Substituted pyridone GPR84 antagonists and uses thereof

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same for inhibiting GRR84 and treating GPR84 mediated conditions.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of the U.S. Provisional Patent Application Ser. No. 63 / 394,372, filed on Aug. 2, 2022, the content of which is incorporated herein by reference in its entirety. Technical field

[0003] The present invention relates to compounds and methods suitable for antagonizing G - protein - coupled receptor 84 (GPR84). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions to treat various disorders. Background art

[0004] G - protein - coupled receptor 84 (GPR84), also known as EX33, GPCR4, G - protein - coupled receptor 84, is a medium - chain fatty acid receptor that is mainly expressed in immune cells and up - regulated 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, and also using degenerate primer reverse transcriptase - polymerase chain reaction (RT - PCR) methods aimed at identifying novel chemokine receptors expressed in neutrophils (Yousefi S et al 2001. J Leukoc Biol. 69, 1045 - 1052.).

[0006] GPR84 was an orphan GPCR until medium - chain free fatty acids (FFAs) with a carbon chain length of 9 - 14 were identified as ligands for this receptor (Wang J et al., 2006. J Biol Chem. 281, 34457 - 34464.). It has been 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 has also been 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).

[0007] It has been shown that GPR84 is expressed in immune cells including but not limited to polymorphonuclear leukocytes (PMN), 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 are measured in neutrophils and eosinophils compared to T cells and B cells. GPR84 has been demonstrated to be expressed in tissues that may be involved in the propagation of an inflammatory response, such as the lung, spleen, and bone marrow.

[0008] For example, in a recent review, du Bois reported the current state of treatment for interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF). There are nearly 300 different injurious or inflammatory etiologies for interstitial lung diseases 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. Drug Discov. 9, 129 - 140.), and combination therapies involving anti - inflammatory treatment can be advantageously used.

[0009] After LPS stimulation, GPR84 expression in monocytes / macrophages is highly up - regulated (Wang et al., 2006).

[0010] GPR84 knockout (KO) mice survive and are indistinguishable from wild - type littermate control mice (Venkataraman & Kuo 2005). Proliferation of T cells and B cells in response to various mitogens has been reported to be common in GPR84 - deficient mice (Venkataraman & Kuo 2005). T - helper cell 2 (Th2) - differentiated T cells from GPR84 KO mice secrete higher levels of IL4, IL5, and IL13 (the three major Th2 cytokines) compared to wild - type littermate control mice. In contrast, the production of the Th1 cytokine INFγ in Th1 - differentiated T cells from GPR84 KO mice and wild - type littermates is similar (Venkataraman & Kuo 2005).

[0011] In addition, capric acid, undecanoic acid, and lauric acid dose - dependently increased the secretion of interleukin - 12p40 subunit (IL - 12 p40) by LPS - stimulated RAW264.7 murine macrophage - like cells. The pro - inflammatory cytokine IL - 12 plays a key role in promoting cell - mediated immunity to eliminate pathogens by inducing and maintaining a T - helper cell 1 (Th1) response and inhibiting a T - helper cell 2 (Th2) response. Medium - chain FFA may affect the Th1 / Th2 balance by directly acting on GPR84.

[0012] Berry et al. discovered a whole blood 393-gene transcriptional signature of active tuberculosis (TB) (Berry MPR et al. 2010. Nature 466, 973-977.). GPR84 is part of the whole blood 393-gene transcriptional signature of active TB, indicating a potential role of GPR84 in infectious diseases.

[0013] 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), indicating its role in neuroinflammatory processes. These results suggest that GPR84 is upregulated not only in the central nervous system 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), Parkinson's disease (PD).

[0014] GPR84 expression has also been observed in adipocytes and 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 the expression of GPR84, exacerbating the vicious cycle between obesity and diabetes / obesity. Therefore, inhibiting GPR84 activity may be beneficial for the treatment of endocrine and / or metabolic diseases.

[0015] After nerve injury, GPR84 expression in microglia around neurons is also upregulated. (Gamo et al., 2008. J. Neurosi. 28(46), 11980-11988.). In addition, in GPR84 knockout mice, the hypersensitivity of mouse models of inflammation and neuropathic pain to mechanical stimuli is significantly reduced or completely abolished (Nicol LSC et al., 2015. J. Neurosci. 35, 8959-8969.). Therefore, molecules that block GPR84 activation may have the potential to provide broad-spectrum analgesic effects.

[0016] Compared with hematopoietic stem cells from healthy donors, GPR84 expression is increased in human leukemia stem cells (LSCs) of patients with acute myeloid leukemia (AML). GPR84 simultaneously enhances β-catenin signaling and the oncogenic transcriptional program that is essential 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 the LSC frequency, and impairs the reconstitution of stem cell-derived MLL leukemia, which represents a particularly aggressive and drug-resistant subtype of AML. Targeting the oncogenic GPR84 / β-catenin signaling axis may represent a novel therapeutic strategy for AML and potentially other leukemias.

[0017] In M1 macrophages isolated from atherosclerotic lesions of LDLR− / − mice fed a Western diet, GPR84 expression was increased 49.9-fold (Kadl A et al. 2010. Circ.Res. 107, 737 - 746.). Thus, molecules targeting GPR84 may have potential benefits in the treatment of atherosclerosis.

[0018] In experimental esophagitis, GPR84 is upregulated in esophageal tissue, mainly in epithelial cells, and is significantly reduced in rats treated with omeprazole (a proton pump inhibitor) or STW5, a herbal preparation that improves esophagitis without affecting the pH of the reflux fluid (Abdel-Aziz H et al. 2015. Mol.Med 21, 1011 - 1024.). Western blot and immunohistochemical results in rat tissues and HET-1A cells (a human esophageal squamous cell line) support this finding. GPR84 was also found to be significantly upregulated in esophageal biopsies from patients with grade B reflux esophagitis. Thus, molecules that block GPR84 receptor activity may represent a novel therapeutic modality for the treatment of esophagitis.

[0019] Therefore, for patients suffering from inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function, the identification and development of novel compounds, the processes for preparing these compounds, and their use in the preparation of medicaments would be highly desirable.

[0020] In addition, it remains desirable to identify and develop novel compounds for the preparation of drugs for preventing and / or treating one or more fibrotic diseases, more specifically NASH and / or IPF. SUMMARY OF THE INVENTION

[0021] The present invention provides compounds and methods suitable 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 said compositions to treat various conditions.

[0022] One aspect of the present invention provides a collection of compounds defined by Formula I:

[0023]

[0024] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description. Also provided are pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

[0025] Another aspect of the present invention provides a collection of compounds defined by Formula II:

[0026]

[0027] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description. Also provided are pharmaceutical compositions comprising a compound of Formula II and a pharmaceutically acceptable carrier.

[0028] Another aspect of the present invention provides a collection of compounds defined by Formula III:

[0029]

[0030] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description. Also provided are pharmaceutical compositions comprising a compound of Formula III and a pharmaceutically acceptable carrier.

[0031] Another aspect of the present invention provides a collection of compounds defined by Formula IV:

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description. Also provided are pharmaceutical compositions comprising a compound of Formula IV and a pharmaceutically acceptable carrier.

[0034] Another aspect of the present invention provides a method of treating a GPR84-mediated condition, disease, or disorder in a patient. The method comprises administering to the patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II, or III. In certain embodiments, the compound is a compound of Formula IV. Exemplary GPR84-mediated conditions, diseases, or disorders include fibrotic diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, diseases involving impaired immune cell function, neuroinflammatory conditions, neurodegenerative disorders, inflammatory disorders, multiple sclerosis, or pain.

[0035] Another aspect of the present invention provides a method for inhibiting GPR84. The method comprises contacting GPR84 with an effective amount of a compound described herein to inhibit GPR84.

[0036] The compounds provided by the present invention can also be used for the study of GPR84 in biological and pathological phenomena; the study of the fibrosis process occurring in body tissues; and the in vitro or in vivo comparative evaluation of new GPR84 inhibitors or other regulators of neutrophil and macrophage chemotaxis. Detailed Description

[0037] 1. General description of certain embodiments of the present invention:

[0038] In one aspect, the present invention provides a compound of formula I:

[0039]

[0040] or a pharmaceutically acceptable salt thereof, wherein each of the variables is defined individually and in combination as described below and in the embodiments herein.

[0041] Another aspect of the present invention provides a compound of formula II:

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description.

[0044] Another aspect of the present invention provides a compound of formula III:

[0045]

[0046] or a pharmaceutically acceptable salt thereof, wherein the variables are defined as in the detailed description.

[0047] Another aspect of the present invention provides a compound of formula IV:

[0048]

[0049]

[0050] or a pharmaceutically acceptable salt thereof, wherein each of the variables is defined individually and in combination as described below and in the embodiments herein.

[0051] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein, such as a compound of Formula I, II or III, and a pharmaceutically acceptable carrier, adjuvant or diluent. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound described herein, such as a compound of Formula IV, and a pharmaceutically acceptable carrier, adjuvant or diluent.

[0052] In some embodiments, the present invention provides a method for treating a GPR84-mediated disease, disorder or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I, II or III, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating a GPR84-mediated disease, disorder or condition, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula IV, or a pharmaceutically acceptable salt thereof.

[0053] 2. Compounds and Definitions;

[0054] The compounds of the present invention include those compounds generally described herein and further exemplified by the classes, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions shall apply. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition. Additionally, 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, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0055] 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 bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units), provided that it is not aromatic (also referred to herein as "cycloaliphatic") and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C 3 -C 6 hydrocarbon that has a single point of attachment to the remainder of the molecule. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0056] As used herein, the term "bridged bicyclic" refers to any bicyclic system, i.e., carbocyclic or heterocyclic, that is saturated or partially unsaturated and has at least one bridge bond. As defined by IUPAC, a "bridge bond" is a non-branched or valence bond of multiple atoms or one atom that connects two bridgeheads, where a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (other than 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 set forth below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic group is optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0057]

[0058]

[0059] The term "lower alkyl" means a C 1-4 straight-chain or branched alkyl. Exemplary lower alkyls are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0060] The term "lower haloalkyl" means a C 1-4 straight-chain or branched alkyl that is substituted with one or more halogen atoms.

[0061] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; any quaternized form of any basic nitrogen; or a replaceable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0062] As used herein, the term "unsaturated" means that a moiety has one or more unsaturated units.

[0063] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight-chain or branched hydrocarbon chain" refers to a divalent alkylene, alkenylene, and alkynylene chain that is defined herein as straight-chain or branched.

[0064] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is polymethylene, i.e., -(CH 2 ) n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0065] The term "-(C 0 alkylene)-" refers to a bond. Thus, the term "-(C 0-3 alkylene)-" encompasses a bond (i.e., C 0 ) and a -(C 1-3 alkylene)- group.

[0066] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene that contains at least one double bond and in which one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described below for substituted aliphatic groups.

[0067] The term "halogen group" means F, Cl, Br, or I.

[0068] The term "aryl", when used alone or as part of a larger moiety, such as in "aralkyl", "aralkoxy", 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" may be used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system which may carry one or more substituents and includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracenyl, etc. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings are also included within the scope of the term "aryl", such as indanyl, phthalimido, naphthalimido, phenanthridinyl, or tetrahydronaphthyl, etc. The term "phenylene" refers to a polyvalent phenyl having appropriate open valences to occupy the groups attached thereto. For example, "phenylene" is a divalent phenyl if attached to two groups (e.g., ); "phenylene" is a trivalent phenyl if attached to three groups (e.g., ). The term "arylene" refers to a divalent aryl.

[0069] The terms "heteroaryl" and "heteroar-", when used alone or as part of a larger moiety (such as "heteroalkyl" or "heteroalkoxy"), refer to a group having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having 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 basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, wherein unless otherwise specified, the group or the 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, benzofuryl, dibenzofuryl, indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. Heteroaryl 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 "heteroalkyl" refers to an alkyl substituted by a heteroaryl, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

[0070] The term "heteroarylene" refers to a polyvalent heteroaryl having suitable open valences to accommodate the groups to which it is attached. For example, a "heteroarylene" is a divalent heteroaryl if attached to two groups; a "heteroarylene" is a trivalent heteroaryl if attached to three groups. The term "pyridinylene" refers to a polyvalent pyridine radical having suitable open valences to accommodate the groups to which it is attached. For example, a "pyridinylene" is a divalent pyridyl (e.g., ); a "pyridinylene" is a trivalent pyridyl if attached to three groups (e.g., ).

[0071] 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, which 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 the ring atoms of a heterocycle, the term "nitrogen" includes substituted nitrogen. By way of example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0072] The heterocycle can be attached to its pendant groups at any heteroatom or carbon atom, resulting in a stable structure, and any ring atom can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxolanyl, dioxolyl, diazepanyl, oxazepanyl, thiazepanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclic ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. The heterocyclyl can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently and optionally substituted.

[0073] As used herein, the term "partially unsaturated" refers to a cyclic moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0074] As described herein, the compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from the designated group, the substituents at each position may be the same or different. Combinations of substituents contemplated by the present invention are preferably combinations that form stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its generation, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0075] Suitable monovalent substituents on a substitutable carbon atom 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 may be substituted with R o ; -(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph, which may be substituted with R o ; -CH=CHPh-, which may be substituted with R o ; (CH 2 ) 0-4 O(CH 2 )0-1 -pyridyl, which may be substituted by R o ; -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)R o ; -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; -(CH 2 ) 0-4 C(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)Ro 2 ; -OP(O)R o 2 ; -OP(O)(OR o ) 2 ; -SiR o 3 ; -(C 1-4 linear or branched alkylene)O-N(R o ) 2 ; or -(C 1-4 linear or branched alkylene)C(O)O-N(R o ) 2 , where each R o may be substituted as defined below and is 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 aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, two independently occurring R o together with one or more intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0076] In certain embodiments, suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group are independently halo; -(CH 2 ) 0-4 R o ; -(CH 2 ) 0-4 OR o ; -O(CH 2 ) 0-4 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 may be substituted by R o ; -(CH 2 ) 0-4 O(CH 2 )0-1 Ph, which may be substituted by R o -CH=CHPh-, which may be substituted by R o (CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl, which may be substituted by R o -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)R o ;-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;-(CH 2 ) 0-4 C(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)OSiRo 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(ORo )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 linear or branched alkylene)O-N(R o ) 2 ;or-(C 1-4 linear or branched alkylene)C(O)O-N(R o ) 2 ,where each R o may be substituted as defined below and is 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 3-6 membered saturated,partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen or sulfur,or regardless of the above definition,two independently occurring R o together with one or more of their intervening atoms form a 3-12 membered saturated,partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen,oxygen or sulfur,which may be substituted as defined below.

[0077] R o (or the ring formed by two independently occurring R o together with their intervening atoms)the suitable monovalent substituents on are independently halo,-(CH 2 ) 0-2 R · ,-(haloR · ),-(CH 2 ) 0-2 OH,-(CH 2 ) 0-2 OR · ,-(CH 2 ) 0-2 CH(OR · ) 2 ;-O(haloR · ),-CN,-N 3 ,-(CH 2 ) 0-2C(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 a straight-chain or branched alkylene)C(O)OR · or -SSR · , where each R · is unsubstituted or, in the presence of "halo" in front, is substituted only by one or more halo groups and is independently selected from C 1-4 aliphatic groups, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 - 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents of the saturated carbon atoms of R o include =O and =S.

[0078] Suitable divalent substituents on the saturated carbon atoms of a group that is "optionally substituted" include the following: =O, =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-substituted as defined below 1-6 aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the adjacent replaceable carbon of the "optionally substituted" group include: -O(CR * 2 ) 2-3 O-, where R * each occurrence is independently selected from hydrogen, C-substituted as defined below 1-6 aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0079] R * suitable substituents on the aliphatic group of include halo, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , where each R · is unsubstituted or, in the presence of "halo" in front, is substituted only by one or more halo groups and is 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.

[0080] Suitable substituents on the replaceable nitrogen of the "optionally substituted" group include or where each is independently hydrogen, C-substituted as defined below 1-6 aliphatic group, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, two independently occurring Together with one or more intervening atoms, form a 3- to 12-membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0081] Suitable substituents on the aliphatic group of are independently halo, -R · , -(haloR · ), -OH, -OR · , -O(haloR · ), -CN, -C(O)OH, -C(O)OR · , -NH 2 , -NHR · , -NR · 2 or -NO 2 , where each R · is unsubstituted or, in the case of being preceded by "halo", is substituted only by one or more halo groups and is independently a C 1-4 aliphatic group, -CH 2 Ph, -O(CH 2 ) 0-1 Ph or a 5- to 6-membered saturated, partially unsaturated or aryl ring having 0 to 4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0082] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are within the scope of sound medical judgment, suitable for contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in detail by S.M. Berge et al. in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed by the reaction of an amino group with an inorganic acid (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods well known in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphates, glucuronates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactates, lactobionates, laurates, laurylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectates, persulfates, 3-phenylpropionates, phosphates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, etc.

[0083] 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 such as halide ions, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0084] Unless otherwise stated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the described structures; for example, the R and S configurations at each asymmetric center, the Z and E double bond isomers, and the Z and E conformational isomers. Accordingly, single stereoisomers 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 indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. The invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the invention in which hydrogen is replaced by deuterium or tritium or carbon is replaced by 13 C- or 14 C-enriched carbon are within the scope of the invention. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the invention.

[0085] By methods known to those skilled in the art, such as by chromatography and / or fractional crystallization, diastereomeric mixtures can be separated into their individual diastereomers based on differences in physical chemical aspects. Enantiomeric mixtures can be converted into diastereomeric mixtures by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), the diastereomers separated, and the individual diastereomers converted (e.g., hydrolyzed) into the corresponding pure enantiomers, thereby separating the 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., an amino group) or an acidic functional group (e.g., a carboxylic acid group), diastereomeric salts are formed with a suitable optically active acid or base, and the diastereomers thus formed are resolved by fractional crystallization or chromatography methods known in the art, followed by recovery of the pure enantiomers.

[0086] The individual stereoisomers of the compounds of the invention can, for example, be substantially free of other isomers or can, for example, be in the form of a racemate or admixed with all other or other selected stereoisomers. The chiral centers in the compounds of the invention can have the S or R configuration as defined by the IUPAC 1974 recommendations. Further, if the compounds described herein can exist in the form of atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered to be a part of the invention.

[0087] Chemical names, common names, and chemical structures can be used interchangeably to describe the same structure. If 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 having an unsaturated valence state in the text, schemes, examples, and tables herein are assumed to have a sufficient number of hydrogen atoms to saturate the valence.

[0088] Unless the context dictates otherwise, as used herein, the terms "a" and "an" mean "one or more" and include plural referents.

[0089] The term "alkyl" refers to saturated straight-chain or branched-chain hydrocarbons, such as straight-chain or branched-chain groups having 1-12, 1-10, or 1-6 carbon atoms, which are 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.

[0090] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group derived from a cycloalkane having 3-12, 3-8, 4-8, or 4-6 carbon atoms, which is 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.

[0091] 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.

[0092] 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.

[0093] The terms "alkenyl" and "alkynyl" are well - recognized in the art and refer to unsaturated aliphatic groups of similar length that may substitute the above - defined alkyl groups but contain at least one double bond or triple bond, respectively.

[0094] The term "carbocyclylene" refers to a polyvalent carbocyclic group having appropriate open valences to accommodate the groups attached thereto. For example, "carbocyclylene" is a divalent carbocyclic group if attached to two groups; "carbocyclylene" is a trivalent carbocyclic group if attached to three groups.

[0095] The term "alkoxyl" or "alkoxy" is well - recognized in the art and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert - butoxy, etc. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halogen group. Exemplary haloalkoxy groups include -OCH 2 F, -OCHF 2 、 -OCF 3 、 -OCH 2 CF 3 、 -OCF 2 CF 3 etc. The term "hydroxyalkoxy" refers to an alkoxy group substituted with at least one hydroxyl 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.

