N-(phenylaminocarbonyl)tetrahydro-isoquinolines and related compounds as modulators of GPR65

Abstract

The present invention relates to a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof, wherein ring A is a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, or a 9- or 10-membered bicyclic aromatic or heteroaromatic ring, each of which may be selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are F, Cl, Br, I, CN, alkoxy, NR 11 R 11 , OH, alkyl, haloalkyl, and aralkyl, and Y and Z are each independently selected from CR 10 R 10 ' and R 10 and R 10 R' are each independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, I, and haloalkyl; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; at least two of R2, R3, and R4 are other than H; and R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl; N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; N-(3,4-dichlorophenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide; N-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-5(4H)-carboxamide; and N-(3,4-dichlorophenyl)-4-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide A further aspect of the invention relates to such compounds for use in the fields of immuno-oncology, immunology, and related applications. [Formula 1] JPEG2023528074000174.jpg69137

Description

[Technical Field]

[0001] The present invention relates to compounds capable of modulating GPR65, which have potential therapeutic applications in the treatment of a variety of disorders, including proliferative and immune disorders. [Background technology]

[0002] GPR65 is a G-protein-coupled receptor (GPCR) that is primarily expressed in immune cells and is activated by extracellular acidic pH, leading to an increase in cytoplasmic cyclic adenosine monophosphate (cAMP) (Non-Patent Document 1). It has long been known that tumors typically undergo a switch in cellular metabolism from oxidative phosphorylation to aerobic glycolysis, which in turn generates an acidic extracellular microenvironment (Non-Patent Document 2). Recently, it has been shown that this acidic microenvironment triggers activation of GPR65 in tumor-associated macrophages, leading to an increase in cytoplasmic cAMP, which in turn leads to the transcription of inducible cAMP early repressor (ICER). This in turn suppresses tumor necrosis factor alpha (TNFα) secretion, biasing macrophages toward an anti-inflammatory, tumor-permissive phenotype (Non-Patent Document 3). Thus, this GPR65-dependent pathway appears to represent a mechanism by which tumors exploit these acidic microenvironments to evade detection by the immune system.

[0003] Autoimmune diseases are also often associated with a local acidic microenvironment (e.g., inflamed joints). Recent experiments also suggest that GPR65 acts via ICER in CD4+ T cells to suppress IL-2, thus biasing the cells toward a pro-inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune disease (Non-Patent Document 4). Supporting this is the recent discovery that ICER is required for Th17 differentiation (Non-Patent Document 5) and that agonism of GPR65 leads to increased Th17 differentiation (Non-Patent Document 6). Indeed, mutations at the GPR65 site are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Non-Patent Document 7). One recent study found that mice with CD4+ T cells lacking GPR65 were protected from the development of autoimmune encephalomyelitis (EAE) (Non-Patent Document 7). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Wang, J. et al. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633 [Non-patent document 2] Damaghi, M. et al. (2013). pH Sensing and Regulation in Cancer. Frontiers in Physiology [Non-patent document 3] Bohn, T. et al. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 1319-1326 [Non-patent document 4] Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517 [Non-Patent Document 5] Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993 [Non-patent document 6] Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2 / CREB pathway. The Journal of Immunology, 200 (Supplement) [Non-Patent Document 7] Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412 Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, GPR65 appears to act through ICER to promote an anti-inflammatory and tumor-permissive phenotype in tumor-associated macrophages and a pro-inflammatory Th17 phenotype in CD4+ T cells associated with autoimmune diseases. Therefore, GPR65 signaling represents an interesting pathway for therapeutic intervention for the treatment of both cancer and autoimmune diseases. Therefore, there is a continuing need to develop novel small molecule GPR65 modulators. [Means for solving the problem]

[0006] The present invention seeks to provide compounds capable of modulating GPR65. As will be apparent from the above discussion, such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative and immune disorders, as well as asthma and chronic obstructive pulmonary disease.

[0007] Description of the Invention A first aspect of the present invention is a compound of formula (Ia)

[0008] [ka] [In the formula, Ring A is a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, or a 9- or 10-membered bicyclic aromatic or heteroaromatic ring, each of which is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, I, and haloalkyl; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; at least two of R2, R3 and R4 are other than H; R 11 and R11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl; The compound is N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; N-(3,4-dichlorophenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide; N-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-5(4H)-carboxamide; or N-(3,4-dichlorophenyl)-4-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

[0009] Advantageously, the compounds claimed according to the present invention are capable of modulating GPR65, and therefore are of therapeutic interest for the treatment of various disorders, e.g., in the fields of oncology, immuno-oncology and immunology.

[0010] A second aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

[0011] [ka] During the ceremony, Ring A is a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, or a 9- or 10-membered bicyclic aromatic or heteroaromatic ring, each of which is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, I, and haloalkyl; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; at least two of R2, R3 and R4 are other than H; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl.

[0012] Another aspect of the present invention relates to a compound of formula (I) as described above for use in the treatment or prophylaxis of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

[0013] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound described above and a pharmaceutically acceptable diluent, excipient, or carrier.

[0014] Another aspect of the invention relates to a compound or a pharmaceutical composition as described above for use as a medicament.

[0015] Another aspect of the present invention relates to a compound or a pharmaceutical composition as described above for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

[0016] Another aspect of the invention relates to a method of treating a disorder, comprising administering to a subject a compound or pharmaceutical composition described above. DETAILED DESCRIPTION OF THE INVENTION

[0017] The present invention relates to compounds capable of modulating GPR65.

[0018] "Alkyl" is defined herein as a straight or branched chain alkyl radical, preferably C 1-20 Alkyl, more preferably C 1-12 Alkyl, even more preferably C 1-10 Alkyl or C 1-6 Alkyl, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, alkyl is C 1-3 It is alkyl.

[0019] As used herein, the term "aryl" refers to an optionally benzo-fused C 6-12 It refers to an aromatic group such as phenyl or naphthyl. Preferably, the aryl group is phenyl.

[0020] "Haloalkyl" is defined herein as a straight or branched alkyl radical as defined above, e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, which is substituted with one or more halogen atoms (which may be the same or different), e.g., fluorine, chlorine, bromine, and iodine. Preferably, haloalkyl is C 1-20 Haloalkyl, more preferably C 1-12 Haloalkyl, even more preferably C 1-10 Haloalkyl or C 1-6 Haloalkyl, or C 1-3 haloalkyl. Preferred examples are CF3 and CHF2, with CF3 being especially preferred.

[0021] "Alkoxy" is defined herein as an oxygen atom attached to an alkyl group as defined above, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, and hexoxy. Preferably, alkoxy is C 1-20 Alkoxy, more preferably C 1-12 Alkoxy, even more preferably C 1-10 Alkoxy or C 1-6 Alkoxy or C 1-3 Alkoxy is a preferred example of methoxy (-OCH3).

[0022] "Heteroaryl" as used herein refers to a monocyclic or bicyclic C alkyl group containing one or more heteroatoms (which may be the same or different), such as oxygen, nitrogen, or sulfur. 2-12It is defined as an aromatic ring. Examples of suitable heteroaryl groups include thienyl, furanyl, pyrrolyl, pyridinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrimidinyl, pyrazinyl, triazinyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, and the like; or pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and the like.

[0023] "Aralkyl" is defined herein as an alkyl group, as defined above, substituted with one or more aryl groups, as defined above.

[0024] Compounds of formula (Ia) One aspect of the present invention relates to compounds of formula (Ia):

[0025] [ka] During the ceremony, Ring A is a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, or a 9- or 10-membered bicyclic aromatic or heteroaromatic ring, each of which is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, I, and haloalkyl; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; at least two of R2, R3 and R4 are other than H; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl.

[0026] Preferably, the compound is N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; N-(3,4-dichlorophenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide; N-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-5(4H)-carboxamide; and N-(3,4-dichlorophenyl)-4-methyl-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-carboxamide It is a compound other than

[0027] Preferably, the compound of formula (Ia) is not compound 1, 8, 11, 80 or 81 described herein.

[0028] In formula (Ia), and for other embodiments, preferably alkyl is C 1- C6 alkyl and haloalkyl are C 1- C6 haloalkyl and alkoxy are C 1- It is a C6 alkoxy.

[0029] In one embodiment, the optional substituents on the A ring are F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl and haloalkyl.

[0030] In one embodiment, the compounds described herein contain an optionally substituted 5- or 6-membered monocyclic aromatic or heteroaromatic ring A fused to a nitrogen-containing ring. The optional substituents are F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 It may be substituted with one or more substituents each independently selected from the group consisting of , OH, alkyl, haloalkyl, and aralkyl.

[0031] In a preferred embodiment, ring A is selected from halo, CN, C1-C6 alkoxy, NR 11 R 11', OH, C1-C6 alkyl, phenyl, SO2-alkyl, CO2-alkyl, thienyl, halo-substituted pyridinyl, and C1-C6 haloalkyl. More preferably, ring A is optionally substituted with one or more substituents selected from Me, Cl, F, CN, MeO, NH2, OH, CO2Me, SO2Me, thienyl, and fluoropyridinyl.

[0032] In some cases, ring A can exist in more than one tautomeric form. By way of illustration, when the aromatic heterocycle is substituted with an OH group, ring A can exist as two possible tautomers as shown below:

[0033] [ka]

[0034] The 2-pyridone tautomer is believed to be the predominant solid form. In solution, the energy difference between the two tautomeric forms is believed to be minimal and depends on the polarity of the solvent. Those skilled in the art will recognize that other hydroxy-substituted N-containing heteroaromatic groups (e.g., pyrimidine, other pyridine positional isomers) can also be represented in the tautomeric form shown above. The term "heteroaromatic" as used herein encompasses all tautomeric forms of the compound.

[0035] In one preferred embodiment, the monocyclic aromatic or heteroaromatic ring A fused to the nitrogen-containing ring is a group selected from benzene, pyridine, pyridone, pyridine N-oxide, pyridazine, pyrimidine, pyrimidone, pyrazine, triazine, pyrrole, furan, thiophene, pyrazole, isoxazole, imidazole, oxazole, oxadiazole, and thiazole, each of which may be substituted.

[0036] In one preferred embodiment, the monocyclic aromatic or heteroaromatic ring A is a group selected from benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine and isoxazole, each of which may be substituted.

[0037] In one preferred embodiment, ring A is a group selected from benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, and isoxazole, each of which is selected from F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, phenyl, SO2-alkyl, CO2-alkyl, thienyl, halo-substituted pyridinyl, and C1-C6 haloalkyl.

[0038] In one preferred embodiment, ring A is a group selected from benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, and isoxazole, each of which is selected from F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, SO2-alkyl, CO2-alkyl, I, and C1-C6 haloalkyl.

[0039] In a preferred embodiment, ring A is selected from the group consisting of F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 In a preferred embodiment, ring A is a benzene group optionally substituted with one or more substituents selected from F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11', OH, C1-C6 alkyl, SO2-alkyl, CO2-alkyl, I, and C1-C6 haloalkyl.

[0040] In a preferred embodiment, ring A is selected from the group consisting of F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 is a pyridine group optionally substituted with one or more substituents selected from OH, C1-C6 alkyl, SO2-alkyl, CO2-alkyl, I, and C1-C6 haloalkyl.

[0041] In a preferred embodiment, ring A is selected from the group consisting of F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, SO2-alkyl, CO2-alkyl, I, and C1-C6 haloalkyl.

[0042] In a preferred embodiment, ring A is a 9- or 10-membered bicyclic heteroaromatic ring containing 1 to 4 nitrogen atoms, more preferably 1 to 3 nitrogen atoms. Preferably, the 9- or 10-membered bicyclic heteroaromatic ring containing 1 to 4 nitrogen atoms is selected from triazolopyridines and imidazopyridines, each of which is optionally substituted. More preferably, the 9- or 10-membered bicyclic heteroaromatic ring containing 1 to 4 nitrogen atoms is selected from [1,2,4]triazolo[4,3-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, imidazo[1,5-a]pyridine, and imidazo[1,2-a]pyridine, each of which is optionally substituted.

[0043] Preferably, the 9- or 10-membered bicyclic aromatic heterocycle is selected from halo, CN, C1-C6 alkoxy, NR 11 R 11', OH, C1-C6 alkyl, phenyl, SO2-alkyl, CO2-alkyl, thienyl, halo-substituted pyridinyl, and C1-C6 haloalkyl. More preferably, the 9- or 10-membered bicyclic aromatic heterocycle is optionally substituted with one or more substituents selected from Me, Cl, F, CN, MeO, NH2, OH, CO2Me, SO2Me, thienyl, and fluoropyridinyl.

[0044] Preferably, ring A is as defined below, with the wavy line representing the bond to the ring containing N, Z, and Y:

[0045] [ka]

[0046] In one preferred embodiment, ring A is [ka] TIFF0007755319000007.tif228170 (wherein R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, C1-C6 alkoxy, CO2-alkyl, SO2-alkyl, NR 11 R 11 ', optionally substituted heteroaryl, OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl; R 14 is H or alkyl).

[0047] In a preferred embodiment, R6, R7, R8, and R9 are each independently H, F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', heteroaryl, OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl; R 14 is H or alkyl.

[0048] In a preferred embodiment, R6, R7, R8, and R9 are each independently H, F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl; R 14 is H or alkyl.

[0049] More preferably, R 14 is H or Me, more preferably H.

[0050] In one preferred embodiment, ring A is selected from groups (i), (ii) and (iv) to (xxxiii).

[0051] In one preferred embodiment, ring A is not (xix).

[0052] In one preferred embodiment, ring A is not (iii).

[0053] In a preferred embodiment, ring A is not (vi).

[0054] In one preferred embodiment, ring A is selected from groups (ii), (iv), (v), (vii) to (xviii), and (xx) to (xxxiii).

[0055] In one preferred embodiment, ring A is selected from groups (i), (ii), (iv), (v), (vii) to (xviii) and (xx) to (xxxiii).

[0056] In one preferred embodiment, ring A is selected from groups (i) to (viii), (ix), (xi), (xix) and (xxxii).

[0057] In one preferred embodiment, ring A is selected from groups (i) to (viii).

[0058] In one preferred embodiment, ring A is selected from groups (i), (ii), (vi), (vii) and (x).

[0059] In one preferred embodiment, the compound is a compound of formula (Ia)-(i):

[0060] [ka] In the formula, R1~R9, R 14 , Z, and Y are as defined above. Preferably, for this embodiment, at least one of R6-R9 is other than H. Preferably, at least one of R6-R9 is selected from Cl, F, Me, CN, OMe, OH, CF3, CO2Me, SO2Me, and optionally substituted heteroaryl (more preferably, the optionally substituted heteroaryl is fluoropyridinyl, oxadiazolyl, or thienyl). Preferably, one or two of R6-R9 are selected from Cl, F, Me, CN, OMe, OH, CF3, CO2Me, SO2Me, and optionally substituted heteroaryl (more preferably, the optionally substituted heteroaryl is fluoropyridinyl, oxadiazolyl, or thienyl), and the remainder of R6-R9 are hydrogen. More preferably, one of R6 to R9 is selected from Cl, F, Me, CN, OMe, OH, CF3, CO2Me, SO2Me and optionally substituted heteroaryl (more preferably, the optionally substituted heteroaryl is fluoropyridinyl, oxadiazolyl or thienyl), and the remainder of R6 to R9 are hydrogen.

[0061] In one preferred embodiment, the compound is a compound of formula (Ia)-(ii):

[0062] [ka] In the formula, R1~R7, R9, R 14 , Z and Y are as defined above.

[0063] In one preferred embodiment, the compound is a compound of formula (Ia)-(iv):

[0064] [ka] In the formula, R1~R8, R 14 , Z and Y are as defined above.

[0065] In one preferred embodiment, the compound is a compound of formula (Ia)-(vii):

[0066] [ka] In the formula, R1~R6, R8, R9, R 14 , Z and Y are as defined above.

[0067] In one preferred embodiment, the compound is a compound of formula (Ia)-(x):

[0068] [ka] In the formula, R1~R6, R9, R 14 , Z and Y are as defined above.

