Heteroaryl carboxamides and related GPR84 antagonists and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for inhibiting GPR84 and treating GPR84 mediated conditions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 394,371 filed on August 2, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention provides compounds and methods useful for antagonizing G protein coupled receptor 84 (GPR84). The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods of using the compositions to treat various disorders. Background Art

[0004] 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.

[0005] GPR84 was isolated and identified from human B cells (Wittenberger et al., 2001. J. Mol. Biol. 307, 799-813.) as a result of an expressed sequence tag data mining strategy, while also using a degenerate primer reverse transcriptase-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 medium-chain free fatty acids (FFAs) with a carbon chain length of 9-14 were identified as ligands for the receptor (Wang J et al., 2006. J. Biol. Chem. 281, 34457-34464.). It is described that GPR84 can 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. It is also described that three small molecules have some GPR84 agonist activity: 3,3'-diindolylmethane (DIM) (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.).

[0006] GPR84 has been shown to be expressed in immune cells, at least 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 has been shown to be expressed in tissues that may be involved in the propagation of inflammatory responses, such as the lungs, spleen, and bone marrow.

[0007] For example, in a recent review, du Bois reports on the current status of treatment for interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). Interstitial lung diseases have nearly 300 different damaging or inflammatory causes that can lead to diffuse lung scarring, and the initial stages of IPF pathology are likely to involve inflammation (du Bois RM..2010.Nat.Rev.DrugDiscov.9,129-140.), and combination therapies involving anti-inflammatory treatments can be used to advantage.

[0008] GPR84 expression is highly upregulated in monocytes / macrophages following LPS stimulation (Wang et al., 2006).

[0009] GPR84 knockout (KO) mice survive and are indistinguishable from wild-type littermate controls (Venkataraman & Kuo 2005). It has been reported that proliferation of T cells and B cells in response to various mitogens is common in GPR84-deficient mice (Venkataraman & Kuo 2005). T helper 2 (Th2) differentiated T cells of GPR84 KO mice secrete higher levels of IL4, IL5, and IL13 (the three main Th 2 In contrast, the production of the Th1 cytokine INFγ in Th1-differentiated T cells was similar between GPR84 KO mice and their wild-type littermates (Venkataraman & Kuo 2005).

[0010] In addition, capric, undecanoic, and lauric acids dose-dependently increased the secretion of interleukin-12p40 subunit (IL-12p40) from LPS-stimulated RAW264.7 murine macrophage-like cells. The proinflammatory cytokine IL-12 plays a key role in promoting cell-mediated immunity to eliminate pathogens by inducing and maintaining T helper 1 (Th1) responses and inhibiting T helper 2 (Th2) responses. Medium-chain FFAs may affect the Th1 / Th2 balance by directly acting on GPR84.

[0011] Berry et al. discovered a whole blood 393 gene transcriptional signature for active tuberculosis (TB) (Berry MPR et al. 2010. Nature 466, 973–977.) GPR84 is part of the whole blood 393 gene transcriptional signature for active TB, suggesting that GPR84 has a potential role in infectious diseases.

[0012] GPR84 expression has also been described in microglia, the major immune effector cells of the central nervous system (CNS) of myeloid monocyte origin (Bouchard C et al. 2007. Glia 55, 790–800.). As observed in peripheral immune cells, GPR84 expression in microglia is highly inducible under inflammatory conditions such as TNFα and IL1 treatment, and is also significantly induced in endotoxemia and experimental autoimmune encephalomyelitis (EAE), suggesting a role in neuroinflammatory processes. These results suggest that GPR84 is upregulated not only in the CNS during endotoxemia and multiple sclerosis, but also in all neurological diseases that produce TNFα or IL-1β proinflammatory cytokines, including brain injury, infection, Alzheimer's disease (AD), and Parkinson's disease (PD).

[0013] GPR84 expression has also been observed in adipocytes and has been shown to be enhanced by inflammatory stimuli (Nagasaki H et al. 2012. FEBS Lett. 586, 368–372.) The results suggest that TNFα from infiltrating macrophages triggers GPR84 expression, exacerbating the vicious cycle between obesity and diabetes / obesity, and therefore inhibition of GPR84 activity may be beneficial for the treatment of endocrine and / or metabolic diseases.

[0014] After nerve injury, GPR84 expression in microglia surrounding neurons is also upregulated. (Gamo et al., 2008. J. Neurosi. 28 (46), 11980-11988.). In addition, in GPR84 knockout mice, hypersensitivity to mechanical stimulation in mouse models of inflammation and neuropathic pain was significantly reduced or completely eliminated (Nicol LSC et al., 2015. J. Neurosci. 35, 8959-8969.). Therefore, molecules that block GPR84 activation may have the potential to provide broad-spectrum analgesia.

[0015] GPR84 expression is increased in human leukemic stem cells (LSCs) from patients with acute myeloid leukemia (AML) compared to hematopoietic stem cells from healthy donors. GPR84 simultaneously enhances β-catenin signaling and an oncogenic transcriptional program that is critical for the establishment of MLL leukemia (Dietrich et al., 2014. Blood 124(22), 3284-3294). Inhibition of GPR84 significantly inhibits cell growth in pre-LSCs, reduces LSC frequency, and impairs the reconstitution of stem cell-derived MLL leukemias, which represent a particularly aggressive and drug-resistant subtype of AML. Targeting the oncogenic GPR84 / β-catenin signaling axis may represent a new therapeutic strategy for AML and potentially other leukemias.

[0016] In M1 macrophages isolated from aortic atherosclerotic lesions of LDLR- / - mice fed a Western diet, GPR84 expression increased 49.9-fold (Kadl A et al. 2010. Circ. Res. 107, 737-746.). Therefore, molecules targeting GPR84 may have potential benefits in the treatment of atherosclerosis.

[0017] In experimental esophagitis, GPR84 is upregulated in esophageal tissue, mainly in epithelial cells, and significantly decreased in rats treated with omeprazole (a proton pump inhibitor) or STW5, a herbal preparation that improves esophagitis without affecting reflux fluid pH (Abdel-Aziz H et al. 2015. Mol. Med. 21, 1011-1024.). Western blot and immunohistochemistry results of rat tissue and HET-1A cells (a human esophageal squamous cell line) support this finding. GPR84 was also found to be significantly upregulated in esophageal biopsies of patients with grade B reflux esophagitis. Therefore, molecules that block the activity of the GPR84 receptor may represent a new therapeutic paradigm for the treatment of esophagitis.

[0018] Therefore, the identification and development of novel compounds, processes for preparing these compounds, and their use in the preparation of medicaments would be highly desirable for patients suffering from inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemias, and / or diseases involving impaired immune cell function.

[0019] Additionally, it remains desirable to identify and develop novel compounds for the preparation of medicaments for the prevention and / or treatment of one or more fibrotic diseases, more specifically NASH and / or IPF. Summary of the invention

[0020] The present invention provides compounds and methods useful for antagonizing G protein coupled receptor 84 (GPR84). The present invention also provides pharmaceutical compositions comprising the compounds of the present invention and methods of using the compositions to treat various disorders.

[0021] One aspect of the present invention provides a collection of compounds defined by Formula I:

[0022]

[0023] or a pharmaceutically acceptable salt thereof, wherein A 1 , A 2 , L 1 , L 2 , R 1 and R 2 Each of which is as defined below and described in the embodiments herein. Also provided is a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0024] Another aspect of the present invention provides a group of compounds defined by formula II:

[0025]

[0026] or a pharmaceutically acceptable salt thereof, wherein A 1 , A 2 , L 1 , L 2 , R 1 and R 2 Each of which is as defined below and described in the embodiments herein. Also provided is a pharmaceutical composition comprising a compound of Formula II and a pharmaceutically acceptable carrier.

[0027] Another aspect of the present invention provides a method for treating a GPR84-mediated condition, disease or illness in a patient. The method comprises administering a therapeutically effective amount of a compound described herein, such as a compound of Formula I or II, to the patient in need. In certain embodiments, the compound is a compound of Formula II. Exemplary GPR84-mediated conditions, diseases or illnesses include fibrotic diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, diseases involving impaired immune cell function, neuroinflammatory conditions, neurodegenerative diseases, inflammatory diseases, multiple sclerosis or pain.

[0028] Another aspect of the present invention provides a method of inhibiting GPR84. The method comprises contacting GPR84 with an effective amount of a compound described herein to inhibit GPR84.

[0029] The compounds provided by the present invention can also be used for the study of GPR84 in biological and pathological phenomena; the study of fibrosis processes occurring in body tissues; and the in vitro or in vivo comparative evaluation of new GPR84 inhibitors or other modulators of chemotaxis of neutrophils and macrophages. DETAILED DESCRIPTION

[0030] 1. General Description of Certain Embodiments of the Invention:

[0031] In certain aspects, the present invention provides compounds of formula I:

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein A 1 , A 2 , L 1 , L 2 , R 1 and R 2 Each of which, individually and in combination, is as defined below and described in the embodiments herein.

[0034] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, adjuvant or diluent.

[0035] In some embodiments, the present invention provides a method of treating a GPR84-mediated disease, condition or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

[0036] 2. Compounds and Definitions:

[0037] The compounds of the present invention include those compounds generally described herein and further illustrated by the categories, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For purposes of the present invention, chemical elements are identified according to the Periodic Table of 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, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0038] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic hydrocarbon or a bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units), but it is not aromatic (also referred to herein as "cycloaliphatic") and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet 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, "cycloaliphatic" refers to a monocyclic C 2-1 ... 3 -C 6 A hydrocarbon having a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0039] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system, i.e., carbocyclic or heterocyclic ring, with at least one bridge bond. As defined by IUPAC, a "bridge bond" is a non-branched chain of multiple atoms or an atom or a valence bond connecting two bridgeheads, wherein a "bridgehead" is any backbone atom of a ring system bonded to three or more backbone atoms (except hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic group is optionally substituted by one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0040]

[0041] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0042] The term "lower haloalkyl" refers to a C 1-4 Straight chain or branched chain alkyl.

[0043] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (such as in N-substituted pyrrolidinyl)).

[0044] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0045] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains as defined herein, which are straight or branched.

[0046] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH 2 ) n -, wherein 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 chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0047] The term "-(C 0 Thus, the term "-(C 0-3 "alkylene)-" encompasses bonds (i.e., C 0 ) and -(C 1-3 alkylene)-group.

[0048] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0049] The term "halo" means F, Cl, Br or I.

[0050] The term "aryl" as used alone or as part of a larger moiety in "aralkyl", "aralkyloxy" or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system has 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that can carry one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc. As used herein, the term "aryl" also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindanyl, phthalimide, naphthimide, phenanthridinyl or tetrahydronaphthyl, etc. The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to occupy the groups to which it is attached. For example, if "phenylene" has two groups attached, it is a divalent phenyl group (e.g., ); "phenylene" is a trivalent phenyl group if it has three groups attached to it (e.g., The term "arylene" refers to a divalent aromatic group.

[0051] The terms "heteroaryl" and "heteroar-" (e.g., "heteroaralkyl" or "heteroaralkoxy"), used alone or as part of a larger moiety, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in a cyclic array; and having from one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroaromatic-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein unless otherwise specified, the group 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, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl and tetrahydroisoquinolyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl" or "heteroaromatic", any of which includes an optionally substituted ring. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0052] The term "heteroarylene" refers to a polyvalent heteroaryl radical having an appropriate number of open valences to occupy the groups to which it is attached. For example, if a "heteroarylene" has two groups attached, it is a divalent heteroaryl radical; if a "heteroarylene" has three groups attached, it is a trivalent heteroaryl radical. The term "pyridylene" refers to a polyvalent pyridyl radical having an appropriate number of open valences to occupy the groups to which it is attached. For example, if a "pyridylene" has two groups attached, it is a divalent pyridyl radical (e.g., ); "pyridylene" is a trivalent pyridyl if it has three groups attached (e.g., ).

[0053] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic group" and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. When used with respect to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0054] The heterocycle may be attached to its side group at any heteroatom or carbon atom to produce a stable structure, and any ring atom may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepanyl, oxazepanyl, thiazepanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group may be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl moieties are independently and optionally substituted. The term "oxoheterocyclyl" refers to a heterocyclyl group substituted with an oxo group. The term "oxoheterocyclylene" refers to a multivalent oxoheterocyclylene group having an appropriate number of open valencies to occupy the groups to which it is attached. For example, "oxoheterocyclylene" is a divalent oxoheterocyclylene group if two groups are attached; "oxoheterocyclylene" is a trivalent oxoheterocyclylene group if three groups are attached.

[0055] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings with multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0056] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted" means that one or more hydrogens of the specified moiety are replaced by suitable substituents, whether or not the term "optionally" is present in front. Unless otherwise indicated, the "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent at each position may be the same or different. The combination of substituents envisioned by the present invention is preferably a combination that forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow it to be produced, detected, and in certain embodiments recovered, purified, and used for one or more of the purposes disclosed herein.

[0057] Suitable monovalent substituents on substitutable carbon atoms of an "optionally substituted" group are independently halo; -(CH 2 )0-4 R o ;-(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 R o ;-O-(CH 2 ) 0-4 C(O)OR o ;-(CH 2 ) 0-4 CH(OR o ) 2 ;-(CH 2 ) 0- 4 SR o ;-(CH 2 ) 0-4 Ph, which can be o Substitution; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph, which can be o Substitution; -CH=CHPh-, which can be R o Replacement; (CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which may be R o Replacement; -NO 2 ;-CN;-N 3 ;-(CH 2 ) 0-4 N(R o ) 2 ;-(CH 2 ) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH 2 ) 0-4 N(R o )C(O)NR o 2 ;-N(R o )C(S)NR o 2 ;-(CH 2 ) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)Ro ;-N(R o )N(R o )C(O)NR o 2 ;-N(R o )N(R o )C(O)OR o ;-N(R o )C(NR o )N(R o )2;-( CH2)0-4C(O)R o ； -C(S)R o ;-(CH 2 ) 0-4 C(O)OR o ;-(CH 2 ) 0-4 C(O)SR o ;-(CH 2 ) 0-4 C(O)OSiR o 3 ;-(CH 2 ) 0-4 OC(O)R o ;-OC(O)(CH 2 ) 0-4 SR o ;-SC(S)SR o ;-(CH 2 ) 0-4 SC(O)R o ;-(CH 2 ) 0-4 C(O)NR o 2 ;-C(S)NR o 2 ;-C(S)SR o ;-SC(S)SR o 、-(CH 2 ) 0-4 OC(O)NR o 2 ;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH 2 C(O)R o ;-C(NOR o )R o ;-(CH 2 ) 0-4 SSR o ;-(CH 2) 0-4 S(O) 2 R o ;-(CH 2 ) 0-4 S(O) 2 OR o ;-(CH 2 ) 0-4 OS(O) 2 R o ; -S(O) 2 NR o 2 ;-(CH 2 ) 0-4 S(O)R o ;-N(R o )S(O) 2 NR o 2 ;-N(R o )S(O) 2 R o ;-N(OR o )R o ; -C(NH)NR o 2 ;-P(O) 2 R o ;-P(O)R o 2 ;-OP(O)R o 2 ;-OP(O)(OR o ) 2 ;-SiR o 3 ;-(C 1-4 Straight or branched alkylene)ON(R o ) 2 ; or -(C 1-4 Straight or branched alkylene)C(O)ON(R o ) 2 , where each R o may be substituted (e.g., by one, two, or more substituents) as defined below and are independently hydrogen, C 1-6 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph, -CH 2 -(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of R oTogether with its one or more intervening atoms it forms a 3-12 membered saturated, partially unsaturated or aromatic mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0058] R o (or two independent occurrences of R o Suitable monovalent substituents on the ring formed by taking together with their intervening atoms are independently halo, -(CH 2 ) 0-2 R · 、-(halogen R · )、-(CH 2 ) 0-2 OH, -(CH 2 ) 0-2 OR · 、-(CH 2 ) 0-2 CH(OR · ) 2 ; -O(halogen R · ), -CN, -N 3 、-(CH 2 ) 0-2 C(O)R · 、-(CH 2 ) 0-2 C(O)OH, -(CH 2 ) 0-2 C(O)OR · 、-(CH 2 ) 0-2 SR · 、-(CH 2 ) 0-2 SH, -(CH 2 ) 0-2 NH 2 、-(CH 2 ) 0-2 NHR · 、-(CH 2 ) 0-2 NR · 2 、-NO 2 、-SiR · 3 、-OSiR · 3 、-C(O)SR · 、-(C 1-4 Straight or branched alkylene)C(O)OR · or -SSR · , where each R ·unsubstituted or, when preceded by "halo", substituted only by one or more halo groups, and independently selected from C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents for saturated carbon atoms of include =0 and =S.

[0059] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2 、=NNHC(O)R * 、=NNHC(O)OR * 、=NNHS(O) 2 R * , =NR * , =NOR * 、-O(C(R * 2 )) 2-3 O-or-S(C(R * 2 )) 2-3 S-, where R * Each occurrence is independently selected from hydrogen, C 1-6 aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the adjacent substitutable carbon of an "optionally substituted" group include: -O(CR * 2 ) 2-3 O-, where R * Each occurrence is independently selected from hydrogen, C 1-6 an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0060] R * Suitable substituents on the aliphatic group include halo, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH 2 、-NHR · 、-NR ·2 or-NO 2 , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halo groups, and independently C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0061] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, regardless of the above definitions, two independent occurrences of Together with its one or more intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0062] Suitable substituents on the aliphatic group are independently halo, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH 2 、-NHR · 、-NR · 2 or-NO 2 , where each R · unsubstituted or, when preceded by "halo", substituted only by one or more halo groups, and independently C 1-4 Aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0063] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which are 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 formed of amino groups with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or organic acids (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0064] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, etc. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium and amine cations formed using counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates).