[0096] The term "oxo group" is well - recognized in the art and refers to the "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0097] The symbol " " represents a point of attachment.

[0098] When a chemical structure containing a ring is depicted with a substituent having a bond crossing a ring bond, the substituent can be attached at any available position on the ring. For example, the chemical structure encompasses In the case of polycyclic fused rings, when a chemical structure containing polycyclic fused rings is described as containing one or more substituents having a bond spanning multiple rings, the one or more substituents can independently be attached to any of the rings spanned by that bond. For example, the chemical structure encompasses, for example,

[0099] When any substituent or variable occurs more than once in any component or in the compounds of the present invention, its definition at each occurrence is independent of its definition at every other occurrence, unless otherwise specified.

[0100] One or more compounds of the present invention may exist in unsolvated forms as well as solvated forms 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. Such physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated into the lattice of the crystalline solid. "Solvate" encompasses both the solution phase and isolable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. "Hydrate" refers to a solvate in which the solvent molecule is H 2 O.

[0101] As used herein, a "GPR84 antagonist" or "GPR84 inhibitor" is a molecule that reduces, inhibits, or otherwise attenuates one or more of the biological activities of GPR84 (e.g., Gαi signaling, increased immune cell migration, and pro-inflammatory 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 of 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 decreases the activity of GPR84. The compounds disclosed in the present invention bind directly to GPR84 and inhibit its activity.

[0102] A "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 the amount of at least one biological activity of GPR84 by a statistically greater amount 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 50 is the IC of the antagonist for the non-target 50about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or lower. The compounds disclosed in the present invention 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, the GPR84 antagonist specifically inhibits the activity of GPR84. In some of these embodiments, the IC 50 of the GPR84 antagonist against a closely related GPCR (e.g., free fatty acid receptor (FFAR), such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2) or GPR120 (FFAR4)) or other types of GPCRs (e.g., class A GPCRs) is 50 about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or lower.

[0103] The compounds of the present invention can be tethered to a detectable moiety. It should be understood that such compounds can be used as imaging agents. Those of ordinary skill in the art will recognize that the detectable moiety can be attached to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety capable of covalently linking to the detectable moiety. Such moieties are well known to those of ordinary skill in the art and include groups containing, for example, a carboxylate moiety, an amino moiety, a thiol moiety, a hydroxyl moiety, and the like. It should be understood that such moieties can be attached to the provided compound directly or via a tethering group (e.g., a divalent saturated or unsaturated hydrocarbon chain). In some embodiments, such moieties can be attached via click chemistry. In some embodiments, such moieties can be attached via a 1,3-cycloaddition of an azide compound and an alkyne, 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 can be attached via strained alkynes. Methods using strained alkynes to achieve rapid Cu-free click chemistry are known in the art and include those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0104] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected (e.g., primary labels and secondary labels). Primary labels, such as radioisotopes (e.g., tritium, 32 P, 33 P, 35 S, or 14 C), mass tags, and fluorescent labels are signal-generating reporter genes that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0105] As used herein, the term "secondary label" refers to a moiety that requires the presence of a second intermediate to generate a detectable signal (e.g., biotin and various protein antigens). In the case of biotin, the second intermediate can include streptavidin-enzyme conjugates. In the case of antigen labels, the second intermediate can include antibody-enzyme conjugates. Some fluorescent groups act as secondary labels because they transfer energy to another group by non-radiative fluorescence resonance energy transfer (FRET) methods, and the second group generates the detection signal.

[0106] As used herein, the terms "fluorescent label", "fluorescent dye", and "fluorophore" refer to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to: Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), dansyl, Dapoxyl, dialkylaminocoumarin, 4′,5′-dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, eosin, erythrosin, fluorescein, FAM, hydroxycoumarin, 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, RhodolGreen, 2′,4′,5′,7′-tetrabromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0107] As used herein, the term "mass tag" refers to any moiety that can be specifically detected by virtue of its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretically releasable tags such as N-[3-[4′-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceryl]isopiperidinecarboxylic acid, 4′-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]acetophenone, and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Pat. Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides with altered length and base composition, oligopeptides, oligosaccharides, and other synthetic polymers with altered length and monomer composition. A wide variety of organic molecules (neutral and charged (biomolecules or synthetic compounds)) with an appropriate mass range (100 - 2000 daltons) can also be used as mass tags.

[0108] The compounds of the invention can be tethered to an E3 ligase binding moiety. It should be understood that such compounds can be used as degraders (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41(5), 305 - 31; Ottis and Crews, ACS Chem. Biol. 2017, 12(4), 892 - 898.). One of ordinary skill in the art will recognize that the E3 ligase binding moiety can be attached to the provided compounds via suitable substituents as defined above. Such degraders have been found to be useful for targeted degradation of G protein-coupled receptors (Li et al., Acta Pharm. Sin. B. 2020, 10(9), 1669 - 1679.).

[0109] 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.

[0110] The compounds of the invention can be tethered to a lysosome targeting moiety. It should be understood that such compounds can be used as degraders (see, for example, Banik et al., 2020. Nature 584, 291 - 297.). One of ordinary skill in the art will recognize that the lysosome targeting moiety can be attached to the provided compounds via suitable substituents as defined above. Such degraders have been found to be useful for targeted degradation of secreted and membrane proteins (Banik et al., 2020).

[0111] As used herein, the term "lysosome targeting moiety" may be used interchangeably with the term "lysosome binding moiety" and refers to any moiety capable of binding to and / or recruiting a cell surface lysosome targeting receptor (e.g., the cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

[0112] As used herein, the terms "measurable affinity" and "inhibit in a measurable manner" mean a measurable change in GPR84 activity between a sample containing a compound or composition of the invention and a GPR84 GPCR and an equivalent sample containing the GPR84 GPCR in the absence of the compound or composition.

[0113] Throughout the specification, when a composition is described as having, including, or containing a particular component, or when a process and method are described as having, including, or containing a particular step, it is further contemplated that the compositions of the invention exist consisting essentially of or consisting of the recited components, and that the processes and methods according to the invention exist consisting essentially of or consisting of the recited process steps.

[0114] In general, unless otherwise stated, percentages of compositions are by weight.

[0115] 3. Description of Exemplary Embodiments:

[0116] As described above, in certain embodiments, the present invention provides a compound of Formula I:

[0117]

[0118] or a pharmaceutically acceptable salt thereof, wherein:

[0119] R 1 is -O-(C 1-5 alkylene)-Z 1 or Y 1 ;

[0120] R 2 each occurrence independently represents C 1-4 alkyl or Y 2 ;

[0121] R 3 is one of the following:

[0122] (a)-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl;

[0123] (b) C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0124] (c) Y 3 ;

[0125] R 4 each occurrence independently represents hydrogen or methyl;

[0126] R 5 and R 8 each occurrence independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0127] R 6 and R 9 each occurrence independently represents hydrogen or C 1-4 alkyl;

[0128] R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3-7-membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11-membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl and each ring are substituted with p substituents independently selected from a halogen group and C 1-4 alkyl;

[0129] A 1 is phenylene, pyridylene or piperidinylene, each of which is substituted by q occurrences of R 8 ; or A 1 is Y4 ;

[0130] X 1 is O or S;

[0131] Z 1 is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 4 ); 2 wherein the heteroaryl, heterocyclic and phenyl rings are substituted by n occurrences of R 5 ;

[0132] Z 2 is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0133] Z 3 is hydroxy, C 1-4 alkoxy, -N(R 9 ), -C(O)N(R 2 ), or a 4- to 8-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is optionally substituted by -C(O)(C 9 aliphatic group); 2 ; 1-6 ;

[0134] L 1 is C 1-4 alkylene, C 3-4 haloalkylene, C 1-4 hydroxyalkylene, cyclopropylidene or Y 5 ;

[0135] Y 1 is one of the following:

[0136] (a) -O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 ), -O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ;

[0137] (b) -O-(C 1-5 haloalkylene)-N(R 6 ) 2 、-O-(C 1-5(Alkylene)-(C 3-6 (Cycloalkylene)-N(R 6 ) 2 ), or -O-(C 1-5 (Alkylene)-(a 3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ;

[0138] (c)-S-(C 1-5 (Alkylene)-Z 2 , -OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; where each Z 2 is substituted with n occurrences of R 5 ; or

[0139] (d)-O-(C 1-5 (Alkylene)-Z 2 , where Z 2 is substituted with (i) one -N(R 6 )SO 2 -(C 1-4 (Alkyl) or -N(R 6 )SO 2 -(C 1-4 (Haloalkyl) and (ii) n occurrences of R 5 ;

[0140] Y 2 each occurrence independently represents C 1-4 (Haloalkyl), C 1-4 (Alkoxy), or C 3-6 (Cycloalkyl);

[0141] Y 3 is one of the following:

[0142] (a)-(C 2-4 (Alkynylene)-(a cyclopropyl group substituted with 1 or 2 groups independently selected from halogen, C 1-4 (Alkyl), C 1-4 (Haloalkyl), and hydroxy), -C≡CC≡C-(C 1-5 (Aliphatic group)), -C≡C-CN, -(C 3-6 (Cycloalkylene)-(C 3-6 (Cycloalkyl)), -(C 3-6 (Cycloalkylene)-(C 1-4 (Haloalkyl)), -(Arylene)-(C 1-4 (Haloalkyl)), or C 1-4 (Haloalkyl);

[0143] (b) - O - (C 1-8 alkylene) - Z 3 or hydroxy; or

[0144] (c) - N(R 9 ) 2 、 - (a 3 - 7 - membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur) - (C 3-6 cycloalkyl), or - N(R 9 )C(O) - (a 5 - 6 - membered heteroaryl having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0145] Y 4 is - C≡C -, cyclohexylene, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene or phenylene; wherein the phenylene is substituted by 1 cyano, hydroxy or - N(R 6 ) 2 ;

[0146] Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene or - (C 1-4 alkoxy or C 3-6 cycloalkyl substituted C 1-4 alkylene) -; and

[0147] m, n, p and q independently represent 0, 1 or 2;

[0148] wherein Y 1 , Y 2 , Y 3 , Y 4 or Y 5 occurs at least once.

[0149] The definitions of the variables in Formula I above cover multiple chemical groups. This application contemplates the following embodiments, where, for example, i) the definition of a variable is a single chemical group selected from the above chemical groups, ii) the definition of a 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, where the variables are defined by (i) or (ii).

[0150] In certain embodiments, the compound is a compound of Formula I.

[0151] As generally defined above, R 1 is - O - (C 1-5 alkylene) - Z 1 or Y 1 . In some embodiments, R 1 is - O - (C1-5 -alkylene)-Z 1 . In some embodiments, R 1 is Y 1 . In some embodiments, R 1 is -O-(C 1-3 -alkylene)-Z 1 or Y 1 . In some embodiments, R 1 is -O-(C 3-5 -alkylene)-Z 1 or Y 1 . In some embodiments, R 1 is -OCH 2 -Z 1 or Y 1 . In some embodiments, R 1 is -O-(C 1-3 -alkylene)-Z 1 . In some embodiments, R 1 is -O-(C 3-5 -alkylene)-Z 1 . In some embodiments, R 1 is -OCH 2 -Z 1 .

[0152] In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is

[0153] In some embodiments, R 1 is selected from those disclosed in Table 1 below.

[0154] As generally defined above, R 2 independently represents C 1-4 alkyl or Y 2 each time it appears. In some embodiments, R 2 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 2 independently represents Y 2 each time it appears. In some embodiments, R 2 independently represents C 1-2 alkyl or Y 2 each time it appears. In some embodiments, R 2 independently represents C 1-2 alkyl each time it appears. In some embodiments, R 2is methyl. In some embodiments, R 2 is ethyl. In some embodiments, R 2 is propyl. In some embodiments, R 2 is isopropyl. In some embodiments, R 2 is butyl. In some embodiments, R 2 is isobutyl. In some embodiments, R 2 is Y 2 , and Y 2 independently represents, each occurrence, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl. In some embodiments, R 2 is Y 2 , and Y 2 independently represents, each occurrence, C 1-4 haloalkyl or C 1-4 alkoxy. In some embodiments, R 2 is Y 2 , and Y 2 independently represents, each occurrence, C 3-6 cycloalkyl.

[0155] In some embodiments, R 2 is selected from those disclosed in Table 1 below.

[0156] As generally defined above, R 3 is one of the following:

[0157] (a)-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl), or C 1-6 alkyl;

[0158] (b)C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur); or

[0159] (c)Y 3 。

[0160] In some embodiments, R 3 is one of the following:

[0161] (a)-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5- or 6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl; or

[0162] (b)C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0163] In some embodiments, R 3 is one of the following:

[0164] ·-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl) or -(5- or 6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl); or

[0165] ·-O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0166] In some embodiments, R 3 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl. In some embodiments, R 3 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl). In some embodiments, R 3 is -C≡C-(C 3-6 cycloalkyl). In some embodiments, R 3 is -(C 2-4 alkynylene)-(cyclopropyl). In some embodiments, R 3 is -(C 2-4 alkenylene)-(C 3-6 cycloalkyl). In some embodiments, R 3 is -(C 0-4 alkylene)-(C 3-6 cycloalkyl). In some embodiments, R 3 is -(phenylene)-(C 3-6 cycloalkyl). In some embodiments, R 3 is -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl). In some embodiments, R 3 is -C≡C-(C 1-4 alkyl). In some embodiments, R 3 is C 1-6 alkyl.

[0167] In some embodiments, R 3 is -C(H)=C(H)-(cyclopropyl), -(C 0-2 alkylene)-(cyclopropyl), -(phenylene)-(cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl) or -C≡C-(C 1-4 alkyl). In some embodiments, R 3 is In some embodiments, R 3 is -C(H)=C(H)-(cyclopropyl). In some embodiments, R 3 is -(C 0-2 alkylene)-(cyclopropyl). In some embodiments, R3 is -(phenylene)-(cyclopropyl). In some embodiments, R 3 is -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl). In some embodiments, R 3 is -C≡C-(C 1-4 alkyl). In some embodiments, R 3 is C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is C 1-6 alkoxy. In some embodiments, R 3 is C 1-6 haloalkoxy. In some embodiments, R 3 is -O-(C 0-6 alkylene)-phenyl. In some embodiments, R 3 is -O-(C 0-6 alkylene)-(5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is Y 3 . In some embodiments, R 3 is Y 3 , and Y 3 is -(C 2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and hydroxy). In some embodiments, R 3 is Y 3 , and Y 3 is -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, or C 1-4 haloalkyl. In some embodiments, R 3 is Y 3 , and Y 3 is --(C 3-6 subcycloalkyl)-(C 3-6 subcycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), or -(phenylene)-(C 1-4 haloalkyl). In some embodiments, R 3 is Y 3 , and Y3 is -O-(C 1-8 alkylene)-Z 3 or a hydroxyl group.

[0168] In some embodiments, R 3 is selected from those depicted in Table 1.

[0169] As generally defined above, R 4 independently represents hydrogen or methyl each time it appears. In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is methyl. In some embodiments, R 4 is selected from those depicted in Table 1.

[0170] As generally defined above, R 5 and R 8 independently represent a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl each time they appear. In some embodiments, R 5 independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl each time it appears. In some embodiments, R 5 independently represents a halogen group each time it appears. In some embodiments, R 5 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 5 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 5 independently represents C 1-4 alkoxy each time it appears. In some embodiments, R 5 independently represents C 3-6 cycloalkyl each time it appears. In some embodiments, R 5 independently represents methoxy, chlorine, fluorine, methyl, ethyl, isopropyl, cyclopropyl, or trifluoromethyl each time it appears. In some embodiments, R 5 independently represents methoxy, chlorine, fluorine, or trifluoromethyl each time it appears. In some embodiments, R 5 independently represents chlorine, fluorine, or trifluoromethyl each time it appears. In some embodiments, R 5 independently represents methyl, ethyl, isopropyl, or cyclopropyl each time it appears. In some embodiments, R 5 independently represents methyl, ethyl, or isopropyl each time it appears.

[0171] In some embodiments, R 5 is methoxy. In some embodiments, R 5 is chloro. In some embodiments, R 5 is fluoro. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is isopropyl. In some embodiments, R 5 is cyclopropyl. In some embodiments, R 5 is trifluoromethyl.

[0172] In some embodiments, R 5 is independently selected, each time it appears, from those depicted in Table 1.

[0173] As generally defined above, R 6 and R 9 each independently represent hydrogen or C 1-4 alkyl each time they appear. In some embodiments, R 6 is independently hydrogen or C 1-4 alkyl each time it appears. In some embodiments, R 6 is independently C 1-4 alkyl each time it appears. In some embodiments, R 6 is hydrogen. In some embodiments, R 6 is independently methyl or hydrogen each time it appears. In some embodiments, R 6 is methyl. In some embodiments, R 6 is selected from those depicted in Table 1.

[0174] As generally defined above, R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl and each ring are substituted with p substituents independently selected from halo and C 1-4 alkyl.

[0175] In some embodiments, R 7 is C 3-6A cycloalkyl group or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8-11 membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl group and each ring are substituted with p substituents independently selected from halo and C 1-4 alkyl.

[0176] In some embodiments, R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom; wherein the cycloalkyl group and each ring are substituted with p substituents independently selected from halo and C 1-4 alkyl.

[0177] In some embodiments, R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form an 8-11 membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl group and each ring are substituted with p substituents independently selected from halo and C 1-4 alkyl.

[0178] In some embodiments, R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the cycloalkyl group and the heterocycle are substituted with p substituents independently selected from halo and C 1-4 alkyl. In some embodiments, R 7 is C 2-6 alkyl. In some embodiments, R 7 is C 2-4 alkyl. In some embodiments, R 7 is C 1-4Halogenated alkyl. In some embodiments, R 7 is C 1-2 halogenated alkyl. In some embodiments, R 7 is a C 1-4 cycloalkyl substituted with p substituents independently selected from halogen and C 3-6 alkyl. In some embodiments, R 7 is C 3-6 cycloalkyl. In some embodiments, R 7 is cyclopropyl. In some embodiments, R 7 is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein the ring is substituted with p substituents independently selected from halogen and C 1-4 alkyl. In some embodiments, R 7 is a 4- to 6-membered saturated monocyclic heterocycle having 1 nitrogen or oxygen atom; wherein the ring is substituted with p substituents independently selected from halogen and C 1-4 alkyl. In some embodiments, R 7 is a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 7 is a 4- to 6-membered saturated monocyclic heterocycle having 1 nitrogen or oxygen atom.

[0179] In some embodiments, R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3- to 7-membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8- to 11-membered spiro ring containing 2 nitrogen atoms; wherein each ring is substituted with p substituents independently selected from halogen and C 1-4 alkyl.

[0180] In some embodiments, R 7 and R 6 together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom; wherein the ring is substituted with p substituents independently selected from halogen and C 1-4 alkyl. In some embodiments, R 7 and R 6 together with the nitrogen atom to which they are attached form a 5- to 6-membered saturated ring containing 1 nitrogen atom; wherein the ring is substituted with p substituents independently selected from halogen and C 1-4 alkyl. In some embodiments, R 7 and R 6Together with the nitrogen atom to which they are attached, form a 3-7 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom. In some embodiments, R 7 and R 6 Together with the nitrogen atom to which they are attached, form a 5-6 membered saturated ring containing 1 nitrogen atom. In some embodiments, R 7 and R 6 Together with the nitrogen atom to which they are attached, form an 8-11 membered spiro ring containing 2 nitrogen atoms; wherein the ring is substituted with p substituents independently selected from halo and C 1-4 alkyl. In some embodiments, R 7 and R 6 Together with the nitrogen atom to which they are attached, form an 8-11 membered saturated spiro ring containing 2 nitrogen atoms; wherein the ring is substituted with p substituents independently selected from halo and C 1-4 alkyl. In some embodiments, R 7 and R 6 Together with the nitrogen atom to which they are attached, form an 8-11 membered spiro ring containing 2 nitrogen atoms. In some embodiments, R 7 and R 6 Together with the nitrogen atom to which they are attached, form an 8-11 membered saturated spiro ring containing 2 nitrogen atoms.

