Aryltriazolyl and related GPR84 antagonists and uses thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application Serial No. 63 / 394,381, filed on August 2, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present invention relates to compounds and methods useful 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 the compositions to treat various conditions. Background Art

[0004] G protein-coupled receptor 84 (GPR84), also known as EX33, GPCR4, and G protein-coupled receptor 84, is a medium-chain fatty acid receptor that is primarily expressed in immune cells and upregulated under inflammatory conditions.

[0005] GPR84 was isolated and identified from human B cells (Wittenberger et al., 2001. J. Mol. Biol. 307, 799-813.) as a result of an expressed sequence tag data mining strategy, while also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) approach to identify novel chemokine receptors expressed in neutrophils (Yousefi S et al., 2001. J. Leukoc. Biol. 69, 1045-1052.). GPR84 remained an orphan GPCR until medium-chain free fatty acids (FFAs) with carbon chain lengths 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 decanoic acid (C10:0), undecanoic acid (C11:0), and lauric acid (C12:0) with potencies of 5 μM, 9 μM, and 11 μM, respectively. Three small molecules have also been described as having some GPR84 agonist activity: 3,3′-diindolylmethane (DIM) (Wang et al., 2006), embelin (Hakak Y et al., 2007. WO2007027661(A2).), and n-octylaminouracil (6-OAU) (Suzuki M et al., 2013. J. Biol. Chem. 288, 10684-10691.).

[0006] GPR84 has been shown to be expressed in immune cells, including, but not limited to, polymorphonuclear leukocytes (PMNs), neutrophils, monocytes, T cells, and B cells. (Hakak et al. 2007; Venkataraman C, Kuo F. 2005. Immunol. Lett. 101, 144-153; Wang et al. 2006; Yousefi et al. 2001). GPR84 levels were higher in neutrophils and eosinophils than in T cells and B cells. GPR84 has been shown to be expressed in tissues that may be involved in the propagation of inflammatory responses, such as the lungs, spleen, and bone marrow.

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

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

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

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

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

[0012] GPR84 expression has also been described in microglia, which are the main 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 that it plays a role in neuroinflammatory processes. These results indicate that GPR84 is not only upregulated 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), and Parkinson's disease (PD).

[0013] GPR84 expression has also been observed in adipocytes and has been shown to be enhanced by inflammatory stimuli (Nagasaki H et al. 2012. FEBS Lett. 586, 368-372.). These results suggest that TNFα from infiltrating macrophages triggers GPR84 expression, 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.

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

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

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

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

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

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

[0020] It has now been discovered that the compounds of the present invention and pharmaceutically acceptable compositions thereof are effective as antagonists of GPR84. In certain embodiments, the present invention provides compounds having the formulae presented herein.

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

[0022]

[0023] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Also provided are pharmaceutical compositions comprising a compound of Formula I and a pharmaceutically acceptable carrier.

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

[0025]

[0026] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Also provided are pharmaceutical compositions comprising a compound of Formula II and a pharmaceutically acceptable carrier.

[0027] Another aspect of the present invention provides a group of compounds defined by formula III:

[0028]

[0029] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein. Also provided is a pharmaceutical composition comprising a compound of Formula III and a pharmaceutically acceptable carrier.

[0030] Another aspect of the present invention provides a method for treating a GPR84-mediated condition, disease or illness in a patient. The method comprises administering to the patient in need thereof a therapeutically effective amount of a compound as described herein, such as a compound of Formula I or II. In certain embodiments, the compound is a compound of Formula III. Exemplary GPR84-mediated conditions, diseases or illnesses include fibrotic diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, diseases involving impaired immune cell function, neuroinflammatory conditions, neurodegenerative diseases, inflammatory diseases, multiple sclerosis or pain.

[0031] Another aspect of the present invention provides a method of inhibiting GPR84. The method comprises contacting GPR84 with an effective amount of a compound described herein to inhibit GPR84.

[0032] The compounds provided by the present invention can also be used to study the role of GPR84 in biological and pathological phenomena; study the fibrotic process occurring in body tissues; and conduct in vitro or in vivo comparative evaluation of new GPR84 inhibitors or other modulators of neutrophil and macrophage chemotaxis. DETAILED DESCRIPTION

[0033] 1. General Description of Certain Embodiments of the Invention:

[0034] In certain aspects, the present invention provides compounds of formula I:

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined below and as described in the embodiments herein.

[0037] In certain aspects, the present invention provides compounds of formula II:

[0038]

[0039] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、L 2 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined below and as described in the embodiments herein.

[0040] In certain aspects, the present invention provides compounds of formula III:

[0041]

[0042] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined below and as described in the embodiments herein.

[0043] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0044] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of Formula II and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0045] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula III and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0046] In some embodiments, the present invention provides a method of treating a GPR84-mediated disease, condition, or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0047] In some embodiments, the present invention provides a method of treating a GPR84-mediated disease, condition, or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula II or a pharmaceutically acceptable salt thereof.

[0048] In some embodiments, the present invention provides a method of treating a GPR84-mediated disease, condition, or disorder, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula III or a pharmaceutically acceptable salt thereof.

[0049] 2. Compounds and definitions;

[0050] The compounds of the present invention include those compounds generally described herein and further illustrated 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, the general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th edition, eds. Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0051] As used herein, the term "aliphatic" or "aliphatic group" means a straight (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain (which is fully saturated or contains one or more unsaturated units) or a monocyclic or bicyclic hydrocarbon (which is fully saturated or contains one or more unsaturated units), but which is not aromatic (also referred to herein as "cycloaliphatic") and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and heterocycles thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0052] As used herein, the term "bridged bicyclic" refers to any saturated or partially unsaturated bicyclic system, i.e., carbocyclic or heterocyclic ring, with at least one bridge bond. As defined by IUPAC, a "bridge bond" is a non-branched chain of multiple atoms or an atom or a valence bond connecting two bridge heads, wherein a "bridge head" is any backbone atom of a ring system bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Such bridged bicyclic groups are well known in the art and include those groups described below, wherein each group is connected to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise stated, the bridged bicyclic group is optionally substituted by one or more substituents as described for an aliphatic group. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclic groups include:

[0053]

[0054] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0055] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0056] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0057] As used herein, the term "unsaturated" means that the moiety has one or more units of unsaturation.

[0058] As used herein, the term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated straight or branched hydrocarbon chain" refers to divalent alkylene, alkenylene and alkynylene chains as defined herein that are straight or branched.

[0059] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, wherein n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0060] The term "-(C0 alkylene)-" refers to a bond. Thus, the term "-(C0 alkylene)-" 0-3 Alkylene)-" encompasses bonds (i.e., C0) and -(C 1-3 alkylene)-group.

[0061] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond and in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0062] The term "halogen" means F, Cl, Br or I.

[0063] The term "aryl" as used alone or as part of a larger moiety in "aralkyl," "aralkyloxy," or "aryloxyalkyl" refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system that can carry one or more substituents, including but not limited to phenyl, biphenyl, naphthyl, anthracenyl, etc. As used herein, groups in which an aromatic ring is fused to one or more non-aromatic rings, such as dihydroindanyl, phthalimide, naphthimide, phenanthridinyl, or tetrahydronaphthyl, are also included within the scope of the term "aryl." The term "phenylene" refers to a polyvalent phenyl group having an appropriate number of open valences to occupy the groups to which it is attached. For example, "phenylene" is a divalent phenyl group (e.g., ); "phenylene" is a trivalent phenyl group if it has three groups attached to it (e.g., ). The term "arylene" refers to a divalent aromatic group.

[0064] The terms "heteroaryl" and "heteroar-" (e.g., "heteroaralkyl" or "heteroaralkoxy"), used alone or as part of a larger moiety, refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic array; and having one to five heteroatoms other than carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur; and any quaternized form of a basic nitrogen. Heteroaryl includes, but is not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein, unless otherwise indicated, the group or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolyl, and tetrahydroisoquinolyl. The heteroaryl group may be monocyclic or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring," "heteroaryl," or "heteroaromatic," any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0065] The term "heteroarylene" refers to a polyvalent heteroaryl radical having an appropriate number of open valences to occupy the groups to which it is attached. For example, a "heteroarylene" is a divalent heteroaryl radical if two groups are attached; a "heteroarylene" is a trivalent heteroaryl radical if three groups are attached. The term "pyridylene" refers to a polyvalent pyridyl radical having an appropriate number of open valences to occupy the groups to which it is attached. For example, a "pyridylene" is a divalent pyridyl radical if two groups are attached (e.g., ); "pyridylene" is a trivalent pyridyl group if it has three groups attached (e.g., ).

[0066] As used herein, the terms "heterocycle," "heterocyclyl," "heterocyclic group," and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen," when used with respect to a ring atom of a heterocycle, includes substituted nitrogen. For example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or + NR (as in N-substituted pyrrolidinyl).

[0067] The heterocycle can be attached to its side group at any heteroatom or carbon atom to produce 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, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolane, diazepanyl, oxazepanyl, thiazepanyl, morpholinyl, 2-oxa-6-azaspiro[3.3]heptane, and quinuclidinyl. The terms "heterocycle," "heterocyclyl," "heterocyclyl ring," "heterocyclic group," "heterocyclic moiety," and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl group, wherein the alkyl and heterocyclyl portions are independently and optionally substituted.

[0068] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. As defined herein, the term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties.

[0069] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", 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 can be substituted by more than one substituent selected from a designated group, the substituents at each position may be the same or different. The combination of substituents envisioned by the present invention is preferably a combination that forms a stable or chemically feasible compound. As used herein, the term "stable" refers to a compound that does not substantially change when subjected to conditions that allow its production, detection, and in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0070] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0- 4SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh-, which can be R o Substituted; (CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 04 N(R o )C(O)NR o 2;-N(R o )C(S)NR o2;-(CH2) 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;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0- 4OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4OS(O)2R o ;-S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R 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)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definitions, two independent occurrences of R o Together with its one or more intervening atoms, it forms 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.

[0071] In certain embodiments, suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0-4 R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ;-O-(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2)0-4 O(CH2) 0-1 Ph, which can be R o Substitution; -CH=CHPh-, which can be R o Substituted; (CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 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;-(CH2) 0-4 C(O)R o :-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR o ;-SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o 、-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2; -(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R 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)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1-6 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definitions, two independent occurrences of R oTogether with its one or more intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be substituted as defined below.

[0072] R o (or by two independent occurrences of R o Suitable monovalent substituents on the ring formed by the ring and its intervening atoms are independently halogen, -(CH2) 0-2 R · 、-(halogen R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2;-O(halogen R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0- 2SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · , where each R · unsubstituted or, in the case of "halo" preceding it, substituted only with one or more halogens, and independently selected from C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. o Suitable divalent substituents for a saturated carbon atom of include =0 and =S.

[0073] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR * 2. =NNHC(O)R* 、=NNHC(O)OR * 、=NNHS(O)2R * 、=NR * 、=NOR * 、-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, where R * Each occurrence is independently selected from hydrogen, C 1-6 an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR * 2) 2-3 O-, where R * Each occurrence is independently selected from hydrogen, C 1-6 an aliphatic group, or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0074] R * Suitable substituents on the aliphatic group include halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0075] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1-6aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, regardless of the above definitions, two independent occurrences of Together with its one or more intervening atoms, it forms a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0076] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogen R · ), -OH, -OR · 、-O(halogen R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · unsubstituted or, when preceded by "halo", substituted only with one or more halogens, and independently C 1-4 Aliphatic groups, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0077] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, etc., within the scope of reasonable medical judgment and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J Pharmaceutical Sciences, 1977, 66, 1-19, which 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 of an amino group with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or an organic acid (e.g., acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid), or salts formed by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0078] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Other pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions (e.g., halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates).

[0079] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the present invention. The present invention includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds comprising the replacement of a hydrogen by deuterium or tritium or a carbon by 13 C- or 14 Compounds having the structures of the present invention that are C-enriched, carbon-substituted, and have the structures of the present invention are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents according to the present invention.

[0080] By methods well known to those skilled in the art, for example, by chromatography and / or fractional crystallization, diastereomeric mixtures can be separated into their individual diastereomers based on the differences in physical chemistry. Enantiomeric mixtures can be converted into diastereomeric mixtures by reacting with appropriate optically active compounds (for example, chiral auxiliary agents, such as chiral alcohols or Mosher's acid chlorides), separating diastereomers and converting (for example, hydrolyzing) a single diastereomer into the corresponding pure enantiomer, and separating enantiomers. Alternatively, the specific enantiomer of the compounds of this invention can be prepared by asymmetric synthesis. Further, when containing a basic functional group (for example, amino) or an acidic functional group (for example, carboxylic acid) in a molecule, diastereomeric salts are formed with appropriate optically active acids or bases, and the diastereomers thus formed are then split by fractional crystallization or chromatographic methods known in the art, and the pure enantiomer is subsequently recovered.

[0081] Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other or other selected stereoisomers. The chiral centers in the compounds of the invention may have the S or R configuration as defined by the IUPAC 1974 recommendations. In addition, if the compounds described herein may exist as atropisomers (e.g., substituted biaryls), all forms of such atropisomers are considered part of this invention.

[0082] Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a chemical compound, and there is an ambiguity between the structure and the name, the structure controls. It should also be noted that any carbon and heteroatom with unsaturated valences in the text, schemes, examples, and tables herein are assumed to have sufficient hydrogen atoms to satisfy the valences.

[0083] As used herein, the terms "a" and "an" mean "one or more" and include the plural unless the context is inappropriate.

[0084] The term "alkyl" refers to a saturated straight or branched chain hydrocarbon, such as a straight or branched chain group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C 12 Alkyl, C1-C 10 Alkyl and C1-C6 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-di-methyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like.

[0085] The term "cycloalkyl" refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group having 3-12, 3-8, 4-8, or 4-6 carbon atoms derived from a cycloalkane, referred to herein as, for example, a "C3-C6 cycloalkyl." Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term "cycloalkylene" refers to a divalent cycloalkyl group.

[0086] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, etc. The term "haloalkylene" refers to a divalent haloalkyl group.

[0087] The term "deuterated alkyl" refers to an alkyl group substituted with at least one deuterium.

[0088] The term "hydroxyalkyl" refers to an alkyl group substituted with at least one hydroxy group. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0089] The terms "alkenyl" and "alkynyl" are art-recognized and refer to unsaturated aliphatic groups of similar length and which may replace the alkyl groups described above, but that contain at least one double or triple bond, respectively.

[0090] The term "carbocyclylene" refers to a polyvalent carbocyclyl group having an appropriate number of open valences to occupy the groups to which it is attached. For example, a carbocyclylene group having two groups attached is a divalent carbocyclyl group; a carbocyclylene group having three groups attached is a trivalent carbocyclyl group.

[0091] The term "alkoxyl" or "alkoxy" is art-recognized and refers to an alkyl group as defined above having an oxygen group attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. The term "haloalkoxy" refers to an alkoxy group substituted with at least one halo group. Exemplary haloalkoxy groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like. The term "hydroxyalkoxy" refers to an alkoxy group substituted with at least one hydroxy group. Exemplary hydroxyalkoxy groups include -OCH2CH2OH, -OCH2C(H)(OH)CH2CH2OH, and the like. The term "alkyleneoxy" refers to a divalent alkoxy group.

[0092] The term "oxo" is art-recognized and refers to a "=O" substituent. For example, cyclopentane substituted with an oxo group is cyclopentanone.

[0093] symbol Indicates a connection point.

[0094] When a chemical structure containing a ring is depicted with a substituent having a bond that crosses a ring bond, the substituent can be attached at any available position on the ring. For example, the chemical structure Covered In the case of polycyclic fused rings, when a chemical structure containing a polycyclic fused ring is described as having one or more substituents having a bond spanning multiple rings, the one or more substituents can be independently attached to any ring spanned by the bond. For example, the chemical structure Covering e.g.

[0095] When any substituent or variable occurs more than one time in any constituent or compound of the invention, its definition on each occurrence is independent of its definition at every other occurrence unless otherwise indicated.

[0096] One or more compounds of the present invention may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol, etc., and the present invention is intended to include both solvated and unsolvated forms. The term "solvate or solvated" means the physical association of a compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic bonding and covalent bonding, including hydrogen bonding. In some cases, the solvate will be able to separate, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses solution phase and separable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, etc. "Hydrate" refers to a solvate in which the solvent molecule is H2O.

[0097] As used herein, a "GPR84 antagonist" or "GPR84 inhibitor" is a molecule that reduces, inhibits, or otherwise reduces 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 by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% compared to an appropriate control. In some embodiments, a GPR84 antagonist reduces, inhibits, or otherwise reduces the activity of GPR84. The compounds disclosed herein bind directly to GPR84 and inhibit its activity.

[0098] "Specific antagonist" means an agent that reduces, inhibits, or otherwise decreases the activity of a defined target to a greater extent than an unrelated target. For example, a GPR84-specific antagonist reduces at least one biological activity of GPR84 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In some embodiments, the IC of the antagonist for the target is greater than the IC of the antagonist for the target. 50 The IC of the antagonist for the non-target 50 The compounds disclosed herein may or may not be specific GPR84 antagonists. A specific GPR84 antagonist reduces the biological activity of GPR84 by an amount that is statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, a GPR84 antagonist specifically inhibits the activity of GPR84. In some of these embodiments, the GPR84 antagonist has an IC of 0.01% or less against GPR84.50 IC for GPR84 antagonists against closely related GPCRs (e.g., free fatty acid receptors (FFARs), such as GPR40 (FFAR1), GPR41 (FFAR3), GPR43 (FFAR2), or GPR120 (FFAR4)) or other types of GPCRs (e.g., type A GPCRs) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the total weight of the formulation.

[0099] The compounds of the present invention can be tethered to a detectable portion. It should be understood that such compounds can be used as developer. One of ordinary skill in the art will recognize that the detectable portion can be connected to the provided compound via a suitable substituent. As used herein, the term "suitable substituent" refers to a portion that can be covalently connected to a detectable portion. Such portions are well known to those of ordinary skill in the art and include groups containing, for example, carboxylate moieties, amino moieties, thiol moieties, or hydroxyl moieties. It should be understood that such portions can be directly or via a tethered group (e.g., a divalent saturated or unsaturated hydrocarbon chain) connected to the provided compound. In some embodiments, such portions can be connected via click chemistry. In some embodiments, such portions can be connected via 1,3-cycloaddition of 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 may be attached via strained alkynes. Methods for using strained alkynes to achieve fast Cu-free click chemistry are known in the art and include those described by Jewett et al., J. Am. Chem. Soc. 2010, 132(11), 3688-3690.

[0100] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety (e.g., primary and secondary labels) that is capable of being detected. Primary labels, such as radioisotopes (e.g., tritium, 32 p、 33 p、 35 S or 14 C) Mass tags and fluorescent labels are signal-generating reporters that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0101] As used herein, the term "secondary label" refers to a moiety (e.g., biotin and various protein antigens) that requires the presence of a second intermediate to produce a detectable signal. In the case of biotin, the secondary intermediate may include a streptavidin-enzyme conjugate. In the case of antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group using a non-radiative fluorescence resonance energy transfer (FRET) method, and the second group produces a detection signal.