[0069] In one preferred embodiment, ring A is selected from groups (i), (ii), (vi) and (vii).

[0070] In one preferred embodiment, ring A is selected from groups (i), (ii), (vii) and (x).

[0071] In one preferred embodiment, ring A is (i): Preferably, for this embodiment, at least one of R6 to R9 is other than H.

[0072] In one preferred embodiment, ring A is (ii).

[0073] In one preferred embodiment, ring A is (iii).

[0074] In one preferred embodiment, ring A is (iv).

[0075] In one preferred embodiment, ring A is (v).

[0076] In one preferred embodiment, ring A is (vi).

[0077] In one preferred embodiment, ring A is (vii): In one preferred embodiment, ring A is (viii):

[0078] In one preferred embodiment, ring A is (x).

[0079] In one preferred embodiment, ring A is a 9- or 10-membered bicyclic aromatic heterocycle containing 1 to 4 nitrogen atoms selected from groups (xxi) to (xxviii).

[0080] In one preferred embodiment, ring A is (i): R7 is Cl or F and R6, R8 and R9 are all H, or R8 is Cl, F, CN, CO2Me or heteroaryl and R6, R7 and R9 are all H; or R9 is F, and R6, R7 and R8 are all H.

[0081] In one preferred embodiment, ring A is (ii): R6, R7 and R9 are all H, or R7 is F or NH2 and R6 and R9 are H, or R9 is F, and R6 and R7 are H.

[0082] In one preferred embodiment, R 11 and R 11 is selected from H and alkyl, more preferably selected from H and Me, and even more preferably R 11 and R11 ' are both H.

[0083] In one preferred embodiment, ring A is (x), and R, R and R 14 are all H.

[0084] In one preferred embodiment, ring A is (vii), R8 is F, and R6 and R9 are H.

[0085] In a preferred embodiment, Y and Z are each independently selected from CH2, CHMe, CHF, CF2, C(CH3)2, C(CF3)2, more preferably both are CH2. In a preferred embodiment, one of Z and Y is CHMe and the other is CH2. In a preferred embodiment, Y is CHMe and Z is CH2. In a preferred embodiment, Z is CHMe and Y is CH2. In a more preferred embodiment, Z and Y are both CH2.

[0086] In one preferred embodiment, R1 is selected from H, haloalkyl and F, more preferably H.

[0087] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and C1-C6 haloalkyl.

[0088] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and CF n H 3-n and n is 1, 2, or 3.

[0089] In a preferred embodiment, R2 and R3 are each independently Cl, Br, and CF n H 3-n and n is 1, 2, or 3. In a preferred embodiment, n is 3.

[0090] In one preferred embodiment, R2 and R3 are each independently selected from Cl and CF3.

[0091] In a preferred embodiment, one of R2 and R3 is Cl and the other is CF3.

[0092] More preferably, R2 is Cl and R3 is CF3, or R2 is Cl and R3 is Cl.

[0093] In one preferred embodiment, R4 is selected from H and Cl, preferably H.

[0094] In one preferred embodiment, R5 is H or CF3, more preferably H.

[0095] In one preferred embodiment, one of R2 and R3 is Cl and the other is CF3, and R1, R4 and R5 are all H.

[0096] In one preferred embodiment, R2 is Cl, R3 is CF3, and R1, R4 and R5 are all H.

[0097] In one preferred embodiment, R3 is Cl, R2 is CF3, and R1, R4 and R5 are all H.

[0098] In another preferred embodiment, R2 and R3 are both Cl, and R1, R4 and R5 are all H.

[0099] The following preferred definitions for R6 to R9 apply to all of the groups (i) to (xxxiii) of A defined herein.

[0100] In one preferred embodiment, R6 is selected from H, Me, F, Cl, OMe and CN.

[0101] In a preferred embodiment, R6 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3' and R 11 and R 11Each ' is independently selected from H and C1-C6 alkyl. More preferably, R 11 and R 11 ' are both H.

[0102] In one preferred embodiment, R6 is selected from H, F, Cl, CN, methoxy, and CH3, and is preferably H.

[0103] In one preferred embodiment, R7 is selected from H, Cl, F, Me, CN, OMe, CF3, NH2, OH, and CO2Me.

[0104] In a preferred embodiment, R7 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3' and R 11 and R 11 Each ' is independently selected from H and C1-C6 alkyl. More preferably, R 11 and R 11 ' are both H.

[0105] In a preferred embodiment, R7 is selected from H, NH2, F, Cl, CN, methoxy, CH3, and CF3. More preferably, R7 is selected from H, NH2, F, and Cl. Even more preferably, R7 is H.

[0106] In a preferred embodiment, R8 is selected from H, CN, F, Cl, OMe, CF3, NH2, OH, CO2Me, SO2Me, Me and optionally substituted heteroaryl (more preferably fluoropyridinyl, thienyl or oxadiazolyl).

[0107] In a preferred embodiment, R8 is H, F, OH, CN, methoxy, NR 11 R 11 ', phenyl, CF3, CF2H, NHSO2CH3, NHCOCH3, and NHCHF2; R 11 and R 11Each ' is independently selected from H and C1-C6 alkyl. More preferably, R 11 and R 11 ' are both H.

[0108] In one preferred embodiment, R8 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably H, F, Cl, and CN. More preferably, R8 is selected from F and Cl.

[0109] In one preferred embodiment, R8 is F.

[0110] In one preferred embodiment, R9 is selected from H, F, Cl, Me, CF3, NH2, OMe, and CN.

[0111] In a preferred embodiment, R9 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3', and R 11 and R 11 Each ' is independently selected from H and C1-C6 alkyl. More preferably, R 11 and R 11 ' are both H.

[0112] In one preferred embodiment, R9 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably H, F, and CN. More preferably, R9 is H.

[0113] In one preferred embodiment, the compound is:

[0114] [ka] TIFF0007755319000014.tif228162TIFF0007755319000015.tif208160TIFF0007755319000016.tif208160TIFF0007755319000017.tif209164 TIFF0007755319000018.tif203165TIFF0007755319000019.tif210162TIFF0007755319000020.tif233170TIFF0007755319000021.tif213162 TIFF0007755319000022.tif214166TIFF0007755319000023.tif215163TIFF0007755319000024.tif222160JPEG0007755319000025.jpg130166 and pharmaceutically acceptable salts and solvates thereof.

[0115] Compounds of formula (Ia') and (Ib') One aspect of the present invention is a compound of formula (Ia')

[0116] [ka] [In the formula, Ring A is a 5- or 6-membered aromatic or heteroaromatic ring, and the aromatic or heteroaromatic ring is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 , OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl; The compound is N-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3-chlorophenyl)-3,4-dihydro-2(1H)-isoquinolinecarboxamide; N-(4-chlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(2,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(2-chlorophenyl)-3,4-dihydro-1H-isoquinoline-2-carboxamide; or N-(3,4-dichlorophenyl)-6,7-dihydro-4H-[1,2]oxazolo[4,5-c]pyridine-5-carboxamide or a pharmaceutically acceptable salt or solvate thereof.

[0117] Another aspect of the present invention relates to a compound of formula (Ib') or a pharmaceutically acceptable salt or solvate thereof:

[0118] [ka] During the ceremony, Ring A is a 5- or 6-membered aromatic or heteroaromatic ring, and the aromatic or heteroaromatic ring is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 , OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl, Ring A is [ka] (wherein R6, R7, R8, and R9 are all H, and Z and Y are CH2). R2 and R3 are each independently selected from F, Cl, Br, I, CN, and haloalkyl, and R2 and R3 are not both Cl; Ring A is [ka] If R 1 , R 4 and R 5 are all H, Z and Y are CH2, and R2 and R3 are not both Cl.

[0119] In formula (Ia') and (Ib'), preferably alkyl is C 1- C6 alkyl and haloalkyl are C 1- C6 haloalkyl and alkoxy are C 1- It is a C6 alkoxy.

[0120] In a preferred embodiment, the optionally substituted aromatic or heteroaromatic ring is a benzene, pyridine, pyridine N-oxide, pyridazine, pyrimidine, pyrazine, triazine, pyrrole, furan, thiophene, pyrazole, isoxazole, imidazole, oxazole, or thiazole ring. The term "heteroaromatic" as used herein also encompasses moieties that exist in tautomeric forms, such as, but not limited to, pyridone, pyrimidone, and the like. The aromatic or heteroaromatic ring A is fused with an adjacent nitrogen-containing heterocyclic group to form a fused bicyclic ring system.

[0121] Preferably, the optionally substituted aromatic or heteroaromatic ring is a benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, or isoxazole ring.

[0122] In a preferred embodiment, ring A is selected from the group consisting of F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl, and is a benzene, pyridine, pyridone, pyridine N-oxide, pyrimidine, pyrimidone, pyridazine, pyrazine, or isoxazole ring optionally substituted with one or more substituents selected from C1-C6 alkyl, phenyl, and C1-C6 haloalkyl.

[0123] In one preferred embodiment, ring A is [ka] TIFF0007755319000031.tif91170 wherein R6, R7, R8, and R9 are each independently selected from H, F, Cl, Br, I, CN, C1-C6 alkoxy, NR 11 R 11 ', OH, C1-C6 alkyl, phenyl, and C1-C6 haloalkyl).

[0124] In one preferred embodiment, ring A is selected from: [ka]

[0125] In one preferred embodiment, ring A is selected from: [ka]

[0126] In one preferred embodiment, ring A is selected from: [ka]

[0127] In one preferred embodiment, Y and Z are each independently selected from CH2, CF2, C(CH3)2, C(CF3)2, and preferably both are CH2.

[0128] In one preferred embodiment, Y is CH2.

[0129] In one preferred embodiment, Z is CH2.

[0130] In one preferred embodiment, R1 is selected from H and F, preferably H.

[0131] In one preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and C1-C6 haloalkyl.

[0132] In a preferred embodiment, R2 and R3 are each independently selected from F, Cl, Br, I, CN, and CF n H 3-n and n is 1, 2, or 3, preferably 3.

[0133] In a preferred embodiment, R2 and R3 are each independently Cl, Br, and CF n H 3-n and n is 1, 2, or 3, preferably 3.

[0134] In one preferred embodiment, R2 and R3 are each independently selected from Cl and CF3, preferably R2 and R3 are not both CF3, more preferably R2 is Cl and R3 is CF3, or R2 is Cl and R3 is Cl.

[0135] In one preferred embodiment, R4 is selected from H and Cl, preferably H.

[0136] In one preferred embodiment, R5 is H.

[0137] In a preferred embodiment, R6 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3', and R 11 and R 11 are each independently selected from H and C1-C6 alkyl, preferably both are H.

[0138] In one preferred embodiment, R6 is selected from H, F, Cl, CN, methoxy, and CH3, and is preferably H.

[0139] In a preferred embodiment, R7 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3', and R 11 and R 11 are each independently selected from H and C1-C6 alkyl, preferably both are H.

[0140] In one preferred embodiment, R7 is selected from H, NH2, F, Cl, CN, methoxy, CH3, and CF3, preferably H, NH2, F, or Cl, more preferably H.

[0141] In a preferred embodiment, R8 is H, F, OH, CN, methoxy, NR 11 R 11 ', phenyl, CF3, CF2H, NHSO2CH3, NHCOCH3, and NHCHF2; R 11 and R 11 are each independently selected from H and C1-C6 alkyl, preferably both are H.

[0142] In one preferred embodiment, R8 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, Cl, and CN, more preferably selected from F and Cl.

[0143] In one preferred embodiment, R8 is F.

[0144] In one preferred embodiment, R9 is H, F, Cl, CN, methoxy, CH3, NR 11 R 11 CF3', and R 11 and R 11 are each independently selected from H and C1-C6 alkyl, preferably both are H.

[0145] In one preferred embodiment, R9 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, and CN; R9 is more preferably H.

[0146] In a particularly preferred embodiment, for compounds of formula (Ia') or (Ib'): Ring A is selected from: [ka] Y and Z are both CH2; R1, R4, and R5 are all H; R2 and R3 are each independently selected from Cl and CF3, preferably R2 and R3 are not both CF3, more preferably R2 is Cl and R3 is CF3, or R2 is Cl and R3 is Cl; R6 is selected from H, F, Cl, CN, methoxy, and CH3, preferably H; R7 is selected from H, NH2, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, NH2, F, or Cl, more preferably H; R8 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, Cl, and CN, more preferably selected from F and Cl; R9 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, and CN; R9 is more preferably H.

[0147] In an even more preferred embodiment, for compounds of formula (Ia') or (Ib'): Ring A is selected from: [ka] Y and Z are both CH2; R1, R4, and R5 are all H; R2 and R3 are each independently selected from Cl and CF3, preferably R2 and R3 are not both CF3, more preferably R2 is Cl and R3 is CF3, or R2 is Cl and R3 is Cl; R6 is selected from H, F, Cl, CN, methoxy, and CH3, preferably H; R7 is selected from H, NH2, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, NH2, F, and Cl, R7 is more preferably H; R8 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, Cl, and CN, more preferably selected from F and Cl; R9 is selected from H, F, Cl, CN, methoxy, CH3, and CF3, preferably selected from H, F, and CN; R9 is more preferably H.

[0148] Compound of formula (Ic') Another aspect of the present invention relates to a compound of formula (Ic') or a pharmaceutically acceptable salt or solvate thereof:

[0149] [ka] During the ceremony, Ring A is a 5- or 6-membered aromatic or heteroaromatic ring; The aromatic ring may be selected from the group consisting of F, Cl, Br, I, CN, alkoxy, and NR 11 R 11 ', OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl or heteroaryl substituents are F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; The aromatic heterocycle is other than isoxazolyl and is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, and NR 11 R 11 , OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl or heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl.

[0150] In one preferred embodiment, ring A is a substituted benzene group or an optionally substituted 6-membered heteroaromatic group.

[0151] The preferred embodiments defined above for formulae (Ia') and (Ib') apply equally to compounds of formula (Ic').

[0152] Exemplary compounds of Formula (Ic') include the following compounds described herein: 1-9, 12-24, 27-39, 42-47, 49-67, 70-79, and 82-87, and pharmaceutically acceptable salts and solvates thereof.

[0153] method A further aspect of the present invention is a process for preparing a compound of formula (I), (Ia), (Ia'), (Ib') or (Ic') as defined herein, comprising reacting a compound of formula (II) with a compound of formula (III) (wherein R 1-5 , Z, Y and A are as defined above) to form a compound of formula (Ia), (Ia'), (Ib'), or (Ic'):

[0154] [ka]

[0155] In a preferred embodiment, the reaction occurs in the presence of a base, preferably N,N-diisopropylethylamine (DIPEA) or triethylamine. Preferably, the reaction occurs in an organic solvent. Suitable organic solvents include, but are not limited to, dichloromethane, tetrahydrofuran, and dimethylformamide, or a mixture of two or more thereof. Those skilled in the art will recognize that other bases and solvents are also suitable.

[0156] therapeutic use A further aspect of the present invention relates to the compounds described herein for use in medicine. The compounds have particular uses in the fields of oncology, immuno-oncology, and immunology, as described in more detail below. In a preferred embodiment, the compounds of the present invention modulate GPR65, more preferably inhibit GPR65 signaling.

[0157] Yet another aspect of the present invention pertains to compounds described herein for use as pharmaceuticals.

[0158] One aspect of the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament:

[0159] [ka] During the ceremony, Ring A is a 5- or 6-membered monocyclic aromatic or heteroaromatic ring, or a 9- or 10-membered bicyclic aromatic or heteroaromatic ring, each of which is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 ', OH, SO2-alkyl, CO2-alkyl, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, I, and haloalkyl; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; at least two of R2, R3 and R4 are other than H; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl.

[0160] Ring A and groups Y, Z, and R 1-13Preferred definitions for are as provided above for compounds of formula (Ia), (Ia'), (Ib') and (Ic').

[0161] In formula (I), preferably alkyl is C 1- C6 alkyl and haloalkyl are C 1- C6 haloalkyl and alkoxy are C 1- It is a C6 alkoxy.

