some embodiments, the present invention provides a compound of formula I as defined above or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I as defined above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a pharmaceutical.

[0257] In the chemical structures of Table 1 above and in the Examples below, stereocenters are described according to extended stereogram form (MDL / Biovia, e.g., using the labels "or1", "or2", "abs", "and1").

[0258] In some embodiments, the present invention also provides a compound of formula I as described herein, or a pharmaceutical composition as described herein, for use in a method for inhibiting GPR84 as described herein, a method for modulating an immune response in a subject in need thereof as described herein, and / or a method for treating a GPR84-dependent disorder as described herein.

[0259] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for inhibiting GPR84 as described herein.

[0260] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for modulating an immune response in a subject in need thereof, as described herein.

[0261] In some embodiments, the present invention also provides a compound of formula I as described herein or a pharmaceutical composition as described herein for use in a method for treating a GPR84-dependent disorder as described herein.

[0262] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting GPR84, modulating an immune response in a subject in need thereof, and / or treating a GPR84-dependent disorder.

[0263] In some embodiments, the present invention also provides the use of a compound of Formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting GPR84.

[0264] In some embodiments, the present invention also provides the use of a compound of Formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

[0265] In some embodiments, the present invention also provides the use of a compound of Formula I as described herein or a pharmaceutical composition as described herein for the manufacture of a medicament for treating a GPR84-dependent disorder.

[0266] In some embodiments, the present invention also provides the use of a compound of formula I as described herein, or a pharmaceutical composition as described herein, in a method for inhibiting GPR84 as described herein, a method for modulating an immune response in a subject in need thereof as described herein, and / or a method for treating a GPR84-dependent disorder as described herein.

[0267] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for inhibiting GPR84 as described herein.

[0268] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for modulating an immune response in a subject in need thereof.

[0269] In some embodiments, the present invention also provides the use of a compound of formula I as described herein or a pharmaceutical composition as described herein in a method for treating a GPR84-dependent disorder as described herein.

[0270] 4. General Methods of Providing Compounds of the Invention The compounds of the invention may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds, and as described in detail in the Examples herein.

[0271] 5. Uses, Formulation and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective to measurably inhibit GPR84 or a variant thereof in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to measurably inhibit GPR84 or a variant thereof in a biological sample or a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0272] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0273] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the compositions of the present disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fatty acids, water, partial glyceride mixtures of salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0274] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention, or an inhibitory active metabolite or residue thereof.

[0275] As used herein, the term "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of GPR84 or a mutant thereof.

[0276] The subject matter disclosed herein includes the prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the present invention.Therefore, metabolites include compounds produced by a process comprising contacting the compounds of the present invention with mammals for a sufficient period of time to produce its metabolic product.When the compounds of the present invention are bases, desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, or organic acids such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acids such as glucuronic acid or galacturonic acid, alpha hydroxy acids such as citric acid or tartaric acid, amino acids such as aspartic acid or glutamic acid, aromatic acids such as benzoic acid or cinnamic acid, sulfonic acids such as p-toluenesulfonic acid or ethanesulfonic acid, etc. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, by treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Specific examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0277] The compounds of the present invention may be in the form of a "prodrug," which includes compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of a compound, or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treating with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate ester), lower alkenyl ester, di-lower alkylamino lower alkyl ester (e.g., dimethylaminoethyl ester), acylamino lower alkyl ester (e.g., acetyloxymethyl ester), acyloxy lower alkyl ester (e.g., pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl lower alkyl ester (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl lower alkyl ester, amide, lower alkyl amide, di-lower alkyl amide, and hydroxyamide. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In some embodiments, the compounds of the present invention are prodrugs of any of the formulas described herein.

[0278] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0279] For this purpose, any sterile fixed oil can be used, including synthetic mono- or diglycerides.Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions.These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions.Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0280] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also generally added.For oral administration in capsule form, useful diluents include lactose and dry cornstarch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifier and suspending agent.If desired, certain sweeteners, flavorings or colorings can also be added.

[0281] Alternatively, the pharmaceutically acceptable composition of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating additive that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0282] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0283] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0284] For topical application, pharmaceutically acceptable compositions can be formulated into a suitable ointment, which contains the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include but are not limited to mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water.Alternatively, pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream, which contains the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0285] For ophthalmic use, pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions may be formulated into an ointment, such as petrolatum.

[0286] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0287] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0288] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, the provided compositions are formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0289] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, the patient's age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0290] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for inhibiting the signaling activity of one or more GPCRs. In some embodiments, the GPCR inhibited by the compounds and methods of the present invention is GPR84.

[0291] The compounds disclosed herein find use in inhibiting the activity of GPR84. GPR84 is a GPR expressed on the surface of immune cells. i GPR84 is a G protein-coupled receptor (GPCR) that regulates innate immune responses in conditions such as fibrotic disorders.

[0292] Multiple studies have shown that GPR84 may be a potential target for the treatment of obesity and / or metabolic dysfunction.

[0293] GPR84 gene expression in differentiated human adipocytes in culture is highly upregulated by the major pro-inflammatory cytokines TNF-α and IL-1β (Muredda et al. 2017. Arch. Physiol. Biochem. 124(2), 97-108.). These data confirm the activation of pro-inflammatory GPR84 signaling associated with adipocyte inflammation, first described by Nagasaki in 2012 (Nagasaki et al. 2012, FEBS Letters, 586, 368-372).

[0294] IL-33, a member of the IL-1β superfamily, strongly upregulates GPR84 mRNA expression in human differentiated adipocytes in an autocrine manner, which correlates with enhanced production of pro-inflammatory cytokines and chemokines such as IL-1β, CCL2, IL6, CXCL2, and CSF3 (Zaibi et al. 2018. Cytokine, 110, 189-193). This suggests that activation of GPR84 by pro-inflammatory stimuli in adipocytes leads to the release of additional pro-inflammatory cytokines, thereby identifying the existence of a putative autocrine positive feedback loop.

[0295] In patients with NASH, GPR84 expression in the liver is upregulated, which correlates with disease severity. GPR84 is upregulated in activated human and mouse macrophages and neutrophils. GPR84 mediates myeloid cell infiltration, which promotes steatohepatitis and fibrosis. Pharmacological inhibition of GPR84, as well as selonsertib (an ASK1 inhibitor), significantly reduced macrophage accumulation, inflammation, and fibrosis in NASH models. These findings suggest that GPR84 promotes myeloid cell infiltration in liver injury and is a valid therapeutic target for steatohepatitis and fibrosis in NAFLD / NASH (Puengel et al. 2020. J. Clin. Med. 9(4), 1140).

[0296] Deletion of GPR84 in mice was associated with reduced NAFLD-induced liver injury. Treatment with PBI-4547 (a putative GPR84 antagonist) reduced NAFLD-induced damage in liver and adipose tissue and promoted fatty acid oxidation (Simard et al. 2020. Sci. Rep. 10(1), 12778).

[0297] Mice with a global deletion of Gpr84 (Gpr84 knockout (KO)) exhibit mild impairment of glucose tolerance when fed an MCFA-enriched diet. This study demonstrated the regulation of mitochondrial metabolism in mouse skeletal muscle by the medium-chain fatty acid receptor GPR84, which plays an important role in glycemic control (Montgomery MK, et al. 2019. FASEBJ. 33(11), 12264-12276).

[0298] Nutrient-sensing receptors on enteroendocrine (EEC) cells regulate appetite by detecting luminal contents. Peiris et al. evaluated the effects of obesity and gastric bypass-induced weight loss on the expression of nutrient-sensing G protein-coupled receptors (GPCRs) and found that GPR84 expression was increased in obese mice. Furthermore, obesity-induced overexpression of GPR84 was further increased after Roux-en-Y gastric bypass (RYGB). Several nutrient-sensing receptors, including GPR84, induced activation of colonic EECs. Significant adaptive changes in the expression of these receptors occur in response to diet and weight loss induced by RYGB or calorie restriction. (Peiris M, et al. 2018. Nutrients. 10(10), 1529)

[0299] We investigated the effects of GPR84 deletion on the development of obesity and diabetes in mice fed a diet rich in long-chain fatty acids (LCFA) or medium-chain fatty acids (MCFA). We found no effect on body weight or glucose tolerance in mice fed either a high-MCFA or LCFA diet. GPR84 may affect lipid metabolism, as GPR84KO mice had smaller livers and increased myocardial triglyceride accumulation when fed an LCFA diet, and increased hepatic triglyceride accumulation in response to increased dietary MCFA. (Du Toit et al. 2018 Eur. J. Nutr. 57(5), 1737-1746)

[0300] A review by Hara et al. showed that GPR84 and other free fatty acid receptors (FFARs), which are primarily involved in energy metabolism, are considered important therapeutic targets in the pathogenesis of obesity and type 2 diabetes (Hara et al. 2014. Biochim. Biophys. Acta. 1841(9), 1292-300).

[0301] A study conducted by Nagasaki et al. in mice showed that a high-fat diet upregulated GPR84 expression in the fat pad. These results suggest that GPR84 appears in adipocytes in response to TNFα from infiltrating macrophages, exacerbating the vicious cycle between adiposity and obesity-induced diabetes. (Nagasaki H.et al.2012.FEBS Lett.586(4),368-72)

[0302] Fibrosis is a process that can be caused by chronic tissue injury due to toxic substances, viral infection, inflammation, or mechanical stress (Nanthakumar et al., 2015. Nature Reviews Drug Discovery 14, 693-720); it can be defined as the abnormal or excessive production and accumulation of extracellular matrix (ECM).

[0303] In particular, fibrosis is a major driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), progressive liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and progressive kidney disease. These conditions remain undertreated despite an increasing number of clinical trials, reflecting an improved understanding of disease mechanisms and the need to identify new therapies, particularly in IPF (Nanthakumar et al., 2015).

[0304] Nonalcoholic fatty liver disease (NAFLD), initially characterized by pure steatosis that progresses to nonalcoholic steatohepatitis (NASH), is primarily caused by excessive energy intake and physical inactivity, apart from genetic defects, and is closely associated with obesity, insulin resistance, and other associated metabolic complications (Neuschwander-Tetri BA and Caldwell SH, 2003, Hepatology 37, 1202-1219). Untreated NASH can lead to fatal liver failure.

[0305] The mechanisms driving the progression of NAFLD to NASH and end-stage liver disease are complex and may be triggered by acute inflammatory injury and oxidative stress (Day and James 1998, Hepatology 27, 1463-1466).