[0102] As used herein, the terms "fluorescent label," "fluorescent dye," and "fluorophore" refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, Cyanine Dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, Dialkylaminocoumarins, 4′,5′-dichloro-2′,7′-dimethoxy-fluorescein, DM-NERF, Eosin, Erythrosin, Fluorescein, FAM, Hydroxycoumarins, IRDye (IRD40, IRD 700, IRD 800), JOE, Lissamine Rhodamine B, Marina Blue, Methoxycoumarin, Naphthylfluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, Pyrene, Rhodamine B, Rhodamine 6G, Rhodamine Green, Rhodamine Red, Rhodol Green, 2',4',5',7'-tetrakis-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0103] 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]isonipic acid, 4′-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxy)]methylacetophenone, and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patents 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of varying length and base composition, oligopeptides of varying length and monomer composition, oligosaccharides, and other synthetic polymers. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), with an appropriate mass range (100-2000 Daltons) can also be used as mass tags.

[0104] The compounds of the present invention can be tethered to the E3 ligase binding moiety. It should be understood that such compounds can be used as degradation agents (see, for example, Kostic and Jones, Trends Pharmacol. Sci., 2020, 41 (5), 305-31; Ottis and Crews, ACSChem. Biol. 2017, 12 (4), 892-898.). One of ordinary skill in the art will recognize that the E3 ligase binding moiety can be connected to the provided compound via a suitable substituent as defined above. Such degradation agents have been found to be useful for targeted degradation of G protein-coupled receptors (Li et al., Acta Pharm. Sin. B. 2020, 10 (9), 1669-1679.).

[0105] 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.

[0106] The compounds of the present invention can be tethered to the lysosomal targeting moiety. It should be understood that such compounds can be used as degradation agents (see, for example, Banik et al., 2020.Nature 584, 291-297.). One of ordinary skill in the art will recognize that the lysosomal targeting moiety can be connected to the provided compound via a suitable substituent as defined above. It has been found that such degradation agents can be used for targeted degradation of secretory and membrane proteins (Banik et al., 2020).

[0107] As used herein, the term "lysosomal targeting moiety" is used interchangeably with the term "lysosomal binding moiety" and refers to any moiety capable of binding to and / or recruiting a cell surface lysosomal targeting receptor (e.g., the cation-independent mannose-6-phosphate receptor, CI-M6PR) for targeted degradation.

[0108] As used herein, the terms "measurable affinity" and "measurably inhibit" mean a measurable change in GPR84 activity between a sample comprising a compound of the invention, or composition thereof, and GPR84 GPCR and an equivalent sample comprising GPR84 GPCR in the absence of the compound, or composition thereof.

[0109] Throughout this specification, when compositions are described as having, including, or comprising specific components, or when processes and methods are described as having, including, or comprising specific steps, it is also contemplated that there are compositions of the invention consisting essentially of, or consisting of, the recited components, and that there are processes and methods according to the invention consisting essentially of, or consisting of, the recited process steps.

[0110] Generally, percentages of compositions specified are by weight unless otherwise indicated.

[0111] 3. Description of exemplary embodiments:

[0112] As described above, in certain embodiments, the present invention provides a compound of formula I:

[0113]

[0114] or a pharmaceutically acceptable salt thereof, wherein:

[0115] R 1 for or Y 1 ;

[0116] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ;

[0117] R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ;

[0118] R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring;

[0119] R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0120] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing one nitrogen atom;

[0121] A 1 for or Y 4 , where ** is the same as A 2 connection points;

[0122] A 2 is phenylene, i.e., a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Y 5 ; wherein phenylene and heteroarylene are represented by n occurrences of R 3 replace;

[0123] L 1 C 1-3 alkylene;

[0124] Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、

[0125] Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C1 -5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substituted), -C≡C-(C 1-3 alkylene)-(imidazolyl)-(phenylene)-N(R 7 )(R 8 ), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(, 7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6 cycloalkyl), or hydrogen;

[0126] Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 deuterated alkyl)2;

[0127] Y 4 for

[0128] Among them, ** is the same as A2 connection points;

[0129] Y 5 quilt n occurrences of R 3 replace;

[0130] Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -N(R 7 )-(C 1-10 optionally substituted aliphatic)- or C 1-6 hydroxyalkyl;

[0131] Z 2 One of the following:

[0132] (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0133] (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0134] (c) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0135] n is 0, 1, or 2;

[0136] where Y 1 、Y 2 、Y 3 、Y 4 or Y 5 occurs at least once; and

[0137] The condition is that when Y 4 for When R 3 Not a methyl group.

[0138] The definitions of the variables in the above formula I encompass a plurality of chemical groups. The present application contemplates embodiments in which, 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) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0139] In certain embodiments, the compound is a compound of Formula I.

[0140] As generally defined above, R 1 for or Y 1 In some embodiments, R 1 yes In some embodiments, R 1 Y 1 In some embodiments, R 1 Y 1 , and Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 In some embodiments, R 1 Y 1 , and Y 1 -C(O)N(R 7 )(R 8 ). In some embodiments, R 1 Y 1 , and Y 1 -N(R 7 )C(O)(R 6 ) or -CO2R 7 In some embodiments, R 1 Y 1 , and Y 1 for In some embodiments, R 1 Y 1 , and Y 1 for

[0141] In some embodiments, R 1 Select from those depicted in Table 1.

[0142] As generally defined above, R 2For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 In some embodiments, R 2 -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 In some embodiments, R 2 -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is separated by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 In some embodiments, R 2 -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 In some embodiments, R 2 Y 2 .

[0143] In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7Cycloalkyl), -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

[0144] In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl) or -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 In some embodiments, R 2 -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

[0145] In some embodiments, R 2 Y 2 , and Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substituted), -C≡C-(C 1-3 alkylene)-(imidazolylene)-(phenylene)-N(R 7 )(R 8 ), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8)、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6 cycloalkyl), or hydrogen.

[0146] In some embodiments, R 2 Y 2 , and Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 Or -C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, R 2 Y 2 , and Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 In some embodiments, R 2 Y 2 , and Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 alkyl substituted), or In some embodiments, R 2 Y 2 , and Y 2 for In some embodiments, R 2 Y 2 , and Y 2 -(C appears 1 or 2 times 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-O-C3-6 cycloalkyl substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), or -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 In some embodiments, R 2 Y 2 , and Y 2 For-(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ) or C 3-7 In some embodiments, R 2 Y 2 , and Y 2is -(a saturated heterocyclic group containing 7-10 membered spirocyclic hydroxyl substituted with 1, 2 or 3 heteroatoms selected from nitrogen and oxygen) or -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur) or hydrogen.

[0147] In some embodiments, R 2 Select from those depicted in Table 1.

[0148] As generally defined above, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 .

[0149] In some embodiments, R 3 Each occurrence independently represents a halo. In some embodiments, R 3 Each occurrence represents C independently 1-4 In some embodiments, R 3 Each occurrence represents C independently 1-4 In some embodiments, R 3 Each occurrence represents C independently 1-4 In some embodiments, R 3 Each occurrence represents C independently 3-6 In some embodiments, R 3 Each occurrence represents -OC independently 3-6 In some embodiments, R 3 Each occurrence independently represents -N(R 7 )(R 8 ) or Y 3 .

[0150] In some embodiments, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 In some embodiments, R 3 Each occurrence represents C independently 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R8 ) or Y 3 In some embodiments, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 3-6 In some embodiments, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

[0151] In some embodiments, R 3 Select from those depicted in Table 1.

[0152] As generally defined above, R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring. 4 and R 5 Independently C 1-6 In some embodiments, R 4 and R 5 C 1-2 In some embodiments, R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring. 4 and R 5 Independently C 1-3 In some embodiments, R 4 and R 5 Independently C 2-6 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 C 1-6 In some embodiments, R 4 C 1-3 In some embodiments, R 4In some embodiments, R 4 In some embodiments, R 5 C 1-6 In some embodiments, R 5 C 1-3 In some embodiments, R 5 In some embodiments, R 5 In some embodiments, R 4 and R 5 In some embodiments, R 4 and R 5 Not the same.

[0153] In some embodiments, R 4 and R 5 Each is independently selected from those depicted in Table 1.

[0154] As generally defined above, R 6 C 1-6 Alkyl or C 3-6 In some embodiments, R 6 C 1-6 In some embodiments, R 6 C 3-6 In some embodiments, R 6 C 1-3 In some embodiments, R 6 C 2-6 In some embodiments, R 6 In some embodiments, R 6 In some embodiments, R 6 Select from those depicted in Table 1.

[0155] As generally defined above, R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Each occurrence independently represents hydrogen. In some embodiments, R 7 and R 8 Each occurrence represents C independently 1-6 In some embodiments, R 7 and R 8Each occurrence represents C independently 3-6 In some embodiments, R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Each occurrence represents C independently 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Each occurrence independently represents hydrogen; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0156] In some embodiments, R 7 and R 8 Each occurrence is independently selected from those depicted in Table 1.

[0157] As generally defined above, A 1 for or Y 4 , where ** is the same as A 2 In some embodiments, A 1 for Among them, ** is the same as A 2 In some embodiments, R 1 Y 4 In some embodiments, A 1 for or Y 4 , where ** is the same as A 2 In some embodiments, A 1 for Among them, ** is the same as A 2 In some embodiments, A 1 Y 4 And Y 4 for Among them, ** is the same as A 2 In some embodiments, A 1 Y4 And Y 4 for Among them, ** is the same as A 2 connection point.

[0158] In some embodiments, A 1 Y 4 And Y 4 for Among them, ** is the same as A 2 In some embodiments, A 1 Y 4 And Y 4 for Among them, ** is the same as A 2 connection point.

[0159] In some embodiments, A 1 Select from those depicted in Table 1.

[0160] As generally defined above, A 2 is phenylene, i.e., a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Y 5 ; wherein phenylene and heteroarylene are represented by n occurrences of R 3 In some embodiments, A 2 is R that appears n times 3 In some embodiments, A 2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 In some embodiments, A 2 Y 5 In some embodiments, A 2 is R that appears n times 3 In some embodiments, A 2 Y 5 , and Y 5 is R that appears n times 3 Replaced In some embodiments, A 2 Select from those depicted in Table 1.

[0161] As generally defined above, L 1 C 1-3 In some embodiments, L 1 C 1-2 In some embodiments, L 1 C 2-3In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 In some embodiments, L 1 Select from those depicted in Table 1.

[0162] As generally defined above, Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 In some embodiments, Y 1 -C(O)N(R 7 )(R 8 ). In some embodiments, Y 1 -N(R 7 )C(O)(R 6 ). In some embodiments, Y 1 -CO2R 7 In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for In some embodiments, Y 1 for

[0163] In some embodiments, Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ) or -CO2R 7In some embodiments, Y 1 -N(R 7 )C(O)(R 6 ) or -CO2R 7 In some embodiments, Y 1 -C(O)N(R 7 )(R 8 ) or -CO2R 7 In some embodiments, Y 1 -C(O)N(R 7 )(R 8 ) or -N(R 7 )C(O)(R 6 ).

[0164] In some embodiments, Y 1 for In some embodiments, Y 1 -C(O)N(R 7 )(R 8 ), -N(R 7 )C(O)(R 6 ), -CO2R 7 、

[0165] In some embodiments, Y 1 -C(O)N(R 7 )(R 8 ), -N(R 7 )C(O)(R 6 ), -CO2R 7 、

[0166] In some embodiments, Y 1 Select from those depicted in Table 1.

[0167] As generally defined above, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substituted), -C≡C-(C 1-3 alkylene)-(imidazolylene)-(phenylene)-N(R 7 )(R 8 ), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7)-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6 cycloalkyl), or hydrogen.

[0168] In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 ). In some embodiments, Y 2 =-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 In some embodiments, Y 2 =-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 3-6 In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 1-5 In some embodiments, Y 2 =-C≡C-(C 1-5 In some embodiments, Y 2 In some embodiments, Y 2 is -C≡C-(C(CH3)2(OH)). In some embodiments, Y 2 In some embodiments, Y 2 =-C≡C-(C1-3 Alkylene)-N(R 7 )(a 4-6 membered saturated heterocyclic group containing 1 oxygen atom). In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or in some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 for In some embodiments, Y 2 -(C appears 1 or 2 times 1-4 Alkyl-substituted azetidinyl)-Z 2 In some embodiments, Y 2 For - (by a C 1-4 A haloalkyl group and a C 1-4 In some embodiments, Y 2 For - (by a C 1-4 Alkyl and a -C 1-3 Alkylene-OC 3-6 In some embodiments, Y 2 For - (by a C 1-4 a haloalkyl group and a C 1-4 In some embodiments, Y 2 For - (by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 In some embodiments, Y 2 For-(C 0-3In some embodiments, Y 2 C 1-4 In some embodiments, Y 2 For-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, Y 2 -O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, Y 2 -N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, Y 2 C 3-7 In some embodiments, Y 2 is -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen). In some embodiments, Y 2 -C(O)N(R7)-(C 1-3 In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 For (C 1-4 In some embodiments, Y 2 For-(C 1-4 alkylene)-(C 3-6 In some embodiments, Y 2 For hydrogen.

[0169] In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or (C 1-4 alkylene)-(C 3-6 cycloalkyl).

[0170] In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution),

[0171] In some embodiments, Y 2 yes -(C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6 cycloalkyl), or hydrogen.

[0172] In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C0-3 Alkylene)-N(R 7 )C(O)R 6 Or -C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 In some embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 alkyl substituted), or

[0173] In some embodiments, Y 2 for

[0174] In some embodiments, Y 2 -(C appears 1 or 2 times 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), or -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4In some embodiments, Y 2 For-(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ) or C 3-7 In some embodiments, Y 2 is -(a saturated heterocyclic group containing 7-10 membered spirocyclic hydroxyl substituted with 1, 2 or 3 heteroatoms selected from nitrogen and oxygen) or -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur) or hydrogen.

[0175] In some embodiments, Y 2 Select from those depicted in Table 1.

[0176] As generally defined above, Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 In some embodiments, Y 3 -N(R 7 )(C 1-4 In some embodiments, Y 3 -N(R 7 )(C 1-3 In some embodiments, Y 3 -N(R 7 )(C 2-4 In some embodiments, Y 3 -N(C 1-4 In some embodiments, Y 3 Select from those depicted in Table 1.

[0177] As generally defined above, Y 4 for Among them, ** is the same as A2 connection point.

[0178] In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for wherein ** is the point of attachment to A2. In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 In some embodiments, Y 4 for Among them, ** is the same as A 2 connection point.

[0179] In some embodiments, Y 4 Select from those depicted in Table 1.

[0180] As generally defined above, Y 5 quilt n occurrences of R 3 replace;

[0181] In some embodiments, Y 5 Select from those depicted in Table 1.

[0182] As generally defined above, Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -N(R 7 )-(C 1-10 optionally substituted aliphatic)-, or C 1-6 In some embodiments, Z 1 C 1-10 In some embodiments, Z 1 For-(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 In some embodiments, Z 1 -N(R 7 )-(C 0-3 (alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In some embodiments, Z 1 For-(C 0-3 (alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In some embodiments, Z 1 -N(R 7 )-(C 1-10 In some embodiments, Z 1 C 1-6 Hydroxyalkyl.

[0183] In some embodiments, Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or -(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0184] In some embodiments, Z 1 For-(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or -(C 0-3 (alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In some embodiments, Z 1 C 1-10 Aliphatic or C 1-6 In some embodiments, Z 1 C 1-10 Aliphatic or -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 In some embodiments, Z 1 -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 Hydroxyalkyl.

[0185] In some embodiments, Z 1 Select from those depicted in Table 1.

[0186] As generally defined above, Z 2 One of the following:

[0187] (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0188] (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0189] (c) 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0190] In some embodiments, Z 2 is a 3-7 membered saturated heterocyclic group, which is replaced by 1 or 2 occurrences of R 3 In some embodiments, Z 2 For-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 (alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In some embodiments, Z 2 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0191] In some embodiments, Z 2 One of the following:

[0192] (a)-(C 0-3 Alkylene)-N(R7)-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0193] (b) 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0194] In some embodiments, Z 2 One of the following:

[0195] (a) 1 or 2 occurrences of R 3 substituted 3-7 membered saturated heterocyclic group, or

[0196] (b) 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0197] In some embodiments, Z 2 One of the following:

[0198] (a) 1 or 2 occurrences of R 3 substituted 3-7 membered saturated heterocyclic group, or

[0199] (b)-(C 0-3 Alkylene)-N(R7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

[0200] In some embodiments, Z 2 Select from those depicted in Table 1.

[0201] As generally defined above, n is 0, 1, or 2. 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.

[0202] As generally defined above, the compound of formula I contains Y 1 、Y 2 、Y 3 、Y 4 or Y 5 In some embodiments, the compound of formula I comprises Y 2 、Y 3 、Y 4 or Y 5 In some embodiments, the compound of formula I comprises Y 1 、Y 3 、Y 4 or Y 5 In some embodiments, the compound of formula I comprises Y 1 、Y 2 、Y 4 or Y 5 In some embodiments, the compound of formula I comprises Y 1 、Y 2 、Y 3 or Y 5 In some embodiments, the compound of formula I comprises Y 1 、Y 2 、Y 3 or Y 4 At least one occurrence of .

[0203] In some embodiments, the compound of Formula I comprises Y 1 In some embodiments, the compound of formula I comprises Y 2 In some embodiments, the compound of formula I comprises Y 3 In some embodiments, the compound of formula I comprises Y 4In some embodiments, the compound of formula I comprises Y 5 At least one occurrence of .

[0204] In some embodiments, the present invention provides a compound of Formula Ia or Ib, or a pharmaceutically acceptable salt thereof:

[0205]

[0206] where R 2 、R 3 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、Y 2 、Y 3 、Y 4 、Y 5 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0207] In some embodiments, the present invention provides a compound of formula Ia or Ib

[0208]

[0209] where R 2 、R 3 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、Y 2 、Y 3 、Y 4 、Y 5 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0210] In some embodiments, the present invention provides a compound of Formula Ic, or a pharmaceutically acceptable salt thereof:

[0211]

[0212] where R 2 、R 3 、R 6 、R 7 、R 8 、A 1 、A2 、L 1 、Y 2 、Y 3 、Y 4 、Y 5 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0213] In some embodiments, the present invention provides a compound of formula Ic

[0214]

[0215] where R 2 、R 3 、R 6 、R 7 、R 8 、A 1 、A 2 、L 1 、Y 2 、Y 3 、Y 4 、Y 5 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0216] In some embodiments, the present invention provides a compound of Formula Id or Ie, or a pharmaceutically acceptable salt thereof:

[0217]

[0218] where R 2 、R 6 、R 7 、R 8 、L 1 、Y 2 、Y 3 , Z 1 and Z 2 Each of which, individually and in combination, is as defined above and as described in the embodiments herein.

[0219] In some embodiments, the present invention provides a compound of Formula Id or Ie:

[0220]

[0221] where R 2 、R 6 、R 7 、R 8 、L 1 、Y2 、Y 3 、Z 1 and Z 2 Each of which, individually and in combination, is as defined above and as described in the embodiments herein.

[0222] In some embodiments, the present invention provides a compound of formula If, or a pharmaceutically acceptable salt thereof,

[0223]

[0224] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0225] In some embodiments, the present invention provides a compound of formula If:

[0226]

[0227] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0228] In some embodiments, the present invention provides a compound of Formula Ig, or a pharmaceutically acceptable salt thereof:

[0229]

[0230] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 、Z 1 、Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0231] In some embodiments, the present invention provides a compound of formula Ig:

[0232]

[0233] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0234] In some embodiments, the present invention provides a compound of Formula Ih, or a pharmaceutically acceptable salt thereof:

[0235]

[0236] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0237] In some embodiments, the present invention provides a compound of formula Ih:

[0238]

[0239] where R 2 、R 3 、R 6 、R 7 、R 8 、Y 2 、Y 3 , Z 1 , Z 2 Each of and n, individually and in combination, is as defined above and as described in the embodiments herein.