[0162] Preferably, the compounds of formula (I) are for use in the treatment or prevention of a disease or disorder selected from a proliferative disorder, an autoimmune disorder, asthma and chronic obstructive pulmonary disease.

[0163] One preferred embodiment of the present invention relates to a compound as described herein for use in the treatment or prevention of a disorder selected from a proliferative disorder and an immune disorder.

[0164] Another preferred embodiment of the present invention relates to a compound described herein for use in the treatment or prevention of asthma and / or chronic obstructive pulmonary disease (COPD). GPR65 variant / SNP (rs6574978) has been shown to be associated with asthma / COPD syndrome with a near GWAS significance p-value (1.18×10e-7) (Hardin, M. et al. (2014). The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014 Aug;44(2):341-50). Furthermore, pH-mediated GPR65 activation (low / acidic pH in asthmatic lungs) promotes eosinophil survival in a cAMP-dependent manner, contributing to disease progression / exacerbation. It is also known that asthma symptoms are attenuated in GPR65 KO mice (Kottyan, L. et al. (2009). Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood. 2009 Sep 24;114(13):2774-82).

[0165] Another aspect of the present invention relates to a compound described herein for use in the treatment or prevention of acute respiratory distress syndrome (ARDS). GPR65 has been shown to be protective in a model of LPS-induced acute lung injury (Tsurumaki, H. et al. (2015). Int J Mol Sci. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury. Dec 4;16(12):28931-42).

[0166] One aspect of the present invention pertains to compounds, as described herein, for use in the treatment of a proliferative disorder. Preferably, the proliferative disorder is cancer or leukemia.

[0167] In a preferred embodiment, the cancer is a solid tumor and / or its metastases.

[0168] In another preferred embodiment, the cancer is selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), pancreatic adenocarcinoma, triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, lung carcinosarcoma, ovarian cancer, and glioma, preferably glioblastoma (GBM).

[0169] Without wishing to be bound by theory, it is understood that GPR65 modulators can prevent the increase in cytoplasmic cAMP in tumor-associated macrophages (TAMs), natural killer (NK) cells, and subsets of T cells that normally results from their exposure to an acidic tumor microenvironment and concomitant GPR65 activation. This reduction in cytoplasmic cAMP levels, in turn, reduces the levels of ICER pro-inflammatory mediators, such as CXCL10 and TNFα, preventing the polarization of TAMs and the alteration of other immune cells associated with a non-inflammatory and tumor-permissive environment. Therefore, GPR65 modulators are expected to increase tumor visibility to the immune system and increase immune-mediated tumor clearance. This suggests that modulation of GPR65 activity may be an effective treatment for cancer, either as a monotherapy or in combination with cancer immunotherapy (vaccines, drugs that promote T cell-mediated immune responses), or in patients who do not respond to immunomodulatory approaches such as PD1 / PDL-1 blockade.

[0170] Another aspect of the present invention pertains to the compounds described herein for use in the treatment of immune disorders, preferably autoimmune diseases.

[0171] In one embodiment, the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's disease), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathy, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorders, autoimmune polyendocrinopathy and autoimmune myocarditis, type I diabetes mellitus, and atopic dermatitis.

[0172] In particularly preferred embodiments, the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis (MS).

[0173] Without wishing to be bound by theory, it is understood that GPR65 modulators prevent the upregulation of ICER in CD4+ T cells. This is then expected to prevent the ICER-associated IL-2 suppression, which biases CD4+ T cells toward the pro-inflammatory Th17 phenotype associated with increased pathogenicity in the context of autoimmune disease. This is supported by the fact that mutations at the GPR65 position are associated with several autoimmune diseases, such as multiple sclerosis, ankylosing spondylitis, inflammatory bowel disease, and Crohn's disease (Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412). This suggests that modulation of GPR65 activity may be an effective treatment for autoimmune diseases.

[0174] Another aspect relates to a compound as described herein for use in the treatment or prevention of a disorder caused by, related to, or accompanied by aberrant activity towards GPR65.

[0175] Another aspect relates to a compound described herein for use in the treatment or prevention of a disease or disorder associated with GPR65.

[0176] Another aspect of the present invention relates to a method of treating the disorders described above, comprising administering to a subject a compound described herein.

[0177] Another aspect of the present invention relates to a method of treating a disease or disorder associated with GPR65 in a subject. The method according to this aspect of the present invention is effected by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention as described herein above, either by itself or, more preferably, as part of a pharmaceutical composition, e.g., in admixture with a pharmaceutically acceptable carrier, as described in detail herein below.

[0178] Yet another aspect of the present invention relates to a method of treating a subject having a condition that is alleviated by modulation of GPR65, comprising administering to the subject a therapeutically effective amount of a compound according to the present invention.

[0179] Another aspect relates to a method for treating a condition by alleviating the modulation of GPR65, comprising administering to a subject a therapeutically effective amount of a compound according to the invention.

[0180] Preferably, the subject is a mammal, more preferably a human.

[0181] The term "method" refers to methods, means, techniques and procedures for accomplishing a given task, including, but not limited to, methods, means, techniques and procedures that are known to or readily developed by practitioners of the chemical, pharmacological, biological, biochemical and medical arts from known methods, means, techniques and procedures.

[0182] As used herein, the term "treating" includes suppressing, substantially inhibiting, slowing or reversing the progression of a disease or disorder, substantially ameliorating a clinical symptom of a disease or disorder, or substantially preventing the appearance of a clinical symptom of a disease or disorder.

[0183] As used herein, the term "preventing" refers to a method for barring an organism from acquiring a disorder or disease in the first place.

[0184] The term "therapeutically effective amount" refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.

[0185] For any compound used in the present invention, the therapeutically effective amount, also referred to herein as the therapeutically effective dose, can also be estimated initially from cell culture assays. For example, a dose can be formulated in animal models to compare the IC 50 or IC 100 A circulating concentration range comprising: 0.01 to 0.01% of the active ingredient in the compound of formula (I) can be achieved. Such information can be used to more accurately determine useful doses in humans. Initial doses can also be predicted from in vivo data. Using these initial guidelines, one skilled in the art can determine effective doses in humans.

[0186] Furthermore, the toxicity and therapeutic efficacy of the compounds described herein can be evaluated in cell cultures or experimental animals, e.g., by LD 50 and ED 50 The dose ratio between toxic and therapeutic effects is the therapeutic index, and the LD 50 and ED 50 Therapeutic indices can be expressed as a ratio between ED and ED . Compounds that exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in humans. The dosage of such compounds is preferably adjusted to produce little or no toxicity. 50The dosage may vary within this range depending upon the dosage form and route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (see, e.g., Fingl et al., 1975, The Pharmacological Basis of Therapeutics, chapter 1, page 1).

[0187] Dosage and interval can be individually adjusted to achieve plasma levels of the active compound sufficient to maintain therapeutic efficacy. Typical patient doses for oral administration range from about 50 to 2000 mg / day, generally from about 100 to 1000 mg / day, preferably from about 150 to 700 mg / day, and most preferably from about 250 to 500 mg / day or from 50 to 100 mg / day. Preferably, therapeutically effective serum levels are achieved by administering multiple doses daily. In cases of local administration or selective uptake, effective local drug concentrations may not be related to plasma concentrations. One of ordinary skill in the art can optimize a therapeutically effective local dose without undue experimentation.

[0188] As used herein, "GPR65-associated disease or disorder" refers to a disease or disorder characterized by inappropriate GPR65 activity. Inappropriate GPR65 activity refers to, for example, either an increase or decrease in GPR65 activity compared to the activity in a healthy subject, as measured by an enzyme or cellular assay. Inappropriate activity may also be due to overexpression of GPR65 in diseased tissue compared to healthy adjacent tissue.

[0189] Preferred diseases or disorders that the compounds described herein may be useful for treating or preventing include proliferative disorders and immune disorders as described herein earlier, as well as asthma and chronic obstructive pulmonary disease.

[0190] The present invention further provides the use of a compound as defined herein in the preparation of a medicament for the treatment of a disease in which it is desirable to modulate GPR65, including proliferative and immune disorders as described hereinbefore, as well as asthma and chronic obstructive pulmonary disease.

[0191] As used herein, the phrase "preparation of a medicament" includes the direct use of the components of the present invention as a medicament, in addition to their use in any stage of the preparation of such a medicament.

[0192] In a preferred embodiment, the compound prevents the expected increase in cytoplasmic cAMP levels following GPR65 activation at acidic pH. This prevention of cAMP accumulation is in turn expected to prevent unwanted downstream signaling via ICER, as described in the accompanying Examples section. The "Human GPR65 Cyclic Adenylate (cAMP) Homogeneous Time-Resolved Fluorescence (HTRF) Antagonist Assay," or simply "cAMP Assay," described below, can be used to measure the potency of GPR65 modulators, which is expressed as the concentration of compound required to reduce by 50% the increase in cAMP concentration due to GPR65 activation (i.e., IC 50 ).

[0193] In one preferred embodiment, the compound has an IC of less than about 25 μM in the cAMP assay. 50 More preferably, the compounds have an IC value of less than about 10 μM in the cAMP assay, more preferably less than about 5 μM, even more preferably less than about 1 μM, and even more preferably less than about 0.1 μM. 50 Indicates the value.

[0194] In another preferred embodiment, the compounds exhibit hGPR65 IC50 values ​​of less than 5 μM, more preferably less than 500 nM, in the above-mentioned assay.

[0195] In one preferred embodiment, the compound according to the invention or for use according to the invention is a compound selected from:

[0196] [ka] TIFF0007755319000041.tif215165TIFF0007755319000042.tif232164TIFF0007755319000043.tif204162TIFF000 7755319000044.tif207163TIFF0007755319000045.tif206167TIFF0007755319000046.tif209170TIFF0007755319 000047.tif215162TIFF0007755319000048.tif229162TIFF0007755319000049.tif205165TIFF0007755319000050. tif211163TIFF0007755319000051.tif218160TIFF0007755319000052.tif212161TIFF0007755319000053.tif94161

[0197] and pharmaceutically acceptable salts and solvates thereof.

[0198] Preferred compounds according to the invention or for use according to the invention:

[0199] [Table 1] TIFF0007755319000055.tif240162TIFF0007755319000056.tif242162TIFF0007755319000057.t if242160TIFF0007755319000058.tif237160TIFF0007755319000059.tif239160TIFF0007755319 000060.tif230158TIFF0007755319000061.tif239160TIFF0007755319000062.tif241161TIFF00 07755319000063.tif239161TIFF0007755319000064.tif236160TIFF0007755319000065.tif44164

[0200] and the pharmaceutically acceptable salts and solvates thereof are alternatively described above.

[0201] In one preferred embodiment, the compound according to the invention or for use according to the invention is selected from: 1, 5-7, 10-17, 19, 25-27, 29-33, 35-45, 47-55, 57-61, 63, 64, 66, 67, 71, 74, 76, 79-83, 85-91, 93, 96, 98, 101-104, 106, 108, 109, 112-114, 117-118, 120, 123, 126, 129 and 131-140.

[0202] In a more preferred embodiment, the compound according to the invention or for use according to the invention is selected from the following: 14, 30, 31, 33, 36, 37, 39-44, 52-54, 74, 76, 79, 82, 83, 85, 93, 104, 106, 108, 109, 112-114, 117, 120, 123 and 140.

[0203] A further aspect of the invention relates to a compound of formula (I'), or a pharmaceutically acceptable salt or solvate thereof, for use as a medicament.

[0204] [ka] During the ceremony, Ring A is a 5- or 6-membered aromatic or heteroaromatic ring, and the aromatic or heteroaromatic ring is selected from the group consisting of F, Cl, Br, I, CN, alkoxy, NR 11 R 11 , OH, alkyl, haloalkyl, aralkyl, aryl, and heteroaryl, wherein the aryl and heteroaryl substituents are selected from F, Cl, Br, I, CN, alkoxy, NR 11 R 11 substituted with one or more substituents each independently selected from , OH, alkyl, haloalkyl, and aralkyl; Y and Z each independently represent CH2 and CR 10 R 10 ' is selected from R 10 and R 10 each ' is independently selected from H, F, alkyl, and haloalkyl; R1, R4, and R5 are each independently selected from H, F, Cl, Br, and I; R2 and R3 are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; R 11 and R 11 ' are each independently H, alkyl, haloalkyl, COR 12 , and SO2R 13 Selected from R 12 and R 13 are both alkyl.

[0205] A, Z, Y, R 1 -R 5 Preferred definitions for are as described above for formulae (I), (Ia), (Ia') and (Ib').

[0206] Pharmaceutical Composition For use according to the present invention, the compounds described herein or their physiologically acceptable salts, esters, or other physiologically functional derivatives may be presented as pharmaceutical formulations comprising the compound or its physiologically acceptable salts, esters, or other physiologically functional derivatives together with one or more pharmaceutically acceptable carriers, diluents, or excipients for the compound, and optionally other therapeutic and / or prophylactic ingredients. The carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof. Pharmaceutical compositions may be in amounts for use in human and veterinary medicine for humans or animals.

[0207] Examples of such excipients suitable for the various different forms of pharmaceutical compositions described herein can be found in "Handbook of Pharmaceutical Excipients, 2000." nd Edition, (1994), Edited by A Wade and PJ Weller. The carrier, or, if more than one carrier is present, each of the carriers must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0208] Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985).

[0209] Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, etc. Examples of suitable diluents include ethanol, glycerol and water.

[0210] The selection of pharmaceutical carrier, excipient, or diluent can be made with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical composition can include as, or in addition to, the carrier, excipient, or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), buffer(s), flavoring agent(s), surfactant(s), thickening agent(s), preservative(s) (including antioxidants), and the like, as well as substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0211] Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose and polyethylene glycol.

[0212] Examples of suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.

[0213] Preservatives, stabilizers, dyes, and even flavoring agents may be provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid, and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may also be used.

[0214] Pharmaceutical formulations include those suitable for oral, topical (including cutaneous, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, intramuscular and intravenous), nasal and pulmonary administration, e.g., by inhalation. The formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the active compound with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0215] Pharmaceutical formulations suitable for oral administration in which the carrier is solid are most preferably presented as unit-dose formulations, such as boluses, capsules, or tablets, each containing a predetermined amount of the active compound. Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by mixing the active compound in a free-flowing form, such as a powder or granules, with optional binders, lubricants, inert diluents, glidants, surface-active agents, or dispersing agents, and compressing in a suitable machine. Molded tablets can be made by molding the active compound with an inert liquid diluent. Tablets may be optionally coated, or, if uncoated, may optionally be scored. Capsules can also be prepared by filling the active compound, alone or in admixture with one or more accessory ingredients, into capsule shells, which are then sealed in the usual manner. Cachets are similar to capsules, in that the active compound, along with any accessory ingredient(s), is sealed within a rice paper shell. The active compound may also be formulated as dispersible granules, which may, for example, be suspended in water before administration or sprinkled on food. The granules may also be packaged, for example, in a sachet. Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water liquid emulsion.

[0216] Formulations for oral administration include controlled-release dosage forms, such as tablets in which the active compound is formulated in a suitable release-controlling matrix or coated with a suitable release-controlling film. Such formulations can be particularly advantageous for prophylactic use.

[0217] Pharmaceutical preparations suitable for rectal administration, in which the carrier is solid, are most preferably presented as unit-dose suppositories.Suitable carriers include cocoa butter and other materials commonly used in the art.Suppositories can be conveniently formed by mixing the active compound with softened or melted carrier(s), followed by cooling and shaping in molds.Pharmaceutical preparations suitable for parenteral administration include sterile solutions or suspensions of the active compound in aqueous or oily vehicles.

[0218] Injectable preparations can be adapted for bolus injection or continuous infusion.Such preparations are conveniently presented in unit doses or in multi-dose containers that are sealed after the formulation is introduced until needed for use.Alternatively, the active compound may be in powder form, which is constituted before use with a suitable vehicle, for example, sterile, pyrogen-free water.

[0219] The active compounds may also be formulated as long-acting depot preparations, which can be administered, for example, subcutaneously or intramuscularly, by intramuscular injection or implantation. The depot preparations may, for example, comprise suitable polymeric or hydrophobic materials, or ion exchange resins. Such long-acting formulations are particularly advantageous for prophylactic use.