[0306] GPR84 (also known as EX33) was isolated and characterized from human B cells (Wittenberger et al. 2001, J. Mol. Biol. 307, 799-813) and using a degenerate primer reverse transcriptase polymerase chain reaction (RT-PCR) approach (Yousefi et al. 2001). It remained an orphan GPCR until the identification of medium-chain free fatty acids (FFAs) with carbon chain lengths of 9–14 as ligands for this receptor (Wang et al. 2006).

[0307] GPR84 is activated by medium-chain FFAs such as capric acid (Cl 0:0), undecanoic acid (Cl 1:0), and lauric acid (Cl 12:0), amplifies the production of pro-inflammatory cytokines / chemokines (e.g., TNFα, IL-6, IL-8, and CCL2) stimulated by lipopolysaccharide, and is highly expressed in neutrophils and monocytes (macrophages) (Miyamoto et al. 2016, Int. J. Mol. Sci. 17(4)450).

[0308] In contrast, GPR84 ligand-mediated neutrophil and monocyte / macrophage chemotaxis is inhibited by GPR84 antagonists (Suzuki M et al. 2013. J. Biol. Chem. 288, 10684-10691).

[0309] Monocyte / macrophage recruitment to the liver may appear to coincide with fibrogenesis in patients with chronic liver disease (Marra et al 1998. Am. J. Pathol. 152, 423-430; Zimmermann et al. 2010. PLOS ONE 5, el 1049), but this has not led to novel therapeutic approaches.

[0310] Currently, there are no approved medications available for the treatment of NASH, and liver transplantation remains the last option for end-stage disease. For example, in the case of IPF, only two drugs have been approved despite their undesirable side effects (Brunnemer et al. 2018. Respiration 95, 301-309; Lancaster et al., 2017, Eur. Respir. Rev. 26, 170057; Richeldi et al., 2014, N. Engl. J. Med. 370, 2071-2082). Therefore, improved treatments are clearly needed (Raghu, 2015, Am J Respir Crit Care Med 191(3)252-4).

[0311] The potent and selective GPR84 inhibitor GLPG1205, administered once daily at 3 mg / kg and 10 mg / kg, reduced disease activity index scores and neutrophil infiltration in a mouse model of dextran sulfate sodium-induced chronic inflammatory bowel disease, demonstrating efficacy similar to that of the positive control compound sulfasalazine (Labeguere F, et al. 2020. J Med Chem. 63(22), 13526-13545).

[0312] A study by Nguyen et al. showed that PBI-4050 (a GPR84 antagonist / GPR40 agonist) attenuated pulmonary hypertension, pulmonary fibrosis, and right ventricular dysfunction in heart failure, indicating that GPR84 antagonists are a novel and promising treatment targeting pulmonary remodeling in Group II pulmonary hypertension (Nguyen et al. 2020. Cardiovasc Res. 116(1), 171-182).

[0313] A study by Gagnon et al. demonstrated that GPR40 and GPR84 may be promising molecular targets in fibrotic pathways. Administration of PBI-4050, a GPR84 antagonist and GPR40 agonist, significantly reduced fibrosis in many injury scenarios, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models (Gagnon et al. 2018. Am J Pathol. 188(5), 1132-1148).

[0314] Studies have also linked GPR84 to acute lung injury and / or inflammation.

[0315] A review by Alavi et al. summarizes studies on GPR17, GPR30, GPR37, GPR40, GPR50, GPR54, GPR56, GPR65, GPR68, GPR75, GPR84, GPR97, GPR109, GPR124, and GPR126, which have been reported to have significant effects in the prevention and / or treatment of multiple sclerosis (MS) in preclinical studies (Alavi et al. 2019. Life Sci. 224, 33-40).

[0316] GPR84 expression in several mouse tissues is enhanced under inflammatory stimuli, such as endotoxemia, hyperglycemia, and hypercholesterolemia. These stimuli also increase GPR84 expression in macrophages, while a selective GPR84 receptor agonist (6-OAU) induced enhanced secretion of pro-inflammatory cytokines and phagocytosis in macrophages (Recio et al. 2018. Front. Immunol. 9, 1419). These results reveal that once inflammation is established, GPR84 functions as an enhancer of inflammatory signaling in macrophages, and molecules that antagonize the GPR84 receptor may be potential therapeutic tools for inflammatory and metabolic diseases.

[0317] The discovery of DL-175, a potent, selective, and structurally novel molecule that exerts distinct functional effects in macrophages compared to other GPR84 ligands (Lucy et al. 2019. ACS Chem. Biol. 14(9), 2055-2064). This study confirms that GPR84 agonism leads to enhanced macrophage chemotaxis and / or phagocytosis (also known as macrophage activation).

[0318] GPR84 was one of a few highly enriched pro-inflammatory neutrophil-associated genes in an analysis of an RNA-seq dataset from BALF cells of COVID-19 patients (Didangelos, A. 2020. mSphere. 5(3), e00367-20).

[0319] In an acute lung inflammation model, LPS stimulates CD11 expression in alveolar macrophages. lo CD11 caused more inflammation from the condition hi This induced a switch to a pulmonary inflammatory state, which exacerbated the lung injury process (Ying et al. 2020. Mucosal Immunol. 13(6), 892-907). GPR84 is highly expressed in diseased lung tissue and is involved in cytokine release, phagocytosis, and state switching of alveolar macrophages. GPR84 may be a potential therapeutic target for acute respiratory distress syndrome.

[0320] Kose et al. prepared the first GPR84 agonist radioligand (tritiated) to study the binding affinity of the receptor ligand. They noted that GPR84 was found to be involved in inflammatory processes related to gastroesophageal reflux disease, inflammatory bowel disease, multiple sclerosis, neuropathic pain, and Alzheimer's disease. Furthermore, GPR84 is associated with obesity and diabetes. Preliminary evidence suggests that GPR84 may be associated with leukemia development, osteoclastogenesis, and organ fibrosis, a pathological consequence of many inflammatory and metabolic diseases. (Kose M, et al. 2020. J. Med. Chem. 63(5), 2391-2410).

[0321] A comprehensive glycoprotein analysis by Muller et al. identified GPR84 as a marker of endotoxin-resistant monocytes and a modulator of TNFα expression. (Mulle rMM,et al.2017 SciRep.7(1),838).

[0322] GPR84 regulates IL-4 production by T lymphocytes in response to CD3 cross-linking, revealing a novel role for GPR84 in regulating early IL-4 gene expression in activated T cells (Venkataraman C, et al. 2005. Immunol Lett. 101(2), 144-53).

[0323] Furthermore, GPR84 has been associated with neuropathic pain and / or neuropathy.

[0324] Gao et al. demonstrated that DOK3 is involved in the activation of microglial cells in neuropathic pain by interacting with GPR84, revealing a physical association between DOK3 and GPR84 in the induction of inflammatory responses. This suggests that targeting the adaptor protein DOK3 may open new avenues for pharmaceutical approaches to alleviate spinal neuropathic pain (Gao WS, et al. 2020. Aging (Albany NY). 12).

[0325] A study by Kozela et al. on the behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive impairment induced by repeated administration of ketamine (KET) demonstrated that CBD reversed KET-induced transcriptional changes, including the Gpr84 gene (Kozela E, et al. 2020. Mol Neurobiol. 57(3), 1733-1747).

[0326] A study by Wei et al. demonstrated that agonists of G protein-coupled receptor 84 (GPR84) altered cell morphology and motility but did not induce pro-inflammatory responses in microglia. This study suggests that microglial GPR84 may be a therapeutic target for microglia-related diseases such as multiple sclerosis and Alzheimer's disease (Wei L, et al. 2017. J Neuroinflammation. 14(1), 198).

[0327] Nicol et al. studied the role of GPR84 in experimental neuropathic pain and demonstrated that GPR84 is a pro-inflammatory receptor that contributes to nociceptive signaling through regulation of macrophages, whereas the absence of GPR84 impairs the response of these cells to inflammatory injury (NicolLS,et al.2015.J Neurosci.35(23),8959-69).

[0328] Mededdu et al. found that Gpr84 expression is induced in both microglia and astrocytes and is upregulated in the CNS after viral infection, indicating that Gpr84 expression may be a useful measure of glial activation upon injury or damage to the CNS (Madeddu S, et al. 2015. PLoS One. 10(7), e0127336).

[0329] Bouchard et al. found that mice with endotoxemia strongly and persistently express GPR84 in microglia, making it a sensitive marker of microglial activation and potentially playing an important regulatory role in neuroimmunological processes, acting downstream of the effects of pro-inflammatory mediators (Bouchard C, et al. 2007. Glia. 55(8), 790-800).

[0330] GPR84 has also been implicated in inflammatory bowel disease as a potential disease target.

[0331] Planell et al. identified GPR84 as a transcriptional blood biomarker useful as a non-invasive surrogate marker of mucosal healing and endoscopic response in ulcerative colitis. Over 14 weeks of treatment, response to anti-TNF therapy induced changes in circulating HP, CD177, GPR84, and S100A12 transcripts that correlated with changes in endoscopic activity (Planell N, et al. 2017. J Crohns Colitis. 11(11), 1335-1346).

[0332] A study by Abdel-Aziz et al. found that GPR84 and TREM-1 signaling contribute to the pathogenesis of reflux esophagitis, indicating that GPR84 plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD) (Abdel-Aziz, et al. 2016 Mol Med. 21(1), 1011-1024).

[0333] Dietrich et al. demonstrated that GPR84 maintains aberrant β-catenin signaling in leukemic stem cells (LSCs) to maintain stem cell-derived mixed lineage leukemia (MLL) leukemogenesis. This is a previously unrecognized role of GPR84 in maintaining fully developed acute myeloid leukemia (AML) by maintaining aberrant β-catenin signaling in LSCs, suggesting that targeting the oncogenic GPR84 / β-catenin signaling axis may be a novel therapeutic strategy for AML (Dietrich PA, et al. 2014. Blood 124(22),3284-94).

[0334] Deng et al. identified GPR84 among a set of differentially expressed genes (DEGs) useful as a candidate biomarker for the prognosis of hepatocellular carcinoma (HCC) by mining the Cancer Genome Atlas (TCGA) database for tumor microenvironment-related genes with prognostic value in HCC (Deng Z, et al. 2019. Biomed Res Int. 2019, 2408348).

[0335] GeneChip expression profiling by Wang et al. revealed changes in energy metabolism-related genes, such as GPR84, in bone cells under high magnetic fields with large gradients. Identification of genes sensitive to specific environments, such as GPR84, may provide potential targets for the prevention and treatment of bone loss or osteoporosis (Wang Y, et al. 2015. PLoS One. 10(1), e0116359).