[0240] Another aspect of the present invention provides a compound of formula IA:

[0241]

[0242] or a pharmaceutically acceptable salt thereof, wherein:

[0243] R 1 for or Y 1 ;

[0244] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ;

[0245] R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ;

[0246] R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring;

[0247] R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0248] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing one nitrogen atom;

[0249] A 1 for or Y 4 , where ** is the same as A 2 connection points;

[0250] A 2 is phenylene, i.e., a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Y 5 ; wherein phenylene and heteroarylene are represented by n occurrences of R 3 replace;

[0251] L 1 C 1-3 alkylene;

[0252] Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、

[0253] Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7)(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -(C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6 cycloalkyl), or hydrogen;

[0254] Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 deuterated alkyl)2;

[0255] Y 4 for Among them, ** is the same as A 2 connection points;

[0256] Y 5 quilt n occurrences of R 3 replace;

[0257] Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -N(R 7 )-(C 1-10 optionally substituted aliphatic)- or C 1-6 hydroxyalkyl;

[0258] Z 2 One of the following:

[0259] (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0260] (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0261] (c) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0262] n is 0, 1, or 2.

[0263] In certain embodiments, the definitions of the variables in Formula IA are one of the embodiments described above for Formula I. In certain embodiments, when Y 4 for Then R 3 Not meth.

[0264] Another aspect of the present invention provides a compound of formula II:

[0265]

[0266] or a pharmaceutically acceptable salt thereof, wherein:

[0267] R 1 for or Y 1 ;

[0268] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(C 2-4 Alkynylidene)-(occurred 0, 1 or 2 times by R 10 Substituted phenyl), -(C 2-4 Alkynylidene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ;

[0269] R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7)(R 8 ) or Y 3 ;

[0270] R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring;

[0271] R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0272] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing one nitrogen atom:

[0273] R 9 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0274] R 10 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl;

[0275] A 1 for or Y 4 , where ** is related to L 2 connection points;

[0276] A 2 is phenylene or Y 5 , where the phenylene group is replaced by n occurrences of R 3 replace;

[0277] L 1 C 1-3 alkylene;

[0278] L 2 -N(R 9 )-、Y 6 or C 1-4 Alkoxy-substituted C 1-4 alkylene;

[0279] Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 replace;

[0280] Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -(1 or 2 occurrences of C 1-4Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-4 Haloalkoxy-substituted azetidinyl)-, -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 0-4 alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 hydroxyalkyl, or hydrogen;

[0281] Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 deuterated alkyl)2;

[0282] Y 4 for Where ** is the same as L 2 connection points;

[0283] Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 replace;

[0284] Y 6 (a)-C≡C- or -(C 1-4 Alkylene)(C(H)(C 1-4 Alkoxy)-, (b) 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 Alkylene, (c) -SC 1-4 Alkyl substituted C 1-4 Alkylene, or (d) -CH2- or -O-;

[0285] Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 hydroxyalkyl;

[0286] Z 2 One of the following:

[0287] (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0288] (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0289] (c) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0290] n is 0, 1, or 2;

[0291] where Y 1 、Y 2 、Y 3、Y 4 、Y 5 or Y 6 occurs at least once; and

[0292] The condition is that if A 1 for And Y 6 When it is -CH2- or -O-, then R 3 Not a methyl group.

[0293] The definitions of the variables in Formula II above encompass a plurality of chemical groups. The present application contemplates embodiments in which, 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) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0294] In certain embodiments, the compound is of Formula II.

[0295] As generally defined above, R 1 for or Y 1 In certain embodiments, R 1 for In certain embodiments, R 1 Y 1 .

[0296] In some embodiments, R 1 Select from those depicted in Table 2.

[0297] As generally defined above, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(C 2-4 Alkynylidene)-(occurred 0, 1 or 2 times by R 10 Substituted phenyl), -(C 2-4 Alkynylidene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 In certain embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl) or -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 In certain embodiments, R 2 For-(C 2-4 Alkynylidene)-(occurred 0, 1 or 2 times by R 10 Substituted phenyl), -(C 2-4 Alkynylidene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 In certain embodiments, R 2 Y 2 In certain embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 3-7 In certain embodiments, R 2 For-(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 In certain embodiments, R 2 -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is replaced by 0, 1 or 2 independently selected C1-6 Alkyl and C 1-6 In certain embodiments, R 2 -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is separated by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 In certain embodiments, R 2 -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(occurred 0, 1 or 2 times by R 10 In some embodiments, R 2 For-(C 2-4 Alkynylidene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 In some embodiments, R 2 Select from those depicted in Table 2.

[0298] As generally defined above, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 In certain embodiments, R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 In certain embodiments, R 3 Y 3 In certain embodiments, R 3 In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 1-4 In certain embodiments, R 3 C 3-6In certain embodiments, R 3 For-OC 3-6 In certain embodiments, R 3 -N(R 7 )(R 8 ). In some embodiments, R 3 Select from those depicted in Table 2 below.

[0299] As generally defined above, R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring. 4 and R 5 Independently C 1-6 In certain embodiments, R 4 and R 5 Independently C 1-2 In certain embodiments, R 4 and R 5 In certain embodiments, R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring. 4 and R 5 Together with their intervening atoms, they form a 3-membered saturated carbocyclic ring. 4 is selected from those depicted in Table 2 below. In some embodiments, R 5 Select from those depicted in Table 2 below.

[0300] As generally defined above, R 6 C 1-6 Alkyl or C 3-6 In certain embodiments, R 6 C 1-6 In certain embodiments, R 6 C 3-6 In some embodiments, R 6 Select from those depicted in Table 2 below.

[0301] As generally defined above, R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 7 Each occurrence independently represents hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 7 In certain embodiments, R 7 C 1-6 In certain embodiments, R 7 C 3-6 In certain embodiments, R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom. 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl, or C 3-6 In certain embodiments, R 8 In certain embodiments, R 8 C 1-6 In certain embodiments, R 8 C 3-6 In some embodiments, R 7 is selected from those depicted in Table 2 below. In some embodiments, R 8 Select from those depicted in Table 2 below.

[0302] As generally defined above, R 9 For hydrogen, C 1-6 Alkyl or C 3-6 In certain embodiments, R 9 In certain embodiments, R 9 C 1-6 In certain embodiments, R 9 C 3-6 In some embodiments, R 9 Select from those depicted in Table 2 below.

[0303] As generally defined above, R 10 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 3-6 In some embodiments, R 10 Select from those depicted in Table 2 below.

[0304] In certain embodiments, R 10 In certain embodiments, R10 C 1-4 In certain embodiments, R 10 C 1-4 In certain embodiments, R 10 C 1-4 In certain embodiments, R 10 C 3-6 Cycloalkyl.

[0305] As generally defined above, A 1 for or Y 4 , where ** is related to L 2 In certain embodiments, A 1 for Where ** is the same as L 2 In certain embodiments, A 1 Y 4 In some embodiments, A 1 Select from those depicted in Table 2 below.

[0306] As generally defined above, A 2 is phenylene or Y 5 , where the phenylene group is replaced by n occurrences of R 3 In certain embodiments, A 2 is R that appears n times 3 In certain embodiments, A 2 Y 5 In some embodiments, A 2 Select from those depicted in Table 2 below.

[0307] As generally defined above, L 1 C 1-3 In certain embodiments, L 1 In some embodiments, L 1 Select from those depicted in Table 2.

[0308] As generally defined above, L 2 -N(R 9 )-、Y 6 or C 1-4 Alkoxy-substituted C 1-4 In certain embodiments, L 2 -N(R 9 )-. In certain embodiments, L 2 Y 6 In certain embodiments, L 2 For C 1-4Alkoxy-substituted C 1-4 In some embodiments, L 2 Select from those depicted in Table 2.

[0309] As generally defined above, Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 In certain embodiments, Y 1 -C(O)N(R 7 )(R 8 ). In certain embodiments, Y 1 -N(R 7 )C(O)(R 6 ) or -CO2R 7 In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 In certain embodiments, Y 1 -N(R 7 )C(O)(R 6 ). In certain embodiments, Y 1 -CO2R 7 In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In certain embodiments, Y 1 for In some embodiments, Y 1 Select from those depicted in Table 2.

[0310] As generally defined above, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C0-3 alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -(C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-4 haloalkoxy-substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 0-4 alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ), or -C≡C-(C 1-3 Alkylene)-N(R 7 )(R8 )). In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 Alkyl substitution),

[0311] In certain embodiments, Y 2 for In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 ). In certain embodiments, Y 2 =-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 In certain embodiments, Y 2 =-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8 ). In certain embodiments, Y 2=-C≡C-(C 1-3 Alkylene)-O-(C 3-6 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-O-(C 1-5 In certain embodiments, Y 2 =-C≡C-(C 1-5 In certain embodiments, Y 2 In certain embodiments, Y 2 is -C≡C-(C(CH3)2(OH))). In certain embodiments, Y 2 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )(a 4-6 membered saturated heterocyclic group containing 1 oxygen atom). In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 In certain embodiments, Y 2 =-C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 In certain embodiments, Y 2 for In certain embodiments, Y 2 for In certain embodiments, Y 2 for In certain embodiments, Y 2 for

[0312] In certain embodiments, Y 2 for In certain embodiments, Y 2 for In certain embodiments, Y 2 for In certain embodiments, Y 2 -(C appears 1 or 2 times 1-4 Alkyl-substituted azetidinyl)-Z 2 In certain embodiments, Y 2 For - (by a C 1-4 a haloalkyl group and a C1-4 In certain embodiments, Y 2 For - (by a C 1-4 Alkyl and a -C 1-3 Alkylene-OC 3-6 In certain embodiments, Y 2 For - (by a C 1-4 a haloalkyl group and a C 1-4 In certain embodiments, Y 2 For - (by a C 1-4 Alkyl and a C 1-4 In certain embodiments, Y 2 For-(C 0-3 In certain embodiments, Y 2 C 1-4 In certain embodiments, Y 2 For-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ). In certain embodiments, Y 2 -O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ). In certain embodiments, Y 2 -N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ). In certain embodiments, Y 2 C 3-7 In certain embodiments, Y 2 is -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclyl containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen). In certain embodiments, Y 2 -C(O)N(R 7 )-(C 1-3 In certain embodiments, Y 2 In certain embodiments, Y 2 In certain embodiments, Y 2 For-(C 1-4 In certain embodiments, Y 2 For-(C0-4 alkylene)-(C 3-6 In certain embodiments, Y 2 C 1-4 In certain embodiments, Y 2 C 1-6 In certain embodiments, Y 2 For hydrogen.

[0313] In certain embodiments, Y 2 -(C appears 1 or 2 times 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), or -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 In certain embodiments, Y 2 For-(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ) or C 3-7 In certain embodiments, Y 2 -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C0-4 alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 Hydroxyalkyl, or hydrogen.

[0314] In some embodiments, Y 2 Select from those depicted in Table 2.

[0315] As generally defined above, Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 In certain embodiments, Y 3 -N(H)(C 1-4 In some embodiments, Y 3 -N(C 1-4 In some embodiments, Y 3 Select from those depicted in Table 2.

[0316] As generally defined above, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 connection point.

[0317] In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 connection point.

[0318] In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In some embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 for Where ** is the same as L 2 In certain embodiments, Y 4 In certain embodiments, Y 4 for Where ** is the same as L 2 In some embodiments, Y 4 Select from those depicted in Table 2.

[0319] As generally defined above, Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 In certain embodiments, Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 In certain embodiments, Y 5 is R that appears n times 3In some embodiments, Y 5 Select from those depicted in Table 2.

[0320] As generally defined above, Y 6 (a)-C≡C- or -(C 1-4 Alkylene)(C(H)(C 1-4 Alkoxy)-, (b) 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 Alkylene, (c) -SC 1-4 Alkyl substituted C 1-4 In certain embodiments, Y 6 In certain embodiments, Y 6 For-(C 1-4 Alkylene)(C(H)(C 1-4 In certain embodiments, Y 6 is 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 In certain embodiments, Y 6 For the SC 1-4 Alkyl substituted C 1-4 In certain embodiments, Y 6 In certain embodiments, Y 6 In some embodiments, Y 6 Select from those depicted in Table 2.

[0321] As generally defined above, Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 In certain embodiments, Z 1 C 1-10 Aliphatic or -(C 0-3Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 In certain embodiments, Z 1 -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 In some embodiments, Z 1 Select from those depicted in Table 2.

[0322] As generally defined above, Z 2 One of the following:

[0323] (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0324] (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0325] (c) 5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0326] In certain embodiments, Z 2 For R that appears 1 or 2 times 3 In certain embodiments, Z 2 For-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 (alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur). In certain embodiments, Z 2 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur. 1 Select from those depicted in Table 2.

[0327] As generally defined above, n is 0, 1, or 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In some embodiments, n is selected from those depicted in Table 2.

[0328] As generally defined above, Y 1 、Y 2 、Y 3 、Y 4 、Y 5 or Y 6 Occurs at least once.

[0329] In certain embodiments, Y 1 In certain embodiments, Y 2 In certain embodiments, Y 3 In certain embodiments, Y 4 In certain embodiments, Y 5 In certain embodiments, Y 6 Appears once.

[0330] In certain embodiments, the compound of Formula II is a compound of Formula IIa or IIb, or a pharmaceutically acceptable salt thereof:

[0331]

[0332] In certain embodiments, the variable L 1 、L 2 、A 1 、A 2 and R 2 The definition of is one of the embodiments described above in conjunction with formula II.

[0333] In certain embodiments, the compound of Formula II is a compound of Formula IIc or a pharmaceutically acceptable salt thereof:

[0334]

[0335] In certain embodiments, the variable L 1 、L 2 、A 1 、A 2 and R 2 The definition of is one of the embodiments described above in conjunction with formula II.

[0336] In certain embodiments, the compound of Formula II is a compound of Formula IId or IIe, or a pharmaceutically acceptable salt thereof:

[0337]

[0338] In certain embodiments, the variable L 1 、L 2 、R 2 and R 3The definition of is one of the embodiments described above in conjunction with formula II.

[0339] In certain embodiments, the compound of Formula II is a compound of Formula IIf or a pharmaceutically acceptable salt thereof:

[0340]

[0341] In certain embodiments, the variable R 7 、R 8 、L 2 、R 2 and R 3 The definition of is one of the embodiments described above in conjunction with formula II.

[0342] In certain embodiments, the compound of Formula II is a compound of Formula IIg or a pharmaceutically acceptable salt thereof:

[0343]

[0344] In certain embodiments, the variable R 7 、R 8 、L 2 、R 2 and R 3 The definition of is one of the embodiments described above in conjunction with formula II.

[0345] Another aspect of the present invention provides a compound of formula II-A:

[0346]

[0347] or a pharmaceutically acceptable salt thereof, wherein:

[0348] R 1 for or Y 1 ;

[0349] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(C 2-4 Alkynylidene)-(occurred 0, 1 or 2 times by R 10 Substituted phenyl), -(C 2-4 Alkynylidene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ;

[0350] R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ;

[0351] R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring;

[0352] R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0353] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing one nitrogen atom;

[0354] R 9 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0355] R 10 Each occurrence independently represents a halogen, C1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl;

[0356] A 1 for or Y 4 , where ** is related to L 2 connection points;

[0357] A 2 is phenylene or Y 5 , where the phenylene group is replaced by n occurrences of R 3 replace;

[0358] L 1 C 1-3 alkylene;

[0359] L 2 -N(R 9 )-、Y 6 or C 1-4 Alkoxy-substituted C 1-4 alkylene;

[0360] Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 replace;

[0361] Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8)、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -(C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-4 haloalkoxy-substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 0-4 alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 hydroxyalkyl, or hydrogen;

[0362] Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 deuterated alkyl)2;

[0363] Y 4 for Where ** is the same as L 2 connection points;

[0364] Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 replace;

[0365] Y 6 (a)-C≡C- or -(C 1-4 Alkylene)(C(H)(C 1-4 Alkoxy)-, (b) 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 Alkylene, (c) -SC 1-4 Alkyl substituted C 1-4 Alkylene, or (d) -CH2- or -O-;

[0366] Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 hydroxyalkyl;

[0367] Z 2 One of the following:

[0368] (d) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0369] (e)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0370] (f) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0371] n is 0, 1, or 2.

[0372] In certain embodiments, the variables in Formula II-A are as defined above in the embodiments of Formula II. 1 for And Y 6 is -CH2- or -O-, then R 3 Not a methyl group.

[0373] In certain embodiments, the present invention provides compounds of formula III:

[0374]

[0375] or a pharmaceutically acceptable salt thereof, wherein:

[0376] R 1 for or Y 1 ;

[0377] R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 alkylene)-(C 1-6 Alkoxy), -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected C 1-6 Alkyl and C1-6 substituted with a hydroxyalkyl group), -(a 7-9 membered saturated spirocyclic heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic group is replaced by 0, 1 or 2 independently selected C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), -(3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), -C(=N(R 7 )2)N(R 7 )2, or Y 2 ;

[0378] R 3 Each occurrence independently represents a halo, a hydroxyl, a C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ;

[0379] R 4 and R 5 Independently C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring;

[0380] R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0381] R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; wherein the ring is substituted with 0, 1 or 2 occurrences of hydroxyl;

[0382] A 1 for or Y 4 , where ** is the same as A 2 connection points;

[0383] A 2is phenylene, i.e., a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Y 5 ; wherein phenylene and heteroarylene are represented by n occurrences of R 3 replace;

[0384] L 1 C 1-3 Alkylene, C 1-3 alkylene halide or covalent bond;

[0385] Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 、 a 5-6 membered heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or -C(O)-(a 5-6 membered saturated heterocyclyl containing 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur), wherein the heteroaryl and heterocyclyl are replaced by 0, 1 or 2 occurrences of R 3 replace;

[0386] Y 2 =-C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C0-3 alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 Halogenated alkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing one oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7)-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substituted), -C≡C-(C 1-3 alkylene)-(imidazolyl)-(phenylene)-N(R 7 )(R 8 ), -(C 1-4 Alkyl-substituted azetidinyl)-Z 2 、-(become a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 a haloalkyl group and a C 1-4 Alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 Alkylene)-CN, -(C2 alkynylene)-CN, C 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 Alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 alkylene)-(C 3-6cycloalkyl), hydrogen, or a 5-6 membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur, wherein the heteroaryl is replaced by 0, 1, 2 or 3 occurrences of R 3 replace;

[0387] Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 deuterated alkyl)2;

[0388] Y 4 for A 5-6 membered saturated heterocyclylene containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroarylene containing 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein ** is 2 connection points;

[0389] Y 5 quilt n occurrences of R 3 replace;

[0390] Z 1 C 1-10 Aliphatic group, -(C 0-3 Alkylene)-(3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is separated by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with hydroxyalkyl), -N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -N(R 7 )-(C 1-10 optionally substituted aliphatic)- or C 1-6 hydroxyalkyl;

[0391] Z 2 One of the following:

[0392] (d) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group,

[0393] (e)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or

[0394] (f) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and

[0395] n is 0, 1, or 2.

[0396] The definitions of the variables in Formula III above encompass a plurality of chemical groups. The present application contemplates embodiments in which, 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) a compound is defined by a combination of variables, wherein the variable is defined by either (i) or (ii).