[0220] Formulations suitable for pulmonary administration via the buccal cavity are presented so that particles containing the active compound, desirably having a diameter in the range of 0.5 to 7 microns, are delivered to the recipient's bronchial tree.

[0221] One possibility is that such formulations are in the form of finely divided powders, which can be conveniently presented in either pierceable capsules, for example made of gelatin, for use in inhalation devices, or alternatively in self-propelling formulations containing the active compound, a suitable liquid or gaseous propellant, and optionally other ingredients, such as surfactants and / or solid diluents. Suitable liquid propellants include propane and chlorofluorocarbons, as well as suitable gaseous propellants, including carbon dioxide. Self-propelling formulations in which the active compound is dispensed in the form of droplets of solution or suspension can also be used.

[0222] Such self-propelling formulations are similar to those known in the art and can be prepared by established procedures. Suitably, the self-propelling formulations are presented in a container equipped with either a manually actuable or automatically functioning valve having the desired spray characteristics; advantageously, the valve is of the metered type that delivers a fixed volume, e.g., 25 to 100 microliters, upon each actuation thereof.

[0223] As a further possibility, the active compound may be in the form of a solution or suspension for use in an atomizer or nebulizer, which utilizes accelerated airflow or ultrasonic agitation to produce a fine droplet mist for inhalation.

[0224] Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed, such formulations should desirably have a particle diameter in the 10-200 micron range to allow retention in the nasal cavity. This can be achieved, if necessary, by the use of powders of appropriate particle size or by selection of an appropriate valve. Other suitable formulations include coarse powders having particle diameters in the 20-500 micron range, for administration by rapid inhalation via the nasal passage from a container held close to the nose, and nasal drops containing 0.2-5% w / v of the active compound in an aqueous or oily solution or suspension.

[0225] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Furthermore, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions containing saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Preservatives and other additives, such as antibacterial agents, antioxidants, chelating agents, inert gases, and the like, may also be present.

[0226] Suitable formulations for topical administration may be provided, for example, as gels, creams, or ointments. Such preparations may also be applied to the wound or ulcer, for example, by spreading them directly on the surface of the wound or ulcer, or by holding them on a suitable support, such as a bandage, gauze, mesh, etc., which is then applied to and over the area to be treated.

[0227] Liquid or powder formulations may also be provided that can be sprayed or sprinkled directly onto the area to be treated, such as a wound or ulcer. Alternatively, a carrier, such as a bandage, gauze, mesh, etc., can be sprayed or sprinkled with the formulation and then applied to the area to be treated.

[0228] According to a further aspect of the present invention there is provided a process for the preparation of a pharmaceutical or veterinary composition as described above, which process comprises the step of bringing into association, for example by admixture, the active compound(s) with the carrier.

[0229] In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product. The invention extends to a process for preparing a pharmaceutical composition which comprises combining or associating a compound described herein with a pharmaceutically or veterinarily acceptable carrier or vehicle.

[0230] Salts / Esters The compounds of the present invention may exist as salts or esters, particularly as pharmaceutically and veterinarily acceptable salts or esters.

[0231] Pharmaceutically acceptable salts of the compounds of the present invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts can be found in Bergeetal, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example, with strong inorganic acids such as mineral acids, for example with hydrohalic acids, such as hydrochlorides, hydrobromides and hydroiodides, sulfuric acid, phosphates, sulfates, bisulfates, hemisulfates, thiocyanates, persulfates and sulfonic acids; with strong organic carboxylic acids, for example unsubstituted or substituted (e.g., by halogen), alkanecarboxylic acids of 1 to 4 carbon atoms, such as acetic acid; with saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid or tetraphthalic acid; with hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid or citric acid; with amino acids, such as aspartic acid or glutamic acid; with benzoic acid; or with organic sulfonic acids, for example unsubstituted or substituted (e.g., by halogen), (C1-C4)-alkylsulfonic acids or arylsulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Salts that are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.

[0232] Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, propionate, tartrate, lactate, lactic acid salt ... tobionate, pivalate, camphorate, undecanoate and succinate salts, organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric acid and sulfonic acid.

[0233] Esters are formed using either organic acids or alcohols / hydroxides, depending on the functional group to be esterified. Organic acids include carboxylic acids, such as unsubstituted or substituted (e.g., by halogen) alkanecarboxylic acids of 1 to 12 carbon atoms, such as acetic acid; saturated or unsaturated dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, phthalic acid, or tetraphthalic acid; hydroxycarboxylic acids, such as ascorbic acid, glycolic acid, lactic acid, malic acid, tartaric acid, or citric acid; amino acids, such as aspartic acid or glutamic acid; benzoic acid; or organic sulfonic acids, such as unsubstituted or substituted (e.g., by halogen), (C1-C4)-alkylsulfonic acids or arylsulfonic acids, such as methanesulfonic acid or p-toluenesulfonic acid. Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and aluminum hydroxide. Alcohols include alkane alcohols of 1 to 12 carbon atoms which may be unsubstituted or substituted (eg, with halogen).

[0234] Enantiomers / Tautomers In all aspects of the invention discussed above, the invention includes, where appropriate, all enantiomers, diastereoisomers, and tautomers of the compounds of the invention. Those skilled in the art will recognize compounds that possess optical properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and / or tautomers can be isolated / prepared by methods known in the art.

[0235] Enantiomers are characterized by the absolute configuration of their chiral centers and are described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such conventions are well known in the art (see, for example, 'Advanced Organic Chemistry', 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985).

[0236] Compounds of the invention that contain chiral centers can be used as racemic mixtures, enantiomerically enriched mixtures, or racemic mixtures can be separated using well-known techniques and the individual enantiomers used alone.

[0237] Stereoisomers and geometric isomers Some compounds of the present invention can exist as stereoisomers and / or geometric isomers. For example, they may possess one or more asymmetric and / or geometric centers and thus may exist in two or more stereoisomeric and / or geometric forms. The present invention contemplates the use of all individual stereoisomers and geometric isomers of these compounds, as well as mixtures thereof. The terms used in the claims encompass these forms, provided that the forms retain the appropriate functional activity (although not necessarily to the same degree).

[0238] The present invention also includes all suitable isotopic variations of the compounds or pharmaceutically acceptable salts thereof. An isotopic variation of a compound of the present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from that normally found in nature. Examples of isotopes that can be incorporated into the drug and its pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 17 O. 18 O. 31 P, 32 P, 35 S, 18 F and 36 Certain isotopic variations of the Agents and pharmaceutically acceptable salts thereof, such as radioactive isotopes, e.g., 3 H or 14 Those incorporating C are useful in drug and / or substrate tissue distribution studies. Tritium-labeled, i.e., 3 H, and carbon-14, i.e., 14 C isotopes are particularly preferred for their ease of preparation and detectability. Further isotopes, such as deuterium, i.e. 2 Substitution with H may be preferred in some circumstances because it may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. For example, the present invention includes compounds of general formula (I) in which any hydrogen atom is replaced with a deuterium atom. Isotopic variations of the present agents and pharmaceutically acceptable salts thereof can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.

[0239] Atropisomers Some of the compounds of the present invention can exist as atropisomers. Atropisomers are stereoisomers resulting from restricted rotation around a single bond, where energy differences due to steric strain or other factors create a barrier to rotation high enough to allow the isolation of individual conformers. The present invention encompasses all such atropisomers. The present invention also encompasses rotational isomers of the compounds.

[0240] Prodrug The present invention further includes prodrug forms of the compounds of the invention, i.e., covalently bonded compounds that release the active parent drug in vivo. Such prodrugs are generally compounds of the invention modified at one or more appropriate groups such that the modifications can be reversed upon administration to a human or mammalian subject. Reversal is usually achieved by enzymes naturally present in such subjects, although it is also possible to administer a second agent with such prodrugs to effect reversal in vivo. Examples of such modifications include esters (e.g., any of those described above), in which case reversal may be achieved by esterases, etc. Other such systems are known to those skilled in the art.

[0241] solvate The present invention also includes solvated forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvates are hydrates.

[0242] Use in combination A further aspect of the present invention relates to a combination comprising a compound described herein and one or more additional active agents. In a particularly preferred embodiment, one or more compounds of the present invention are administered in combination with one or more additional active agents, such as a commercially available existing drug. In such cases, the compound of the present invention may be administered subsequently to one or more other active agents, simultaneously or sequentially.

[0243] Drugs are generally more effective when used in combination. In particular, combination therapy is desirable to avoid overlapping of major toxicities, mechanisms of action, and resistance mechanisms(ies). Furthermore, it is also desirable to administer most drugs at their maximum tolerated doses with minimal time intervals between doses. The main advantage of combining chemotherapeutic drugs is that they can promote additive or possible synergistic effects through biochemical interactions, and also reduce the occurrence of resistance.

[0244] Beneficial combinations can be suggested by studying the activity of a test compound with an agent known or suspected to be valuable in treating a particular disorder. This procedure can also be used to determine the order of drug administration, i.e., before, simultaneously with, or after delivery. Such scheduling can be a feature of all active agents identified herein.

[0245] In the context of cancer, the compounds of the present invention can be used in combination with immunotherapy, e.g., cancer vaccines and / or other immune modulators, e.g., agents that block PD1 / PDL-1 interaction. Thus, in one preferred embodiment, the additional active agent is an immunotherapy agent, more preferably a cancer immunotherapy agent. "Immunotherapeutic agent" refers to a treatment that uses the subject's own immune system to fight diseases such as cancer. For other disorders, the compounds of the present invention can be used in combination with agents that block or reduce inflammation, e.g., antibodies that target pro-inflammatory cytokines.

[0246] polymorphism The present invention further relates to the compounds of the present invention in their various crystalline, polymorphic and hydrated (anhydrous) forms. It is well established within the pharmaceutical industry that chemical compounds can be isolated in any of these forms by slight variations in the method of purification and / or isolation from the solvents used in the synthetic preparation of such compounds.

[0247] Administration The pharmaceutical compositions of the present invention can be adapted for rectal, nasal, intrabronchial, topical (including oral buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration. Preferably, the formulation is an orally administered formulation. The formulation may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or subunit of a unit dose. For example, the formulation may be in the form of tablets and sustained-release capsules, and may be prepared by any method well known in the art of pharmacy.

[0248] Formulations for oral administration herein may be presented as discrete units such as capsules, gels, drops, cachets, pills, or tablets, each containing a predetermined amount of active agent; as powders or granules; as a solution, emulsion, or suspension of the active agent in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil liquid emulsion; or as a bolus, etc. Preferably, these compositions contain 1 to 250 mg, and more preferably 10 to 100 mg, of active ingredient per dose.

[0249] For compositions for oral administration (e.g., tablets and capsules), the term "acceptable carrier" includes vehicles, e.g., common excipients, such as binders, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropyl-methylcellulose, sucrose, and starch; fillers and carriers, e.g., corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride, and alginic acid; and lubricants, e.g., magnesium stearate, sodium stearate, and other metallic stearates, glycerol stearate stearate, silicone fluid, talc wax, oils, and colloidal silica. Flavoring agents, e.g., peppermint, oil of wintergreen, cherry flavor, and the like, can also be used. It may be desirable to add coloring agents to make the dosage form easily identifiable. Tablets can also be coated by methods well known in the art.

[0250] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active agent into a free-flowing form, such as a powder or granules, in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. Tablets can be coated or scored, and can be formulated to provide slow or controlled release of the active agent.

[0251] Other formulations suitable for oral administration include lozenges comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base, e.g., gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.

[0252] Other dosage forms include solutions or emulsions, which can be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally or intramuscularly and are prepared from sterile or sterilizable solutions. Injectable forms usually contain 10 to 1000 mg, preferably 10 to 250 mg, of the active ingredient per dose.

[0253] Pharmaceutical compositions of the present invention may also be in the form of a suppository, pessary, suspension, emulsion, lotion, ointment, cream, gel, spray, liquid or dusting powder.

[0254] An alternative means of transdermal administration is administration by the use of a skin patch. For example, the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycol or liquid paraffin. The active ingredient can also be incorporated into an ointment consisting of a white wax or white soft paraffin base, at a concentration of 1 to 10% by weight, together with such stabilizers and preservatives as may be required.

[0255] dose Those skilled in the art can easily determine the appropriate dosage of one of the compositions of the present invention to be administered to a subject without undue experimentation.Usually, a doctor will determine the actual dosage that is most suitable for each patient, and this depends on various factors, including the activity of the specific compound used, the metabolic stability and duration of action of that compound, age, body weight, general health, sex, diet, mode and time of administration, excretion rate, drug combinations, the severity of specific conditions, and the individual receiving therapy.The dosages disclosed herein are exemplary of the average case.Of course, there may be individual cases where higher or lower dosage ranges are beneficial, and such dosage ranges are within the scope of the present invention.

[0256] Dosages are further modified depending on the mode of administration of the compound. For example, to achieve an "effective dose" for acute therapy, parenteral administration of the compound is generally preferred. Infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with appropriate excipients, is most effective, although intramuscular bolus injections are also useful. Typically, parenteral doses range from about 0.01 to about 100 mg, preferably 0.1 to 20 mg, in a manner that maintains plasma drug concentrations at a level effective to modulate GPR65. The compound can be administered one to four times daily at a level that achieves a total daily dose of about 0.4 to about 400 mg. The precise amount of a compound of the present invention that is therapeutically effective, and the route by which such a compound is best administered, can be readily determined by one of skill in the art by comparing the blood concentration of the drug with the concentration required to have a therapeutic effect.

[0257] The compounds of the present invention may also be orally administered to a patient in a manner that provides a drug concentration sufficient to achieve one or more of the therapeutic indications disclosed herein. Typically, a pharmaceutical composition containing the compound is administered in an oral dose of about 0.1 to about 500 mg, or about 0.1 to about 50 mg, in a manner consistent with the patient's condition. Preferably, the oral dose is about 0.5 to about 50 mg, or about 0.5 to about 20 mg.

[0258] No unacceptable toxicological effects are expected when the compounds of the present invention are administered in accordance with the present invention. Compounds of the present invention that may have good bioavailability can be tested in one of several biological assays to determine the concentration of compound required to have a given pharmacological effect.

[0259] The present invention is further illustrated by the following non-limiting examples. [Example]

[0260] Where the preparation of starting materials is not described, they are either commercially available, known in the literature, or readily obtainable by those skilled in the art using standard procedures. Where compounds are shown to be prepared analogously to preceding examples or intermediates, it will be apparent to those skilled in the art that reaction times, number of equivalents of reagents, solvents, concentrations, and temperatures may each be modified depending on the specific reaction, and that it may be necessary or desirable to perform different work-up or purification techniques.

[0261] General Scheme Abbreviation A list of some common abbreviations is provided below, however, other abbreviations not listed will be understood by those skilled in the art when used.

[0262] AcOH: acetic acid; d: doublet; DCM: dichloromethane; DIPEA: N,N-diisopropylethylamine; DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; (ES + ): electrospray ionization positive mode; h: hour; HPLC: high-performance liquid chromatography; Hz: hertz; J: coupling constant M: molar; m: multiplet [M+H]+: protonated molecular ion; mCPBA: metachloroperbenzoic acid; MeCN: acetonitrile; MHz: megahertz; min: minute; ml: milliliter; MS: mass spectrometry; m / z: mass-to-charge ratio; NMR: nuclear magnetic resonance; Pd-177: allyl[4,5-bis(diphenylphosphino)-9,9-dimethylxanthene]palladium(II) chloride; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PDA: photodiode array; RT: room temperature; Rt: retention time; s: singlet; t: triplet; UPLC: ultra-high performance liquid chromatography; UV: ultraviolet.

[0263] Other abbreviations are intended to convey their generally accepted meaning.

[0264] General experimental conditions All starting materials and solvents were either commercially available or prepared according to literature methods. Appropriate isocyanate starting materials were obtained from Sigma Aldrich or Enamine store. Appropriate cyclic amine starting materials were obtained from Sigma Aldrich, Enamine store, Fluorochem, or Asta Tech Inc. Unless otherwise noted, reaction mixtures were magnetically stirred and reactions were carried out at room temperature (approximately 20°C).