[0181] In some embodiments, R 7 is selected from those depicted in Table 1.

[0182] As generally defined above, R 5 and R 8 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl. In some embodiments, R 8 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl.

[0183] In some embodiments, R 8 each occurrence independently represents halo. In some embodiments, R 8 each occurrence independently represents C 1-4 alkyl. In some embodiments, R 8 each occurrence independently represents C 1-4 haloalkyl. In some embodiments, R 8 each occurrence independently represents C 1-4Alkoxy. In some embodiments, R 8 independently represents C each time it appears 3-6 Cycloalkyl. In some embodiments, R 8 independently represents methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl each time it appears. In some embodiments, R 8 independently represents methoxy, chloro, fluoro or trifluoromethyl each time it appears. In some embodiments, R 8 independently represents chloro, fluoro or trifluoromethyl each time it appears. In some embodiments, R 8 independently represents methyl, ethyl, isopropyl or cyclopropyl each time it appears. In some embodiments, R 8 independently represents methyl, ethyl or isopropyl each time it appears.

[0184] In some embodiments, R 8 is methoxy. In some embodiments, R 8 is chloro. In some embodiments, R 8 is fluoro. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is isopropyl. In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8 is trifluoromethyl.

[0185] In some embodiments, R 8 independently represents, each time it appears, those depicted in Table 1.

[0186] As generally defined above, R 6 and R 9 each independently represents hydrogen or C each time they appear 1-4 alkyl. In some embodiments, R 9 independently represents hydrogen or C each time it appears 1-4 alkyl. In some embodiments, R 9 independently represents C each time it appears 1-4 alkyl. In some embodiments, R 9 is hydrogen. In some embodiments, R 9 independently represents methyl or hydrogen each time it appears. In some embodiments, R 9 is methyl. In some embodiments, R 9 is selected from those depicted in Table 1.

[0187] As generally defined above, A 1is phenylene, pyridylene or piperidylene, each substituted by q occurrences of R 8 ; or A 1 is Y 4 .

[0188] In some embodiments, A 1 is phenylene, pyridylene or piperidylene, each substituted by q occurrences of R 8 . In some embodiments, A 1 is pyridylene or piperidylene, each substituted by q occurrences of R 8 . In some embodiments, A 1 is Y 4 .

[0189] In some embodiments, A 1 is phenylene substituted by q occurrences of R 8 . In some embodiments, A 1 is pyridylene substituted by q occurrences of R 8 . In some embodiments, A 1 is piperidylene substituted by q occurrences of R 8 . In some embodiments, A 1 is phenylene substituted by 1 occurrence of R 8 . In some embodiments, A 1 is pyridylene substituted by 1 occurrence of R 8 . In some embodiments, A 1 is piperidylene substituted by 1 occurrence of R 8 . In some embodiments, A 1 is phenylene. In some embodiments, A 1 is pyridylene. In some embodiments, A 1 is piperidylene.

[0190] In some embodiments, A 1 is Y 4 , and Y 4 is -C≡C-, cyclohexylene, oxazolyl, pyridazinyl, azetidinyl, pyrrolidinyl or phenylene; wherein the phenylene is substituted by 1 cyano, hydroxyl or -N(R 6 ) 2取代 . In some embodiments, A 1 is Y 4 , and Y 4 is -C≡C-, cyclohexylene, or phenylene; wherein the phenylene is substituted by 1 cyano, hydroxyl or -N(R 6 ) 2is substituted. In some embodiments, A 1 is Y 4 , and Y 4 is oxazolyl, pyridazinyl, azetidinyl or pyrrolidinyl.

[0191] In some embodiments, A 1 is In some embodiments, A 1 is In some embodiments, A 1 is In some embodiments, A 1 is In some embodiments, A 1 is

[0192] In some embodiments, A 1 is selected from those depicted in Table 1.

[0193] As generally defined above, X 1 is O or S. In some embodiments, X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is selected from those depicted in Table 1.

[0194] As generally defined above, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 4 ) 2 ; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 5 .

[0195] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl and heterocycle are substituted with n occurrences of R 5 .

[0196] In some embodiments, Z 1 is phenyl or -C(O)N(R 4 ) 2 ; wherein the benzene ring is substituted with n occurrences of R 5 .

[0197] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or phenyl; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 5 .

[0198] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl is substituted with n occurrences of R 5 . In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heterocycle is substituted with n occurrences of R 5 . In some embodiments, Z 1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocycle is substituted with n occurrences of R 5 . In some embodiments, Z 1 is phenyl; wherein the phenyl is substituted with n occurrences of R 5 . In some embodiments, Z 1 is -C(O)N(R 4 ). 2 . In some embodiments, Z 1 is -C(O)N(CH 3 ). 2 .

[0199] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z 1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z 1 is phenyl.

[0200] In some embodiments, Z 1 is a 6 membered heteroaryl having 1, 2 or 3 nitrogen atoms, wherein the heteroaryl is substituted with n occurrences of R 5 . In some embodiments, Z 1 is a 6 membered heteroaryl having 1, 2 or 3 nitrogen atoms. In some embodiments, Z 1 is pyrimidinyl. In some embodiments, Z1 is pyrimidin-2-yl.

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

[0202] As generally defined above, Z 2 is a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0203] In some embodiments, Z 2 is a 5- or 6-membered heteroaryl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z 2 is a 5- or 6-membered heteroaryl having 2 or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0204] In some embodiments, Z 2 is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z 2 is a 6-membered heteroaryl having 1, 2, or 3 nitrogen atoms. In some embodiments, Z 2 is a 5-membered heteroaryl having 1 heteroatom independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z 2 is pyridyl. In some embodiments, Z 2 is a 5-membered heteroaryl having 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Z 2 is a 6-membered heteroaryl having 2 nitrogen atoms. In some embodiments, Z 2 is pyrimidinyl. In some embodiments, Z 2 is pyrimidin-2-yl.

[0205] In some embodiments, Z 2 is selected from those depicted in Table 1.

[0206] As generally defined above, Z 3 is hydroxy, C 1-4 alkoxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 , or a 4- to 8-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein said ring is optionally substituted with -C(O)(C 1-6 aliphatic group).

[0207] In some embodiments, Z 3 is hydroxy, C 1-4 alkoxy, -N(R 9 ) 2or -C(O)N(R 9 ) 2 . In some embodiments, Z 3 is hydroxy or C 1-4 alkoxy. In some embodiments, Z 3 is -N(R 9 ) 2 or -C(O)N(R 9 ) 2 .

[0208] In some embodiments, Z 3 is C 1-4 alkoxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 or a 4- to 8-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with -C(O)(C 1-6 aliphatic group).

[0209] In some embodiments, Z 3 is -N(R 9 ) 2 , -C(O)N(R 9 ) 2 or a 4- to 8-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with -C(O)(C 1-6 aliphatic group).

[0210] In some embodiments, Z 3 is hydroxy. In some embodiments, Z 3 is C 1-4 alkoxy. In some embodiments, Z 3 is methoxy. In some embodiments, Z 3 is -N(R 9 ) 2 . In some embodiments, Z 3 is -N(CH 3 ) 2 . In some embodiments, Z 3 is -C(O)N(R 9 ) 2 . In some embodiments, Z 3 is a 4- to 8-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the ring is optionally substituted with -C(O)(C 1-6 aliphatic group). In some embodiments, Z 3is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen.

[0211] In some embodiments, Z 3 is selected from those depicted in Table 1.

[0212] As generally defined above, L 1 is C 1-4 alkylene, C 3-4 haloalkylene, C 1-4 hydroxyalkylene, cyclopropylidene or Y 5 .

[0213] In some embodiments, L 1 is C 1-4 alkylene, C 3-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene. In some embodiments, L 1 is C 1-4 alkylene, C 3-4 haloalkylene or C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 3-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene.

[0214] In some embodiments, L 1 is C 1-4 alkylene. In some embodiments, L 1 is C 1-2 alkylene. In some embodiments, L 1 is -C(H)(CH 3 )-. In some embodiments, L 1 is C 3-4 haloalkylene. In some embodiments, L 1 is C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-2 hydroxyalkylene. In some embodiments, L 1 is cyclopropylidene. In some embodiments, L 1 is Y 5 .

[0215] In some embodiments, L 1 is Y 5 , and Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene or is substituted with -(C 1-4 alkoxy or C 3-6Cycloalkyl-substituted C 1-4 -alkylene)-.

[0216] In some embodiments, L 1 is selected from those depicted in Table 1 below.

[0217] As generally defined above, Y 1 is one of the following:

[0218] (a) -O-(C 1-5 -alkylene)-C(O)N(R 6 )(R 7 )、-O-(C 1-5 -alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 -alkylene)-CO 2 R 6 ;

[0219] (b) -O-(C 1-5 -haloalkylene)-N(R 6 ) 2 、-O-(C 1-5 -alkylene)-(C 3-6 -cycloalkyl)-N(R 6 ) 2 , or -O-(C 1-5 -alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ;

[0220] (c) -S-(C 1-5 -alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; where each Z 2 is substituted with n occurrences of R 5 ; or

[0221] (d) -O-(C 1-5 -alkylene)-Z 2 , where Z 2 is substituted with (i) one -N(R 6 )SO 2 -(C 1-4 -alkyl) or -N(R 6 )SO 2 -(C 1-4 -haloalkyl) and (ii) n occurrences of R 5 .

[0222] In some embodiments, Y 1 is one of the following:

[0223] (a) -O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 )、-O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ;

[0224] (b) -O-(C 1-5 haloalkylene)-N(R 6 ) 2 、-O-(C 1-5 alkylene)-(C 3-6 subcycloalkylene)-N(R 6 ) 2 , or -O-(C 1-5 alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ; or

[0225] (c) -S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted with n occurrences of R 5 .

[0226] In some embodiments, Y 1 is one of the following:

[0227] · -O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 )、-O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ;

[0228] · -O-(C 1-5(haloalkylene)-N(R 6 ) 2 、-O-(C 1-5 alkylene)-(C 3-6 subcycloalkylene)-N(R 6 ) 2 ,or -O-(C 1-5 alkylene)-(3 - 7 - membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ; or

[0229] · -O-(C 1-5 alkylene)-Z 2 where Z 2 is substituted by (i) one -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 substituted.

[0230] In some embodiments, Y 1 is one of the following:

[0231] · -O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 )、-O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ;

[0232] · -S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; where each Z 2 is substituted by n occurrences of R 5 substituted; or

[0233] · -O-(C 1-5 alkylene)-Z2, where Z 2 is substituted by (i) one -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6)SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 substituted.

[0234] In some embodiments, Y 1 is one of the following:

[0235] · -O-(C 1-5 haloalkylene)-N(R 6 ) 2 、-O-(C 1-5 alkylene)-(C 3-6 subcycloalkyl)-N(R 6 ) 2 , or -O-(C 1-5 alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ;

[0236] · -S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted by n occurrences of R 5 ; or

[0237] · -O-(C 1-5 alkylene)-Z 2 , wherein Z 2 is substituted by (i) one -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 substituted.

[0238] In some embodiments, Y 1 is one of the following:

[0239] · -S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted by n occurrences of R 5 ; or

[0240] ·-O-(C 1-5 -alkylene)-Z 2 , wherein Z 2 is substituted by (i) a -N(R 6 )SO 2 -(C 1-4 -alkyl) or -N(R 6 )SO 2 -(C 1-4 -haloalkyl) and (ii) n occurrences of R 5 .

[0241] In some embodiments, Y 1 is -O-(C 1-5 -alkylene)-C(O)N(R 6 )(R 7 ), -O-(C 1-5 -alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 -alkylene)-CO 2 R 6 . In some embodiments, Y 1 is -O-(C 1-5 -alkylene)-C(O)N(R 6 )(R 7 ). In some embodiments, Y 1 is -OCH 2 -C(O)N(R 6 )(R 7 ), -OCH 2 -SO 2 N(R 6 ) 2 or -OCH 2 -CO 2 R 6 . In some embodiments, Y 1 is -OCH 2 -C(O)N(R 6 )(R 7 ).

[0242] In some embodiments, Y 1 is -O-(C 1-5 -haloalkylene)-N(R 6 ) 2 , -O-(C 1-5 -alkylene)-(C 3-6 -subcycloalkyl)-N(R 6 ) 2 , or -O-(C 1-5(alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 . In some embodiments, Y 1 is -OCH 2 -N(R 6 ) 2 , -OCH 2 -(C 3-6 subcycloalkyl)-N(R 6 ) 2 , or -OCH 2 -(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 .

[0243] In some embodiments, Y 1 is -S-(C 1-5 alkylene)-Z 2 , -OC(O)-Z 2 , or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted with n occurrences of R 5 .

[0244] In some embodiments, Y 1 is -O-(C 1-5 alkylene)-Z 2 , wherein Z 2 is substituted with (i) one -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 .

[0245] In some embodiments, Y 1 is selected from those depicted in Table 1.

[0246] As generally defined above, Y 2 independently represents, each time it occurs, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl. In some embodiments, Y 2 independently represents, each time it occurs, C 1-3 haloalkyl or C 1-3 alkoxy.

[0247] In some embodiments, Y 2 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, Y 2 is trifluoromethyl. In some embodiments, Y 2 independently represents C 1-4 alkoxy each time it appears. In some embodiments, Y 2 is methoxy. In some embodiments, Y 2 independently represents C 3-6 cycloalkyl each time it appears. In some embodiments, Y 2 is cyclopropyl. In some embodiments, Y 2 is independently selected from those depicted in Table 1 each time it appears.

[0248] As generally defined above, Y 3 is one of the following:

[0249] (a)-(C 2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and hydroxy), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl), or C 1-4 haloalkyl;

[0250] (b)-O-(C 1-8 alkylene)-Z 3 or hydroxy; or

[0251] (c)-N(R 9 ) 2 , -(3-7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C 3-6 cycloalkyl), or -N(R 9 )C(O)-(5-6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0252] In some embodiments, Y 3 is one of the following:

[0253] (a)-(C 2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C1-4 alkyl, C 1-4 cyclopropyl substituted with haloalkyl and hydroxy groups), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl) or C 1-4 haloalkyl; or

[0254] (b) -O-(C 1-8 alkylene)-Z 3 or hydroxy.

[0255] In some embodiments, Y 3 is one of the following:

[0256] · -O-(C 1-8 alkylene)-Z 3 or hydroxy; or

[0257] · -N(R 9 ) 2 , -(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur)-(C 3-6 cycloalkyl), or -N(R 9 )C(O)-(5- to 6-membered heteroaryl having 1 - 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0258] In some embodiments, Y 3 is one of the following:

[0259] · -(C 2-4 alkynylene)-(cyclopropyl substituted with 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl and hydroxy groups), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl) or C 1-4 haloalkyl; or

[0260] · -N(R 9 ) 2, -(a 3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C 3-6 cycloalkyl), or -N(R 9 ))C(O)-(a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0261] In some embodiments, Y 3 is -(C 2-4 alkynylene)-(a cyclopropyl group substituted by 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and hydroxy), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl), or C 1-4 haloalkyl. In some embodiments, Y 3 is -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, or C 1-4 haloalkyl. In some embodiments, Y 3 is -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), or -(phenylene)-(C 1-4 haloalkyl).

[0262] In some embodiments, Y 3 is -(C 2-4 alkynylene)-(a cyclopropyl group substituted by 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, and hydroxy). In some embodiments, Y 3 is -C≡C-C≡C-(C 1-5 aliphatic group). In some embodiments, Y 3 is -C≡C-CN. In some embodiments, Y 3 is In some embodiments, Y 3 is -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl). In some embodiments, Y 3is -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl). In some embodiments, Y 3 is -(phenylene)-(C 1-4 haloalkyl). In some embodiments, Y 3 is C 1-4 haloalkyl.

[0263] In some embodiments, Y 3 is -O-(C 1-8 alkylene)-Z 3 or hydroxy. In some embodiments, Y 3 is -O-(C 1-8 alkylene)-Z 3 . In some embodiments, Y 3 is hydroxy.

[0264] In some embodiments, Y 3 is -N(R 9 ) 2 , -(3-7 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur)-(C 3-6 cycloalkyl), or -N(R 9 )C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Y 3 is -N(R 9 ) 2 . In some embodiments, Y 3 is -(3-7 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl). In some embodiments, Y 3 is -N(R 9 )C(O)-(5-6 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0265] In some embodiments, Y 3 is selected from those depicted in Table 1.

[0266] As generally defined above, Y 4 is -C≡C-, cyclohexylene, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene or phenylene; wherein the phenylene is substituted with 1 cyano, hydroxy or -N(R 6 ) 2 .

[0267] In some embodiments, Y 4is a cyclohexylene, an oxazolyl, a pyridazinyl, an azetidinyl, a pyrrolidinyl or a phenyl; wherein the phenyl is substituted by 1 cyano group, a hydroxyl group or -N(R 6 ) 2 .

[0268] In some embodiments, Y 4 is an oxazolyl, a pyridazinyl, an azetidinyl or a pyrrolidinyl. In some embodiments, Y 4 is -C≡C-, a cyclohexylene, or a phenyl; wherein the phenyl is substituted by 1 cyano group, a hydroxyl group or -N(R 6 ) 2 .

[0269] In some embodiments, Y 4 is -C≡C-. In some embodiments, Y 4 is a cyclohexylene. In some embodiments, Y 4 is In some embodiments, Y 4 is In some embodiments, Y 4 is In some embodiments, Y 4 is an oxazolyl. In some embodiments, Y 4 is a pyridazinyl. In some embodiments, Y 4 is an azetidinyl. In some embodiments, Y 4 is a pyrrolidinyl. In some embodiments, Y 4 is a phenyl substituted by 1 cyano group, a hydroxyl group or -N(R 6 ) 2 .

[0270] In some embodiments, Y 4 is selected from those depicted in Table 1.

[0271] As generally defined above, Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene or -(C 1-4 alkoxy or C 3-6 cycloalkyl substituted C 1-4 alkylene)-. In some embodiments, Y 5 is C 2-4 alkenylene or C 1-2 haloalkylene. In some embodiments, Y 5 is C 1-2haloalkylene or -(C 1-4 alkoxy or C 3-6 cycloalkyl-substituted C 1-4 alkylene)-. In some embodiments, Y 5 is C 2-4 alkenylene or -(C 1-4 alkoxy or C 3-6 cycloalkyl-substituted C 1-4 alkylene)-.

[0272] In some embodiments, Y 5 is C 2-4 alkenylene. In some embodiments, Y 5 is C 1-2 haloalkylene. In some embodiments, Y 5 is -(C 1-4 alkoxy or C 3-6 cycloalkyl-substituted C 1-4 alkylene)-. In some embodiments, Y 5 is selected from those depicted in Table 1.

[0273] As generally defined above, m, n, p, and q independently represent 0, 1, or 2.

[0274] In some embodiments, m, n, p, and q independently represent 1 or 2. In some embodiments, m, n, p, and q independently represent 0 or 1. In some embodiments, m, n, p, and q independently represent 0 or 2.

[0275] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is selected from those depicted in Table 1.

[0276] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is selected from those depicted in Table 1.

[0277] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 0 or 1. In some embodiments, p is 1 or 2. In some embodiments, p is selected from those depicted in Table 1.

[0278] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is selected from those depicted in Table 1.

[0279] As generally defined above, the compound of formula I contains Y 1 , Y 2 , Y 3 , Y 4 or Y 5 at least once. In some embodiments, the compound of formula I comprises Y 2 , Y 3 , Y 4 or Y 5 at least once. In some embodiments, the compound of formula I comprises Y 1 , Y 3 , Y 4 or Y 5 at least once. In some embodiments, the compound of formula I comprises Y 1 , Y 2 , Y 4 or Y 5 at least once. In some embodiments, the compound of formula I comprises Y 1 , Y 2 , Y 3 or Y 5 at least once. In some embodiments, the compound of formula I comprises Y 1 , Y 2 , Y 3 or Y 4 at least once.