[0397] In certain embodiments, L 1 C 1-3 In certain embodiments, L 1 C 1-3 In certain embodiments, L 1 It is a covalent bond.

[0398] In certain embodiments, R 2 Y 2 , where Y 2 is a 5-6 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the heteroaryl group is replaced by 0, 1, 2 or 3 occurrences of R 3 replace.

[0399] One aspect of the present invention provides a compound of Table 1, Table 2, or Table 3, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of Table 1, Table 2, or Table 3. Another aspect of the present invention provides a compound of Table 1, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of Table 1. Another aspect of the present invention provides a compound within the range of I-1 to I-213 in Table 1, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound within the range of I-1 to I-213 in Table 1. Another aspect of the present invention provides a compound of Table 2, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of Table 2. Another aspect of the present invention provides a compound within the range of I-29 to I-209 in Table 2, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound within the range of I-29 to I-209 in Table 2. Another aspect of the present invention provides a compound of Table 3, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides a compound of Table 3. Another aspect of the present invention provides a compound within the range of I-2 to I-192 in Table 3, or a pharmaceutically acceptable salt thereof. Another aspect of the present invention provides compounds within the range of 1-2 to 1-192 in Table 3.

[0400] Table 1.

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420] Table 2.

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427] Table 3.

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

[0436]

[0437]

[0438]

[0439] In some embodiments, the present invention provides a compound described herein (e.g., a compound of Formula I or II as defined above, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition as defined above, and a pharmaceutically acceptable carrier, adjuvant, or vehicle for use as a medicament.

[0440] In some embodiments, the present invention also provides a compound described herein (e.g., a compound of Formula I or II) or a pharmaceutical composition described herein, for use in a method of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0441] In some embodiments, the present invention also provides a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for use in a method of inhibiting GPR84 as described herein.

[0442] In some embodiments, the present invention also provides a compound described herein (e.g., a compound of Formula I or II) or a pharmaceutical composition described herein or as described herein for use in a method of modulating an immune response in a subject in need thereof as described herein.

[0443] In some embodiments, the present invention also provides a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for use in a method of treating a GPR84-dependent disorder as described herein.

[0444] In some embodiments, the present invention also provides the use of a compound described herein (e.g., a compound of Formula I or II) or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting GPR84, a medicament for modulating an immune response in a subject in need thereof, and / or a medicament for treating a GPR84-dependent disorder.

[0445] In some embodiments, the present invention also provides the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for the manufacture of a medicament for inhibiting GPR84.

[0446] In some embodiments, the present invention also provides the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for the manufacture of a medicament for modulating an immune response in a subject in need thereof.

[0447] In some embodiments, the present invention also provides the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for the manufacture of a medicament for treating a GPR84-dependent disorder.

[0448] In some embodiments, the present invention also provides the use of a compound described herein (e.g., a compound of Formula I or II) or a pharmaceutical composition described herein, for use in a method of inhibiting GPR84 as described herein, for use in a method of modulating an immune response in a subject in need thereof as described herein, and / or for use in a method of treating a GPR84-dependent disorder as described herein.

[0449] In some embodiments, the present invention also provides for the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for use in a method of inhibiting GPR84 as described herein.

[0450] In some embodiments, the present invention also provides for the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for use in a method of modulating an immune response in a subject in need thereof as described herein.

[0451] In some embodiments, the present invention also provides for the use of a compound described herein (eg, a compound of Formula I or II) or a pharmaceutical composition described herein for use in a method of treating a GPR84-dependent disorder as described herein.

[0452] 4. General Methods for Providing Compounds of the Invention

[0453] The compounds of the present invention can be prepared or isolated by the methods described in detail in the Examples herein.

[0454] 5. Use, preparation and administration

[0455] Pharmaceutically acceptable compositions

[0456] 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 and measurably inhibit GPR84 or a mutant thereof in a biological sample or patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it can effectively and measurably inhibit GPR84 or a mutant thereof in a biological sample or patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0457] Another aspect of the present invention provides a pharmaceutical composition comprising a compound described herein (eg, a compound of Formula I or II) and a pharmaceutically acceptable carrier.

[0458] As used herein, the term "patient" means an animal, preferably a mammal and most preferably a human.

[0459] 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 with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers; aluminum oxide; aluminum stearate; lecithin, serum proteins such as human serum albumin; buffer substances such as phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes such as protamine sulfate; disodium hydrogen phosphate; dipotassium hydrogen phosphate; sodium chloride; zinc salts; colloidal silicon dioxide; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol and lanolin.

[0460] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that is capable of providing, directly or indirectly, a compound of the invention or an inhibitory active metabolite or residue thereof when administered to a recipient.

[0461] As used herein, the term "inhibitory active metabolite or residue thereof" means a metabolite or residue thereof that is also an inhibitor of GPR84 or a mutant thereof.

[0462] The subject matter disclosed herein includes prodrugs, metabolites, derivatives and pharmaceutically acceptable salts of the compounds of this invention. Metabolites include compounds produced by the following method, the method including: contacting the compounds of this invention with mammals for a period of time sufficient to produce their metabolites. If the compounds of this invention are alkali, then any suitable method available in the art can be used to prepare the required pharmaceutically acceptable salt, for example, free alkali is treated with the following: inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc., or organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (such as glucuronic acid or galacturonic acid), alpha hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc. If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (e.g., glycine and arginine), ammonia, primary, secondary and tertiary amines, and cyclic amines (e.g., piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0463] The compounds of the present invention may be in the form of "prodrugs", which include compounds with moieties that can be metabolized in vivo. Typically, prodrugs are metabolized in vivo by esterases or by other mechanisms that activate drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound in its free acid form or hydroxyl group with a suitable esterifying agent, respectively. The hydroxyl group can be converted into an ester by treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted branched or unbranched lower alkyl ester moieties (e.g., propionate), lower alkenyl esters, di-lower alkyl-amino lower alkyl esters (e.g., dimethylaminoethyl ester), acylamino lower alkyl esters (e.g., acetoxymethyl ester), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenyl esters), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g., methyl, halo, or methoxy-substituted) aryl and aryl-lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Prodrugs that are converted to active forms in vivo via other mechanisms are also included. In various aspects, the compounds of the present invention are prodrugs of any formula herein.

[0464] 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, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in nontoxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media.

[0465] For this purpose, any gentle fixed oil can be adopted, including synthetic monoglycerides or diglycerides. For example, fatty acids of oleic acid and their glyceride derivatives can be used to prepare injectables, such as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other conventional surfactants (such as Tween, Span and other emulsifiers) or the bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solids, liquids or other dosage forms can also be used for the purpose of preparation.

[0466] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dry corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0467] 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 medicament 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.

[0468] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application (including diseases of the eyes, skin, or lower intestinal tract). Suitable topical formulations are readily prepared for each of these areas or organs.

[0469] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0470] For topical application, the pharmaceutically acceptable compositions provided can be formulated into a suitable ointment form containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of this invention include, but are not limited to, mineral oil, liquid paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in a suitable lotion or cream form containing an active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0471] For ophthalmic use, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted, sterile saline with or without preservatives (e.g., benzylalkonium chloride), or preferably as solutions in isotonic, pH-adjusted, sterile saline. Alternatively, for ophthalmic use, pharmaceutically acceptable compositions can be formulated as ointments, such as paraffin wax.

[0472] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and may be prepared as solutions in normal saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0473] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0474] The amount of the compound of the invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0475] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the attending physician, as well as the severity of the specific disease being treated. The amount of the compound of the invention in the composition will also depend on the specific compound in the composition.

[0476] Uses of compounds and pharmaceutically acceptable compositions

[0477] The compounds and compositions described herein are generally useful for inhibiting the signaling activity of one or more GPCRs. In some embodiments, the GPCR inhibited by the compounds and methods of the present invention is GPR84.

[0478] One aspect of the present invention provides a method of treating a GPR84-mediated disease, condition, or disorder comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein, such as a compound of Formula I or II, or a pharmaceutically acceptable salt thereof.

[0479] The compounds disclosed in the present invention can be used to inhibit the activity of GPR84. GPR84 is a G protein expressed on the surface of immune cells. i GPR84 is a G protein-coupled receptor (GPCR) that regulates innate immune responses in conditions such as fibrosis.

[0480] Several studies have shown that GPR84 may be a potential target for the treatment of obesity and / or metabolic dysfunction.

[0481] GPR84 gene expression in cultured human differentiated adipocytes is highly upregulated by the major proinflammatory cytokines TNF-α and IL-1β (Muredda et al. 2017. Arch. Physiol. Biochem. 124(2), 97-108.). These data confirm the activation of proinflammatory GPR84 signaling in the context of adipocyte inflammation, first described by Nagasaki in 2012 (Nagasaki et al., 2012, FEBS Letters, 586, 368-372).

[0482] IL-33 is a member of the IL-1β superfamily, which strongly upregulates GPR84 mRNA expression in human differentiated adipocytes in an autocrine manner, which is associated with enhanced production of proinflammatory cytokines and chemokines such as IL-1β, CCL2, IL6, CXCL2, and CSF3 (Zaibi et al., 2018. Cytokine, 110, 189-193). This suggests that proinflammatory stimuli in adipocytes activate GPR84, leading to further proinflammatory cytokine release and confirming the existence of a hypothetical autocrine positive feedback loop.

[0483] GPR84 expression in the liver of NASH patients is upregulated and correlated with disease severity. GPR84 is upregulated in activated human and mouse macrophages and neutrophils. GPR84-mediated myeloid cell infiltration promotes fatty liver inflammation and fibrosis. Similar to silanol (ASK1 inhibitor), pharmacological inhibition of GPR84 can significantly reduce macrophage accumulation, inflammation and fibrosis in NASH models. These findings suggest that GPR84 promotes myeloid cell infiltration in liver injury and is an effective therapeutic target for NAFLD / NASH fatty liver inflammation and fibrosis (Puengel et al., 2020. J. Clin. Med. 9 (4), 1140).

[0484] GPR84 deficiency in mice is associated with reduced NAFLD-induced liver damage. Treatment with PBI-4547, a putative GPR84 antagonist, reduces NAFLD-induced liver and adipose tissue damage and promotes fatty acid oxidation (Simard et al. 2020. Sci. Rep. 10(1), 12778).

[0485] Mice with a global deficiency of Gpr84 (Gpr84 knockout (KO)) exhibit mildly impaired glucose tolerance when fed a diet rich in MCFA. Studies have shown that the medium-chain fatty acid receptor GPR84 regulates mitochondrial metabolism in mouse skeletal muscle and that GPR84 is an important player in glycemic control (Montgomery MK, et al. 2019. FASEB J. 33(11), 12264-12276).

[0486] 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 that GPR84 expression was increased in obese mice. In addition, obesity-induced GPR84 overexpression was further increased after Roux-en-Y gastric bypass (RYGB). Several nutrient-sensing receptors, including GPR84, induce activation of colonic EEC. In response to diet and weight loss induced by RYGB or caloric restriction, the expression of these receptors undergoes profound adaptive changes. (Peiris M, et al. 2018. Nutrients. 10(10), 1529)

[0487] DuToit et al. investigated the effects of GPR84 deletion on the development of obesity and diabetes in mice fed a diet rich in long-chain fatty acids (LCFA) or medium-chain fatty acids (MCFA) and found no effect on body weight or glucose tolerance in mice fed a diet high in MCFA or LCFA. GPR84 may affect lipid metabolism, as GPR84 KO mice had smaller livers and increased myocardial triglyceride accumulation when fed an LCFA diet, whereas hepatic triglyceride accumulation increased in response to increased dietary MCFA. (Du Toit et al. 2018 Eur. J. Nutr. 57(5), 1737-1746)

[0488] A review by Hara et al. indicates that GPR84 and other free fatty acid receptors (FFARs) that are primarily involved in energy metabolism are considered key therapeutic targets in the pathology of obesity and type 2 diabetes. (Hara et al. 2014. Biochim. Biophys. Acta. 1841(9), 1292-300)

[0489] Studies conducted by Nagasaki et al. on mice have shown that a high-fat diet upregulates GPR84 expression in fat pads. These results suggest that GPR84 appears in adipocytes in response to TNFα infiltrating macrophages and exacerbates the vicious cycle between obesity and glycopenia. (Nagasaki H. et al. 2012. FEBS Lett. 586(4), 368-72)

[0490] Fibrosis is a process that can be initiated by chronic tissue damage caused by toxic substances, viral infection, inflammation, or mechanical stress (Nanthakumar et al., 2015. Nature Reviews Drug Discovery 14, 693-720); and can be defined as the abnormal or excessive production and accumulation of extracellular matrix (ECM).

[0491] Specifically, fibrosis is a key driver of progressive organ dysfunction in many inflammatory and metabolic diseases, including idiopathic pulmonary fibrosis (IPF), advanced liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and end-stage renal disease. Despite increasing understanding of the disease mechanisms and a recent increase in the number of clinical trials, indicating the need for new treatments, particularly in IPF, these diseases remain poorly treated (Nanthakumar et al., 2015).

[0492] Non-alcoholic fatty liver disease (NAFLD) is initially characterized by pure steatosis and gradually progresses to non-alcoholic steatohepatitis (NASH). Besides genetic defects, it is primarily caused by excess energy intake and physical inactivity, and is closely associated with metabolic complications such as obesity and insulin resistance (Neuschwander-Tetri BA and Caldwell SH, 2003, Hepatology 37, 1202-1219). If untreated, NASH can lead to fatal liver failure.

[0493] The mechanisms that promote the progression of NAFLD to NASH and advanced liver disease are complex and may be triggered by acute inflammatory damage and oxidative stress (Day and James 1998, Hepatology 27, 1463-1466).

[0494] GPR84 (also known as EX33) has been isolated and characterized from human B cells (Wittenberger et al., 2001, J. Mol. Biol. 307, 799-813) and also using a degenerate primer reverse transcriptase-polymerase chain reaction (RT-PCR) method (Yousefi et al., 2001). It remained an orphan GPCR until medium-chain free fatty acids (FFA) with a carbon chain length of 9-14 were identified as ligands for this receptor (Wang J et al., 2006).

[0495] GPR84 is activated by medium-chain FFAs, such as decanoic acid (C10:0), undecanoic acid (C1 1:0), and lauric acid (12:0), which amplify the production of lipopolysaccharide-stimulated proinflammatory cytokines / chemokines (TNFα, IL-6, IL-8, CCL2, etc.) and are highly expressed in neutrophils and monocytes (macrophages) (Miyamoto et al. 2016, Int. J. Mol. Sci. 17(4)450).

[0496] In contrast, GPR84 ligand-mediated chemotaxis of neutrophils and monocytes / macrophages is inhibited by GPR84 antagonists (Suzuki M et al. 2013. J. Biol. Chem. 288, 10684-10691).

[0497] Although monocyte / macrophage recruitment to the liver appears to coincide with fibrosis in patients with chronic liver disease (Marra et al. 1998. Am. J. Pathol. 152, 423-430; Zimmermann et al. 2010. PLOS ONE 5, e11049), this has not led to new therapeutic approaches.

[0498] There are currently no approved drugs for the treatment of NASH, so liver transplantation remains the last resort for advanced disease states. For example, in IPF, only two drugs have been approved despite adverse side effects (Brunnemer et al., 2018. Respiration 95, 301-309; Lancaster et al., 2017, Eur. Respir. Rev. 26, 170057; Richeldi et al., 2014, N. Engl. J. Med. 370, 2071-2082), so there is a clear need for improved treatments (Raghu, 2015, Am J Respir Crit Care Med 191(3)252-4).

[0499] A potent and selective GPR84 inhibitor, GLPG1205, at once-daily doses of 3 and 10 mg / kg, reduced disease activity index scores and neutrophil infiltration in a mouse model of chronic inflammatory bowel disease induced by dextran sodium sulfate, with efficacy similar to that of the positive control compound sulfasalazine. (Labéguère F, et al. 2020. J Med Chem. 63(22), 13526-13545)

[0500] Nguyen et al. showed that PBI-4050 (a GPR84 antagonist / GPR40 agonist) can reduce pulmonary hypertension, pulmonary fibrosis and right ventricular dysfunction in heart failure. This suggests that GPR84 antagonists are a new and promising therapy for lung remodeling in type II pulmonary hypertension (Nguyen et al. 2020. Cardiovasc Res. 116(1), 171-182).

[0501] Gagnon et al.'s study suggests that GPR40 and GPR84 may represent promising molecular targets in the fibrosis pathway. Administration of PBI-4050, a GPR84 antagonist and GPR40 agonist, significantly reduced fibrosis in a variety of injury scenarios, as evidenced by anti-fibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models (Gagnon et al., 2018. Am J Pathol. 188(5), 1132-1148).

[0502] Studies have also linked GPR84 to acute lung injury and / or inflammation.

[0503] A review by Alavi et al. summarizes studies on GPR17, GPR30, GPR37, GPR40, GPR50, GPR54, GPR56, GPR65, GPR68, GPR75, GPR84, GPR97, GPR109, GPR124, and GPR126, which have been reported in preclinical studies to have significant effects in preventing and / or treating multiple sclerosis (MS) (Alavi et al. 2019. Life Sci. 224, 33-40).

[0504] Under inflammatory stimuli, such as endotoxemia, hyperglycemia and hypercholesterolemia, GPR84 expression in several mouse tissues is enhanced. These stimulants also increase GPR84 expression in macrophages, and selective GPR84 receptor agonists (6-OAU) trigger the secretion enhancement and phagocytosis of proinflammatory cytokines in macrophages (Recio et al. 2018. Front. Immunol. 9, 1419). The results show that once inflammation occurs, GPR84 acts as an enhancer for inflammatory signaling in macrophages, and molecules that antagonize GPR84 receptors may be potential therapeutic tools for inflammatory and metabolic diseases.

[0505] DL-175, a potent and selective structurally novel molecule, was found to cause different functional effects in macrophages compared to other GPR84 ligands (Lucy et al. 2019. ACS Chem. Biol. 14(9), 2055-2064). This study confirmed that GPR84 agonists can lead to enhanced macrophage chemotaxis and / or phagocytosis (also known as macrophage activation).

[0506] GPR84 is one of the few pro-inflammatory neutrophil-related genes that was highly enriched in an RNA sequencing dataset analysis of BALF cells from COVID-19 patients (Didangelos, A. 2020. mSphere. 5(3), e00367-20).

[0507] In an acute lung inflammation model, LPS induces alveolar macrophages to switch from CD11 lo Transition to a more inflammatory CD11 hi state, worsening the lung injury process (Yin et al. 2020. Mucosal Immunol. 13(6), 892-907). GPR84 is highly expressed in diseased lung tissue and is involved in cytokine release, phagocytosis, and alveolar macrophage state transition. GPR84 may represent a potential therapeutic target for acute respiratory distress syndrome.

[0508] et al. prepared the first GPR84 agonist radioligand (tritiated) to study the binding affinity of receptor ligands. They pointed out that GPR84 has been found to be involved in inflammatory processes associated with gastroesophageal reflux disease, inflammatory bowel disease, multiple sclerosis, neuropathic pain, and Alzheimer's disease. In addition, GPR84 is associated with obesity and diabetes. Preliminary evidence suggests that GPR84 may be involved in leukemia formation, osteoclastogenesis, and organ fibrosis (pathological consequences of many inflammatory and metabolic diseases). ( M, et al. 2020. J. Med. Chem. 63(5), 2391-2410).