[0065] 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 for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds of the invention are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, including the replacement of hydrogen by deuterium or tritium or carbon by 13 C- or 14 C-enriched carbon-substituted compounds having the structures of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0066] By methods known to those skilled in the art, for example, by chromatography and / or fractional crystallization, diastereomeric mixtures can be separated into their individual diastereomers based on differences in physicochemical aspects. Enantiomer mixtures can be converted into diastereomeric mixtures by reaction with appropriate optically active compounds (e.g., chiral auxiliary agents, such as chiral alcohols or Mosher's acid chlorides), separating diastereomers and converting (e.g., hydrolyzing) individual diastereomers into corresponding pure enantiomers, and separating enantiomers. Alternatively, specific enantiomers of the compounds of the invention can be prepared by asymmetric synthesis. Further, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxylic acid), diastereomeric salts are formed with appropriate optically active acids or bases, and the diastereomers thus formed are then separated by fractional crystallization or chromatographic methods known in the art, and the pure enantiomers are subsequently recovered.

[0067] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of the invention.

[0068] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a chemical compound, and there is an ambiguity between the structure and the name, the structure shall prevail. It should also be noted that any carbon and heteroatom with unsaturated valence states in the text, schemes, examples, and tables herein are assumed to have sufficient number of hydrogen atoms to satisfy the valence states.

[0069] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0070] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-12, 1-10 or 1-6 carbon atoms, respectively referred to herein as C 1 -C 12 Alkyl, C 1 -C 10 Alkyl and C 1 -C 6 Alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0071] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-8, 4-8 or 4-6 carbon atoms derived from cycloalkane, referred to herein as, for example, "C 3 -C 6 "Cycloalkyl". Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0072] The term "haloalkyl" refers to an alkyl group substituted with at least one halo group. Exemplary haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 、-CH 2 CF 3 , -CF 2 CF 3 etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0073] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Exemplary hydroxyalkyl groups include -CH 2 CH 2 OH, -C(H)(OH)CH 3 、-CH 2 C(H)(OH)CH 2 CH2 OH, etc.

[0074] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length and which may replace the alkyls described above, but that contain at least one double or triple bond, respectively.

[0075] The term "carbocyclylene" refers to a polyvalent carbocyclyl having an appropriate number of open valences to occupy the groups to which it is attached. For example, if a "carbocyclylene" has two groups attached, it is a divalent carbocyclyl; if a "carbocyclylene" has three groups attached, it is a trivalent carbocyclyl.

[0076] The term "alkoxyl" or "alkoxy" is art-recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halo group. Exemplary haloalkoxy groups include -OCH 2 F, -OCHF 2 、-OCF 3 、-OCH 2 CF 3 、-OCF 2 CF 3 The term "hydroxyalkoxy" refers to an alkoxy group substituted with at least one hydroxy group. Exemplary hydroxyalkoxy groups include -OCH 2 CH 2 OH, -OCH 2 C(H)(OH)CH 2 CH 2 OH, etc. The term "alkyleneoxy" refers to a divalent alkoxy group.

[0077] The term "oxo" is art-recognized and refers to a "=0" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0078] symbol Represents a connection point.

[0079] When a chemical structure containing a ring is depicted with a substituent having a bond that crosses a bond of the ring, the substituent may be attached to any available position on the ring. For example, the chemical structure Covered In the case of polycyclic fused rings, when a chemical structure containing polycyclic fused rings is described as containing one or more substituents having bonds spanning multiple rings, the one or more substituents may be independently attached to any ring spanned by the bond. Covering e.g.

[0080] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise stated.

[0081] One or more compounds of the present invention may exist in unsolvated form as well as solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to include both solvated and unsolvated forms. The term "solvate or solvated" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses solution phases and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. "Hydrate" refers to a compound in which the solvent molecule is H 2 Solvates of O.

[0082] As used herein, a "GPR84 antagonist" or "GPR84 inhibitor" is a molecule that reduces, inhibits, or otherwise mitigates one or more of the biological activities of GPR84 (e.g., Gαi signaling, increased immune cell migration, and proinflammatory cytokine secretion). Antagonism using a GPR84 antagonist does not necessarily indicate complete elimination of GPR84 activity. In fact, the activity may be reduced by a statistically significant amount, including, for example, a reduction in the activity of GPR84 by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% compared to an appropriate control. In some embodiments, a GPR84 antagonist reduces, inhibits, or otherwise reduces the activity of GPR84. The compounds disclosed herein bind directly to GPR84 and inhibit its activity.

[0083] "Specific antagonist" means an agent that reduces, inhibits, or otherwise decreases the activity of a defined target to a greater extent than 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 IC of the antagonist for the target is 50 IC of antagonists for non-target 50About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less of the amount of GPR84. The compounds disclosed herein may or may not be specific GPR84 antagonists. The amount by which a specific GPR84 antagonist reduces the biological activity of GPR84 is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, a GPR84 antagonist specifically inhibits the activity of GPR84. In some of these embodiments, the IC of the GPR84 antagonist against GPR84 is 50 The IC of a GPR84 antagonist against a closely related GPCR (e.g., a free fatty acid receptor (FFAR), such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other type of GPCR (e.g., type A GPCR) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of.

[0084] The compounds of the present invention can be tethered to a detectable portion. It should be understood that such compounds can be used as developer. One of ordinary skill in the art will recognize that the detectable portion can be connected to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a portion that can be covalently connected to a detectable portion. Such portions are well known to those of ordinary skill in the art and include groups containing, for example, carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties, etc. It should be understood that such portions can be directly or via a tethered group (e.g., a divalent saturated or unsaturated hydrocarbon chain) connected to the provided compound. In some embodiments, such portions can be connected via click chemistry. In some embodiments, such portions can be connected via 1,3-cycloaddition of azide compounds and alkynes, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew.Chem.Int.Ed.2002,41,2596-99 and Sun et al., Bioconjugate Chem.,2006,17,52-57. In some embodiments, such moieties may be attached via strained alkynes.Methods of using strained alkynes to achieve fast Cu-free click chemistry are known in the art and include those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0085] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety (e.g., primary and secondary labels) that is capable of being detected. Primary labels, such as radioactive isotopes (e.g., tritium, 32 P. 33 P. 35 S or 14 C), mass tags and fluorescent labels are signal-generating reporters that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0086] As used herein, the term "secondary label" refers to a moiety (e.g., biotin and various protein antigens) that requires 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 a non-radiative fluorescence resonance energy transfer (FRET) method, and the second group produces a detection signal.

[0087] 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, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarins, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarin, IRDye (IRD40, IRD 700, IRD 800), JOE, Lissamine Rhodamine B, Marina Blue, Methoxycoumarin, Naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0088] As used herein, the term "mass tag" refers to any moiety that can be specifically 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-methylglyceryl]isopicolinic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020 and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides with varying lengths and base compositions, oligopeptides, oligosaccharides and other synthetic polymers with varying lengths and monomer compositions. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), with an appropriate mass range (100-2000 Daltons) can also be used as mass tags.

[0089] The compounds of the present invention can be tethered to the E3 ligase binding moiety. It should be understood that such compounds can be used as degradation agents (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41 (5), 305-31; Ottis and Crews, ACS Chem. Biol. 2017, 12 (4), 892-898.). One of ordinary skill in the art will recognize that the E3 ligase binding moiety can be connected to the provided compound via a suitable substituent as defined above. Such degradation agents 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.).

[0090] As used herein, the term "E3 ligase binding moiety" is used interchangeably with the term "E3 ligase binder" and refers to any moiety capable of binding to and / or recruiting an E3 ligase (e.g., cIAP1, MDM2, cereblon, VHL, APC / C) for targeted degradation.

[0091] The compounds of the present invention can be tethered to the lysosomal targeting moiety. It should be understood that such compounds can be used as degradation agents (see, for example, Banik et al., 2020. Nature 584, 291-297.). One of ordinary skill in the art will recognize that the lysosomal targeting moiety can be connected to the provided compound via a suitable substituent as defined above. Such degradation agents have been found to be useful for targeted degradation of secretory and membrane proteins (Banik et al., 2020).

[0092] As used herein, the term "lysosomal targeting moiety" is used interchangeably with the term "lysosomal binding moiety" and relates to any moiety capable of binding to and / or recruiting a cell surface lysosomal targeting receptor (e.g., the cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

[0093] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in GPR84 activity between a sample comprising a compound or composition thereof of the invention and GPR84 GPCR and an equivalent sample comprising GPR84 GPCR in the absence of the compound or composition thereof.

[0094] Throughout the specification, when compositions are described as having, including, or comprising specific components, or when processes and methods are described as having, including, or comprising specific steps, it is also contemplated that there are compositions of the invention consisting essentially of, or consisting of, the enumerated components, and that there are processes and methods according to the invention consisting essentially of, or consisting of, the enumerated process steps.

[0095] In general, percentages of compositions specified are by weight unless otherwise indicated.

[0096] 3. Description of exemplary embodiments:

[0097] 3.1 Compounds of formula I:

[0098] As described above, in certain embodiments, the present invention provides a compound of formula I:

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein:

[0101] A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace;

[0102] A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace;

[0103] L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-;

[0104] L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 -or-OC(O)-;

[0105] R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace;

[0106] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen;

[0107] R 3 Each occurrence represents C independently 1-6 Alkyl or halide;

[0108] R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 );

[0109] R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom;

[0110] R 6 C 1-6 Alkyl, C 3-6Cycloalkyl or hydrogen;

[0111] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;

[0112] R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and

[0113] m, n and q are independently 0, 1 or 2;

[0114] If R 1 , L 1 , A 1 and L 2 Together we form Then n is 1 or 2, and R 4 Each occurrence independently represents a halide, a hydroxyl, a C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

[0115] The definitions of the variables in the above formula I cover multiple chemical groups. The present application contemplates the following embodiments, wherein, for example, i) the definition of the variable is a single chemical group selected from the above chemical groups, ii) the definition of the variable is a set of two or more chemical groups selected from the above chemical groups, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0116] In certain embodiments, the compound is a compound of Formula I.

[0117] As generally defined above, A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 In some embodiments, A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by m occurrences of R 3 In some embodiments, A 1is a 6-membered unsaturated oxo-heterocyclylene group containing 1 nitrogen atom, wherein the oxo-heterocyclylene group is replaced by m occurrences of R 3 In some embodiments, A 1 is R that appears m times 3 In some embodiments, A 1 is 1,2,3-triazolylene, imidazolylene, pyrrolylene, pyrazolylene, oxazolylene, thiazolylene or pyridylene, each of which is replaced by m occurrences of R 3 In some embodiments, A 1 is R that appears m times 3 Substituted 1,2,3-triazolylene.

[0118] In some embodiments, A 1 for Its m occurrences of R 3 In some embodiments, A 1 for Its m occurrences of R 3 replace.

[0119] In some embodiments, A 1 for Its m occurrences of R 3 Substitution, where **** is with L 2 In some embodiments, A 1 for Its m occurrences of R 3 Substitution, where **** is with L 2 connection point.

[0120] In some embodiments, A 1 for Its m occurrences of R 3 replace.

[0121] In some embodiments, A 1 for In some embodiments, A 1 for In some embodiments, A 1 for

[0122] In some embodiments, A 1 Select from those depicted in Table 1 below.

[0123] As generally defined above, A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R4 In some embodiments, A 2 is R that appears n times 4 In some embodiments, A 2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 4 In some embodiments, A 2 is a 9-10 membered partially saturated carbocyclic group; 4 In some embodiments, A 2 for It is R that appears n times 4 In some embodiments, A 2 for It is R that appears n times 4 replace.

[0124] In some embodiments, A 2 is R that appears n times 4 Substituted pyridinylene.

[0125] In some embodiments, A 2 for Each of them is represented by n occurrences of R 4 Substitution, where ** is with R 2 In some embodiments, A 2 Select from those depicted in Table 1 below.

[0126] As generally defined above, L 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-. 1 C 1 - 3 A divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-. 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain. 1 -CH 2 -. In some embodiments, L 1 -CH 2 -O-. In some embodiments, L 1 Select from those depicted in Table 1 below.

[0127] As generally defined above, L 2 -C(O)N(R 5 )-、-N(R6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 - or -OC(O)-. In some embodiments, L 2 -N(R 6 )-(C 1-4 Alkylene)-or-(C 1-4 Alkylene)-N(R 6 )-. In some embodiments, L 2 -C(O)N(R 5 )-. In some embodiments, L 2 -N(R 6 )C(O)-. In some embodiments, L 2 -N(R 6 )-. In some embodiments, L 2 -N(R 6 )-(C 1-4 In some embodiments, L 2 -N(R 6 )-CH 2 -. In some embodiments, L 2 For-(C 1-4 Alkylene)-N(R 6 )-. In some embodiments, L 2 -CH 2 -N(R 6 )-. In some embodiments, L 2 -S(O) 2 N(R 5 )-. In some embodiments, L 2 -N(R 6 )S(O) 2 -. In some embodiments, L 2 For -CO 2 -. In some embodiments, L 2 In some embodiments, L 2 Select from those depicted in Table 1 below.

[0128] As generally defined above, R 1 -C(O)N(R7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 In some embodiments, R 1 -C(O)N(R 7 )(R 8 ). In some embodiments, R 1 is a 6-11 membered saturated or partially unsaturated, bridged or spiro, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the bicyclic heterocyclic ring is surrounded by q R 9 In some embodiments, R 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is surrounded by q R 9 replace.

[0129] In some embodiments, R 1 For q R 9 Replaced In some embodiments, R 1 for In some embodiments, R 1 Select from those depicted in Table 1 below.

[0130] As generally defined above, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In some embodiments, R 2 In some embodiments, R 2 =-(C≡C)-(C 3-6 In some embodiments, R 2 =-(C≡C)-(C 3-5 In some embodiments, R 2 In some embodiments, R 2 Select from those depicted in Table 1 below.

[0131] As generally defined above, R 3 Each occurrence represents C independently 1-6 In some embodiments, R3 Each occurrence represents C independently 1-6 In some embodiments, R 3 Each occurrence independently represents a halo. 3 Each occurrence represents C independently 1-3 In some embodiments, R 3 Each occurrence represents C independently 2-6 In some embodiments, R 3 Select from those depicted in Table 1 below.

[0132] As generally defined above, R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ). In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4 Each occurrence independently represents a halo. 4 In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4 Each occurrence represents C independently 3-6 In some embodiments, R 4 Each occurrence represents independently -N(R 7 )(R 8 ).

[0133] In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4 Each occurrence independently represents methyl, fluoro, chloro or bromo. 4 Each occurrence represents C independently 1-3 In some embodiments, R 4 Each occurrence represents C independently 2-6 In some embodiments, R 4 In some embodiments, R 4 Each occurrence independently represents F, Cl or Br. In some embodiments, R 4 Select from those depicted in Table 1 below.

[0134] As generally defined above, R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom. 5 C 1-6 Alkyl, C 3-6 In some embodiments, R 5 C 1-6 In some embodiments, R 5 C 3-6 In some embodiments, R 5 In some embodiments, R 5 -CH 3 In some embodiments, R 5 -CH 2 CH 3 In some embodiments, R 5 -CH 2 CH 2 CH 3 In some embodiments, R 5 C 2-6 In some embodiments, R 5 In some embodiments, R 5 Select from those depicted in Table 1 below.

[0135] In certain embodiments, R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom. 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-membered ring containing 1 nitrogen atom. 5 and one occurrence of R 4 Together with their intervening atoms they form a 6-membered ring containing 1 nitrogen atom.

[0136] As generally defined above, R 6 C 1-6 Alkyl, C 3-6 In some embodiments, R 6 C 1-6 In some embodiments, R 6 C 3-6 In some embodiments, R 6 In some embodiments, R6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 Select from those depicted in Table 1 below.

[0137] As generally defined above, R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom.

[0138] In certain embodiments, R 7 Each occurrence is independently hydrogen, C 1-6 Alkyl, or C 3-6 In some embodiments, R 7 In some embodiments, R 7 Each occurrence represents C independently 1-6 In some embodiments, R 7 In some embodiments, R 7 Each occurrence is independently C 3-6 In some embodiments, R 7 Select from those depicted in Table 1 below.

[0139] In certain embodiments, R 8 Each occurrence is independently hydrogen, C 1-6 Alkyl, or C 3-6 In some embodiments, R 8 In some embodiments, R 8 Each occurrence is independently C 1-6 In some embodiments, R 8 In some embodiments, R 8 Each occurrence is independently C 3-6 In some embodiments, R 8 Select from those depicted in Table 1 below.

[0140] In some embodiments, R 7 and R 8Each occurrence is independently C 1-6 In some embodiments, R 7 and R 8 In some embodiments, R 7 and R 8 For hydrogen.

[0141] In certain embodiments, R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-5 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic ring containing 1 nitrogen atom.

[0142] As generally defined above, R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 In some embodiments, R 9 Each occurrence represents C independently 1-6 In some embodiments, R 9 Each occurrence independently represents a halo. 9 In some embodiments, R 9 Each occurrence represents C independently 1-6 In some embodiments, R 9 Each occurrence represents C independently 3-6 In some embodiments, R 9 In some embodiments, R 9 is methyl, fluoro, bromo or chloro. 9 Select from those depicted in Table 1 below.

[0143] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is selected from those depicted in Table 1 below.

[0144] As generally defined above, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is selected from those depicted in Table 1 below.

[0145] As generally defined above, q is 0, 1, or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is selected from those depicted in Table 1 below.