[0265] Silica gel chromatography was performed on an automated flash chromatography system such as a Combi-Flash Companion, Combi-Flash Rf system, or Revelis X2 flash system using RediSep® Rf or Revelis® or GraceResolv® prepacked silica (230-400 mesh, 40-63 μm) cartridges.

[0266] Analytical UPLC-MS experiments to determine retention times and associated mass ions were performed using a Waters ACQUITY UPLC® H-Class system equipped with an ACQUITY PDA detector and an ACQUITY QDa mass spectrometer or a Waters SQD mass spectrometer running the analytical method described below.

[0267] Preparative HPLC purification was performed using a Waters X-Bridge BEH C18, 5 μm, 19 × 50 mm column using a gradient of MeCN and 10 mM aqueous ammonium bicarbonate. Fractions were collected using a PDA and SQD2 or ACQUITY QDa mass spectrometer with UV detection over a full wavelength range.

[0268] NMR spectra were recorded using a Bruker Avance III HD 500 MHz instrument or a Bruker Avance Neo 400 MHz instrument using either the remaining non-deuterated solvent or tetra-methylsilane as a reference.

[0269] Analysis method Method 1 - Basic 3-Minute Method Column: Waters ACQUITY UPLC® BEH C18, 1.7 μm, 2.1 x 30 mm at 40°C Detection: UV at 210-400 nm, MS with electrospray ionization unless otherwise indicated Solvent: A: 10 mM ammonium bicarbonate aqueous solution, B: MeCN Concentration gradient:

[0270] [Table 2]

[0271] Method 2 - Basic Quarter Method Column: Waters X-Bridge BEH C18, 2.5 μm, 4.6 × 30 mm at 40 °C Detection: UV at 254 nm, MS with electrospray ionization unless otherwise indicated Solvents: A: 0.1% v / v ammonium hydroxide in water, B: MeCN gradient:

[0272] [Table 3]

[0273] Method 3 - Basic Rule of Thirds Column: Waters ACQUITY UPLC (registered trademark) BEH C18, 1.7 μm, 2.1 × 30 mm, 40 °C Solvents: A: 0.1% v / v ammonium hydroxide in water, B: MeCN

[0274] [Table 4]

[0275] Experimental Scheme 1 Compound 1 N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide

[0276] [ka]

[0277] A solution of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine 1a (20 mg, 0.15 mmol) in DMF (1 mL) was added to 1,2-dichloro-4-isocyanatobenzene (34 mg, 0.180 mmol). DIPEA (0.079 mL, 0.450 mmol) was added, and the mixture was stirred at RT for 16 h. The reaction mixture was filtered, and the product was purified by mass-directed HPLC (10-40% MeCN / 10 mM aqueous ammonium bicarbonate, C18) to yield N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide 1 as a colorless solid. UPLC-MS (Method 1) showed m / z values ​​of 323.3, 325.3, and 327.2 [M+H] at 1.14 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ9.03(s,1H), 8.97(s,1H), 8.64(s,1H), 7.85(d,J=2.3Hz,1H), 7.50(d,J=8 .8Hz,1H), 7.47(dd,J=8.9,2.3Hz,1H), 4.70(s,2H), 3.83(t,J=5.9Hz,2H), 2.95(t,J=5.9Hz,2H).

[0278] The following compounds were prepared using the appropriate starting materials in a similar manner to that described in Experimental Scheme 1. In cases where the starting materials are not described in the literature, their synthesis is described below. Key points: (a) Reaction was carried out in THF (b) Reaction was carried out in DCM (c) Reaction was carried out in a mixture of DMF / THF (d) Reaction was carried out in a mixture of DMF / DCM (e) Reaction was carried out with Et3N instead of DIPEA (f) Reaction was carried out without adding DIPEA (g) Product was purified by silica gel chromatography (EtOAc / isohexane) (h) Product was purified by silica gel chromatography (DCM / heptane) (i) Product was purified by RP Flash C18 (MeCN / 10 mM aqueous ammonium bicarbonate) (j) Product was purified by silica gel chromatography (DCM / isohexane) (k) Product was purified by silica gel chromatography (0.7M NH3 in MeOH / DCM) (l) [M+H] + No mass is observed, instead [MH] - was reported.

[0279] [Table 5] TIFF0007755319000072.tif214169TIFF0007755319000073.tif218168TIFF0007755319000074.tif216167TIFF0007755319000075.tif224169TIFF0007755319000076.tif239170TIFF0007755319000077.tif162166TIFF0007755319000078.tif223170TIFF0007755319000079.tif232164TIFF0007755319000080.tif233169TIFF0007755319000081.tif207170TIFF0007755319000082.tif205166TIFF0007755319000083.tif222166TIFF0007755319000084.tif215166TIFF0007755319000085.tif216170TIFF0007755319000086.tif235168TIFF0007755319000087.tif201167TIFF0007755319000088.tif217167TIFF0007755319000089.tif236166TIFF0007755319000090.tif230168TIFF0007755319000091.tif226167TIFF0007755319000092.tif233169TIFF0007755319000093.tif173169TIFF0007755319000094.tif219168TIFF0007755319000095.tif210168TIFF0007755319000096.tif163166TIFF0007755319000097.tif166170TIFF0007755319000098.tif175169TIFF0007755319000099.tif216170TIFF0007755319000100.tif182167JPEG0007755319000101.jpg180170JPEG0007755319000102.jpg210170JPEG0007755319000103.jpg219167JPEG0007755319000104.jpg217170JPEG0007755319000105.jpg222170JPEG0007755319000106.jpg165170JPEG000775 5319000107.jpg227165JPEG0007755319000108.jpg212170JPEG0007755319000109.jpg82169.

[0280] Intermediate 1 (I-1) [ka]

[0281] Step 1: To a solution of urea (1.03 g, 17.2 mmol) in EtOH (10 ml) was added a solution of sodium ethoxide (21% w / w in EtOH) (5.58 g, 6.4 mL, 17.2 mmol). The mixture was stirred for 5 min, then a solution of tert-butyl (Z)-3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate (I-1a) (3.65 g, 14.4 mmol) in EtOH (50 ml) was added. The resulting mixture was heated to reflux for 16 h. The reaction was cooled to RT. Saturated ammonium chloride solution (20 ml) was added and the volatiles were removed in vacuo. The aqueous layer was extracted with EtOAc (3 x 150 ml). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by chromatography on silica gel (0–10% (0.7 M NH3 / MeOH) / DCM) to yield tert-butyl 2-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (I-1b) as a pale yellow solid. 1 H NMR (500MHz, DMSO-d6) δ11.70(s,1H), 8.16(s,1H), 4.28(s,2H), 3.55(t,J=6.0Hz,2H), 2.62(t,J=6.0Hz,2H), 1.42(s,9H).

[0282] Step 2: To a solution of tert-butyl 2-hydroxy-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (I-1b) (0.246 g, 979 μmol) in DCM (10 ml) was added a solution of HCl (4 M in 1,4-dioxane) (2.45 ml, 9.79 mmol). The resulting mixture was stirred at RT for 16 h. The reaction mixture was filtered, and the precipitate was dried under vacuum. The solid was suspended in MeOH (50 ml), SCX (4.9 g, 3.77 mmol) was added, and the mixture was stirred for 3 h. The SCX was washed with MeOH, and the product was eluted with 0.7 M NH3 / MeOH solution and concentrated in vacuo to give 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-ol (I-1) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 5.40 (s, 1H), 3.57 (s, 2H), 2.89 (t, J = 5.9 Hz, 2H), 2.48 (t, J = 5.9 Hz, 2H). (One exchangeable H missing).

[0283] Intermediate 2 (I-2) [ka]

[0284] A solution of 7-methoxy-1,2,3,4-tetrahydro-2,6-naphthyridine (I-2a) (200 mg, 1.22 mmol) in HBr (2.07 ml, 48% w / w, 18.3 mmol) was heated to 100° C. for 10 h. The reaction mixture was cooled to RT, and the reaction mixture was concentrated in vacuo. The residue was dissolved in MeOH (20 ml) and loaded onto an SCX cartridge (40 g, 30 mmol). The SCX was washed with MeOH, and the product was eluted with 0.7 M NH in MeOH and concentrated in vacuo to give 5,6,7,8-tetrahydro-2,6-naphthyridin-3-ol (I-2) as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 11.28 (s, 1H), 7.13 (d, J = 3.4 Hz, 1H), 6.02 (d, J = 3.5 Hz, 1H), 3.75–3.69 (m, 2H), 2.92–2.86 (m, 2H), 2.47 (t, J = 5.9 Hz, 2H). (One exchangeable H is missing.)

[0285] Intermediate 3 (I-3) [ka]

[0286] Step 1: A solution of tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3a) (150 mg, 558 μmol), KFe(CN) (212 mg, 502 μmol), and potassium acetate (46.6 mg, 474 μmol) in a mixture of 1,4-dioxane (4 mL) and water (0.8 mL) was degassed for 5 min, and Pd-174 (20.1 mg, 27.9 μmol) was added. The mixture was degassed for an additional 5 min before heating to 90 °C for 16 h. The reaction was cooled to RT, filtered through a hydrophobic frit, and the filtrate was concentrated in vacuo. The product was purified by chromatography on silica (0-30% EtOAc / isohexane) to give tert-butyl 6-cyano-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3b) as a thick, colorless oil. LCMS (Method 3) m / z 260.1 (M+H) at 1.25 min + (ES + ).

[0287] Step 2: To a solution of tert-butyl 6-cyano-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3b) (15 mg, 58 μmol) in 1,4-dioxane (2 ml) was added 4 M HCl in dioxane (0.29 ml, 1.2 mmol) at 0 °C. The reaction mixture was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo to give 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carbonitrile hydrochloride (I-3) as a brown solid. LCMS (Method 3) m / z 160.0 (M+H) at 0.54 min + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ9.25(s,2H), 8.64(s,1H), 8.00(s,1H), 4.42(s,2H), 3.44~3.40(m,2H), 3.07(t,J=6.3Hz,2H).

[0288] Intermediate 4 (I-4) [ka]

[0289] Step 1: Using essentially the same procedure as for I-3b, tert-butyl 7-cyano-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-4b) was synthesized from tert-butyl 7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-4a). LCMS (Method 2) m / z 260.0 (M+H) at 1.93 min + (ES + ).

[0290] Step 2: Using essentially the same procedure as for I-3, 5,6,7,8-tetrahydro-2,6-naphthyridine-3-carbonitrile hydrochloride (I-4) was synthesized from tert-butyl 7-cyano-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-4b). H NMR (500 MHz, DMSO-d6) δ 9.25 (s, 2H), 8.64 (s, 1H), 8.00 (s, 1H), 4.42 (s, 2H), 3.40 (s, 2H), 3.07 (t, J = 6.3 Hz, 2H).

[0291] Intermediate 5 (I-5) [ka]

[0292] Step 1: tert-Butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3a) (101 mg, 376 μmol) n To a solution of hydrazine hydrate (35% w / w in water) (266 μl, 1.88 mmol) in BuOH (2 ml) was added and the reaction was heated to 130° C. for 60 h. The reaction was cooled to room temperature and diluted with water (5 ml) and DCM (10 ml). The layers were separated and the aqueous layer was further extracted with DCM (3×10 ml). The combined organic layers were passed through a hydrophobic frit and the filtrate concentrated in vacuo to give tert-butyl 6-hydrazineyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-5a) as a colorless oil. LCMS (Method 3) m / z 265.1 (M+H) at 1.58 min + (ES + ).

[0293] Step 2: A solution of tert-butyl 6-hydrazineyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-5a) in triethyl orthoformate (2 mL, 0.01 mol) was heated to 130 °C for 22 h. The reaction mixture was concentrated in vacuo, and the product was purified by chromatography on silica gel (0-5% (0.7 M NH3 / MeOH) / DCM) to give tert-butyl 8,9-dihydro-[1,2,4]triazolo[4,3-b][2,7]naphthyridine-7(6H)-carboxylate (I-5b) as a pale yellow solid. LCMS (Method 2) m / z 275.1 (M+H) at 1.50 min. + (ES + ). 1 H NMR (500MHz, CDCl3) δ8.79(s,1H), 8.03(s,1H), 7.62(s,1H), 4.60(br s,2H), 3.67(t,J=6.5Hz,2H), 3.01(t,J=6.3Hz,2H), 1.51(s,9H).

[0294] Step 3: To a solution of tert-butyl 8,9-dihydro-[1,2,4]triazolo[4,3-b][2,7]naphthyridine-7(6H)-carboxylate (I-5b) (37 mg, 0.13 mmol) in DCM (2 ml) was slowly added TFA (0.1 ml, 1.3 mmol). The reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated in vacuo. The product was purified by ion exchange on SCX (0.6 g, 0.42 mmol), eluting with 0.7 M NH in MeOH, to give 6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-b][2,7]naphthyridine (I-5) as a colorless solid. LCMS (Method 3) m / z 175.1 (M+H) at 0.53 min. + (ES + ).

[0295] Intermediate 6 (I-6) [ka]

[0296] Step 1: To a solution of tert-butyl 6-cyano-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3b) (100 mg, 386 μmol) in EtOH (5 mL) and acetic acid (662 μL, 11.6 mmol), Pd / C 10% (50% paste) (50 mg, 23 μmol) was added. The reaction mixture was stirred under a hydrogen atmosphere (5 bar) at RT for 16 h. The catalyst was filtered off, and the filtrate was concentrated in vacuo. The product was purified on silica gel (0–10% (0.7 M NH3 / MeOH) / DCM) to give tert-butyl 6-(aminomethyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-6a) as a clear, colorless tar. 1 H NMR(500MHz,DMSO-d6)δ8.29(s,1H), 7.22(s,1H), 4.51(s,2H), 3.73(s,2H), 3.56(t,J=5.9Hz,2H), 2.77(t,J=6.0Hz,2H), 2.03(br s,2H), 1.43(s,9H).

[0297] Step 2: A solution of tert-butyl 6-(aminomethyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-6a) (25 mg, 95 μmol) in formic acid (1 mL) was heated at 80° C. for 2 h. The reaction mixture was cooled and concentrated in vacuo. The residue was combined with toluene (3 mL) and POCl (1 mL, 0.01 mol) and heated to 100° C. for 2 h. The reaction mixture was cooled and concentrated in vacuo. The solid residue was combined with saturated NaHCO solution (5 mL), and the product was extracted with 20% MeOH in DCM solution (3×5 mL). The combined organic layers were concentrated in vacuo. The residue was dissolved in 1 M NaOH (1 mL) and EtOH (2 mL) and heated to 100° C. for 16 h. The reaction mixture was cooled and concentrated in vacuo, and the residue was acidified with AcOH, loaded onto SCX (20 g, 14 mmol), and eluted with 0.7 M NH in MeOH to give 6,7,8,9-tetrahydroimidazo[1,5-b][2,7]naphthyridine (I-6) as an orange solid. LCMS (Method 3) m / z 173.8 (M+H) at 0.61 min. + (ES + ). 1H NMR(500MHz,DMSO-d6)δ8.19(s,1H), 8.12(s,1H), 8.06(s,1H), 7.24(d,J=5.5Hz,1H), 7.16(d,J=3.0Hz,1H), 3.46(t,J=6.0Hz,2H), 2.91(t,J=6.2Hz,2H), 2.72~2.66(m,2H).

[0298] Intermediate 7 (I-7) [ka]

[0299] Step 1: To a solution of tert-butyl 7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-3a) (200 mg, 744 μmol) in EtOH (1 ml) was added hydrazine monohydrate (1.12 ml, 14.9 mmol) and the reaction was heated to 150 °C for 94 h. The reaction mixture was cooled, diluted with DCM (5 ml), and concentrated in vacuo. The material was triturated with DCM to give 7-hydrazineyl-1,2,3,4-tetrahydro-2,6-naphthyridine (I-7a) as a brown solid. LCMS (Method 3) m / z 165.5 (M+H) at 0.26 min + (ES + ).