[0280] In some embodiments, the compound of formula I comprises Y 1 . In some embodiments, the compound of formula I comprises Y 2 at least once. In some embodiments, the compound of formula I comprises Y 3 . In some embodiments, the compound of formula I comprises Y 4 . In some embodiments, the compound of formula I comprises Y 5 .

[0281] In some embodiments, the present invention provides a compound of formula I-a

[0282]

[0283] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R3 、L 1 and A 1 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula I-a.

[0284] In some embodiments, the present invention provides a compound of formula I-b, I-c or I-d:

[0285]

[0286] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 、A 1 、Y 1 、Y 3 and Y 4 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula I-b, I-c or I-d.

[0287] In some embodiments, the present invention provides a compound of formula I-c-1, I-c-2, I-d-1 or I-d-2:

[0288]

[0289] or a pharmaceutically acceptable salt thereof, wherein R 3 、A 1 、Y 3 and Y 4 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula I-c-1, I-c-2, I-d-1 or I-d-2.

[0290] In some embodiments, the present invention provides a compound of formula I-b-1, I-b-2, I-d-3 or I-d-4:

[0291]

[0292] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 3 、Y 1 and Y 3 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula I-b-1, I-b-2, I-d-3 or I-d-4.

[0293] In some embodiments, the present invention provides a compound of formula I-b-3 or I-c-3:

[0294]

[0295] or a pharmaceutically acceptable salt thereof, wherein R 1 , A 1 , Y 1 and Y 4 each, independently and in combination, are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula I-b-3 or I-c-3.

[0296] The above description describes a plurality of embodiments related to compounds of formula I. This patent application specifically contemplates combinations of all embodiments.

[0297] As described above, in certain embodiments, the present invention provides a compound of formula II:

[0298]

[0299] or a pharmaceutically acceptable salt thereof, wherein:

[0300] R 1 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl);

[0301] R 2 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0302] R 3 is one of the following:

[0303] (a) hydrogen;

[0304] (b) -(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl; or

[0305] (c)C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur);

[0306] R 4 each occurrence independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0307] A 1 is phenylene or 5- or 6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said phenylene and heteroarylene are substituted by n occurrences of R 4 ;

[0308] X 1 is O or S;

[0309] L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene; and

[0310] m and n independently represent 0, 1 or 2.

[0311] The definitions of the variables in Formula II above cover a plurality of 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 variables are defined by (i) or (ii).

[0312] In certain embodiments, the compound is a compound of Formula II.

[0313] As generally defined above, R 1 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl). In some embodiments, R 1 is -C≡C-(C 3-6 cycloalkyl). In some embodiments, R 1 is In some embodiments, R 1 is selected from those depicted in Table 2 below.

[0314] As generally defined above, R 2 independently represents, each time it appears, a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkyl or C 3-6 cycloalkyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkyl or C 1-4 alkoxy.

[0315] In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 haloalkyl. In some embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 independently represents, each time it appears, C 1-4 alkoxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 independently represents, each time it appears, C 3-6 cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is selected from those depicted in Table 2 below.

[0316] As generally defined above, R 3 is one of the following:

[0317] (a) hydrogen;

[0318] (b) -(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl; or

[0319] (c)C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0320] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is one of the following:

[0321] ·-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl; or

[0322] ·C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0 - 6 alkylene)-(5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0323] In some embodiments, R 3 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C3-6 -(cycloalkyl)-, -(phenylene)-(C 3-6 -(cycloalkyl)-, -(5- or 6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 -(cycloalkyl)-, -C≡C-(C 1-4 -alkyl) or C 1-6 -alkyl.

[0324] In some embodiments, R 3 is -(C 2-4 -alkynylene)-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -C≡C-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -(C 2-4 -alkynylene)-(cyclopropyl). In some embodiments, R 3 is -(C 2-4 -alkenylene)-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -(C 0-4 -alkylene)-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -(phenylene)-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -(5- or 6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 -cycloalkyl). In some embodiments, R 3 is -C≡C-(C 1-4 -alkyl). In some embodiments, R 3 is C 1-6 -alkyl.

[0325] In some embodiments, R 3 is -C(H)=C(H)-(cyclopropyl), -(C 0 - 2 -alkylene)-(cyclopropyl), -(phenylene)-(cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl) or -C≡C-(C 1-4 -alkyl). In some embodiments, R 3 is In some embodiments, R 3 is -C(H)=C(H)-(cyclopropyl). In some embodiments, R 3 is -(C 0-2-(alkylene)-(cyclopropyl). In some embodiments, R 3 is -(phenylene)-(cyclopropyl). In some embodiments, R 3 is -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl). In some embodiments, R 3 is -C≡C-(C 1-4 alkyl).

[0326] In some embodiments, R 3 is C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur). In some embodiments, R 3 is C 1-6 alkoxy. In some embodiments, R 3 is C 1-6 haloalkoxy. In some embodiments, R 3 is -O-(C 0-6 alkylene)-phenyl. In some embodiments, R 3 is -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur).

[0327] In some embodiments, R 3 is -C≡C-(C 3-6 cycloalkyl). In some embodiments, R 1 is In some embodiments, R 3 is selected from those depicted in Table 2 below.

[0328] As generally defined above, R 4 independently represents, each occurrence, a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl. In some embodiments, R 4 independently represents, each occurrence, a halogen group. In some embodiments, R 8 independently represents, each occurrence, C 1-4 alkyl. In some embodiments, R 4 independently represents, each occurrence, C 1-4 haloalkyl. In some embodiments, R 4 independently represents, each occurrence, C 1-4Alkoxy. In some embodiments, R 4 independently represents C 3-6 cycloalkyl each time it appears.

[0329] In some embodiments, R 4 independently represents methoxy, chloro, fluoro, methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methoxy, chloro, fluoro or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents chloro, fluoro or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl, isopropyl or cyclopropyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl or isopropyl each time it appears.

[0330] In some embodiments, R 4 is methoxy. In some embodiments, R 4 is chloro. In some embodiments, R 4 is fluoro. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is trifluoromethyl. In some embodiments, R 4 is selected from those depicted in Table 2 below.

[0331] As generally defined above, A 1 is phenylene or a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said phenylene and heteroarylene are substituted by n occurrences of R 4 substituents.

[0332] In some embodiments, A 1 is phenylene substituted by n occurrences of R 4 substituents. In some embodiments, A 1 is phenylene. In some embodiments, A 1 is

[0333] In some embodiments, A 1 is a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, sulfur, wherein said phenylene and heteroarylene are substituted by n occurrences of R 4 substituents. In some embodiments, A 1is a 5-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen, sulfur, wherein said heteroarylene is substituted with n occurrences of R 4 substituted. In some embodiments, A 1 is a 6-membered heteroarylene having 1, 2 or 3 nitrogen atoms, wherein said heteroarylene is substituted with n occurrences of R 4 substituted. In some embodiments, A 1 is pyridinylene or pyrimidinylene, each of which is substituted with q occurrences of R 4 substituted.

[0334] In some embodiments, A 1 is a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 5-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 6-membered heteroarylene having 1, 2 or 3 nitrogen atoms. In some embodiments, A 1 is pyridinylene or pyrimidinylene.

[0335] In some embodiments, A 1 is selected from those depicted in Table 2 below.

[0336] As generally defined above, X 1 is O or S. In some embodiments, X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is selected from those depicted in Table 2 below.

[0337] As generally defined above, L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene. In some embodiments, L 1 is C 1-4 alkylene, C 1-4 haloalkylene or C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene.

[0338] In some embodiments, L 1 is C 1-4 alkylene. In some embodiments, L 1 is C 1-2 alkylene. In some embodiments, L1 is -C(H)(CH 3 )-. In some embodiments, L 1 is C 1-4 haloalkylene. In some embodiments, L 1 is C 1-2 haloalkylene. In some embodiments, L 1 is -C(H)(CF 3 )-. In some embodiments, L 1 is C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-2 hydroxyalkylene. In some embodiments, L 1 is cyclopropylidene. In some embodiments, L 1 is selected from those depicted in Table 2 below.

[0339] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is selected from those depicted in Table 2 below.

[0340] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is selected from those depicted in Table 2 below.

[0341] In some embodiments, the present invention provides a compound of formula II-a

[0342]

[0343] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , L 1 and A 1 each, individually and in combination, are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula II-a.

[0344] In some embodiments, the present invention provides a compound of formula II-b, II-c, or II-d

[0345]

[0346] or a pharmaceutically acceptable salt thereof, wherein R1 , R 3 and A 1 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of formula II-b, II-e or II-d.

[0347] The foregoing description describes a number of embodiments related to compounds of formula II. This patent application specifically contemplates combinations of all embodiments.

[0348] As described above, in certain embodiments, the present invention provides a compound of formula III:

[0349]

[0350] or a pharmaceutically acceptable salt thereof, wherein:

[0351] R 1 is -O-(C 1-5 alkylene)-Z 1 ;

[0352] R 2 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0353] R 3 each occurrence independently represents hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl;

[0354] R 4 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;

[0355] A 1 is a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0356] X 1 is O or S;

[0357] Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl: or -C(O)N(R 3) 2 ; wherein the heteroaryl, heterocyclic group, and phenyl ring are substituted with n occurrences of R 4 ;

[0358] L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene, or cyclopropylidene; and

[0359] m and n independently represent 0, 1, or 2.

[0360] The definitions of the variables in Formula III above cover multiple chemical groups. The present application contemplates the following embodiments, where, 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, where the variables are defined by (i) or (ii).

[0361] In certain embodiments, the compound is a compound of Formula III.

[0362] As generally defined above, R 1 is -O-(C 1-5 alkylene)-Z 1 . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is selected from those depicted in Table 3 below.

[0363] As generally defined above, each occurrence of R 2 independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl. In some embodiments, each occurrence of R 2 independently represents C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl. In some embodiments, each occurrence of R 2 independently represents C 1-4 alkyl, or C 1-4 haloalkyl. In some embodiments, each occurrence of R 2 independently represents C 1-4 alkyl, or C 3-6Cycloalkyl. In some embodiments, R 2 independently represents C 1-4 alkyl or C 1-4 alkoxy each time it appears.

[0364] In some embodiments, R 2 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 2 is methyl. In some embodiments, R 2 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 independently represents C 1-4 alkoxy each time it appears. In some embodiments, R 2 is methoxy. In some embodiments, R 2 independently represents C 3-6 cycloalkyl each time it appears. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is selected from those depicted in Table 3 below.

[0365] As generally defined above, R 3 independently represents hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl each time it appears. In some embodiments, R 3 independently represents C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl each time it appears. In some embodiments, R 3 independently represents C 1-4 alkyl or C 1-4 haloalkyl each time it appears. In some embodiments, R 3 independently represents C 1-4 alkyl or C 3-6 cycloalkyl each time it appears. In some embodiments, R 3 independently represents hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl each time it appears. In some embodiments, R 3 independently represents hydrogen or C 1-4 alkyl each time it appears. In some embodiments, R 3 independently represents hydrogen or methyl each time it appears.

[0366] In some embodiments, R 3is hydrogen. In some embodiments, R 3 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 3 is methyl. In some embodiments, R 3 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 3 independently represents C 3-6 cycloalkyl each time it appears. In some embodiments, R 3 is selected from those depicted in Table 3 below.

[0367] As generally defined above, R 4 independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl each time it appears. In some embodiments, R 4 independently represents a halogen group each time it appears. In some embodiments, R 8 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 4 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 4 independently represents C 1-4 alkoxy each time it appears. In some embodiments, R 4 independently represents C 3-6 cycloalkyl.

[0368] In some embodiments, R 4 independently represents methoxy, chlorine, fluorine, methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methoxy, chlorine, fluorine or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents chlorine, fluorine or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl, isopropyl or cyclopropyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl or isopropyl each time it appears.

[0369] In some embodiments, R 4 is methoxy. In some embodiments, R 4 is chlorine. In some embodiments, R 4 is fluorine. In some embodiments, R 4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is trifluoromethyl. In some embodiments, R 4 is selected from those depicted in Table 3 below.

[0370] As generally defined above, A 1 is a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 5 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 6 membered heteroarylene having 1, 2 or 3 nitrogen atoms. In some embodiments, A 1 is pyridinylene or pyrimidinylene. In some embodiments, A 1 is pyridinylene. In some embodiments, A 1 is pyrimidinylene. In some embodiments, A 1 is selected from those depicted in Table 3 below.

[0371] As generally defined above, X 1 is O or S. In some embodiments, X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is selected from those depicted in Table 3 below.

[0372] As generally defined above, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 3 ) 2 ; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 4 .

[0373] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl and heterocyclic are substituted with n occurrences of R 4 .

[0374] In some embodiments, Z 1 is phenyl or -C(O)N(R 3 ) 2 ; wherein the benzene ring is substituted with n occurrences of R 4 .

[0375] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or phenyl; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 4 .

[0376] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl is substituted with n occurrences of R 4 . In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heterocycle is substituted with n occurrences of R 4 . In some embodiments, Z 1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocycle is substituted with n occurrences of R 4 . In some embodiments, Z 1 is phenyl; wherein the phenyl is substituted with n occurrences of R 4 . In some embodiments, Z 1 is -C(O)N(R 3 ) 2 . In some embodiments, Z 1 is -C(O)N(CH 3 ) 2 .

[0377] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z 1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z 1 is phenyl.

[0378] In some embodiments, Z 1is a 6-membered heteroaryl having 1, 2 or 3 nitrogen atoms, wherein said heteroaryl is substituted with n occurrences of R 4 substituted. In some embodiments, Z 1 is a 6-membered heteroaryl having 1, 2 or 3 nitrogen atoms. In some embodiments, Z 1 is pyrimidinyl. In some embodiments, Z 1 is pyrimidin-2-yl.

[0379] In some embodiments, Z 1 is selected from those depicted in Table 3 below.

[0380] As generally defined above, L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene. In some embodiments, L 1 is C 1-4 alkylene, C 1-4 haloalkylene or C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene.

[0381] In some embodiments, L 1 is C 1-4 alkylene. In some embodiments, L 1 is C 1-2 alkylene. In some embodiments, L 1 is -C(H)(CH 3 )-. In some embodiments, L 1 is C 1-4 haloalkylene. In some embodiments, L 1 is C 1-2 haloalkylene. In some embodiments, L 1 is -C(H)(CF 3 )-. In some embodiments, L 1 is C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-2 hydroxyalkylene. In some embodiments, L 1 is cyclopropylidene. In some embodiments, L 1 is selected from those depicted in Table 3 below.

[0382] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is selected from those depicted in Table 3 below.

[0383] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is selected from those depicted in Table 3 below.

[0384] As described above, in certain embodiments, the present invention provides a compound of Formula III-1:

[0385]

[0386] or a pharmaceutically acceptable salt thereof, wherein:

[0387] R 1 is -O-(C 1-5 alkylene)-Z 1 ;

[0388] R 2 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl;

[0389] R 3 each occurrence independently represents hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl;

[0390] R 4 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 3-6 cycloalkyl;

[0391] A 1 is a 5-6 membered heteroaryl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0392] X 1 is O or S;

[0393] Z 1a 5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 3 ) 2 ; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 4 ;

[0394] L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene; and

[0395] m and n independently represent 0, 1 or 2.

[0396] The definitions of the variables in Formula III above cover a plurality of chemical groups. The present application contemplates the following embodiments, where, 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, where the variables are defined by (i) or (ii).

[0397] In certain embodiments, the compound is a compound of Formula III-1.

[0398] As generally defined above, R 1 is -O-(C 1-5 alkylene)-Z 1 . In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is In some embodiments, R 1 is selected from those depicted in Table 3 below.

[0399] As generally defined above, R 2 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl. In some embodiments, R 2 each occurrence independently represents C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In some embodiments, R 2 each occurrence independently represents C 1-4alkyl or C 1-4 haloalkyl. In some embodiments, R 2 independently represents, each occurrence, C 1-4 alkyl or C 3-6 cycloalkyl. In some embodiments, R 2 independently represents, each occurrence, C 1-4 alkyl or C 1-4 alkoxy.

[0400] In some embodiments, R 2 independently represents, each occurrence, C 1-4 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 independently represents, each occurrence, C 1-4 haloalkyl. In some embodiments, R 2 is trifluoromethyl. In some embodiments, R 2 independently represents, each occurrence, C 1-4 alkoxy. In some embodiments, R 2 is methoxy. In some embodiments, R 2 independently represents, each occurrence, C 3-6 cycloalkyl. In some embodiments, R 2 is cyclopropyl. In some embodiments, R 2 is selected from those depicted in Table 3 below.

[0401] As generally defined above, R 3 independently represents, each occurrence, hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In some embodiments, R 3 independently represents, each occurrence, C 1-4 alkyl, C 1-4 haloalkyl or C 3-6 cycloalkyl. In some embodiments, R 3 independently represents, each occurrence, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, R 3 independently represents, each occurrence, C 1-4 alkyl or C 3-6 cycloalkyl. In some embodiments, R 3 independently represents, each occurrence, hydrogen, C 1-4 alkyl, or C 1-4 haloalkyl. In some embodiments, R 3 independently represents, each occurrence, hydrogen or C 1-4Alkyl. In some embodiments, R 3 independently represents hydrogen or methyl each time it appears.

[0402] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 3 is methyl. In some embodiments, R 3 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 3 independently represents C 3-6 cycloalkyl each time it appears. In some embodiments, R 3 is selected from those depicted in Table 3 below.

[0403] As generally defined above, R 4 independently represents a halogen group, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl each time it appears. In some embodiments, R 4 independently represents a halogen group each time it appears. In some embodiments, R 8 independently represents C 1-4 alkyl each time it appears. In some embodiments, R 4 independently represents C 1-4 haloalkyl each time it appears. In some embodiments, R 4 independently represents C 1-4 alkoxy each time it appears. In some embodiments, R 4 independently represents C 3-6 cycloalkyl.

[0404] In some embodiments, R 4 independently represents methoxy, chlorine, fluorine, methyl, ethyl, isopropyl, cyclopropyl or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methoxy, chlorine, fluorine or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents chlorine, fluorine or trifluoromethyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl, isopropyl or cyclopropyl each time it appears. In some embodiments, R 4 independently represents methyl, ethyl or isopropyl each time it appears.

[0405] In some embodiments, R 4is methoxy. In some embodiments, R 4 is chloro. In some embodiments, R 4 is fluoro. In some embodiments, R 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is isopropyl. In some embodiments, R 4 is cyclopropyl. In some embodiments, R 4 is trifluoromethyl. In some embodiments, R 4 is selected from those depicted in Table 3 below.

[0406] As generally defined above, A 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 5 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, A 1 is a 6 membered heteroaryl having 1, 2 or 3 nitrogen atoms. In some embodiments, A 1 is pyridyl or pyrimidinyl. In some embodiments, A 1 is pyridyl. In some embodiments, A 1 is pyrimidinyl. In some embodiments, A 1 is selected from those depicted in Table 3 below.

[0407] As generally defined above, X 1 is O or S. In some embodiments, X 1 is O. In some embodiments, X 1 is S. In some embodiments, X 1 is selected from those depicted in Table 3 below.

[0408] As generally defined above, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 3 ) 2 ; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 4 .

[0409] In some embodiments, Z 1is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl and heterocycle are substituted with n occurrences of R 4 substituted.

[0410] In some embodiments, Z 1 is phenyl or -C(O)N(R 3 ) 2 ; wherein the benzene ring is substituted with n occurrences of R 4 substituted.

[0411] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or phenyl; wherein the heteroaryl, heterocyclic group and phenyl ring are substituted with n occurrences of R 4 substituted.