[0146] In certain embodiments, the compound of Formula I is a compound of Formula Ia or Ib:

[0147]

[0148] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R 4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0149] In certain embodiments, the compound of Formula I is a compound of Ic or Id:

[0150]

[0151] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R 4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0152] In certain embodiments, the compound of Formula I is a compound of Formula Ie, If, Ig, Ih, Ii, or Ij:

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0155] In certain embodiments, the compound of Formula I is a compound of Formula Ik or Il:

[0156]

[0157] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0158] In certain embodiments, the compound of Formula I is a compound of Formula Im or In:

[0159]

[0160] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0161] In certain embodiments, the compound of Formula I is a compound of Formula Io, Ip, Iq, Ir, Is, or It:

[0162]

[0163] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0164] The above description describes several embodiments in relation to compounds of formula I. This patent application specifically contemplates the combination of all embodiments.

[0165] Another aspect of the present invention provides a compound of formula IA:

[0166]

[0167] or a pharmaceutically acceptable salt thereof, wherein:

[0168] A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace;

[0169] A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace;

[0170] L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-;

[0171] L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 -or-OC(O)-;

[0172] R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace;

[0173] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen;

[0174] R 3 Each occurrence represents C independently1-6 Alkyl or halide;

[0175] R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 );

[0176] R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom;

[0177] R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen;

[0178] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;

[0179] R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and

[0180] m, n and q are independently 0, 1 or 2.

[0181] In certain embodiments, the definitions of the variables in Formula IA are one of the embodiments described above for Formula I.

[0182] 3.2 Compounds of formula II:

[0183] As described above, in certain embodiments, the present invention provides a compound of formula II:

[0184]

[0185] or a pharmaceutically acceptable salt thereof, wherein:

[0186] A 1is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace;

[0187] A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace;

[0188] L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-;

[0189] L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 -、-OC(O)-、-C(OC 1-4 alkyl)=N- or -(a 4-5 membered saturated monocyclic heterocyclylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(C 1-4 alkyl)-;

[0190] R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace;

[0191] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen;

[0192] R 3Each occurrence represents C independently 1-6 Alkyl or halide;

[0193] R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 );

[0194] R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom;

[0195] R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen;

[0196] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;

[0197] R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and

[0198] m, n and q are independently 0, 1 or 2;

[0199] If R 1 , L 1 , A 1 and L 2 Together we form Then n is 1 or 2, and R 4 Each occurrence independently represents a halide, a hydroxyl, a C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

[0200] The definition of the variables in the above formula II covers multiple chemical groups. The present application contemplates the following embodiments, wherein, for example, i) the definition of the variable is a single chemical group selected from the above chemical groups, ii) the definition of the variable is a set of two or more chemical groups selected from the above chemical groups, and iii) the compound is defined by a combination of variables, wherein the variable is defined by (i) or (ii).

[0201] In certain embodiments, the compound is of Formula II.

[0202] As generally defined above, A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 In some embodiments, A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by m occurrences of R 3 In some embodiments, A 1 is a 6-membered unsaturated oxo-heterocyclylene group containing 1 nitrogen atom, wherein the oxo-heterocyclylene group is replaced by m occurrences of R 3 In some embodiments, A 1 is R that appears m times 3 In some embodiments, A 1 is 1,2,3-triazolylene, imidazolylene, pyrrolylene, pyrazolylene, oxazolylene, thiazolylene or pyridylene, each of which is replaced by m occurrences of R 3 In some embodiments, A 1 is R that appears m times 3 Substituted 1,2,3-triazolylene.

[0203] In some embodiments, A 1 for Its m occurrences of R 3 In some embodiments, A 1 for Its m occurrences of R 3 replace.

[0204] In some embodiments, A 1 for Its m occurrences of R 3 Substitution, where **** is with L 2 In some embodiments, A 1 for Its m occurrences of R 3Substitution, where **** is with L 2 connection point.

[0205] In some embodiments, A 1 for Its m occurrences of R 3 replace.

[0206] In some embodiments, A 1 for In some embodiments, A 1 for In some embodiments, A 1 for

[0207] In some embodiments, A 1 Select from those depicted in Table 1 or Table 1A below.

[0208] As generally defined above, A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 In some embodiments, A 2 is R that appears n times 4 In some embodiments, A 2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 4 In some embodiments, A 2 is a 9-10 membered partially saturated carbocyclic group; 4 In some embodiments, A 2 for It is R that appears n times 4 In some embodiments, A 2 for It is R that appears n times 4 replace.

[0209] In some embodiments, A 2 is R that appears n times 4 Substituted pyridinylene.

[0210] In some embodiments, A 2 for Each of them is represented by n occurrences of R 4 Substitution, where ** is with R 2 In some embodiments, A 2 Select from those depicted in Table 1 or Table 1A below.

[0211] As generally defined above, L 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-. 1 C 1 - 3 A divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-. 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain. 1 -CH 2 -. In some embodiments, L 1 -CH 2 -O-. In some embodiments, L 1 Select from those depicted in Table 1 or Table 1A below.

[0212] As generally defined above, L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 -、-OC(O)-、-C(OC 1-4 alkyl)=N- or -(a 4-5 membered saturated monocyclic heterocyclylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(C 1-4 In some embodiments, L 2 -C(O)N(R 5 )-. In some embodiments, L 2 -N(R 6 )C(O)-. In some embodiments, L 2 -N(R 6 )-. In some embodiments, L 2 -N(R 6 )-(C 1-4 In some embodiments, L 2 -N(R 6 )-CH 2-. In some embodiments, L 2 For-(C 1-4 Alkylene)-N(R 6 )-. In some embodiments, L 2 -CH 2 -N(R 6 )-. In some embodiments, L 2 -S(O) 2 N(R 5 )-. In some embodiments, L 2 -N(R 6 )S(O) 2 -. In some embodiments, L 2 For -CO 2 -. In some embodiments, L 2 In some embodiments, L 2 -C(OC 1-4 In some embodiments, L 2 -(a 4-5 membered saturated monocyclic heterocyclylene group containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(C 1-4 In some embodiments, L 2 Select from those depicted in Table 1 or Table 1A below.

[0213] As generally defined above, R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 In some embodiments, R 1 -C(O)N(R 7 )(R 8 In some embodiments, R 1 is a 6-11 membered saturated or partially unsaturated, bridged or spiro, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the bicyclic heterocyclic ring is surrounded by q R 9 In some embodiments, R 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is surrounded by q R 9 replace.

[0214] In some embodiments, R 1For q R 9 Replaced In some embodiments, R 1 for In some embodiments, R 1 Select from those depicted in Table 1 or Table 1A below.

[0215] As generally defined above, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In some embodiments, R 2 In some embodiments, R 2 =-(C≡C)-(C 3-6 In some embodiments, R 2 =-(C≡C)-(C 3-5 In some embodiments, R 2 In some embodiments, R 2 Select from those depicted in Table 1 or Table 1A below.

[0216] As generally defined above, R 3 Each occurrence represents C independently 1-6 In some embodiments, R 3 Each occurrence represents C independently 1-6 In some embodiments, R 3 Each occurrence independently represents a halo. 3 Each occurrence represents C independently 1-3 In some embodiments, R 3 Each occurrence represents C independently 2-6 In some embodiments, R 3 Select from those depicted in Table 1 or Table 1A below.

[0217] As generally defined above, R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ). In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4Each occurrence independently represents a halo. 4 In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4 Each occurrence represents C independently 3-6 In some embodiments, R 4 Each occurrence represents independently -N(R 7 )(R 8 ).

[0218] In some embodiments, R 4 Each occurrence represents C independently 1-6 In some embodiments, R 4 Each occurrence independently represents methyl, fluoro, chloro or bromo. 4 Each occurrence represents C independently 1-3 In some embodiments, R 4 Each occurrence represents C independently 2-6 In some embodiments, R 4 In some embodiments, R 4 Each occurrence independently represents F, Cl or Br. In some embodiments, R 4 Select from those depicted in Table 1 or Table 1A below.

[0219] As generally defined above, R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom. 5 C 1-6 Alkyl, C 3-6 In some embodiments, R 5 C 1-6 In some embodiments, R 5 C 3-6 In some embodiments, R 5 In some embodiments, R 5 -CH 3 In some embodiments, R 5 -CH 2 CH 3 In some embodiments, R 5 -CH 2 CH2 CH 3 In some embodiments, R 5 C 2-6 In some embodiments, R 5 In some embodiments, R 5 Select from those depicted in Table 1 or Table 1A below.

[0220] In certain embodiments, R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom. 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-membered ring containing 1 nitrogen atom. 5 and one occurrence of R 4 Together with their intervening atoms they form a 6-membered ring containing 1 nitrogen atom.

[0221] As generally defined above, R 6 C 1-6 Alkyl, C 3-6 In some embodiments, R 6 C 1-6 In some embodiments, R 6 C 3-6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 Select from those depicted in Table 1 or Table 1A below.

[0222] As generally defined above, R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom.

[0223] In certain embodiments, R 7 Each occurrence is independently hydrogen, C1-6 Alkyl, or C 3-6 In some embodiments, R 7 In some embodiments, R 7 Each occurrence represents C independently 1-6 In some embodiments, R 7 In some embodiments, R 7 Each occurrence is independently C 3-6 In some embodiments, R 7 Select from those depicted in Table 1 or Table 1A below.

[0224] In certain embodiments, R 8 Each occurrence is independently hydrogen, C 1-6 Alkyl, or C 3-6 In some embodiments, R 8 In some embodiments, R 8 Each occurrence is independently C 1-6 In some embodiments, R 8 In some embodiments, R 8 Each occurrence is independently C 3-6 In some embodiments, R 8 Select from those depicted in Table 1 or Table 1A below.

[0225] In some embodiments, R 7 and R 8 Each occurrence is independently C 1-6 In some embodiments, R 7 and R 8 In some embodiments, R 7 and R 8 For hydrogen.

[0226] In certain embodiments, R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-5 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 5-7 membered heterocyclic ring containing 1 nitrogen atom.

[0227] As generally defined above, R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C1-6 Alkoxy or C 3-6 In some embodiments, R 9 Each occurrence represents C independently 1-6 In some embodiments, R 9 Each occurrence independently represents a halo. 9 In some embodiments, R 9 Each occurrence represents C independently 1-6 In some embodiments, R 9 Each occurrence represents C independently 3-6 In some embodiments, R 9 In some embodiments, R 9 is methyl, fluoro, bromo or chloro. 9 Select from those depicted in Table 1 or Table 1A below.

[0228] As generally defined above, m is 0, 1, or 2. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is selected from those depicted in Table 1 or Table 1A below.

[0229] As generally defined above, n is 0, 1, or 2. In some embodiments, n is 1 or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is selected from those depicted in Table 1 or Table 1A below.

[0230] As generally defined above, q is 0, 1 or 2. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is selected from those depicted in Table 1 or Table 1A below. In certain embodiments, the compound of Formula II is a compound of Formula II-a, II-b or II-a-1, or a pharmaceutically acceptable salt thereof:

[0231]

[0232] In certain embodiments, the compound of formula II is a compound of formula II-a or II-b:

[0233]

[0234] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0235] In certain embodiments, the compound of formula II is a compound of formula II-c or II-d:

[0236]

[0237] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R 4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0238] In certain embodiments, the compound of formula II is a compound of formula II-e, II-f, II-g, II-h, II-i, or II-j:

[0239]

[0240] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 2 , R 4 , R 7 , R 8 , R 9 Each of n, n and q, individually and in combination, is as defined above and described in the embodiments herein.

[0241] In certain embodiments, the compound of formula II is a compound of formula II-k, II-1 or II-k-1, or a pharmaceutically acceptable salt thereof:

[0242]

[0243]

[0244] In certain embodiments, the compound of formula II is a compound of II-k or II-1:

[0245]

[0246] or a pharmaceutically acceptable salt thereof, wherein A 2 , L1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0247] In certain embodiments, the compound of formula II is a compound of formula II-m or II-n:

[0248]

[0249] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0250] In certain embodiments, the compound of formula II is a compound of formula II-o, II-p, II-q, II-r, II-s or II-t:

[0251]

[0252]

[0253] or a pharmaceutically acceptable salt thereof, wherein A 2 , L 1 , R 4 , R 7 , R 8 Each of and n, individually and in combination, is as defined above and described in the embodiments herein.

[0254] The above description describes a number of embodiments in relation to the compound of formula II. This patent application specifically contemplates the combination of all embodiments.

[0255] Another aspect of the present invention provides a compound of formula II-A:

[0256]

[0257] or a pharmaceutically acceptable salt thereof, wherein:

[0258] A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace;

[0259] A2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace;

[0260] L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-;

[0261] L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O) 2 N(R 5 )-、-N(R 6 )S(O) 2 -、-CO 2 -、-OC(O)-、-C(OC 1-4 alkyl)=N- or -(a 4-5 membered saturated monocyclic heterocyclylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(C 1-4 alkyl)-;

[0262] R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace;

[0263] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen;

[0264] R 3 Each occurrence represents C independently 1-6 Alkyl or halide;

[0265] R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 );

[0266] R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom;

[0267] R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen;

[0268] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom;

[0269] R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and

[0270] m, n and q are independently 0, 1 or 2.

[0271] In certain embodiments, the definitions of the variables in Formula II-A are one of the embodiments described above for Formula I.

[0272] 3.3 Exemplary compounds

[0273] Exemplary compounds of the invention are set forth in Table 1 below.

[0274] Table 1. Selected compounds

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286] In some embodiments, the present invention provides a compound as described in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound as described in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound as described in Table 1 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0287] Additional exemplary compounds of the invention are set forth below in Table 1A.

[0288] Table 1A. Selected compounds

[0289]

[0290]

[0291]

[0292]

[0293] In some embodiments, the present invention provides a compound as described in Table 1 or 1A above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound as described in Table 1 or 1A above. In some embodiments, the present invention provides a compound as described in Table 1A above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound as described in Table 1A above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound as described in Table 1 or 1A above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent.

[0294] 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 medicament.

[0295] In the chemical structures in Table 1 above and in the examples below, stereogenic centers are depicted according to the Enhanced Stereo Notation format (MDL / Biovia, eg, using the notations "or1," "or2," "abs," "and1").

[0296] 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 of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0297] 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 of inhibiting GPR84 as described herein.

[0298] 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 of modulating an immune response in a subject in need thereof as described herein.

[0299] 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 of treating a GPR84-dependent disorder as described herein.

[0300] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting GPR84, a medicament for modulating an immune response in a subject in need thereof, and / or a medicament for treating a GPR84-dependent disorder.

[0301] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting GPR84.

[0302] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

[0303] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for the manufacture of a medicament for treating a GPR84-dependent disorder.

[0304] 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 use in a method of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0305] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of inhibiting GPR84 as described herein.

[0306] In some embodiments, the present invention also provides for the use of a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of modulating an immune response in a subject in need thereof as described herein.

[0307] In some embodiments, the present invention also provides the use of a compound of Formula I described herein or a pharmaceutical composition described herein for use in a method of treating a GPR84-dependent disorder as described herein.

[0308] In some embodiments, the present invention provides a compound of formula I or formula II as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I or formula II as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, for use as a medicament.

[0309] In the chemical structures in Table 1A above, stereogenic centers are depicted according to the Enhanced Stereo Notation format (MDL / Biovia, eg, using the notations "or1," "or2," "abs," "and1").

[0310] In some embodiments, the present invention also provides a compound of Formula I or Formula II as described herein or a pharmaceutical composition as described herein, for use in a method of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0311] In some embodiments, the present invention also provides a compound of Formula I or Formula II as described herein or a pharmaceutical composition as described herein for use in a method of inhibiting GPR84 as described herein.

[0312] In some embodiments, the present invention also provides a compound of Formula I or Formula II as described herein or a pharmaceutical composition as described herein for use in a method of modulating an immune response in a subject in need thereof as described herein.

[0313] In some embodiments, the present invention also provides a compound of Formula I or Formula II as described herein or a pharmaceutical composition as described herein for use in a method of treating a GPR84-dependent disorder as described herein.

[0314] In some embodiments, the present invention also provides the use of the compound of Formula I or Formula II described herein or the pharmaceutical composition described herein for the manufacture of an agent for inhibiting GPR84, an agent for modulating the immune response of a subject in need thereof, and / or an agent for treating a GPR84-dependent disorder.

[0315] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting GPR84.

[0316] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

[0317] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for the manufacture of a medicament for treating a GPR84-dependent disorder.

[0318] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II as described herein or a pharmaceutical composition as described herein, for use in a method of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0319] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for use in a method of inhibiting GPR84 as described herein.

[0320] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for use in a method of modulating an immune response in a subject in need thereof as described herein.

[0321] In some embodiments, the present invention also provides the use of a compound of Formula I or Formula II described herein or a pharmaceutical composition described herein for use in a method of treating a GPR84-dependent disorder as described herein.

[0322] 4. General Methods for Providing Compounds of the Invention

[0323] The compounds of the present invention can be prepared or isolated by the methods described in detail in the Examples herein.

[0324] 5. Use, preparation and administration

[0325] Pharmaceutically acceptable compositions

[0326] 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 such that it can effectively inhibit GPR84 or its mutant in a biological sample or patient in a measurable manner. In certain embodiments, the amount of the compound in the composition of the present invention is such that it can effectively inhibit GPR84 or its mutant in a biological sample or patient in a measurable manner. 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.

[0327] As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0328] 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 formulated with it. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin, serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; dipotassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol and lanolin.

[0329] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof when administered to a recipient.

[0330] As used herein, the term "inhibitory active metabolites or residues thereof" means metabolites or residues thereof that are also inhibitors of GPR84 or a mutant thereof.