[0300] Step 2: A solution of 7-hydrazineyl-1,2,3,4-tetrahydro-2,6-naphthyridine (I-7a) in triethyl orthoformate (2 mL, 0.01 mol) was heated to 130 °C for 2 h. The reaction mixture was cooled and concentrated in vacuo to give 6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-b][2,6]naphthyridine (I-7) as a red solid. LCMS (Method 3) m / z 175.3 (M+H) at 0.22 min + (ES + ).

[0301] Intermediate 8 (I-8) [ka]

[0302] Step 1: Using essentially the same procedure as (I-6a), tert-butyl 7-(aminomethyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-8a) was synthesized from tert-butyl 7-cyano-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-4b). LCMS (Method 3) m / z 264.3 (M+H) at 0.99 min. + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ8.28(s,1H), 7.23(s,1H), 4.51(s,2H), 3.74(s,2H), 3.58(t,J=5.8Hz,2H), 2.75(t,J=5.9Hz,2H), 2.16(s,2H), 1.43(s,9H).

[0303] Step 2: A solution of tert-butyl 7-(aminomethyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (I-8a) (20 mg, 76 μmol) in ethyl formate (2 mL, 0.02 mol) was heated to 65 °C for 3 h. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in DCM (2 mL) and POCl (11 μL, 0.11 mmol) was added, followed by EtN (64 μL, 0.46 mmol) and stirred at RT for 2 h. The material was poured into ice water (20 mL) and saturated sodium bicarbonate solution (2 mL) was added. The product was extracted with 10% MeOH in DCM (2 × 20 mL), and the combined organic layers were concentrated in vacuo. The product was purified by silica gel (0-5% (0.7 M NH3 / MeOH) / DCM) to give tert-butyl 6,7-dihydroimidazo[1,5-b][2,6]naphthyridine-8(9H)-carboxylate (I-8b) as a clear tan oil. LCMS (Method 3) m / z 274.3 (M+H) at 1.18 min. + (ES + ). 1H NMR(500MHz,DMSO-d6)δ8.28(d,J=0.8Hz,1H), 8.22(s,1H), 7.42(s,1H), 7.26(d, J=1.0Hz,1H), 4.45(s,2H), 3.50(t,J=6.2Hz,2H), 2.81~2.75(m,2H), 1.43(s,9H).

[0304] Step 3: tert-Butyl 6,7-dihydroimidazo[1,5-b][2,6]naphthyridine-8(9H)-carboxylate (10 mg, 37 μmol) was dissolved in 4 M HCl in 1,4-dioxane (0.46 mL, 1.8 mmol) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo. The product was purified by ion exchange using SCX washes with MeOH (10 mL). The product was eluted with 0.7 M NH3 in MeOH (20 mL) and concentrated in vacuo to give 6,7,8,9-tetrahydroimidazo[1,5-b][2,6]naphthyridine (I-8) as a brown oil. LCMS (Method 3) m / z 173.6 (M−H) at 0.59 min. - (ES - ).

[0305] Intermediate 9 (I-9) [ka]

[0306] Step 1: To a solution of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine HCl (I-9a) (2.00 g, 9.75 mmol) in DCM (10 mL) was added (Boc)O (2.46 mL, 10.7 mmol) and EtN (1.63 mL, 11.7 mmol). The resulting mixture was stirred at RT for 16 h. Water (20 mL) was added, and the product was extracted with EtOAc (3 × 50 mL). The combined organics were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel (0–50% EtOAc / isohexane) to yield tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (I-9b) as a viscous, colorless oil that solidified upon standing. 1 H NMR (500 MHz, chloroform-d) δ 7.40 (d, J = 8.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 4.58 (s, 2H), 3.75 (t, J = 5.9 Hz, 2H), 2.99 (t, J = 6.0 Hz, 2H), 1.52 (s, 9H).

[0307] Step 2: To a solution of tert-butyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (I-9b) (1.00 g, 3.72 mmol) in 1,4-dioxane (10 mL) was added (2,4-dimethoxyphenyl)methanamine (727 μL, 4.84 mmol), followed by CsCO (2.44 g, 7.44 mmol). The reaction mixture was purged with nitrogen for 5 min. Xantphos (215 mg, 372 μmol) and Pd(dba) (170 mg, 186 μmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The reaction mixture was heated to 95 °C for 20 h. The reaction mixture was filtered through a plug of Celite, and the filtrate was concentrated in vacuo. The product was purified by silica gel (0-20% EtOAc / isohexane, then 0-5% 0.7M NH3 / MeOH in DCM) to give tert-butyl 2-((2,4-dimethoxybenzyl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (I-9c) as an orange oil. LCMS (Method 3) m / z 400.3 (M+H) at 1.06 min + (ES + ).

[0308] Step 3: To a solution of tert-butyl 2-((2,4-dimethoxybenzyl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (I-9c) (270 mg, 676 μmol) in DCM (8 mL) was added TFA (1.04 mL, 13.5 mmol), and the reaction mixture was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo, and the product was purified by ion exchange using SCX (20 g, 14 mmol) washings with MeOH (5 mL). The product was eluted with 0.7 M NH in MeOH to give 5,6,7,8-tetrahydro-1,6-naphthyridin-2-amine (I-9) as a brown oil. LCMS (Method 3) m / z 150.1 (M+H) at 0.23 min. + (ES + ). 1H NMR (500 MHz, DMSO-d6) δ 7.01 (d, J = 8.2 Hz, 1H), 6.22 (d, J = 8.2 Hz, 1H), 5.59 (s, 2H), 3.65 (s, 2H), 2.94 (dd, J = 6.7, 5.4 Hz, 2H), 2.52 (d, J = 5.3 Hz, 2H). (NH protons not observed.)

[0309] Intermediate 10 (I-10) [ka]

[0310] Step 1: 6-Bromoisoquinoline (I-10a) (2.5 g, 12 mmol), sodium methanesulfinate (1.8 g, 18 mmol), NaOH (96 mg, 2.4 mmol), copper(I) iodide (0.23 g, 1.2 mmol), and proline (0.28 g, 2.4 mmol) were added to a three-neck round-bottom flask and placed under a steady stream of nitrogen. DMSO (25 mL) was added, and the reaction was sparged with nitrogen for 5 min. The reaction mixture was heated to 95 °C for 20 h. The reaction was cooled to RT and diluted with water (100 mL) and EtOAc (200 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (2 × 200 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The product was purified by silica gel (0-10% (0.7 M NH3 / MeOH) / DCM) to give 6-(methylsulfonyl)isoquinoline (I-10b) as a brown powder. LCMS (Method 2) m / z 208.0 (M+H) at 1.16 min. + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ9.56(s,1H), 8.73(s,1H), 8.66(d,J=1.8Hz,1H), 8.42(d,J=8.6Hz,1H), 8.17~8.11(m,2H), 3.35(s,3H).

[0311] Step 2: To a solution of 6-(methylsulfonyl)isoquinoline (I-10b) (0.50 g, 2.42 mmol) in AcOH (8 ml) was added 5% Pt-C type 128 (0.5 g, 0.1 mmol). The resulting mixture was stirred under hydrogen atmosphere (5 bar) at 25 °C for 72 h. The reaction mixture was cooled to RT and filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated in vacuo to give 6-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline, AcOH (I-10) as a sticky brown oil. LCMS (Method 2) m / z 212.0 (M+H) at 1.00 min + (ES + ). 1 H NMR (500 MHz, DMSO-d6) δ 7.94–7.51 (m, 2H), 7.28 (d, J = 8.7 Hz, 1H), 3.92 (s, 2H), 3.16 (s, 3H), 2.96 (t, J = 5.9 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H). (Exchangeable -NH protons not visible.)

[0312] Intermediate 11 (I-11) [ka]

[0313] Step 1: To a solution of tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3a) (200 mg, 744 μmol) in MeOH (10 mL) and NEt (1.56 mL, 11.2 mmol) was added Pd-dppf (54.5 mg, 74.4 μmol). The reaction mixture was charged with CO (4.5 bar) and heated to 110 °C for 5 h. The reaction was cooled, filtered through Celite, and concentrated in vacuo. The product was purified on silica gel (0–5% (0.7 M NH / MeOH) / DCM) to yield 2-(tert-butyl) 6-methyl 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate (I-11a) as a clear orange oil. LCMS (Method 3) m / z 293.3 (M+H) at 1.19 min + (ES+ ).

[0314] Step 2: To a solution of 2-(tert-butyl) 6-methyl 3,4-dihydro-2,7-naphthyridine-2,6(1H)-dicarboxylate (I-11a) (225 mg, 770 μmol) in DCM (20 mL) was added a 4 M HCl solution in 1,4-dioxane (1.92 mL, 7.70 mmol). The resulting mixture was stirred at RT for 18 h. The solvent was removed in vacuo to give methyl 5,6,7,8-tetrahydro-2,7-naphthyridine-3-carboxylate hydrochloride (I-11) as a brown solid. 1H NMR (500MHz, DMSO-d6) δ9.50(s,2H), 8.58(s,1H), 7.96(s,1H), 4.39(t,J=4.8Hz,2H), 3.90(s,3H), 3.43~3.35(m,2H), 3.11(t,J=6.3Hz,2H).

[0315] Intermediate 12 (I-12) [ka]

[0316] Step 1: To a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (100 mg, 361 μmol), EDCI hydrochloride (104 mg, 541 μmol), and HOBt monohydrate (104 mg, 80% w / w, 541 μmol) in DMF (2 mL) was added N'-hydroxyacetimidamide (35 mg, 469 μmol), and the reaction mixture was stirred at RT for 16 h. An additional portion of N'-hydroxyacetimidamide (35 mg, 469 μmol) and EDCI hydrochloride (104 mg, 541 μmol) was added, followed by EtN (151 μL, 1.08 mmol), and the reaction mixture was stirred for 18 h. The reaction was diluted with EtOAc (20 mL) and washed with sodium bicarbonate solution. The organics were concentrated in vacuo. The product was purified by chromatography on silica gel (0-10% (0.7 M ammonia / MeOH) / DCM) to yield tert-butyl (Z)-6-((((1-aminoethylidene)amino)oxy)carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I-12b as a clear, colorless oil. LCMS (Method 2) m / z 334.2 (M+H) at 1.87 min. + (ES + ).

[0317] Step 2: To a solution of tert-butyl-6-((((1-aminoethylidene)amino)oxy)carbonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I-12b (100 mg, 300 μmol) in THF (2 mL) was added a solution of TBAF (300 μL, 1 M, 300 μmol) in THF. The reaction mixture was stirred at RT for 72 h. The reaction mixture was concentrated in vacuo. The product was purified by chromatography on silica gel (0–20% EtOAc / isohexane) to yield tert-butyl 6-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I-12c as a colorless oil. 1H NMR (500MHz, DMSO-d6) δ7.93~7.84(m,2H), 7.43(d,J=7.9Hz,1H), 4.60(s,2H), 3.59(t,J=5.9Hz,2H), 2.89(t,J=6.0Hz,2H), 2.41(s,3H), 1.43(s,9H).

[0318] Step 3: tert-Butyl 6-(3-methyl-1,2,4-oxadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate I-12c (40 mg, 126 μmol) was dissolved in a solution of HCl in 1,4-dioxane (4 M, 1.5 mL, 6 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated in vacuo to give 3-methyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,2,4-oxadiazole hydrochloride I-12 as a colorless solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.95 (dd, J = 8.2, 1.8 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 4.36 (s, 2H), 3.40 (t, J = 6.3 Hz, 2H), 3.10 (t, J = 6.3 Hz, 2H), 2.42 (s, 3H). Two protons from N-H2 are not observed.

[0319] Experimental Scheme 2 Compound 79 6-((3-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine 2-oxide [ka]

[0320] N-(3-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide (10 mg, 28 μmol) was dissolved in DCM (2 ml) and mCPBA (7.6 mg, 77% w / w, 34 μmol) was added. The reaction mixture was stirred at RT for 16 h. Sodium metabisulfite solution (2 ml) was added and the layers were separated. The solvent was concentrated in vacuo. The product was purified by silica gel chromatography (0-10% (0.7 M NH3 / MeOH) in DCM) to yield 6-((3-chloro-4-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydro-2,6-naphthyridine 2-oxide 79 as a colorless solid. LC-MS (Method 1) m / z 372.3, 374.3 [M+H] at 1.15 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H), 8.16(s,1H), 8.06(dd,J=6.6,1.9Hz,1H), 7.91(d,J=2.1Hz,1H), 7.73(d,J=8 .8Hz,1H), 7.64(d,J=8.9Hz,1H), 7.27(d,J=6.7Hz,1H), 4.63(s,2H), 3.72(t,J=5.9Hz,2H), 2.82(t,J=5.9Hz,2H).

[0321] The following compounds were prepared using procedures similar to those described in Experimental Scheme 2, using appropriate starting materials. [Table 6]

[0322] Experimental Scheme 3 Compound 82 7-Amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide [ka]

[0323] Step 1: tert-Butyl 7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate 82a (700 mg, 2.60 mmol) was added to a solution of 1,4-dioxane (10 mL) and (2,4-dimethoxyphenyl)methanamine 82b (1.57 mL, 10.4 mmol), followed by the addition of CsCO (1.28 g, 3.91 mmol). The reaction mixture was purged with nitrogen for 5 min. Pd-177 (79.3 mg, 104 μmol) and Xantphos (60.3 mg, 0.04 Eq, 104 μmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The reaction mixture was heated to 85 °C for 20 h. The reaction mixture was concentrated in vacuo. The product was purified by silica gel chromatography (0-25% EtOAc in isohexane, then 0-5% (0.7M NH3 / MeOH) in DCM) to give tert-butyl 7-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate 82c as a yellow oil. 1 H NMR(500MHz,DMSO-d6)δ7.76(s,1H), 7.09(d,J=8.3Hz,1H), 6.54(d,J=2.4Hz,1H), 6.47(s,1H), 6.43(dd,J=8.3,2.4Hz,1H), 6.28 (s,1H), 4.35(s,2H), 4.30(d,J=6.0Hz,2H), 3.80(s,3H), 3.73(s,3H), 3.50(t,J=6.0Hz,2H), 2.58(t,J=5.9Hz,2H), 1.42(s,9H).

[0324] Step 2: tert-Butyl 7-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate 82c (360 mg, 901 μmol) was added to a solution of HCl in 1,4-dioxane (4.5 ml, 4 M, 18.0 mmol), and the resulting mixture was stirred at room temperature for 72 h. The solvent was removed in vacuo. The residue was dissolved in MeOH, and SCX was added. The SCX was washed with MeOH (50 ml), and the product was eluted with 0.7 M NH3 / MeOH (100 ml). The eluate was concentrated in vacuo to give 5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine 82d as a yellow glass. LCMS (Method 2) m / z 150.1 [M+H] at 0.45 min + (ES + ). 1 H NMR (500MHz, DMSO-d6) δ7.64(s,1H), 6.09(s,1H), 5.49(s,2H), 3.69(s,2H), 2.89(t,J=5.9Hz,2H), 2.49(d,J=5.7Hz,2H).

[0325] Step 3: To a solution of 5,6,7,8-tetrahydro-2,6-naphthyridin-3-amine 82d (60 mg, 0.4 mmol) in DCM (2 mL) was added DIPEA (0.21 mL, 1.2 mmol) and 1,2-dichloro-4-isocyanatobenzene 82e (91 mg, 0.48 mmol). The reaction mixture was stirred at RT for 1 h. Saturated sodium bicarbonate solution (2 mL) was added, and the product was extracted with 10% MeOH in DCM (3 × 3 mL). The combined organics were concentrated in vacuo. The product was purified by silica gel chromatography (0–5% (0.7 M NH3 / MeOH) / DCM) to yield 7-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide as a pale yellow solid. LCMS (Method 3) m / z 337.3, 379.3 [M+H] at 1.19 min + (ES + ). 1H NMR(500MHz,DMSO-d6)δ8.84(s,1H), 7.86(t,J=1.4Hz,1H), 7.76(s,1H), 7.49(d,J=1.4Hz,2H) , 6.24(d,J=0.9Hz,1H), 5.68(s,2H), 4.50(s,2H), 3.66(t,J=5.9Hz,2H), 2.66(t,J=5.9Hz,2H).