[0509] Global glycoprotein analysis by Müller et al. identified markers for endotoxin-tolerant monocytes and GPR84 as a regulator of TNFα expression (Müller MM, et al. 2017 Sci Rep. 7(1), 838).

[0510] Studies by Venkataraman et al. have shown that GPR84 can regulate IL-4 production 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).

[0511] Additionally, GPR84 has been implicated in neuropathic pain and / or neuropathy.

[0512] Gao et al. demonstrated that DOK3 is involved in microglial activation in neuropathic pain by interacting with GPR84, revealing a physical association between DOK3 and GPR84 in inducing inflammatory responses. They hypothesized that targeting the adaptor protein DOK3 may open new avenues for pharmacological approaches to alleviate spinal neuropathic pain (Gao WS et al. 2020. Aging (Albany NY). 12.).

[0513] Kozela et al. studied the behavioral effects of CBD in a pharmacological model of schizophrenia-like cognitive deficits induced by repeated ketamine (KET) administration and showed that CBD reversed KET-induced transcriptional changes, including the Gpr84 gene (Kozela E et al. 2020. Mol Neurobiol. 57(3), 1733-1747).

[0514] Wei et al.'s study showed that G protein-coupled receptor 84 (GPR84) agonists altered cell morphology and motility but did not induce proinflammatory responses in microglia. This study suggests that microglial GPR84 could be a therapeutic target for microglia-related diseases such as multiple sclerosis and Alzheimer's disease (Wei L, et al. 2017. J Neuroinflammation. 14(1), 198).

[0515] Nicol et al. investigated the role of GPR84 in experimental neuropathic pain and demonstrated that GPR84 is a proinflammatory receptor that promotes nociceptive signaling by regulating macrophages, whereas in its absence, these cells are impaired in their response to inflammatory insults (Nicol LS et al., 2015. J Neurosci. 35(23), 8959-69).

[0516] Mededdu et al. found that Gpr84 expression was induced in both microglia and astrocytes and was upregulated in the central nervous system (CNS) after viral infection, suggesting that Gpr84 expression may be a useful measure of glial cell activation when the central nervous system (CNS) is injured or damaged (Madeddu S, et al. 2015. PLoS One. 10(7), e0127336).

[0517] Bouchard et al. found that mice with endotoxemia strongly and persistently expressed GPR84 in microglia, making GPR84 a sensitive marker of microglial activation, which may play an important regulatory role in neuroimmune processes, acting downstream of proinflammatory mediators (Bouchard C et al. 2007. Glia. 55(8), 790-800).

[0518] GPR84 is also associated with inflammatory bowel disease and is a potential disease target.

[0519] Planell et al. identified GPR84 as a transcriptional blood biomarker that can be used as a non-invasive surrogate marker of mucosal healing and endoscopic response in ulcerative colitis. At 14 weeks of treatment, response to anti-TNF therapy induced changes in blood HP, CD177, GPR84, and S100A12 transcripts that correlated with changes in endoscopic activity (Planell N et al., 2017. J Crohns Colitis. 11(11), 1335-1346).

[0520] Abdel-Aziz et al. found that GPR84 and TREM-1 signaling lead to the onset of reflux esophagitis, suggesting that GPR84 plays an important role in the pathogenesis of gastroesophageal reflux disease (GERD) (Abdel-Aziz, et al. 2016 Mol Med. 21(1), 1011-1024).

[0521] Dietrich et al. demonstrated that GPR84 can maintain stem cell-derived mixed lineage leukemia (MLL) leukemogenesis by maintaining aberrant β-catenin signaling in leukemic stem cells (LSCs), a previously unrecognized role for GPR84 in maintaining fully developed acute myeloid leukemia (AML) by maintaining aberrant β-catenin signaling in LSCs, and suggested that targeting the oncogenic GPR84 / β-catenin signaling axis may represent a new therapeutic strategy for AML (Dietrich PA et al. 2014. Blood. 124(22), 3284-94).

[0522] Deng et al. mined tumor microenvironment-related genes with prognostic value for hepatocellular carcinoma (HCC) from the Cancer Genome Atlas (TCGA) database and identified GPR84 among a group of differentially expressed genes (DEGs), which can be used as a candidate biomarker for HCC prognosis (Deng Z, et al. 2019. Biomed Res Int. 2019, 2408348).

[0523] Wang et al. used gene chip expression profiling to reveal changes in energy metabolism-related genes such as GPR84 in bone cells under high-gradient magnetic fields. The identification of specific environmentally 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).

[0524] Research by Park et al. showed that GPR84 regulates osteoclastogenesis by inhibiting NF-κB and MAPK signaling pathways, revealing that GPR84 acts as a negative regulator of osteoclastogenesis, suggesting that it may become a potential therapeutic target for osteoclast-mediated bone destructive diseases (Park JW, et al. 2018. J Cell Physiol. 233(2), 1481-1489).

[0525] Zhu et al. discovered abnormal gene regulatory pathways in systemic lupus erythematosus (SLE) by genome-wide transcriptional and DNA methylation analysis of peripheral blood mononuclear cells. Compared with SLE lupus nephritis (LN)-patients, the gene expression of MX1, GPR84, and E2F2 was increased in SLE LN-patients (Zhu H, et al. 2016. Arthritis Res Ther. 18, 162).

[0526] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting GPR84, comprising contacting GPR84 with an effective amount of a compound or pharmaceutical composition of the present invention as described herein.

[0527] In certain embodiments, the presently disclosed subject matter relates to a method for modulating an immune response in a subject in need thereof, wherein the method comprises administering to the subject an effective amount of a compound or pharmaceutical composition of the invention as described herein.

[0528] The compounds disclosed herein directly bind to GPR84 and inhibit its signaling activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise attenuate GPR84-mediated inflammatory responses.

[0529] The compounds disclosed herein may or may not be specific GPR84 antagonists. A specific GPR84 antagonist reduces the biological activity of GPR84 by an amount statistically greater than the inhibitory effect of the antagonist on any other protein (e.g., other GPCRs). In certain embodiments, the compounds disclosed herein specifically inhibit the signaling activity of GPR84. In some of these embodiments, the IC of the GPR84 antagonist on GPR84 is greater than the IC of the GPR84 antagonist on GPR84. 50 is the IC of the GPR84 antagonist against another GPCR activated by free fatty acids (FFA) or another GPCR type (e.g., class A GPCR) 50 About 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the total weight of the formulation.

[0530] The compounds disclosed herein can be used in methods for inhibiting GPR84. Such methods comprise contacting GPR84 with an effective amount of a compound disclosed herein. "Contacting" refers to bringing the compound into close enough proximity to an isolated GPR84 GPCR or a cell expressing GPR84 (e.g., a T cell or B cell) to allow the compound to 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.

[0531] Any method known in the art for measuring the signaling activity of GPR84 can be used to determine whether GPR84 has been inhibited, including in vitro assays or measurements of downstream biological effects of GPR84 signaling activity.

[0532] The compounds disclosed herein can be used to treat GPR84-dependent disorders. As used herein, a "GPR84-dependent disorder" is a pathological disorder in which GPR84 activity is necessary for the cause or maintenance of the pathological disorder. In some embodiments, the GPR84-dependent disorder is an inflammatory disorder.

[0533] The compounds disclosed herein can also be used to modulate the immune response of a subject in need thereof. Such methods comprise administering an effective amount of a compound of the present invention.

[0534] As used herein, "modulating an immune response" refers to the modulation of any immunogenic response to an antigen.

[0535] In another aspect of the invention, the present invention provides novel compounds of the invention for use in therapy.

[0536] In another aspect, the present invention provides a method for treating a mammal, including a human, that is susceptible to or has a disorder listed herein, particularly a disorder that may be associated with aberrant GPR84 activity and / or aberrant GPR84 expression and / or aberrant 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, a leukemia, and / or a disease involving impaired immune cell function, the method comprising administering a therapeutically effective amount of one or more of the compounds or pharmaceutical compositions of the present invention as described herein.

[0537] In another aspect, the present invention provides a compound of the present invention for use in treating or preventing a disorder selected from the disorders listed herein, in particular disorders that may be associated with aberrant GPR84 activity and / or aberrant GPR84 expression and / or aberrant GPR84 distribution expression, such as inflammatory diseases, pain, neuroinflammatory disorders, neurodegenerative disorders, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemias and / or diseases involving impaired immune cell function.

[0538] In additional aspects, the present invention provides methods for synthesizing compounds of the invention using the representative synthetic schemes and pathways disclosed herein.

[0539] Therefore, a main object of the present invention is to provide compounds of the invention that can modify the activity of GPR84 and thus prevent or treat any disorder that can be causally related thereto.

[0540] Another object of the present invention is to provide compounds of the present invention, which can treat or alleviate conditions or diseases or symptoms thereof that may be causally related to the activity and / or expression and / or distribution of GPR84, such as inflammatory diseases, pain, neuroinflammatory diseases, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function.

[0541] Another object of the present invention is to provide pharmaceutical compositions that can be used to treat or prevent a variety of disease states, including diseases associated with abnormal GPR84 activity and / or abnormal GPR84 expression and / or abnormal GPR84 distribution, such as inflammatory diseases, pain, neuroinflammatory disorders, neurodegenerative diseases, infectious diseases, autoimmune diseases, endocrine and / or metabolic diseases, cardiovascular diseases, leukemia and / or diseases involving impaired immune cell function.

[0542] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description.

[0543] The present disclosure provides methods of modulating (eg, inhibiting) GPR84 activity comprising administering to a patient a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0544] In one aspect, provided herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof.

[0545] In the methods described herein, a compound of the invention, or a pharmaceutical composition thereof, is administered to a subject having cancer.

[0546] In certain embodiments, the subject matter disclosed herein relates to a method for treating a GPR84-dependent disorder comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition of the invention as described herein. In certain aspects of this embodiment, the GPR84-dependent disorder is cancer.

[0547] 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 adjunctive therapy to increase the efficacy of vaccination.

[0548] In some embodiments, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

[0549] In certain aspects, the present invention provides a method of treating a cell proliferative disorder, including cancer.

[0550] In one aspect, the present invention provides a method of treating a cell proliferative disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.

[0551] In certain embodiments, the cell proliferative disorder is cancer.

[0552] Examples of cancers that may be treated using the compounds of the present disclosure include, but are not limited to, chronic or acute leukemias, including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphomas, and combinations of the aforementioned cancers.

[0553] In some embodiments, cancers that may be treated using the compounds of the present disclosure include, but are not limited to, hematological cancers (e.g., lymphomas, leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), DLBCL, and combinations of the foregoing cancers.

[0554] 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.

[0555] In certain embodiments, the cancer is selected from leukemia and hematological cancers. In specific embodiments, the cancer is present in an adult patient; in other embodiments, the cancer is present in a pediatric patient. In specific embodiments, the cancer is AIDS-related.

[0556] In a specific embodiment, the cancer is selected from leukemia and hematological cancers. In a specific embodiment, the cancer is selected from the group consisting of myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplasia / myeloproliferative neoplasms, acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), myeloproliferative neoplasms (MPN), AML after MPN, AML after MDS, del (5q) related high-risk MDS or AML, blastocyst chronic myeloid leukemia, angioimmunoblastic lymphoma, acute lymphoblastic leukemia, Langerhans cell histiocytosis (Langerans cell histiocytosis), hairy cell leukemia, and plasma cell neoplasms including plasmacytomas and multiple myeloma. The leukemias mentioned herein may be acute or chronic.

[0557] In some embodiments, diseases and indications that may be treated using the disclosed compounds include, but are not limited to, hematological cancers.

[0558] Exemplary hematologic cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplasia syndrome (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, Waldenstrom's macroglobulinemia (Waldenstrom's Macroglobulinemia), hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt's lymphoma.

[0559] As used herein, the term "inflammatory disorder" refers to the group of disorders that includes inflammatory bowel disease (IBD) (e.g., Crohn's disease, ulcerative colitis), rheumatoid arthritis, vasculitis, lung 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 that cause, for example, 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 skin diseases (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncology treatments designed to activate an immune response.

[0560] As used herein, the term "pain" refers to a disease or condition characterized by a sensory discomfort that is usually caused by a sharp or injurious stimulus and includes, but is not limited to, nociceptive pain, inflammatory pain (associated with tissue damage and inflammatory cell infiltration), and neuropathic or dysfunctional pain (caused by damage to or abnormal function of the nervous system) and / or pain associated with or caused by a disorder mentioned herein. Pain can be acute or chronic.

[0561] As used herein, the term "neuroinflammatory condition" refers to a disease or disorder characterized by sudden neurological deficits associated with inflammation, demyelination, and axonal damage, including but not limited to conditions such as Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0562] As used herein, the term "neurodegenerative disease" refers to a disease or condition characterized by the gradual loss of neuronal structure or function (including neuronal death), including but not limited to dementia, degenerative dementia, senile dementia, vascular dementia, dementia associated with intracranial space-occupying lesions, mild cognitive impairment associated with aging, age-related memory impairment and / or peripheral neuropathy. Specifically, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, amyotrophic lateral sclerosis (ALS), motor neuron disease (MND), spinocerebellar ataxia (SCA), and / or spinal muscular atrophy (SMA). More specifically, the term refers to retinopathy, glaucoma, macular degeneration, stroke, cerebral ischemia, traumatic brain injury, Alzheimer's disease, Pick's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob disease, and / or amyotrophic lateral sclerosis (ALS).

[0563] As used herein, the term "infectious disease" refers to bacterial infectious diseases and includes, but is not limited to, conditions such as sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, or Enterobacter species.

[0564] As used herein, the term "autoimmune disease" refers to a group of diseases including obstructive airway diseases (including diseases such as COPD (chronic obstructive pulmonary disease)), psoriasis, asthma (e.g., intrinsic asthma, extrinsic asthma, pneumoconiosis, infantile asthma), especially chronic or refractory asthma (e.g., late asthma and airway hyperresponsiveness), bronchitis (including bronchial asthma), systemic lupus erythematosus (SLE), multiple sclerosis, type I diabetes and its related complications, atopic eczema (atopic dermatitis), contact dermatitis and eczematous dermatitis, vasculitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), atherosclerosis, and amyotrophic lateral sclerosis. More specifically, the term refers to COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0565] As used herein, the term "endocrine and / or metabolic disease" refers to a group of diseases involving an excess or deficiency of certain hormones in the body, while metabolic disorders affect the body's ability to process certain nutrients and vitamins. Endocrine diseases include hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal gland 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.

[0566] As used herein, the term "cardiovascular disease" refers to a disease that affects the heart or blood vessels or both. Specifically, cardiovascular disease includes arrhythmias (atrial or ventricular or both); atherosclerosis and its sequelae; angina pectoris; arrhythmias; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysms; vasculitis, stroke; peripheral occlusive arterial disease of a limb, organ or tissue; reperfusion injury after ischemia of the brain, heart, kidney or other organs or tissues; endotoxin, surgical or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including vasoconstriction associated with migraine); vascular abnormalities, inflammation, and dysfunction limited to a single organ or tissue. More specifically, the term refers to atherosclerosis.

[0567] As used herein, the term "leukemia" refers to neoplastic diseases of the blood and blood-forming organs. Such diseases can cause bone marrow and immune system dysfunction, which makes the host highly susceptible to infection and bleeding. In particular, the term leukemia refers to acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).

[0568] As used herein, the term "disease" refers to impaired immune cell function and includes conditions with symptoms such as recurrent and protracted viral and bacterial infections and slow recovery. Other hidden symptoms may be the inability to kill parasites, yeast, and bacterial pathogens in the intestines or throughout the body.

[0569] As used herein, the term "fibrotic disease" refers to a disease that results in excessive scarring due to excessive production, deposition, and contraction of the extracellular matrix and is associated with abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased recruitment of fibroblasts, including but not limited to fibrosis in individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal system, and digestive tract. Specifically, the term fibrotic disease refers to idiopathic pulmonary fibrosis (IPF); cystic fibrosis; other diffuse parenchymal lung diseases of varying etiology, including iatrogenic drug-induced fibrosis, occupational and / or environmental fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonitis), collagen vascular diseases, pulmonary alveolar proteinoses, Langerhans cell granulomatosis, lymphangioleiomyomatosis, hereditary diseases (Hermanski-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation-induced fibrosis; chronic obstructive pulmonary disease; scleroderma; bleomycin-induced pulmonary fibrosis; chronic asthma; silicosis; asbestos-induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); renal fibrosis; tubulointerstitial fibrosis; glomerulonephritis; diabetic nephropathy, focal segmental glomerulosclerosis; and IgA nephropathy. Hypertension; Alport's disease; intestinal fibrosis; liver fibrosis; cirrhosis; alcoholic liver fibrosis; toxic / drug-induced liver fibrosis; hemochromatosis; alcoholic steatohepatitis (ASH), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD); cholestasis, bile duct injury; primary sclerosing cholangitis (PSC), primary biliary cirrhosis (PBC); liver fibrosis caused by infection; liver fibrosis caused by viruses; autoimmune hepatitis; corneal scarring; hypertrophic scarring; Dupuytren's disease, keloids, skin fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD)-related musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease or chronic lymphocytic 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.

[0570] In some embodiments, the compounds of the invention are useful for preventing or reducing the risk of developing any of the diseases mentioned herein; for example, preventing or reducing the risk of developing a disease, disorder, or condition in an individual who may be susceptible to the disease, disorder, or condition but who has not yet experienced or manifested the pathology or symptomology of the disease.

[0571] The compounds disclosed herein can be administered in any suitable manner known in the art. In some embodiments, the compounds of the present invention or their pharmaceutically acceptable salts, prodrugs, metabolites or derivatives are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, intratumorally or intranasally.

[0572] In some embodiments, the GPR84 antagonist is administered continuously. In other embodiments, the GPR84 antagonist is administered intermittently. Furthermore, treating a subject with an effective amount of a GPR84 antagonist may include a single treatment or may include a series of treatments.

[0573] It will be understood that the appropriate dosage of the active compound depends on a variety of factors within the knowledge of the ordinary skilled physician or veterinarian. The dosage of the active compound will vary, for example, depending on the age, weight, general health, sex and diet of the subject, the time of administration, the route of administration, the rate of excretion and any drug combinations.

[0574] It is also understood that the effective dosage of a compound of the invention, or a pharmaceutically acceptable salt, prodrug, metabolite or derivative thereof, used for treatment may be increased or decreased over a specific treatment period. Changes in dosage may occur and become apparent from the results of diagnostic assays.

[0575] In some embodiments, the GPR84 antagonist is administered to the subject at a dose of between about 0.001 μg / kg and about 1000 mg / kg, including but not limited to about 0.001 μg / kg, 0.01 μg / kg, 0.05 μg / kg, 0.1 μg / kg, 0.5 μg / kg, 1 μg / kg, 10 μg / kg, 25 μg / kg, 50 μg / kg, 100 μg / kg, 250 μg / kg, 500 μg / kg, 1 mg / kg, 5 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg, 100 mg / kg, and 200 mg / kg.

[0576] In the methods described herein, the methods can further comprise administering a chemotherapeutic agent to the 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 prior to administering the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administering the compound or composition.

[0577] As used herein, the term "treatment" refers to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein or one or more of its symptoms. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered when symptoms are not present. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., based on a history of symptoms and / or based on hereditary or other sensitivity factors). Treatment may also be continued after symptoms subside, for example to prevent or delay their recurrence.