[0331] The subject matter disclosed herein includes prodrugs, metabolites, derivatives and pharmaceutically acceptable salts of the compounds of the present invention. Metabolites include compounds produced by the following method, the method comprising: contacting the compounds of the present invention with mammals for a period of time sufficient to produce their metabolites. If the compounds of the present invention are alkalis, the desired pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, free alkalis are treated with the following: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., 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, pyranosidic acid (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 may be prepared by any suitable method, for example, by treating 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, etc. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary and tertiary amines and cyclic amines (e.g., piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0332] The compounds of the present invention may be in the form of "prodrugs", which include compounds with moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or by other mechanisms that can activate 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 separation and purification of the compound, or by reacting the purified compound with its free acid form or hydroxyl with a suitable esterifying agent, respectively. Hydroxyl groups can be converted into esters via treatment with carboxylic acids. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl esters), substituted (e.g., methyl, halo or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides and hydroxyamides. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In various aspects, the compounds of the present invention are prodrugs of any formula herein.

[0333] The composition of the present invention can 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, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspension media.

[0334] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. For example, fatty acids of oleic acid and their glyceride derivatives can be used to prepare injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other conventional surfactants (such as Tween, Span and other emulsifiers) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms can also be used for the purpose of preparation.

[0335] The pharmaceutically acceptable compositions 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. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When aqueous suspensions are needed for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings or coloring agents may also be added.

[0336] Alternatively, the pharmaceutically acceptable compositions of the present invention can be used in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the medicament with a suitable non-irritating excipient, which is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0337] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0338] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0339] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment form containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated in a suitable lotion or cream form containing an active component 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, cetostearyl alcohol, 2-octyl dodecanol, benzyl alcohol, and water.

[0340] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline with or without preservatives (e.g., benzylalkonium chloride), or preferably as solutions in isotonic, pH-adjusted, sterile saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated as ointments, such as paraffin.

[0341] The pharmaceutically acceptable compositions of the present 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 physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and / or other conventional solubilizing or dispersing agents.

[0342] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may 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.

[0343] The amount of the compound of the invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration. Preferably, the provided compositions should be formulated so that the inhibitor can be administered at a dosage of between 0.01-100 mg / kg body weight / day to a patient receiving these compositions.

[0344] It should 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 specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the attending physician, as well as the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0345] Uses of compounds and pharmaceutically acceptable compositions

[0346] 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 invention is GPR84.

[0347] The compounds disclosed in the present invention can be used to inhibit the activity of GPR84. GPR84 is a G expressed on the surface of immune cells. i GPR84 regulates the innate immune response in conditions such as fibrotic disorders.

[0348] Several studies have shown that GPR84 may be a potential target for the treatment of obesity and / or metabolic dysfunction.

[0349] GPR84 gene expression in cultured human differentiated adipocytes is highly upregulated by the major proinflammatory cytokines TNF-α and IL-1β (Muredda et al. 2017. Arch. Physiol. Biochem. 124(2), 97-108.). These data confirm the activation of proinflammatory GPR84 signaling in the context of adipocyte inflammation, first described by Nagasaki in 2012 (Nagasaki et al., 2012, FEBS Letters, 586, 368-372).

[0350] IL-33 is a member of the IL-1β superfamily, which strongly upregulates GPR84 mRNA expression in human differentiated adipocytes in an autocrine manner, which is associated with enhanced production of proinflammatory cytokines and chemokines such as IL-1β, CCL2, IL6, CXCL2, and CSF3 (Zaibi et al., 2018. Cytokine, 110, 189-193). This suggests that proinflammatory stimuli in adipocytes activate GPR84, leading to further proinflammatory cytokine release and confirming the existence of a putative autocrine positive feedback loop.

[0351] GPR84 expression is upregulated in the liver of NASH patients and is associated with disease severity. GPR84 is upregulated in activated human and mouse macrophages and neutrophils. GPR84-mediated myeloid cell infiltration promotes fatty liver inflammation and fibrosis. Similar to silanol (ASK1 inhibitor), pharmacological inhibition of GPR84 significantly reduced macrophage accumulation, inflammation, and fibrosis in NASH models. These findings suggest that GPR84 promotes myeloid cell infiltration in liver injury and is an effective therapeutic target for NAFLD / NASH fatty liver inflammation and fibrosis (Puengel et al., 2020. J. Clin. Med. 9(4), 1140).

[0352] GPR84 deficiency in mice is associated with reduced NAFLD-induced liver damage. Treatment with PBI-4547, a putative GPR84 antagonist, reduces NAFLD-induced liver and adipose tissue damage and promotes fatty acid oxidation (Simard et al. 2020. Sci. Rep. 10(1), 12778).

[0353] Mice with global deficiency of Gpr84 [Gpr84 knockout (KO)] show mildly impaired glucose tolerance when fed a diet rich in MCFA. Studies have shown that the medium-chain fatty acid receptor GPR84 regulates mitochondrial metabolism in mouse skeletal muscle and that GPR84 is an important player in glycemic control (Montgomery MK, et al. 2019. FASEB J. 33(11), 12264-12276).

[0354] Nutrient-sensing receptors located on enteroendocrine (EEC) cells regulate appetite by sensing 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 GPR84 overexpression was further increased after Roux-en-Y gastric bypass (RYGB). Several nutrient-sensing receptors, including GPR84, induce activation of colonic EECs. In response to diet and weight loss induced by RYGB or caloric restriction, the expression of these receptors undergoes profound adaptive changes. (Peiris M, et al. 2018. Nutrients. 10(10), 1529)

[0355] Du Toit et al. investigated the effects of GPR84 deficiency 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) and found no effect on body weight or glucose tolerance in mice fed a diet high in MCFA or LCFA. GPR84 may affect lipid metabolism, as GPR84 KO mice had smaller livers and increased myocardial triglyceride accumulation when fed an LCFA diet, whereas hepatic triglyceride accumulation increased in response to increased MCFA in the diet. (DuToit et al. 2018 Eur. J. Nutr. 57(5), 1737-1746)

[0356] A review by Hara et al. indicates that GPR84 and other free fatty acid receptors (FFARs) that are primarily involved in energy metabolism are considered key therapeutic targets in the pathology of obesity and type 2 diabetes. (Hara et al. 2014. Biochim. Biophys. Acta. 1841(9), 1292-300)

[0357] Studies conducted by Nagasaki et al. on mice showed that a high-fat diet upregulates GPR84 expression in fat pads. These results suggest that GPR84 appears in adipocytes in response to TNFα infiltrating macrophages and exacerbates the vicious cycle between obesity and glycosylation. (Nagasaki H. et al. 2012. FEBS Lett. 586(4), 368-72)

[0358] Fibrosis is a process that can be initiated by chronic tissue damage caused by toxic substances, viral infection, inflammation or mechanical stress (Nanthakumar et al., 2015. Nature Reviews Drug Discovery 14, 693-720); and can be defined as the abnormal or excessive production and accumulation of extracellular matrix (ECM).

[0359] Specifically, fibrosis is a key driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), advanced liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and end-stage renal disease. Despite increasing understanding of the disease mechanisms and a recent increase in the number of clinical trials, indicating the need for new therapeutic approaches, particularly in IPF, these diseases remain poorly treated (Nanthakumar et al., 2015).

[0360] Non-alcoholic fatty liver disease (NAFLD) is initially characterized by pure steatosis and gradually progresses to non-alcoholic steatohepatitis (NASH). In addition to genetic defects, it is mainly caused by excess energy intake and lack of physical activity, and is closely related to metabolic complications such as obesity and insulin resistance. (Neuschwander-Tetri BA and Caldwell SH, 2003, Hepatology 37, 1202-1219). If not treated, NASH will lead to fatal liver failure.

[0361] The mechanisms that promote the progression of NAFLD to NASH and advanced liver disease are complex and are likely triggered by acute inflammatory injury and oxidative stress (Day and James 1998, Hepatology 27, 1463-1466).

[0362] GPR84 (also known as EX33) has been isolated and characterized from human B cells (Wittenberger et al., 2001, J. Mol. Biol. 307, 799-813) and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach (Yousefi et al., 2001). It remained an orphan GPCR until medium-chain free fatty acids (FFAs) with carbon chain lengths of 9-14 were identified as ligands for this receptor (Wang J et al., 2006).

[0363] GPR84 is activated by medium-chain FFAs, such as capric acid (Cl 0:0), undecanoic acid (Cl 1:0), and lauric acid (12:0), which can amplify the production of lipopolysaccharide-stimulated proinflammatory cytokines / chemokines (TNFα, IL-6, IL-8, CCL2, etc.) and is highly expressed in neutrophils and monocytes (macrophages) (Miyamoto et al. 2016, Int. J. Mol. Sci. 17(4)450).

[0364] In contrast, GPR84 ligand-mediated chemotaxis of neutrophils and monocytes / macrophages is inhibited by GPR84 antagonists (Suzuki M et al. 2013. J. Biol. Chem. 288, 10684-10691).

[0365] Although recruitment of monocytes / macrophages to the liver appears to occur concurrently with fibrosis 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), this has not led to new therapeutic approaches.

[0366] There are currently no approved drugs for the treatment of NASH, so liver transplantation remains the last option for advanced disease conditions. For example, in IPF, only two drugs have been approved despite adverse 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), so there is a clear need for improved treatments (Raghu, 2015, Am J Respir Crit Care Med 191 (3) 252-4).

[0367] The potent and selective GPR84 inhibitor GLPG1205, at once-daily doses of 3 and 10 mg / kg, reduced disease activity index scores and neutrophil infiltration in a mouse dextran sulfate sodium-induced chronic inflammatory bowel disease model, with efficacy similar to that of the positive control compound sulfasalazine. (Labéguère F, et al. 2020. J Med Chem. 63(22), 13526-13545)

[0368] Nguyen et al. showed that PBI-4050 (a GPR84 antagonist / GPR40 agonist) can reduce pulmonary hypertension, pulmonary fibrosis and right ventricular dysfunction in heart failure. This suggests that GPR84 antagonists are a new and promising therapy for lung remodeling in type II pulmonary hypertension (Nguyen et al. 2020. Cardiovasc Res. 116(1), 171-182).

[0369] Gagnon et al. showed that GPR40 and GPR84 may represent promising molecular targets in the fibrosis pathway. Administration of PBI-4050 (a GPR84 antagonist and GPR40 agonist) significantly reduced fibrosis in a variety of injury scenarios, as evidenced by anti-fibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models (Gagnon et al., 2018. Am J Pathol. 188(5), 1132-1148).

[0370] Studies have also linked GPR84 to acute lung injury and / or inflammation.

[0371] 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 reported significant effects in the prevention and / or treatment of multiple sclerosis (MS) in preclinical studies (Alavi et al. 2019. Life Sci. 224, 33-40).

[0372] GPR84 expression is enhanced in several mouse tissues under inflammatory stimuli, such as endotoxemia, hyperglycemia, and hypercholesterolemia. These stimuli also increase GPR84 expression in macrophages, and a selective GPR84 receptor agonist (6-OAU) triggers enhanced secretion of proinflammatory cytokines and phagocytosis in macrophages (Recio et al. 2018. Front. Immunol. 9, 1419). The results suggest that once inflammation occurs, GPR84 acts 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.

[0373] DL-175, a potent and selective structurally novel molecule, was found to cause different functional effects in macrophages compared to other GPR84 ligands (Lucy et al. 2019. ACS Chem. Biol. 14(9), 2055-2064). This study confirmed that GPR84 agonists can lead to enhanced macrophage chemotaxis and / or phagocytosis (also known as macrophage activation)

[0374] GPR84 is one of the few pro-inflammatory neutrophil-related genes that was highly enriched in an RNA sequencing dataset analysis of BALF cells from COVID-19 patients (Didangelos, A. 2020. mSphere. 5(3), e00367-20).

[0375] In an acute lung inflammation model, LPS induces alveolar macrophages to shift from CD11 lo Transition to a more inflammatory CD11 hi state, which worsens the lung injury process (Yin 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 alveolar macrophage state transition. GPR84 may represent a potential therapeutic target for acute respiratory distress syndrome.

[0376] et al. prepared the first GPR84 agonist radioligand (tritiated) for studying the binding affinity of receptor ligands. They noted that GPR84 has been found to be involved in inflammatory processes associated with gastroesophageal reflux disease, inflammatory bowel disease, multiple sclerosis, neuropathic pain, and Alzheimer's disease. In addition, GPR84 has been associated with obesity and diabetes. Preliminary evidence suggests that GPR84 may be involved in leukemogenesis, osteoclastogenesis, and organ fibrosis (pathological consequences of many inflammatory and metabolic diseases). ( M, et al. 2020. J. Med. Chem. 63(5), 2391-2410).

[0377] Global analysis of glycoproteins by Müller et al. identified markers for endotoxin-tolerant monocytes and GPR84 as a regulator of TNFα expression (Müller MM, et al. 2017 Sci Rep. 7(1), 838).

[0378] Research by Venkataraman et al. showed that GPR84 can regulate IL-4 produced by T lymphocytes in CD3 cross-linking reactions, revealing a new role of GPR84 in regulating early IL-4 gene expression in activated T cells (Venkataraman C et al. 2005. Immunol Lett. 101(2), 144-53).

[0379] Additionally, GPR84 has been implicated in neuropathic pain and / or neuropathy.

[0380] Gao et al. demonstrated that DOK3 is involved in microglial activation in neuropathic pain by interacting with GPR84, revealing a physical association between DOK3 and GPR84 in inducing inflammatory responses. They hypothesized that targeting the adaptor protein DOK3 may open new avenues for pharmacological approaches to relieve spinal neuropathic pain (Gao WS et al. 2020. Aging (Albany NY). 12.).

[0381] Kozela et al. studied the behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration and showed that CBD reversed KET-induced transcriptional changes, including the Gpr84 gene (Kozela E et al. 2020. Mol Neurobiol. 57(3), 1733-1747).

[0382] Wei et al.'s study showed that G protein-coupled receptor 84 (GPR84) agonists alter cell morphology and motility but do not induce proinflammatory responses in microglia. This study suggests that microglial GPR84 could 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).

[0383] Nicol et al. investigated the role of GPR84 in experimental neuropathic pain and demonstrated that GPR84 is a pro-inflammatory receptor that promotes nociceptive signaling by regulating macrophages, whereas in its absence, these cells are impaired in their response to inflammatory insults (Nicol LS et al., 2015. J Neurosci. 35(23), 8959-69).

[0384] Mededdu et al. found that Gpr84 expression was induced in both microglia and astrocytes and was upregulated in the central nervous system (CNS) after viral infection, suggesting that Gpr 84 expression may be a useful measure of glial cell activation when the central nervous system (CNS) is injured or damaged (Madeddu S, et al. 2015. PLoS One. 10(7), e0127336).

[0385] Bouchard et al. found that mice with endotoxemia strongly and persistently expressed GPR84 in microglia, making GPR84 a sensitive marker of microglial activation and likely to play an important regulatory role in neuroimmune processes, acting downstream of proinflammatory mediators (Bouchard C et al. 2007. Glia. 55(8), 790-800).

[0386] GPR84 is also associated with inflammatory bowel disease and is a potential disease target.

[0387] Planell et al. identified GPR84 as a transcriptional blood biomarker that can be used as a non-invasive surrogate marker of mucosal healing and endoscopic response in ulcerative colitis. At 14 weeks of treatment, response to anti-TNF therapy induced changes in blood 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).

[0388] Abdel-Aziz et al. found that GPR84 and TREM-1 signaling lead to the onset of reflux esophagitis, suggesting 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).

[0389] Dietrich et al. demonstrated that GPR84 can maintain stem cell-derived mixed lineage leukemia (MLL) leukemogenesis by maintaining aberrant b-catenin signaling in leukemic stem cells (LSCs), a previously unrecognized role for GPR84 in maintaining fully developed acute myeloid leukemia (AML) by maintaining aberrant b-catenin signaling in LSCs, and suggested that targeting the oncogenic GPR84 / b-catenin signaling axis may represent a new AML therapeutic strategy (Dietrich PA et al. 2014. Blood. 124(22), 3284-94).

[0390] Deng et al. mined tumor microenvironment-related genes with prognostic value for hepatocellular carcinoma (HCC) from the Cancer Genome Atlas (TCGA) database and identified GPR84 among a group of differentially expressed genes (DEGs), which can be used as a candidate biomarker for HCC prognosis (Deng Z, et al. 2019. Biomed Res Int. 2019, 2408348).

[0391] Wang et al. used gene chip expression profiling to reveal changes in energy metabolism-related genes such as GPR84 in bone cells under the action of high gradient high magnetic fields. The identification of special environmental sensitive genes such as GPR84 may provide some potential targets for the prevention and treatment of bone loss or osteoporosis (Wang Y, et al. 2015. PLoS One. 10 (1), e0116359).

[0392] The study by Park et al. showed that GPR84 regulates osteoclastogenesis by inhibiting NF-κB and MAPK signaling pathways, revealing that GPR84 acts as a negative regulator of osteoclastogenesis, suggesting that it may become a potential therapeutic target for osteoclast-mediated bone destructive diseases (Park JW, et al. 2018. J Cell Physiol. 233(2), 1481-1489).

[0393] Zhu et al. discovered abnormal gene regulatory pathways in systemic lupus erythematosus by whole-genome transcription and DNA methylation analysis of peripheral blood mononuclear cells. Compared with systemic lupus erythematosus (SLE) lupus nephritis (LN)-patients, gene expression of MX1, GPR84, and E2F2 was increased in SLE LN-patients (Zhu H, et al. 2016. Arthritis Res Ther. 18, 162).

[0394] 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 or pharmaceutical composition of the invention as described herein.

[0395] In certain embodiments, the subject matter disclosed herein relates 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.