[0412] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heteroaryl is substituted with n occurrences of R 4 substituted. In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the heterocycle is substituted with n occurrences of R 4 substituted. In some embodiments, Z 1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen; wherein the heterocycle is substituted with n occurrences of R 4 substituted. In some embodiments, Z 1 is phenyl; wherein the phenyl is substituted with n occurrences of R 4 substituted. In some embodiments, Z 1 is -C(O)N(R 3 ) 2 . In some embodiments, Z 1 is -C(O)N(CH 3 ) 2 .

[0413] In some embodiments, Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z 1 is a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Z1 is a 5-6 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen and oxygen. In some embodiments, Z 1 is phenyl.

[0414] In some embodiments, Z 1 is a 6-membered heteroaryl having 1, 2 or 3 nitrogen atoms, wherein said heteroaryl is substituted with n occurrences of R 4 . In some embodiments, Z 1 is a 6-membered heteroaryl having 1, 2 or 3 nitrogen atoms. In some embodiments, Z 1 is pyrimidinyl. In some embodiments, Z 1 is pyrimidin-2-yl.

[0415] In some embodiments, Z 1 is selected from those depicted in Table 3 below.

[0416] As generally defined above, L 1 is C 1-4 alkylene, C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene. In some embodiments, L 1 is C 1-4 alkylene, C 1-4 haloalkylene or C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene.

[0417] In some embodiments, L 1 is C 1-4 alkylene. In some embodiments, L 1 is C 1-2 alkylene. In some embodiments, L 1 is -C(H)(CH 3 )-. In some embodiments, L 1 is C 1-4 haloalkylene. In some embodiments, L 1 is C 1-2 haloalkylene. In some embodiments, L 1 is -C(H)(CF 3 )-. In some embodiments, L 1 is C 1-4 hydroxyalkylene. In some embodiments, L 1 is C 1-2 hydroxyalkylene. In some embodiments, L 1is a cyclopropylidene. In some embodiments, L 1 is selected from those depicted in Table 3 below.

[0418] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is selected from those depicted in Table 3 below.

[0419] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is selected from those depicted in Table 3 below.

[0420] In some embodiments, the present invention provides a compound of Formula III-a:

[0421]

[0422] or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , L 1 , and A 1 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of Formula III-a.

[0423] In some embodiments, the present invention provides a compound of Formula III-b or III-c:

[0424]

[0425] or a pharmaceutically acceptable salt thereof, wherein R 1 and A 1 each individually and in combination are as defined above and as described in the embodiments herein. In some embodiments, the compound is a compound of Formula III-a or III-c.

[0426] The above description describes a number of embodiments related to the compounds of Formula III. This patent application specifically contemplates all combinations of the embodiments.

[0427] In certain embodiments, the present invention provides a compound of Formula IV:

[0428]

[0429]

[0430] or a pharmaceutically acceptable salt thereof, wherein:

[0431] R 1 is -O-(C 1-5 alkylene)-Z 1 、-(C 1-5 alkylene)-Z 1 or Y 1 ;

[0432] R 2 each occurrence independently represents C 1-4 alkyl or Y 2 ;

[0433] R 3 is one of the following:

[0434] (a)-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl;

[0435] (b)C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur); or

[0436] (c)Y 3 ;

[0437] R 4 each occurrence independently represents hydrogen, methyl or C 3-6 cycloalkyl;

[0438] R 5 and R 8 each occurrence independently represents halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or oxo.

[0439] R6 and R 9 each independently represents hydrogen or C 1-4 alkyl each time it appears;

[0440] R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, -CH 2 C(O)OH, -CH 2 CH 2 -OCH 3 or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3-8 membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1, 2 or 3 additional nitrogen atoms, or (ii) an 8-11 membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl and each ring are substituted by p substituents independently selected from halo, hydroxy, oxo, -C(O)OH, -S(O) 2 CH 3 、-S(O)2N(R 9 ) 2 、-N(R 9 )S(O) 2 CH 3 、-CH 2 -OCH 3 、-C(O)NH 2 、C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl, cyano and C 1-4 alkyl substituents;

[0441] A 1 is phenylene, pyridinylene or piperidinylene, each of which is substituted by q occurrences of R 8 ; or A 1 is Y 4 ;

[0442] X 1 is O or S;

[0443] Z 1 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; -C(O)N(R 4 ) 2 ; -C 1-5Hydroxyalkyl; or -C(O)-(C 1-4 alkyl); wherein the heteroaryl, heterocyclic and phenyl rings are substituted by n occurrences of R 5 ;

[0444] Z 2 is a 5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur;

[0445] Z 3 is hydroxy, C 1-4 alkoxy, -N(R 9 ) 2 , -C(O)N(R 9 ) 2 or a 4-8 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein said ring is optionally substituted by -C(O)(C 1-6 aliphatic group);

[0446] L 1 is C 1-4 alkylene, C 3-4 haloalkylene, C 1-4 hydroxyalkylene, cyclopropylidene or Y 5 ;

[0447] Y 1 is one of the following:

[0448] (a) -O-(C 1 - 5 alkylene)-C(O)N(R 6 )(R 7 ), -O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ;

[0449] (b) -O-(C 1-5 haloalkylene)-N(R 6 ) 2 , -O-(C 1-5 alkylene)-(C 3-6 cycloalkylene)-N(R 6 ) 2 , -O-(C 1-5 alkylene)-C(O)-(C 3-6 cycloalkylene), or -O-(C 1-5 alkylene)-(a 3-7 membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(R6 ) 2 ;

[0450] (c)-S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted by n occurrences of R 5 ; or

[0451] (d)-O-(C 1-5 alkylene)-Z 2 , wherein Z 2 is substituted by (i) one -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 ;

[0452] Y 2 independently represents C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl each time it occurs;

[0453] Y 3 is one of the following:

[0454] (a)-(C 2-4 alkynylene)-(a cyclopropyl group substituted by 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl and hydroxy), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl) or C 1-4 haloalkyl;

[0455] (b)-O-(C 1-8 alkylene)-Z 3 or hydroxy; or

[0456] (c)-N(R 9 ) 2, -(a 3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-(C 3-6 cycloalkyl), or -N(R 9 )(C(O)-(a 5- to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

[0457] Y 4 is -C≡C-, cyclohexylene, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene, or phenylene; wherein the phenylene is substituted with 1 cyano group, hydroxyl group, or -N(R 6 )); 2 substituted;

[0458] Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene, or -(an alkylene substituted with C 1-4 alkoxy or C 3-6 cycloalkyl)-; and 1-4 ); and

[0459] m, n, p, and q independently represent 0, 1, or 2.

[0460] The definitions of the variables in Formula I above cover a plurality of chemical groups. The present application contemplates the following embodiments, wherein, for example, i) the definition of a variable is a single chemical group selected from the above chemical groups, ii) the definition of a 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 variables are defined by (i) or (ii).

[0461] In certain embodiments, the compound is a compound of Formula IV.

[0462] Exemplary compounds of the present invention are set forth in Table 1.

[0463] Table 1.

[0464]

[0465]

[0466]

[0467]

[0468]

[0469]

[0470]

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488] Additional exemplary compounds of the present invention are set forth in Table 2 below.

[0489] Table 2.

[0490]

[0491]

[0492] Additional exemplary compounds of the present invention are set forth in Table 3 below.

[0493] Table 3.

[0494]

[0495] Additional exemplary compounds of the present invention are set forth in Table 4 below.

[0496] Table 4.

[0497]

[0498]

[0499] Additional exemplary compounds of the present invention are set forth in Table 5 below.

[0500] Table 5.

[0501]

[0502]

[0503]

[0504]

[0505]

[0506]

[0507]

[0508]

[0509]

[0510]

[0511]

[0512] In some embodiments, the present invention provides a compound set forth in Table 1, 2, 3, 4, or 5 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, 2, 3, 4, or 5 above. In some embodiments, the present invention provides a compound set forth in Table 1, 2, 3, or 4 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1, 2, 3, or 4 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1, 2, 3, or 4 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. In some embodiments, the present invention provides a compound set forth in Table 4 or 5 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 4 or 5 above.

[0513] In some embodiments, the present invention provides a compound selected from Compounds I-1 to I-214, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from Compounds I-1 to I-214. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound selected from Compounds I-1 to I-214, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0514] In some embodiments, the present invention provides a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0515] In some embodiments, the present invention provides a compound selected from Compounds I-1 to I-214 set forth in Table 1 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from Compounds I-1 to I-214 set forth in Table 1 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound selected from Compounds I-1 to I-214 set forth in Table 1 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0516] In some embodiments, the present invention provides a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound set forth in Table 2 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound set forth in Table 2 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0517] In some embodiments, the present invention provides a compound selected from Compounds I-90 to I-95 and I-144 set forth in Table 2 above, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound selected from Compounds I-90 to I-95 and I-144 set forth in Table 2 above. In some embodiments, the present invention provides a pharmaceutical composition comprising a compound selected from Compounds I-90 to I-95 and I-144 set forth in Table 2 above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0518] In some embodiments, the present invention provides the compounds set forth in Table 3 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds set forth in Table 3 above. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in Table 3 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0519] In some embodiments, the present invention provides compounds selected from Compounds I-96 to I-99 set forth in Table 3 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides compounds selected from Compounds I-96 to I-99 set forth in Table 3 above. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds selected from Compounds I-96 to I-99 set forth in Table 3 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0520] In some embodiments, the present invention provides the compounds set forth in Table 4 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds set forth in Table 4 above. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in Table 4 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0521] In some embodiments, the present invention provides compounds selected from Compounds I-89, I-118, I-119 and I-123 set forth in Table 4 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides compounds selected from Compounds I-89, I-118, I-119 and I-123 set forth in Table 4 above. In some embodiments, the present invention provides a pharmaceutical composition comprising compounds selected from Compounds I-89, I-118, I-119 and I-123 set forth in Table 4 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0522] In some embodiments, the present invention provides the compounds set forth in Table 5 above, or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides the compounds set forth in Table 5 above. In some embodiments, the present invention provides a pharmaceutical composition comprising the compounds set forth in Table 4 above, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or diluent.

[0523] In some embodiments, the present invention provides a compound as described herein, such as a compound of Formula I, II or III as defined above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as described herein, such as a compound of Formula I, II or III as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, which is used as a medicament.

[0524] In some embodiments, the present invention further provides a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, which is used in the method for inhibiting GPR84 as described herein, in the method for modulating the immune response of a subject in need thereof as described herein, and / or in the method for treating a GPR84-dependent disorder as described herein.

[0525] In some embodiments, the present invention further provides a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, which is used in the method for inhibiting GPR84 as described herein.

[0526] In some embodiments, the present invention further provides a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, which is used in the method for modulating the immune response of a subject in need thereof as described herein.

[0527] In some embodiments, the present invention further provides a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, which is used in the method for treating a GPR84-dependent disorder as described herein.

[0528] In some embodiments, the present invention further provides the use of a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, for manufacturing a medicament for inhibiting GPR84, a medicament for modulating the immune response of a subject in need thereof, and / or a medicament for treating a GPR84-dependent disorder.

[0529] In some embodiments, the present invention further provides the use of a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, for manufacturing a medicament for inhibiting GPR84.

[0530] In some embodiments, the present invention further provides the use of a compound as described herein, such as a compound of Formula I, II or III or the pharmaceutical composition as described herein, for manufacturing a medicament for modulating the immune response of a subject in need thereof.

[0531] In some embodiments, the present invention also provides the use of the compounds described herein, such as compounds of Formula I, II or III or the pharmaceutical compositions described herein, for the manufacture of a medicament for treating GPR84-dependent disorders.

[0532] In some embodiments, the present invention also provides the use of the compounds described herein, such as compounds of Formula I, II or III or the pharmaceutical compositions described herein, in the methods for inhibiting GPR84 as described herein, in the methods for modulating the immune response of a subject in need thereof as described herein and / or in the methods for treating GPR84-dependent disorders as described herein.

[0533] In some embodiments, the present invention also provides the use of the compounds described herein, such as compounds of Formula I, II or III or the pharmaceutical compositions described herein, in the methods for inhibiting GPR84 as described herein.

[0534] In some embodiments, the present invention also provides the use of the compounds described herein, such as compounds of Formula I, II or III or the pharmaceutical compositions described herein, in the methods for modulating the immune response of a subject in need thereof as described herein.

[0535] In some embodiments, the present invention also provides the use of the compounds described herein, such as compounds of Formula I, II or III or the pharmaceutical compositions described herein, in the methods for treating GPR84-dependent disorders as described herein.

[0536] 4. General methods for providing the compounds of the present invention

[0537] The compounds of the present invention can be prepared or isolated by the methods described in detail in the examples herein.

[0538] 5. Use, formulation and administration

[0539] Pharmaceutically acceptable compositions

[0540] 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 a 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 a 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.

[0541] As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0542] 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 therewith. 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; alumina; aluminum stearate; lecithin, serum proteins such as human serum albumin; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of partial glycerides of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; dipotassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethylcellulose; polyacrylates; waxes; polyethylene-polypropylene-block polymers; polyethylene glycol and lanolin.

[0543] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of directly or indirectly providing the compound of the present invention or its inhibitory active metabolite or residue.

[0544] As used herein, the term "its inhibitory active metabolite or residue" means its metabolite or residue that is also an inhibitor of GPR84 or its mutant.

[0545] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of the invention. Metabolites include compounds produced by a method comprising contacting a compound of the invention with a mammal for a period of time sufficient to produce its metabolites. If the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, e.g., treating the free base with 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, pyranosyl acids (e.g., glucuronic acid or galacturonic acid), α-hydroxy acids (e.g., citric acid or tartaric acid), amino acids (e.g., aspartic acid or glutamic acid), aromatic acids (e.g., benzoic acid or cinnamic acid), sulfonic acids (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, e.g., 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. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary amines, secondary amines, 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.

[0546] The compounds of the invention can be in the form of “prodrugs,” which include compounds having moieties that are metabolizable in vivo. Generally, prodrugs are metabolized in vivo by esterases or by other mechanisms that activate the drug. Examples of prodrugs and their uses are well known in the art (see, e.g., Berge et al., (1977) “Pharmaceutical Salts,” J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by separately reacting the purified compound in its free acid form or hydroxy group with a suitable esterifying agent. Hydroxy groups can be converted to esters by 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 ester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., with methyl, halo, or methoxy substituents) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxy amides. Also included are prodrugs that are converted to the active form in vivo by other mechanisms. In various aspects, the compounds of the invention are prodrugs of any of the formulas herein.

[0547] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implantable reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraliver, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or an oily suspension. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium.

[0548] For this purpose, any mild fixed oil can be employed, including synthetic mono- or di-glycerides. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersing agent, such as carboxymethyl cellulose or similar dispersing agents commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants (such as Tweens, Spans and other emulsifying agents) or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for the purposes of formulation.

[0549] The pharmaceutically acceptable compositions of the present invention can be administered orally 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 dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0550] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These suppositories can be prepared by mixing the drug with a suitable non-irritating excipient that 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.

[0551] The pharmaceutically acceptable compositions of the present invention may also be administered topically, especially when the treatment target includes areas or organs that are readily accessible by topical administration (including diseases of the eye, skin, or lower intestine). Suitable topical formulations are readily prepared for each of these areas or organs.

[0552] Topical administration to the lower intestine can be achieved in the form of rectal suppository formulations (see above) or in the form of suitable enema formulations. Topical transdermal patches can also be used.

[0553] For topical administration, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment form containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream form containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetostearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0554] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micron-sized suspension or, preferably, as a solution in isotonic, pH-adjusted, sterile physiological saline, with or without a preservative (such as benzylalkonium chloride). Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as an ointment, such as petrolatum.

[0555] 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 pharmaceutical formulation technology and can be prepared as a solution in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0556] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0557] The amount of the compounds of the present invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the provided compositions should be formulated such that an inhibitor can be administered to a patient receiving these compositions at a dose between 0.01 - 100 mg / kg body weight / day.

[0558] 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 particular 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 particular disease being treated. The amount of the compounds of the present invention in the composition will also depend on the particular compound in the composition.

[0559] Use of the Compounds and Pharmaceutically Acceptable Compositions

[0560] The compounds and compositions described herein are generally suitable for inhibiting the signaling activity of one or more GPCRs. In some embodiments, the GPCRs inhibited by the compounds and methods of the present invention are GPR84.

[0561] The compounds disclosed in the present invention can be used to inhibit the activity of GPR84. GPR84 is a G i protein-coupled receptor (GPCR) coupled to G proteins that is expressed on the surface of immune cells. GPR84 regulates the innate immune response in conditions such as fibrotic disorders.

[0562] Multiple studies have shown that GPR84 may be a potential target for treating obesity and / or metabolic dysfunction.

[0563] GPR84 gene expression in cultured human differentiated adipocytes is highly upregulated by the major pro-inflammatory cytokines TNF-α and IL-1β (Muredda et al. 2017. Arch. Physiol. Biochem. 124(2), 97 - 108). These data confirm the activation of pro-inflammatory GPR84 signaling in the context of adipocyte inflammation, first described by Nagasaki in 2012 (Nagasaki et al., 2012, FEBS Letters, 586, 368 - 372).

[0564] IL-33 is a member of the IL-1β superfamily and strongly upregulates GPR84 mRNA expression in human differentiated adipocytes in an autocrine manner, which is associated with enhanced production of pro-inflammatory cytokines and chemokines such as IL-1β, CCL2, IL6, CXCL2, and CSF3 (Zaibi et al., 2018. Cytokine, 110, 189-193). This suggests that activation of GPR84 by pro-inflammatory stimuli in adipocytes leads to further release of pro-inflammatory cytokines and identifies the existence of a putative autocrine positive feedback loop.

[0565] GPR84 expression is upregulated in the livers 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 steatohepatitis and fibrosis. Similar to selonsertib (ASK1 inhibitor), pharmacological inhibition of GPR84 significantly reduces 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 steatohepatitis and fibrosis (Puengel et al., 2020. J. Clin. Med. 9(4), 1140).

[0566] Deletion of GPR84 in mice is associated with reduced NAFLD-induced liver injury. Treatment with PBI-4547 (putative GPR84 antagonist) reduces NAFLD-induced liver and adipose tissue injury and promotes fatty acid oxidation (Simard et al. 2020. Sci. Rep. 10(1), 12778).

[0567] Mice with global deletion of Gpr84 [Gpr84 knockout (KO)] show mild impairment of 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 GPR84 is an important player in blood glucose control (Montgomery MK, et al. 2019. FASEB J. 33(11), 12264-12276).

[0568] Nutrient-sensing receptors located on enteroendocrine (EEC) cells regulate appetite by detecting luminal contents. Peiris et al. evaluated the effects of obesity and gastric bypass-induced weight loss on the expression of nutrient-sensing G protein-coupled receptors (GPCRs) and found increased expression of GPR84 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 the activation of colonic EECs. In response to diet and weight loss induced by RYGB or caloric restriction, profound adaptive changes in the expression of these receptors occur. (Peiris M, et al 2018. Nutrients. 10(10), 1529)

[0569] DuToit et al. investigated the effects of GPR84 deletion on the development of obesity and diabetes in mice fed a long-chain fatty acid (LCFA)- or medium-chain fatty acid (MCFA)-rich diet and found no effect on body weight or glucose tolerance in mice fed a high MCFA or LCFA diet. GPR84 may affect lipid metabolism, as GPR84KO mice had smaller livers and increased myocardial triglyceride accumulation when fed an LCFA diet, while liver triglyceride accumulation increased in response to increased MCFA in the diet. (DuToit et al 2018 Eur. J. Nutr: 57(5), 1737-1746)

[0570] A review by Hara et al. indicated that GPR84 and other free fatty acid receptors (FFARs) mainly involved in energy metabolism are regarded as key therapeutic targets in the pathology of obesity and type 2 diabetes. (Hara et al 2014. Biochim. Biophys. Acta. 1841(9), 1292-300)

[0571] A study by Nagasaki et al. in 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 from infiltrating macrophages and exacerbates the vicious cycle between obesity and gluco-obesity. (Nagasaki H. et al 2012. FEBS Lett. 586(4), 368-72)

[0572] Fibrosis is a process triggered by chronic tissue damage caused by toxic substances, viral infections, 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 the extracellular matrix (ECM).