[0578] The term "administration" or "administering" includes a route by which a compound is introduced into a subject to exert its intended function. Examples of routes of administration that can be used include injection (subcutaneous, intravenous, parenteral, intraperitoneal, intrathecal), topical, oral, inhalation, rectal, and transdermal.

[0579] The term "effective amount" includes an amount effective to achieve the desired result at the desired dosages and for the desired period of time. The effective amount of a compound may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit the desired response in the subject. Dosage regimens may be adjusted to provide the optimal therapeutic response.

[0580] As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean administering a compound, drug, or other substance so that it enters the patient's system and thereby undergoes metabolism and other similar processes.

[0581] The phrase "therapeutically effective amount" means an amount of a compound of the invention that achieves the following effects: (i) treating or preventing a specific disease, disorder or condition, (ii) alleviating, ameliorating or eliminating one or more symptoms of a specific disease, disorder or condition, or (iii) preventing or delaying the onset of one or more symptoms of a specific disease, disorder or condition described herein. In the case of cancer, a therapeutically effective amount of a drug can reduce the number of cancer cells; reduce tumor size; inhibit (i.e., slow down and preferably stop to some extent) cancer cell infiltration into peripheral organs; inhibit (i.e., slow down and preferably stop to some extent) tumor metastasis; inhibit tumor growth to some extent; and / or alleviate to some extent one or more of the symptoms associated with cancer. To the extent that a drug can prevent the growth of existing cancer cells and / or kill existing cancer cells, it can be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0582] The term "subject" refers to an animal, such as a mammal, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0583] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in 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).

[0584] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of an endocrine and / or therapeutic agent for preventing and / or treating one or more fibrotic diseases. In a specific embodiment, the fibrotic disease is NASH and / or NAFLD. In a most specific embodiment, the fibrotic disease is NASH. In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0585] In terms of additional treatment methods, the present invention provides a method for preventing and / or treating a mammal suffering from a fibrotic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention as described herein, or the pharmaceutical compositions for treating or preventing the disease. In specific embodiments, 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).

[0586] 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 additional therapeutic agent is a fibrotic disease therapeutic agent. In a specific embodiment, the fibrotic disease is NASH and / or NAFLD. In a most specific embodiment, the fibrotic disease is NASH. In another most specific embodiment, the fibrotic disease is idiopathic pulmonary fibrosis (IPF).

[0587] In one embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the prevention and / or treatment of a subject presenting a NAS score of at least 3, at least 4, at least 5, at least 6 or at least 7.

[0588] In another embodiment, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for preventing and / or treating a subject presenting a NAS score>5.

[0589] In additional therapeutic methods, the present invention provides a method for preventing and / or treating a mammal presenting with a NAS score > 5, comprising administering an effective amount of one or more of the compounds of the present invention or pharmaceutical compositions described herein for treating or preventing the fibrotic disease, particularly NASH and / or NAFLD, more particularly NASH.

[0590] In further methods of treatment embodiments, the method for preventing and / or treating mammals includes measuring the forced vital capacity (FVC) of the subject, wherein FVC does not decline after treatment. In a specific embodiment, FVC does not reduce during the treatment period of 12,16,20 or 26 weeks. In another embodiment, the method includes measuring the FVC of the subject, wherein FVC increases by at least 1mL, at least 2mL, at least 3mL, at least 4mL, at least 5mL, at least 6mL, at least 7mL or at least 8mL. In a specific embodiment, FVC increases by at least 1mL, at least 2mL, at least 3mL, at least 4mL, at least 5mL, at least 6mL, at least 7mL or at least 8mL during the treatment period of 12,16,20 or 26 weeks.

[0591] In one embodiment, the method comprises measuring airway volume, wherein the airway volume is reduced by no more than 5 mL / L, no more than 4 mL / L, or no more than 3 mL / L. In specific embodiments, the airway volume is reduced by no more than 5 mL / L, no more than 4 mL / L, or no more than 3 mL / L after 12, 16, 20, or 26 weeks of treatment.

[0592] Combination therapy

[0593] Depending on the particular condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are referred to as "appropriate for the disease or condition being treated."

[0594] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0595] The compounds of the present invention are useful as therapeutic agents for treating conditions in mammals that are causally related to or attributable to aberrant GPR84 activity and / or aberrant GPR84 expression and / or aberrant GPR84 distribution.

[0596] Therefore, 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.

[0597] Thus, in one aspect, the present invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use as a medicament.

[0598] 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.

[0599] In another aspect, the present invention provides a method of treating a mammal having or at risk of developing a disease disclosed herein. In a specific aspect, the present invention provides a method of treating a mammal having or at risk of developing an inflammatory disorder, pain, a neuroinflammatory disorder, a neurodegenerative disorder, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, a leukemia, and / or a disease involving impaired immune cell function in a mammal, including a human, comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions as described herein.

[0600] In one aspect, the present invention provides a compound of this invention or a pharmaceutical composition comprising a compound of this invention for use in preventing and / or treating inflammatory diseases. In a specific embodiment, the inflammatory disease is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatosis (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma and skin and / or colon inflammation caused by oncology treatments intended to activate immune responses.

[0601] On the other hand, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for the manufacture of a medicament for preventing and / or treating an inflammatory disease. In a specific embodiment, the inflammatory disease is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In another specific embodiment, the inflammatory disease is selected from uveitis, periodontitis, esophagitis, neutrophilic dermatosis (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma and skin and / or colon inflammation caused by oncology treatments intended to activate an immune response.

[0602] In another aspect, the present invention provides a method of treating a mammal having or at risk of developing a disease selected from an inflammatory disorder (e.g., inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis), a pulmonary disease (e.g., chronic obstructive pulmonary disease (COPD) and interstitial lung disease (e.g., idiopathic pulmonary fibrosis (IPF))), a neuroinflammatory disorder, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, and / or a disease involving impaired immune cell function, comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions as described herein.

[0603] In terms of additional treatment methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an inflammatory disease, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions as described herein. In one embodiment, the inflammatory disease is selected from inflammatory bowel disease (IBD), rheumatoid arthritis, vasculitis, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF). In another embodiment, the inflammatory disease is selected from uveitis, periodontitis, esophagitis, neutrophilic skin diseases (e.g., pyoderma gangrenosum, Sweet's syndrome), severe asthma, and skin and / or colon inflammation caused by oncology treatments designed to activate an immune response.

[0604] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in preventing and / or treating pain. In a specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0605] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in the manufacture of a medicament for preventing and / or treating pain. In a specific embodiment, the pain is acute or chronic and is selected from nociceptive pain, inflammatory pain, and neuropathic or dysfunctional pain.

[0606] In additional therapeutic methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from pain, comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention as 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.

[0607] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in preventing and / or treating neuroinflammatory diseases, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, or autoimmune encephalomyelitis.

[0608] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention, which comprises a compound of the present invention suitable for the manufacture of a medicament for preventing and / or treating neuroinflammatory diseases, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, and autoimmune encephalomyelitis.

[0609] In additional therapeutic methods, the present invention provides methods for treating and / or preventing a mammal susceptible to or suffering from a neuroinflammatory disorder, Guillain-Barré syndrome (GBS), multiple sclerosis, axonal degeneration, or autoimmune encephalomyelitis, comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention as described herein.

[0610] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising a compound of the present invention for use in preventing and / or treating an infectious disease. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacter species.

[0611] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating an infectious disease. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacter species.

[0612] In terms of additional therapeutic methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an infectious disease, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions as described herein. In a specific embodiment, the infectious disease is selected from sepsis, septicemia, endotoxemia, systemic inflammatory response syndrome (SIRS), gastritis, enteritis, enterocolitis, tuberculosis, and other infections involving, for example, Yersinia, Salmonella, Chlamydia, Shigella, and Enterobacter species.

[0613] In one aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in preventing and / or treating an autoimmune disease and / or a disease involving impaired immune cell function. In a specific embodiment, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0614] In another aspect, the present invention provides a compound of the present invention or a pharmaceutical composition comprising the compound of the present invention for use in the manufacture of a medicament for preventing and / or treating an autoimmune disease and / or a disease involving impaired immune cell function. In a specific embodiment, the autoimmune disease and / or a disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0615] In terms of additional therapeutic methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an autoimmune disease and / or a disease involving impaired immune cell function, the method comprising administering an effective amount of one or more of the compounds or pharmaceutical compositions of the present invention as described herein. In a specific embodiment, the autoimmune disease and / or disease involving impaired immune cell function is selected from COPD, asthma, psoriasis, systemic lupus erythematosus, type I diabetes, vasculitis, and inflammatory bowel disease.

[0616] In one aspect, the invention provides the compounds of this invention or a pharmaceutical composition comprising the compounds of this invention for use in preventing and / or treating endocrine and / or metabolic diseases. In a specific embodiment, endocrine and / or metabolic diseases are selected from hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal disease (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets.

[0617] On the other hand, the present invention provides the compounds of this invention or a pharmaceutical composition comprising the compounds of this invention for the manufacture of 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 hypertrophy, parathyroid disease, diabetes, adrenal diseases (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout and rickets.

[0618] In terms of additional therapeutic methods, the present invention provides a method for treating and / or preventing a mammal susceptible to or suffering from an endocrine and / or metabolic disease, the method comprising administering an effective amount of one or more of the compounds of the present invention, or pharmaceutical compositions, as described herein. In a specific embodiment, the endocrine and / or metabolic disease is selected from hypothyroidism, congenital adrenal hypertrophy, parathyroid disease, diabetes, adrenal disease (including Cushing's syndrome and Addison's disease), ovarian dysfunction (including polycystic ovary syndrome), cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, and rickets.

[0619] As another aspect of the present invention, there is provided a compound of the present invention, in particular for use as a medicament in the treatment or prevention of the aforementioned conditions and diseases. Also provided herein is the use of the compound in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.

[0620] A specific embodiment of the method of the present invention comprises administering to a subject having an inflammatory disorder an effective amount of a compound of the present invention for a period of time sufficient to reduce the level of inflammation in the subject and preferably terminate the process causing the inflammation. A specific embodiment of the method comprises administering to a subject susceptible to or suffering from the development of an inflammatory disorder an effective amount of a compound of the present invention for a period of time sufficient to reduce or prevent inflammation in the patient and preferably terminate the process causing the inflammation, respectively.

[0621] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for about 1 to about 120 hours and particularly 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 2 g / day.

[0622] Transdermal administration is generally chosen to provide blood levels similar to or lower than those achieved using injection administration.

[0623] When used to prevent the onset of a disorder, the compounds of the invention should be administered to patients at risk of developing the disorder, typically on the advice of and under the supervision of a physician, at the dosage levels described above. Patients at risk of developing 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.

[0624] The compounds of the present invention can be administered as the sole active agent or they can be administered in combination with other therapeutic agents, including other compounds that exhibit the same or similar therapeutic activity and are determined to be safe and effective for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for a significant reduction in the dose of each agent to be used, thereby reducing the side effects seen.

[0625] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory disorders; specific agents include, but are not limited to, immunomodulators such as azathioprine, corticosteroids (e.g., prednisolone or dexamethasone), cyclophosphamide, cyclosporine A, tacrolimus, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g., ), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0626] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of arthritis (e.g., rheumatoid arthritis); specific agents include, but are not limited to, analgesics, nonsteroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (such as, but not limited to, methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, and cyclosporine), and biologic DMARDS (such as, but not limited to, infliximab, etanercept, adalimumab, rituximab, golimumab, becerizumab, tocilizumab, interleukin 1 blockers, and abatacept).

[0627] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of an autoimmune disease; specific agents include, but are not limited to, glucocorticoids, cytostatic agents (e.g., purine analogs), alkylating agents (e.g., nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compounds, etc.), antimetabolites (e.g., methotrexate, azathioprine, and mercaptopurine), cytotoxic antibiotics (e.g., actinomycin D anthracyclines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g., anti-CD20, anti-CD25, or anti-CD3 (OTK3) monoclonal antibodies), and ), cyclosporine, tacrolimus, rapamycin (sirolimus), interferons (eg, IFN-β), TNF-binding proteins (eg, infliximab Etanercept or adalimumab ), mycophenolate mofetil, fingolimod, and myriocin.

[0628] 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 in the human body; specific agents include, but are not limited to, aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, macrolides, monobactams, nitrofurans, penicillins, polypeptides, quinolinones, sulfonamides, tetracyclines, antimycobacterial agents, and chloramphenicol, fosfomycin, linezolid, metronidazole, mupirocin, rifamycins, thiamphenicol, and tinidazole.

[0629] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of vasculitis, specific agents including but not limited to steroids (e.g., prednisone, prednisolone), cyclophosphamide, and in the case of skin infections, a final antibiotic (e.g., cephalexin).

[0630] In one embodiment, the compounds of this invention are co-administered with another therapeutic agent for the treatment and / or prevention of esophagitis; specific agents include, but are not limited to, antacids (e.g., formulations containing aluminum hydroxide, magnesium hydroxide, and / or simethicone), H2-antagonists (e.g., cimetidine, ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, rabeprazole, pantoprazole), and glucocorticoids (e.g., prednisone, budesonide).

[0631] 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.

[0632] In one embodiment, the compounds of the present invention are co-administered with another therapeutic agent for the treatment and / or prevention of asthma and / or rhinitis and / or COPD; specific agents include, but are not limited to, beta2-adrenoceptor agonists (e.g., salbutamol, levalbuterol, terbutaline, and bitolterol), epinephrine (inhaled or tablet), anticholinergics (e.g., ipratropium bromide), glucocorticoids (oral or inhaled), long-acting beta2-agonists (e.g., salmeterol, formoterol, bambuterol, and sustained-release oral albuterol), combinations of inhaled steroids with long-acting bronchodilators (e.g., fluticasone / salmeterol, budesonide), and steroids. In some cases, the drug may include 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 the IgE response (e.g., omalizumab), antihistamines (e.g., cetirizine, cinnarizine, fexofenadine), and vasoconstrictors (e.g., oxymethazoline, xylomethazoline, nafazoline, and tramazoline).

[0633] In addition, the compounds of the present invention may be administered in combination with emergency therapies for asthma and / or COPD, including administration of oxygen or heliox, nebulized albuterol or terbutaline (optionally in combination with an anticholinergic agent (e.g., ipratropium bromide)), systemic steroids (oral or intravenous, such as prednisone, prednisolone, methylprednisolone, dexamethasone, or hydroxycorticosterone), intravenous albuterol, nonspecific beta agonists, injectable or inhaled agents (e.g., epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergic agents (IV or nebulized agents, such as glycopyrrolate, atropine, ipratropium bromide), methylxanthines (theophylline, aminophylline, bamiphylline), inhaled anesthetics with a bronchodilator effect (e.g., isoflurane, halothane, enflurane), ketamine, and intravenous magnesium sulfate.

[0634] In one embodiment, the compounds of this invention are co-administered with another therapeutic agent for the treatment and / or prevention of inflammatory bowel disease (IBD); specific agents include, but are not limited to, glucocorticoids (e.g., prednisone, budesonide); synthetic disease-modifying, immunomodulatory agents (e.g., methotrexate, leflunomide, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, and cyclosporine) and biologic disease-modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0635] In one embodiment, the compounds of this invention are co-administered with another therapeutic agent for the treatment and / or prevention of pain, such as non-narcotic and narcotic analgesics; specific agents include, but are not limited to, acetaminophen, acetylsalicylic acid, NSAIDs, codeine, dihydrocodeine, tramadol, pentazocine, meperidine, tilidine, buprenorfine, fentanyl, hydromorphone, methadone, morphine, oxycodone, pirithromide, tapentadol, or a combination thereof.

[0636] Leukemia treatment courses include chemotherapy, biological therapy, targeted therapy, radiation therapy, bone marrow transplantation, and / or a combination thereof.

[0637] Examples of other therapeutic agents for acute lymphoblastic leukemia (ALL) include methotrexate, nelarabine, asparaginase, Erwinia chrysanthemi, belintoxan, daunorubicin, clofarabine, cyclophosphamide, cytarabine, dasatinib, doxorubicin, imatinib, ponatinib, vincristine, mercaptopurine, pegaspargase, and / or prednisone.

[0638] Examples of other therapeutic agents for acute myeloid leukemia (AML) include arsenic trioxide, daunorubicin, cyclophosphamide, cytarabine, doxorubicin, idarubicin, mitoxantrone, and / or vincristine.

[0639] Examples of other therapeutic agents for chronic lymphocytic leukemia (CLL) include alemtuzumab, chlorambucil, ofatumumab, bendamustine, cyclophosphamide, fludarabine, obinutuzumab, ibrutinib, idelalisib, nitrogen mustard, prednisone, and / or rituximab.

[0640] Examples of other therapeutic agents for chronic myeloid leukemia (CML) include bosutinib, busulfan, cyclophosphamide, cytarabine, dasatinib, imatinib, ponatinib, nitrogen mustard, nilotinib, and / or omatase.

[0641] Examples of other therapeutic agents for hairy cell leukemia include cladiribine, pentostatin, and / or interferon alpha-2b.

[0642] As will be apparent to those skilled in the art, co-administration includes any means of delivering two or more therapeutic agents to a patient as part of the same treatment regimen. While two or more agents can be administered simultaneously in a single formulation, this is not required. The agents can be in different formulations and administered at different times.

[0643] In one embodiment, the compounds of the present 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 present 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 present invention are co-administered with another therapeutic agent for the treatment and / or prevention of fibrotic diseases.

[0644] In one embodiment, other therapeutic agents used to treat and / or prevent fibrotic diseases include, but are not limited to, 5-methyl-1-phenyl-2-(1H)-pyridone (pirfenidone); nintedanib ( or ); STX-100 (ClinicalTrials.gov identifier NCT01371305), FG-3019 (ClinicalTrials.gov identifier NCT01890265), lebrevicaulmab (CAS n#953400-68-5); tarotuzumab (CAS n#1044515-88-9), CC-90001 (ClinicalTrials.gov identifier NCT03142191), teluzumab (MN-001; ClinicalTrials.gov identifier NCT02503657), ND-L02-s0201 (ClinicalTrials.gov identifier NCT02503657). In one embodiment, another therapeutic agent for treating and / or preventing a fibrotic disease is an autotaxin (or ectonucleotide pyrophosphatase / phosphodiesterase 2 or NPP2 or ENPP2) inhibitor, examples of which are described in WO 2014 / 139882, such as GLPG1690.

[0645] In one embodiment, the compounds of the invention are co-administered with another therapeutic agent for the treatment and / or prevention of NASH, specific agents include, but are not limited to, weight loss therapeutics (e.g., sibutramine or orlistat), insulin sensitizers (e.g., metformin, thiazolidinediones, rosiglitazone, or pioglitazone), lipid-lowering agents (e.g., gemfibrozil), antioxidants (e.g., vitamin E, N-acetylcysteine, betaine, or pentoxifylline), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, monounsaturated fatty acids, or polyunsaturated fatty acids. FXR agonists (e.g., obeticholic acid), LOXL2 antagonists (e.g., simtulizumab), ASK1 antagonists (e.g., selosulphonate), PPAR agonists (e.g., clofibrate, gemfibrozil, ciprofibrate, bezafibrate, fenofibrate, thiazolidinediones, ibuprofen, GW-9662, aleglitazar, muraglitazar, or tesaglitazar), acetyl CoA-carboxylase (ACC) antagonists (e.g., NDI-010976, PF-05221304), CCR2 / CCR5 (e.g., senevir), VAP1 antagonists.