[0396] The compounds disclosed herein directly bind to GPR84 and inhibit its signaling activity. In some embodiments, the compounds disclosed herein reduce, inhibit or otherwise attenuate GPR84-mediated inflammatory responses.

[0397] The compounds disclosed herein may or may not be specific GPR84 antagonists. A specific GPR84 antagonist reduces the biological activity of GPR84 by an amount statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, the compounds disclosed herein 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 the GPR84 antagonist against another GPCR activated by free fatty acids (FFA) or other GPCR types (e.g., class A GPCRs) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the total amount.

[0398] The compounds disclosed herein can be used in methods for inhibiting GPR84. Such methods include contacting GPR84 with an effective amount of a compound disclosed herein. "Contacting" is intended to bring 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 by administering the compound to a subject.

[0399] Any method known in the art for measuring the signaling activity of GPR84 can be used to determine whether GPR84 has been inhibited, including in vitro assays or measurements of downstream biological effects of GPR84 signaling activity.

[0400] The compounds disclosed herein can be used to treat GPR84-dependent disorders. As used herein, a "GPR84-dependent disorder" is a pathological disorder in which GPR84 activity is necessary for the cause or maintenance of the pathological disorder. In some embodiments, the GPR84-dependent disorder is an inflammatory disorder.

[0401] The compounds disclosed herein can also be used to modulate the immune response of a subject in need thereof. Such methods comprise administering an effective amount of a compound of the invention.

[0402] As used herein, "modulating an immune response" refers to the modulation of any immunogenic response to an antigen.

[0403] In another aspect of the invention, the invention provides novel compounds of the invention for use in therapy.

[0404] In another aspect of the present invention, the present invention provides a method for treating a mammal, including a human, that is susceptible to or suffers from a disorder listed herein, particularly a disorder that may be associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or a disease involving impaired immune cell function, the method comprising administering a therapeutically effective amount of one or more of the compounds of the present invention or the pharmaceutical compositions described herein.

[0405] In another aspect, the present invention provides a compound of the present invention for use in treating or preventing a disorder selected from the disorders listed herein, in particular disorders that may be associated with abnormal activity of GPR84 and / or abnormal GPR84 expression and / or abnormal GPR84 distribution expression, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function.

[0406] In additional aspects, the invention provides methods of synthesizing compounds of the invention using the representative synthetic schemes and pathways disclosed herein.

[0407] Therefore, a main object of the present invention is to provide compounds of the present invention which can alter the activity of GPR84 and thus prevent or treat any disorder which may be causally related thereto.

[0408] Another object of the present invention is to provide compounds of the present invention, which can treat or alleviate conditions or diseases or their symptoms that may be causally related to the activity and / or expression and / or distribution of GPR84, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function.

[0409] Another object of the present invention is to provide pharmaceutical compositions that can be used to treat or prevent a variety of disease states, including diseases associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as inflammatory diseases, pain, neuroinflammatory disorders, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function.

[0410] Other objects and advantages will become apparent to those skilled in the art from consideration of the following detailed description.

[0411] The present disclosure provides methods of modulating (eg, inhibiting) GPR84 activity, the methods comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0412] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof.

[0413] In the methods described herein, a compound of the invention or a pharmaceutical composition thereof is administered to a subject having cancer.

[0414] In certain embodiments, the subject matter disclosed herein relates to a method for treating a GPR84-dependent disorder, comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the invention as described herein. In certain aspects of this embodiment, the GPR84-dependent disorder is cancer.

[0415] In some embodiments, the subject matter disclosed herein relates to a method for treating a chronic viral infection. In some embodiments, the subject matter disclosed herein relates to using a GPR84 inhibitor as an adjunct therapy to increase the efficacy of vaccination.

[0416] 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.

[0417] In certain aspects, the invention provides a method of treating a cell proliferative disorder, including cancer.

[0418] In one aspect, the present invention provides a method of treating a cell proliferative disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0419] In certain embodiments, the cell proliferative disorder is cancer.

[0420] Examples of cancers that may be treated using the compounds of the present disclosure include, but are not limited to, chronic or acute leukemias, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors in children, lymphocytic lymphomas, and combinations of the described cancers.

[0421] In some embodiments, cancers that may be treated using the compounds of the present disclosure include, but are not limited to, blood cancers (e.g., lymphomas, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of the aforementioned cancers.

[0422] In certain embodiments, the cancer is leukemia. In another embodiment, the cancer is selected from the group consisting of acute myeloid leukemia and chronic myeloid leukemia.

[0423] In certain embodiments, the cancer is selected from leukemia and hematological cancers. In specific embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In specific embodiments, the cancer is AIDS-related.

[0424] In a specific embodiment, the cancer is selected from leukemia and hematological cancer. In a specific embodiment, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndrome, myelodysplasia / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), AML after MPN, AML after MDS, del (5q) related high-risk MDS or AML, blastocyst chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis, hairy cell leukemia, and plasma cell neoplasms including plasmacytoma and multiple myeloma. The leukemia mentioned herein may be acute or chronic.

[0425] In some embodiments, diseases and indications that may be treated using the disclosed compounds include, but are not limited to, hematological cancers.

[0426] Exemplary hematologic 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 lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia (Waldenstrom's Macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0427] As used herein, the term "inflammatory disorder" refers to the group of disorders that includes inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, lung disease (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung disease (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway disease (e.g., asthma, rhinitis), and endotoxin-driven disease states (e.g., complications after bypass surgery or chronic endotoxin states that cause, for example, chronic heart failure). Specifically, the term refers to rheumatoid arthritis, allergic airway disease (e.g., asthma), and inflammatory bowel disease. In another specific aspect, the term refers to uveitis, periodontitis, esophagitis, neutrophilic skin diseases (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncology treatments designed to activate an immune response.

[0428] As used herein, the term "pain" refers to a disease or condition characterized by a sensory discomfort that is usually caused by a severe or damaging stimulus and includes, but is 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 a disorder mentioned herein. Pain can be acute or chronic.

[0429] As used herein, the term "neuroinflammatory condition" refers to a disease or disorder characterized by sudden neurological deficits associated with inflammation, demyelination, and axonal damage, including but not limited to conditions such as Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0430] As used herein, the term "neurodegenerative disease" refers to a disease or condition characterized by a gradual loss of neuronal structure or function (including neuronal death), including but not limited to dementia, degenerative dementia, senile dementia, vascular dementia, dementia associated with intracranial space-occupying lesions, mild cognitive impairment associated with aging, age-related memory impairment and / or peripheral neuropathy. Specifically, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's disease, 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, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and / or amyotrophic lateral sclerosis (ALS).

[0431] As used herein, the term "infectious disease" refers to bacterial infectious diseases and includes, but is not limited to, conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacter species.

[0432] As used herein, the term "autoimmune disease" refers to a group of diseases including obstructive airway diseases (including diseases such as COPD (chronic obstructive pulmonary disease)), psoriasis, asthma (e.g., intrinsic asthma, extrinsic asthma, pneumoconiosis, infantile asthma), especially chronic or refractory asthma (e.g., late asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes and its related complications, atopic eczema (atopic dermatitis), contact dermatitis and eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis and inflammatory bowel disease.

[0433] As used herein, the term "endocrine and / or metabolic disease" refers to a group of diseases involving an excess or deficiency of certain hormones in the body, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine diseases include hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), and ovarian dysfunction (including polycystic ovary syndrome), among others. Some examples of metabolic disorders include cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets. A specific example of a metabolic disorder is obesity.

[0434] As used herein, the term "cardiovascular disease" refers to diseases that affect the heart or blood vessels or both. Specifically, cardiovascular disease includes arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; arrhythmias; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, and dysfunction confined to a single organ or tissue. More specifically, the term refers to atherosclerosis.

[0435] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, which makes the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0436] As used herein, the term "disease" involves impaired immune cell function and includes conditions with symptoms such as recurrent and protracted viral and bacterial infections and slow recovery. Other invisible symptoms may be the inability to kill parasites, yeast and bacterial pathogens in the intestines or throughout the body.

[0437] As used herein, the term "fibrotic disease" refers to a disease that results in excessive scarring due to excessive production, deposition, and contraction of the extracellular matrix and is associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including but not limited to fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract. Specifically, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of varying etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmental fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular disease, pulmonary alveolar proteinosis, Langerhans cell granuloma, lymphangioleiomyomatosis, hereditary 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 ; hypertension; Alport's disease; intestinal fibrosis; liver fibrosis; cirrhosis; alcoholic liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD); cholestasis, bile duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); infection-induced liver fibrosis; virus-induced liver fibrosis; autoimmune hepatitis; corneal scars; hypertrophic scars; 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. More specifically, the term "fibrotic disease" refers to idiopathic pulmonary fibrosis (IPF), Dupuytren's disease, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), alcoholic steatohepatitis (ASH), portal hypertension, systemic sclerosis, renal fibrosis and skin fibrosis. Most specifically, the term "fibrotic disease" refers to non-alcoholic steatohepatitis (NASH) and / or non-alcoholic fatty liver disease (NAFLD). Alternatively, most specifically, the term "fibrotic disease" refers to IPF.

[0438] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, disorder or condition in an individual who may be susceptible to the disease, disorder or condition but has not yet experienced or manifested the pathology or symptomology of the disease.

[0439] The compounds disclosed herein can be administered in any suitable manner known in the art. In some embodiments, the compounds of the invention or their pharmaceutically acceptable salts, prodrugs, metabolites or derivatives are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally or intranasally.

[0440] In some embodiments, the GPR84 antagonist is administered continuously. In other embodiments, the GPR84 antagonist is administered intermittently. In addition, treating a subject with an effective amount of a GPR84 antagonist may include a single treatment or may include a series of treatments.

[0441] It should be understood that the appropriate dosage of the active compound depends on a variety of factors within the knowledge of the physician or veterinarian of ordinary skill. The dosage of the active compound will vary, for example, depending on the age, weight, general health, sex and diet of the subject, the time of administration, the route of administration, the excretion rate and any drug combination.

[0442] It is also understood that the effective dose of a compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof used for treatment may be increased or decreased over a specific treatment period. Changes in dose may occur and become apparent from the results of diagnostic assays.

[0443] In some embodiments, the GPR84 antagonist is administered to the subject at a dose of between about 0.001 μg / kg and about 1000 mg / kg, including 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.

[0444] In the methods described herein, the methods may also include administering a chemotherapeutic agent to the subject. In some aspects of this embodiment, the chemotherapeutic agent and the compound or composition are administered to the subject simultaneously. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject before administering the compound or composition. In some aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administering the compound or composition.

[0445] As used herein, the term "treatment / treat / treating" refers to reversing, alleviating a disease or disorder as described herein or one or more symptoms thereof, delaying its onset, or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered when symptoms are not present. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on hereditary or other sensitivity factors). Treatment may also be continued after symptoms subside, for example to prevent or delay their recurrence.

[0446] The term "administration" or "administering" includes a route of introducing a compound into a subject to exert 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.

[0447] The term "effective amount" includes an amount effective to achieve the desired result at the desired dosage and time period. The effective amount of a compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit the desired response in the subject. The dosage regimen may be adjusted to provide the optimal therapeutic response.

[0448] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean administration of a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.

[0449] The phrase "therapeutically effective amount" means an amount of a compound of the invention that achieves the following effects: (i) treating or preventing a specific disease, disorder or condition, (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease, disorder or condition, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, disorder or condition described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate one or more of the symptoms associated with cancer to some extent. To the extent that a drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0450] The term "subject" refers to an animal, such as a mammal, 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.

[0451] In one embodiment, the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for preventing and / or treating 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).

[0452] In another embodiment, the present invention provides a compound of the invention or a pharmaceutical composition comprising the compound of the invention for use in the manufacture of an endocrine and / or therapeutic agent for preventing and / or treating 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).

[0453] In terms of additional treatment methods, 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 as described herein, or the pharmaceutical composition for treating or preventing the 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).

[0454] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the invention and another additional therapeutic agent. In a specific embodiment, the other therapeutic agent is a fibrotic disease therapeutic agent. 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).

[0455] 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 a subject presenting a NAS score of at least 3, at least 4, at least 5, at least 6 or at least 7.

[0456] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating a subject presenting with a NAS score>5.

[0457] In terms of additional treatment methods, the present invention provides a method for preventing and / or treating a mammal presenting 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 treating or preventing the fibrotic disease, particularly NASH and / or NAFLD, more particularly NASH.

[0458] In further treatment method embodiments, the method for preventing and / or treating mammals includes measuring the forced vital capacity (FVC) of the subject, wherein the FVC does not decline after treatment. In a specific embodiment, FVC does not decrease during the treatment period of 12,16,20 or 26 weeks. In another embodiment, the method includes measuring the FVC of 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 7 mL or at least 8 mL. In a specific embodiment, 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 during the treatment period of 12,16,20 or 26 weeks.

[0459] In one embodiment, the method comprises measuring airway volume, wherein the airway volume decreases by no more than 5 mL / L, no more than 4 mL / l, or no more than 3 mL / L. In specific embodiments, after 12, 16, 20, or 26 weeks of treatment, the airway volume decreases by no more than 5 mL / L, no more than 4 mL / l, or no more than 3 mL / L.

[0460] Combination therapy

[0461] Depending on the specific disorder or disease to be treated, additional therapeutic agents that are normally administered to treat that disorder may be administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a specific disease or disorder are referred to as "appropriate for the disease or disorder being treated."

[0462] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0463] The compounds of the present invention are useful as therapeutic agents for treating a condition in a mammal that is causally related to or attributable to aberrant activity of GPR84 and / or aberrant expression of GPR84 and / or aberrant distribution of GPR84.

[0464] Therefore, the compounds and pharmaceutical compositions of the present invention can be used as therapeutic agents for preventing and / or treating inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function in mammals including humans.

[0465] 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.

[0466] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament.

[0467] In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of a disease disclosed herein. In a specific aspect, the present invention provides a method of treating a mammal suffering from or at risk of an inflammatory disorder, pain, a neuroinflammatory disorder, a neurodegenerative disorder, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, a leukemia, and / or a disease involving impaired immune cell function in a mammal including a human, the method comprising administering an effective amount of one or more of the compounds of the present invention described herein, or the pharmaceutical compositions.

[0468] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for preventing and / or treating inflammatory diseases. In a specific embodiment, the inflammatory disease 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 disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatosis (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma and skin and / or colon inflammation caused by oncology treatment intended to activate immune response.

[0469] On the other hand, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for the manufacture of a medicament for preventing and / or treating an inflammatory disease. In a specific embodiment, the inflammatory disease 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 disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatosis (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma and skin and / or colon inflammation caused by oncology treatments intended to activate immune responses.

[0470] In another aspect, the present invention provides a method of treating a mammal having or at risk of developing a disease selected from an inflammatory disease (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), a pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung disease (e.g., idiopathic pulmonary fibrosis (IPF))), a neuroinflammatory disease, 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 one or more of the compounds of the present invention, or the pharmaceutical compositions described herein.

[0471] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an inflammatory disorder, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions described herein. In one embodiment, the inflammatory disorder is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In another embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatosis (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncology treatments intended to activate an immune response.

[0472] 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 preventing and / or treating pain. In a specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0473] 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 preventing and / or treating pain. In a specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0474] In terms of additional methods of treatment, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from pain, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions described herein. In a specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0475] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in preventing and / or treating neuroinflammatory diseases, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0476] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which comprises a compound of the present invention suitable for the manufacture of a medicament for preventing and / or treating neuroinflammatory diseases, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0477] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from a neuroinflammatory disorder, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, or autoimmune encephalomyelitis, the method comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention described herein.

[0478] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in preventing and / or treating an infectious disease. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, Enterobacter species.

[0479] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating an infectious disease. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, Enterobacter species.

[0480] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an infectious disease, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions described herein. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, Enterobacter species.

[0481] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in preventing and / or treating an autoimmune disease and / or a disease involving impaired immune cell function. In a specific embodiment, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0482] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating an autoimmune disease and / or a disease involving impaired immune cell function. In a specific embodiment, the autoimmune disease and / or the disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis and inflammatory bowel disease.

[0483] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an autoimmune disease and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions described herein. In a specific embodiment, the autoimmune disease and / or the disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0484] In one aspect, the invention provides the compounds of this invention or a pharmaceutical composition comprising the compounds of this invention, which is used to prevent and / or treat endocrine and / or metabolic diseases. In a specific embodiment, endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets.

[0485] On the other hand, the invention provides the compounds of this invention or a pharmaceutical composition comprising the compounds of this invention, which is used to manufacture a medicament for preventing and / or treating endocrine and / or metabolic diseases. In a specific embodiment, endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets.

[0486] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an endocrine and / or metabolic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions as described herein. In a specific embodiment, the endocrine and / or metabolic disease is selected from hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal disease (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets.

[0487] As another aspect of the present invention, a compound of the present invention is provided, which is particularly useful as a medicament in the treatment or prevention of the aforementioned disorders and diseases. Also provided herein is the use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned disorders and diseases.

[0488] A specific embodiment of the method of the present invention comprises administering to a subject suffering from an inflammatory disorder an effective amount of a compound of the present invention for a period of time sufficient to reduce the level of inflammation in the subject and preferably terminate the process causing the inflammation. A specific embodiment of the method comprises administering to a subject susceptible to or suffering from the development of an inflammatory disorder an effective amount of a compound of the present invention for a period of time sufficient to respectively reduce or prevent inflammation in the patient and preferably terminate the process causing the inflammation.

[0489] 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 and especially 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 2 g / day.

[0490] Transdermal administration is generally selected to provide blood levels similar to or lower than those achieved using administration by injection.