[0336] A study by Park et al. demonstrated that GPR84 controls osteoclastogenesis through inhibition of the NF-κB and MAPK signaling pathways, revealing that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that GPR84 may be a potential therapeutic target for osteoclast-mediated bone destructive diseases (Park JW, et al. 2018. J Cell Physiol. 233(2), 1481-1489).

[0337] Zhu et al.'s genome-wide transcriptional and DNA methylation analysis of peripheral blood mononuclear cells identified aberrant gene regulatory pathways in systemic lupus erythematosus. Gene expression of MX1, GPR84, and E2F2 was increased in lupus nephritis (LN)+ patients with systemic lupus erythematosus (SLE) compared with SLELN- patients (Zhu H, et al. 2016. Arthritis Res Ther. 18, 162).

[0338] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting GPR84, comprising contacting GPR84 with an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0339] In certain embodiments, the presently disclosed subject matter is directed to a method for modulating an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound of the invention or a pharmaceutical composition described herein.

[0340] The compounds disclosed herein directly bind to GPR84 and inhibit its signaling activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise alleviate GPR84-mediated inflammatory responses.

[0341] The compounds disclosed herein may or may not be specific GPR84 antagonists. A particular 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 compounds of the present disclosure specifically inhibit the signaling activity of GPR84. In some of these embodiments, the IC of the GPR84 antagonist on GPR84 is 50 is the IC of a GPR84 antagonist against another GPCR activated by free fatty acids (FFAs) or another type of GPCR (e.g., class A GPCR) 50 Approximately 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, and 0.001% lower.

[0342] The compounds disclosed herein can be used in methods for inhibiting GPR84. Such methods include contacting GPR84 with an effective amount of a compound of the present disclosure. "Contacting" means bringing the compound sufficiently close to an isolated GPR84 GPCR or a cell expressing GPR84 (e.g., a T cell or a B cell) so that the compound can bind to GPR84 and inhibit its activity. The compound can be contacted with GPR84 in vitro or in vivo via administration of the compound to a subject.

[0343] Any method known in the art for measuring the signaling activity of GPR84 may be used to determine whether GPR84 is inhibited, such as in vitro assays or measuring the downstream biological effects of GPR84 signaling activity.

[0344] The compounds disclosed herein can be used to treat GPR84-dependent disorders. As used herein, a "GPR84-dependent disorder" is a pathological condition in which GPR84 activity is required for the development or maintenance of the pathological condition. In some embodiments, the GPR84-dependent disorder is an inflammatory condition.

[0345] The compounds of the present disclosure also find use in modulating the immune response in a subject in need thereof. Such a method comprises administering an effective amount of a compound of the present invention.

[0346] As used herein, "modulating an immune response" refers to modulating any immunogenic response to an antigen.

[0347] In another aspect of the invention, the invention provides novel compounds of the invention for use in therapy.

[0348] In a further aspect of the present invention, the present invention provides a method for treating a mammal susceptible to or suffering from one of the following disease conditions listed herein: in particular conditions that may be associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function; the method comprises administering a therapeutically effective amount of a compound of the present invention or one or more pharmaceutical compositions described herein.

[0349] In a further aspect, the present invention provides a compound of the present invention for use in the treatment or prevention of a condition selected from those listed herein below: in particular conditions that may be associated with abnormal activity of GPR84 and / or abnormal expression of GPR84 and / or abnormal distribution of GPR84, such as inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0350] In a further aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic protocols and routes disclosed herein.

[0351] It is therefore a primary object of the present invention to provide compounds of the present invention that are capable of modifying the activity of GPR84 and thereby preventing or treating any condition that may be causally linked thereto.

[0352] It is a further object of the present invention to provide compounds of the present invention that are capable of treating or alleviating conditions or diseases or symptoms thereof, such as inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function that may be causally linked to the activity and / or expression and / or distribution of GPR84.

[0353] Yet another object of the present invention is to provide pharmaceutical compositions that can be used for the treatment or prevention of various pathological conditions associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0354] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

[0355] The present disclosure provides methods for modulating (e.g., inhibiting) GPR84 activity, the methods comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0356] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0357] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject with cancer.

[0358] In certain embodiments, the presently disclosed subject matter relates to a method for treating a GPR84-dependent disorder, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutical composition described herein. In certain aspects of this embodiment, the GPR84-dependent disorder is cancer.

[0359] In some embodiments, the subject matter disclosed herein relates to methods for treating chronic viral infections, hi some embodiments, the subject matter disclosed herein relates to the use of GPR84 inhibitors as adjuvant therapy to enhance the efficacy of vaccination.

[0360] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

[0361] In certain aspects, the present invention provides methods of treating cell proliferation disorders, such as cancer.

[0362] In one aspect, the invention provides a method of treating a cell proliferation disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof.

[0363] In certain embodiments, the cell proliferative disorder is cancer.

[0364] Examples of cancers that can be treated using the compounds of the present disclosure include, but are not limited to, chronic or acute leukemia, such as acute myeloid leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, and combinations of these cancers.

[0365] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, hematological cancers (e.g., lymphoma, leukemia, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of these cancers.

[0366] In certain embodiments, the cancer is leukemia, hi another embodiment, the cancer is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia.

[0367] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is present in an adult patient; in additional embodiments, the cancer is present in a pediatric patient. In certain embodiments, the cancer is AIDS-related.

[0368] In certain embodiments, the cancer is selected from leukemia and blood cancer. In certain embodiments, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), myeloproliferative neoplasms (MPN), AML after MPN, AML after MDS, del(5q)-related high-risk MDS or AML, chronic myeloid leukemia in blast crisis, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms, such as plasmacytoma and multiple myeloma. The leukemia referred to herein may be acute or chronic.

[0369] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers.

[0370] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocytosis (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic leukemia (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0371] The term "inflammatory condition(s)" as used herein refers to a group of conditions such as inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, pulmonary diseases (e.g., chronic obstructive pulmonary disease (COPD) and pulmonary interstitial diseases (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway diseases (e.g., asthma, rhinitis), and endotoxin-induced conditions (e.g., complications after bypass surgery or chronic endotoxin states contributing to, for example, chronic heart failure). In particular, the term refers to rheumatoid arthritis, allergic airway diseases (e.g., asthma), and inflammatory bowel disease. In more particular embodiments, the term refers to uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and inflammation of the skin and / or colon caused by tumor treatments aimed at activating the immune response.

[0372] The term "pain," as used herein, refers to a disease or disorder characterized by an unpleasant sensation, often caused by intense or noxious stimuli, including, but not limited to, nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration), and neuropathic or dysfunctional pain (caused by damage to or abnormal function of the nervous system), and / or pain associated with or caused by the conditions described herein. Pain can be acute or chronic.

[0373] As used herein, the term "neuroinflammatory condition" refers to a disease or disorder characterized by sudden neurological deficits associated with inflammation, demyelination, and axonal injury, including, but not limited to, conditions such as Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0374] As used herein, the term "neurodegenerative condition" refers to a disease or disorder characterized by the progressive loss of neuronal structure or function, such as neuronal death, including, but not limited to, conditions such as dementia, degenerative dementia, senile dementia, vascular dementia, dementia associated with intracranial space-occupying lesions, age-associated mild cognitive impairment, age-associated memory impairment, and / or peripheral neuropathy. In particular, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), spinocerebellar ataxia (SCA), and / or spinal muscular atrophy (SMA). More specifically, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, Creutzfeldt-Jakob disease, and / or amyotrophic lateral sclerosis (ALS).

[0375] As used herein, the term "infectious disease" refers to bacterial infections, including, but not limited to, sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0376] The term "autoimmune disease(s)" as used herein refers to a group of diseases such as obstructive airway diseases (COPD (chronic obstructive pulmonary disease)), psoriasis, asthma (e.g., intrinsic asthma, extrinsic asthma, dust asthma, etc., conditions such as infantile asthma), particularly chronic or severe asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis including bronchial asthma, systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes and its associated complications, atopic eczema (atopic dermatitis), contact dermatitis and further eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. In particular, the term refers to COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0377] As used herein, the term "endocrine and / or metabolic disorder(s)" refers to a group of conditions involving the body's overproduction or underproduction of certain hormones, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine disorders include, among others, hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, diabetes, adrenal gland diseases (such as Cushing's syndrome and Addison's disease), and ovarian insufficiency (including polycystic ovary syndrome). Examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A specific example of a metabolic disorder is obesity.

[0378] As used herein, the term " cardiovascular disease " refers to the disease that affects the heart or blood vessel, or both.In particular, cardiovascular disease includes arrhythmia (atrium or ventricle, or both); atherosclerosis and its sequelae; angina pectoris; cardiac rhythm disorder; myocardial ischemia; myocardial infarction; aneurysm of the heart or blood vessel; vasculitis, stroke; peripheral occlusive arterial disease of limbs, organs, or tissue; post-ischemic reperfusion injury of the brain, heart, kidney, or other organs or tissues; endotoxic shock, surgical shock, or traumatic shock; hypertension, valvular heart disease, heart failure, blood pressure abnormalities; shock; vasoconstriction (including those related to migraine); vascular abnormalities, inflammation, dysfunction that are limited to a single organ or tissue.In particular, this term refers to atherosclerosis.

[0379] The term "leukemia" as used herein refers to neoplastic diseases of blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, making the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0380] As used herein, the term "diseases involving impaired immune cell function" includes conditions with symptoms such as recurrent and prolonged viral and bacterial infections and slow recovery. Other less visible symptoms include the inability to kill parasites, yeast, and bacterial pathogens in the intestine or throughout the body.

[0381] As used herein, the term "fibrotic disease" refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and is associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts. This includes, but is not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and gastrointestinal tract. In particular, the term fibrotic diseases includes idiopathic pulmonary fibrosis (IPF); cystic fibrosis; other diffuse parenchymal lung diseases of various etiologies, e.g., iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis; granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis); collagen vascular diseases; pulmonary alveolar proteinosis; Langerhans cell granulomatosis; lymphangioleiomyomatosis; genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation-induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; tubulointerstitial fibrosis; glomerulonephritis; diabetic nephropathy; focal segmental glomerulosclerosis; IgA nephropathy; and hypertension. ; Alport; intestinal fibrosis; liver fibrosis; cirrhosis; alcohol-induced liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD); cholestasis, bile duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); infectious liver fibrosis; viral-induced liver fibrosis; and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease; keloids; skin fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD)-related musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, or chronic lymphocytic fibrosis.More specifically, the term "fibrotic disease" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), portal hypertension, systemic sclerosis, renal fibrosis, and skin fibrosis. Most specifically, the term "fibrotic disease" refers to nonalcoholic steatohepatitis (NASH) and / or nonalcoholic fatty liver disease (NAFLD). Alternatively, most specifically, the term "fibrotic disease" refers to IPF.