[0646] Examples of agents that may also be combined with the combinations of the present invention include, but are not limited to: for the treatment of Alzheimer's disease, e.g. and For the treatment of HIV, such as ritonavir; for the treatment of Parkinson's disease, such as L-dopa / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; for the treatment of multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; for asthma treatment, such as albuterol and Agents used to treat schizophrenia, such as Zyprexa, Risperdal, Seroquel, and Haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and antiparkinsonian agents; Agents for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating 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 treating immunodeficiency disorders, such as gamma globulin.

[0647] In certain embodiments, the combination therapies of the invention, or pharmaceutically acceptable compositions thereof, are administered in combination with monoclonal antibodies or siRNA therapeutics.

[0648] Those additional agents may be administered separately from the provided combination therapy as part of a multiple-dose regimen. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of the invention into a single composition. If administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or within a certain time period of each other (generally within five hours of each other).

[0649] As used herein, the term "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0650] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount that would normally be administered in the form of a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the compositions disclosed herein will preferably be in the range of about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0651] In one embodiment, the invention provides a composition comprising a compound of formula I or II and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of formula I or II, or can be administered before or after administering the compound of formula I or II. Suitable therapeutic agents are described in more detail below. In certain embodiments, the compound of formula I or II 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 or II 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.

[0652] In another embodiment, the present invention provides a method of treating an inflammatory disease, condition or disorder by administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biologics and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and steroids. and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat Sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold glucosinolate gold thiomalate and Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Becelimumab and adalimumab "Anti-IL-1" agents such as anakinra and Linacept Canakinumab Anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab "Anti-T cell" agents such as abatacept "Anti-IL-6" agents such as tocilizumab Diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin ( or ) and warfarin Antidiarrheal drugs such as diphenhydramine and loperamide Bile acid binders such as cholestyramine and alosetron Lubiprostone Laxatives such as milk of magnesia, polyethylene glycol and Anticholinergics or antispasmodics such as dicyclomine Beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone budesonide and flunisolide Sodium cromoglycate Methylxanthines such as theophylline and aminophylline, IgE antibodies such as omalizumab Nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine and zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz Nevirapine and etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Sanavi Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir ( or ) and tipranavir Enfuvirtide and Maravero Integrase inhibitors such as raltegravir Doxorubicin vincristine Bortezomib and dexamethasone With lenalidomide or any combination thereof.

[0653] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as gold glucosinolate gold thiomalate and Auranofin D-Penicillamine ( or ), azathioprine Cyclophosphamide Chlorambucil Cyclosporine Leflunomide and "anti-TNF" agents such as etanercept Infliximab Golimumab Becelimumab and adalimumab "Anti-IL-1" agents such as anakinra and Linacept Antibodies such as rituximab "Anti-T cell" agents such as abatacept and "anti-IL-6" agents such as tocilizumab

[0654] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) and monoclonal antibodies such as tanezumab.

[0655] In some embodiments, the present invention provides a method for treating cutaneous lupus erythematosus or systemic lupus erythematosus, comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac, and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarial drugs such as hydroxychloroquine and chloroquine Cyclophosphamide methotrexate Azathioprine and anticoagulants such as heparin ( or ) and warfarin

[0656] In some embodiments, the present invention provides a method of treating Crohn's disease, ulcerative colitis, or inflammatory bowel disease, comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of mesalamine, Sulfasalazine Antidiarrheal drugs such as diphenhydramine and loperamide Bile acid binders such as cholestyramine and alosetron Lubiprostone Laxatives such as milk of magnesia, polyethylene glycol and and anticholinergics or antispasmodics such as dicyclomine Anti-TNF therapy, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0657] In some embodiments, the present invention provides a method of treating asthma comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from: Beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( Know ), triamcinolone acetonide Mometasone budesonide Flunisolide and Sodium cromoglycate Methylxanthines such as theophylline and aminophylline, and IgE antibodies such as omalizumab

[0658] In some embodiments, the present invention provides a method of treating COPD comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of: beta-2 agonists such as albuterol ( HFA, HFA), levosalbutamol Metaproterenol Piributerol acetate Terbutaline sulfate Salmeterol xinafoate and formoterol Anticholinergics such as ipratropium bromide and tiotropium bromide Methylxanthines such as theophylline and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone budesonide Flunisolide and

[0659] In another embodiment, the present invention provides a method of treating a hematological malignancy comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0660] In another embodiment, the present invention provides a method of treating solid tumors, comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0661] In another embodiment, the present invention provides a method of treating a hematologic malignancy comprising administering to a patient in need thereof a compound of Formula I or II and an inhibitor of the hedgehog (Hh) signaling pathway. In some embodiments, the hematologic malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0662] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL) comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of: rituximab Cyclophosphamide Doxorubicin vincristine Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0663] In another embodiment, the present invention provides a method of treating multiple myeloma comprising administering to a patient in need thereof a compound of Formula I or II and one or more additional therapeutic agents selected from the group consisting of: bortezomib; and dexamethasone Hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide

[0664] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I or II 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, Lymeneuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, on's disease), opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease disease), chronic fatigue, dysautonomia, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvar pain, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, infusions, anaphylaxis, allergies (e.g., to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx) Allergies), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpurapurpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, lung inflammation, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), , follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma lymphoma / leukemia, or lymphomatoid granuloma, breast cancer, prostate cancer), or mast cell cancer (e.g., mast cell tumor, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, osteoarthritis (including but not limited to rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis, and Reiter's disease),disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, post-angioplasty reocclusion, post-angioplasty restenosis, post-aortocoronary artery bypass graft reocclusion, post-aortocoronary artery bypass graft restenosis, stroke, transient ischemic attack, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjögren's disease, tissue transplant rejection, hyperacute transplant rejection, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD) , autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes mellitus, 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 reactions (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Grave's disease.

[0665] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I or II and a PI3K inhibitor, wherein the disease is selected from the group consisting of cancer, neurodegenerative disorders, angiogenic disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, disorders associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, disorders associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, pathological immune disorders involving T cell activation, cardiovascular diseases, and CNS disorders.

[0666] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a compound of Formula I or II and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumors; carcinomas or solid tumors of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testicles, genitourinary tract, esophagus, larynx, skin, bone or thyroid; sarcoma; glioblastoma; neuroblastoma; blastoma; multiple myeloma or gastrointestinal cancer, especially colon cancer or colorectal adenoma or head and neck tumors; epidermal 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, including diseases such as Cowden syndrome, Lhermitte-Dudos disease and Bannayan-Zonana syndrome. syndrome); or diseases in which the PI3K / PKB pathway is abnormally activated; asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection; acute lung injury (ALI); adult / acute respiratory distress syndrome (ARDS); chronic obstructive pulmonary, airway, or lung disease (COPD, COAD, or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, and other conditions induced by other drug therapies, especially is an exacerbation of airway hyperresponsiveness caused by other inhaled drug therapy; bronchitis of any type or origin, including but not limited to acute, arachidonic, catarrhal, croupus, chronic or tuberculous bronchitis; pneumoconiosis of any type or origin (inflammatory, usually occupational lung disease, whether chronic or acute, often associated with airway obstruction and caused by repeated inhalation of dust), including, for example, aluminosis, anthracosis, asbestosis, lithophilia, alopecia, siderosis, silicosis, fumigation and byssinusitis;Loffler's syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related conditions affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata; erythema multiforme; dermatitis herpetiformis; scleroderma; vitiligo; hypersensitivity vasculitis; urticaria; bullous pemphigoid; lupus erythematosus; pemphigus; epidermolysis bullosa acquisita; conjunctivitis; dry eye; and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and autoimmune reactions with autoimmune components or etiologies Inflammatory diseases related to or with an autoimmune component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia); cutaneous lupus erythematosus; systemic lupus erythematosus; rheumatoid arthritis; polychondritis; scleroderma; Wegener granulamatosis; dermatomyositis; chronic active hepatitis; myasthenia gravis; Steven-Johnson syndrome syndrome); idiopathic sprue; autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease); endocrine eye diseases; Grave's disease; sarcoidosis; alveolitis; chronic hypersensitivity pneumonitis; multiple sclerosis; primary biliary cirrhosis; uveitis (anterior and posterior); dry eye and vernal keratoconjunctivitis; interstitial pulmonary fibrosis; psoriatic arthritis and glomerulonephritis (with and without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy); restenosis; cardiomegaly; atherosclerosis; myocardial infarction; ischemic stroke and congestive heart failure; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis; Huntington's disease; and cerebral ischemia; as well as neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, and hypoxia.

[0667] In some embodiments, the present invention provides a method of treating a disease or reducing the severity of a disease, the method comprising administering a compound of Formula I or II and a Bcl-2 inhibitor to a patient in need thereof, wherein the disease is an inflammatory disorder, an autoimmune disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplant-related disorder. In some embodiments, the disorder is a proliferative disorder, lupus, or lupus nephritis. In some embodiments, the proliferative disorder is chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Hodgkin's disease, small cell lung cancer, non-small cell lung cancer, myelodysplastic syndrome, lymphoma, hematologic neoplasm, or solid tumor.

[0668] In some embodiments, the disease is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder or a disorder associated with transplantation. In some embodiments, the JH2 binding compound is a compound of formula I or II. Other suitable JH2 domain binding compounds include those described in WO2014074660A1, WO2014074661A1, WO2015089143A1, the full text of each of which is incorporated herein by reference. Suitable JH1 domain binding compounds include those described in WO2015131080A1, the full text of which is incorporated herein by reference.

[0669] The compounds and compositions according to the methods of the present invention can be administered in any effective amount and any effective route of administration for treating or reducing the severity of autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, or transplant-related disorders. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds of the present invention are preferably formulated in unit dosage form to achieve ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to a physically discrete unit of a medicament suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder to be treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and the excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0670] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally (e.g., oral or nasal sprays), etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally to achieve the desired therapeutic effect at dosage levels of about 0.01 mg to about 50 mg, and preferably about 1 mg to about 25 mg, per kg of subject body weight per day, once or more per day.

[0671] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan; and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0672] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution (USP) and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used to prepare injectables.

[0673] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0674] To prolong the effect of the compounds of the present invention, it is generally necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. Thus the absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable reservoir forms are manufactured by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the compound release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Reservoir-type injectable formulations are also prepared by embedding the compound in liposomes or microemulsions compatible with body tissues.

[0675] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0676] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as 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) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solubilizers, such as paraffin, f) absorption enhancers, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0677] Solid compositions of similar types can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as other coatings well-known in the field of enteric coatings and pharmaceutical formulations. They can optionally contain opacifiers and can also have compositions that only release or optionally release active ingredients in a delayed manner in or preferentially in a certain part of the intestinal tract. Examples of spendable embedded compositions include polymeric substances and waxes. Solid compositions of similar types can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycol.

[0678] The active compound may also be present in a microencapsulated form together with one or more excipients as noted above. Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings, release-controlled coatings and other coatings well-known in the field of pharmaceutical formulations. In such solid dosage forms, the active compound may be mixed with at least one inert diluent (e.g., sucrose, lactose or starch). As is normal practice, such dosage forms may also include additional substances other than the inert diluent, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also include a buffer. It may optionally contain an emulsifier and may also have a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract or optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0679] The dosage form for topical or transdermal administration of the compounds of this invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservative or buffer that may be needed under aseptic conditions. Ophthalmic preparations, ear drops and eye drops are also encompassed within the scope of the present invention. In addition, the present invention encompasses the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the transdermal amount of the compound. Rate control can be achieved by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0680] According to one embodiment, the present invention relates to a method of inhibiting GPR84 activity in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0681] According to another embodiment, the present invention relates to a method of inhibiting the activity of GPR84 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0682] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0683] Inhibition of GPR84 (or its mutant) activity in biological samples is suitable for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and bioassays.

[0684] Another embodiment of the present invention is directed to a method of inhibiting GPR84 activity in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound.

[0685] According to another embodiment, the present 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 present invention or a composition comprising the compound. According to certain embodiments, the present invention relates to a method of reversibly or irreversibly inhibiting one or more of GPR84 or a mutant thereof in a patient, the method comprising the step of administering to the patient a compound of the present invention or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a condition mediated by GPR84 or a mutant thereof in a patient in need thereof, the method comprising the step of administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein.

[0686] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are referred to as "appropriate for the disease or condition being treated."

[0687] The compounds of the present invention may also be used to advantage in combination with other therapeutic compounds. In some embodiments, the other therapeutic compound is an anti-proliferative compound. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors: compounds used to treat hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors, such as those from Conforma Therapeutics' 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; and temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer, and leucovorin. As used herein, the term "aromatase inhibitor" refers to a compound that inhibits estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane; and in particular non-steroidal, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin TM Formestane is sold under the trade name Lentaron TM Fadrozole is sold under the trade name Afema TM Anastrozole is sold under the trade name Arimidex TM Letrozole is sold under the trade name Femara TM or Femar TM Aminglutethimide is sold under the trade name Orimeten TM The combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0688] As used herein, the term "anti-estrogen" refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex. TM Raloxifene hydrochloride is sold under the trade name Evista TM Fulvestrant is sold under the trade name Fas1odex. TM Administration. The combinations of the invention comprising a chemotherapeutic agent which is an antiestrogen are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0689] As used herein, the term "antiandrogen" refers to any substance that is capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex). TM As used herein, the term "gonadotropin-releasing hormone agonist" includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is available under the trade name Zoladex. TM Application.

[0690] As used herein, the term "topoisomerase I inhibitor" includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is available, for example, in its marketed form, for example under the trademark Camptosar. TM Topotecan is sold under the trade name Hycamptin TM Sale.

[0691] As used herein, the term "topoisomerase II inhibitors" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name Etopophos TM Teniposide is sold under the trade name VM26-Bristol. Doxorubicin is sold under the trade name Acriblastin TM or Adriamycin TM Epirubicin is sold under the trade name Farmorubicin TM Idarubicin is sold under the trade name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0692] The term "microtubule active agent" refers to microtubule stabilizing, microtubule destabilizing compounds and microtubule polymerization inhibitors, including but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine; discodermolide; colchicine and epothilone and its derivatives. Pacific paclitaxel is sold under the trade name Taxol TM Docetaxel is sold under the trade name TaxotereTM Vinblastine sulfate is sold under the trade name Vinblastin R.p TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0693] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin. TM Ifosfamide is sold under the trade name Holoxan TM Sale.

[0694] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0695] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folic acid antagonists (e.g., pemetrexed). Capecitabine is marketed under the trade name Xeloda TM Gemcitabine is sold under the trade name Gemzar TM Sale.

[0696] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin is available, for example, in the form in which it is marketed, for example, under the trademark Carboplat TM Oxaliplatin can be used, for example, in the form in which it is marketed, for example under the trademark Eloxatin TM Application.

[0697] As used herein, the term "compounds that target / reduce the activity of protein or lipid kinases, or protein or lipid phosphatases; or other anti-angiogenic compounds" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as: a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, in particular compounds that inhibit PDGF receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit fibroblast growth factor receptor (F c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, in particular compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or aprelimin 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. h) compounds that target, decrease or inhibit the activity of c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, decrease 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, decrease 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, decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as those from Park eDavis's imatinib or nilotinib (AMN107), PD180970, AG957, NSC680410, PD173955; or dasatinib (BMS-354825); j) compounds that target, decrease, or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, BTK, and TEC families, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, such as midostaurin;Examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTIs; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example, compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrphostins, such as tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG 494; tyrphostin AG 556, AG957, and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, Adastin); 1) Compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4, as homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family, especially compounds, proteins or antibodies that inhibit the binding of EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or EGF or EGF-related ligands CP 358774, ZD 1839, ZM105180; Herceptin TM ), Cetuximab (Erbitux TM), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of c-Met receptor, for example, compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of c-Met receptor. 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, decrease or inhibit the kinase activity of P13 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL -719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, decrease, or inhibit signaling through the Hedgehog (Hh) or Smoothened (SMO) receptor pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[0698] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors suitable for use in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparcoxib, pectecoxib, PF-4691502, BYL-719, datoxib, XL-147, XL-765, and idelalisib.

[0699] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds that have inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0700] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds that have inhibitory activity on spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0701] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitor (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), and HA14-2 (and its analogs; see WO2008118802). In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptide mimetic.

[0702] Further examples of BTK inhibiting compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0703] Further examples of SYK inhibiting compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0704] Other examples of PI3K inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0705] Further examples of JAK inhibitory compounds and conditions treatable by combinations of such compounds with the compounds of the present invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0706] Other antiangiogenic compounds include compounds with another mechanism of activity (e.g., unrelated to protein or lipid kinase inhibition), such as thalidomide. TM ) and TNP-470.

[0707] Examples of proteasome inhibitors suitable for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporin A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0708] Compounds that target, decrease or inhibit the activity of a protein or lipid phosphatase are, for example, phosphatase 1 inhibitors, phosphatase 2A inhibitors or CDC25 inhibitors, such as okadaic acid or a derivative thereof.

[0709] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-tocopherol, γ-tocopherol, or δ-tocopherol, or α-tocotrienol, γ-tocotrienol, or δ-tocotrienol.

[0710] As used herein, the term cyclooxygenase inhibitors includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives such as celecoxib (Celebrex T...

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R 1 for or Y 1 ; R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 Alkylene)-(C 1-6 alkoxy), -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(a 7-9 membered saturated spirocyclic heterocyclic radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic radical is replaced by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(3-7 membered saturated heterocyclylene radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ; R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ; R 4 and R 5 Independently for C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring; R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl; R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; A 1 for or Y 4 , where ** is related to A 2 The connection point; A 2 is phenylene, i.e. a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or Y 5 ; where phenylene and heteroarylene are represented by n occurrences of R 3 replace; L 1 C 1-3 Alkylene; Y 1 is -C(O)N(R 7 )(R 8 ), -N(R 7 )C(O)(R 6 ), -CO2R 7 , Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 haloalkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing 1 oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R7)-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substitution), -C≡C-(C 1-3 alkylene)-(imidazolylene)-(phenylene)-N(R 7 )(R 8 ), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 ,-(by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a -(C 0-4 Alkylene)-(C 1-4 haloalkoxy)substituted azetidinyl), -(C 0-3 -(C2 alkynyl)-CN, 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 1-4 Alkylene)-(C 3-6 cycloalkyl), or hydrogen; Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 Deuterated alkyl)2; Y 4 for Where ** is the same as A 2 The connection point; Y 5 quilt The number of occurrences of R 3 replace; Z 1 C 1-10 Aliphatic group, -(C 0-3 (a 3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 Hydroxyalkyl group substitution), -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur),-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -N(R 7 )-(C 1-10 Optionally substituted aliphatic)- or C 1-6 Hydroxyalkyl; Z 2 Is one of the following: (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group, (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or (c) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and n is 0, 1, or 2; where Y 1 , Y 2 , Y 3 , Y 4 or Y 5 occurs at least once; and The condition is that when Y 4 for When R 3 Not a methyl group.

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

3. The compound according to claim 1 or 2, wherein R 1 for 4. A compound as described in any one of claims 1 to 3, wherein R 4 and R 5 Independently for C 1-6 alkyl.

5. The compound of any one of claims 1 to 3, wherein R 4 and R 5 It is methyl.

6. The compound of any one of claims 1 to 3, wherein R 4 and R 5 Together with their intervening atoms they form a 3-5 membered saturated carbocyclic ring.