[0491] When used to prevent the onset of a disorder, the compounds of the invention should be administered to patients at risk of the disorder at the dosage levels described above, usually on the advice of a physician and under the supervision of a physician. Patients at risk of a particular disorder typically include those with a family history of the disorder, or those who have been identified by genetic testing or screening as being particularly susceptible to the disorder.

[0492] The compounds of the present invention may be administered as a single active agent or they may be administered in combination with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and are determined to be safe and effective for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows a significant reduction in the dose of each agent to be used, thereby reducing the side effects seen.

[0493] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory disorders; specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., ), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0494] In one embodiment, the compounds of the invention are 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 (such as, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporine), and biologic DMARDS (such as, but not limited to, infliximab, etanercept, adalimumab, rituximab, golimumab, becelimumab, tocilizumab, interleukin 1 blockers, and abatacept).

[0495] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of an autoimmune disease; specific agents include, but are not limited to, glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, etc.), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., actinomycin D anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, and ), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (eg, IFN-β), TNF-binding proteins (eg, infliximab Etanercept Adalimumab ), mycophenolate mofetil, fingolimod and myriocin.

[0496] In one embodiment, the compounds of the 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 invention are co-administered with another therapeutic agent for the treatment and / or prevention of infection of 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, quinolinones, sulfonamides, tetracyclines, antimycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycins, thiamphenicol, and tinidazole.

[0497] 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, terminal antibiotics (e.g., cephalexin).

[0498] In one embodiment, the compounds of the invention are 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 silicone), H2-antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide).

[0499] 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.

[0500] 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, beta2-adrenoceptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting beta2-agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral salbutamol), combinations of inhaled steroids with long-acting bronchodilators (e.g., fluticasone / salmeterol, budesonide, The invention relates to 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 the IgE response (e.g., omalizumab), antihistamines (e.g., ceterizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, nafazoline, and tramazoline).

[0501] In addition, the compounds of the invention may be administered in combination with emergency therapies for asthma and / or COPD, such therapies include oxygen or heliox administration, nebulized albuterol or terbutaline (optionally in combination with an anticholinergic agent such as ipratropium bromide), systemic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone, or hydroxycorticosterone), intravenous albuterol, nonspecific beta agonists, injectable or inhaled agents (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergic agents (IV or nebulized agents, such as glycopyrrolate, atropine, ipratropium bromide), methylxanthines (theophylline, aminophylline, bamiphylline), inhaled anesthetics with bronchodilatory effects (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0502] In one embodiment, the compounds of the invention are 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, immunomodulatory agents (e.g., methotrexate, leflunomide, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, and cyclosporine) and biologic disease-modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0503] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of pain, such as non-narcotic and narcotic analgesics; specific agents include, but are not limited to, acetaminophen, acetylsalicylic acid, NSAIDs, codeine, dihydrocodeine, tramadol, pentazocine, meperidine, tilidine, buprenorfine, fentanyl, hydromorphone, methadone, morphine, oxycodone, piritramide, tapentadol, or a combination thereof.

[0504] Leukemia treatment courses include chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation, and / or a combination thereof.

[0505] Examples of other therapeutic agents for acute lymphoblastic leukemia (ALL) include methotrexate, nelarabine, asparaginase, Erwinia chrysanthemi, belintoumab, daunorubicin, clofarabine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib vincristine, mercaptopurine, pegaspargase, and / or prednisone.

[0506] Examples of other therapeutic agents for acute myeloid leukemia (AML) include arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and / or vincristine.

[0507] Examples of other therapeutic agents for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, nitrogen mustard, prednisone, and / or rituximab.

[0508] Examples of other therapeutic agents for chronic myeloid leukemia (CML) include bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, nitrogen mustard, nilotinib, and / or omatasine.

[0509] Examples of other therapeutic agents for hairy cell leukemia include cladiribine, pentostatin, and / or interferon alpha-2b.

[0510] As will be apparent to those skilled in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. While two or more agents may be administered simultaneously in a single formulation, this is not required. The agents may be in different formulations and administered at different times.

[0511] In one embodiment, the compounds of the invention are co-administered with one or more other therapeutic agents for the treatment and / or prevention of fibrotic diseases. In a specific embodiment, the compounds of the invention are co-administered with one or two other therapeutic agents for the treatment and / or prevention of fibrotic diseases. In a more specific embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of fibrotic diseases.

[0512] In one embodiment, other therapeutic agents used to treat and / or prevent fibrotic diseases include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone); nintedanib ( or ); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), rebrestinumab (CAS n#953400-68-5); tarotuzumab (CAS n#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), telust (MN-001; ClinicalTrials.gov identifier NCT02503657), ND-L02-s020l (ClinicalTrials.gov identifier NCT03538301), KD025 (ClinicalTrials.gov identifier NCT02688647), TD139 (ClinicalTrials.gov identifier NCT02257177), V AY736 (ClinicalTrials.gov identifier NCT03287414), PRM-151 (ClinicalTrials.gov identifier NCT02550873) and PBI-4050 (ClinicalTrials.gov identifier NCT02538536). In a specific embodiment, another therapeutic agent for treating and / or preventing a fibrotic disease is an autotaxin (or ectonucleotide pyrophosphatase / phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are described in WO 2014 / 139882, such as GLPG1690.

[0513] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of NASH, specific agents include but are not limited to weight loss therapeutics (e.g., sibutramine or orlistat), insulin sensitizers (e.g., metformin, thiazolidinediones, rosiglitazone, or pioglitazone), lipid-lowering agents (e.g., gemfibrozil), antioxidants (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, monounsaturated fatty acids, or polyunsaturated fatty acids. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., simtuzumab), ASK1 antagonists (e.g., selosertib), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones, ibuprofen, GW-9662, aleglitazar, moraglitazar, or tesaglitazar), acetyl CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2 / CCR5 (e.g., senevirol), VAP1 antagonists.

[0514] Examples of agents that may also be combined with the combinations of the present invention include, but are not limited to: for the treatment of Alzheimer's disease, e.g. and for the treatment of HIV, such as ritonavir; for the treatment of Parkinson's disease, such as L-dopa / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; for agents used to treat multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; for asthma treatments, such as albuterol and Agents used to treat schizophrenia, such as zyprexa, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, 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 anti-Parkinson's disease agents; Agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferons and antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemic agents and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic breakdown) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), agents for the treatment of immunodeficiency disorders, such as gamma globulin.

[0515] In certain embodiments, the combination therapies of the invention, or pharmaceutically acceptable compositions thereof, are administered in combination with a monoclonal antibody or siRNA therapeutic.

[0516] Those additional agents may be administered separately from the provided combination therapy as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention into a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (usually within five hours of each other).

[0517] As used herein, the term "combination (combination / combined)" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0518] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in the form of a composition comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein will preferably be in the range of about 50% to 100% of the amount normally present in a composition comprising the agent as the only therapeutically active agent.

[0519] In one embodiment, the invention provides a composition comprising a compound of formula I and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of formula I, or can 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 can 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 therapeutic agent. In other embodiments, the compound of formula I can 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 the therapeutic agent.

[0520] In another embodiment, the present invention provides a method of treating an inflammatory disease, condition or disorder 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 biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat Sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold thioglucosinolate gold thiomalate Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Certolizumab PEGylated Adalimumab "Anti-IL-1" agents such as anakinra and linacept Canakinumab Anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab "Anti-T cell" agents such as abatacept “Anti-IL-6” agents such as tocilizumab Diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine, alosetron Lubiprostone Laxatives such as milk of magnesia, polyethylene glycol and Anticholinergics or antispasmodics such as dicyclomine Beta-2 agonists such as salbutamol (V HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol Hydroxynaphthoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium Inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide Sodium cromoglycate Methylxanthines such as theophylline and aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz Nevirapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Sanavi Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ) and tipranavir Enfuvirtide and Maravero Integrase inhibitors such as raltegravir Doxorubicin Vincristine Bortezomib and dexamethasone Lenalidomide or any combination thereof.

[0521] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold thioglucosinolate gold thiomalate Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Certolizumab PEGylated Adalimumab "Anti-IL-1" agents such as anakinra and linacept Antibodies such as rituximab "Anti-T cell" agents such as abatacept and “anti-IL-6” agents such as tocilizumab

[0522] 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 the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) and monoclonal antibodies such as tanezumab.

[0523] In some embodiments, the present invention provides a method of treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate Azathioprine and anticoagulants such as heparin ( or ) and warfarin

[0524] In some embodiments, the present invention provides a method 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 the group consisting of mesalamine Sulfasalazine Antidiarrheal drugs such as diphenoxylate and loperamide Bile acid binders such as cholestyramine, alosetron Lubiprostone Laxatives such as milk of magnesia, polyethylene glycol and and anticholinergics or antispasmodics such as dicyclomine Anti-TNF therapy, steroids, and antibiotics such as metronidazole (Flagyl) or ciprofloxacin (ciprofloxacin).

[0525] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from: Beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol Hydroxynaphthoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium Inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and Sodium cromoglycate Methylxanthines such as theophylline and aminophylline, and IgE antibodies such as omalizumab

[0526] 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 one or more additional therapeutic agents selected from the group consisting of: a beta-2 agonist such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol Hydroxynaphthoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium Methylxanthines such as theophylline and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide Flunisolide and

[0527] In another embodiment, the present invention provides a method of treating a hematological malignancy, the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0528] In another embodiment, the present invention provides a method of treating solid tumors, the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0529] In another embodiment, the present invention provides a method for treating a hematological malignancy, the method comprising administering a compound of formula I and a hedgehog (Hh) signaling pathway inhibitor to a patient in need thereof. 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 on July 17, and incorporated herein by reference in its entirety).

[0530] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: Rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0531] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a compound of Formula I and one or more additional therapeutic agents selected from the group consisting of: bortezomib and dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide

[0532] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, the method comprising administering to a patient in need thereof a compound of formula I and a BT K inhibitor, 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, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, Lymeneuroborrelio sis), Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody 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, Behcet's disease disease), chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvar pain, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, anaphylaxis, allergies (e.g., to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx) allergies), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpurapurpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g. diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also called plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal 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 lymphoma / leukemia, or lymphomatoid granuloma, breast cancer, prostate cancer), or mast cell cancer (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, osteoarthritis (including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease),isease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass grafting, restenosis after aortocoronary bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn of the skin, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune The diseases described herein include 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, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Grave's disease.

[0533] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, the method comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, disorders associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, disorders associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune disorders involving T cell activation, cardiovascular diseases and CNS disorders.

[0534] In another embodiment, the present invention provides a method of treating or reducing the severity of a disease, the method comprising administering a compound of formula I and a PI3K inhibitor to a patient in need thereof, 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 glands, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid; sarcoma; glioblastoma; neuroblastoma blastoma; multiple myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or head and neck tumors; epidermal hyperproliferation; psoriasis; prostatic hyperplasia; neoplasia; neoplasia of epithelial characteristics; adenoma; adenocarcinoma; keratoacanthoma; epidermoid carcinoma; large cell carcinoma; non-small cell lung cancer; lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)); breast cancer; follicular carcinoma; undifferentiated carcinoma; papillary carcinoma; seminoma; melanoma or leukemia, diseases including Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also known as Hodgkin's or Hodgkin's disease)); syndrome); or diseases in which the PI3K / PKB pathway is abnormally activated; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection; acute lung injury (ALI); adult / acute respiratory distress syndrome (ARDS); chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and other conditions induced by other drug therapies, especially is an exacerbation of airway hyperresponsiveness caused by other inhaled drug therapy; bronchitis of any type or origin, including but not limited to acute, arachidonic, catarrhal, croupus, chronic or tuberculous bronchitis; pneumoconiosis of any type or origin (inflammatory, usually occupational lung disease, whether chronic or acute, often accompanied by airway obstruction and caused by repeated inhalation of dust), including, for example, aluminum deposition, carbon deposition, asbestosis, stone deposition, eyelash abscess, siderosis, silica deposition, fumigation and byssinusitis;Loffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related conditions affecting the airways caused by 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; dry eye; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and autoimmune reactions with autoimmune components or etiologies Inflammatory diseases related to or with an autoimmune component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia); cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener granulamatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Steven-Johnson syndrome syndrome); idiopathic sprue; autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease); endocrine eye diseases; Grave's disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry eye and vernal keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including, for example, 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 cerebral ischemia; as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0535] In some embodiments, the present invention provides a method of treating a disease or reducing the severity of a disease, the method comprising administering a compound of formula I and a Bcl-2 inhibitor to a patient in need thereof, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. 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.

[0536] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation. 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, WO2015089143A1, each of which is incorporated herein by reference in its entirety. Suitable JH1 domain binding compounds include those described in WO2015131080A1, which are incorporated herein by reference in their entirety.

[0537] The compounds and compositions according to the methods of the present invention can be administered using any effective dosage and any effective administration route for treating autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or disorders associated with transplantation or reducing their severity. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, etc. The compounds of the present invention are preferably formulated in unit dosage forms to achieve ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physical discrete unit of a medicament suitable for a patient to be treated. However, it should 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 reasonable medical judgment. The specific effective dosage level for any particular patient or organism will depend on a variety of factors, including the disorder to be treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination or simultaneously with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0538] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (such as by powders, ointments or drops), buccally (such as oral or nasal sprays), 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 at dosage levels of about 0.01 mg to about 50 mg and preferably about 1 mg to about 25 mg per kg of subject body weight per day, once or more per day.

[0539] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly 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 may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatics.

[0540] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0541] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0542] To prolong the effect of the compounds of the present invention, it is usually necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. Thus the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally is achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir-type injectable preparations are also prepared by embedding the compound in a liposome or microemulsion compatible with body tissues.

[0543] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0544] 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 extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants, such as glycerol, d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) disintegrators, such as paraffin, f) absorption promoters, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, 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 form may also comprise buffering agents.

[0545] Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the field of pharmaceutical formulation. They can optionally contain opacifiers and can also have compositions that release active ingredients only or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0546] The active compound may also be present in a microencapsulated form together with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well known in the field of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As normal practice, such dosage forms may also include additional substances in addition to inert diluents, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. It may optionally contain an emulsifier, and may also have a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0547] The dosage form for topical or transdermal administration of the compounds of the invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active component is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer that may be needed under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the additional advantage of providing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispersing compounds in appropriate media. Absorption enhancers can also be used to increase the transdermal amount of the compound. Rate control can be achieved by providing a rate-controlled membrane or by dispersing the compound in a polymer matrix or gel.

[0548] According to one embodiment, the present invention relates to a method of 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 the compound.

[0549] According to another embodiment, the present invention relates to a method of inhibiting the activity of GPR84 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0550] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0551] Inhibition of GPR84 (or its mutant) activity in biological samples is useful for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassays.

[0552] Another embodiment of the present invention is directed to a method of inhibiting GPR84 activity in a patient, said method comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

[0553] According to another embodiment, the present invention relates to a method of inhibiting the activity of a patient's GPR84 or a mutant thereof, the method comprising the step of 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 of reversibly or irreversibly inhibiting one or more of a patient's GPR84 or a mutant thereof, 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 condition mediated by GPR84 or a mutant 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 conditions are described in detail herein.

[0554] Depending on the particular disorder or disease to be treated, additional therapeutic agents that are normally administered to treat that disorder may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or disorder are referred to as "appropriate for the disease or disorder being treated."

[0555] The compounds of the present invention may also be used in combination with other therapeutic compounds to advantage. In some embodiments, the other therapeutic compound is an antiproliferative compound. 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; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors, such as those from Conforma Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin. As used herein, the term "aromatase inhibitor" relates to a compound that inhibits estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and in particular non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin TM Formestane is sold under the trade name Lentaron TM Fadrozole is sold under the trade name Afema TM Anastrozole is sold under the trade name Arimidex TM Letrozole is sold under the trade name Femara TM or Femar TM Aminoglutethimide is sold under the trade name Orimeten TM The combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0556] As used herein, the term "anti-estrogen" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex TM Raloxifene hydrochloride is sold under the trade name Evista TM Fulvestrant is sold under the trade name Faslodex TM Administration. The combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0557] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological action of androgens and includes, but is not limited to, bicalutamide (Casodex TM As used herein, the term "gonadotropin-releasing hormone agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the trade name Zoladex TM Application.

[0558] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be marketed, for example, in its marketed form, for example under the trademark Camptosar TM Topotecan is sold under the trade name Hycamptin TM Sale.

[0559] As used herein, the term "topoisomerase II inhibitors" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin TM or Adriamycin TM Epirubicin is sold under the trade name Farmorubicin TM Idarubicin is sold under the trade name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0560] The term "microtubule active agent" refers to microtubule stabilizing, 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 and epothilone and its derivatives. Pacific paclitaxel is sold under the trade name Taxol TM Docetaxel is sold under the trade name TaxotereTM Vinblastine sulfate is sold under the trade name Vinblastin RP TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0561] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin. TM Ifosfamide is sold under the trade name Holoxan TM Sale.

[0562] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0563] The term "anti-neoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is marketed under the trade name Xeloda TM Gemcitabine is sold under the trade name Gemzar TM Sale.

[0564] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be marketed, for example, in the form in which it is marketed, for example under the trademark Carboplat TM Oxaliplatin can be used, for example, in the form in which it is marketed, for example under the trademark Eloxatin TM Application.