[0326] The following compounds were prepared using procedures similar to those described in Experimental Scheme 3, using appropriate starting materials. [Table 7]

[0327] Experimental Scheme 4 Compound 85 N-(3,4-dichlorophenyl)-6-fluoro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide [ka]

[0328] A solution of 6-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (65 mg, 0.19 mmol) in AcOH (2 ml) was added to a solution of tetrafluoroboric acid in water (3.0 ml, 48% w / w, 19 mmol) at 0° C. A solution of sodium nitrite (27 mg, 0.39 mmol) in water (1 ml) was added dropwise over 20 min, and the reaction mixture was stirred at 0° C. for an additional 1 h. The reaction mixture was added to an ice-cold solution of NaHCO (10 ml), and the product was extracted using a 20% MeOH solution in DCM (3×25 ml). The solvent was dried over sodium sulfate, and the solvent was removed under reduced pressure. The product was purified by silica gel chromatography (0-0.75% (0.7 M NH3 / MeOH) / DCM) to give N-(3,4-dichlorophenyl)-6-fluoro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide 85 as a colorless solid. LCMS (Method 3) m / z 338.1, 340.1 [MH] at 1.32 min. - (ES - ). 1 H NMR(500MHz,DMSO-d6)δ8.94(s,1H), 8.10(s,1H), 7.87~7.83(m,1H), 7.53~7.45(m,2 H), 7.06(d,J=1.9Hz,1H), 4.67(s,2H), 3.71(t,J=6.0Hz,2H), 2.94(t,J=5.9Hz,2H).

[0329] The following compounds were prepared by procedures similar to those described in Experimental Scheme 4 using appropriate starting materials. [Table 8] JPEG0007755319000128.jpg153162

[0330] Experimental Scheme 5 Compound 92 N-(3,4-dichlorophenyl)-7-methyl-6-oxo-3,4,6,7-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide [ka]

[0331] To a solution of N-(3,4-dichlorophenyl)-6-oxo-3,4,6,7-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide (76) (25 mg, 74 μmol) in DMF (2 mL) was added MeI (4.6 μL, 74 μmol) and potassium carbonate (31 mg, 0.22 mmol), and the reaction mixture was stirred at RT for 36 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (10 mL) and 20% (0.7 M NH in MeOH) in DCM (20 mL), and the organic layer was concentrated in vacuo. The product was purified via mass-directed RP-preparative HPLC (20-50% ammonium bicarbonate in MeCN) to give N-(3,4-dichlorophenyl)-7-methyl-6-oxo-3,4,6,7-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide 92 as a white solid. LCMS (Method 1) m / z 352.4, 354.3 [M+H] at 1.32 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.79(s,1H), 7.85(d,J=2.0Hz,1H), 7.63(s,1H), 7.52~7.44(m,2 H), 6.26(s,1H), 4.38(s,2H), 3.60(t,J=6.1Hz,2H), 3.39(s,3H), 2.77(t,J=6.0Hz,2H).

[0332] Experimental Scheme 6 Compound 95 N-(3,4-dichlorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxamide [ka]

[0333] A solution of N-(3,4-dichlorophenyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (15) (25 mg, 71 μmol) was dissolved in DCM (0.5 ml) and the solution was cooled to −78°C. A solution of boron tribromide (93 μl, 93 μmol) (1 M solution in DCM) was added dropwise, and the mixture was stirred at −78°C for 5 min and then warmed to 0°C for 1 h. The reaction mixture was cooled to −78°C, and anhydrous MeOH (1 ml) was added. The reaction mixture was warmed to RT for 30 min. The reaction mixture was concentrated in vacuo, and the residue was purified by chromatography on a RP Flash C18 (5-65% MeCN / 10 mM ammonium bicarbonate) to produce N-(3,4-dichlorophenyl)-6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxamide (95) as a white solid. LCMS (Method 3) m / z 337.2, 339.2, 341.2 at 1.32 min [M+H] + (ES + ). 1 H NMR(500MHz,d6-DMSO)δ1H NMR(500MHz,DMSO-d6)δ9.29(s,1H), 8.81(s,1H), 7.87(d,J=2.1Hz,1H), 7.53~7.43(m,2H), 6.96(d,J=8.2Hz,1H), 6. 61(dd,J=8.2,2.5Hz,1H), 6.58(d,J=2.5Hz,1H), 4.51(s,2H), 3.64(t,J=5.9,5.9Hz,2H), 2.76(t,J=5.9,5.9Hz,2H).

[0334] Experimental Scheme 7 Compound 97 8-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide [ka]

[0335] 7-((3-Chloro-4-(trifluoromethyl)phenyl)carbamoyl)-5,6,7,8-tetrahydro-2,7-naphthyridine 2-oxide (94) (20 mg, 54 μmol) was dissolved in POCl3 (15 μl, 0.16 mmol), and the reaction mixture was heated to reflux for 16 h. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was stirred in ice-water, and saturated sodium bicarbonate solution (10 ml) was added. The aqueous mixture was extracted with 10% MeOH in DCM (30 ml), dried over sodium sulfate, and concentrated in vacuo. The product was purified on silica (0–5% MeOH in DCM) to give 8-chloro-N-(3-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide as a white solid. LCMS (Method 1) m / z 390.0, 392.0 [M+H] at 1.50 min + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ9.33(s,1H), 8.22(d,J=5.0Hz,1H), 7.91(s,1H), 7.73~7.75(m,1H), 7.64( d,J=8.9Hz,1H), 7.30(d,J=5.0Hz,1H), 4.64(s,2H), 3.76(t,J=5.8Hz,2H), 2.93(t,J=5.8Hz,2H).

[0336] Experimental Scheme 8 Compound 104 N-(3-chloro-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide [ka]

[0337] Step 1: Using essentially the same procedure as in 82c, tert-butyl 6-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (104a) was synthesized from tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (I-3a).1 H NMR(500MHz,DMSO-d6)δ7.77(s,1H), 7.08(d,J=8.3Hz,1H), 6.56~6.50(m,2H), 6.43(dt,J=8.3,1.9Hz,1H), 6.29(s,1 H), 4.35~4.28(m,4H), 3.80(s,3H), 3.72(s,3H), 3.46(t,J=6.0Hz,2H), 2.62(t,J=6.0Hz,2H), 1.42(d,J=1.3Hz,9H).

[0338] Step 2: Using essentially the same procedure as in 82d, 5,6,7,8-tetrahydro-2,7-naphthyridin-3-amine (104b) was synthesized from tert-butyl 6-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (104a). 1 H NMR (500 MHz, DMSO-d6) δ 7.60 (d, J = 0.9 Hz, 1H), 6.15 (d, J = 1.2 Hz, 1H), 5.50 (s, 2H), 3.69 (s, 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.55 (d, J = 6.0 Hz, 2H). (One exchangeable H is missing.)

[0339] Step 3: Using essentially the same procedure as in 82, 6-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (104c) was synthesized from 5,6,7,8-tetrahydro-2,7-naphthyridine-3-amine (104b). LCMS (Method 3) m / z 371.1, 373.1 [M+H] at 1.98 min. + (ES + ).

[0340] Step 4: Using essentially the same procedure as in 85, N-(3-chloro-4-(trifluoromethyl)phenyl)-6-fluoro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (104) was synthesized from 6-amino-N-(3-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (104c). LCMS (Method 3) m / z 374.1, 376.1 [M+H] at 1.28 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ9.21(s,1H), 8.11(s,1H), 7.91(d,J=2.1Hz,1H), 7.74(d,J=8.8Hz,1H), 7.64 (dd,J=8.6,2.1Hz,1H), 7.09~7.05(m,1H), 4.70(s,2H), 3.74(t,J=5.9Hz,2H), 2.96(t,J=5.9Hz,2H).

[0341] Experimental Scheme 9 Compound 110 N-(3,4-dichlorophenyl)-8,9-dihydroimidazo[1,2-b][2,7]naphthyridine-7(6H)-carboxamide [ka]

[0342] To a solution of 6-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (84) (45 mg, 0.13 mmol) in EtOH (4 mL) was added sodium bicarbonate (22 mg, 0.27 mmol) and 2-chloroacetaldehyde (25 μL, 50% w / w, 0.20 mmol), and the reaction mixture was heated to 85 °C for 16 h. The reaction mixture was concentrated in vacuo, and the product was purified on silica gel (0–4.5% (0.7 M NH3 / MeOH) / DCM) to give N-(3,4-dichlorophenyl)-8,9-dihydroimidazo[1,2-b][2,7]naphthyridine-7(6H)-carboxamide (110) as a clear, colorless glass. LCMS (Method 3) m / z 361.5, 363.3 [M+H] at 1.25 min + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.81(s,1H), 8.50(s,1H), 7.89~7.85(m,2H), 7.53~7.46(m ,3H), 7.44(s,1H), 4.64(d,J=1.1Hz,2H), 3.69(t,J=6.2Hz,2H), 3.04~2.98(m,2H).

[0343] The following compounds were prepared using procedures similar to those described in Experimental Scheme 9, using appropriate starting materials. [Table 9]

[0344] Experimental Scheme 10 Compound 111 N-(3,4-dichlorophenyl)-8,9-dihydro-[1,2,4]triazolo[1,5-b][2,7]naphthyridine-7(6H)-carboxamide [ka]

[0345] Step 1: To a solution of 6-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (84) (45 mg, 0.13 mmol) in 2-propanol (2 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (23 μL, 0.17 mmol), and the reaction mixture was heated to 90° C. for 3 h. The temperature was reduced to 50° C., and hydroxylamine hydrochloride (12 mg, 0.17 mmol) was added. The reaction mixture was stirred at 50° C. for 3 h. The reaction mixture was concentrated in vacuo, and the product was purified on silica gel (40 g cartridge, 0–5% MeOH / DCM) to give (Z)-N-(3,4-dichlorophenyl)-6-(((hydroxyamino)methylene)amino)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (111a) as a pale white solid.

[0346] Step 2: To a solution of (Z)-N-(3,4-dichlorophenyl)-6-(((hydroxyamino)methylene)amino)-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (111a) in THF (5 mL) was added TFAA (10 μL, 71 μmol) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with DCM (5 mL) and washed with saturated sodium bicarbonate solution (5 mL), and the organic layer was concentrated in vacuo. The product was purified on silica gel (0–4.5% (0.7 M NH3 / MeOH) / DCM) to yield N-(3,4-dichlorophenyl)-8,9-dihydro-[1,2,4]triazolo[1,5-b][2,7]naphthyridine-7(6H)-carboxamide (111) as a pale white solid. LCMS (Method 3) m / z 362.5, 364.3 [M+H] at 1.19 min + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.97(s,1H), 8.87(s,1H), 8.43(s,1H), 7.86(t,J=1.4Hz,1H), 7.7 3(s,1H), 7.50(d,J=1.4Hz,2H), 4.73(s,2H), 3.73(t,J=6.2Hz,2H), 3.10(t,J=6.0Hz,2H).

[0347] The following compounds were prepared using the appropriate starting materials in a procedure similar to that described in Experimental Scheme 10. [Table 10]

[0348] Experimental Scheme 11 Compound 112 N-(4,5-dichloro-2-fluorophenyl)-6-oxo-3,4,6,7-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide [ka]

[0349] To a solution of triphosgene (28.8 mg, 97.2 μmol) in THF (2 mL) was added dropwise a solution of 4,5-dichloro-2-fluoroaniline (112a) (50 mg, 278 μmol) and triethylamine (116 μl, 833 μmol) in THF (1 mL). The resulting mixture was stirred at RT for 30 min. A solution of 5,6,7,8-tetrahydro-2,7-naphthyridin-3(2H)-one (112b) (42 mg, 278 μmol) in THF (1 mL) and DMF (2 mL) was added, and the mixture was stirred at RT for 16 h. The reaction mixture was filtered and concentrated in vacuo. The product was purified by RP Flash C18 (15-75% MeCN / 10 mM ammonium bicarbonate) to give N-(4,5-dichloro-2-fluorophenyl)-6-oxo-3,4,6,7-tetrahydro-2,7-naphthyridine-2(1H)-carboxamide (112) as a colorless solid. LCMS (Method 3) m / z 356.2, 358.2 [M+H] at 1.03 min. + (ES + ). 1H NMR(500MHz,DMSO-d6)δ11.38(s,1H), 8.48(s,1H), 7.82(d,J=7.6Hz,1H), 7.69(d,J=10.3H) z,1H), 7.32(s,1H), 6.20(s,1H), 4.38(s,2H), 3.59(t,J=6.1Hz,2H), 2.77(t,J=6.1Hz,2H).

[0350] The following compounds were prepared using procedures similar to those described in Experimental Scheme 11, using appropriate starting materials. Key points: (a) The reaction was carried out in DCM. [Table 11]

[0351] Experimental Scheme 12 Compound 119 5-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide [ka]

[0352] Step 1: To a solution of tert-butyl 5-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (119a) (750 mg, 2.79 mmol) in 1,4-dioxane (10 mL) was added (2,4-dimethoxyphenyl)methanamine (545 μL, 3.63 mmol) and CsCO (1.83 g, 5.58 mmol), and the reaction mixture was purged with nitrogen for 5 min. Xantphos (161 mg, 279 μmol) and Pd(dba) (128 mg, 140 μmol) were added, and the reaction mixture was purged with nitrogen for an additional 5 min. The reaction mixture was heated to 95 °C for 20 h, cooled, filtered through a plug of Celite, and concentrated in vacuo. The residue was purified on silica (0-20% EtOAc / isohexane) to give tert-butyl 5-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (119b) as a brown oil. 1 H NMR(500MHz,DMSO-d6)δ7.73(d,J=5.2Hz,1H), 6.99(d,J=8.3Hz,1H), 6.53(d,J=2.4Hz,1H), 6.40(dd,J=8.3,2.4Hz,1H), 6.33(d,J=5.3Hz, 1H), 6.18(s,1H), 4.45(d,J=5.8Hz,2H), 4.37(s,2H), 3.80(s,3H), 3.71(s,3H), 3.61(d,J=6.0Hz,2H), 2.46(t,J=6.0Hz,2H), 1.42(s,9H).

[0353] Step 2: tert-Butyl 5-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (119b) (580 mg, 1.45 mmol) was dissolved in a solution of HCl in 1,4-dioxane (7.26 ml, 4 M, 29.0 mmol) and stirred at RT for 16 h. The reaction mixture was concentrated in vacuo, and the residue was loaded onto an SCX cartridge in MeOH (50 ml). The product was eluted with 0.7 M NH in MeOH (100 ml) and concentrated in vacuo to give N-(2,4-dimethoxybenzyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (119c) as a brown oil. LCMS (Method 3) m / z 303.3 [M+H] at 1.06 min. + (ES + ).

[0354] Step 3: To a solution of N-(2,4-dimethoxybenzyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine HCl (119c) (370 mg, 1.10 mmol) in DCM (5 mL) was added DIPEA (0.58 mL, 3.31 mmol), followed by the dropwise addition of 1,2-dichloro-4-isocyanatobenzene (207 mg, 1.10 mmol) in DCM (2 mL). The reaction mixture was stirred at RT for 0.5 h. The reaction mixture was diluted with saturated sodium bicarbonate solution (5 mL) and extracted with 10% MeOH in DCM (3 mL). The aqueous layer was extracted with 10% MeOH in DCM (2 × 3 mL). The combined organic layers were concentrated in vacuo and the product was purified on silica gel (0-5% (0.7M NH3 / MeOH) / DCM) to give N-(3,4-dichlorophenyl)-5-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide (119d) as a clear white solid. LCMS (Method 3) m / z 487.0, 489.2 [M+H] at 1.64 min. + (ES + ).