[0573] Specifically, fibrosis is a key driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), advanced liver disease (such as non-alcoholic steatohepatitis (NASH)), and advanced kidney disease. Despite the increasing understanding of the mechanisms of this disease and the recent increase in the number of clinical trials, indicating the need to find new treatment methods, especially in IPF, these diseases still remain poorly treated (Nanthakumar et al., 2015).

[0574] Non-alcoholic fatty liver disease (NAFLD) is initially characterized by pure steatosis and gradually progresses to non-alcoholic steatohepatitis (NASH), which is mainly caused by excessive energy intake and lack of physical activity, in addition to genetic defects, 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 left untreated, NASH can lead to fatal liver failure.

[0575] The mechanisms promoting the progression of NAFLD to NASH and advanced liver disease are complex and may be triggered by acute inflammatory injury and oxidative stress. (Day and James 1998, Hepatology 27, 1463-1466).

[0576] 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 the degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) method has also been used (Yousefi et al., 2001). It has been an orphan GPCR until medium-chain free fatty acids (FFAs) with a carbon chain length of 9-14 were identified as ligands for this receptor (Wang J et al., 2006).

[0577] GPR84 is activated by medium-chain FFAs, such as capric acid (C10:0), undecanoic acid (C11:0), and lauric acid (12:0), which can amplify the production of lipopolysaccharide-stimulated pro-inflammatory 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).

[0578] In contrast, GPR84 ligand-mediated neutrophil and monocyte / macrophage chemotaxis is inhibited by GPR84 antagonists (Suzuki M et al. 2013. J. Biol. Chem. 288, 10684-10691.).

[0579] Although in patients with chronic liver disease, the recruitment of monocytes / macrophages to the liver appears to occur concomitantly with fibrosis (Marra et al. 1998. Am. J. Pathol. 152, 423-430; Zimmermann et al. 2010. PLOS ONE 5, e11049), this has not led to new treatment approaches.

[0580] There are currently no approved drugs for the treatment of NASH, so liver transplantation remains the last option for advanced disease states. For example, in the case of IPF, although with adverse side effects, only two drugs are approved (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 an obvious need for improved treatment methods (Raghu, 2015, Am J Respir Crit Care Med 191(3)252-4).

[0581] The potent and selective GPR84 inhibitor GLPG1205 at once-daily doses of 3 and 10 mg / kg reduces the disease activity index score and neutrophil infiltration in a murine dextran sodium sulfate-induced model of chronic inflammatory bowel disease, with efficacy similar to that of the positive control compound sulfasalazine. (Labéguère F, et al. 2020. J Med Chem. 63(22), 13526-13545)

[0582] The study by Nguyen et al. showed that PBI-4050, a GPR84 antagonist / GPR40 agonist, reduces pulmonary arterial hypertension, pulmonary fibrosis, and right ventricular dysfunction in heart failure. This suggests that GPR84 antagonists are a novel and promising therapy for pulmonary remodeling in type II pulmonary hypertension (Nguyen et al. 2020. Cardiovasc Res. 116(1), 171-182).

[0583] Studies by Gagnon et al. have shown that GPR40 and GPR84 may represent promising molecular targets in the fibrotic pathway. Administration of PBI-4050, a GPR84 antagonist and GPR40 agonist, significantly reduces fibrosis in multiple injury settings, as demonstrated by the anti-fibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models (Gagnon et al., 2018. Am J Pathol. 188(5)).

[0584] The study also links GPR84 to acute lung injury and / or inflammation.

[0585] 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).

[0586] Under inflammatory stimuli such as endotoxemia, hyperglycemia, and hypercholesterolemia, GPR84 expression is enhanced in several mouse tissues. These stimuli also increase GPR84 expression in macrophages, and the selective GPR84 receptor agonist (6 - OAU) triggers enhanced secretion of pro - inflammatory 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.

[0587] DL - 175, a potent and structurally novel selective 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)

[0588] GPR84 is one of the few pro - inflammatory neutrophil - related genes highly enriched in the RNA sequencing dataset analysis of BALF cells from COVID - 19 patients (Didangelos, A. 2020. mSphere. 5(3), e00367 - 20).

[0589] In an acute lung inflammation model, LPS induces alveolar macrophages to change from CD11 lo to a more inflammatory CD11 hi state, exacerbating 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 the state transition of alveolar macrophages. GPR84 may represent a potential therapeutic target for acute respiratory distress syndrome.

[0590] et al. prepared the first GPR84 agonist radioligand (tritiated) for studying the binding affinity of receptor - ligand. They pointed out that GPR84 was 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 is related to obesity and diabetes. Preliminary evidence suggests that GPR84 may be involved in leukemia formation, osteoclastogenesis, and organ fibrosis (a pathological outcome of many inflammatory and metabolic diseases). ( M, et al. 2020. J. Med. Chem. 63(5), 2391 - 2410).

[0591] The global analysis of glycoproteins by Müller et al. identified markers of endotoxin - tolerant monocytes and GPR84 as a regulator of TNFα expression. (Müller MM, et al. 2017 Sci Rep. 7(1), 838).

[0592] The study 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).

[0593] In addition, GPR84 is related to neuropathic pain and / or neuropathy.

[0594] Gao et al. demonstrated that DOK3 is involved in microglial activation in neuropathic pain by interacting with GPR84, revealing the physical association of DOK3 and GPR84 in inducing inflammatory responses. They hypothesized that targeting the adaptor protein DOK3 may open up new avenues for drug approaches to relieve spinal neuropathic pain (Gao WS et al. 2020. Aging (Albany NY). 12.).

[0595] Kozela et al. investigated 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).

[0596] Wei et al. showed that the G protein-coupled receptor 84 (GPR84) agonist altered cell morphology and motility but did not induce a pro-inflammatory response in microglia. This study suggested 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. JNeuroinflammation. 14(1), 198).

[0597] 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, and in its absence, these cells are impaired in their response to inflammatory injury (Nicol LS et al., 2015. J Neurosci. 35(23), 8959-69).

[0598] Mededdu et al. found that Gpr84 was induced in both microglia and astrocytes and was upregulated in the central nervous system (CNS) after viral infection, suggesting that Gpr84 expression might be a useful measure of glial cell activation when the CNS is damaged or impaired (Madeddu S, et al. 2015. PLoS One. 10(7), e0127336).

[0599] Bouchard et al. found that mice with endotoxemia strongly and persistently expressed GPR84 in microglia, making GPR84 a sensitive marker of microglial activation and potentially playing an important regulatory role in neuroimmune processes, acting downstream of pro-inflammatory mediators (Bouchard C et al. 2007. Glia. 55(8), 790-800).

[0600] GPR84 is also associated with inflammatory bowel disease and is a potential disease target.

[0601] Planell et al. identified GPR84 as a transcriptional blood biomarker that can be used as a non-invasive surrogate marker for mucosal healing and endoscopic response in ulcerative colitis. At 14 weeks of treatment, the response to anti-TNF treatment induced changes in the transcripts of blood HP, CD177, GPR84, and S100A12, which were associated with changes in endoscopic activity (Planell N et al., 2017. J Crohns Colitis. 11(11), 1335-1346).

[0602] Abdel-Aziz et al. found that GPR84 and TREM-1 signaling contribute to the pathogenesis 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).

[0603] Dietrich et al. demonstrated that GPR84 can maintain stem cell-derived mixed lineage leukemia (MLL) leukemogenesis by maintaining abnormal β-catenin signaling in leukemia stem cells (LSCs), which is a previously unrecognized role of GPR84 in maintaining fully developed acute myeloid leukemia (AML) by maintaining abnormal β-catenin signaling in LSCs, and suggested that targeting the oncogenic GPR84 / β-catenin signaling axis may represent a novel therapeutic strategy for AML (Dietrich PA et al. 2014. Blood. 124(22), 3284-94).

[0604] 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 set of differentially expressed genes (DEGs) that can serve as a candidate biomarker for HCC prognosis (Deng Z, et al. 2019. Biomed Res Int. 2019, 2408348).

[0605] Wang et al. revealed changes in energy metabolism-related genes such as GPR84 in osteocytes under the action of large-gradient high magnetic fields through gene chip expression profiling. The identification of special environment-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).

[0606] Studies by Park et al. have shown that GPR84 regulates osteoclastogenesis by inhibiting the NF-κB and MAPK signaling pathways, revealing that GPR84 functions as a negative regulator of osteoclastogenesis and suggesting that it may be a potential therapeutic target for osteoclast-mediated bone destructive diseases (Park JW, et al. 2018. J Cell Physiol. 233(2), 1481-1489).

[0607] Through genome-wide transcription and DNA methylation analysis of peripheral blood mononuclear cells, Zhu et al. discovered abnormal gene regulatory pathways in systemic lupus erythematosus. Compared with patients with systemic lupus erythematosus (SLE) lupus nephritis (LN), the gene expression of MX1, GPR84, and E2F2 was increased in patients with SLE LN (Zhu H, et al. 2016. Arthritis Res Ther. 18, 162).

[0608] In one embodiment, the subject matter disclosed herein relates to a method of inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of a compound or pharmaceutical composition of the invention described herein.

[0609] In certain embodiments, the subject matter disclosed herein relates to a method for modulating the immune response of a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound or pharmaceutical composition of the invention described herein.

[0610] The compounds disclosed in the present invention directly bind to GPR84 and inhibit its signaling activity. In some embodiments, the compounds disclosed in the present invention reduce, inhibit, or otherwise attenuate the GPR84-mediated inflammatory response.

[0611] The compounds disclosed in the present invention 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, the compounds disclosed in the present invention specifically inhibit the signaling activity of GPR84. In some of these embodiments, the IC 50 of the GPR84 antagonist for another GPCR activated by free fatty acids (FFAs) or other GPCR types (e.g., class A GPCRs) 50 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the IC

[0612] The compounds disclosed by the present invention can be used in methods for inhibiting GPR84. Such methods include contacting GPR84 with an effective amount of the compounds disclosed by the present invention. "Contacting" is intended to bring the compound close enough to the isolated GPR84 GPCR or cells expressing GPR84 (e.g., T cells or B cells) such 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.

[0613] 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 measuring the downstream biological effects of GPR84 signaling activity.

[0614] The compounds disclosed by the present invention 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 causation or maintenance of the pathological disorder. In some embodiments, the GPR84-dependent disorder is an inflammatory disorder.

[0615] The compounds disclosed by the present invention can also be used to modulate the immune response of a subject in need thereof. Such methods include administering an effective amount of the compounds of the present invention.

[0616] As used herein, "modulating the immune response" refers to the modulation of any immunogenic response to an antigen.

[0617] In another aspect of the present invention, the present invention provides novel compounds of the present invention for use in therapy.

[0618] In another aspect of the present invention, the present invention provides a method for treating a mammal, including a human, at risk of or suffering from a disorder listed herein, particularly a disorder that may be related to abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as 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, leukemia, and / or a disease involving impaired immune cell function, the method including administering a therapeutically effective amount of one or more of the compounds of the present invention described herein, or a pharmaceutical composition.

[0619] On the other hand, the present invention provides the compounds of the present invention for treating or preventing a disorder selected from the disorders listed herein, particularly disorders that may be associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution expression, such as inflammatory diseases, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0620] In a further aspect, the present invention provides methods for synthesizing the compounds of the present invention using the representative synthetic schemes and routes disclosed herein.

[0621] Thus, a primary object of the present invention is to provide the compounds of the present invention that can alter the activity of GPR84 and thus prevent or treat any disorder that may be causally related thereto.

[0622] Another object of the present invention is to provide the compounds of the present invention that can treat or alleviate a condition or disease or its symptoms that may be causally related to the activity and / or expression and / or distribution of GPR84, such as inflammatory disorders, 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.

[0623] 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 disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function.

[0624] Other objects and advantages will be apparent to those skilled in the art upon consideration of the following detailed description.

[0625] The present disclosure provides methods for modulating (e.g., inhibiting) GPR84 activity, the methods comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0626] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0627] In the methods described herein, a compound of the present invention or a pharmaceutical composition thereof is administered to a subject having cancer.

[0628] In certain embodiments, the subject matter disclosed herein relates to a method for treating GPR84-dependent disorders, the method comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the invention described herein. In certain aspects of this embodiment, the GPR84-dependent disorder is cancer.

[0629] In some embodiments, the subject matter disclosed herein relates to a method for treating chronic viral infections. In some embodiments, the subject matter disclosed herein relates to using a GPR84 inhibitor as an adjuvant therapy to increase the efficacy of vaccination.

[0630] In some embodiments, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0631] In certain aspects, the invention provides a method for treating cell proliferative disorders, including cancer.

[0632] In one aspect, the invention provides a method for treating a cell proliferative disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0633] In certain embodiments, the cell proliferative disorder is cancer.

[0634] Examples of cancers that can be treated with the compounds of the present disclosure include, but are not limited to, chronic or acute leukemia, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, pediatric solid tumors, lymphocytic lymphoma, and combinations of said cancers.

[0635] In some embodiments, cancers that can be treated with the compounds of the present disclosure include, but are not limited to, blood cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of said cancers.

[0636] 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.

[0637] In certain embodiments, the cancer is selected from leukemia and blood cancers. In a specific embodiment, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In a specific embodiment, the cancer is AIDS-related.

[0638] In specific embodiments, the cancer is selected from leukemia and blood cancers. In specific embodiments, the cancer is selected from the group consisting of: myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasm (MPN), post-MPN AML, post-MDS AML, del(5q)-associated high-risk MDS or AML, blast-phase 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 can be acute or chronic.

[0639] In some embodiments, the diseases and indications treatable with the compounds of the present disclosure include, but are not limited to, hematological cancers.

[0640] Exemplary hematological cancers include lymphomas and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin lymphoma, myeloproliferative diseases (such as 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, hairy cell lymphoma, chronic myelomonocytic lymphoma, and Burkitt's lymphoma.

[0641] As used herein, the term 'inflammatory disorder' refers to a group of disorders including: inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (e.g., idiopathic pulmonary fibrosis (IPF))), psoriasis, gout, allergic airway diseases (e.g., asthma, rhinitis), and endotoxin-driven disease states (e.g., complications after bypass surgery or chronic endotoxin states causing, e.g., chronic heart failure). Specifically, the term refers to rheumatoid arthritis, allergic airway diseases (e.g., asthma), and inflammatory bowel disease. In another specific aspect, the term refers to uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncology treatments aimed at activating the immune response.

[0642] As used herein, the term 'pain' refers to a disease or condition characterized by a sensation of discomfort, which sensation is typically caused by intense or damaging stimuli 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 or dysfunction of the nervous system) and / or pain associated with or caused by the disorders mentioned herein. Pain can be acute or chronic.

[0643] As used herein, the term 'neuritic condition' refers to a disease or condition characterized by a sudden neurological deficit associated with inflammation, demyelination, and axonal injury, including but not limited to conditions such as Guillain - Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0644] As used herein, the term "neurodegenerative disease" refers to a disease or disorder characterized by a progressive 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, age-related mild cognitive impairment, age-related memory impairment, and / or peripheral neuropathy, etc. 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).

[0645] As used herein, the term "infectious disease" refers to bacterial infectious diseases and includes but is not limited to disorders such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, the genera Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacter species.

[0646] 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 (such as endogenous asthma, exogenous asthma, pneumoconiosis, infantile asthma), especially chronic or refractory asthma (such as late-stage 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 (such as 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.

[0647] As used herein, the term "endocrine and / or metabolic disease" refers to a group of diseases involving excessive or insufficient amounts 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 hyperplasia, parathyroid diseases, 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.

[0648] As used herein, the term "cardiovascular disease" refers to diseases that affect the heart or blood vessels or both. Specifically, cardiovascular diseases include arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina; arrhythmias; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral obstructive arterial disease of the limbs, organs, or tissues; reperfusion injury after ischemia of the brain, heart, kidney, or other organs or tissues; endotoxin, surgical, or traumatic shock; hypertension, heart valve disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, and insufficiency confined to a single organ or tissue. More specifically, the term refers to atherosclerosis.

[0649] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause dysfunctions of the bone marrow and immune system, which make the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0650] As used herein, the term "disease" involves impaired immune cell function, including conditions with symptoms such as recurrent and persistent viral and bacterial infections and slow recovery. Other hidden symptoms may be the inability to kill parasites, yeast, and bacterial pathogens in the gut or throughout the body.

[0651] As used herein, the term "fibrotic disease" refers to a disease of excessive scarring due to the overproduction, deposition, and contraction of the extracellular matrix, and is associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment, including but not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and digestive tract. Specifically, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies, including iatrogenic drug-induced fibrosis, occupational and / or environmental fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, genetic diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation 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 disease; intestinal fibrosis; liver fibrosis; cirrhosis; alcoholic liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; alcoholic steatohepatitis (ASH), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD); cholestasis, bile duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); infection-induced liver fibrosis; virus-induced liver fibrosis; autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloid, skin fibrosis; scleroderma of the skin; 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 particularly, 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.

[0652] In some embodiments, the compounds of the invention can be used to prevent or reduce the risk of developing any of the diseases mentioned herein; for example, to prevent or reduce the risk of developing a disease, disorder or condition in an individual who may be predisposed to the disease but has not yet experienced or manifested the pathology or symptomatology of the disease.

[0653] The compounds disclosed in the present invention can be administered in any suitable manner known in the art. In some embodiments, the compounds of the invention or pharmaceutically acceptable salts, prodrugs, metabolites or derivatives thereof are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally or intranasally.

[0654] 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 can include a single treatment or can include a series of treatments.

[0655] It is understood that the appropriate dose of the active compound depends on a variety of factors within the knowledge of a physician or veterinarian of ordinary skill. The dose 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 rate of excretion, and any combination of drugs.

[0656] It is also understood that the effective dose of the compound of the invention or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof for treatment can be increased or decreased within a particular treatment course. Changes in dose can be made and become apparent from the results of diagnostic assays.

[0657] In some embodiments, the GPR84 antagonist is administered to the subject at a dose 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.

[0658] In the methods described herein, the methods can further include administering a chemotherapeutic agent to a subject. In certain aspects of this embodiment, the chemotherapeutic agent and the compound or composition are administered to the subject simultaneously. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject before the compound or composition is administered. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after the compound or composition is administered.

[0659] As used herein, the term “treatment / treat / treating” refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder or one or more of its symptoms as described herein. In some embodiments, treatment can be administered after one or more symptoms have appeared. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual before the onset of symptoms (e.g., based on a symptom history and / or based on genetic or other susceptibility factors). Treatment can also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

[0660] The term “administration” or “administering” includes the routes by which a compound is introduced into a subject to perform its intended function. Examples of administration routes that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0661] The term “effective amount” includes an amount that is effective to achieve a desired result at the desired dosage and for the desired period of time. The effective amount of a compound can vary depending on, for example, the disease state, age, and weight of the subject, and the ability of the compound to elicit the desired response in the subject. Dosage regimens can be adjusted to provide an optimal therapeutic response.

[0662] As used herein, the phrases “systemic administration,” “systemically administering,” “peripheral administration,” and “peripherally administering” mean administering a compound, drug, or other substance such that it enters the patient's system and thus undergoes metabolism and other similar processes.

[0663] The phrase "therapeutically effective amount" means an amount of a compound of the invention that achieves one or more of the following: (i) treats or prevents a specific disease, disorder, or condition, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a specific disease, disorder, or condition, or (iii) prevents or delays 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 may reduce the number of cancer cells; reduce the size of a tumor; inhibit (i.e., slow down and preferably stop to some extent) the invasion of cancer cells into surrounding organs; inhibit (i.e., slow down and preferably stop to some extent) the metastasis of a tumor carcinoma; 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 may be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to progression (TTP) and / or determining the response rate (RR).