[0382] In some embodiments, the compounds of the invention may be useful in preventing or reducing the risk of developing any of the diseases mentioned herein, for example, in preventing or reducing the risk of developing a disease, condition, or disorder in individuals who may be predisposed to the disease, condition, or disorder but who have not yet experienced or exhibited the pathology or symptoms of the disease.

[0383] The compounds disclosed herein can be administered by any suitable method known in the art, hi some embodiments, the compounds of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implant, by inhalation, intrathecally, intracerebroventricularly, intratumorally, or intranasally.

[0384] In some embodiments, the GPR84 antagonist is administered continuously. In other embodiments, the GPR84 antagonist is administered intermittently. Moreover, treatment of a subject with an effective amount of a GPR84 antagonist can include one treatment or can include a series of treatments.

[0385] It is understood that the appropriate dose of the active compound depends on several factors within the knowledge of a physician or veterinarian with ordinary skill. The dose(s) of the active compound will vary depending on, for example, the subject's age, weight, general condition, sex, and diet, administration time, administration route, excretion rate, and any drug combinations.

[0386] It will also be understood that the effective dosage of the compounds of the invention or pharmaceutically acceptable salts, prodrugs, metabolites or derivatives thereof used for treatment may increase or decrease during the course of a particular treatment. Variations in dosage may occur and may become apparent from the results of diagnostic assays.

[0387] In some embodiments, the GPR84 antagonist is administered to a subject at a dose of about 0.001 μg / kg to about 1000 mg / kg, for example, but not limited to, about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0388] In the methods described herein, the method can further include administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject before administration of the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or composition.

[0389] As used herein, the terms "treatment," "treat," and "treating," as described herein, refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have manifested. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may continue after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0390] The term "administration" or "administering" includes the route of introducing a compound(s) into a subject to perform its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0391] The term "effective amount" includes the amount that is effective at the dosage and duration necessary to achieve desired results.The effective amount of a compound can vary depending on factors such as the disease state, age, and weight of the subject, and the ability of the compound to induce desired responses in the subject.The dosage regimen can be adjusted to provide optimal therapeutic response.

[0392] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" mean "administration of a compound(s), drug, or other substance such that it enters the patient's body and is therefore subject to metabolic and other similar processes."

[0393] The phrase "therapeutically effective amount" refers to an amount of a compound of the present invention that (i) treats or prevents a particular disease, condition, or disorder, (ii) attenuates, improves, or eliminates one or more symptoms of a particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein. In the case of cancer, a therapeutically effective amount of a drug may reduce the number of cancer cells, reduce tumor size, inhibit (i.e., slow to some extent and preferably stop) cancer cell invasion into peripheral organs, inhibit (i.e., slow to some extent and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer. To the extent that a drug can prevent the growth of and / or kill existing cancer cells, the drug may be cytostatic and / or cytotoxic. With respect to cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0394] The term "subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0395] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of one or more fibrotic diseases.In a specific embodiment, the fibrotic disease is NASH and / or NAFLD.In a most specific embodiment, the fibrotic disease is NASH.In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0396] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in manufacturing a medicament for use in the prevention and / or treatment of one or more fibrotic diseases.In a specific embodiment, the fibrotic disease is NASH and / or NAFLD.In a most specific embodiment, the fibrotic disease is NASH.In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0397] In another aspect of the method of treatment, the present invention provides a method for preventing and / or treating a mammal suffering from a fibrotic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for treating or preventing the condition.In a specific embodiment, the fibrotic disease is NASH and / or NAFLD.In a most specific embodiment, the fibrotic disease is NASH.In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0398] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for a fibrotic disease. In a specific embodiment, the fibrotic disease is NASH and / or NAFLD. In a most specific embodiment, the fibrotic disease is NASH. In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0399] In one embodiment, the invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the prevention and / or treatment of a subject exhibiting a NAS score of at least 3, at least 4, at least 5, at least 6, or at least 7.

[0400] In another embodiment, the invention provides a compound of the invention for use in the manufacture of a medicament, or a pharmaceutical composition comprising a compound of the invention, for use in the prevention and / or treatment of a subject exhibiting a NAS score >5.

[0401] In a further method of treatment aspect, the present invention provides a method for the prevention and / or treatment of a mammal presenting with a NAS score >5, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for the treatment or prevention of a fibrotic disease, particularly NASH and / or NAFLD, more particularly NASH.

[0402] In further embodiments of the method of treatment, the method of prevention and / or treatment of a mammal comprises measuring forced vital capacity (FVC) in the subject, wherein the FVC does not decline after treatment. In certain embodiments, the FVC does not decline over a 12-week, 16-week, 20-week, or 26-week treatment period. In another embodiment, the method comprises measuring FVC in the subject, wherein the FVC increases by at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 1 mL, at least 7 mL, or at least 8 mL. In certain embodiments, the FVC increases by at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, or at least 8 mL over a 12-week, 16-week, 20-week, or 26-week treatment period.

[0403] In one embodiment, the method includes measuring airway volume, and the reduction in airway volume is 5 mL / L or less, 4 mL / L or less, or 3 mL / L or less. In certain embodiments, the reduction in airway volume is 5 mL / L or less, 4 mL / L or less, or 3 mL / L or less after 12, 16, 20, or 26 weeks of treatment.

[0404] Combination therapy

[0405] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0406] In certain embodiments, a provided combination or composition thereof is administered in combination with another therapeutic agent.

[0407] The compounds of the present invention may be used as therapeutic agents to treat mammalian conditions causally associated with or resulting from abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution.

[0408] Accordingly, the compounds and pharmaceutical compositions of the present invention find use in mammals, e.g., humans, as medicaments for the treatment of or the prevention and / or treatment of inflammatory conditions, pain, neuroinflammatory conditions, neurodegenerative conditions, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0409] Thus, in one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use as a medicament.

[0410] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament.

[0411] In yet another aspect, the present invention provides methods for treating a mammal having or at risk of having a disease disclosed herein. In certain aspects, the present invention provides methods for treating a mammal, including a human, having or at risk of having an inflammatory condition, pain, a neuroinflammatory condition, a neurodegenerative condition, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, leukemia, and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein.

[0412] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of an inflammatory condition. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by tumor therapy aimed at activating the immune response.

[0413] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for the prevention and / or treatment of an inflammatory condition. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by tumor therapy aimed at activating the immune response.

[0414] In another aspect, the invention provides a method of treating a mammal having or at risk for a disease selected from an inflammatory condition (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), a pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD) and a pulmonary interstitial disease (e.g., idiopathic pulmonary fibrosis (IPF))), a neuroinflammatory condition, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions described herein.

[0415] In a further method of treatment aspect, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an inflammatory condition, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the inflammatory condition is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory condition is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by tumor treatments aimed at activating the immune response.

[0416] In one aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the prevention and / or treatment of pain. In certain embodiments, the pain is acute or chronic and selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0417] In another aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the manufacture of a medicament for the prevention and / or treatment of pain. In certain embodiments, the pain is acute or chronic and selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0418] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from pain, the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0419] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prophylaxis and / or treatment of neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0420] In another aspect, the present invention provides a compound of the invention, or a pharmaceutical composition comprising a compound of the invention, for use in the manufacture of a medicament for use in the prevention and / or treatment of neuroinflammatory conditions, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0421] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from a neuroinflammatory condition, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, the method comprising administering an effective amount of a compound of the invention, or one or more of the pharmaceutical compositions described herein.

[0422] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of infectious disease(s). In certain embodiments, the infectious disease(s) is / are selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0423] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for the prevention and / or treatment of infectious disease(s). In certain embodiments, the infectious disease(s) is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0424] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an infectious disease(s), the method comprising administering an effective amount of a compound of the invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infectious diseases, such as those involving Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacteriaceae species.

[0425] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of an autoimmune disease and / or a disease involving impaired immune cell function. In certain embodiments, the autoimmune disease and / or the disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0426] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for use in the prevention and / or treatment of an autoimmune disease and / or a disease involving impaired immune cell function. In certain embodiments, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0427] In a further method of treatment aspect, the present invention provides a method for treating and / or preventing an autoimmune disease and / or a disease involving impaired immune cell function in a mammal susceptible to or suffering from the same, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type 1 diabetes, vasculitis, and inflammatory bowel disease.

[0428] In one aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the prevention and / or treatment of an endocrine and / or metabolic disorder. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0429] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutical composition comprising a compound of the present invention, for use in the manufacture of a medicament for the prevention and / or treatment of an endocrine and / or metabolic disorder. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0430] In a further method of treatment aspect, the present invention provides a method for the treatment and / or prophylaxis of a mammal susceptible to or suffering from an endocrine and / or metabolic disorder, the method comprising administering an effective amount of a compound of the present invention or one or more of the pharmaceutical compositions described herein. In certain embodiments, the endocrine and / or metabolic disorder is selected from hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes, diseases of the adrenal gland (such as Cushing's syndrome and Addison's disease), ovarian insufficiency (such as polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0431] As a further aspect of the present invention, there is provided a compound of the present invention for use as a medicament, particularly in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of a compound in the manufacture of a medicament for treating or preventing one of the aforementioned conditions and diseases.

[0432] A particular regimen of this method comprises administering to a subject suffering from an inflammatory condition an effective amount of a compound of the invention for a period of time sufficient to reduce the level of inflammation in the subject, preferably terminating the processes that cause said inflammation. A particular embodiment of this method comprises administering to a subject suffering from or susceptible to developing an inflammatory condition an effective amount of a compound of the invention for a period of time sufficient to reduce or prevent inflammation in the patient, respectively, and preferably halt the processes that cause inflammation.

[0433] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is not expected to exceed about 2 g / day for a human patient weighing 40 to 80 kg.

[0434] Transdermal doses are generally selected to provide blood levels that are similar to or lower than those achieved using injection doses.