[0565] As used herein, the term "compounds that target / reduce the activity of protein or lipid kinases, or protein or lipid phosphatases; or other anti-angiogenic compounds" 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 receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor receptor (F c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of Trk receptor tyrosine kinase family, or aprelin B4 inhibitor; e) compounds that target, reduce or inhibit the activity of AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit Kit / SCFR receptor tyrosine h) compounds that target, reduce or inhibit the activity of c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially 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, such as compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, such as from Park eDavis's imatinib or nilotinib (AMN107), PD180970, AG957, NSC680410, PD173955; or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families 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), including staurosporine derivatives, such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrphostin, such as tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) targeting, decreasing or inhibiting the epidermal growth factor family of receptor tyrosine kinases (EGFR 1 Compounds that inhibit the activity of EGF receptor family members, such as ErbB2, ErbB3, ErbB4, in the form of homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit the binding of EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or EGF or EGF related ligands CP 358774, ZD 1839, ZM105180; Herceptin TM ), Cetuximab (Erbitux TM), 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 c-Met receptor, for example, compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit the kinase of c-Met receptor Compounds that target, reduce or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502 , BYL-719, dactolisib, XL-147, XL-765 and idelalisib; and q) compounds that target, decrease or inhibit signaling of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0566] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in 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 suitable for use in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, picoxib, PF-4691502, BYL-719, datoxib, XL-147, XL-765, and idelalisib.

[0567] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0568] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity on spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0569] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, AB T-731, ABT-737, apogossypol, Ascenta's pan-B cl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Gen asense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

[0570] Further examples of BTK inhibiting compounds and conditions that can be treated by combinations of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0571] Further examples of SYK inhibiting compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0572] Other examples of PI3K inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0573] Further examples of JAK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0574] Other antiangiogenic compounds include compounds with another mechanism of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0575] Examples of proteasome inhibitors suitable for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0576] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[0577] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, alpha-, gamma- or delta-tocopherol, or alpha-, gamma- or delta-tocotrienol.

[0578] As used herein, the term cyclooxygenase inhibitors includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0579] As used herein, the term "bisphosphonate" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM Clodronic acid is sold under the trade name Bonefos TM Tiludronic acid is sold under the trade name Skelid TM Pamidronate is sold under the trade name Aredia TM Alendronate is sold under the trade name Fosamax TM Ibandronic acid is sold under the trade name Bondranat TM Risedronate is sold under the trade name Actonel TM Zoledronic acid is sold under the trade name Zometa TM The term "mTOR inhibitor" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (Certican TM ), CCI-779 and ABT578.

[0580] As used herein, the term "heparinase inhibitor" refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. The term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or an interferon.

[0581] As used herein, the term "inhibitor of an oncogenic isoform of Ras" (e.g., H-Ras, K-Ras, or N-Ras) refers to a compound that targets, decreases, or inhibits the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor," such as L-744832, DK8G557, or R115777 (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets telomerase, reduces or inhibits its activity. Compounds that target telomerase, reduce or inhibit its activity are particularly compounds that inhibit telomerase receptors, such as telomestatin.

[0582] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets methionine aminopeptidase, reduces or inhibits its activity. Compounds that target methionine aminopeptidase, reduce or inhibit its activity include but are not limited to bengamide or its derivatives.

[0583] As used herein, the term "proteasome inhibitor" refers to a compound that targets the proteasome, reduces or inhibits its activity. Compounds that target, reduce or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade TM ) and MLN341.

[0584] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) includes, but is not limited to, collagen peptide mimetics and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydrooxalyl ester peptide mimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0585] As used herein, the term "compounds for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c) and busulfan (bisulfan); ALK inhibitors, which are compounds that target, decrease or inhibit polymorphic lymphoma kinase and Bcl-2 inhibitors.

[0586] Compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R) are particularly compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0587] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity; compounds that downgrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target HSP90, reduce or inhibit its intrinsic ATPase activity are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

[0588] As used herein, the term "anti-proliferative antibodies" includes, but is not limited to, trastuzumab (Herceptin TM ), trastuzumab-DM1, erbitux, bevacizumab (Avastin TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0589] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be combined with standard leukemia therapy, especially with a therapy for the treatment of AML. In particular, the compounds of the present invention can be used in combination with, for example, farnesyl transferase inhibitors and / or other drugs suitable for the treatment of AML such as daunorubicin, adriamycin (Adriamycin), Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412. In some embodiments, the present invention provides a method for treating AML associated with ITD and / or D835Y mutations, the method 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), a staurosporine derivative (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.

[0590] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analog that is a 2'-α-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are purine analogs of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Targeted histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), compounds that reduce or inhibit their activity inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 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-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell injury methods refer to methods such as ionizing radiation. The term "ionizing radiation" as mentioned above and below means ionizing radiation that occurs in the form of electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha particles and beta particles). Ionizing radiation is provided in, but not limited to, radiotherapy 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, volume 1, pages 248-275 (1993).

[0591] 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, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C to resist ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0592] Also particularly included are those compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof; 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM ;Endostatin TM ; anthranilamide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab; VEGF aptamers, such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (Avastin TM ).

[0593] As used herein, photodynamic therapy refers to a therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of, for example, Visudyne TM and porfimer sodium.

[0594] As used herein, angiostatic steroids refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone estrogen and dexamethasone.

[0595] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0596] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormone compounds and 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.

[0597] The compounds of the present invention are also suitable for use as adjunctive therapeutic compounds in combination with other drugs such as anti-inflammatory drugs, bronchodilators or antihistamines, in particular for the treatment of obstructive or inflammatory airway diseases such as those mentioned above, for example as a synergist of the therapeutic activity of such drugs or as a method of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other bulk drugs in the form of a fixed pharmaceutical composition or they may be administered separately before, at the same time or after other bulk drugs. Therefore, the present invention includes a combination of the compounds of the present invention as described above with an anti-inflammatory drug substance, a bronchodilator drug substance, an antihistamine drug substance or an antitussive drug substance, the drug composition of the compound of the present invention and the drug substance being the same or different.

[0598] Suitable anti-inflammatory drugs include steroids, in particular glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; nonsteroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast ( GlaxoSmithKline), Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Arofylline (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 beta-2 adrenergic receptor agonists, such as salbutamol (hydroxyterbutaline), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol and especially formoterol and pharmaceutically acceptable salts thereof. Suitable bronchodilators include anticholinergic or antimuscarinic compounds, in particular ipratropium bromide, oxitropium bromide, tiotropium bromide salts and CHF 4226 (Chiesi) and glycopyrrolate.

[0599] Suitable antihistamine APIs include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, nitrogen ebastine, epinastine, mizolastine, and tefenadine.

[0600] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are those with antagonists of chemokine receptors, for example 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 the 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-ammonium chloride (TAK-770).

[0601] The structures of the active compounds identified by code numbers, generic or trade names can be taken from the official standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0602] Exemplary Immuno-Oncology Agents

[0603] In some embodiments, one or more other therapeutic agents are immuno-oncology agents. As used herein, the term "immuno-oncology agent" refers to an agent that effectively enhances, stimulates and / or upregulates an immune response in a subject. In some embodiments, the administration of an immuno-oncology agent together with a compound of the invention has a synergistic effect in treating cancer.

[0604] Immuno-oncology agents can be, for example, small molecule drugs, antibodies, or biological molecules or small molecules. 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 a humanized or human antibody.

[0605] In some embodiments, the immuno-oncology agent is (i) an agonist of a stimulatory (including co-stimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on T cells, both of which result in expansion of antigen-specific T cell responses.

[0606] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes 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 co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, which 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, T ACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0607] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (eg, IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0608] In some embodiments, the combination of the compounds of the present invention and immuno-oncology agents can stimulate T cell responses. In some embodiments, immuno-oncology agents are: (i) antagonists (e.g., immune checkpoint inhibitors) of proteins 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 that inhibit T cell activation; or (ii) agonists of proteins 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 that stimulate T cell activation.

[0609] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on a NK cell or an agonist of an activating receptor on a NK cell. In some embodiments, the immuno-oncology agent is an antagonist of a KIR, such as lirilumab.

[0610] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including but not limited to a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249, WO13169264, WO14 / 036357).

[0611] In some embodiments, the immuno-oncology agent is selected from agonists that bind positive co-stimulatory receptors; blockers that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells; agents that overcome unique immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion); and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0612] In some embodiments, the tumor immunotherapy agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0613] 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 a programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab) or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of a fusion of the extracellular domain (B7-DC) of PD-L2 and the Fc portion of IgG1, referred to as AMP-224.

[0614] In some embodiments, the tumor immunotherapy agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist 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).

[0615] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218) or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0616] 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).

[0617] 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).

[0618] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacado stat (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).

[0619] 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.

[0620] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0621] 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.

[0622] 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.

[0623] In some embodiments, the immuno-oncology agent is MGA271 (directed against B7H3) (WO 11 / 109400).

[0624] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, belintoumab, BMS-936559, catumaxomab, durvalumab, icadolizumab, epratuzumab, indolimumab, inotuzumab, inteludomab, or mumab), ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0625] In some embodiments, the immuno-oncology agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses, increase the number of tumor tissue structures, including some tumor types that have not been conventionally considered to be sensitive 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 ( Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

[0626] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide ( Celgene; lenalidomide ( Celgene; ingenol mebutate ( LEO Pharma).

[0627] In some embodiments, the tumor immunotherapy agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous and nodular lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from an oncolytic virus therapy, such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase-(TK-) deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Oncolytics Biotech, a respiratory enteric orphan virus variant (reovirus), which does not replicate in cells that are not activated by RAS, in multiple 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); Enfamil (NG-348, PsiOxus, formerly ColoAd1), an engineered , 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); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), vaccinia viruses engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), respectively, in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0628] In some embodiments, the immuno-oncology agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeting hard-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (Vira Therapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express a glycoprotein designed to produce an antigen-specific CD8 + Antigens to which T cells respond.

[0629] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0630] The following CAR has been constructed, which consists of a binding domain that can be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, and an intracellular domain as the functional end of a T cell receptor (TCR), such as a CD3-ζ signaling domain from a TCR that can generate an activation signal in a T lymphocyte. Upon antigen binding, such CARs are connected to endogenous signaling pathways in effector cells and generate activation signals similar to those triggered by the TCR complex.

[0631] For example, in some embodiments, the CAR-T cell is one of the cells described in U.S. Pat. No. 8,906,682 (June et al.; hereby incorporated by reference in its entirety), which discloses a CAR-T cell engineered to include an extracellular domain having an antigen binding domain (e.g., a domain that binds to CD19) fused to an intracellular signaling domain of a T cell antigen receptor complex ζ chain (e.g., CD3ζ). When expressed in T cells, CARs are able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials using CAR-T in various indications are in progress. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0632] In some embodiments, the immunostimulator 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 and the differentiation of innate immune cell subsets expressing IL-17 (e.g., 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).

[0633] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being studied for use in B-cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which are being studied for use in head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0634] 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) Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0635] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0636] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 and a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been 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.

[0637] In some embodiments, the immuno-oncology agent is selected from the immuno-oncology agents described in Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. 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 immuno-oncology agent is a small molecule targeting an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the tumor immunotherapy agent is a small molecule agent selected from the small molecule agents listed in Table 2 of Jerry L. Adams et al.

[0638] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent targeting a pathway as described in Peter L. Toogood.

[0639] In some embodiments, the immuno-oncology agent is selected from Sandra L. Ross et al., "Bispecific T cell engager Antibody constructs can mediate bystander tumor cell killing”, PLoS ONE 12(8): e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager. Antibody Constructs. In some embodiments, the bispecific T cell engager The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager Antibody constructs activate T cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on neighboring cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, which results in induced bystander cell lysis. In some embodiments, the bystander cell is in a solid tumor. In some embodiments, the lysed bystander cell is near Activated T cells. In some embodiments, the adjacent cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the adjacent cells include EGFR negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is a tumor-infiltrating T cell expanded ex vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly connects T cells to tumor-associated surface antigens (TAA).

[0640] Exemplary Immune Checkpoint Inhibitors

[0641] In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0642] As used herein, the term "checkpoint inhibitor" refers to an agent that is useful for preventing cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune destruction is called "T cell exhaustion", which is caused by long-term exposure to antigens that cause upregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune responses.

[0643] PD-1 and co-inhibitory receptors such as cytotoxic T lymphocyte antigen 4 (CTLA-4), B and T lymphocyte attenuator (BTLA; CD272), T cell immunoglobulin and mucin domain-3 (Tim-3), lymphocyte activation gene-3 (Lag-3; CD223) and other receptors are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to indicate whether cell cycle progression and other intracellular signaling processes will continue.

[0644] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1. PD-1 binds to the planned cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby suppressing the tumor's ability to suppress the host's anti-tumor immune response.

[0645] In some embodiments, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In some embodiments, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In some embodiments, the checkpoint inhibitor inhibits a checkpoint protein selected from the following: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In some embodiments, the checkpoint inhibitor interacts with a ligand selected from the following checkpoint proteins: CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In some embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In some embodiments, the interleukin is IL-7 or IL-15. In some embodiments, the interleukin is glycosylated IL-7. In an additional aspect, the vaccine is a dendritic cell (DC) vaccine.

[0646] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors or antibodies, which bind to and block or inhibit immune checkpoint receptor ligands. Illustrative checkpoint molecules that can be targeted for blocking or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 molecule family, and expressed in all NK, γδ and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK 1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD 160, and CGEN-15049. Illustrative immune checkpoint inhibitors include, but are not limited to, tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0647] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of: nivolumab Ipilimumab and pembrolizumab In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb; pembrolizumab (anti-PD-1 antibody, Merck); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb; Durvalumab (anti-PD-L1 antibody, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Genentech).

[0648] In some embodiments, the checkpoint inhibitor is selected from the group consisting of: lanlizumab (MK-3475), nivolumab (BMS-936558), pilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, levolumab, IPH2101, pembrolizumab and tremelimumab.

[0649] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; or PDR001 (Novartis), an inhibitory antibody that binds to PD-1 in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for multiple indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung cancer, and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, hepatocellular carcinoma, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic undifferentiated thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody being studied in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0650] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin containing protein-3 (TIM-3). TIM-3 inhibitors available in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody studied in advanced malignant diseases (NCT02608268).

[0651] In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immunoreceptor with an Ig domain and an ITIM domain or TIGIT (an immunoreceptor on certain T cells and NK cells). TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0652] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is studied in malignant diseases (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein, which is studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833) and metastatic breast cancer (NCT00349934).

[0653] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody in metastatic renal cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZeneca ), an agonist anti-OX40 antibody in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody (Medimmune / AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody in advanced cancer (NCT02737475).

[0654] Checkpoint inhibitors useful in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981); and CTX-471 (Compass Therapeutics), an agonistic anti-CD137 antibody in metastatic or locally advanced malignant disease (NCT03881488).

[0655] Checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include: varimumab (CDX-1127, Celldex Therapeutics), agonistic anti-CD27 antibodies in head and neck squamous cell carcinoma, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

[0656] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include: TRX518 (Leap Therapeutics), an agonist anti-GITR antibody in malignant melanoma and other solid malignancies (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonist anti-GITR antibody in solid tumors and lymphomas (NCT02740270); INCAGN01876 (Incyte / Agenus), an agonist anti-GITR antibody in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonist anti-GITR antibody in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonist hexameric GITR-ligand molecule with a human IgG1 Fc domain in advanced solid tumors (NCT02583165).

[0657] Checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include: MEDI-570 (Medimmune), an agonistic anti-ICOS antibody in lymphoma (NCT02520791); GSK3359609 (Merck), an agonistic anti-ICOS antibody in Phase 1 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in Phase 1 (NCT02904226).

[0658] Checkpoint inhibitors useful in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include: levofloxacin (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, InnatePharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2) in lymphoma (NCT02593045).

[0659] Checkpoint inhibitors useful in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPα). CD47 / SIRPa inhibitors being studied in clinical trials include: ALX-148 (Alexo Therapeutics), an antagonist variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein generated by linking the N-terminal CD47 binding domain of SIRPa to the Fc domain of human IgG1 that acts by binding human CD47 and preventing it from delivering its "do not eat" signal to macrophages in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody in leukemia (NCT02641002); and Hu5F9-G4 (Forty- Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0660] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0661] Checkpoint inhibitors that can be used in the present invention include agonists of stimulator of interferon genes (STING, also known as transmembrane protein 173 or TMEM173). Agonists of STING that are being studied in clinical trials include: MK-1454 (Merck), an agonist synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide in Phase 1 (NCT02675439 and NCT03172936).

[0662] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include: pexidartinib (PLX3397, Plexxikon), a small molecule inhibitor of CSF1R in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710), and melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, gastrointestinal stromal tumor (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY302285 5, Lilly), an anti-CSF-1R antibody in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide, Novartis), an orally active inhibitor of CSF1R in advanced solid tumors (NCT02829723).

[0663] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), anti-NKG2A antibodies in head and neck tumors (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0664] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pirizumab.

[0665] The compounds of the invention may also be used in combination with known treatment methods, such as administration of hormones or radiation. In certain embodiments, provided compounds are useful as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0666] The compounds of the present invention may be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapies may be administered in the form of a fixed combination of the compounds of the present invention and one or more other therapeutic compounds or in an interlaced or independent manner, or in combination with one or more other therapeutic compounds. In addition or in addition, the compounds of the present invention may be combined with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor therapy. As described above, long-term therapy is also possible, as is adjuvant therapy in the case of other treatment strategies. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemoprevention (e.g., for patients at risk).

[0667] Those additional agents may be administered separately from the composition containing the compounds of the invention as part of a multiple dosing regimen. Alternatively, those agents may be part of a single dosage form, mixed with the compounds of the invention into a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (usually within five hours of each other).

[0668] As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Therefore, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0669] The amount of the compound of the invention and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) which can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the compound of the invention can be administered.