[0664] The term "subject" refers to an animal, such as a mammal, including but not limited to a primate (e.g., human), bovine, ovine, caprine, equine, canine, feline, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human.

[0665] In one embodiment, the present 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).

[0666] In another embodiment, the present invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for manufacturing 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).

[0667] 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 invention described herein, or a pharmaceutical composition, for treating or preventing the disorder. 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).

[0668] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another additional therapeutic agent. In a specific embodiment, the other therapeutic agent is a therapeutic agent for 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).

[0669] 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 preventing and / or treating a subject presenting a NAS score of at least 3, at least 4, at least 5, at least 6 or at least 7.

[0670] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for manufacturing a medicament for preventing and / or treating a subject presenting a NAS score > 5.

[0671] 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 described herein, or a pharmaceutical composition, for treating or preventing the fibrotic disease, particularly NASH and / or NAFLD, more particularly NASH.

[0672] In a further embodiment of the treatment method, the method for preventing and / or treating a mammal comprises measuring the forced vital capacity (FVC) of the subject, wherein the FVC does not decrease after treatment. In a specific embodiment, the FVC does not decrease within a treatment period of 12, 16, 20 or 26 weeks. In another embodiment, the method comprises 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, 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 within a treatment period of 12, 16, 20 or 26 weeks.

[0673] In one embodiment, the method comprises measuring the airway volume, wherein the airway volume decreases by no more than 5 mL / L, no more than 4 mL / 1, or no more than 3 mL / L. In a specific embodiment, 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 / 1, or no more than 3 mL / L.

[0674] Combination therapy

[0675] Depending on the particular disorder or disease to be treated, additional therapeutic agents that are typically administered to treat the disorder may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or disorder are referred to as "suitable for the disease or disorder being treated".

[0676] In certain embodiments, a combination or a composition thereof is provided by administering in combination with another therapeutic agent.

[0677] The compounds of the present invention can be used as therapeutic agents for treating disorders in mammals that are causally related to or attributable to abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution.

[0678] Accordingly, the compounds and pharmaceutical compositions of the present invention can be used as therapeutic agents for preventing and / or treating inflammatory disorders, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia, and / or diseases involving impaired immune cell function in mammals including humans.

[0679] Accordingly, 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 as a medicament.

[0680] 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.

[0681] In another aspect, the present invention provides a method of treating a mammal suffering from or at risk of developing a disease disclosed herein. In a particular aspect, the present invention provides a method of treating a mammal including a human suffering from or at risk of developing an inflammatory disorder, pain, neuroinflammatory disorder, neurodegenerative disorder, infectious disease, autoimmune disease, endocrine and / or metabolic disease, cardiovascular disease, leukemia, 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.

[0682] 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 preventing and / or treating an inflammatory disorder. In a specific 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 specific embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncological treatments aimed at activating an immune response. 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 manufacturing a medicament for preventing and / or treating an inflammatory disorder. In a specific 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 specific embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncological treatments aimed at activating an immune response.

[0683] In another aspect, the present invention provides a method for a mammal suffering from or at risk of developing a disease selected from inflammatory disorders (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), lung diseases (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung diseases (e.g., idiopathic pulmonary fibrosis (IPF))), neuroinflammatory disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, and / or diseases involving impaired immune cell function, the method comprising administering an effective amount of one or more of the compounds of the present invention described herein, or a pharmaceutical composition.

[0684] In an additional aspect of methods of treatment, 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 described herein, or a pharmaceutical composition. In a specific 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 specific embodiment, the inflammatory disorder is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatoses (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncological treatments aimed at activating an immune response.

[0685] In one aspect, the present invention provides the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention 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.

[0686] In another aspect, the present invention provides the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for manufacturing 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.

[0687] In an additional method of treatment, the present invention provides a method of 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.

[0688] In one aspect, the present invention provides the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for preventing and / or treating neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0689] In another aspect, the present invention provides the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention, which comprise the compounds of the present invention suitable for manufacturing a medicament for preventing and / or treating neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis.

[0690] In an additional method of treatment, the present invention provides a method of treating and / or preventing a mammal susceptible to or suffering from neuroinflammatory disorders, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, autoimmune encephalomyelitis, the method comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein.

[0691] In one aspect, the present invention provides the compounds of the present invention or pharmaceutical compositions comprising the compounds of the present invention for preventing and / or treating infectious diseases. In a specific embodiment, the infectious diseases are 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.

[0692] 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 infectious diseases. In a specific embodiment, the infectious diseases are selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacter species.

[0693] In a further aspect of the method of treatment, the present invention provides a method of 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 diseases are selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacter species.

[0694] 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 preventing and / or treating autoimmune diseases and / or diseases involving impaired immune cell function. In a specific embodiment, the autoimmune diseases and / or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0695] 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 autoimmune diseases and / or diseases involving impaired immune cell function. In a specific embodiment, the autoimmune diseases and / or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0696] In a further aspect of the method of treatment, the present invention provides a method of 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 diseases and / or diseases involving impaired immune cell function are selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0697] 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 preventing and / or treating endocrine and / or metabolic diseases. In a specific embodiment, the endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, 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.

[0698] 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 manufacturing a medicament for preventing and / or treating endocrine and / or metabolic diseases. In a specific embodiment, the endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, 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.

[0699] In an additional therapeutic method aspect, the present invention provides a method of 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 described herein, or a pharmaceutical composition. In a specific embodiment, the endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hyperplasia, parathyroid diseases, 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.

[0700] As another aspect of the present invention, there is provided a compound of the present invention for use as a medicament, particularly in the treatment or prevention of the foregoing disorders and diseases. There is also provided herein the use of said compound in the manufacture of a medicament for the treatment or prevention of one of the foregoing disorders and diseases.

[0701] A specific protocol of the method of the present invention includes administering to a subject suffering from an inflammatory disorder an effective amount of a compound of the present invention for a time sufficient to reduce the level of inflammation in said subject and preferably to terminate the process causing said inflammation. A specific embodiment of the method includes 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 time sufficient to reduce or prevent the inflammation in said patient, respectively, and preferably to terminate the process causing said inflammation.

[0702] The infusion dosage levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 h and especially 24 to 96 h. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve a sufficient steady state level. For a 40 to 80 kg human patient, the maximum total dose is expected not to exceed about 2 g / day.

[0703] Transdermal administration is generally selected to provide blood levels similar to or lower than those achieved using infusion administration.

[0704] When used to prevent the onset of a disorder, the compounds of the invention should generally be administered, on the advice of and under the supervision of a physician, at the dosage levels described above to patients at risk of having the disorder. Patients at risk of having a particular disorder generally 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.

[0705] The compounds of the invention may be administered as the sole active agent or they may be combined with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and that have been determined to be safe and effective for such combination administration. In one specific embodiment, co - administration of two (or more) agents allows for a significant reduction in the dose of each agent to be used, thereby reducing the side effects seen.

[0706] 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, paracetamol, ibuprofen, naproxen and piroxicam.

[0707] 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, non - steroidal anti - inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (e.g. but not limited to methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine and cyclosporine) and biological DMARDS (e.g. but not limited to infliximab, etanercept, adalimumab, rituximab, golimumab, certolizumab pegol, tocilizumab, interleukin 1 blockers and abatacept).

[0708] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of autoimmune diseases; specific agents include, but are not limited to: glucocorticoids, cell growth inhibitors (e.g., purine analogs), alkylating agents (e.g., nitrogen mustard (cyclophosphamide), nitrosoureas, platinum compounds, etc.), antimetabolites (e.g., e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., e.g., actinomycin D anthracycline, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies, and ), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (e.g., IFN-β), TNF-binding proteins (e.g., infliximab etanercept or adalimumab ), mycophenolate mofetil, fingolimod, and myriocin.

[0709] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of infectious diseases; specific agents include, but are not limited to, antibiotics. In a specific embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of 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, quinolones, sulfonamides, tetracyclines, anti-mycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycin, thiamphenicol, and tinidazole.

[0710] In one embodiment, the compounds of the present 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, definitive antibiotics (e.g., cephalexin).

[0711] In one embodiment, the compounds of the present 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., preparations containing aluminum hydroxide, magnesium hydroxide, and / or dimethicone), H2-antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide).

[0712] 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.

[0713] 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: β2-adrenergic receptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting β2-agonists (e.g., salmeterol, formoterol, bambuterol, and sustained release oral salbutamol), combinations of inhaled steroids and long-acting bronchodilators (e.g., fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g., montelukast, zafirlukast, and zileuton), mediator release inhibitors (e.g., cromoglycate and ketotifen), phosphodiesterase-4 inhibitors (e.g., roflumilast), biologic modulators of IgE response (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, nafazoline, and tramazoline).

[0714] In addition, the compounds of the present invention can be co-administered in combination with emergency therapies for asthma and / or COPD, such therapies including administration of oxygen or heliox, nebulized salbutamol 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 hydrocortisone), intravenous salbutamol, non-specific β-agonists, injectable or inhaled agents (such as adrenaline, isoetharine, isoprenaline, metaproterenol), anticholinergic agents (IV or nebulized, such as glycopyrronium bromide, atropine, ipratropium bromide), methylxanthines (theophylline, aminophylline, bamiphylline), inhaled anesthetics having bronchodilatory effects (such as isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.

[0715] In one embodiment, the compounds of the present 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 (such as prednisone, budesonide); synthetic disease-modifying, immunomodulatory agents (such as methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6-mercaptopurine and cyclosporine) and biologic disease-modifying, immunomodulatory agents (infliximab, adalimumab, rituximab and abatacept).

[0716] In one embodiment, the compounds of the present 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: paracetamol, acetylsalicylic acid, NSAIDs, codeine, dihydrocodeine, tramadol, pentazocine, pethidine, tilidine, buprenorfine, fentanyl, hydromorfon, methadon, morphine, oxycodone, piminodine, tapentadol or combinations thereof.

[0717] The treatment process for leukemia includes chemotherapy, biotherapy, targeted therapy, radiotherapy, bone marrow transplantation and / or combinations thereof.

[0718] Examples of other therapeutic agents for acute lymphoblastic leukemia (ALL) include methotrexate, nelarabine, asparaginase, Erwinia chrysanthemi, blinatumomab, daunorubicin, clofarabine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase and / or prednisone.

[0719] Examples of other therapeutic agents for acute myeloid leukemia (AML) include arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and / or vincristine.

[0720] Examples of other therapeutic agents for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, mechlorethamine, prednisone, and / or rituximab.

[0721] Examples of other therapeutic agents for chronic myeloid leukemia (CML) include bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, mechlorethamine, nilotinib, and / or omacetaxine.

[0722] Examples of other therapeutic agents for hairy cell leukemia include cladribine, pentostatin, and / or interferon α-2b.

[0723] As will be apparent to those skilled in the art, co-administration includes any manner of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. While the two or more agents can be co-administered simultaneously in a single formulation, this is not required. The agents can be administered in different formulations and at different times.

[0724] 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.

[0725] In one embodiment, other therapeutic agents for the treatment and / or prevention of 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), lebrikizumab (CAS n#953400-68-5); talokinumab (CAS n#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), telustat (MN-001; ClinicalTrials.gov identifier NCT02503657), ND-L02-s0201 (ClinicalTrials.gov identifier NCT03538301), KD025 (ClinicalTrials.gov identifier NCT02688647), TD139 (ClinicalTrials.gov identifier NCT02257177), VAY736 (ClinicalTrials.gov identifier NCT03287414), PRM-151 (ClinicalTrials.gov identifier NCT02550873) and PBI-4050 (ClinicalTrials.gov identifier NCT02538536). In one specific embodiment, another therapeutic agent for treating and / or preventing fibrotic diseases is an autocrine motility factor (or ectonucleotide pyrophosphatase / phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are described in WO 2014 / 139882, such as GLPG1690.

[0726] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for treating and / or preventing NASH, specific agents including but not limited to weight loss therapeutic agents (such as sibutramine or orlistat), insulin sensitizers (such as metformin, thiazolidinedione, rosiglitazone or pioglitazone), lipid-lowering agents (such as gemfibrozil), antioxidants (such as vitamin E, N-acetylcysteine, betaine or pentoxifylline), angiotensin converting enzyme inhibitors, angiotensin receptor blockers, monounsaturated fatty acids or polyunsaturated fatty acids. FXR agonists (such as obeticholic acid), LOXL2 antagonists (such as sintilimab), ASK1 antagonists (such as selonsertib), PPAR agonists (such as clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinedione, ibuprofen, GW-9662, aleglitazar, moglitazar or tesaglitazar), acetyl-CoA carboxylase (ACC) antagonists (such as NDI-010976, PF-05221304), CCR2 / CCR5 (such as cenicriviroc), VAP1 antagonists.

[0727] Examples of agents that can be combined with the combinations of the present invention include, but are not limited to: for the treatment of Alzheimer's disease, such as and for the treatment of HIV, such as ritonavir; for the treatment of Parkinson's disease, such as L-dopa / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (e.g., and ), and mitoxantrone; for the treatment of asthma, such as albuterol and agents for the treatment of 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, interferons, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's agents; agents for the treatment of cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium ion 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, antileukemic 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.

[0728] In certain embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or an siRNA therapeutic agent.

[0729] Those additional agents can be administered separately from the provided combination therapy as part of a multiple dosing regimen. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of the present invention into a single composition. If administered as part of a multiple dosing regimen, the two active agents can be provided simultaneously, sequentially, or at intervals of a certain period of time from each other (usually within five hours of each other).

[0730] As used herein, the terms "combination / combined" and related terms refer to the administration of the therapeutic agents according to the present invention either simultaneously or sequentially. For example, the combinations 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.

[0731] The amount of the additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would typically be administered in a composition containing the therapeutic agent as the sole active agent. The amount of the additional therapeutic agent in the compositions disclosed herein will preferably be in the range of about 50% to 100% of the amount that is typically present in a composition containing the agent as the sole therapeutic active agent.

[0732] In one embodiment, the present 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.

[0733] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering a compound of Formula I and one or more additional therapeutic agents to a patient in need thereof. Such additional therapeutic agents can be small molecules or recombinant biological agents, and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, colchicine corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat sulfasalazine antimalarial drugs such as hydroxychloroquine and chloroquine methotrexate gold salts such as aurothioglucose Aurothiomalate and auranofin D-penicillamine ( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and “anti-TNF” agents such as etanercept infliximab golimumab pegolized certolizumab and adalimumab “anti-IL-1” agents such as anakinra and rilonacept 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 agents such as diphenoxylate and loperamide bile acid binders such as cholestyramine, alosetron lubiprostone laxatives such as magnesium oxide emulsion, polyethylene glycol and anticholinergic or antispasmodic agents such as dicyclomine β-2 agonists such as salbutamol ( HFA, HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergic agents such as ipratropium bromide and tiotropium inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone Budesonide and flunisolide Sodium cromoglicate 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 Fosamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir( or ) and tipranavir Entry inhibitors such as enfuvirtide and maraviroc Integrase inhibitors such as raltegravir Doxorubicin Vincristine Bortezomib and dexamethasone in combination with lenalidomide or any combination thereof.

[0734] In another embodiment, the present invention provides a method for 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: non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine antimalarial drugs such as hydroxychloroquine and chloroquine methotrexate gold salts such as aurothioglucose aurothiomalate and auranofin D - penicillamine( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and "anti - TNF" agents such as etanercept infliximab golimumab pegolized certolizumab and adalimumab "anti - IL - 1" agents such as anakinra and rilonacept antibodies such as rituximab "anti - T cell" agents such as abatacept and "anti - IL - 6" agents such as tocilizumab

[0735] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, non - steroidal anti - inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, diclofenac, cortisone, hyaluronic acid( or ) and monoclonal antibodies such as ranibizumab.

[0736] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, the method comprising administering to a patient in need a compound of formula I and one or more additional therapeutic agents selected from: acetaminophen, non - steroidal anti - inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial drugs such as hydroxychloroquine and chloroquine Cyclophosphamide Methotrexate Azathioprine and anticoagulants such as heparin ( or ) and warfarin

[0737] In some embodiments, the present invention provides a method for treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: mesalamine Sulfasalazine antidiarrheals such as diphenoxylate and loperamide bile acid binders such as cholestyramine, alosetron lubiprostone laxatives such as magnesium oxide emulsion, polyethylene glycol and and anticholinergic or antispasmodic agents such as dicyclomine anti-TNF therapeutic agents, steroids, and antibiotics such as metronidazole (Flagyl) or ciprofloxacin.

[0738] In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need thereof a compound of formula I and one or more additional therapeutic agents selected from: β-2 agonists such as albuterol ( HFA, HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergic agents 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

[0739] In some embodiments, the present invention provides a method for treating COPD, 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 following: β-2 agonists such as albuterol ( A HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate 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

[0740] In another embodiment, the present invention provides a method for treating hematological malignancies, 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 following: rituximab cyclophosphamide doxorubicin vincristine prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0741] In another embodiment, the present invention provides a method for 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 following: rituximab cyclophosphamide doxorubicin vincristine prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0742] In another embodiment, the present invention provides a method for treating hematological malignancies, 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), and incorporated herein by reference in its entirety).

[0743] In another embodiment, the present invention provides a method for treating diffuse large B-cell lymphoma (DLBCL), the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from the following to a patient in need thereof: rituximab cyclophosphamide doxorubicin vincristine prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0744] In another embodiment, the present invention provides a method for treating multiple myeloma, the method comprising administering a compound of formula I and one or more additional therapeutic agents selected from the following to a patient in need thereof: bortezomib and dexamethasone a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and lenalidomide

[0745] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof a compound of Formula I and a BTK 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, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, 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 totalis, Behcet'sdisease), chronic fatigue, autonomic nervous system disorders, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative diseases, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, infusion, systemic allergic reactions, allergies (such as allergies to plant pollen, latex, drugs, food, insect poisons, animal hair, animal dander, dust mites or cockroach excrement), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, 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 purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin 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 lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer), or mast cell cancers (such as mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, osteoarticular diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter'sdisease), Behçet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis), thromboembolic disorders (such as myocardial infarction, angina pectoris, restenosis after angioplasty, reocclusion after angioplasty, restenosis after aortic coronary bypass grafting, reocclusion after aortic coronary bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorders, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue transplantation rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular diseases (also known as autoimmune polyglandular syndromes), 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, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury) and Graves' disease.

[0746] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need a compound of formula I and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenesis disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, disorders related to organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, disorders related to cell death, thrombin-induced platelet aggregation, chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune disorders involving T cell activation, cardiovascular disorders and CNS disorders.

[0747] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof a compound of formula I and a PI3K inhibitor for myeloid leukemia, wherein the disease is selected from benign or malignant tumors; carcinomas or solid tumors of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid; sarcoma; glioblastoma; neuroblastoma; multiple myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or head and neck tumors; epidermal hyperplasia; 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; or a disease in which the PI3K / PKB pathway is abnormally activated; asthma of any type or origin, including endogenous (non-allergic) asthma and exogenous (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection; acute lung injury (ALI); adult / acute respiratory distress syndrome (ARDS); chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema and deterioration of airway hyperreactivity caused by other drug therapies, especially other inhaled drug therapies; bronchitis of any type or origin, including but not limited to acute, peanut aspiration, 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, aluminosis, anthracosis, asbestosis, talcosis, madarosis, siderosis, silicosis, smutosis and byssinosis;Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, 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 inflammatory diseases in which the autoimmune response and autoimmune components or etiologies are related or have autoimmune components or etiologies, including autoimmune blood disorders (such as hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia); cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener granulomatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Steven-Johnson syndrome; idiopathic sprue; autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease); endocrine ophthalmopathy; Graves' disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry eye and vernal keratoconjunctivitis; interstitial lung fibrosis; psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, such as including idiopathic nephrotic syndrome or minimal change nephropathy); restenosis; cardiac hypertrophy; atherosclerosis; myocardial infarction; ischemic stroke and congestive heart failure; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.;

[0748] In some embodiments, the present invention provides a method of treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof a compound of Formula I and a Bcl-2 inhibitor, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related 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, hematopoietic neoplasm, or solid tumor.