[0355] Step 4: N-(3,4-dichlorophenyl)-5-((2,4-dimethoxybenzyl)amino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide (119d) (295 mg, 605 μmol) was combined with DCM (8 mL), TFA (1.9 mL, 24.2 mmol) was added, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, and the product was purified on silica gel (0-5% (0.7 M NH3 / MeOH) / DCM) to yield 5-amino-N-(3,4-dichlorophenyl)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxamide (119) as a clear, colorless glass. LCMS (Method 3) m / z 337.2, 339.2 [M+H] at 1.21 min. + (ES + ). 1 H NMR(500MHz,DMSO-d6)δ8.93(s,1H), 7.85(t,J=1.4Hz,1H), 7.73(d,J=5.2Hz,1H), 7.48(d,J=1.3Hz ,2H), 6.36(d,J=5.2Hz,1H), 5.76(s,2H), 4.50(s,2H), 3.73(t,J=5.9Hz,2H), 2.46(t,J=5.9Hz,2H)

[0356] Experimental Scheme 13 Compound 126 N-(3,4-dichlorophenyl)-6-(2-fluoropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide [ka]

[0357] Step 1: A vessel was charged with tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-carboxylate (126a) (50 mg, 0.16 mmol), Pd(dppf)Cl (12 mg, 16 μmol), and (2-fluoropyridin-3-yl)boronic acid (126b) (45 mg, 0.32 mmol), evacuated, and refilled with nitrogen (3 times). 1,4-Dioxane (0.5 mL) was added, purged with nitrogen, and refilled (3 times). Aqueous dipotassium phosphate (0.64 mL, 0.5 M, 0.32 mmol) was added, and the reaction was heated to 80 °C for 72 h. The reaction was cooled to RT, filtered through a pad of Celite, and washed with EtOAc (20 mL). The product was purified on silica gel (0-50% EtOAc / isohexane) to give tert-butyl 6-(2-fluoropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (126c) as a sticky white oil. LCMS (Method 2) m / z 329.1 [M+H] at 2.56 min. + (ES + ). 1 H NMR (500MHz, CDCl3) δ8.27~8.11(m,1H), 7.85(ddd,J=9.6,7.4,1.8Hz,1H), 7.38(d,J=8.2Hz,1H), 7.34(s,1H), 7 .28(dd,J=5.1,1.9Hz,1H), 7.21(d,J=8.1Hz,1H), 4.63(s,2H), 3.69(s,2H), 2.90(t,J=5.8Hz,2H), 1.50(s,9H).

[0358] Step 2: To a solution of tert-butyl 6-(2-fluoropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (126c) (39.2 mg, 119 μmol) in DCM (1 ml) was added HCl in 1,4-dioxane (298 μl, 4 M, 1.19 mmol). The reaction was stirred at RT for 17 h. The reaction mixture was concentrated in vacuo. The residue was redissolved in DCM (1 ml). 1,2-Dichloro-4-isocyanatobenzene (25 mg, 131 μmol) was added, followed by DIPEA (62 μl, 358 μmol). The reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the product was purified by silica gel (0-40% EtOAc / isohexane) to yield N-(3,4-dichlorophenyl)-6-(2-fluoropyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxamide (126) as a pale white powder: LCMS (Method 3) m / z 414.2 (M-H)-(ES-) at 1.64 min. 1 H NMR(500MHz,DMSO-d6)δ8.90(s,1H), 8.23(dd,J=4.0,2.4Hz,1H), 8.10(ddd,J=10.0,7.5,2.0Hz,1H), 7.88(d,J= 2.1Hz,1H), 7.54~7.43(m,5H), 7.32(d,J=8.5Hz,1H), 4.70(s,2H), 3.74(t,J=5.9Hz,2H), 2.93(t,J=5.8Hz,2H).

[0359] The following compounds were prepared using procedures similar to those described in Experimental Scheme 13, using appropriate starting materials. Key points: (a) The reaction was carried out using pinacol boronic ester. [Table 12]

[0360] Human GPR65 cyclic adenosine monophosphate (cAMP) homogeneous time-resolved fluorescence (HTRF) antagonist assay procedure I C 50 The data was obtained by the following procedure: 1321N1 human astrocytoma cells stably expressing human recombinant GPR65 (1321N1-hrGPR65 cells, EuroscreenFast) were cultured according to the supplier's instructions.

[0361] The compounds were tested for their ability to antagonize GPR65 by measuring the concentration of cytoplasmic cAMP, then treating cells with pH 7.2 to activate GPR65 signaling, and adding the compound to be tested.The degree to which the compound added inhibits the expected increase in cAMP concentration upon GPR65 activation indicates its effectiveness.The assay was performed according to the EuroscreenFast assay methodology as follows.

[0362] On assay day 1, test compounds were added to a 384-well, low-volume white microtiter plate by ultrasonic dispensing. KRH buffer (5 mM KCl, 1.25 mM MgSO, 124 mM NaCl, 25 mM HEPES, 13.3 mM glucose, 1.25 mM KHPO, and 1.45 mM CaCl) was adjusted to pH 6.5, pH 7.6, and pH 8.4 by adding NaOH. 1321N1-hGPR65 cells were quickly thawed, diluted in KRH, pH 7.6, centrifuged at 300 × g for 5 minutes, and resuspended in assay buffer (KRH, pH 7.6, supplemented with 1 mM 3-isobutyl-1-methylxanthine (IBMX) and 200 μM ethylenediaminetetraacetic acid (EDTA)). Cells were added to the assay plate at a concentration of 2,000 cells per well in a volume of 5 μl. The assay plate was centrifuged briefly at 100×g and then incubated at room temperature for 30 minutes. Cells were stimulated by adding KRH (5 μL), pH 6.5, to bring the assay pH to 7.2, while control wells received KRH (5 μL), pH 8.4, to bring the assay pH to 7.9. The assay plate was centrifuged briefly at 100×g and then incubated at room temperature for 30 minutes.

[0363] cAMP accumulation was detected using a cAMP HTRF kit (Cisbio). d2-labeled cAMP and cryptate-labeled anti-cAMP antibody in lysis and detection buffer (Cisbio) were added to the assay plate, and the plate was incubated at room temperature for 1 hour. HTRF measurements were performed using a Pherastar FSX instrument. Acceptor and donor emission signals were measured at 665 nm and 620 nm, respectively, and the HTRF ratio was calculated as the signal 665nm / signal 620nm x10 4 The data were normalized to high and low control values ​​and fitted with a 4-parameter logistic regression to determine the hGPR65 IC50 values ​​for the test compounds, which are shown in Table 1.

[0364] Various modifications and variations of the above-described aspects of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes of carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

[0365] [Table 13] JPEG0007755319000143.jpg65169

[0366] (References) Bohn, T. et al. (2018). Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nature Immunology, 1319-1326 Damaghi, M. et al. (2013). pH Sensing and Regulation in Cancer. Frontiers in Physiology Gaublomme, J. et al. (2015). Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell, 1400-1412 Hernandez, J. (2018). GPR65, a critical regulator of Th17 cell pathogenicity, is regulated by the CRTC2 / CREB pathway. The Journal of Immunology, 200 (Supplement) Korn, T. et al. (2009). IL-17 and Th17 Cells. Annual Reviews in Immunology, 485-517 Wang, J. et al. (2004). TDAG8 is a proton-sensing and psychosine-sensitive G-protein-coupled receptor. Journal of Biological Chemistry, 45626-45633 Yoshida, N. et al. (2016). ICER is requisite for Th17 differentiation. Nature Communications, 12993 Hardin, M. et al. (2014). The clinical and genetic features of COPD-asthma overlap syndrome. Eur Respir J. 2014 Aug;44(2):341-50 Kottyan, L. et al. (2009). Eosinophil viability is increased by acidic pH in a cAMP- and GPR65-dependent manner. Blood. 2009 Sep 24;114(13):2774-82 Tsurumaki, H. et al (2015). Int J Mol Sci. Protective Role of Proton-Sensing TDAG8 in Lipopolysaccharide-Induced Acute Lung Injury. Dec 4;16(12):28931-42

Claims

1. Compounds of formula (Ia) 【Chemical 1】 [In the formula, Ring A represented by the following formula: 【Chemistry 2】 【Chemistry 3】 【change】 and the wavy line from ring A indicates the attachment of ring A to the ring containing N, Z, and Y, as follows: 【Chemistry 4】 Y and Z are each independently CR １０ R １０ ' and R １０ and R １０ each ' is independently selected from H and alkyl; R １ , R ４ , and R ５ are each independently selected from H, F, Cl, Br, I, and haloalkyl; R ２ and R ３ are each independently selected from Cl, Br, I, and haloalkyl; R 6 , R 7 , R 8 and R 9 are each independently selected from H, F, Cl, Br, I, CN, CO 2 -alkyl, SO 2 -alkyl, OH, C 1 -C 6 alkyl, optionally substituted heteroaryl, phenyl, and C 1 -C 6 haloalkyl; R 14 is H or alkyl; The compound is N-(3,4-dichlorophenyl)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxamide; N-(3,4-dichlorophenyl)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxamide; N-(4-chloro-3-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; N-(3,4-dichlorophenyl)-3,4-dihydroisoquinoline-2(1H)-carboxamide; and A compound other than N-(3,4-dichlorophenyl)-6,7-dihydroisoxazolo[4,5-c]pyridine-5(4H)-carboxamide, or a pharmaceutically acceptable salt or solvate thereof.

2. The compound of claim 1 , wherein ring A is selected from groups (i) to (viii), (ix), (xi), and (xix).

3. The compound of claim 1, wherein ring A is selected from groups (i) to (x).

4. 2. The compound of claim 1, wherein ring A is selected from groups (i), (ii), (vii) and (x).

5. Y and Z are each independently CH ２ 5. The compound of claim 1, wherein the alkyl group is selected from the group consisting of C(CH 3 ) 2 , CHMe, and C(CH 3 ) 2 .

6. The compound of claim 5, wherein Y and Z are both CH 2 .

7. R １ The compound of any one of claims 1 to 6, wherein is selected from H, haloalkyl and F.

8. The compound of claim 7, wherein R 1 is H.

9. R ２ and R ３ The compound of any of claims 1 to 8, wherein each is independently selected from Cl, Br, I, and C 1 -C 6 haloalkyl.

10. R ２ and R ３ are each independently Cl, Br, and CF ｎ H ３－ｎ and n is 1, 2, or 3.

11. R ２ and R ３ are each independently Cl and CF ３ The compound according to any one of claims 1 to 10, selected from:

12. R ２ and R ３ One of them is Cl and the other is CF ３ 12. The compound of claim 11, wherein:

13. R ２ and R ３ The compound of claim 11 , wherein both are Cl.

14. R ４ The compound according to any one of claims 1 to 13, wherein is selected from H and Cl.

15. The compound of claim 14, wherein R 4 is H.

16. R ５ is H or CF ３ The compound according to any one of claims 1 to 15, 17. The compound of claim 16, wherein R 5 is H.

18. R ６ The compound of any one of claims 1 to 17, wherein is selected from H, F, Cl, CN, CH 3 and CF 3 .

19. R ６ 19. The compound of claim 18, wherein is selected from H, F, Cl, CN, and CH3.

20. The compound of claim 19, wherein R 6 is H.

21. R ７ The compound of any one of claims 1 to 20, wherein is selected from H, F, Cl, CN, CH 3 and CF 3 .

22. The compound of claim 21, wherein R 7 is selected from H, F, and Cl.

23. The compound of claim 22, wherein R 7 is H.

24. R ８ The compound of any one of claims 1 to 23, wherein is selected from H, F, OH, CN, phenyl, CF3, and CF2H.

25. R ８ The compound of claims 1 to 23, wherein is selected from H, F, Cl, CN, CH 3 and CF 3 .

26. The compound of claim 25, wherein R 8 is selected from H, F, Cl, and CN.

27. The compound of claim 26, wherein R 8 is selected from F and Cl.

28. R ８ The compound according to any one of claims 1 to 27, wherein is F.

29. R ９ The compound of any one of claims 1 to 28, wherein is selected from H, F, Cl, CN, CH 3 and CF 3 .

30. The compound of claim 29, wherein R 9 is selected from H, F, and CN.

31. The compound of claim 30, wherein R 9 is H.

32. below: 【Chemistry 5】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 32. The compound according to any one of claims 1 to 31, selected from: and pharmaceutically acceptable salts and solvates thereof.

33. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS). 【Chemistry 6】 [In the formula, Ring A represented by the following formula: 【Chemistry 7】 【Chemistry 8】 【change】 and the wavy line from ring A indicates the attachment of ring A to the ring containing N, Z, and Y, as follows: 【Chemistry 9】 Y and Z are each independently CR １０ R １０ ' and R １０ and R １０ each ' is independently selected from H and alkyl; R １ , R ４ , and R ５ are each independently selected from H, F, Cl, Br, I, and haloalkyl; R ２ and R ３ are each independently selected from H, F, Cl, Br, I, CN, and haloalkyl; R ２ , R ３ and R ４ are other than H; R 6 , R 7 , R 8 and R 9 are each independently selected from H, F, Cl, Br, I, CN, C 1 -C 6 alkoxy, CO 2 -alkyl, SO 2 -alkyl, NR 11 R 11 ′, OH, C 1 -C 6 alkyl, optionally substituted heteroaryl, phenyl, and C 1 -C 6 haloalkyl; R 14 is H or alkyl; R １１ and R １１ ' are each independently H, alkyl, haloalkyl, COR １２ , and SO ２ R １３ and R １２ and R １３ are both alkyl.

34. A pharmaceutical composition for use as claimed in claim 33, wherein the compound of formula (I) is further defined by any one of claims 1 to 32.

35. A compound comprising the following for use in the treatment or prevention of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS): 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 【change】 1. A pharmaceutical composition comprising a compound selected from:

36. 33. A pharmaceutical composition comprising a compound of formula (Ia) as defined in any of claims 1 to 32, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prophylaxis of a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

37. 37. The pharmaceutical composition for use according to any one of claims 33 to 36, wherein the compound modulates GPR65.

38. 38. The pharmaceutical composition for use according to any one of claims 33 to 37, wherein the disorder is a proliferative disorder.

39. 39. The pharmaceutical composition for use according to claim 38, wherein the proliferative disorder is cancer.

40. A pharmaceutical composition for use according to claim 39, wherein the cancer is a solid tumor and / or its metastasis.

41. 40. The pharmaceutical composition for use according to claim 39, wherein the proliferative disorder is a cancer selected from melanoma, renal cell carcinoma (RCC), gastric cancer, acute myeloid leukemia (AML), pancreatic adenocarcinoma, triple-negative breast cancer (TNBC), colorectal cancer, head and neck cancer, colorectal adenocarcinoma, lung cancer, sarcoma, ovarian cancer, and glioma.

42. A pharmaceutical composition for use according to claim 41, wherein the cancer is glioblastoma (GBM).

43. The pharmaceutical composition for use according to any one of claims 33 to 37, wherein the disorder is an immune disorder.

44. 44. The pharmaceutical composition for use according to claim 43, wherein the immune disorder is an autoimmune disease.

45. 45. The pharmaceutical composition for use according to claim 44, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), autoimmune thyroiditis (Hashimoto's disease), Graves' disease, uveitis (including intermediate uveitis), ulcerative colitis, Crohn's disease, autoimmune uveoretinitis, systemic vasculitis, polymyositis dermatomyositis, systemic sclerosis (scleroderma), Sjogren's syndrome, ankylosing spondylitis and related spondyloarthropathies, sarcoidosis, autoimmune hemolytic anemia, immune platelet disorders, and autoimmune polyendocrinopathy.

46. 46. ​​The pharmaceutical composition for use according to claim 45, wherein the autoimmune disease is selected from psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, and multiple sclerosis.

47. A pharmaceutical composition for use according to any one of claims 33 to 37, wherein the disorder is selected from asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

48. 36. A pharmaceutical composition comprising a compound of formula (I) or (Ia) as defined in any of claims 1 to 35, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a disease or disorder associated with GPR65.

49. 38. Use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, as defined in any of claims 1 to 35, in the preparation of a medicament for treating or preventing a disease or disorder associated with GPR65 in a subject.

50. 38. Use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt or solvate thereof, as defined in any of claims 1 to 35, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, an immune disorder, asthma, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS).

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