[0435] When using the compounds of the present invention to prevent the onset of symptoms, the compounds of the present invention are typically administered to patients at risk of developing symptoms at the dosage levels described above, under the advice and supervision of a physician. Patients at risk of developing a particular condition generally include patients with a family history of the disease or patients identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0436] The compounds of the present invention can be administered as the sole active agent or in combination with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and that have been determined to be safe and effective for such combined administration. In certain embodiments, co-administration of two (or more) agents can allow significantly lower dosages of each to be used, thereby reducing the side effects observed.

[0437] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of an inflammatory condition; specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0438] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis); specific agents include, but are not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (e.g., but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporine), and biologic DMARDS (e.g., but not limited to, infliximab, etanercept, adalimumab, rituximab, golimumab, certolizumab pegol, tocilizumab, interleukin-1 blockers, and abatacept).

[0439] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of autoimmune diseases; specific agents include, but are not limited to, immunomodulatory agents, such as glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, and others), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., anthracyclines, such as dactinomycin, mitomycin C, bromide, etc.), and the like. leiomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab (Remicade®), etanercept (Enbrel®), or adalimumab (Humira®)), mycophenolic acid, fingolimod, and myriocin.

[0440] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of infectious diseases; specific agents include, but are not limited to, antibiotics. In a specific embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of infectious diseases in any organ of the human body; specific agents include, but are not limited to, aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, antimycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol, and tinidazole.

[0441] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of vasculitis; specific agents include, but are not limited to, steroids (e.g., prednisone, prednisolone), cyclophosphamide, and, in the case of skin infections, consequently antibiotics (e.g., cephalexin, etc.).

[0442] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of esophagitis; specific agents include, but are not limited to, antacids (e.g., formulations containing aluminum hydroxide, magnesium hydroxide, and / or simethicone), H2-antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide, etc.).

[0443] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of IPF; specific agents include, but are not limited to, pirfenidone and bosentan.

[0444] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of asthma and / or rhinitis and / or COPD; specific agents include, but are not limited to, beta-2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting beta-2 agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), and combinations of inhaled steroids and long-acting bronchodilators. (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g., roflumilast), biological modulators of IgE responses (e.g., omalizumab), antihistamines (e.g., ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymetazoline, xylomethazoline, naphazoline, and tramazoline).

[0445] Additionally, the compounds of the invention can be administered in combination with emergency treatments for asthma and / or COPD, including oxygen or heliox administration, nebulized salbutamol or terbutaline, optionally with an anticholinergic (e.g., ipratropium), systemic steroids (oral or intravenous (e.g., prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, nonspecific β-agonists, injected or inhaled (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g., glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, amifylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0446] In one embodiment, a compound of the invention is co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory bowel disease (IBD). Specific agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide), synthetic disease-modifying immunomodulators (e.g., methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine, and cyclosporine), and biological disease-modifying immunomodulators (e.g., infliximab, adalimumab, rituximab, and abatacept).

[0447] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of pain, e.g., a non-narcotic analgesic and a narcotic analgesic; specific agents include, but are not limited to, paracetamol, acetylsalicylic acid, NSAIDs, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorphine, fentanyl, hydromorphone, methadone, morphine, oxycodone, piritramide, tapentadol, or combinations thereof.

[0448] Treatment courses for leukemia include chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation, and / or combinations thereof.

[0449] Examples of additional therapeutic agents for acute lymphoblastic leukemia (ALL) include methotrexate, nelarabine, asparaginase Erwinia chrysanthemi, blinatumomab, daunorubicin, clofarabine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib vincristine, mercaptopurine, pegaspargase, and / or prednisone.

[0450] Examples of additional therapeutic agents for acute myeloid leukemia (AML) include arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and / or vincristine.

[0451] Examples of additional therapeutic agents for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, mechlorethamine, prednisone, and / or rituximab.

[0452] Examples of additional therapeutic agents for chronic myeloid leukemia (CML) include bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, mechlorethamine, nilotinib, and / or omacetaxine.

[0453] Examples of additional therapeutic agents for hairy cell leukemia include cladribine, pentostatin, and / or interferon alpha-2b.

[0454] As those skilled in the art will understand, simultaneous administration includes any means of delivering two or more therapeutic agents to patients as part of the same treatment regimen.Two or more agents can be administered simultaneously in one formulation, but this is not necessary.Agents can also be administered in different formulations at different times.

[0455] In one embodiment, the compound of the present invention is co-administered with one or more additional therapeutic agents for the treatment and / or prevention of fibrotic diseases. In certain embodiments, the compound of the present invention is co-administered with one or two additional therapeutic agents for the treatment and / or prevention of fibrotic diseases. In certain embodiments, the compound of the present invention is co-administered with one additional therapeutic agent for the treatment and / or prevention of fibrotic diseases.

[0456] In one embodiment, additional therapeutic agents for the treatment and / or prevention of fibrotic disorders include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone), nintedanib (Ofev® or Vargatef®); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), lebrikizumab (CASn#953400-68-5); tralokinumab (CASn#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), tipelukast (MN-001; ClinicalTrials.gov identifier NCT02503657), ND-L02-s020l (ClinicalTrials.gov identifier NCT02503657), ClinicalTrials.gov identifier NCT03538301), KD025 (ClinicalTrials.gov identifier NCT02688647), TD139 (ClinicalTrials.gov identifier NCT02257177), VAY736 (ClinicalTrials.gov identifier NCT03287414), PRM-151 (ClinicalTrials.gov identifier NCT02550873) and PBI-4050 (ClinicalTrials.gov identifier NCT02538536). In certain embodiments, the additional therapeutic agent for the treatment and / or prevention of fibrotic diseases is an autotaxin (or ectonucleotide pyrophosphatase / phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are those described in WO2014 / 139882, such as GLPG1690.

[0457] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of NASH, including, but not limited to, a weight loss therapeutic agent (e.g., sibutramine or orlistat), an insulin sensitizer (e.g., metformin, thiazolidinedione, rosiglitazone, or pioglitazone), a lipid-lowering agent (e.g., gemfibrozil), an antioxidant (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), an angiotensin-converting enzyme inhibitor, an angiotensin-receptor blocker, a monounsaturated fatty acid, or a polyunsaturated fatty acid. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., simtuzumab), ASK1 antagonists (e.g., selonsertib), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones, ibuprofen, GW-9662, aleglitazar, muraglitazar, or tesaglitazar), acetyl-CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2 / CCR5 (e.g., cenicriviroc), VAP1 antagonists.

[0458] Examples of agents with which the combinations of the present invention can be combined include, but are not limited to, treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for HIV, such as ritonavir; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; treatments for multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®, treatments for schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; cardiovascular disease treatments, such as beta blockers, AC E inhibitors, diuretics, nitrates, calcium channel blockers, and statins; liver disease treatments, such as corticosteroids, cholestyramine, interferons, and antivirals; blood disease treatments, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic degradation inhibitors) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and immunodeficiency disease treatments, such as gamma globulin.

[0459] In certain embodiments, the combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapeutic.

[0460] These additional agents may be administered separately from the combination therapy provided as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the present invention in one composition. When administered as part of a multiple dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0461] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously with another therapeutic agent, sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0462] The amount of additional therapeutic agent present in the compositions of the invention is no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure ranges from about 50% to about 100% of the amount that would normally be present in a composition comprising that therapeutic agent as the only therapeutically active agent.

[0463] In one embodiment, the present invention provides a composition comprising a compound of Formula I and one or more additional therapeutic agents. The therapeutic agents may be administered together with the compound of Formula I, or may be administered before or after the administration of the compound of Formula I. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of Formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the administration of the therapeutic agent. In other embodiments, the compound of formula I may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after administration of the therapeutic agent.

[0464] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biopharmaceuticals, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat (Uloric®), etc. Other drugs include benzodiazepines (Benza®), ... or Cuprimine®), azathioprine (Imuron®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pego anti-IL-1" drugs such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such asAbatacept (Orencia®), “anti-IL-6” agents such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheal agents such as diphenoxylate (Lomotil®) and loperamide ( Imodium®), bile acid binders, e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives, e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, Senokot®, anticholinergics or antispasmodics, e.g., dicyclomine (Bentyl®), Singulair®, beta-2 agonists, e.g., albuterol (Ventolin®), anticholinergics, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids, such as levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids, corticosteroids, such as beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines,For example, theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo)-24®) and aminophylline, IgE antibodies, for example, omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors®, zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), )), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), the non-nucleoside reverse transcriptase inhibitors delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®), and etravirine ( Nucleotide reverse transcriptase inhibitors such as Intelence®, tenofovir (Viread®), protease inhibitors, amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), trademarks), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®),and in combination with dexamethasone (Decadron®), lenalidomide (Revlimid®), or any combination thereof.

[0465] In another embodiment, the present invention provides a combination of a compound of Formula I with aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukemia®), and the like. an®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) such as rilonacept (Arcalyst®), antibodies, e.g., rituximab (Rituxan®), "anti-T cell" agents, e.g., abatacept (Orencia®), and "anti-IL-6" agents, e.g., tocilizumab (Actemra®).

[0466] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, aspirin, ibuprofen, naproxen, etodolac (Lodine®), and nonsteroidal anti-inflammatory drugs (NSAIDS) such as celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies such as tanezumab.

[0467] In some embodiments, the present invention provides methods for treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0468] In some embodiments, the present invention provides methods of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0469] In some embodiments, the present invention provides a method of treating asthma by administering to a patient in need thereof a compound of Formula I and Singulair®, e.g., β2 agonists, albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics, e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids, e.g., prednisone, prednisolone, beclomethasone dipropionate, and administering one or more additional therapeutic agents selected from fluticasone (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®).

[0470] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a compound of Formula I and a β2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine, such as theophylline (Theophylline), or a steroid agent, such as benzodiazepine (Bordeaux®). ... and administering one or more additional therapeutic agents selected from aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®.

[0471] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0472] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0473] In another embodiment, the present invention provides a method for treating a hematological malignancy, comprising administering to a patient in need thereof a compound of Formula I and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL ((Ramirez et al. "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma" Leuk. Res. (2012) published online July 17, and incorporated herein by reference in its entirety).

[0474] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0475] In another embodiment, the present invention provides a method for treating multiple myeloma, comprising administering to a patient in need thereof the compound of Formula I and bortezomib (Velcade®), and one or more additional therapeutic agents selected from dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor in combination with lenalidomide (Revlimid®).