[0749] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplantation-related disorder. In some embodiments, the JH2-binding compound is a compound of Formula I. Other suitable JH2 domain-binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, the entire contents of each of which are incorporated herein by reference. Suitable JH1 domain-binding compounds include those described in WO2015131080A1, the entire contents of which are incorporated herein by reference.

[0750] The compounds and compositions according to the methods of the invention can be administered in any effective dosage amount and by any effective route of administration for treating or alleviating the severity of an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplantation-related disorder. The precise amount required will vary with the different subjects, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated. However, it is to be understood that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound 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 employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration and the excretion rate of the specific compound employed; the duration of the treatment; drugs used in combination with or concurrently with the specific compound employed; and like factors well known in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0751] The pharmaceutically acceptable compositions of the invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccally (such as by oral or nasal sprays), etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at the following dosage levels to obtain the desired therapeutic effect: about 0.01 mg to about 50 mg per kg of subject body weight per day and preferably about 1 mg to about 25 mg, once or more times a day.

[0752] 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 forms may contain inert diluents commonly used in the art, such as water or other solvents; solubilizing agents and emulsifying agents, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 - butanediol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan; and mixtures thereof. In addition to the inert diluent, the oral compositions may also include adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0753] Injectable preparations can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, such as sterile injectable aqueous or oily suspensions. The sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in a non - toxic parenterally acceptable diluent or solvent, such as a solution in 1,3 - butanediol. Acceptable vehicles and solvents that can be employed include water, Ringer's solution (U.S.P.), and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0754] The injectable preparations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0755] To prolong the effect of the compounds of the present invention, it is often necessary to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions 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 parenterally administered compound is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as poly(lactide - co - glycolide). Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable preparations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0756] Compositions for rectal or vaginal administration are preferably suppositories prepared by mixing a compound of the invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or suppository wax which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity and releases the active compound.

[0757] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or calcium phosphate dibasic, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solubilizing agents such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0758] Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents and may also have compositions that release the active ingredient only in or preferentially in a certain part of the intestine or optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols.

[0759] The active compound may also be present in microencapsulated form together with one or more excipients as indicated above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release control coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. As is normal practice, such dosage forms may also contain additional substances in addition to the inert diluent, such as tableting lubricants and other tableting aids such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents. Optionally, it may contain emulsifying agents and may also have compositions that release the active ingredient only in or preferentially in a certain part of the intestine or optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

[0760] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffering agents that may be required under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also covered within the scope of the present invention. Additionally, the present invention covers the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Penetration enhancers may also be used to increase the amount of the compound that penetrates through the skin. The rate may be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0761] According to one embodiment, the present invention relates to a method for inhibiting GPR84 activity in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0762] According to another embodiment, the present invention relates to a method for inhibiting the activity of GPR84 or a mutant thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0763] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials or extracts thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0764] Inhibition of GPR84 (or a mutant thereof) activity in a biological sample is applicable to 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 biological assays.

[0765] Another embodiment of the invention relates to a method of inhibiting GPR84 activity in a patient, the method comprising the step of administering to the patient a compound of the invention or a composition comprising the compound.

[0766] According to another embodiment, the invention relates to a method of inhibiting the activity of GPR84 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound of the invention or a composition comprising the compound. According to certain embodiments, the invention relates to a method of reversibly or irreversibly inhibiting one or more of GPR84 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound of the invention or a composition comprising the compound. In other embodiments, the invention provides a method of treating a disorder mediated by GPR84 or a mutant thereof in a patient in need thereof, the method comprising the step of administering to the patient a compound according to the invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0767] Depending on the particular disorder or disease to be treated, additional therapeutic agents that are typically administered to treat the disorder may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease or disorder are referred to as "suitable for the disease or disorder being treated".

[0768] The compounds of the present invention can also be used in combination with other therapeutic compounds to be in an advantageous position. In some embodiments, the other therapeutic compound is an anti-proliferative compound. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and other anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for treating hematological malignancies; compounds that target, reduce or inhibit Flt-3 activity; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; 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 folinic acid. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone into 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, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is sold under the trade name Aromasin TM and formestane is sold under the trade name Lentaron TM and fadrozole is sold under the trade name Afema TM and anastrozole is sold under the trade name Arimidex TM and letrozole is sold under the trade name Femara TM or Femar TM and aminoglutethimide is sold under the trade name Orimeten TM The combination of the present invention comprising a chemotherapeutic agent as an aromatase inhibitor is particularly suitable for the treatment of hormone receptor-positive tumors, such as breast tumors.

[0769] As used herein, the term "anti-estrogen" refers to a compound that antagonizes the action of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex TM and raloxifene hydrochloride is sold under the trade name Evista TM and fulvestrant can be administered under the trade name Faslodex TM The combination of the present invention comprising a chemotherapeutic agent as an anti-estrogen is particularly suitable for the treatment of estrogen receptor-positive tumors, such as breast tumors.

[0770] As used herein, the term "antiandrogen" refers to any substance 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 may be administered under the trade name Zoladex TM .

[0771] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogs, 9-nitro-camptothecin, and macromolecular camptothecin conjugate PNU-166148. Irinotecan may be administered, for example, in its marketed form, for example, under the trademark Camptosar TM . Topotecan is sold under the trade name Hycamptin TM .

[0772] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines, such as doxorubicin (including liposomal formulations, such as Caelyx TM ), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinone mitoxantrone and losoxantrone, and the podophyllotoxin 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 AcriblastinT M 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

[0773] The term "microtubule active agent" refers to microtubule stabilizers, 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; colchicine, and epothilone and its derivatives. Paclitaxel is sold under the trade name Taxol TM . Docetaxel is sold under the trade name TaxotereTM is sold. Vinblastine sulfate is sold under the trade name Vinblastin R.P TM is sold. Vincristine sulfate is sold under the trade name Farmistin TM is sold.

[0774] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin TM is sold. Ifosfamide is sold under the trade name Holoxan TM is sold.

[0775] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to a compound that inhibits histone deacetylase and has antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0776] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (such as 5-azacytidine and decitabine), methotrexate, and edatrexate, as well as folic acid antagonists (such as pemetrexed). Capecitabine is sold under the trade name Xeloda TM is sold. Gemcitabine is sold under the trade name Gemzar TM is sold.

[0777] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in its marketed form, such as under the trademark Carboplat TM is administered. Oxaliplatin can be administered, for example, in its marketed form, such as under the trademark Eloxatin TM is administered.

[0778] As used herein, the term "compound that targets / reduces protein or lipid kinase activity, or protein or lipid phosphatase activity; or other anti-angiogenic compound" includes, but is not limited to, protein tyrosine kinases 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 the PDGF receptor, such as N-phenyl-2-pyrimidinamine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); 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 the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or epothilone B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase, which is part of the PDGFR family, 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-pyrimidinamine derivatives, such as imatinib or nilotinib (AMN107) from Parke Davis, PD1 80970, AG957, NSC680410, PD173955; or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of members of the protein kinase C (PKC) and Raf families, 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; 11mofosine; RO318220 and RO 320432; GO6976; 1sis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, for example, compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or Tyrphostin, for example, 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 AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); 1) compounds that target, reduce or inhibit the activity of the epidermal growth factor family (EGFR 1 , ErbB2, ErbB3, ErbB4, in the form of homodimers or heterodimers) and its mutants, for example, compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family are particularly compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family such as the EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligand CP 358774, ZD 1839, ZM105180; trastuzumab (Herceptin TM ) and cetuximab (Erbitux TM) Iressa, Tarceva, OSI-774, C1-1033, 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, reduce or inhibit the activity of the c-Met receptor, such as compounds that target, reduce or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF; n) 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, reduce 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, reduce or inhibit the signal transduction of the Hedgehog (Hh) or Smoothened (SMO) pathway, including but not limi...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 is -O-(C 1-5 alkylene)-Z 1 or Y 1 ; R 2 each independently represents C 1-4 alkyl or Y 2 ; R 3 One of the following: (a)-(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6-membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl; (b) C 1-6 alkoxy, C 1-6 haloalkoxy, -O-(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur); or (c)Y 3 ; R 4 Each occurrence independently represents hydrogen or methyl; R 5 and R 8 each independently represents, when it appears, a halogen group, C 1-4 alkyl group, C 1-4 haloalkyl group, C 1-4 alkoxy group or C 3-6 cycloalkyl group; R 6 and R 9 each independently represents hydrogen or C 1-4 alkyl; R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or R 7 and R 6 together with the nitrogen atom to which they are attached form (i) a 3- to 7-membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, or (ii) an 8- to 11-membered spiro ring containing 2 nitrogen atoms; wherein the cycloalkyl and each ring are substituted by p substituents independently selected from halo and C 1-4 alkyl; A 1 is phenylene, pyridylene or piperidinylene, each of which is substituted by q occurrences of R 8 ; or A 1 is Y 4 ; X 1 is O or S; Z 1 is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; a 4- to 8-membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or -C(O)N(R 4 ) 2 ; wherein the heteroaryl, heterocyclic and phenyl rings are substituted with n occurrences of R 5 ; Z 2 is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Z 3 Hydroxyl, C 1-4 Alkoxy, -N(R 9 ) 2 、-C(O)N(R 9 ) 2 or a 4-8 membered saturated monocyclic heterocyclic ring having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is optionally substituted with -C(O)(C 1-6 aliphatic) substituted; L 1 is C 1-4 alkylene, C 3-4 haloalkylene, C 1-4 hydroxyalkylene, cyclopropylidene or Y 5 ; Y 1 One of the following: (a)-O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 )、-O-(C 1-5 alkylene)-SO 2 N(R 6 ) 2 or -O-(C 1-5 alkylene)-CO 2 R 6 ; (b)-O-(C 1-5 haloalkylene)-N(R 6 ) 2 、-O-(C 1-5 alkylene)-(C 3-6 subcycloalkylene)-N(R 6 ) 2 ,or -O-(C 1-5 alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur)-N(R 6 ) 2 ; (c)-S-(C 1-5 alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted by n occurrences of R 5 ; or (d)-O-(C 1-5 alkylene)-Z 2 , wherein Z 2 is substituted by (i) a -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R5 substitution; Y 2 each independently represents C when it appears each time 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl; Y 3 one of the following: (a)-(C 2-4 alkynylene)-(cyclopropyl substituted by 1 or 2 groups independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl and hydroxy), -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), -(phenylene)-(C 1-4 haloalkyl) or C 1-4 haloalkyl; (b)-O-(C 1-8 alkylene)-Z 3 or hydroxy; or (c)-N(R 9 ) 2 、 -(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, sulfur)-(C 3-6 cycloalkyl), or -N(R 9 )C(O)-(5- to 6-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Y 4 is -C≡C-, cyclohexylene, oxazolylene, pyridazinylene, azetidinylene, pyrrolidinylene or phenylene; wherein the phenylene is substituted with 1 cyano group, hydroxyl group or -N(R 6 ) 2 substituted; Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene or -(C 1-4 alkoxy or C 3-6 cycloalkyl-substituted C 1-4 alkylene)-; and m, n, p and q independently represent 0, 1 or 2; and where Y 1 , Y 2 , Y 3 , Y 4 or Y 5 appears at least once.

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

3. The compound according to claim 1, wherein the compound is a compound of formula I-a: or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 3, wherein the compound is a compound of formula I-a.

5. The compound according to any one of claims 1-4, wherein R 2 independently represents C 1-4 alkyl each time it appears.

6. The compound according to any one of claims 1-4, wherein R 2 is Y 2 , and Y 2 each occurrence independently represents C 1-4 haloalkyl, C 1-4 alkoxy or C 3-6 cycloalkyl.

7. The compound according to any one of claims 1-6, wherein L 1 is C 1-4 alkylene.

8. The compound according to any one of claims 1-6, wherein L 1 is C 3-4 haloalkylene, C 1-4 hydroxyalkylene or cyclopropylidene.

9. The compound according to any one of claims 1-6, wherein L 1 is Y 5 , and Y 5 is C 2-4 alkenylene, C 1-2 haloalkylene or -(C 1-4 alkoxy or C 3-6 cycloalkyl-substituted C 1-4 alkylene)-.

10. The compound according to claim 1, wherein the compound is a compound of formula I-b, I-c or I-d: or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 10, wherein the compound is a compound of formula I-b, I-c or I-d.

12. The compound according to any one of claims 1-11, wherein R 1 is -O-(C 1-5 alkylene)-Z 1 .

13. A compound according to any one of claims 1-12, wherein Z 1 is a 5- or 6-membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said heteroaryl is substituted with n occurrences of R 5 substituents.

14. The compound according to any one of claims 1-12, wherein Z 1 is -C(O)N(R 4 ) 2 .

15. A compound according to any one of claims 1-11, wherein R 1 is 16. The compound according to any one of claims 1-11, wherein R 1 is Y 1 .

17. The compound according to any one of claims 1-11 or 16, wherein Y 1 is -O-(C 1-5 alkylene)-C(O)N(R 6 )(R 7 ), -O-(C 1-5 alkylene)-SO 2 N(R 6 ), 2 or -O-(c 1-5 alkylene)-CO 2 R 6 .

18. The compound according to any one of claims 1-11 or 16, wherein Y 1 is -OCH 2 -C(O)N(R 6 )(R 7 ).

19. A compound according to any one of claims 1-11 or 16-18, wherein R 7 is C 2-6 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl or a 4-8 membered saturated or partially unsaturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said cycloalkyl and heterocycle are substituted with p substituents independently selected from halo and C 1-4 alkyl.

20. A compound according to any one of claims 1-11 or 16-18, wherein R 7 and R 6 together with the nitrogen atom to which they are attached form a 3- to 7-membered ring containing 1 nitrogen atom and optionally 1 oxygen atom or 1 additional nitrogen atom, wherein said ring is substituted with p substituents independently selected from halo and C 1-4 alkyl.

21. The compound according to any one of claims 1-11 or 16, wherein Y 1 is -O-(C 1-5 haloalkylene)-N(R 6 ), 2 -O-(C 1-5 alkylene)-(C 3-6 subcycloalkylene)-N(R 6 ), 2 or -O-(C 1-5 alkylene)-(3- to 7-membered saturated monocyclic heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur)-N(R 6 ). 2 .

22. The compound according to any one of claims 1-11 or 16, wherein Y 1 is one of the following: ·-S-(C 1-5 -alkylene)-Z 2 、-OC(O)-Z 2 or -N(R 6 )C(O)-Z 2 ; wherein each Z 2 is substituted with n occurrences of R 5 ; or ·-O-(C 1-5 alkylene)-Z 2 , where Z 2 is substituted by (i) a -N(R 6 )SO 2 -(C 1-4 alkyl) or -N(R 6 )SO 2 -(C 1-4 haloalkyl) and (ii) n occurrences of R 5 substituted.

23. A compound according to any one of claims 1-11, 16 or 22, wherein Z 2 is a pyrimidinyl group.

24. The compound according to any one of claims 1-23, wherein A 1 is a phenylene group substituted by q occurrences of R 8 substituents.

25. The compound according to any one of claims 1-23, wherein A 1 is 26. The compound according to any one of claims 1-23, wherein A 1 is a pyridinylene or piperidinylene group, each of which is substituted by q occurrences of R 8 substituents.

27. The compound according to any one of claims 1-23, wherein A 1 is Y 4 .

28. A compound according to any one of claims 1-23 or 27, wherein Y 4 is -C≡C-, cyclohexylene, or phenylene; wherein the phenylene is substituted with 1 cyano group, hydroxyl group or -N(R 6 ) 2 substituted.

29. A compound according to any one of claims 1-23 or 27, wherein Y 4 is oxazolylidene, pyridazinylidene, azetidinylidene or pyrrolidinylidene.

30. A compound according to any one of claims 1-29, wherein R 3 is -(C 2-4 alkynylene)-(C 3-6 cycloalkyl), -(C 2-4 alkenylene)-(C 3-6 cycloalkyl), -(C 0-4 alkylene)-(C 3-6 cycloalkyl), -(phenylene)-(C 3-6 cycloalkyl), -(5-6 membered heteroarylene having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur)-(C 3-6 cycloalkyl), -C≡C-(C 1-4 alkyl) or C 1-6 alkyl.

31. The compound according to any one of claims 1-29, wherein R 3 is -C(H)=C(H)-(cyclopropyl), -(C 0-2 alkylene)-(cyclopropyl), -(phenylene)-(cyclopropyl), -(6-membered heteroarylene having 1 or 2 nitrogen atoms)-(cyclopropyl) or -C≡C-(C 1-4 alkyl).

32. The compound according to any one of claims 1-29, wherein R 3 is 33. The compound according to any one of claims 1-29, wherein R 3 is C 1-6 alkoxy, C 1-6 haloalkoxy, -(C 0-6 alkylene)-phenyl, or -O-(C 0-6 alkylene)-(5-6 membered heteroaryl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

34. A compound according to any one of claims 1-29, wherein R 3 is Y 3 .

35. A compound according to any one of claims 1-29 or 34, wherein Y 3 is -(C 2-4 alkynylene)-(cyclopropyl substituted by 1 or 2 groups independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl and hydroxy).

36. A compound according to any one of claims 1-29 or 34, wherein Y 3 is -C≡CC≡C-(C 1-5 aliphatic group), -C≡C-CN, or C 1-4 haloalkyl.

37. A compound according to any one of claims 1 - 29 or 34, wherein Y 3 is -(C 3-6 subcycloalkyl)-(C 3-6 cycloalkyl), -(C 3-6 subcycloalkyl)-(C 1-4 haloalkyl), or -(phenylene)-(C 1-4 haloalkyl).

38. The compound according to any one of claims 1-29 or 34, wherein Y 3 is -O-(C 1-8 alkylene)-Z 3 or a hydroxyl group.

39. A compound selected from those depicted in Table 1, Table 2 or Table 3 herein, or a pharmaceutically acceptable salt thereof.

40. A compound selected from those depicted in Table 4 or Table 5 herein, or a pharmaceutically acceptable salt thereof.

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

42. A method of inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of the compound according to any one of claims 1-40 to inhibit GPR84.

43. A method of treating a GPR84-mediated disorder, disease or affliction in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of the compound according to any one of claims 1-40.

44. The method according to claim 43, wherein the disorder, disease or affliction 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 affliction, a neurodegenerative disease, an inflammatory disorder, multiple sclerosis or pain.

45. The method according to claim 43, wherein the disorder, disease or affliction is cancer.

46. The method according to claim 45, wherein the cancer is leukemia or hepatocellular carcinoma (HCC).

47. The method according to claim 45, wherein the cancer is acute myeloid leukemia (AML).

48. The method according to claim 43, wherein the disorder, disease or affliction is a proliferative disease associated with one or more activating mutations in GPR84.

49. The method according to claim 43, wherein the disorder, disease or affliction is a chronic viral infection.

50. The method according to claim 43, wherein the disorder, disease or affliction is an inflammatory disorder selected from the following: 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.

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

52. The method according to claim 43, wherein the disorder, disease or condition is systemic lupus erythematosus (SLE).

53. The method according to claim 43, wherein the disorder, disease or condition is neuropathic pain.

54. The method according to claim 43, wherein the disorder, disease or condition is Alzheimer's disease.

55. The method according to claim 43, wherein the disorder, disease or condition is idiopathic pulmonary fibrosis (IPF).

56. A method of enhancing the efficacy of vaccination in a patient, the method comprising administering to the patient in need thereof a compound according to any one of claims 1-40 as an adjuvant.

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