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

8. The compound of claim 1 or 2, wherein R 1 Y 1 .

9. The compound of claim 1, 2 or 8, wherein Y 1 -C(O)N(R 7 )(R 8 ).

10. The compound of claim 1, 2 or 8, wherein Y 1 -N(R 7 )C(O)(R 6 ) or -CO2R 7 .

11. The compound of claim 1, 2 or 8, wherein Y 1 for 12. The compound of claim 1, 2 or 8, wherein Y 1 for 13. The compound according to claim 1, wherein the compound is a compound of formula Ic or a pharmaceutically acceptable salt thereof:

14. A compound as described in any one of claims 1 to 13, wherein A 1 for Where ** is the same as A 2 connection point.

15. The compound of any one of claims 1 to 13, wherein A 1 Y 4 .

16. A compound as described in any one of claims 1-13 or 15, wherein Y 4 for Where ** is the same as A 2 connection point.

17. A compound as described in any one of claims 1-13 or 15, wherein Y 4 for Where ** is the same as A 2 connection point.

18. A compound as described in any one of claims 1-13 or 15, wherein Y 4 for Where ** is the same as A 2 connection point.

19. A compound as described in any one of claims 1-13 or 15, wherein Y 4 for Where ** is the same as A 2 connection point.

20. The compound of any one of claims 1 to 19, wherein A 2 is R that appears n times 3 Substituted phenylene.

21. A compound as described in any one of claims 1-19, wherein A2 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 replace.

22. A compound as described in any one of claims 1-19, wherein A 2 is R that appears n times 3 Substituted pyridinylene.

23. A compound as described in any one of claims 1-19, wherein A 2 Y 5 .

24. The compound of any one of claims 1-23, wherein n is 1.

25. A compound as described in any one of claims 1 to 24, wherein L 1 It is -CH2-.

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

27. The compound of claim 1, wherein the compound is a compound of formula If or a pharmaceutically acceptable salt thereof:

28. The compound of claim 1, wherein the compound is a compound of formula Ig or a pharmaceutically acceptable salt thereof:

29. The compound of claim 1, wherein the compound is a compound of formula Ih or a pharmaceutically acceptable salt thereof:

30. A compound as described in any one of claims 1 to 29, wherein R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl) or -(C 2-4 Alkynylidene)-(C 1-3 Alkylene)-(C 1-6 alkoxy).

31. A compound as described in any one of claims 1 to 29, wherein R 2 -(a 3-7 membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is replaced by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(a 7-9 membered saturated spirocyclic heterocyclic radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic radical is replaced by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

32. A compound as described in any one of claims 1 to 29, wherein R 2 Y 2 .

33. A compound as described in any one of claims 1-29 or 32, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 Or -C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ).

34. A compound as described in any one of claims 1-29 or 32, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 haloalkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), or -C≡C-(hydroxycyclopropyl).

35. A compound as described in any one of claims 1-26 or 29, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing 1 oxygen atom), -C≡C-(C1-3 alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 alkyl substituted), or 36. A compound as described in any one of claims 1-29 or 32, wherein Y 2 for 37. A compound as described in any one of claims 1-29, 32 or 36, wherein Z 1 C 1-10 Aliphatic or -(C 0-3 (a 3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group).

38. A compound as described in any one of claims 1-29, 32 or 36, wherein Z 1 -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur),-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or C 1-6 Hydroxyalkyl.

39. according to the compound described in any one of claim 1-29 or 32, wherein Y 2 -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 ,-(by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), or -(substituted by a C 1-4 Alkyl and a -(C 0-4 Alkylene)-(C 1-4 (substituted azetidinyl) 40. A compound as described in any one of claims 1-29, 32 or 39, wherein Z 2 For R that appears 1 or 2 times 3 A substituted 3-7 membered saturated heterocyclic group.

41. A compound as described in any one of claims 1-29, 32 or 39, wherein Z 2 For-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

42. A compound as described in any one of claims 1-29, 32 or 39, wherein Z 2 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

43. A compound as described in any one of claims 1-29 or 32, wherein Y 2 For-(C 0-3 -(C2 alkynyl)-CN, 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ) or C 3-7 Cycloalkyl.

44. A compound as described in any one of claims 1-29 or 32, wherein Y 2 is -(a saturated heterocyclic group containing 7-10 membered spirocyclic hydroxyl groups substituted with 1, 2 or 3 heteroatoms selected from nitrogen and oxygen) or -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur) or hydrogen.

45. A compound as described in any one of claims 1-44, wherein R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl or -N(R 7 )(R 8 ).

46. ​​A compound as described in any one of claims 1-44, wherein R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

47. A compound as described in any one of claims 1-44, wherein R 3 Y 3 .

48. A compound of formula II: or a pharmaceutically acceptable salt thereof, wherein: R 1 for or Y 1 ; R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl), -(C 2-4 Alkynylidene)-(C 1-3 Alkylene)-(C 1-6 Alkoxy), -(C 2-4 Alkynylidene)-(with 0, 1 or 2 occurrences of R 10 Substituted phenyl), -(C 2-4 Alkyne)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 Replace), -(C 2-4 Alkynylidene)-(with 0, 1 or 2 occurrences of R 11 Substituted phenyl), -(C 2-4 Alkyne)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 11 substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(a 7-9 membered saturated spirocyclic heterocyclic radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic radical is replaced by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(3-7 membered saturated heterocyclylene radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), or Y 2 ; R 3 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, -N(R 7 )(R 8 ) or Y 3 ; R 4 and R 5 Independently for C 1-6 Alkyl or C 1-2 Deuterated alkyl, or R 4 and R 5 Together with their intervening atoms, they form a 3-5 membered saturated carbocyclic ring; R 6 C 1-6 Alkyl or C 3-6 Cycloalkyl; R 7 and R 8 Each occurrence independently represents hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; or R 7 and R 8 Together with the nitrogen atom to which they are attached, they form a 3-7 membered heterocyclic ring containing 1 nitrogen atom; R 9 For hydrogen, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 10 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy or C 3-6 Cycloalkyl; R 11 Each occurrence independently represents a halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl or C 3-6 Cycloalkyl; A 1 for or Y 4 , where ** is related to L 2 The connection point; A 2 is phenylene or Y 5 , where the phenylene group is replaced by n occurrences of R 3 replace; L 1 C 1-3 Alkylene; L 2 -N(R 9 )-、Y 6 or by C 1-4 Alkoxy substituted C 1-4 Alkylene; Y 1 -C(O)N(R 7 )(R 8 )、-N(R 7 )C(O)(R 6 ), -CO2R 7 , or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 replace; Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8 )、-C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 haloalkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), -C≡C-(hydroxycyclopropyl), -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing 1 oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 Alkylene)-(triazolyl optionally substituted with a phenyl group, the phenyl group optionally substituted with a C 1-3 Alkyl substituted), -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 ,-(by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-3 Alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C 1-4 haloalkoxy-substituted azetidinyl), -(C 0-3 -(C2 alkynyl)-CN, 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ), C 3-7 Cycloalkyl, -(7-10 membered spirocyclic hydroxy substituted saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 0-4 Alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 hydroxyalkyl, or hydrogen; Y 3 -N(R 7 )(C 1-4 deuterated alkyl) or -N(C 1-4 Deuterated alkyl)2; Y 4 for Where ** is related to L 2 The connection point; Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 replace; Y 6 (a) -C≡C- or -(C 1-4 Alkylene)(C(H)(C 1-4 Alkoxy)-, (b) 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 Alkylene, (c) -SC 1-4 Alkyl substituted C 1-4 Alkylene, or (d) -CH2- or -O-; Z 1 C 1-10 Aliphatic group, -(C 0-3 (a 3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 Hydroxyalkyl group substitution), -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur),-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur) or C 1-6 Hydroxyalkyl; Z 2 Is one of the following: (a) 1 or 2 occurrences of R 3 a substituted 3-7 membered saturated heterocyclic group, (b)-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or (c) a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and n is 0, 1, or 2; where Y 1 , Y 2 , Y 3 , Y 4 , Y 5 or Y 6 occurs at least once; and The condition is that if A 1 for And Y 6 When it is -CH2- or -O-, R 3 Not a methyl group.

49. The compound of claim 48, wherein the compound is a compound of formula II.

50. The compound of claim 48 or 49, wherein R 1 for 51. A compound as described in any one of claims 48-50, wherein R 4 and R 5 Each independently is C 1-6 alkyl.

52. A compound as described in any one of claims 48-50, wherein R 4 and R 5 It is methyl.

53. A compound as described in any one of claims 48-50, wherein R 4 and R 5 Together with their intervening atoms they form a 3-5 membered saturated carbocyclic ring.

54. The compound of claim 48, wherein the compound is a compound of formula IIa or IIb or a pharmaceutically acceptable salt thereof:

55. The compound of claim 48 or 49, wherein R 1 Y 1 .

56. A compound as described in claim 48, 49 or 55, wherein Y 1 -C(O)N(R 7 )(R 8 ).

57. The compound of claim 48, 49 or 55, wherein Y 1 -N(R 7 )C(O)(R 6 ) or -CO2R 7 .

58. A compound as described in claim 48, 49 or 55, wherein Y 1 for 59. The compound of claim 48, 49 or 55, wherein Y 1 for 60. The compound of claim 48, 49 or 55, wherein Y 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 replace.

61. The compound of claim 48, wherein the compound is a compound of formula IIc or a pharmaceutically acceptable salt thereof:

62. A compound as described in any one of claims 48-61, wherein A 1 for Where ** is related to L 2 connection point.

63. A compound as described in any one of claims 48-61, wherein A 1 for Where ** is related to L 2 connection point.

64. A compound as described in any one of claims 48-61, wherein A 1 Y 4 .

65. A compound as described in any one of claims 48-61 or 64, wherein Y 4 for Where ** is related to L 2 connection point.

66. A compound as described in any one of claims 48-61 or 64, wherein Y 4 for Where ** is related to L 2 connection point.

67. A compound as described in any one of claims 48-61 or 64, wherein Y 4 for Where ** is related to L 2 connection point.

68. A compound as described in any one of claims 48-67, wherein A 2 is R that appears n times 3 Substituted phenylene.

69. A compound as described in any one of claims 48-67, wherein A 2 Y 5 .

70. A compound as described in any one of claims 48-67 or 69, wherein Y 5 is a 5-6 membered heteroarylene group containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein the heteroarylene group is replaced by n occurrences of R 3 replace.

71. A compound as described in any one of claims 48-67 or 69, wherein Y 5 is R that appears n times 3 Substituted pyridinylene.

72. A compound as described in any one of claims 48-71, wherein n is 1.

73. A compound as described in any one of claims 48-72, wherein L 1 It is -CH2-.

74. The compound of claim 48, wherein the compound is a compound of formula IId or IIe or a pharmaceutically acceptable salt thereof:

75. The compound of claim 48, wherein the compound is a compound of formula If or a pharmaceutically acceptable salt thereof:

76. The compound of claim 48, wherein the compound is a compound of formula IIg or a pharmaceutically acceptable salt thereof:

77. A compound as described in any one of claims 48-76, wherein R 2 For-(C 2-4 Alkynylidene)-(C 3-7 Cycloalkyl) or -(C 2-4 Alkynylidene)-(C 1-3 Alkylene)-(C 1-6 alkoxy).

78. A compound as described in any one of claims 48-76, wherein R 2 For-(C 2-4 Alkynylidene)-(with 0, 1 or 2 occurrences of R 10 Substituted phenyl), -(C 2-4 Alkyne)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the heteroaryl is replaced by 0, 1 or 2 occurrences of R 10 substituted), -(containing 1 or 2 heteroatoms selected from nitrogen and oxygen 3-7 membered saturated heterocyclic group, wherein the heterocyclic group is substituted by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl radical), -(a 7-9 membered saturated spirocyclic heterocyclic radical containing 1 or 2 heteroatoms selected from nitrogen and oxygen, wherein the spirocyclic heterocyclic radical is replaced by 0, 1 or 2 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group), or -(3-7 membered saturated heterocyclylene containing 1 or 2 heteroatoms selected from nitrogen and oxygen)-(C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen).

79. A compound as described in any one of claims 48-76, wherein R 2 Y 2 .

80. A compound as described in any one of claims 48-76 or 79, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )SO2-R 6 、-C≡C-(C 1-3 Alkylene)-SO2-N(R 7 )(R 8 )、-C≡C-(C 0-3 Alkylene)-N(R 7 )C(O)R 6 、-C≡C-(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 ), or -C≡C-(C 1-3 Alkylene)-N(R 7 )(R 8 ).

81. A compound as described in any one of claims 48-76 or 79, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-O-(C 3-6 Cycloalkyl), -C≡C-(C 1-3 Alkylene)-O-(C 1-5 haloalkyl), -C≡C-(C 1-5 haloalkyl), -C≡C-(cyclobutyl), -C≡C-(C(CH3)2(OH)), or -C≡C-(hydroxycyclopropyl).

82. A compound as described in any one of claims 48-76 or 79, wherein Y 2 = -C≡C-(C 1-3 Alkylene)-N(R 7 )(4-6 membered saturated heterocyclic group containing 1 oxygen atom), -C≡C-(C 1-3 Alkylene)-N(R 7 )-(C 0-3 Alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), -C≡C-(C 1-3 alkylene)-(triazolyl optionally substituted with one phenyl group, the phenyl group optionally substituted with one C 1-3 alkyl substituted), or 83. A compound as described in any one of claims 48-76 or 79, wherein Y2 is 84. A compound as described in any one of claims 48-76, 79 or 83, wherein Z 1 C 1-10 Aliphatic or -(C 0-3 (a 3-7 membered saturated heterocyclic group containing 1, 2 or 3 heteroatoms selected from nitrogen and oxygen, wherein the heterocyclic group is substituted by 1, 2 or 3 independently selected from C 1-6 Alkyl and C 1-6 substituted with a hydroxyalkyl group).

85. A compound as described in any one of claims 48-76, 79 or 83, wherein Z 1 -N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur),-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur), or C 1-6 Hydroxyalkyl.

86. according to the compound described in any one of claim 48-76 or 79, wherein Y 2 -(1 or 2 occurrences of C 1-4 Alkyl-substituted azetidinyl)-Z 2 ,-(by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), -(substituted by a C 1-4 Alkyl and a C1-3 alkylene-OC 3-6 Cycloalkyl-substituted azetidinyl), -(substituted by a C 1-4 A haloalkyl group and a C 1-4 alkyl-substituted azetidinyl), or -(substituted by a C 1-4 Alkyl and a -(C 0-4 Alkylene)-(C 1-4 (substituted azetidinyl) 87. A compound as described in any one of claims 48-76, 79 or 86, wherein Z 2 For R that appears 1 or 2 times 3 A substituted 3-7 membered saturated heterocyclic group.

88. A compound as described in any one of claims 48-76, 79 or 86, wherein Z 2 For-(C 0-3 Alkylene)-N(R 7 )-(C 0-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur).

89. A compound as described in any one of claims 48-76, 79 or 86, wherein Z 2 is a 5-6 membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

90. A compound as described in any one of claims 48-76 or 79, wherein Y2 is -(C 0-3 -(C2 alkynyl)-CN, 1-4 Haloalkyl, -(C 0-3 Alkylene)-C(O)N(R 7 )(R 8 )、-O-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 )、-N(R 7 )-(C 1-3 Alkylene)-C(O)N(R 7 )(R 8 ) or C 3-7 Cycloalkyl.

91. A compound as described in any one of claims 48-76 or 79, wherein Y 2 is -(a saturated heterocyclic group containing 7-10 membered spirocyclic hydroxyl groups substituted with 1, 2 or 3 heteroatoms selected from nitrogen and oxygen), -C(O)N(R 7 )-(C 1-3 alkylene)-(5-6 membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from oxygen, nitrogen and sulfur), phenyl, benzyl, (C 1-4 alkylene)-(5-6 membered heteroaryl containing 1 or 2 heteroatoms selected from nitrogen and oxygen), (C 0-4 Alkylene)-(C 3-6 Cycloalkyl), C 1-4 Alkoxy, C 1-6 Hydroxyalkyl, or hydrogen.

92. as described in any one of claims 48-91 compound, wherein R3 represents halogen, C 1-4 Alkyl, C 1-4 Haloalkyl or C 1-4 Alkoxy.

93. A compound as described in any one of claims 48-91, wherein R 3 Y 3 .

94. A compound as described in any one of claims 48-93, wherein L 2 -N(R 9 )-.

95. A compound as described in any one of claims 48-93, wherein L 2 For C 1-4 Alkoxy substituted C 1-4 Alkylene.

96. A compound as described in any one of claims 48-93, wherein L 2 Y 6 .

97. A compound as described in any one of claims 48-93 or 96, wherein Y 6 It is -C≡C-.

98. A compound as described in any one of claims 48-93 or 96, wherein Y 6 For-(C 1-4 Alkylene)(C(H)(C 1-4 Alkoxy)-.

99. A compound as described in any one of claims 48-93 or 96, wherein Y 6 is 0 or 1 C 3-5 Cycloalkyl substituted C 2-4 Alkylene.

100. A compound as described in any one of claims 48-93 or 96, wherein Y 6 For SC 1-4 Alkyl substituted C 1-4 Alkylene.

101. A compound of Table 1, Table 2 or Table 3, or a pharmaceutically acceptable salt thereof.

102. A pharmaceutical composition comprising a compound according to any one of claims 1-101 and a pharmaceutically acceptable carrier.

103. A method of inhibiting GPR84, the method comprising contacting GPR84 with an effective amount of a compound of any one of claims 1-101 to inhibit GPR84.

104. A method of treating a GPR84-mediated condition, disease or disorder in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-101.

105. The method of claim 104, wherein the condition, disease or disorder is a proliferative disease, a fibrotic disease, an infectious disease, an autoimmune disease, an endocrine and / or metabolic disease, a cardiovascular disease, a disease involving impaired immune cell function, a neuroinflammatory disorder, a neurodegenerative disease, an inflammatory disorder, multiple sclerosis or pain.

106. The method of claim 104, wherein the condition, disease or disorder is cancer.

107. The method of claim 106, wherein the cancer is leukemia or hepatocellular carcinoma (HCC).

108. The method of claim 106, wherein the cancer is acute myeloid leukemia (AML).

109. The method of claim 104, wherein the condition, disease or disorder is a proliferative disease associated with one or more activating mutations in GPR84.

110. The method of claim 104, wherein the condition, disease or disorder is a chronic viral infection.

111. The method of claim 104, wherein the condition, disease or disorder is an inflammatory disorder selected from the group consisting of rheumatoid arthritis, chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis (IPF), psoriasis, Crohn's disease, ulcerative colitis, uveitis, periodontitis, esophagitis, gastroesophageal reflux disease (GERD), inflammatory bowel disease, or pyoderma gangrenosum.

112. The method of claim 104, wherein the condition, disease or disorder is non-alcoholic steatohepatitis (NASH) or idiopathic pulmonary fibrosis (IPF).

113. The method of claim 104, wherein the condition, disease or disorder is systemic lupus erythematosus (SLE).

114. The method of claim 104, wherein the condition, disease or disorder is neuropathic pain.

115. The method of claim 104, wherein the condition, disease or disorder is Alzheimer's disease.

116. The method of claim 104, wherein the condition, disease or disorder is idiopathic pulmonary fibrosis (IPF).

117. A method of improving the efficacy of vaccination in a patient, comprising administering to the patient in need thereof a compound of any one of claims 1-101 as an adjuvant.

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