[0476] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering a compound of Formula I and a BTK inhibitor to a patient in need thereof, wherein the disease is selected from: inflammatory bowel disease, arthritis, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, ord's thyroiditis. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis , scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, dysautonomia, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV) type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx), type 1 hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, gallbladder inflammation, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Scholein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis,Phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders, such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, lymph node marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colon cancer, pancreatic cancer, bone and joint diseases, including, but not limited to, rheumatoid arthritis, seronegative spondylitis, psoriatic arthritis, and Reiter's disease, Chronic hepatitis, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases, thromboembolic diseases (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, hypertension Irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, cutaneous lupus erythematosus, systemic lupus erythematosus (SLE),Rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0477] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disease, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disease, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disease, a destructive bone disease, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0478] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a PI3K inhibitor, wherein the disease is selected from: benign or malignant tumors, carcinomas or solid tumors of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, abdomen, stomach tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer, large intestine cancer, thyroid cancer, thyroid cancer, urinary tract ... intestinal carcinoma, head and neck tumors, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphomas (e.g., non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin's disease or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, diseases such as Cowden syndrome, Lhermitte-Dudos disease, and Banayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated, intrinsic (non-allergic) asthma Asthma of any type or cause, including both respiratory and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), for example, difficulty breathing associated with chronic bronchitis or emphysema, exacerbation of airway hyperresponsiveness due to other medications, especially other inhaled medications, regardless of type or cause, including, but not limited to: Bronchitis, acute of any type or cause, arachidonic bronchitis, catarrhal bronchitis, croupus bronchitis, chronic bronchitis or phthinoid bronchitis, pneumoconiosis (inflammatory, generally occupational, lung disease, often with airway obstruction, chronic or acute, caused by repeated inhalation of dust), e.g., aluminum lung disease, anthracosis, asbestosis, stone disease, trichiasis, siderosis, silicosis, tobacco disease and cotton fibrolosis, Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestation (e.g., tropical eosinophilia), bronchopulmonary aspergillosis,Polyarteritis nodosa (e.g., Churg-Strauss syndrome), eosinophil-related diseases affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose such as allergic rhinitis, inflammatory diseases involving an autoimmune response or with an autoimmune component or etiology, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, true erythroid aplasia, and idiopathic thrombocytopenia), cutaneous lupus erythematosus, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic rhinitis, and chronic urticaria. Active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (such as ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, e.g., idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by cerebral ischemia, trauma, glutamate neurotoxicity and hypoxia.

[0479] In some embodiments, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disease. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematological neoplasm, or solid tumor.

[0480] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the JH2-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, and WO2015089143A1, each of which is incorporated by reference in its entirety. Suitable JH1 domain-binding compounds include those described in WO2015131080(A1), each of which is incorporated by reference in its entirety.

[0481] The compounds and compositions of the present invention can be administered in any amount and via any route effective for treating or reducing the severity of autoimmune, inflammatory, proliferative, endocrine, neurological, or transplant-related disorders. The exact amount required may vary from subject to subject, depending on the subject's race, age, and general condition, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the term "dosage unit form" refers to a physically discrete unit of agent appropriate for the patient being treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will vary depending on a variety of factors, such as the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, general condition, sex, and diet; the time of administration, route of administration, and rate of excretion of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in the medical field. As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0482] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as powders, ointments, or drops), bucally, orally, or as a nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg of subject body weight / day to about 50 mg / kg of subject body weight / day, preferably about 1 mg / kg of subject body weight / day to about 25 mg / kg of subject body weight / day, to achieve the desired therapeutic effect.

[0483] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and fragrances.

[0484] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any brand of fixed oil can be used, including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[0485] Injectable preparations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0486] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of a compound depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0487] For example, compositions for rectal or vaginal administration are preferably suppositories which can be prepared, for example, by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or a suppository wax which is solid at ambient temperature but liquid at body temperature and thus will melt in the rectum or vaginal cavity and release the active compound.

[0488] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or fillers such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retardants such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0489] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar, high molecular weight polyethylene glycols, and similar additives. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings known in the pharmaceutical formulation art. They can optionally contain opacifying agents, or can be of a composition that preferably releases the active ingredient(s) only in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using additives such as lactose or milk sugar, and high molecular weight polyethylene glycols.

[0490] The active compound may also be in micro-encapsulated form with one or more of the additives mentioned above.Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation field.In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch.According to common practices, these dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose.In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents.They may optionally contain opacifying agents, or may be of a composition that releases the active ingredient(s) only in a certain part of the intestinal tract, optionally in a delayed manner.Examples of embedding compositions that can be used include polymeric substances and waxes.

[0491] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0492] According to one embodiment, the present invention relates to a method for inhibiting GPR84 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising a compound.

[0493] According to another embodiment, the present invention relates to a method for inhibiting the activity of GPR84 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound or a composition comprising a compound of the present invention.

[0494] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsies or extracts thereof obtained from mammals, and blood, saliva, urine, feces, sperm, tears, or other bodily fluids or extracts thereof.

[0495] Inhibition of GPR84 (or its variants) activity in biological samples is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0496] Another embodiment of the invention relates to a method of inhibiting GPR84 activity in a patient, comprising the step of administering to the patient a compound of the invention, or a composition comprising a compound.

[0497] According to another embodiment, the present invention relates to a method for inhibiting the activity of GPR84 or a variant thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method for reversibly or irreversibly inhibiting the activity of one or more of GPR84 or its variants in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a disorder mediated by GPR84 or a variant thereof in a patient in need thereof, the method comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0498] Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0499] The compounds of the present invention can also be advantageously used in combination with other therapeutic compounds.In some embodiments, the other therapeutic compounds are antiproliferative compounds.Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity; and further antiangiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptides. telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors, such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer and leucovorin). The term "aromatase inhibitor", as used herein, relates to a compound which inhibits the production of estrogens, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively.The term includes, but is not limited to, atamestane, exemestane, and formestane, particularly non-steroids, especially aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin™. Formestane is sold under the trade name Lentaron™. Fadrozole is sold under the trade name Afema™. Anastrozole is sold under the trade name Arimidex™. Letrozole is sold under the trade name Femara™ or Femar™. Aminoglutethimide is sold under the trade name Orimeten™. Combinations of the present invention containing a chemotherapeutic agent that is an aromatase inhibitor are particularly useful in the treatment of hormone receptor-positive tumors, such as breast tumors.

[0500] The term "antiestrogen" as used herein refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex™. Raloxifene hydrochloride is sold under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0501] The term "antiandrogen" as used herein refers to any substance capable of inhibiting the biological effects of androgen hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0502] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form that it is marketed under the trademark Camptosar™. Topotecan is sold under the trade name Hycamptin™.

[0503] The term "topoisomerase II inhibitors" as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and podophyllotoxin, etoposide, and teniposide. Etoposide is sold under the trade name Etopophos™. Teniposide is sold under the trade name VM26-Bristol. Doxorubicin is sold under the trade name Acriblastin™ or Adriamycin™. Epirubicin is sold under the trade name Farmorubicin™. Idarubicin is sold under the trade name Zavedos™. Mitoxantrone is sold under the trade name Novantron.

[0504] The term "microtubule activator" refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubule polymerization inhibitors, including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; cochicine, epothilones, and their derivatives. Paclitaxel is sold under the trade name Taxol™. Docetaxel is sold under the trade name Taxotere™. Vinblastine sulfate is sold under the trade name Vinblastine RP™. Vincristine sulfate is sold under the trade name Farmistin™.

[0505] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin™. Ifosfamide is sold under the trade name Holoxan™.

[0506] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including but not limited to suberoylanilide hydroxamic acid (SAHA).

[0507] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is sold under the trade name Xeloda™. Gemcitabine is sold under the trade name Gemzar™.

[0508] The term "platin compounds" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum, and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0509] The term "compounds that target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity, or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), for example compounds that target, reduce or inhibit the activity of PDGFR, in particular compounds that inhibit PDGF receptors, for example N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example IGF- compounds that target, reduce or inhibit the activity of IR, in particular compounds that inhibit the kinase activity of the IGF-I receptor or antibodies that target the extracellular domain of the IGF-I receptor or its growth factors; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the Axl receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, reduce, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, for example, compounds that target reducing or inhibiting the activity of c-Abl family members and their gene fusion products; for example, N-phenyl-2-pyrimidine-amine derivatives such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 or dasatinib (BMS-35) from ParkeDavis. 4825);j) compounds that target, decrease, or inhibit the activity of: protein kinase C (PKC) and members of the Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC families, and / or members of the cyclin-dependent kinase family (CDK), such as staurosporine derivatives, e.g., midostaurin; further exemplary compounds include UCN-01, safingol, and BAY4. 3-9006, bryostatin 1, perifosine; ilmofosine; RO318220 and RO320432; GO6976; lsis3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds which target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, for example, protein tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins. Tyrphostins, such as compounds that target, decrease, or inhibit the activity of tyrphostins, e.g., tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin);l) Compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, for example, compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, in particular members of the EGF receptor tyrosine kinase family, for example, EGF receptor, ErbB2, ErbB3, and ErbB4, or inhibit EGF or EGF-related ligands, CP358774, Z D1839, ZM105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease, or inhibit the activity of the c-Met receptor, e.g., For example, compounds that target, decrease, or inhibit the activity of c-Met, particularly compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or that bind to HGF; n) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), such as, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, mometasone, and the like. rotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, decrease, or inhibit the kinase activity of PI3 kinase (PI3K), such as, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupalisib, pictorelisib, PF-4691502, BYL-719, ductrib, XL-147, XL-765, and idelalisib;q) Compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothing Mechanism (SMO) pathways, such as, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib);

[0510] As used herein, the term "PI3K inhibitor" includes compounds that have inhibitory activity against one or more enzymes of the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupallisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0511] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), such as, but not limited to, AVL-292 and ibrutinib.

[0512] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, for example, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0513] The term "Bcl-2 inhibitors" as used herein includes compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), such as, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor Acenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and analogs; see WO2008118802), navitoclax (and analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0514] Further examples of BTK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2008039218 and WO2011090760, which are incorporated herein by reference in their entireties.

[0515] Further examples of SYK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO2003063794, WO2005007623 and WO2006078846, which are incorporated herein by reference in their entireties.

[0516] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729, which are incorporated herein by reference in their entireties.

[0517] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, which are incorporated herein by reference in their entireties.