[0670] In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only the therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dose of between 0.01-1,000 mg / kg body weight / day.

[0671] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in the form of a composition comprising the therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein will preferably be in the range of about 50% to 100% of the amount normally present in a composition comprising the agent as the only therapeutically active agent.

[0672] The compounds of the present invention or their pharmaceutical compositions may also be incorporated into compositions for coating implantable medical devices, such as prostheses, ar...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace; A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace; L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-; L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O)2N(R 5 )-、-N(R 6 )S(O)2-, -CO2- or -OC(O)-; R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace; R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen; R 3 Each occurrence represents C independently 1-6 Alkyl or halide; R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ); R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom; R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and m, n and q are independently 0, 1 or 2; If R 1 , L 1 , A 1 and L 2 Together we form Then n is 1 or 2, and R 4 Each occurrence independently represents a halide, a hydroxyl, a C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

2. The compound of claim 1, wherein the compound is a compound of formula I.

3. The compound according to claim 1 or 2, wherein A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by m occurrences of R 3 replace.

4. The compound according to claim 1 or 2, wherein A 1 is 1,2,3-triazolylene, imidazolylene, pyrrolylene, pyrazolylene, oxazolylene, thiazolylene or pyridylene, each of which is replaced by m occurrences of R 3 replace.

5. The compound according to claim 1 or 2, wherein A 1 is R that appears m times 3 Substituted 1,2,3-triazolylene.

6. The compound according to claim 1 or 2, wherein A 1 is a 6-membered unsaturated oxo-heterocyclylene group containing 1 nitrogen atom, wherein the oxo-heterocyclylene group is replaced by m occurrences of R 3 replace.

7. The compound according to claim 1 or 2, wherein A 1 for Its m occurrences of R 3 replace.

8. The compound of claim 1 or 2, wherein A 1 is R that appears m times 3 Substituted phenylene.

9. The compound of claim 1 or 2, wherein A 1 is R that appears m times 3 Replaced 10. The compound of any one of claims 1 to 9, wherein m is 1.

11. The compound of any one of claims 1 to 9, wherein m is 0.

12. The compound of any one of claims 1 to 11, wherein L 2 -C(O)N(R 5 )-.

13. A compound as described in any one of claims 1 to 11, wherein L 2 -N(R 6 )C(O)-.

14. The compound of any one of claims 1 to 11, wherein L 2 -N(R 6 )-.

15. The compound of any one of claims 1 to 11, wherein L 2 -N(R 6 )-(C 1-4 Alkylene)-or-(C 1-4 Alkylene)-N(R 6 )-.

16. A compound as described in any one of claims 1 to 12, wherein R 5 C 1-6 alkyl.

17. A compound as described in any one of claims 1 to 12, wherein R 5 It is methyl.

18. A compound as described in any one of claims 1 to 12, wherein R 5 C 3-6 Cycloalkyl.

19. A compound as described in any one of claims 1 to 12, wherein R 5 It is cyclopropyl.

20. The compound of any one of claims 1 to 12, wherein R 5 For hydrogen.

21. A compound as described in any one of claims 1 to 12, wherein R 5 and one occurrence of R 4 Together with their intervening atoms they form a 5-6 membered ring containing 1 nitrogen atom.

22. A compound as described in any one of claims 1-11 or 13-15, wherein R 6 C 1-6 alkyl.

23. A compound as described in any one of claims 1-11 or 13-15, wherein R 6 It is methyl.

24. A compound as described in any one of claims 1-11 or 13-15, wherein R 6 For hydrogen.

25. The compound of claim 1, wherein the compound is a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof:

26. The compound of claim 1, wherein the compound is a compound of formula Ic or Id, or a pharmaceutically acceptable salt thereof:

27. The compound of claim 1, wherein the compound is any one of Formula Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt thereof:

28. A compound as described in any one of claims 1 to 27, wherein R 1 -C(O)N(R 7 )(R 8 ).

29. A compound as described in any one of claims 1 to 28, wherein R 7 and R 8 Independently for C 1-6 alkyl.

30. A compound as described in any one of claims 1-27, wherein R 1 is a 6-11 membered saturated or partially unsaturated, bridged or spiro, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the bicyclic heterocyclic ring is surrounded by q R 9 replace.

31. A compound as described in any one of claims 1 to 27, wherein R 1 For q R 9 Replaced 32. A compound as described in any one of claims 1-27, 30 or 31, wherein q is 0.

33. A compound as described in any one of claims 1 to 32, wherein R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl).

34. A compound as described in any one of claims 1 to 32, wherein R 2 =-(C≡C)-(C 3-5 cycloalkyl).

35. A compound as described in any one of claims 1-32, wherein R 2 It is -(C≡C)-(cyclopropyl).

36. The compound of claim 1, wherein the compound is a compound of formula Ik or Il, or a pharmaceutically acceptable salt thereof:

37. The compound of claim 1, wherein the compound is a compound of formula Im or In, or a pharmaceutically acceptable salt thereof:

38. The compound of claim 1, wherein the compound is any one of Formula Io, Ip, Iq, Ir, Is or It, or a pharmaceutically acceptable salt thereof:

39. A compound as described in any one of claims 1-38, wherein A 2 is R that appears n times 4 Substituted phenylene.

40. A compound as described in any one of claims 1-38, wherein A 2 is R that appears n times 4 Replaced 41. A compound as described in any one of claims 1-38, wherein A 2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 4 replace.

42. A compound as described in any one of claims 1-38, wherein A 2 is R that appears n times 4 Substituted pyridinylene.

43. A compound as described in any one of claims 1-38, wherein A 2 is R that appears n times 4 Substituted 9-10 membered partially saturated carbocyclylene.

44. A compound as described in any one of claims 1-35, wherein A 2 for Each of them is represented by n occurrences of R 4 Replacement, where ** is the same as R 2 connection point.

45. A compound as described in any one of claims 1-44, wherein R 4 Each occurrence represents C independently 1-6 Alkyl or halide.

46. ​​A compound as described in any one of claims 1-44, wherein R 4 Each occurrence independently represents methyl, fluoro, chloro or bromo.

47. A compound as described in any one of claims 1-44, wherein R 4 It is methyl.

48. The compound of any one of claims 1-47, wherein n is 1.

49. A compound as described in any one of claims 1-47, wherein n is 2.

50. A compound as described in any one of claims 1-49, wherein L 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain.

51. A compound as described in any one of claims 1-49, wherein L 1 It is -CH2-.

52. A compound as described in any one of claims 1-49, wherein L 1 It is -CH2-O-.

53. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising a compound according to any one of claims 1-53 and a pharmaceutically acceptable carrier.

55. A method of inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of a compound of any one of claims 1-53 to inhibit GPR84.

56. A method of treating a GPR84-mediated condition, disease or disorder in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-53.

57. The method of claim 56, wherein the condition, disease or disorder is a proliferative disease, 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 disorder, a neurodegenerative disease, an inflammatory disorder, multiple sclerosis or pain.

58. The method of claim 56, wherein the condition, disease or disorder is cancer.

59. The method of claim 58, wherein the cancer is leukemia or hepatocellular carcinoma (HCC).

60. The method of claim 58, wherein the cancer is acute myeloid leukemia (AML).

61. The method of claim 56, wherein the condition, disease or disorder is a proliferative disease associated with one or more activating mutations in GPR84.

62. The method of claim 56, wherein the condition, disease or disorder is a chronic viral infection.

63. The method of claim 56, wherein the condition, disease or disorder is an inflammatory disorder selected from the group consisting of 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.

64. The method of claim 56, wherein the condition, disease or disorder is non-alcoholic steatohepatitis (NASH) or idiopathic pulmonary fibrosis (IPF).

65. The method of claim 56, wherein the condition, disease or disorder is systemic lupus erythematosus (SLE).

66. The method of claim 56, wherein the condition, disease or disorder is neuropathic pain.

67. The method of claim 56, wherein the condition, disease or disorder is Alzheimer's disease.

68. The method of claim 56, wherein the condition, disease or disorder is idiopathic pulmonary fibrosis (IPF).

69. A method of improving the efficacy of vaccination in a patient, comprising administering to the patient in need thereof a compound of any one of claims 1-53 as an adjuvant.

70. A compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 membered unsaturated oxoheterocyclylene group containing 1 nitrogen atom; or a phenylene group; each of which is replaced by m occurrences of R 3 replace; A 2 is phenylene, i.e., a 5-6 membered heteroarylene containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 9-10 membered partially saturated carbocyclylene; each of which is replaced by n occurrences of R 4 replace; L 1 C 1-6 a divalent straight or branched saturated hydrocarbon chain, wherein one methylene unit of the chain is optionally substituted by -O-; L 2 -C(O)N(R 5 )-、-N(R 6 )C(O)-、-N(R 6 )-、-N(R 6 )-(C 1-4 Alkylene)-, -(C 1-4 Alkylene)-N(R 6 )-、-S(O)2N(R 5 )-、-N(R 6 )S(O)2-, -CO2-, -OC(O)-, -C(OC 1-4 alkyl)=N- or -(a 4-5 membered saturated monocyclic heterocyclylene containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(C 1-4 alkyl)-; R 1 -C(O)N(R 7 )(R 8 ), i.e., a 6-11-membered saturated or partially unsaturated, bridged or spiro bicyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein each of the bicyclic heterocycle and the monocyclic heterocycle is surrounded by q R 9 replace; R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl) or hydrogen; R 3 Each occurrence represents C independently 1-6 Alkyl or halide; R 4 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ); R 5 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; or R 5 and one occurrence of R 4 Together with their intervening atoms, they form a 5-6 membered ring containing 1 nitrogen atom; R 6 C 1-6 Alkyl, C 3-6 Cycloalkyl or hydrogen; R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R 9 Each occurrence represents C independently 1-6 Alkyl, halogen, hydroxyl, C 1-6 Alkoxy or C 3-6 cycloalkyl; and m, n and q are independently 0, 1 or 2; If R 1 , L 1 , A 1 and L 2 Together we form Then n is 1 or 2, and R 4 Each occurrence independently represents a halide, a hydroxyl, a C 1-6 Alkoxy, C 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

71. The compound of claim 70, wherein the compound is a compound of formula II.

72. The compound of claim 70 or 71, wherein A 1 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by m occurrences of R 3 replace.

73. The compound of claim 70 or 71, wherein A 1 is 1,2,3-triazolylene, imidazolylene, pyrrolylene, pyrazolylene, oxazolylene, thiazolylene or pyridylene, each of which is replaced by m occurrences of R 3 replace.

74. The compound of claim 70 or 71, wherein A 1 is R that appears m times 3 Substituted 1,2,3-triazolylene.

75. The compound of claim 70 or 71, wherein A 1 is a 6-membered unsaturated oxo-heterocyclylene group containing 1 nitrogen atom, wherein the oxo-heterocyclylene group is replaced by m occurrences of R 3 replace.

76. The compound of claim 70 or 71, wherein A 1 for Its m occurrences of R 3 replace.

77. The compound of claim 1 or 2, wherein A 1 is R that appears m times 3 Substituted phenylene.

78. The compound of claim 70 or 71, wherein A 1 is R that appears m times 3 Replaced 79. The compound of any one of claims 70-78, wherein m is 1.

80. The compound of any one of claims 70-78, wherein m is 0.

81. A compound as described in any one of claims 70-80, wherein L 2 -C(O)N(R 5 )-.

82. A compound as described in any one of claims 70-80, wherein L 2 -N(R 6 )C(O)-.

83. A compound as described in any one of claims 70-80, wherein L 2 -N(R 6 )-.

84. A compound as described in any one of claims 70-80, wherein L 2 -N(R 6 )-(C 1-4 Alkylene)-or-(C 1-4 Alkylene)-N(R 6 )-.

85. A compound as described in any one of claims 70-81, wherein R 5 C 1-6 alkyl.

86. A compound as described in any one of claims 70-81, wherein R 5 It is methyl.

87. A compound as described in any one of claims 70-81, wherein R 5 C 3-6 Cycloalkyl.

88. A compound as described in any one of claims 70-81, wherein R 5 It is cyclopropyl.

89. A compound as described in any one of claims 70-81, wherein R 5 For hydrogen.

90. The compound of any one of claims 70-81, wherein R 5 and one occurrence of R 4 Together with their intervening atoms they form a 5-6 membered ring containing 1 nitrogen atom.

91. A compound as described in any one of claims 70-80 or 81-83, wherein R 6 C 1-6 alkyl.

92. A compound as described in any one of claims 70-80 or 81-83, wherein R 6 It is methyl.

93. A compound as described in any one of claims 70-80 or 81-83, wherein R 6 For hydrogen.

94. The compound of claim 70, wherein the compound is a compound of formula II-a, II-b or II-a-1, or a pharmaceutically acceptable salt thereof:

95. The compound of claim 70, wherein the compound is a compound of formula II-c or II-d, or a pharmaceutically acceptable salt thereof:

96. The compound of claim 70, wherein the compound is any one of Formula II-e, II-f, II-g, II-h, II-i or II-j, or a pharmaceutically acceptable salt thereof:

97. A compound as described in any one of claims 70-96, wherein R 1 -C(O)N(R 7 )(R 8 ).

98. A compound as described in any one of claims 70-97, wherein R 7 and R 8 Independently for C 1-6 alkyl.

99. The compound of any one of claims 70-96, wherein R 1 is a 6-11 membered saturated or partially unsaturated, bridged or spiro, bicyclic heterocyclic ring containing 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the bicyclic heterocyclic ring is surrounded by q R 9 replace.

100. A compound as described in any one of claims 70-96, wherein R 1 For q R 9 Replaced 101. The compound of any one of claims 70-96, 99 or 100, wherein q is 0.

102. A compound as described in any one of claims 70-101, wherein R 2 For-(C 2-4 Alkynylidene)-(C 3-7 cycloalkyl).

103. A compound as described in any one of claims 70-101, wherein R 2 =-(C≡C)-(C 3-5 cycloalkyl).

104. A compound as described in any one of claims 70-101, wherein R 2 It is -(C≡C)-(cyclopropyl).

105. The compound of claim 70, wherein the compound is a compound of formula II-k, II-1 or II-k-1, or a pharmaceutically acceptable salt thereof:

106. The compound of claim 70, wherein the compound is a compound of formula II-m or II-n, or a pharmaceutically acceptable salt thereof:

107. The compound of claim 70, wherein the compound is any one of Formula II-o, II-p, II-q, II-r, II-s or II-t, or a pharmaceutically acceptable salt thereof:

108. A compound as described in any one of claims 70-107, wherein A 2 is R that appears n times 4 Substituted phenylene.

109. The compound of any one of claims 70-107, wherein A 2 is R that appears n times 4 Replaced 110. A compound as described in any one of claims 70-107, wherein A 2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 4 replace.

111. A compound as described in any one of claims 70-107, wherein A 2 is R that appears n times 4 Substituted pyridinylene.

112. A compound as described in any one of claims 70-107, wherein A 2 is R that appears n times 4 Substituted 9-10 membered partially saturated carbocyclylene.

113. A compound as described in any one of claims 70-104, wherein A 2 for Each of them is represented by n occurrences of R 4 Replacement, where ** is the same as R 2 connection point.

114. A compound as described in any one of claims 70-113, wherein R 4 Each occurrence represents C independently 1-6 Alkyl or halide.

115. A compound as described in any one of claims 70-113, wherein R 4 Each occurrence independently represents methyl, fluoro, chloro or bromo.

116. A compound as described in any one of claims 70-113, wherein R 4 It is methyl.

117. The compound of any one of claims 70-116, wherein n is 1.

118. The compound of any one of claims 70-116, wherein n is 2.

119. A compound as described in any one of claims 70-118, wherein L 1 C 1-6 A divalent straight or branched saturated hydrocarbon chain.

120. A compound as described in any one of claims 70-118, wherein L 1 It is -CH2-.

121. A compound as described in any one of claims 70-118, wherein L 1 It is -CH2-O-.

122. A compound of Table 1A, or a pharmaceutically acceptable salt thereof.

123. A pharmaceutical composition comprising a compound according to any one of claims 70-122 and a pharmaceutically acceptable carrier.

124. A method of inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of a compound of any one of claims 70-122 to inhibit GPR84.

125. A method of treating a GPR84-mediated condition, disease or disorder in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 70-122.

126. The method of claim 125, wherein the condition, disease or disorder is a proliferative disease, 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 disorder, a neurodegenerative disease, an inflammatory disorder, multiple sclerosis or pain.

127. The method of claim 125, wherein the condition, disease or disorder is cancer.

128. The method of claim 127, wherein the cancer is leukemia or hepatocellular carcinoma (HCC).

129. The method of claim 127, wherein the cancer is acute myeloid leukemia (AML).

130. The method of claim 125, wherein the condition, disease or disorder is a proliferative disease associated with one or more activating mutations in GPR84.

131. The method of claim 125, wherein the condition, disease or disorder is a chronic viral infection.

132. The method of claim 125, wherein the condition, disease or disorder is an inflammatory disorder selected from the group consisting of 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.

133. The method of claim 125, wherein the condition, disease or disorder is non-alcoholic steatohepatitis (NASH) or idiopathic pulmonary fibrosis (IPF).

134. The method of claim 125, wherein the condition, disease or disorder is systemic lupus erythematosus (SLE).

135. The method of claim 125, wherein the condition, disease or disorder is neuropathic pain.

136. The method of claim 125, wherein the condition, disease or disorder is Alzheimer's disease.

137. The method of claim 125, wherein the condition, disease or disorder is idiopathic pulmonary fibrosis (IPF).

138. A method of improving the efficacy of vaccination in a patient, comprising administering to the patient in need thereof a compound of any one of claims 70-122 as an adjuvant.

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