[0518] Additional anti-angiogenic compounds include compounds that have an alternative mechanism for their activity, for example unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0519] Examples of proteasome inhibitors useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0520] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0521] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0522] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0523] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is sold under the trade name Didronel™. Clodronic acid is sold under the trade name Bonefos™. Tiludronic acid is sold under the trade name Skelid™. Pamidronic acid is sold under the trade name Aredia™. Alendronic acid is sold under the trade name Fosamax™. Ibandronic acid is sold under the trade name Bondranat™. Risedronic acid is sold under the trade name Actonel™. Zoledronic acid is sold under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0524] As used herein, the term "heparanase inhibitor" refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to lymphokines or interferons.

[0525] As used herein, the term "inhibitor of Ras oncogenic isoforms," ​​such as H-Ras, K-Ras, or N-Ras, refers to a compound that targets, reduces, or inhibits the oncogenic activity of Ras. For example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0526] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases, or inhibits the activity of methionine aminopeptidase. Compounds that target, decrease, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0527] As used herein, the term "proteasome inhibitor" refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™) and MLN341.

[0528] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551) BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.

[0529] As used herein, the term "compounds used in the treatment of hematological malignancies" includes, but is not limited to, compounds that target, decrease, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c), and bisulfan; ALK inhibitors (compounds that target, decrease, or inhibit anaplastic lymphoma kinase), and Bcl-2 inhibitors.

[0530] Compounds that target, decrease, or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are, in particular, compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.

[0531] The term "HSP90 inhibitor" as used herein includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, and compounds that target, reduce, or inhibit the degradation of HSP90 client proteins via the ubiquitin proteosome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 include, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives, other geldanamycin-related compounds, radicicol, and HDAC inhibitors.

[0532] As used herein, the term "antiproliferative antibody" includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. By antibody is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0533] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapy, particularly in combination with therapy used for the treatment of AML.In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutation, comprising administering the compounds of the present invention together with one or more FLT3 inhibitors. In some embodiments, the FLT3 inhibitor is selected from quizartinib (AC220), staurosporine derivatives (e.g., midostaurin or lestaurtinib), sorafenib, tandutinib, LY-2401401, LS-104, EB-10, famitinib, NOV-110302, NMS-P948, AST-487, G-749, SB-1317, S-209, SC-110219, AKN-028, fedratinib, tozasertib, and sunitinib. In some embodiments, the FLT3 inhibitor is selected from quizartinib, midostaurin, lestaurtinib, sorafenib, and sunitinib.

[0534] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease, or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in US Pat. No. 6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof, particularly lactate. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Approaches that damage tumor cells refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs as electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha particles and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

[0535] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, such as, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0536] Also included are compounds, proteins or monoclonal antibodies, especially VEGF, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Angiostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., VEGF aptamers such as rhuMAb and RHUFab, Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozyme (RPI4610) and bevacizumab (Avastin™), Bevacizumab (Avastin™).

[0537] As used herein, photodynamic therapy refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0538] As used herein, angiogenic antisteroids refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0539] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0540] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds, antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0541] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those described above, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention can be mixed with the other drug substances in a fixed pharmaceutical composition, or can be administered separately, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention described above with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0542] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 agonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247; LTD4 antagonists such as montelukast, zafirlukast; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801(Celgene), SeICID(TM) CC-10004(Celgene), VM554 / UM565(Vernalis), T-440(Tanabe), KW-4490(Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and β2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol, and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts, and CHF4226 (Chiesi), and glycopyrrolate.

[0543] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0544] Other useful combinations of compounds of the invention with anti-inflammatory agents are antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, particularly CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and Takeda antagonists, such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0545] The structures of active compounds identified by code number, generic name or trade name can be obtained from the actual edition of the standard compendium "The Merck Index" or from databases such as international patents (eg IMS World Publications).

[0546] Representative tumor immunotherapy agents In some embodiments, one or more other therapeutic agents are tumor immunotherapeutic agents.As used herein, the term "tumor immunotherapeutic agent" refers to an agent that is effective for enhancing, stimulating, and / or upregulating the immune response in a subject.In some embodiments, administering the tumor immunotherapeutic agent together with the compound of the present invention has a synergistic effect in the treatment of cancer.

[0547] The immuno-oncology agent may be, for example, a small molecule drug, an antibody, or a biological molecule or small molecule. Examples of biological immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human.

[0548] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including costimulatory) signal on T cells, both of which amplify antigen-specific T cell responses.

[0549] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the B7 family, including B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the cognate TNF receptor family. These include CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin alpha / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin alpha 1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0550] In some embodiments, the tumor immunomodulator is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0551] In some embodiments, the combination of the compound of the present invention and an immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent is: (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0552] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0553] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, such as, but not limited to, a CSF-1R antagonist, e.g., a CSF-1R antagonist antibody, e.g., RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0554] In some embodiments, the immuno-oncology agent is selected from one or more of: an agonist agent that ligates positive costimulatory receptors; a blocking agent that attenuates signaling through inhibitory receptors; an antagonist; and one or more agents that increase the frequency of anti-tumor T cells systemically; an agent that overcomes different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction)); an agent that depletes or inhibits Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion); an agent that inhibits metabolic enzymes such as IDO; or reversing / preventing T cell energy or exhaustion); and an agent that causes innate immune activation and / or inflammation at the tumor site.

[0555] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0556] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein called AMP-224, which is composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0557] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0558] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0559] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0560] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0561] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Ikena Oncology, formerly known as Kyn Therapeutics); and NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0562] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0563] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0564] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0565] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0566] In some embodiments, the tumor immunomodulator is MGA271 (directed against B7H3) (WO11 / 109400).

[0567] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0568] In some embodiments, the tumor immunotherapy agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can relieve the suppression of activated tumor-reactive T cells, and clinical trials have shown that they induce durable anti-tumor responses in an increasing number of tumor tissue types, including some tumor types not previously considered susceptible to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who have experienced disease progression during or after previous antiangiogenic therapy.

[0569] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutics that can be used in the present invention include pomalidomide (POMALYST®, Celgene), lenalidomide (REVLIMID®, Celgene); ingenol mebutate (PICATO®, LEOPharma).

[0570] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (PROVENGE®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (IMLYGIC®, BioVex / Amgen, formerly known as T-VEC), a gene-modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma.In some embodiments, the immuno-oncology agent is selected from oncolytic virotherapy, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex), a thymidine kinase (TK)-deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312). Biotherapeutics; colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). pelareorep (REOLYSIN®, Oncolytics), a variant of the respiratory enteric orphan virus (reovirus) that does not replicate in cells without RAS activation, has been shown to be effective in many cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). Biotech); ovarian cancer (NCT02028117); Enadenotsiliev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein in metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucoronidase or β-gal / human sodium iodide symporter (hNIS), respectively, studied in 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0571] In some embodiments, the immuno-oncology agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase that can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics that target difficult-to-treat RAS mutations; TILT-123 (TILT Biotherapeutics), an engineered adenovirus called Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choroiditis virus (LCMV), which expresses antigen-specific CD8 + and (which can be further engineered to express an antigen designed to elicit a T cell response).

[0572] In some embodiments, the tumor immunotherapy agent is a T cell engineered to express a chimeric antigen receptor, or CAR. Such T cells engineered to express a chimeric antigen receptor are called CAR-T cells.

[0573] CARs have been constructed that consist of a binding domain, which may be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, fused to a functional end-domain of the T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, which can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs couple to the endogenous signaling pathways of the effector cell, generating an activation signal similar to that initiated by the TCR complex.

[0574] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (June et al.; incorporated herein by reference in its entirety), which discloses CAR-T cells engineered to contain an extracellular domain with an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T-cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in T cells, the CAR can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, there are over 200 clinical trials underway employing CAR-T cells in a wide range of indications [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0575] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor g (RORgt). RORgt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as the differentiation of IL-17-expressing innate immune cell subpopulations, such as NK cells. In some embodiments, the activator of RORgt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0576] In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that has been studied for B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which has been studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0577] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0578] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, agonists or activators of toll-like receptors, and activators of RORgt.

[0579] In some embodiments, the immune stimulatory therapeutic is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being clinically tested as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immune stimulatory agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 (IL15:sIL-15RA) complexed with the soluble IL-15 binding protein IL-15 receptor alpha chain, and is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0580] In some embodiments, the immuno-oncology agent is selected from those described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, 603-622, the entire contents of which are incorporated herein by reference. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the imm...

Claims

1. Compounds of Formula I: 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 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 carbocycle; Ring B is a 5-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R １ is selected from (i) a 3- to 7-membered saturated or partially unsaturated monocyclic carbocycle; or a 5- to 6-membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 11-membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; and C １～６ Aliphatic; each is R ４ and (ii) is hydrogen; R ２ , R ４ , and R ５ Each instance of ｚ , halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. ２ , -S(O)R, -S(O)NR ２ , -CF ２ R, -CF ３ , -CR ２ (CN), -CR ２ (OR), -CR ２ (NR ２ ), -C(O)R, -C(O)OR, -C(O)NR ２ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ２ , -C(S)NR ２ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR ２ , -N(R)C(NR)NR ２ , -N(R)NR ２ , -N(R)S(O) ２ N.R. ２ , -N(R)S(O) ２ R, -N=S(O)R ２ , -S(NR)(O)R, -N(R)S(O)R, -N(R)CN, -Si(OR)R ２ , -SiR ３ , -P(O)(R)NR ２ , -P(O)(R)OR or -P(O)R ２ or Two R's ２ the groups optionally taken together form =O; Two R's ４ the groups optionally taken together form =O; Two R's ５ the groups optionally taken together form =O; Two R's ２ groups optionally taken together with their intervening atoms form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Two R's ４ groups, optionally together with their intervening atoms, 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 R's ５ groups optionally taken together with their intervening atoms form a 5-8 membered saturated, partially unsaturated, or aryl fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R ｚ The instance of １～６ Independently selected from optionally substituted groups selected from aliphatic, phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; a 4-7 membered saturated or partially unsaturated heterocycle 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; R ３ is hydrogen or optionally substituted C １～６ is an aliphatic group; or Two R's ３ the groups optionally taken together form =O; or R ２ Groups and R ３ groups optionally taken together with their intervening atoms form an optionally substituted 5-8 membered saturated or partially unsaturated fused ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; L １ is one of the following: (a) C １～６ a divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: ２ -, -CH(R)-, -CH(OR)-, -C(F) ２ -, -N(R)-, -S-, -S(O)-, or -S(O) ２ - (substituted with ); (b) Covalent attachment; Each -Cy- is independently an optionally substituted divalent ring selected from phenylene; a 3- to 7-membered saturated or partially unsaturated carbocyclylene; a 4- to 7-membered saturated or partially unsaturated heterocyclylene having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 7- to 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- to 6-membered heteroarylene having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L ２ is a covalent bond or C １～４ wherein one to two methylene units of the chain are independently and optionally -O-, -C(O)-, -C(S)-, -C(R ... ２ -, -CH(R)-, -CR(OR)-, -C(F) ２ -, -N(R)-, -S-, -S(O)-, -CH(CR ３ ) -, -C=(CH ２ ) - or -S(O) ２ is substituted with -; L ３ is one of the following: (a) C １～４ A divalent linear or branched, saturated or unsaturated hydrocarbon chain of the formula: ２ -, -CH(R)-, -CH(OR)-, -C(F) ２ -, -N(R)-, -S-, -S(O)-, or -S(O) ２ - (substituted with ); (b) Covalent attachment; X is one of the following: (a) a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-11 membered saturated or partially unsaturated bridged or spirocyclic bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-10 membered saturated or partially unsaturated bridged tricyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered partially aromatic or heteroaromatic bicyclic heterocycle 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 carbocycle; or phenyl; each of which is selected from q R ５ be replaced with an instance of; or (b) -CH ２ (OR), -CH(R)(OR), or -C(R) ２ (OR); Each instance of R is independently hydrogen, or C １～６ an optionally substituted group selected from aliphatic; phenyl; an 8-10 membered bicyclic aryl ring, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; or 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; an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same atom are optionally joined 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; q is 0, 1, 2, 3, 4, or 5).

2. The compound has any one of formulas I-a, I-b-1, I-b-2, I-b-3, or I-c: 【Chemistry 2】 2. The compound of claim 1, wherein:

3. 2. The compound according to claim 1, wherein the compound has formula If-1, If-2, If-3, If-4, If-5, If-6, If-7, If-8, or If-9: 【Chemistry 3】 2. The compound of claim 1, wherein:

4. The compound has any one of formulas I-g-1, I-g-2, or I-g-3: 【Chemistry 4】 2. The compound of claim 1, wherein:

5. The compound has any one of formulas I-h-1, I-h-2, or I-h-3: 【Chemistry 5】 2. The compound of claim 1, wherein:

6. The compound has any one of formulas I-i-1, I-i-2, or I-i-3: 【Chemistry 6】 2. The compound of claim 1, wherein:

7. The compound has any one of formulas I-j-1, I-j-2, or I-j-3: 【Chemistry 7】 2. The compound of claim 1, wherein:

8. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring A is phenyl, a 4-7 membered saturated or partially unsaturated monocyclic carbocycle; 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

9. Ring A and its R ２ The substituent is 【Chemistry 8】 9. The compound of claim 1 or 8, wherein:

10. Ring A and its R ２ The substituent is 【Chemistry 9】 10. The compound according to any one of claims 1 and 8 to 9, wherein:

11. 11. The compound according to any one of claims 1 and 8 to 10, or a pharma- ceutically acceptable salt thereof, wherein Ring B is a 5-membered monocyclic partially unsaturated heterocyclyl or heteroaryl ring having 2 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

12. Ring B and its R ３ The substituent is 【Chemistry 10】 12. The compound according to any one of claims 1 and 8 to 11, wherein:

13. Two R's ３ The groups taken together form =O, and ring B is 【Chemistry 11】 13. The compound according to any one of claims 1 and 8 to 12, wherein:

14. Ring B and its R ３ The substituent is 【Chemistry 12】 13. The compound according to any one of claims 1 and 8 to 12, wherein:

15. R １ is C １～６ aliphatic; phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocycle; 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 heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 7-11 membered saturated or partially unsaturated spiro or bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, each of which is selected from R ４ 15. The compound of any one of claims 1 and 8 to 14, or a pharma- ceutically acceptable salt thereof, substituted with p instances of:

16. R １ and its R ４ The substituent is 【Chemistry 13】 16. The compound according to any one of claims 1 and 8 to 15, wherein:

17. Two R's ４ The groups taken together form =O, and R １ but, 【Chemistry 14】 17. The compound according to any one of claims 1 and 8 to 16, wherein:

18. Two sets of R ４ The groups taken together form =O, and R １ but, 【Chemistry 15】 17. The compound according to any one of claims 1 and 8 to 16, wherein:

19. L １ が, shared combination, 【Chemistry 16-1】 【Chemistry 16-2】 【Chemistry 16-3】 19. The compound according to any one of claims 1 and 8 to 18, wherein:

20. L ２ が, shared combination, 【Chemistry 17】 20. The compound according to any one of claims 1 and 8 to 19, wherein:

21. L ３ が, shared combination, 【Chemistry 18】 21. The compound according to any one of claims 1 and 8 to 20, wherein:

22. 22. The compound according to any one of claims 1 and 8 to 21, wherein m is 1, 2, 3, or 4, or a pharma- ceutically acceptable salt thereof.

23. 23. The compound according to any one of claims 1 and 8 to 22, wherein n is 1, 2, 3, or 4, or a pharma- ceutically acceptable salt thereof.

24. 24. The compound according to any one of claims 1 and 8 to 23, wherein p is 1, 2, 3, 4, or 5, or a pharma- ceutically acceptable salt thereof.

25. Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen and oxygen, and Ring B is a 5 membered monocyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen and oxygen; R １ is p R ４ is a 3-7 membered saturated monocyclic carbocyclic ring substituted with instances of ２ , R ４ , and R ５ Each instance of ｚ , halogen, -CN, -NO ２ , -OR, -SR, or -NR ２ and R ｚ Each instance of may be independently selected from the optionally substituted C １～６ is aliphatic; R ３ is hydrogen or optionally substituted C １～６ is an aliphatic group; L １ is C ２～４ L is a divalent linear or branched unsaturated hydrocarbon chain of the formula: ２ is a covalent bond; L ３ is C １～４ X is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being joined to q R ５ each instance of R is independently selected from hydrogen and optionally substituted C １～６ 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2.

26. X is a 5-7 membered saturated monocyclic heterocycle having 1 or 2 oxygen atoms, said ring being ５ 30. The compound of claim 1 or 25, or a pharma- ceutically acceptable salt thereof, substituted with an instance of:

27. The compound is 【Chemistry 19】 2. The compound of claim 1, represented by: or a pharma- ceutically acceptable salt thereof.

28. R １ is p R ４ is a 3-7 membered saturated monocyclic carbocyclic ring substituted with instances of ２ and R ５ Each instance of ｚ , halogen, -CN, -NO ２ , -OR, -SR, or -NR ２ and R ｚ Each instance of may be independently selected from the optionally substituted C １～６ is aliphatic; R ３ is hydrogen or optionally substituted C １～６ is an aliphatic group; L ３ is C １～４ X is a 4-8 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, said ring being joined to q R ５ each instance of R is independently selected from hydrogen and optionally substituted C １～６ 28. The compound of claim 27, or a pharma- ceutically acceptable salt thereof, wherein: m is 0, 1, or 2; n is 0 or 1; p is 0, 1, or 2; and q is 0, 1, or 2.

29. X is a 5-7 membered saturated monocyclic heterocycle having 1 or 2 oxygen atoms, said ring being ５ 29. The compound of claim 27 or 28, or a pharma- ceutically acceptable salt thereof, substituted with an instance of:

30. The compound has formula I-ii-1 or I-ii-2: 【Chemistry 20】 (In the formula, R ２’ is R ２ 2. The compound of claim 1, wherein:

31. R ２’ But -NR ２ 31. The compound of claim 30, wherein:

32. R ２’ But -N(CH ３ ) ２ 31. The compound of claim 30, wherein:

33. The compound has formula I-jj-1 or I-jj-2: 【Chemistry 21】 2. The compound of claim 1, wherein:

34. The compound has any one of formulas I-kk-1 or I-kk-2: 【Chemical 22】 (In the formula, R ２’ is R ２ 2. The compound of claim 1, wherein:

35. R ２’ But -NR ２ 35. The compound of claim 34, wherein:

36. R ２’ But -N(CH ３ ) ２ 35. The compound of claim 34, wherein:

37. The compound has any one of formulas I-ll-1 or I-ll-2: 【Chemistry 23】 2. The compound of claim 1, wherein:

38. R ２ is F, or a pharma- ceutically acceptable salt thereof.

39. 2. The compound of claim 1, wherein the compound is selected from those shown in Table 1, or a pharma- ceutically acceptable salt thereof.

40. 40. A pharmaceutical composition comprising a compound according to any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

41. A medicament for inhibiting GPR84 in a biological sample, comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40.

42. A medicament comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40, for treating a GPR84-mediated disorder, disease or condition in a patient.

43. 43. The pharmaceutical of claim 42, wherein the disorder, disease or condition is a proliferative disorder, a fibrotic disease, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, a disease involving impaired immune cell function, a neuroinflammatory condition, a neurodegenerative condition, an inflammatory condition, multiple sclerosis, or pain.

44. The pharmaceutical composition of claim 42, wherein the disorder, disease or condition is cancer.

45. The pharmaceutical composition of claim 44, wherein the cancer is leukemia or hepatocellular carcinoma (HCC).

46. The pharmaceutical composition of claim 44, wherein the cancer is acute myeloid leukemia (AML).

47. 43. The medicament of claim 42, wherein the disorder, disease or condition is a proliferative disorder associated with one or more activating mutations in GPR84.

48. 43. The method of claim 42, wherein the disorder, disease or condition is a chronic viral infection.

49. 44. The pharmaceutical composition of claim 42 or 43, wherein the disorder, disease or condition is an inflammatory condition selected from rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis (IPF), psoriasis, Crohn's disease, ulcerative colitis, uveitis, periodontitis, esophagitis, gastroesophageal reflux disease (GERD), inflammatory bowel disease, or pyoderma gangrenosum.

50. 43. The method of claim 42, wherein the disorder, disease or condition is non-alcoholic steatohepatitis (NASH) or idiopathic pulmonary fibrosis (IPF).

51. 43. The method of claim 42, wherein the disorder, disease or condition is systemic lupus erythematosus.

52. 43. The method of claim 42, wherein the disorder, disease or condition is neuropathic pain.

53. The method of claim 42, wherein the disorder, disease or condition is Alzheimer's disease.

54. The pharmaceutical of claim 42, wherein the disorder, disease or condition is idiopathic pulmonary fibrosis (IPF).

55. A medicament for enhancing the efficacy of vaccination in a patient, comprising a compound according to any one of claims 1 to 39 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 40 as an adjuvant.

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